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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 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, 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 Open superstar 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 30 year tenure till date Dec 2017, Around 35 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, 50 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 19 lakh plus views on New Drug Approvals Blog in 216 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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FDA approves first treatment for pediatric patients with lupus


The U.S. Food and Drug Administration today approved Benlysta (belimumab) intravenous (IV) infusion for treatment of children with systemic lupus erythematosus (SLE) – often referred to as simply “lupus” – a serious chronic disease that causes inflammation and damage to various body tissues and organs. This is the first time that the FDA has approved a treatment for pediatric patients with SLE. Benlysta has been approved for use in adult patients since 2011.
“The agency expedited the review and approval of this application because Benlysta IV fulfils an unmet need for therapies, specifically in pediatric patients with SLE. While there is no cure for lupus, treatment can help our youngest patients control their disease with the hope of …

April 26, 2019

Release

The U.S. Food and Drug Administration today approved Benlysta (belimumab) intravenous (IV) infusion for treatment of children with systemic lupus erythematosus (SLE) – often referred to as simply “lupus” – a serious chronic disease that causes inflammation and damage to various body tissues and organs. This is the first time that the FDA has approved a treatment for pediatric patients with SLE. Benlysta has been approved for use in adult patients since 2011.

“The agency expedited the review and approval of this application because Benlysta IV fulfils an unmet need for therapies, specifically in pediatric patients with SLE. While there is no cure for lupus, treatment can help our youngest patients control their disease with the hope of improving their quality of life and lowering their risk of long-term organ damage and disability,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.

While childhood-onset SLE is rare, when diagnosed, it is generally more active in children and adolescents than adult patients, particularly in how it impacts organs such as the kidneys and central nervous system. As a result of the disease starting early in life, pediatric patients with SLE are at a higher risk for developing increased organ damage and complications from the disease as well as adverse events from the life-long treatments usually required.

The efficacy of Benlysta IV for the treatment of SLE in pediatric patients was studied over 52 weeks in 93 pediatric patients with SLE. The proportion of pediatric patients achieving the composite primary endpoint, the SLE response index (SRI-4), was higher in pediatric patients receiving Benlysta IV plus standard therapy compared to placebo plus standard therapy. Pediatric patients who received Benlysta IV plus standard therapy also had a lower risk of experiencing a severe flare, as well as longer duration of time until a severe flare (160 days versus 82 days). The drug’s safety and pharmacokinetic profiles in pediatric patients were consistent with those in adults with SLE.

Benlysta’s doctor and patient information includes a warning for mortality, serious infections, hypersensitivity and depression, based on data from the clinical studies in adults with SLE. The drug should not be administered with live vaccines. The manufacturer is required to provide a Medication Guide to inform patients of the risks associated with Benlysta.

The most common side effects in patients included nausea, diarrhea and fever. Patients also commonly experienced infusion reactions, so healthcare professionals are advised to pre-treat patients with an antihistamine.

The FDA granted this application a Priority Review designation. The FDA granted the approval of Benlysta to GlaxoSmithKline.

////////////Benlysta, belimumab, fda 2019, Priority Review, GlaxoSmithKline
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TAFENOQUINE タフェノキン


Tafenoquine(RS)-Tafenoquin Structural Formula V1.svg

ChemSpider 2D Image | Tafenoquine | C24H28F3N3O3

Tafenoquine

タフェノキン

N-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl]pentane-1,4-diamine

1,4-Pentanediamine, N4-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinyl]-
106635-80-7 [RN]
262P8GS9L9
7835
N4-{2,6-Dimethoxy-4-methyl-5-[3-(trifluormethyl)phenoxy]-8-chinolinyl}-1,4-pentandiamin
WR-238605, WR 238605, cas no 106635-80-7, Tafenoquine succinate, Etaquine, SB-252263, WR-238605
N(4)-(2,6-Dimethoxy-4-methyl-5-((3-trifluoromethyl)phenoxy)-8-quinolinyl)-1,4-pentanediamine
Molecular Formula: C24H28F3N3O3
Molecular Weight: 463.49263

Medicines for Malaria Venture
Walter Reed Army Institute (Originator)

PATENT  US 4617394

Synonyms

  • Etaquine[5]
  • WR 238605 [5]
  • SB-252263

New Drug Application (NDA): 210795
Company: GLAXOSMITHKLINE

FDA approved on July 20, 2018

FDA

Orphan

This new drug application provides for the use of KRINTAFEL (tafenoquine) tablets for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute P. vivax infection….https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/210795Orig1s000Ltr.pdf

Tafenoquine under the commercial name of Krintafel is an 8-aminoquinoline drug manufactured by GlaxoSmithKline that is being investigated as a potential treatment for malaria, as well as for malaria prevention.[2][3]

The proposed indication for tafenoquine is for treatment of the hypnozoite stages of Plasmodium vivax and Plasmodium ovale that are responsible for relapse of these malaria species even when the blood stages are successfully cleared. This is only now achieved by administration of daily primaquine for 14 days. The main advantage of tafenoquine is that it has a long half-life (2–3 weeks) and therefore a single treatment may be sufficient to clear hypnozoites. The shorter regimen has been described as an advantage.[4]

Like primaquine, tafenoquine causes hemolysis in people with G6PD deficiency.[2] Indeed, the long half-life of tafenoquine suggests that particular care should be taken to ensure that individuals with severe G6PD deficiency do not receive the drug.

The dose of tafenoquine has not been firmly established, but for the treatment of Plasmodium vivax malaria, a dose of 800 mg over three days has been used.[5]

Image result for TAFENOQUINE IR

In 2018 United States Food and Drug Administration (FDA) approved single dose tafenoquine for the radical cure (prevention of relapse) of Plasmodium vivax malaria[6].

Tafenoquine is used for the treatment and prevention of relapse of Vivax malaria in patients 16 years and older. Tafenoquine is not indicated to treat acute vivax malaria.[1]

Malaria is a disease that remains to occur in many tropical countries. Vivax malaria, caused by Plasmodium vivax, is known to be less virulent and seldom causes death. However, it causes a substantive illness-related burden in endemic areas and it is known to present dormant forms in the hepatocytes named hypnozoites which can remain dormant for weeks or even months. This dormant form produces ongoing relapses

FDA Approves Tafenoquine, First New P VivaxMalaria Treatment in 60 Years

JUL 23, 2018

The US Food and Drug Administration (FDA) has approved, under Priority Review, GlaxoSmithKline (GSK)’s tafenoquine (Krintafel), which is the first single-dose medicine for the prevention of  Plasmodium vivax (P vivax) malaria relapse in patients over the age of 16 years who are receiving antimalarial therapy. This is the first drug to be approved for the treatment of P vivax in over 60 years.

“[The] approval of Krintafel, the first new treatment for Plasmodium vivax malaria in over 60 years, is a significant milestone for people living with this type of relapsing malaria.” Hal Barron, MD, chief scientific officer and president of research and development of  GSK, said in the announcement, “Together with our partner, Medicines for Malaria Venture (MMV), we believe Krintafel will be an important medicine for patients with malaria and contribute to the ongoing effort to eradicate this disease.”

Tafenoquine is an 8-aminoquinoline derivative with activity against all stages of the P vivax lifecycle, including hypnozoites. It was first synthesized by scientists at the Walter Reed Army Institute of Research in 1978, and in 2008, GSK entered into a collaboration with MMV, to develop tafenoquine as an anti-relapse medicine.

After an infected mosquito bite, the P vivax parasite infects the blood and causes an acute malaria episode and can also lie dormant in the liver (in a form known as hypnozoite) from where it periodically reactivates to cause relapses, which can occur weeks, months, or years after the onset of the initial infection. The dormant liver forms cannot be readily treated with most anti-malarial treatments. Primaquine, an 8-aminoquinolone, has been the only FDA-approved medicine that targeted the dormant liver stage to prevent relapse; however, effectiveness only occurs after 14 days and the treatment has shown to have poor compliance.

“The US FDA’s approval of Krintafel is a major milestone and a significant contribution towards global efforts to eradicate malaria,” commented David Reddy, PhD, chief executive officer of MMV in a recent statement, “The world has waited decades for a new medicine to counter P vivax malaria relapse. Today, we can say the wait is over. Moreover, as the first ever single-dose for this indication, Krintafel will help improve patient compliance.”

Approval for tafenoquine was granted based on the efficacy and safety data gleaned from a comprehensive global clinical development program for P vivaxprevention of relapse which has been designed by GSK and MMV in agreement with the FDA. The program consisted of 13 studies assessing the safety of a 300 mg single-dose of tafenoquine, including 3 double-blind studies referred to as DETECTIVE Parts 1 and 2 and GATHER.

With the approval of tafenoquine, GSK has also been awarded a tropical disease priority review voucher by the FDA. Additionally, GSK is waiting for a decision from Australian Therapeutics Good Administration regarding the regulatory submission for the drug.

P vivax malaria has caused around 8.5 million clinical infections each year, primarily in South Asia, South-East Asia, Latin America, and the Horn of Africa, a peninsula in East Africa. Symptoms include fever, chills, vomiting, malaise, headache and muscle pain, and can lead to death in severe cases.

Tafenoquine should not be administered to: patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency or have not been tested for G6PD deficiency, patients who are breastfeeding a child known to have G6PD deficiency or one that has not been tested for G6PD deficiency, or patients who are allergic to tafenoquine or any of the ingredients in tafenoquine or who have had an allergic reaction to similar medicines containing 8-aminoquinolines

Stereochemistry

Tafenoquine contains a stereocenter and consists of two enantiomers. This is a mixture of (R) – and the (S) – Form:

Enantiomers of tafenoquine
(R)-Tafenoquin Structural Formula V1.svg
(R)-Form
(S)-Tafenoquin Structural Formula V1.svg
(S)-Form

CLIP

US 4431807

Nitration of 1,2-dimethoxybenzene (XXIX) with HNO3/AcOH gives 4,5-dimethoxy-1,2-dinitrobenzene (XXX), which is treated with ammonia in hot methanol to yield 4,5-dimethoxy-2-nitroaniline (XXXI). Cyclization of compound (XXXI) with buten-2-one (XXXII) by means of H3PO4 and H3AsO4 affords 5,6-dimethoxy-4-methyl-8-nitroquinoline (XXXIII), which is selectively mono-demethylated by means of HCl in ethanol to provide 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (XXXIV). Reaction of quinoline (XXXIV) with POCl3 gives the corresponding 5-chloro derivative (XXXV), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH to yield the diaryl ether (XXXVI). Finally, the nitro group of (XXXVI) is reduced by means of H2 over PtO2 in THF or H2 over Raney nickel.

Nitration of 2-fluoroanisole (XXXVII) with HNO3/Ac2O gives 3-fluoro-4-methoxynitrobenzene (XXXVIII), which is reduced to the corresponding aniline (XXXIX) with SnCl2/HCl. Reaction of compound (XXXIX) with Ac2O yields the acetanilide (XL), which is nitrated with HNO3 to afford 5-fluoro-4-methoxy-2-nitroacetanilide (XLI). Hydrolysis of (XLI) with NaOH provides 5-fluoro-4-methoxy-2-nitroaniline (XLII), which is cyclized with buten-2-one (XXXII) by means of As2O5 and H3PO4 to furnish 5-fluoro-6-methoxy-4-methyl-8-nitroquinoline (XLIII). Condensation of quinoline (XLIII) with 3-(trifluoromethyl)phenol (IV) by means of K2CO3 gives the diaryl ether (XXXIV), which is finally reduced by means of H2 over PtO2 in THF.

CLIP

US 4617394

Reaction of 8-amino-6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinoline (XIV) with phthalic anhydride (XV) affords the phthalimido derivative (XVI), which is oxidized with MCPBA to yield the quinoline N-oxide (XVII). Treatment of compound (XVII) with neutral alumina gives the quinolone derivative (XVIII), which by reaction with POCl3 in refluxing CHCl3 provides the 2-chloroquinoline derivative (XIX). Alternatively, reaction of the quinoline N-oxide (XVII) with POCl3 as before also gives the 2-chloroquinoline derivative (XIX) The removal of the phthalimido group of compound (XIX) by means of hydrazine in refluxing ethanol gives the chlorinated aminoquinoline (XX), which is finally treated with MeONa in hot DMF.

CLIP

US 6479660; WO 9713753

Chlorination of 6-methoxy-4-methylquinolin-2(1H)-one (I) with SO2Cl2 in hot acetic acid gives the 5-chloro derivative (II), which is nitrated with HNO3 in H2SO4 to yield the 8-nitroquinolinone (III). Condensation of compound (III) with 3-(trifluoromethyl)phenol (IV) by means of KOH in NMP provides the diaryl ether (V), which is treated with refluxing POCl3 to afford the 2-chloroquinoline (VI). Reaction of compound (VI) with MeONa in refluxing methanol results in the 2,6-dimethoxyquinoline derivative (VII), which is reduced with hydrazine over Pd/C to give the 8-aminoquinoline derivative (VIII). Condensation of aminoquinoline (VIII) with N-(4-iodopentyl)phthalimide (IX) by means of diisopropylamine in hot NMP yields the phthalimido precursor (X), which is finally cleaved with hydrazine in refluxing ethanol.

Reaction of 1,4-dibromopentane (XI) with potassium phthalimide (XII) gives N-(4-bromopentyl)phthalimide (XIII), which is then treated with NaI in refluxing acetone.

Reaction of 4-methoxyaniline (XXI) with ethyl acetoacetate (XXII) by means of triethanolamine in refluxing xylene gives the acetoacetanilide (XXIII), which is cyclized by means of hot triethanolamine and H2SO4 to yield 6-methoxy-4-methylquinolin-2(1H)-one (I), which is treated with refluxing POCl3 to provide 2-chloro-6-methoxy-4-methylquinoline (XXIV). Reaction of compound (XXIV) with SO2Cl2 in hot AcOH affords 2,5-dichloro-6-methoxy-4-methylquinoline (XXV), which is treated with MeONa in refluxing methanol to furnish 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Alternatively, the reaction of compound (XXIV) with MeONa as before gives 2,6-dimethoxy-4-methylquinoline (XXVII), which is treated with SO2Cl2 in hot AcOH to give the already described 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Nitration of compound (XXVI) with KNO3 and P2O5 gives the 8-nitroquinoline derivative (XXVIII), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH in hot NMP to yield the diaryl ether (VII). Finally, the nitro group of compound (VII) is reduced with hydrazine over Pd/C.

PAPER

http://pubs.rsc.org/en/Content/ArticleLanding/2017/RA/C7RA04867J#!divAbstract

An antimalarial drug, tafenoquine, as a fluorescent receptor for ratiometric detection of hypochlorite

 Author affiliations

Abstract

Tafenoquine (TQ), a fluorescent antimalarial drug, was used as a receptor for the fluorometric detection of hypochlorite (OCl). TQ itself exhibits a strong fluorescence at 476 nm, but OCl-selective cyclization of its pentan-1,4-diamine moiety creates a blue-shifted fluorescence at 361 nm. This ratiometric response facilitates rapid, selective, and sensitive detection of OCl in aqueous media with physiological pH. This response is also applicable to a simple test kit analysis and allows fluorometric OCl imaging in living cells.

Graphical abstract: An antimalarial drug, tafenoquine, as a fluorescent receptor for ratiometric detection of hypochlorite

1 H NMR (300 MHz, CDCl3, TMS) d (ppm): 7.32 (q, 1H, J ¼ 18 Hz), 7.21 (d, 1H, J ¼ 6 Hz), 7.07 (s, 1H), 6.94 (d, 1H, J ¼ 6 Hz), 6.64 (s, 1H), 6.50 (s, 1H), 5.84 (d, 1H, J ¼ 6 Hz), 4.00 (s, 3H), 3.79 (s, 3H), 3.66 (s, 1H), 2.78 (d, 2H, J ¼ 6 Hz), 2.55 (s, 3H), 1.69 (dd, 6H, J ¼ 6 Hz, J ¼ 9 Hz), 1.35 (d, 3H, J ¼ 6 Hz).

13C NMR (100 MHz, CDCl3, TMS) d (ppm): 159.64, 148.961, 146.339, 142.010, 132.085, 131.760, 131.007, 129.968, 126.917, 125.344, 122.636, 120.681, 118.006, 115.256, 112.052, 94.996, 56.989, 52.870, 48.446, 42.248, 34.439, 30.130, 23.103, 20.833.

MS (m/z): M+ calcd for C24H28F3N3O3: 463.2083; found (ESI): 464.17 (M + H)+ .

PAPER

J Med Chem 1989,32(8),1728-32

https://pubs.acs.org/doi/pdf/10.1021/jm00128a010

Synthesis of the intermediate diazepinone (IV) is accomplished by a one-pot synthesis. Condensation of 2-chloro-3-aminopyridine (I) with the anthranilic ester (II) is effected in the presence of potassium tert-butoxide as a catalyst. The resulting anthranilic amide (III) is cyclized under the influence of catalytic amounts of sulfuric acid. Treatment of (IV) with chloroacetylchloride in toluene yields the corresponding choroacetamide (V). The side chain of AQ-RA 741 is prepared starting from 4-picoline, which is alkylated by reaction with 3-(diethylamino)propylchloride in the presence of n-butyllithium. Hydrogenation of (VIII) using platinum dioxide as a catalyst furnishes the diamine (IX), which is coupled with (V) in the presence of catalytic amounts of sodium iodide in acetone leading to AQ-RA 741 as its free base.

Image result for tafenoquine DRUG FUTURE

Image result for tafenoquine DRUG FUTURE

CLIP

Image result for TAFENOQUINE IR

Image result for TAFENOQUINE IR

References

  1. Jump up to:a b Peters W (1999). “The evolution of tafenoquine–antimalarial for a new millennium?”J R Soc Med92 (7): 345–352. PMC 1297286Freely accessiblePMID 10615272.
  2. Jump up to:a b Shanks GD, Oloo AJ, Aleman GM, et al. (2001). “A New Primaquine Analogue, Tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria”. Clin Infect Dis33 (12): 1968–74. doi:10.1086/324081JSTOR 4482936PMID 11700577.
  3. Jump up^ Lell B, Faucher JF, Missinou MA, et al. (2000). “Malaria chemoprophylaxis with tafenoquine: a randomised study”. Lancet355 (9220): 2041–5. doi:10.1016/S0140-6736(00)02352-7PMID 10885356.
  4. Jump up^ Elmes NJ, Nasveld PE, Kitchener SJ, Kocisko DA, Edstein MD (November 2008). “The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific”Transactions of the Royal Society of Tropical Medicine and Hygiene102 (11): 1095–101. doi:10.1016/j.trstmh.2008.04.024PMID 18541280.
  5. Jump up^ Nasveld P, Kitchener S (2005). “Treatment of acute vivax malaria with tafenoquine”. Trans R Soc Trop Med Hyg99 (1): 2–5. doi:10.1016/j.trstmh.2004.01.013PMID 15550254.
  6. Jump up^ “Drugs@FDA: FDA Approved Drug Products”http://www.accessdata.fda.gov. Retrieved 2018-07-23.
  1.  Shanks GD, Oloo AJ, Aleman GM et al. (2001). “A New Primaquine Analogue, Tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria”. Clin Infect Dis 33 (12): 1968–74. doi:10.1086/324081JSTOR 4482936.PMID 11700577.
  2. Lell B, Faucher JF, Missinou MA et al. (2000). “Malaria chemoprophylaxis with tafenoquine: a randomised study”.Lancet 355 (9220): 2041–5. doi:10.1016/S0140-6736(00)02352-7PMID 10885356.
  3.  Elmes NJ, Nasveld PE, Kitchener SJ, Kocisko DA, Edstein MD (November 2008). “The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific”Transactions of the Royal Society of Tropical Medicine and Hygiene 102 (11): 1095–101.doi:10.1016/j.trstmh.2008.04.024PMID 18541280.
  4.  Nasvelda P, Kitchener S. (2005). “Treatment of acute vivax malaria with tafenoquine”. Trans R Soc Trop Med Hyg 99 (1): 2–5. doi:10.1016/j.trstmh.2004.01.013PMID 15550254.
  5.  Peters W (1999). “The evolution of tafenoquine–antimalarial for a new millennium?”. J R Soc Med 92 (7): 345–352.PMID 10615272.
  6. J Med Chem 1982,25(9),1094
8-3-2007
Methods and compositions for treating diseases associated with pathogenic proteins
12-6-2006
Process for the preparation of quinoline derivatives
3-14-2002
PROCESS FOR THE PREPARATION OF ANTI-MALARIAL DRUGS
4-2-1998
MULTIDENTATE METAL COMPLEXES AND METHODS OF MAKING AND USING THEREOF
4-18-1997
PROCESS FOR THE PREPARATION OF ANTI-MALARIAL DRUGS
12-20-1996
MULTIDENTATE METAL COMPLEXES AND METHODS OF MAKING AND USING THEREOF
12-15-1993
Use of interferon and a substance with an antimalarial activity for the treatment of malaria infections
10-15-1986
4-methyl-5-(unsubstituted and substituted phenoxy)-2,6-dimethoxy-8-(aminoalkylamino) quinolines
Title: Tafenoquine
CAS Registry Number: 106635-80-7
CAS Name: N4[2,6-Dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinyl]-1,4-pentanediamine
Additional Names: 8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinoline
Manufacturers’ Codes: WR-238605
Molecular Formula: C24H28F3N3O3
Molecular Weight: 463.49
Percent Composition: C 62.19%, H 6.09%, F 12.30%, N 9.07%, O 10.36%
Literature References: Analog of primaquine, q.v. Prepn: P. Blumbergs, M. P. LaMontagne, US 4617394 (1986 to U.S. Sec. Army); M. P. LaMontagne et al., J. Med. Chem. 32, 1728 (1989). HPLC determn in blood and plasma: D. A. Kocisko et al., Ther. Drug Monit. 22, 184 (2000). Metabolism: O. R. Idowu et al., Drug Metab. Dispos. 23, 1 (1995). Clinical pharmacokinetics: M. D. Edstein et al., Br. J. Pharmacol. 52, 663 (2001). Clinical evaluation in prevention of malaria relapse: D. S. Walsh et al., J. Infect. Dis. 180, 1282 (1999); in malaria prophylaxis: B. Lell et al., Lancet 355, 2041 (2000); B. R. Hale et al., Clin. Infect. Dis. 36, 541 (2003).
Derivative Type: Succinate
CAS Registry Number: 106635-81-8
Trademarks: Etaquine (GSK)
Molecular Formula: C24H28F3N3O3.C4H6O4
Molecular Weight: 581.58
Percent Composition: C 57.83%, H 5.89%, F 9.80%, N 7.23%, O 19.26%
Properties: Crystals from acetonitrile, mp 146-149°. LD50 in male, female rats (mg/kg): 102, 71 i.p.; 429, 416 orally (LaMontagne).
Melting point: mp 146-149°
Toxicity data: LD50 in male, female rats (mg/kg): 102, 71 i.p.; 429, 416 orally (LaMontagne)
Therap-Cat: Antimalarial.
Keywords: Antimalarial.
Tafenoquine
(RS)-Tafenoquin Structural Formula V1.svg
Clinical data
Synonyms Etaquine,[1] WR 238605,[1] SB-252263
ATC code
  • none
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
Chemical and physical data
Formula C24H28F3N3O3
Molar mass 463.493 g/mol
3D model (JSmol)

OLD CLIP

April 28, 2014
GlaxoSmithKline (GSK) and Medicines for Malaria Venture (MMV) announced the start of a Phase 3 global program to evaluate the efficacy and safety of tafenoquine, an investigational medicine which is being developed for the treatment and relapse prevention (radical cure) of Plasmodium vivax (P. vivax) malaria.

P. vivax malaria, a form of the disease caused by one of several species of Plasmodium parasites known to infect humans, occurs primarily in South and South East Asia, Latin America and the horn of Africa. Severe anemia, malnutrition and respiratory distress are among the most serious consequences described to be caused by the infection.

The Phase 3 program includes two randomized, double-blind treatment studies to investigate tafenoquine in adult patients with P. vivax malaria. The DETECTIVE study (TAF112582) aims to evaluate the efficacy, safety and tolerability of tafenoquine as a radical cure for P. vivax malaria, co-administered with chloroquine, a blood stage anti-malarial treatment. The GATHER study (TAF116564) aims to assess the incidence of hemolysis and safety and efficacy of tafenoquine compared to primaquine, the only approved treatment currently available for the radical cure of P. vivax malaria.

Tafenoquine is not yet approved or licensed for use anywhere in the world.

“P. vivax malaria can affect people of all ages and is particularly insidious because it has the potential to remain dormant within the body in excess of a year, and causes some patients to experience repeated episodes of illness after the first mosquito bite,” said Nicholas Cammack, head, Tres Cantos Medicines Development Center for Diseases of the Developing World.  “Our investigation of tafenoquine for the treatment of P. vivax malaria is part of GSK’s efforts to tackle the global burden of malaria. Working with our partners, including MMV, we are determined to stop malaria in all its forms.”

“One of the big challenges we face in tackling malaria is to have new medicines to prevent relapse, caused by dormant forms of P. vivax,” said Dr. Timothy Wells, MMV’s chief scientific officer. “The Phase 3 program is designed to build upon the promising results of the Phase 2b study which showed that treatment with tafenoquine prevented relapses. If successful, tafenoquine has the potential to become a major contributor to malaria elimination. It’s a great privilege to be working with GSK on this project; they have a clear commitment to changing the face of public health in the countries in which we are working.”

/////////////Tafenoquine, タフェノキン , Orphan, FDA 2018,  KRINTAFEL, Priority Review, GlaxoSmithKline
COC1=CC(C)=C2C(OC3=CC=CC(=C3)C(F)(F)F)=C(OC)C=C(NC(C)CCCN)C2=N1

Glaxo……..Will help the world’s poorest people access copycat versions of its medicines at affordable prices.


Glaxo to Stop Seeking Drug Patents in Low-Income Countries

Drugmaker says move could help poor nations access cheaper copycat versions of its medicines

 

GlaxoSmithKline’s CEO Andrew Witty said revenue or profit in the countries in question won’t be significantly affected.
GlaxoSmithKline’s CEO Andrew Witty below

LONDON— GlaxoSmithKline PLC said it would stop seeking patents for its drugs in low-income countries, a move the drugmaker said could help the world’s poorest people access copycat versions of its medicines at affordable prices.

The U.K.-based company said it would take this approach in low-income and least-developed countries, a group totaling around 85 nations. In so-called lower-middle-income countries, a group of 51 nations that includes Vietnam, Cameroon and Sri Lanka, it said it would file patents but aim to grant licenses to generic manufacturers to supply low-cost versions of its drugs in those markets in return for a small royalty.

Glaxo previously filed patents in most lower-middle-income countries, and in low-income nations where a patent office exists. But that “patchwork” approach meant that generic drugmakers held back from manufacturing copycat medicines for these markets owing to the risk of being sued by pharmaceutical companies, according to Glaxo Chief Executive Andrew Witty.,,,,,,,,,continue reading

http://www.wsj.com/articles/glaxo-to-stop-seeking-drug-patents-in-low-income-countries-1459443494?mod=pls_whats_news_us_business_f&utm_content=buffer1d705&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer

/////////Glaxo Chief Executive,  Andrew Witty, filed patents, low income,poor nations, cheaper,  copycat versions, medicines, GlaxoSmithKline

Daprodustat, ダプロデュスタット


ChemSpider 2D Image | daprodustat | C19H27N3O6

Figure imgf000039_0001Daprodustat.png

Daprodustat, GSK1278863

ダプロデュスタット

CAS 960539-70-2

GSK1278863; GSK 1278863; GSK-1278863; Daprodustat

C19H27N3O6
Exact Mass: 393.18999

(1,3-dicyclohexyl-2,4,6-trioxohexahydropyrimidine-5-carbonyl)glycine

N-[(l,3-dicyclohexyl-6-hydroxy-2,4-dioxo-l,2,3,4- tetrahydro-5-pyrimidinyl)carbonyl]glycine

2-(1,3-dicyclohexyl-2,4,6-triohexahydropyrimidine-5-carboxamide acetic acid
Mechanism of Action: HIF-prolyl hydroxylase inhibitor
Indication: anemia, diabetic wounds, and reduction of ischemic complications
Development Stage: Phase II
Developer:GlaxoSmithKline

UNII:JVR38ZM64B

ダプロデュスタット
Daprodustat

C19H27N3O6 : 393.43
[960539-70-2]

Daprodustat , also known as GSK1278863, is a novel HIF-prolyl hydroxylase inhibitor. Hypoxia inducible factor (HIF) stabilization by HIF-prolyl hydroxylase (PHD) inhibitors may improve ischemic conditions such as peripheral artery disease (PAD). Short-term treatment with a novel HIF-prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication-limited peripheral artery disease

  • Originator GlaxoSmithKline
  • Class Antianaemics; Pyrimidines; Small molecules
  • Mechanism of ActionErythropoiesis stimulants; Prolyl hydroxylase inhibitors
  • Phase II Anaemia; Perioperative ischaemia
  • Phase I Diabetic foot ulcer; Tendon injuries
  • DiscontinuedPeripheral arterial disorders

Most Recent Events

  • 27 Jul 2015No recent reports of development identified – Phase-II for Anaemia in India and New Zealand (PO)
  • 27 Jul 2015Daprodustat is still in phase II trials for Anaemia in the USA, Australia, Canada, Czech Republic, Denmark, France, Germany, Hungary, Japan, Poland, Russia, Spain, South Korea, and United Kingdom
  • 01 Jun 2015GlaxoSmithKline completes a phase I trial in Tendon injuries (In volunteers) in USA (PO) (NCT02231190)
WHO ATC code: B03 (Antianemic Preparations)C (Cardiovascular System)

C01 (Cardiac Therapy)

D03 (Preparations for Treatment of Wounds and Ulcers)

M09A-X (Other drugs for disorders of the musculo-skeletal system)

EPhMRA code: B3 (Anti-Anaemic Preparations)C1 (Cardiac Therapy)

C6A (Other Cardiovascular Products)

D3A (Wound Healing Agents)

M5X (All Other Musculoskeletal Products)

Daprodustat (INN) (GSK1278863) is a drug which acts as a HIF prolyl-hydroxylase inhibitor and thereby increases endogenous production of erythropoietin, which stimulates production of hemoglobin and red blood cells. It is in Phase III clinical trials for the treatment of anemia secondary to chronic kidney disease.[1][2] Due to its potential applications in athletic doping, it has also been incorporated into screens for performance-enhancing drugs.[3]

SYN 1

SYN 2

PATENT

WO 2007150011

https://www.google.com.ar/patents/WO2007150011A2

Illustrated Methods of preparation

Scheme 1

Figure imgf000023_0001

a) 1. NaH, THF, rt 2. R1NCO, 60 0C; b) 1. NaH, THF or dioxane, rt 2. R4NCX, heat; c) H2NCH2CO2H, DBU, EtOH, 1600C, microwave.

Scheme 2

Figure imgf000023_0002

a) R1NH2, CH2Cl2 or R1NH2-HCl, base, CH2Cl2; b) CH2(C(O)Cl)2, CH2Cl2, reflux or CH2(CO2Et)2, NaOEt, MeO(CH2)2OH, reflux or 1. EtO2CCH2COCl, CHCl3, 70 0C 2.

DBU, CHCl3, 70 0C; c) 1. YCNCH2CO2Et,, EtPr’2N, CHCl3 or CH2Cl2 2. aq NaOH, EtOH, rt. Scheme 3 (for R1 = R4)

a) CDI,

Figure imgf000024_0001

DMF, 70 0C or , EtOAc, rt

Scheme 4

Figure imgf000024_0002

a) OCNCH2CO2Et, EtPr’2N, CHCl3 or CH2Cl2; b) 1. R1HaI, Na/K2CO3, DMF or DMA, 100 0C or R1HaI, pol-BEMP, DMF, 120 0C, microwave 2. aq NaOH, MeOH or EtOH, rt.

Scheme 5

Figure imgf000024_0003

a) 1. CH2(CO2H)2, THF, O 0C – rt 2. EtOH, reflux; b) 1. OCNCH2CO2Et, EtPr’2N, CH2Cl2 2. aq NaOH, EtOH, rt.

Scheme 6

Figure imgf000024_0004

a) 1. Phthalimide, DIAD, PPh3, THF 2. (NH2)2, EtOH, reflux.

Scheme 7

Figure imgf000025_0001

a) Ac2O, AcOH, 130 0C.

Example 18

Figure imgf000039_0001

N-T(1 ,3-Dicvclohexyl-6-hydroxy-2,4-dioxo- 1 ,2,3,4-tetrahvdro-5-pyrimidinyl)carbonyl1grycine Method 1

18.1a) h3-Dicvclohexyl-2A6(lH,3H,5H)-pyrimidinetrione. Dicyclohexylurea (3.0 g, 13.39 mmoles) was stirred in chloroform (80 mL) and treated with a solution of malonyl dichloride (1.3 mL, 13.39 mmoles) in chloroform (20 mL), added dropwise under argon. The mixture was heated at 500C for 4 hours, wasahed with 1 molar hydrochloric acid and evaporated onto silica gel. Flash chromatography (10-30% ethyl acetate in hexane) to give the title compound (2.13 g, 55%). 1Η NMR (400 MHz, OMSO-d6) δ ppm 4.46 (tt, J=12.13, 3.54 Hz, 2 H), 3.69 (s, 2 H), 2.15 (qd, J=12.46, 3.28 Hz, 4 H), 1.77 (d, J=13.14 Hz, 4 H), 1.59 (t, J=12.76 Hz, 6 H), 1.26 (q, J=12.97 Hz, 4 H), 1.04 – 1.16 (m, 2 H)

18.1b) N-r(1.3-Dicvclohexyl-6-hvdroxy-2.4-dioxo-1.2.3.4-tetrahvdro-5- pyrimidinvDcarbonyll glycine. Ethyl isocyanatoacetate (802 uL, 7.15 mmoles) was added to a mixture of l,3-dicyclohexyl-2,4,6(lH,3H,5H)-pyrimidinetrione (2.1 g, 7.15 mmoles) and diisopropylethylamine (2.47 mL, 14.3 mmoles) in dichloromethane (100 mL) and stirred overnight. The reaction mixture was washed with 1 molar hydrochloric acid (x2) and evaporated. The residue was dissolved in ethanol (10 mL) and treated with 1.0 molar sodium hydroxide (5 mL). The mixture was stirred for 72 hours, acidified and extracted into ethyl acetate. Some ester remained, therefore the solution was evaporated and ther residue was dissolved in 1 molar soldium hydroxide solution with warming and strred for 2 hours. The mixture was acidified with IM HCl and extracted with ethyl acetate (x2). The combined extracts were washed with 1 molar hydrochloric acid , dried and evaporated to a solid which was slurried in a mixture of diethyl ether and hexane, collected, washed with the same solvent mixture and dried to give the title compound (1.86 g, 66%). IH NMR (400 MHz, DMSO-^6) δ ppm 13.07 (br. s., 1 H), 10.19 (t, J=5.31 Hz, 1 H), 4.63 (t, J=10.99 Hz, 2 H), 4.12 (d, J=5.56 Hz, 2 H), 2.27 (q, J=I 1.71 Hz, 4 H), 1.79 (d, J=12.88 Hz, 4 H), 1.50 – 1.69 (m, 6 H), 1.28 (q, J=12.97 Hz, 4 H), 1.12 (q, J=12.72 Hz, 2 H)

Method 2

18.2a) 1.3-Dicvclohexyl-2.4.6πH.3H.5H)-pyrimidinetrione. A solution of N5N- dicyclohexylcarbodiimide (254 g; 1.23 mol.) in anhydrous TΗF (700 mL) was added dropwise to a cold (0 0C) solution of malonic acid (64.1 g; 0.616 mol.) in anhydrous TΗF (300 mL) over a period of- 30 minutes. The mixture was stirred and allowed to warm to room temperature over 2 h. (After 1 h, the mixture became very thick with precipitate so further anhydrous TΗF (500 mL) was added to facilitate agitation.). The mixture was filtered and the filtrate evaporated to afford a yellow solid which was immediately slurried in ethanol (1 L) and heated to reflux temperature. The mixture was then allowed to cool to room temperature then filtered and the solid washed with cold ethanol (250 mL) to afford the title compound (129.4 g; 72%) as a colorless solid. 1Η NMR (400 MHz, DMSO-(Z6) δ ppm 1.03 – 1.18 (m, 2 H) 1.18 – 1.34 (m, 4 H) 1.59 (t, J=13.14 Hz, 6 H) 1.76 (d, J=12.88 Hz, 4 H) 2.04 – 2.24 (m, 4 H) 3.69 (s, 2 H) 4.35 – 4.54 (m, 2 H).

18.2b) Ethyl N-[(l .3-dicvclohexyl-6-hvdroxy-2.4-dioxo- 1.2.3.4-tetrahydro-5- pyrimidinyPcarbonyll glycinate. A solution of l,3-dicyclohexyl-2,4,6(lH,3H,5H)-pyrimidinetrione (120.0 g; 0.41 mol.) and diisopropylethylamine (105.8 g; 0.82 mol.) in dichloromethane (1 L) was stirred and treated dropwise with a solution of ethyl isocyanatoacetate (53.0 g; 0.41 mol.) in dichloromethane (500 mL) and the mixture was then stirred at room temperature overnight. The mixture was then treated dropwise with 6M aq. hydrochloric acid (500 mL) and the separated organic layer was dried and evaporated. The resulting solid was slurried in hexanes (500 mL) and heated to reflux temperature. The mixture was then allowed to cool and filtered to afford ethyl N- [(1 ,3-dicyclohexyl-6-hydroxy-2,4-dioxo- 1 ,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (159.1 g; 92%) as a cream powder. IH NMR (400 MHz, CHLOROFORM-,/) δ ppm 1.24 (s, 2 H) 1.37 (s, 7 H) 1.52 – 1.76 (m, 6 H) 1.78 – 1.94 (m, 4 H) 2.25 – 2.48 (m, 4 H) 4.17 (d, J=5.81 Hz, 2 H) 4.28 (q, J=7.24 Hz, 2 H) 4.74 (s, 2 H) 10.37 (t, J=4.67 Hz, 1 H). 18.2c)

N-rπ^-Dicyclohexyl-ό-hydroxy^^-dioxo-l^J^-tetralivdro-S- pyrimidinyDcarbonyll glycine. A stirred suspension of ethyl Ν-[(l,3-dicyclohexyl-6-hydroxy-2,4- dioxo-l,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (159.0 g; 0.377 mol.) in ethanol (1.5 L) was treated dropwise with 6M aq. Sodium hydroxide (250 mL) and stirred at room temperature for 3 h. The solution was then acidified by the dropwise addition of 6M aq. hydrochloric acid (300 mL), diluted with water (IL) and then filtered. The crude solid was slurried in water (2 L) then stirred vigorously and heated at 35 0C for 1 h and filtered and dried. The solid material (~ 138 g) was then crystallized from glacial acetic acid (1.5 L) (with hot filtration to remove a small amount of insoluble material). The solid, which crystallized upon cooling, was collected and washed with cold glacial acetic acid (3 x 100 mL) to afford N-[(l,3-dicyclohexyl-6-hydroxy-2,4-dioxo-l,2,3,4- tetrahydro-5-pyrimidinyl)carbonyl]glycine (116.2 g; 78%) as a colorless solid.

IH NMR (400 MHz, DMSO-(Z6) δ ppm 1.11 (d, J=12.88 Hz, 2 H) 1.27 (q, J=12.80 Hz, 4 H) 1.62 (s, 6 H) 1.70 – 1.90 (m, J=12.88 Hz, 4 H) 2.11 – 2.44 (m, 4 H) 4.11 (d, J=5.81 Hz, 2 H) 4.45 – 4.77 (m, 2 H) 10.19 (t, J=5.81 Hz, 1 H) 13.08 (s, 1 H).

References

  1. Jump up^ Schmid H, Jelkmann W. Investigational therapies for renal disease-induced anemia. Expert Opin Investig Drugs. 2016 Aug;25(8):901-16. doi:10.1080/13543784.2016.1182981PMID 27122198. Missing or empty |title= (help)
  2. Jump up^ Ariazi JL, Duffy KJ, Adams DF, Fitch DM, Luo L, Pappalardi M, Biju M, DiFilippo EH, Shaw T, Wiggall K, Erickson-Miller C. Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia. J Pharmacol Exp Ther. 2017 Dec;363(3):336-347. doi:10.1124/jpet.117.242503PMID 28928122. Missing or empty |title= (help)
  3. Jump up^ Thevis M, Milosovich S, Licea-Perez H, Knecht D, Cavalier T, Schänzer W. Mass spectrometric characterization of a prolyl hydroxylase inhibitor GSK1278863, its bishydroxylated metabolite, and its implementation into routine doping controls. Drug Test Anal. 2016 Aug;8(8):858-63. doi:10.1002/dta.1870PMID 26361079. Missing or empty |title= (help)
Daprodustat
Daprodustat structure.png
Clinical data
Synonyms GSK1278863
ATC code
  • None
Identifiers
CAS Number
PubChem CID
Chemical and physical data
Formula C19H27N3O6
Molar mass 393.44 g/mol
3D model (JSmol)

//////////////Daprodustat, GSK1278863, ダプロデュスタット , HIF-prolyl hydroxylase inhibitor, anemia, diabetic wounds, reduction of ischemic complications, Phase II, GlaxoSmithKline

  1. Daprodustat
  2. 960539-70-2
  3. GSK1278863
  4. UNII-JVR38ZM64B
  5. GSK-1278863
  6. JVR38ZM64B
  7. N-((1,3-Dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl)glycine
  8. Daprodustat [USAN:INN]
  9. GSK 1278863
  10. D0F6JC
  11. Daprodustat(GSK1278863)
  12. Daprodustat; GSK1278863
  13. Daprodustat (JAN/USAN/INN)
  14. GTPL8455
  15. Daprodustat (GSK1278863)
  16. CHEMBL3544988
  17. BCP16766
  18. EX-A1121
  19. KS-00000M8Z
  20. s8171

C1CCC(CC1)N2C(=O)C(C(=O)N(C2=O)C3CCCCC3)C(=O)NCC(=O)O

Firategrast, T-0047


Japan

Firategrast.png

Firategrast, 402567-16-2;

Firategrast, MS, Alpha4beta1 integrin

PHASE 2 GSK

Mitsubishi Tanabe Pharma INNOVATOR

Tanabe Seiyaku Co

Glaxo Group Limited, Mitsubishi Tanabe Pharma Corporation

SB 683699, SB-683699, UNII-OJY3SK9H5F
Firategrast; UNII-OJY3SK9H5F; SB-683699; Firategrast (USAN); 402567-16-2; SB683699; T-0047  
Molecular Formula: C27H27F2NO6
Molecular Weight: 499.503186 g/mol
SYSTEMATIC NAME:
1,1′-Biphenyl)-4-propanoic acid, alpha-((2,6-difluorobenzoyl)amino)-4′-(ethoxymethyl)-2′,6′-dimethoxy-, (alphaS)-
N-(2,6-Difluorobenzoyl)-4-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-L-phenylalanine
N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl) -L-phenylalanine .
2S)-2-((2,6-Difluorobenzoyl)amino)-3-(4′-(ethoxymethyl)-2′,6′-dimethoxybiphenyl-4- yl)propanoic acid
(2S)-2-{[(2,6- difluorophenyl)carbonyl]amino}-3-[4′-[(ethyloxy)methyl]-2′,6′-bis(methyloxy)-4- biphenylyl]propanoic acid
(2S)-2-[[2,6-bis(fluoranyl)phenyl]carbonylamino]-3-[4-[4-(ethoxymethyl)-2,6-dimethoxy-phenyl]phenyl]propanoic acid

Pharmacological half-life is 2.5 – 4.5 hours, compared to 11 days for natalizumab, a drug in the same class

Orally bioavailable small molecule α4-integrin antagonist
see

http://www.msdiscovery.org/node/1377#node-biblio-1338

http://multiple-sclerosis-research.blogspot.com/2012/01/research-oral-tysabri-analogue.html

SB683699 is an alpha4 integrin antagonist that had been studied in phase II trials at GlaxoSmithKline under a license from Mitsubishi Tanabe Pharma for the oral treatment of multiple sclerosis (MS) in Europe. GlaxoSmithKline and Tanabe Seiyaku (now Mitsubishi Tanabe Pharma) had been studying the drug candidate for the treatment of asthma, rheumatoid arthritis (RA) and Crohn’s disease

MECHANISMS/EFFECTS

HUMAN:

Similar mechanism of action to natalizumab (α4-integrin blocker), but its faster elimination could improve safety profile

 Firategrast
Firategrast
SYNTHESIS
………………….
PATENT

Scheme 1

Figure imgf000010_0001

Scheme 2

Figure imgf000012_0001

In a further aspect the present invention provides for a process for the preparation of compound of formula (II) which comprises coupling the compound of formula (V)

Figure imgf000012_0002

Suitable coupling conditions for the compound of formula (V) and the compound of formula (VI) include those shown in Scheme 2. In a further aspect of the invention there is provided the compound of formula (V):

Figure imgf000013_0001

1H NMR characterisation data for the compound of formula (V) were generated on an isolated and purified batch. 1H-NMR spectra were recorded on a Bruker Avance 400 at 400MHz, using TMS as an internal reference.1H NMR (400 MHz, DMSO-D6) δ ppm 1.17 (t, J=7.09 Hz, 3 H) 2.96 (dd, J=13.82, 9.90 Hz, 1 H) 3.1 1 (dd, J=13.82, 5.26 Hz, 1 H) 4.12 (q, J=7.09 Hz, 2 H) 4.63 (ddd, J=9.78, 7.82, 5.38 Hz, 1 H) 7.15 (t, J=7.95 Hz, 2 H) 7.25 (d, J=8.31 Hz, 2 H) 7.47 – 7.55 (m, 3 H) 9.23 (d, J=7.83 Hz, 1 H).

The present invention provides a process for the preparation of the compound of formula

Figure imgf000003_0001

which process comprises the steps: a) hydrolysis of an ester of formula (I la):

Figure imgf000004_0001

Recrvstallisation of (2S)-2-{r(2,6-difluorophenyl)carbonyllamino)-3-r4′-r(ethyloxy)methyll- 2′,6′-bis(methyloxy)-4-biphenylyllpropanoic acid

(2S)-2-{[(2,6-difluorophenyl)carbonyl]amino}-3-[4′-[(ethyloxy)methyl]-2′,6′-bis(methyloxy)- 4-biphenylyl]propanoic acid (9.38Kg) was charged into a clean reactor, followed by ethyl acetate (46.9L). The solution was heated to 50°C and filtered into the pre-warmed (35°C) crystallizing vessel. A line-wash with ethyl acetate (9.4L) was carried out. The combined ethyl acetate solutions were heated to 50°C, stirred to ensure complete dissolution. Filtered heptane (9.4L) was added maintaining the temperature at 50°C then the solution cooled to 30°C and seeded with (2S)-2-{[(2,6-difluorophenyl)carbonyl]amino}-3-[4 – [(ethyloxy)methyl]-2′,6′-bis(methyloxy)-4-biphenylyl]propanoic acid (47g) slurried in 1 :9 ethyl acetate:heptane (0.47L). The slurry was aged for 2 hours at 30°C. Filtered heptane (75L) was added over 3 hours. The slurry was then cooled to 0°C over 1 hour. The mixture was aged at 0°C for 1 hour then the solid was filtered off, washed with isopropyl ether (29.6L and dried under vacuum at 50±3°C to give the product (8.55Kg, 91 %). Characterised by having an infrared absorption spectrum with significant absorption bands at about 754, 768, 800, 820, 849, 866, 1006, 1 100, 1 122, 1 157, 1 188, 1225, 1242, 1268, 1292, 1317, 1352, 1417, 1466, 1530, 1580, 1624, 1650, 1662, 171 1 , 1728, 2938, 3302cm

…………………………………..
PATENT

Example 10: N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl) -L-phenylalanine ethyl ester.

(1) The product obtained in Example l-(4) (2.1 g) was acylated with 2 , 6-difluorobenzoyl chloride in a similar manner as described in Example 1 -(5) to give N- (2, 6-difluorobenzoyl) – 4- (2 , 6-dimethoxy-4-hydroxymethylphenyl) -L-phenylalanine ethyl ester (2.75 g) . mp . 70-72 °C; IR (Nujol) 3400, 3263, 1735, 1654, 1624 cm“1; MS (APCI) m/z 500 (M+H) . (2) To a solution of the product obtained above (1.72 g) in DMSO (20 ml) were added Et3N (4.8 ml) and S03«pyridine (5.6 g) successively at room temperature. The whole mixture was stirred at room temperature for 25 minutes. The reaction mixture was poured into ice-water, and then the mixture was extracted with EtOAc. The organic layer was sequentially washed with 5% aqueous HCl, H20 and brine, dried (Na2S04) and then evaporated. The residue was purified by column chromatography (silica gel; eluent: n-hexane/EtOAc 5:1 to 1:1) to yield N-(2,6- difluorobenzoyl) -4- (2 , 6-dimethoxy-4-formylphenyl) -L- phenylalanine ethyl ester (1.54 g) . mp. 114-116°C; IR (Nujol)

3332, 1735, 1695, 1657, 1644, 1623 cm“1; MS (APCI) m/z 498 (M+H) .

(3) The product obtained above (716 mg) was converted into the title compound (428 mg) in a similar manner as described in Example 1- (7) . mp . 87-89°C; IR (Neat+CHC13) 3300, 1739, 1668 cm 1; MS (APCI) m/z 528 (M+H) .

Example 11: N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl ) -L-phenylalanine methyl ester.

(1) The product obtained in Example 2- (4) (1.00 g) was acylated with 2 , 6-difluorobenzoyl chloride to give N-(2,6- difluorobenzoyl) -4- (2 , 6-dimethoxy-4-hydroxymethylphenyl) -L- phenylalanine methyl ester (873 mg) in a similar manner as described in Example l-(5). IR (Nujol) 3257, 1743, 1655, 1624 cm 1; MS (APCI +Q1MS) m/z 503 (M+NH4) , 486 (M+H) . (2) The product obtained above (860 mg) was converted into the title compound (220 mg) in a similar manner as described in Example 2- (6) and (7).

Example 12: N- (2 , 6-Difluorobenzoyl) -4- (2 , 6-dimethoxy-4- ethoxymethylphenyl) -L-phenylalanine .

The product obtained in Example 10 (200 mg) was hydrolyzed in a similar manner as described in Example 3 to give the title compound (160 mg) . The product obtained in Example 11 (220 mg) was also hydrolyzed in a similar manner as described in Example 3 to give the title compound (167 mg) . mp. 156-158°C; IR (Nujol) 1735, 1655 cm“1; MS (ESI) m/z 498 (M-H) .

…………………….

PATENT

 https://www.google.com/patents/WO2003072536A1?cl=en

OUT LINE

phenylalanine derivative of the formula (I) :

Figure imgf000003_0001

wherein X1 is a halogen atom, X2 is a halogen atom, Q is a group of the formula -CH2– or -(CH2)2– and Y is a lower alkyl group, or a pharmaceutically acceptable salt thereof, which has excellent inhibitory activity against α4 integrin-mediated cell adhesion.

Thus, the present invention relates to a process for preparing a compound of the formula (I) :

Figure imgf000004_0001

wherein the symbols are the same as defined above, or a pharmaceutically acceptable salt thereof, comprising : (1) coupling a compound of the formula (VI) :

Figure imgf000004_0002

wherein Z is a leaving group, R1NH is a protected amino group and C02R is a protected carboxyl group with a compound of the formula (V) :

Figure imgf000004_0003

wherein the symbols are the same as defined above, removing the protecting group from the protected amino group, and if necessary, converting the resulting compound into a salt, to yield a compound of the formula (IV) :

Figure imgf000005_0001

wherein the symbols are the same as defined above, or a salt thereof,

(2) condensing the compound (IV) or a salt thereof with a compound of the formula (III) :

Figure imgf000005_0002

wherein the symbols are the same as defined above, a salt or a reactive derivative thereof to yield a compound of the formula (II) :

Figure imgf000005_0003

Ethyl (ocS) – – [ [ (1, 1-dimethylethoxy) carbonyl] amino] -4- hydroxybenzene propionate and ethyl (otS) -α- [ [ (1, 1- dimethylethoxy) carbonyl] amino] -4-

(trifluoromethanesulfonyloxy) benzene propionate are described in J. Med. Chem. , 33: 1620 (1990) and JP-A-7- 157472, respectively. 4-Bromo-3, 5-dimethoxybenzyl alcohol is described in, for example, J. Med. Chem. , 20: 299 (1977), and can also be prepared according to the following process.

Figure imgf000019_0001

Firstly, 4-bromo-3, 5-dihydroxybenzoic acid is methylated to give methyl 4-bromo-3, 5-dimethoxybenzoate, which is then reduced to yield 4-bromo-3, 5-dimethoxy benzyl alcohol. The methylation can be carried out by reacting with dimethyl sulfate in the presence of a base in a suitable solvent (e.g., ethyl acetate). The reduction can be carried out by reacting with an reducing agent (e.g., lithium alminium hydride, sodium borohydride and calcium borohydride) in a suitable solvent (e.g., tetrahydrofuran) .

EXAMPLES

The following Examples are provided to further illustrate the process of preparation according to the present invention. In the following examples, some compounds may be referred to by different compound name depending on the nomenclature, as illustrated below.

Ethyl (αS) -α-amino-4′ -ethoxymethyl-2′ , 6′ – dimethoxy (1, 1′ -biphenyl) -4-propionate

Another name: ethyl (2S) -2-amino-3- [4- (4-ethoxymethyl- 2, 6-dimethoxyphenyl) phenyl]propanoate

Ethyl (αS) – [ [1, 1-dimethylethoxy] carbonyl] amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1,1′ -biphenyl) -4-propionate

Another name 1: ethyl (2S) -2- [ (t-butoxycarbonyl) – amino] -3- [4- (4-ethoxymethyl-2, 6-dimethoxyphenyl) – phenyl]propanoate

Another name 2: Ethyl N- (t-butoxycarbonyl) -4- (4- ethoxymethyl-2, 6-dimethoxyphenyl) -L-phenylalanine

Ethyl (αS) – – [ (2, 6-difluorobenzoyl) amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1, 1′ -biphenyl) -4-propionate Another name 1: Ethyl (2S) -2- [ (2, 6- difluorobenzoyl) amino] -3- [4- (4-ethoxymethyl-2, 6- di ethoxyphenyl) phenyl] propanoate

Another name 2: Ethyl N- [2 , 6-difluorobenzoyl) -4- (4- ethoxymethyl-2, 6-dimethoxyphenyl) -L-phenylalanine

(ocS) – – [ (2, 6-Difluorobenzoyl) amino] -4′ -ethoxymethyl- 2′ , 6′ -dimethox (1,1′ -biphenyl) -4-propionic acid

Another name 1: (2S) -2- [ (2, 6-difluorobenzoyl) amino] -3- [4- (4-ethoxymethyl-2, 6-dimethoxyphenyl) phenyl]propanoic acid

Another name 2: N- [ 2 , 6-difluorobenzoyl) -4- (4- ethoxymethyl-2, 6-dimethoxyphenyl) -L-phenylalanine

EXAMPLE 1 (1) Under nitrogen atmosphere, pyridine (130.3 g) and trifluoromethanesulfonic anhydride (170.4 g) were added dropwise to a solution of ethyl (αS) -α- [ [ (1, 1- dimethylethoxy) carbonyl] amino] -4-hydroxybenzenepropionate

(170.0 g) in dichloromethane (1.7 L) at 10 ° C or below. After stirring for 1 hour at the same temperature, water

(850 ml) was added dropwise to the mixture and the mixture was stirred for 2 hours at the same temperature. The organic layer was washed with 10 % aqueous citric acid solution and aqueous saturated sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was removed in vacuo to yield ethyl (αS) -α- [ [ (1, 1- dimethylethoxy) carbonyl] amino] -4-

(trifluoromethanesulfonyloxy)benzenepropionate (242.5 g) as oil . MS (m/z) : 441 (M+) (2) Under nitrogen atmosphere, to a mixture of ethyl (αS)- – [ [ (1, 1-dimethylethoxy) carbonyl] amino] -4-

(trifluoromethanesulfonyloxy) benzenepropionate (66.2g), 4- ethoxymethyl-2, 6-dimethoxyphenylboric acid (54.0 g) , triphenylphosphine (9.83 g) and N-methylpyrrolidone (330 ml) were added palladium acetate (1.68 g) and diisopropylamine (24.9 g ), and the mixture was heated at 90 °C. After stirring for 1 hour at the same temperature, the mixture was cooled and toluene and water were added. The organic layers were washed with 10% aqueous citric acid solution and saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo to yield ethyl (αS) -α- [[ (1, 1-dimethylethoxy) carbonyl] amino] – 4′ -ethoxymethyl-2′ , 6′ -dimethox (1,1′ -biphenyl) -4-propionate (90.1 g) as oil.

The product was dissolved in ethanol (330 ml) , and after addition of p-toluenesulfonic acid monohydrate (28.5 g) , the mixture was stirred for 2 hours at 75 °C. After cooling to room temperature, the mixture was filtrated over charcoal and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate with heating. After cooling, the crystalline precipitates were collected by filtration and dried to yield ethyl (αS)-α- amino-4′ -ethoxymethyl-2′ , 6′ -dimethoxy (1, 1′ -biphenyl) -4- propionate p-toluenesulfonate (63.4 g) .

MS (m/z) : 387 (M+-p-toluenesulfonic acid), M.p. 127-129°C

(3) To a mixture of ethyl (αS) -α-amino-4′ -ethoxymethyl- 2′ , 6′ -dimethox (1, 1′ -biphenyl) -4-propionate p- toluenesulfonate (29.0 g) , sodium hydrogen carbonate (15. 2 g) , water (290 ml) and ethyl acetate (290 ml) was added dropwise 2, 6-difluorobenzoyl chloride (9. 6 g) at 15 °C or below and the mixture was stirred for 30 minutes at the same temperature. The ethyl acetate layer was washed with saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was recrystallized from isopropanol-water to yield ethyl (αS) -oi- [ (2, 6-difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethox (1, 1′ -biphenyl) -4-propionate (26.4 g) . MS (m/z) : 527 (M+) , M.p. 87-89°C (4) To a solution of sodium hydroxide (2.9 g) in water- tetrahydrofuran (317 ml-159 ml) was added ethyl (oιS)-α- [ (2, 6-difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethoxy (1, 1′ -biphenyl) -4-propionate (31.7 g) at 15°C and the mixture was stirred for 4 hours at the same temperature. After neutralizing with IN HC1, the organic solvent was removed in vacuo. The aqueous layer was cooled, the crystalline precipitates were collected by filtration and recrystallized from ethanol-water to yield (αS) -a- [ (2, 6- difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethoxy (1, 1′ -biphenyl) -4-propionic acid (28.8 g) . MS (m/z): 499 (M+) , M.p. 154-155°C

EXAMPLE 2 (1) Under nitrogen atmosphere, a mixture of ethyl (oιS)-o:- [[ (1, 1-dimethylethoxy) carbonyl] amino] -4-bromobenzene propanoate (11.17 g) , 4-ethoxymethyl-2, 6- dimethoxyphenylboronic acid (10.80 g ), palladium acetate (0.34 g), triphenylphosphine (1.57 g) , anhydrous potassium carbonate (12.44 g) , iV-methylpyrrolidone (56 ml) and water (11 ml) was stirred for 50 minutes at 80 °C. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was washed with 10% aqueous citric acid solution and saturated aqueous NaCl solution, dried over magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure to yield ethyl (αS)-α- [ [ (1, 1-dimethylethoxy) carbonyl] amino] -4′ -ethoxymethyl- 2′ , 6′ -dimethox (1, 1′ -biphenyl) -4-propionate (20.4 g) as oil. The product was dissolved in ethanol (100 ml) , and after addition of p-toluenesulfonic acid monohydrate (5.7 g) , the mixture was stirred for 1.5 hours at 75 °C. After cooling, the mixture was filtrated over charcoal and the filtrate was concentrated under reduced pressure. The residue was suspended in toluene with heating. After cooling, the crystalline precipitates were collected by filtration and dried to yield ethyl (αS) – -amino-4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1,1′ -biphenyl) -4-propionate p- toluenesulfonate (13.80 g) . (2) The compound obtained in the above step (1) was treated in the same manner as described in Example 1 (2) to (4) to yield (αS) -a- [ [2 , 6-difluorobenzoyl) amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1, 1′ -biphenyl) -4-propionic acid. The physicochemical data were the same as that obtained in Example 1.

EXAMPLE 3

To a solution of ethyl (αS) -α- [ (2, 6- difluorobenzoyl) amino] -4′ -ethoxymethyl-2′ , 6′ – dimethox (1, 1′ -biphenyl) -4-propionate (500 g ) in water (12.6 ml) and dioxane (50 ml) was added hydrochloric acid (12.4 g) and the mixture was stirred for 60 hours at 60 “C. The organic solvent was removed in vacuo and the aqueous layer was cooled. The crystalline precipitates were collected by filtration and recrystallized from ethanol- water to yield (αS) – – [ (2, 6-difluorobenzoyl) amino] -4′ – ethoxymethyl-2′ , 6′ -dimethoxy (1,1′ -biphenyl) -4-propionic acid (426 mg) . The physicochemical data were the same as that obtained in Example 1.

REFERENCE EXAMPLE 1

(1) To a mixture of 4-bromo-3, 5-dimethoxybenzylalcohol (44.5 g) , triethylammonium benzyl chloride (2.05 g) and 20% aqueous sodium hydroxide solution (288 g) was added diethyl sulfate (41.7 g) under ice-cooling, and the mixture was stirred overnight at 25-30 °C. After stirring for 1 hour at 70 °C, the mixture was cooled and extracted with toluene. The toluene layer was washed with water and saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo to yield 4-bromo-3, 5- dimethoxybenzyl ethyl ether (49.5 g) as colorless oil. MS (m/z): 276 (M++2) , 274 (M+)

(2) Under nitrogen atmosphere, to a solution of 4-bromo- 3, 5-dimethoxybenzyl ethyl ether (440.0 g) in tetrahydrofuran (4.0 L) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 1.1 L) at -60°C. After stirring for 15 minutes at the same temperature, trimethyl borate (249.3 g) was added. The temperature of the mixture was gradually elevated, followed by stirring for 1 hour under ice-cooling. To the mixture was added dropwise 10% aqueous sulfuric acid solution (835 g ) . The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated aqueous NaCl solution. After drying over magnesium sulfate, the solvent was removed in vacuo. The residue was dissolved in isopropyl ether with heating and cooled. The crystalline precipitates were collected by filtration and dried to yield 4-ethyoxymethyl-2, 6- dimetoxyphenylboronic acid (312.9 g) . M.p. 59-61°C

REFERENCE EXAMPLE 2

(1) To a suspension of 4-bromo-3, 5-dihydroxybenzoic acid (95.0 kg) in ethyl acetate (950 L) were added anhydrous potassium carbonate (270.8 kg) and dimethyl sulfate (174.7 kg) . The mixture was heated at 50-80 ‘C for about 4 hours and partitioned by adding water. The organic layer was washed with water and saturated aqueous NaCl solution and concentrated under reduced pressure. The residue was suspended into methanol, stirred under heating and cooled. The crystalline precipitates were collected by filtration and dried to yield methyl 4-bromo-3, 5-dimethoxybenzoate (98.8 kg) as pale yellow crystals. MS (m/z): 277 (M++2) , 275 (M+) , M.p. 120-122°C

(2) To a solution of calcium chloride (46.5 kg) in ethanol (336 L) were added tetrahydrofuran (672 L) and methyl 4- bromo-3, 5-dimethoxybenzoate (96.0 kg) to obtain a suspension. To the suspension was added sodium borohydride

(31.7 kg) by portions at room temperature, and the mixture was stirred for about 9 hours at temperature of room temperature to 45 °C. The reaction mixture was added dropwise to aqueous HC1 solution and stirred for about 16 hours at room temperature. Organic solvent was removed in vacuo, and water (1440 L) was added to the residue and stirred for 1 hour at 50 °C. After cooling, the crystalline precipitates were collected by filtration and dried to yield 4-bromo-3, 5-dimethoxybenzyl alcohol (83.3 kg) as colorless crystals. MS (m/z): 249 (M++2), 247 (M+) , M.p. 100-102°C.

INDUSTRIAL APPLICABILITY The process for preparation of the present invention makes it possible to afford a compound of the formula (I) or a pharmaceutically acceptable salt thereof with high- purity, in a high yield and inexpensively, and, therefore, the process of the present invention is industrially very useful.

References

GlaxoSmithKline website
US8822527 16 Out 2012 2 Set 2014 Biotheryx, Inc. Substituted biaryl alkyl amides
WO2002018320A2 27 Ago 2001 7 Mar 2002 Tanabe Seiyaku Co INHIBITORS OF α4 MEDIATED CELL ADHESION
WO2003072536A1 27 Fev 2003 4 Set 2003 Tanabe Seiyaku Co A process for preparing a phenylalanine derivative and intermediates thereof
WO2003072537A2 6 Fev 2003 4 Set 2003 Abbott Lab Selective protein tyrosine phosphatatase inhibitors

Mitsubishi Tanabe Pharma Corporation

Mitsubishi Tanabe Pharma Corporation
Pharmacological research building

Mitsubishi Tanabe Pharma Corporation
■Mitsubishi Tanabe Pharma Corporation
Pharmacological research building

 

 

 

 

 

 

 

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

 

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Sun Pharma to acquire GSK’s Australian opiates business


Sun Pharma to acquire GSK’s Australian opiates business

India-based Sun Pharmaceutical Industries has agreed to acquire GlaxoSmithKline’s (GSK) opiates business in Australia.

The agreement has been signed by wholly-owned subsidiaries of both firms, with the financial terms not disclosed.

Sun Pharma API business executive vice-president Iftach Seri said: “The global opiates market holds good potential and the addition of GSK’s Opiates business will strengthen our positioning further.”

http://www.pharmaceutical-technology.com/news/newssun-pharma-to-acquire-gsks-australian-opiates-business-4524031?WT.mc_id=DN_News

http://indianexpress.com/article/business/business-others/sun-pharma-to-buy-gsks-opiates-biz-in-australia/

Sun Pharmaceutical Industries Ltd(SUN.NS), India’s largest drugmaker by sales, said on Tuesday it has agreed to buy GlaxoSmithKline’s(GSK.L) opiates business in Australia to strengthen its pain management portfolio.

The business consists of analgesics made from raw materials found in opium poppy plants, and includes two manufacturing sites in the states of Tasmania and Victoria.

Financial details of the deal were not disclosed. A Sun Pharma spokesman declined to comment. Glaxo did not immediately respond to a request seeking comment.

Glaxo supplies a quarter of the world’s medicinal opiate needs from poppies grown by farmers in Tasmania, according to the company website. The company’s Australian opiates business brought in revenue of A$89 million ($69.63 million) in 2013.

Australia’s poppy industry is the world’s largest legal supplier of pharmaceutical grade opiates for painkillers, and Glaxo is one of three firms that control the crop and production in Tasmania.

The other two are Johnson & Johnson’s (JNJ.N) unit Tasmanian Alkaloids, and privately-held TPI Enterprises.

Glaxo’s decision to part with the opiates business comes as Tasmania’s poppy industry is facing a tough crop and the United Nations is expected to cut the state’s poppy crop area this week.

Glaxo said the deal would allow it to “focus on delivering its innovative product portfolio” in Australia.

“The opiates business has been an important part of our Australian business for many years, but as our portfolio transitions, we believe now is the right time to hand this business over to someone else,” Steve Morris, general manager of GSK Opiates, said in a statement.

The business employs 185 staff, including 155 in Victoria state and 30 in Tasmania state. Sun Pharma said it would hire all employees from both sites.

“The acquisition is a part of our strategy towards building our portfolio of opiates and accessing strong capabilities in this segment,” said Iftach Seri, executive vice president of the active pharmaceuticals ingredients business at Sun Pharma.

Both companies said they expect to close the deal by August.

Sun Pharma shares closed 1.93 percent higher on Tuesday, while the broader Nifty rose 0.44 percent.

($1 = 1.2781 Australian dollars)

Epelsiban being developed by GlaxoSmithKline for the treatment of premature ejaculation in men.


Epelsiban.svg

Epelsiban

557296
GSK-557296
GSK-557296-B

(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione

(3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethylpyridin-3-yl)-2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione

(3R, 6R)-3-(2,3-dihydro-1 H-inden-2-yl)-1-[(1R)- 1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1 S)-1-methylpropyl]-2,5- piperazinedione

Glaxo Group Limited  INNOVATOR

Epelsiban (GSK-557,296-B)[1][2] is an oral drug which acts as a selective, sub-nanomolar (Ki=0.13 nM) oxytocin receptor antagonist with >31000-fold selectivity over the related vasopressin receptors and is being developed by GlaxoSmithKline for the treatment of premature ejaculation in men.[3][4]

EPELSIBAN BESYLATE.png

benzenesulfonic acid;(3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethylpyridin-3-yl)-2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione,CAS 1159097-48-9

UNII-H629P9T4UN, GSK557296B, Epelsiban besylate (USAN), Epelsiban besylate [USAN], 1159097-48-9, H629P9T4UN

GSK-557296 is being developed in early clinical studies at GlaxoSmithKline for enhancement of embryo and or blastocyst implantation in women undergoing IVF treatment. The product has been in phase II clinical development for the treatment of premature ejaculation.

Preterm labor is a major clinical problem leading to death and disability in newborns and accounts for 10% of all births and causes 70% of all infant mortality and morbidity.

Oxytocin (OT) is a potent stimulant of uterine contractions and is responsible for the initiation of labor via the interaction with the OT receptors in the mammalian uterus. OT antagonists have been shown to inhibit uterine contractions and delay preterm delivery. So there is increasing interest in OT antagonists because of their potential application in the prevention of preterm labor. Although several tocolytics have already been approved in clinical practice, they have harmful maternal or fetal side effects.

The first clinically tested OT antagonist atosiban has a much more tolerable side effect profile and has recently been approved for use in Europe. However, atosiban is a peptide and a mixed OT/vasopressin V1a receptor antagonist that has to be given by iv infusion and is not suitable for long-term maintenance treatment, as it is not orally bioavailable.

Hence there has been considerable interest in overcoming the shortcomings of the peptide OT antagonists by identifying orally active nonpeptide OT antagonists with a higher degree of selectivity toward the vasopressin receptors (V1a, V1b, V2) with good oral bioavailability. Although several templates have been investigated as potential selective OT antagonists, few have achieved the required selectivity for the OT receptor vs the vasopressin receptors combined with the bioavailability and physical chemical properties required for an efficacious oral drug.

Therefore our objective was to design a potent, orally active OT antagonist with high levels of selectivity over the vasopressin receptor with good oral bioavailability in humans that would delay labor safely by greater than seven days and with improved infant outcome, as shown by a reduced combined morbidity score.

Patent Submitted Granted
Compounds [US7919492] 2010-12-02 2011-04-05
Piperazinediones as Oxytocin Receptor Antagonists [US7550462] 2007-11-01 2009-06-23
Compounds [US8202864] 2011-06-23 2012-06-19
Novel compounds [US2009247541] 2009-10-01

………………………………………

PATENT

https://www.google.com/patents/US7919492

 

Example 3

Method A

(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione

as a white lyophilisate (88 mg, 23%) after freeze-drying from 1,4-dioxane

HPLC Rt=2.70 minutes (gradient 2); m/z [M+H]+=519

1H NMR (CDCl3) δ 7.49 (d, 1H), 7.27-7.15 (m, 4H), 7.10 (d, 1H), 6.68 (s, 1H), 6.40 (d, 1H), 4.10 (dd, 1H), 4.01 (d, 1H), 3.74-3.52 (m, 5H), 3.28-3.07 (m, 5H), 2.97-2.84 (m, 2H), 2.79-2.71 (m, 1H), 2.62 (s, 3H), 2.59 (s, 3H), 1.65-1.53 (m, 1H), 0.98-0.80 (m, 2H), 0.70 (t, 3H), 0.45 (d, 3H).

Example 3

Method B

(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione

A suspension of {(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}(2,6-dimethyl-3-pyridinyl)acetic acid hydrochloride (5.0 g, 10.3 mmol) (intermediate 5) in dry dichloromethane (50 ml) was treated with 1,1-carbonyldiimidazole (2.6 g, 16 mmol) and the reaction mixture was stirred under nitrogen for 18 hours. Morpholine (4.8 ml, 55 mmol) was added and the resultant solution was left to stand under nitrogen for 18 hours. The solvent was removed in vacuo and the residue was separated between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was dissolved in dichloromethane. This was applied to a basic alumina cartridge (240 g) and eluted using a gradient of 0-7.5% methanol in diethyl ether (9CV), 7.5-10% methanol in diethyl ether (1CV) and 10% methanol in diethyl ether (1CV). The required fractions were combined and evaporated in vacuo to give (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione as a white solid (2.4 g, 45%).

HPLC Rt=2.72 minutes (gradient 2); m/z [M+H]+=519

 

………………………………………

WO 2011051814

 http://www.google.com/patents/WO2011051814A1?cl=en

This invention relates to novel crystalline forms of (3R, 6R)-3-(2,3-dihydro-1 H- inden-2-yl)-1 -[(1 R)-1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1 S)-1 – methylpropyl]-2,5-piperazinedione benzenesulfonate salt, processes for their preparation, pharmaceutical compositions containing them and to their use in medicine. The benzenesulfonate salt of Compound A is represented by the following structure:

Figure imgf000004_0001

In one aspect, the present invention provides a crystalline form of {3R, 6R)-3- (2,3-dihydro-1 H-inden-2-yl)-1 -[(1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate, wherein said crystalline form provides an X-ray powder diffraction pattern substantially in accordance with Figure 1 .

In another aspect, the invention encompasses a crystalline form of (3R, 6R)-3- (2,3-dihydro-1 H-inden-2-yl)-1 -[(1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate, wherein said crystalline form is characterized by an X-ray powder diffraction pattern comprising the peaks:

Figure imgf000004_0002

In an additional aspect, the invention includes a crystalline form of {3R, 6R)-3- (2,3-dihydro-1 H-inden-2-yl)-1 -[(1 R)-1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate hydrate, wherein said compound is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 2.

In certain aspects, the invention encompasses a crystalline form of (3R, 6R)-3- (2,3-dihydro-1 H-inden-2-yl)-1 -[(1 R)-1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate hydrate, wherein said compound is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 2 In one aspect, the invention also provides a crystalline form of {3R, 6R)-3-(2,3- dihydro-1 H-inden-2-yl)-1-[(1 R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]- 6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate hydrate, wherein said crystalline form is characterized by an X-ray powder diffraction pattern comprising the peaks:

Figure imgf000005_0001

Experimental

Process Scheme

Figure imgf000012_0001

Stage 4

Acetone / Water Recrystallisation

Compound A-form I Ste8e 5 Besylate salt

MW 676.83 Acetone / Water

Recrystallisation MW 676.83 Process description for isolation of Compound A-Form 1

Stage 0

methyl d-alloisoleucinate hydrochloride (Compound 2) was charged to ethyl acetate. A solution of potassium carbonate in water was then added. The mixture was then stirred vigorously at room temperature for 1 hour. The two layers were separated and the aqueous layer further extracted with ethyl acetate. The organic layers were combined and washed with brine. The organic layers were then concentrated in vacuo and filtered to yield methyl D-alloisoleucinate (Compound 3) as a pale yellow oil.

Stage 1

2,6-dimethyl-3-pyridinecarbaldehyde (Compound 4) in methanol at ambient temperature was treated with D-alloisoleucinate (Compound 3) in methanol followed by 2,2,2- trifluoroethanol and the reaction mixture was warmed to 40°C. When formation of the intermediate imine (methyl A/-[(2,6-dimethyl-3-pyridinyl)methylidene]-D-alloisoleucine) was complete Compound 5 was added followed by 1-isocyano-2- [(phenylmethyl)oxy]benzene (Compound 6) and the reaction mixture was stirred at 40°C until formation of Compound 7 was deemed complete.

Stage 2

Palladium on carbon catalyst was treated with a solution of Compound 7 in methanol and 2,2,2-trifluoroethanol and diluted with acetic acid. The vessel was purged with nitrogen and the reaction mixture warmed to 50°C and hydrogenated at 4.0-4.5 barg. When the reaction was deemed complete it was cooled to ambient temperature and the catalyst removed by filtration and washed through with methanol. The organic solution of 2- {(3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-6-[(1 S)-1 -methylpropyl]-2,5-dioxo-1-piperazinyl}- 2-(2,6-dimethyl-3-pyridinyl)-/\/-(2-hydroxyphenyl)acetamide (Compound 8) was concentrated at reduced pressure and then diluted with /so-propyl acetate and concentrated at reduced pressure.

The residue was diluted with /so-propyl acetate and washed with aqueous ammonia. The aqueous phase was separated and extracted into another portion of /so-propyl acetate. The combined organic phases were washed with water, concentrated by distillation at reduced pressure, diluted with /so-propyl acetate and concentrated by distillation at reduced pressure, to leave a concentrated solution of 2-{(3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-6-[(1 S)-1 -methylpropyl]-2,5-dioxo-1 – piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-/\/-(2-hydroxyphenyl)acetamide (Compound 8). The product was finally dissolved in 1 ,4-dioxane for the next stage and stored into drums.

Stage 3 Solution of 2-{(3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-6-[(1 S)-1 -methylpropyl]-2,5-dioxo-1 – piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-/\/-(2-hydroxyphenyl)acetamide (Compound 8) in 1 ,4-dioxane was treated with 1 ,1 ‘-carbonyl diimidazole at ambient temperature to form a solution containing (3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-1 -[1-(2,6-dimethyl-3-pyridinyl)- 2-oxo-2-(2-oxo-1 ,3-benzoxazol-3(2H)-yl)ethyl]-6-[(1 S)-1 -methylpropyl]-2,5- piperazinedione (Compound 9).

In a separate vessel morpholine in 1 ,4-dioxane was heated to 80-85°C. The solution containing (3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-1-[1 – (2,6-dimethyl-3-pyridinyl)-2-oxo-2-(2-oxo-1 ,3-benzoxazol-3(2H)-yl)ethyl]-6-[(1 S)-1- methylpropyl]-2,5-piperazinedione (Compound 9) was slowly added to the morpholine in 1 ,4-dioxane. The reaction mixture was stirred for one hour at 80-85°C and cooled before concentration by distillation at reduced pressure.

The concentrated solution of Compound A was diluted with /so-propyl acetate and washed with aqueous sodium hydroxide followed by water. The /so-propyl acetate solution of COMPOUND A was then concentrated by distillation at reduced pressure and cooled to ambient temperature. The concentrated solution of Compound A was then diluted with acetone and treated with benzenesulfonic acid and seed crystals were added and the reaction mixture stirred until crystallisation occurred. The slurry of Compound A besylate was heated to 50°C, a temperature cycle was performed, and finally the slurry was cooled to -10°C and isolated by filtration. The filter cake was washed with cold acetone (-10°C) to give Compound A besylate (intermediate grade) as a wet cake.

Yield: 44% from Compound 5

39% from Compound 5

Stage 4

Compound A besylate (intermediate grade wet cake, Compound A besylate ) was suspended in acetone (17.4 vol including acetone content of wet cake) and heated to 55- 60°C. Water (0.66 vol) was added until dissolution was observed. The reaction mixture was then filtered into another vessel and the lines washed through with acetone (3.2 vol). The temperature of the reaction mixture was adjusted to 45-50°C before the addition of seed crystals (0.00025wt). When crystallisation was complete the reaction mixture was cooled to 20-25°C and stirred at 20-25°C for 30mins.

The reaction mixture was heated to 45-50°C and stirred at 45-50°C for 30mins. The reaction mixture was cooled to 20-25°C and stirred at 20-25°C for 30mins. The reaction mixture was heated to 45-50°C and stirred at 45-50°C for 30mins. The reaction mixture was cooled to -3-2°C over 4.5 h and stirred for at least 1 h before the product was isolated by filtration. The wet cake was washed with acetone at 0°C (3 x 3.1 vol) and blown dry before being unloaded. COMPOUND A besylate was dried at 50°C under vacuum for 3 days. Compound A besylate was then milled. Yield: 66% Stage 5

Compound A besylate (OBU-D-02) was suspended in acetone (8 vol) and water (1 .1 vol) and heated to 48-52°C until dissolution was observed. The reaction mixture was then filtered into another vessel and the lines washed through with acetone (2 vol). The reaction mixture was cooled to 20-25°C before the addition of Form 1 seed crystals (0.0025wt). When crystallisation was complete the reaction mixture was cooled to 0-5°C over 1 h and stirred at 0-5°C for 30mins. The reaction mixture was heated to 20-25°C and stirred at 20-25°C for 30mins. The reaction mixture was cooled to 0-5°C over 1 h and stirred at 0-5°C for 30mins.

The reaction mixture was heated to 20-25°C and stirred at 20-25°C for 30mins. The reaction mixture was cooled to -12— 8°C over 3.5 h and stirred for 15 h before the product was isolated by filtration. The wet cake was washed with acetone at -10°C (2 x 3 vol) and blown dry before being unloaded. Compound A besylate was dried at ambient temperature under vacuum for 6 days with a wet nitrogen bleed to afford Form 1 . Compound A besylate was then milled. Yield: 67%

Recrystallisation of Compound A besylate anhydrate (Form 2)

Figure imgf000015_0001

Besylate salt ………………………………………………………………Besylate salt

C30H38 4O4■ C6H603S C30H38 4O4

MW 676.83 MW 676.83

COMPOUND A besylate is charged to the vessel and treated with methyl ethyl ketone (MEK) (8vol) and water (0.35vol) and the solution heated until dissolution is observed (ca. 55-60°C). The solution is then filtered and recharged to the vessel. Pressure is then reduced to 650mbar and the reaction mixture heated further to distil out solvent. MEK is added at the same rate as solvent is removed by distillation keeping the reaction mixture volume constant. After 4 volumes of MEK have been added the reaction mixture is treated with Form 2 seed crystals (2%wt) and the distillation continued in the same manner until another 7 volumes of MEK has been added. The vacuum is then released to an atmospheric pressure of nitrogen and the temperature of the reaction mixture adjusted to 65°C. The reaction mixture is then filtered and washed with pre heated MEK (2vol at 65°C). The purified COMPOUND A besylate anhydrate is then sucked dry and dried further in a vacuum oven at 65°C at l OOmbar with a nitrogen bleed. Yield 89%

NMR data is the same for Forms 1 and 2.

1 H NMR (500MHz, DMSO-d6) 5ppm 0.71-0.80(m, 6H) 0.87-0.98(m, 1 H) 1 .31 (br. S, 1 H) 1.69(br. S, 1 H) 2.68(s, 3H) 2.69(s, 3H) 2.72-2.79(m, 1 H) 2.80-2.87(m, 1 H) 2.88-3.01 (m, 3H) 3.18-3.25(m, 1 H) 3.27-3.33(m, 1 H) 3.38-3.46(m, 1 H) 3.47-3.52(m, 1 H)3.53-3.57(m, 1 H) 3.60-3.71 (m, 3H) 3.83(dd, J=9.46,3.15 Hz, 1 H) 3.89 (br. S, 1 H)6.10(br. S, 1 H) 7.1 1 – 7.14(m, 2H) 7.19-7.23(m, 2H) 7.30-7.35(m, 3H)7.59-7.63(m, 2H) 7.67(d, J=7.25Hz, 1 H) 8.12(br. S, 1 H) 8.50(d, J=3.78Hz, 1 H)

 

Compounds of the present invention can be tested according to the description of International Publication No. WO2006000399 (US2007254888A1 ).

 

………………………………………..

PAPER

J. Med. Chem., 2012, 55 (2), pp 783–796
DOI: 10.1021/jm201287w

http://pubs.acs.org/doi/abs/10.1021/jm201287w

Abstract Image

A six-stage stereoselective synthesis of indanyl-7-(3′-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3′-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pKi > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2′,6′-dimethyl-3′-pyridyl Rsec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pKi = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.

(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione (69 EPELSIBAN)

A ………………………. gave colorless needles (75%)
mp 140 °C.
1H NMR (CDCl3) δ 7.49 (d, J =7.8 Hz, 1H, pyridyl-4H),
7.26–7.15 (m, 4H, indanyl-arylH),
7.10 (d, J =8.1 Hz, 1H, pyridyl-5H),
6.68 (s, 1H, NCHpyridyl),
6.49 (d, J = 2.8 Hz, 1H, lactam-NH),
4.10 (dd, J = 10.1 Hz, 4.0 Hz, 1H, NCHindanyl),
4.01 (d, J = 4.5 Hz, NCHsec-butyl),
3.75–2.71 (m, 13H, 8× morpholinyl-H, indanyl-3H, –1H, –2H),
2.62 and 2.58 (2s, 6H, pyridyl-2Me,-6Me),
1.64–1.52 (m, 1H, CHHMe),
0.98–0.79 (m, 2H, CHHMe, CHMeCH2),
0.70 (t, J = 7.1 Hz, 3H, CH2Me),
0.45 (d, J = 6.8 Hz, 3H, CHMe).
LCMS m/z 519 (MH+) single component, gradient 2 (tR 2.70 min).
HRMS calcd for C30H38N4O4(MH+) 519.29658, found 519.29667.
HPLC: 100% (tR 10.388 min).
EPELSIBAN BESYLATE SALT
To a ……………………………….give the besylate (3.214 g, 92.6%) as white crystals of 69B
mp 179–183 °C.
1H NMR (CD3OD) δ 8.30 (d, 1H, J = 8.1 Hz, pyridyl-4H),
7.84–7.80 (m, 2H, PhSO3ortho-H),
7.78 (d, J = 8.3 Hz, 1H, pyridyl-5H),
7.45–7.38 (m, 3H, PhSO3meta-H, para-H),
7.23–7.09 (m, 4H, indanyl-arylH),
6.08 (broad s, 1H, NCHpyridyl),
4.00 (d, J =4.6 Hz, 1H, NCHsec-butyl),
3.92 (d, J = 9.9 Hz, 1H, NCHindanyl),
3.78–3.39 and 3.14–2.80 (m, 13H, 8× morpholinyl-H, indanyl-3H, –1H, –2H)),
2.79 and 2.78 (2s, 6H, pyridyl-2Me, -6Me),
1.85–1.74 (m, 1H, CHHMe),
1.59–1.48 (m, 1H, CHHMe),
1.15–1.01 (m, 1H, CHMeCH2),
0.92 (d, J =6.3 Hz, 3H, CHMe),
0.85 (t, J = 7.3 Hz, 3H, CH2Me).
LCMS m/z 519 MH+ single components, tR2.72 min;
circular dichroism (CH3CN) λmax 225.4 nm, dE −15.70, E15086; λmax 276 nm, dE 3.82, E5172.
HRMS calcd for C30H38N4O4 (MH+) 519.2971, found 519.2972.
Anal. (C30H38N4O4·C6H6O3S·3.0H2O) C, H, N, S.

References

  1. Borthwick AD, Liddle J, Davies DE, Exall AM, Hamlett C, Hickey DM, Mason AM, Smith IE, Nerozzi F, Peace S, Pollard D, Sollis SL, Allen MJ, Woollard PM, Pullen MA, Westfall TD, Stanislaus DJ (January 2012). “Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: synthesis, pharmacokinetics, and in vivo potency”. Journal of Medicinal Chemistry 55 (2): 783–96. doi:10.1021/jm201287w. PMID 205501.

 

 

Epelsiban
Epelsiban.svg
Systematic (IUPAC) name
(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethylpyridin-3-yl)-2-(morpholin-4-yl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]piperazine-2,5-dione
Clinical data
Legal status
  • Non-regulated
Identifiers
CAS number 872599-83-2
1159097-48-9 (besylate)
ATC code None
PubChem CID 11634973
ChemSpider 9809717
KEGG D10117 Yes
Chemical data
Formula C30H38N4O4 
Molecular mass 518.6 g/mol
Cited Patent Filing date Publication date Applicant Title
WO2003053443A1 Dec 20, 2002 Jul 3, 2003 Glaxo Group Ltd Substituted diketopiperazines as oxytocin antagonists
WO2006000399A1 Jun 21, 2005 Jan 5, 2006 Glaxo Group Ltd Novel compounds
EP2005006760W Title not available
US6914160 Jul 31, 2003 Jul 5, 2005 Pfizer Inc Oxytocin inhibitors
US20070254888 Jun 21, 2005 Nov 1, 2007 Glaxo Group Limited Piperazinediones as Oxytocin Receptor Antagonists
US8202864 * Feb 25, 2011 Jun 19, 2012 Glaxo Group Limited Compounds
US8716286 Oct 28, 2010 May 6, 2014 Glaxo Group Limited Crystalline forms of (3R, 6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione
US8742099 May 20, 2013 Jun 3, 2014 Glaxo Group Limited Compounds
US8815856 Mar 18, 2014 Aug 26, 2014 Glaxo Group Limited Crystalline forms of (3R, 6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione
US20120202811 * Apr 19, 2012 Aug 9, 2012 Glaxo Group Limited Novel compounds

Foretinib (Exelixis, GlaxoSmithKline, XL-880)


Foretinib.svg

Foretinib (Exelixis, GlaxoSmithKline) (XL-880)

CAS No.:849217-64-7, 937176-80-2
Formula:C34H34F2N4O6
M.Wt:632.24

GSK1363089, XL880

1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Foretinib is an experimental drug candidate for the treatment of cancer.[1] It was discovered by Exelixis and is under development by GlaxoSmithKline.[2] It is currently in Phase II clinical trials.[3] As of December 2012 no phase III trials are registered.[3]

Foretinib is an inhibitor of the kinase enzymes c-Met and vascular endothelial growth factor receptor 2 (VEGFR-2).[4]

Foretinib is an orally bioavailable small molecule with potential antineoplastic activity. MET/VEGFR2 inhibitor GSK1363089 binds to and selectively inhibits hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor 2 (VEGFR2), which may result in the inhibition of tumor angiogenesis, tumor cell proliferation and metastasis. The proto-oncogene c-MET has been found to be over-expressed in a variety of cancers. VEGFR2 is found on endothelial and hematopoietic cells and mediates the development of the vasculature and hematopoietic cells through VEGF signaling.

Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met and KDR with IC50 of 0.4 nM and 0.9 nM. Less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

 

Foretinib.png

 

………………………………..

Patent Submitted Granted
Preparation of a Quinolinyloxydiphenylcyclopropanedicarboxamide [US2010081805] 2010-04-01
C-Met Modulators and Method of Use [US2012022065] 2012-01-26
C-Met Modulators and Method of Use [US2011077233] 2011-03-31
c-Met modulators and methods of use [US7579473] 2009-07-02 2009-08-25
c-MET MODULATORS AND METHODS OF USE [US8067436] 2009-04-23 2011-11-29
C-MET MODULATORS AND METHOD OF USE [US8178532] 2007-09-27 2012-05-15
Method of Treating Cancer using a cMet and AXL Inhibitor and an ErbB Inhibitor [US2009274693] 2009-11-05
c-MET MODULATORS AND METHOD OF USE [US2007244116] 2007-10-18
c-Met modulators and methods of use [US2007054928] 2007-03-08

………………………………….

http://www.google.com/patents/WO2014067417A1?cl=en

Foretinib (GSK1363089, XL880) quinoline compounds are, an oral c-Met and VEGFR / KDR kinase inhibitor of c-Met kinase and KDR kinase IC 5Q Wo port respectively 0.4 0.8 nM, the current has entered Phase II clinical study (WO2010036831Al). Clinical studies have shown that, Foretinib variety of people, such as human lung cancer cells, human gastric cancer cells and other tumor cell lines showed a significant inhibitory effect, an IC 50 value of 0.004 g / mL.

Figure imgf000004_0001

 

 

 

……………………………

http://www.google.com/patents/WO2014145693A1?cl=en

Accordingly, small-molecule compounds that specifically inhibit, regulate, and/or modulate the signal transduction of kinases, particularly including Ret, c-Met, and VEGFR2 described above, are particularly desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis. One such small-molecule is XL880, known variously as N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-(4-fluorophenyl)cyclopropane-l,l- dicarboxamide and alternatively as foretimb. Foretimb has the chemical structure:

[0007] WO 2005/030140 describes the synthesis of foretinib (Example 44) and also discloses the therapeutic activity of this molecule to inhibit, regulate, and/or modulate the signal transduction of kinases (Assays, Table 4, entry 312). Example 44 begins at paragraph [0349] in WO 2005/030140.

Figure imgf000034_0001

 

 

Figure imgf000032_0001

……………………………………

 

WO 2012044577 A1…….Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases

Figure imgf000020_0003
Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)
Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)WO 2012044577 A1…….Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases
 http://www.google.com/patents/WO2012044577A1?cl=en

In another embodiment, the compound of Formula I is Compound 1 :
Figure imgf000005_0001
Compound 1
or a pharmaceutically acceptable salt thereof. Compound I is known as N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N’-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide. WO 2005/030140 describes the synthesis of N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy }phenyl)-N’-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide (Example 12, 37, 38, and 48) and also discloses the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 289). Example 48 is on paragraph [0353] in WO 2005/030140.
[0013] In another embodiment, the compound of Formula I is Compound 2:
Figure imgf000005_0002
Compound 2
Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)
or a pharmaceutically acceptable salt thereof. Compound 2 is known as is N-[3-fluoro-4- ({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-(4- fluorophenyl)cyc!opropane- 1,1 -dicarboxamide. WO 2005-030140 describes the synthesis of Compound (I) (Examples 25, 30, 36, 42, 43 and 44) and also discloses the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 312). Compound 2 has been measured to have a c-Met IC50 value of about 0.6 nanomolar (nM). PC1YUS09/064341, which claims priority to U.S. provisional application 61/199,088, filed November 13, 2008, describes a scaled-up synthesis of Compound I.

Scheme 2

Preparation of 4-Chloro-6,7-dimethoxy-quinoIine

[00173] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg) and the filter bed was washed with DCM (1 18.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound. (35.6 kg).

Preparation of -(6, 7 -Dimethoxy-quinoline- -yloxy)-phenylamine

[00174] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 °C. This mixture was then heated to 100- 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 °C and water (pre-cooled, 2-7 °C, 587 L) charged at a rate to maintain 15-30 °C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4- yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7- dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 21 1.4 kg) and DMA (108.8 kg) for approximately lhour and then cooled to 0-5 °C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 °C to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg). Alternative Preparation of 4-(6, 7-Dimethoxy-quinoIine-4-yloxy)-phenylamine

[00175] 4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-aminophenoI (30.8 kg) and sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35 weight percent in THF) were charged to a reactor, followed by N(N-dimethylacetamide (DMA, 293.3 kg). This mixture was then heated to 105-1 15 °C for approximately 9 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-25 °C and water (315 kg) was added over a two hour period while maintaining the temperature between 20-30 °C. The reaction mixture was then agitated for an additional hour at 20-25 °C. The crude product was collected by filtration and washed with a mixture of 88kg water and 82.1 kg DMA, followed by 175 kg water. The product was dried on a filter drier for 53 hours. The LOD showed less than 1 percent w/w.

[00176] In an alternative procedure, 1.6 equivalents of sodium tert-pentoxide were used and the reaction temperature was increased from 1 10-120 °C. In addition , the cool down temperature was increased to 35-40 °C and the starting temperature of the water addition was adjusted to 35-40 °C, with an allowed exotherm to 45 °C.

Preparation of l-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid

[00177] Triethylamine (19.5 kg) was added to a cooled (approximately 5 °C) solution of cyclopropane-l,l-dicarboxylic acid (24.7 kg) in THF (89.6 kg) at a rate such that the batch temperature did not exceed 5 °C. The solution was stirred for approximately 1.3 hours, and then thionyl chloride (23.1 kg) was added, keeping the batch temperature below 10 °C. When the addition was complete, the solution was stirred for approximately 4 hours keeping temperature below 10 °C. A solution of 4-fluoroaniline (18.0 kg) in THF (33.1 kg) was then added at a rate such that the batch temperature did not exceed 10 °C. The mixture was stirred for approximately 10 hours after which the reaction was deemed complete. The reaction mixture was then diluted with isopropyl acetate (218.1 kg). This solution was washed sequentially with aqueous sodium hydroxide (10.4 kg, 50 percent dissolved in 1 19 L of water) further diluted with water (415 L), then with water (100 L) and finally with aqueous sodium chloride (20.0 kg dissolved in 100 L of water). The organic solution was concentrated by vacuum distillation (100 L residual volume) below 40 °C followed by the addition of n- heptane (171.4 kg), which resulted in the precipitation of solid. The solid was recovered by filtration and washed with n-heptane ( 102.4 kg), resulting in wet, crude l-(4-fluoro- phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg). The crude, l-(4-fluoro- phenylcarbamoy -cyclopropanecarboxylic acid was dissolved in methanol (139.7 kg) at approximately 25 °C followed by the addition of water (320 L) resulting in slurry which was recovered by filtration, washed sequentially with water (20 L) and n-heptane (103.1 kg) and then dried on the filter at approximately 25 °C under nitrogen to afford the title compound (25.4 kg).

Preparation of l-(4-Fluoro-phenyIcarbamoyl)-cyclopropanecarbonyl chloride

[00178] Oxalyl chloride ( 12.6 kg) was added to a solution of I -(4-fluoro- phenylcarbamoyD-cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and N, N-dimethylformamide (DMF; 0.23 kg) at a rate such that the batch temperature did not exceed 25 °C. This solution was used in the next step without further processing.

Alternative Preparation of l-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride

[00179] A reactor was charged with l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarboxylic acid (35 kg), 344 g DMF, and 175kg THF. The reaction mixture was adjusted to 12-17 °C and then to the reaction mixture was charged 19.9 kg of oxalyl chloride over a period of 1 hour. The reaction mixture was left stirring at 12-17 °C for 3 to 8 hours. This solution was used in the next step without further processing.

Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4- yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide

[00180] The solution from the previous step containing l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 °C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20-25 °C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 °C and then at approximately 45 °C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD). Alternative Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy- quinoIine-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide

[00181] A reactor was charged with 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (35.7 kg, 1 equivalent), followed by 412.9 kg THF. To the reaction mixture was charged a solution of 48.3 K2C03 in 169 kg water. The acid chloride solution of described in the

Alternative Preparation of l-(4-Fluoro-phenylcarbamoyl)-cvclopropanecarbonyl chloride above was transferred to the reactor containing 4-(6,7-dimethoxy-quinoline-4-yloxy)- phenylamine while maintaining the temperature between 20-30 °C over a minimum of two hours. The reaction mixture was stirred at 20-25 °C for a minimum of three hours. The reaction temperature was then adjusted to 30-25 °C and the mixture was agitated. The agitation was stopped and the phases of the mixture were allowed to separate. The lower aqueous phase was removed and discarded. To the remaining upper organic phase was added 804 kg water. The reaction was left stirring at 15-25 °C for a minimum of 16 hours.

[00182] The product precipitated. The product was filtered and washed with a mixture of 179 kg water and 157.9 kg THF in two portions. The crude product was dried under a vacuum for at least two hours. The dried product was then taken up in 285.1 kg THF. The resulting suspension was transferred to reaction vessel and agitated until the suspension became a clear (dissolved) solution, which required heating to 30-35 °C for approximately 30 minutes. 456 kg water was then added to the solution, as well as 20 kg SDAG-1 ethanol (ethanol denatured with methanol over two hours. The mixture was agitated at 15-25 °C fir at least 16 hours. The product was filtered and washed with a mixture of 143 kg water and 126.7 THF in two portions. The product was dried at a maximum temperature set point of 40 °C.

[00183] In an alternative procedure, the reaction temperature during acid chloride formation was adjusted to 10-15 °C. The recrystallization temperature was changed from 15-25 °C to 45-50 °C for 1 hour and then cooled to 15-25 °C over 2 hours.

Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4- yloxy)-phenyl]-amide (4-fluoro-phenyI)-amide, malate salt

[00184] Cyclopropane- 1 , 1 -dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyI)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor and the mixture was heated to reflux (approximately 74 °C) for approximately 2 hours. The reactor temperature was reduced to 50 to 55 °C and the reactor contents were filtered. These sequential steps described above were repeated two more times starting with similar amounts of starting material (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1 133.2 kg) (approximate residual volume 71 1 L; KF < 0.5 % w/w) at approximately 74 °C. The temperature of the reactor contents was reduced to 20 to 25 °C and held for approximately 4 hours resulting in solid precipitate which was filtered, washed with MEK (448 kg) and dried under vacuum at 50 °C to afford the title compound (45.5 kg).

Alternative Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yIoxy)-phenyl]-amide (4-fluoro-phenyI)-amide, (L) malate salt

[00185] Cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyI)-amide (47.9 kg), L-malic acid (17.2), 658.2 kg methyl ethyl ketone, and 129.1 kg water (37.3 kg) were charged to a reactor and the mixture was heated 50-55 °C for approximately 1-3 hours, and then at 55-60 °C for an addition al 4-5 hours. The mixture was clarified by filtration through a 1 μπι cartridge. The reactor temperature was adjusted to 20-25 °C and vacuum distilled with a vacuum at 150-200 mm Hg with a maximum jacket temperature of 55 °C to the volume range of 558-731 L.

[00186] The vacuum distillation was performed two more times with the charge of 380 kg and 380.2 kg methyl ethyl ketone, respectively. After the third distillation, the volume of the batch was adjusted to 18 v/w of cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyI)-amide by charging 159.9 kg methyl ethyl ketone to give a total volume of 880L. An addition al vacuum distillation was carried out by adjusting 245.7 methyl ethyl ketone. The reaction mixture was left with moderate agitation at 20-25 °C for at least 24 hours. The product was filtered and washed with 415.1 kg methyl ethyl ketone in three portions. The product was dried under a vacuum with the jacket temperature set point at 45 °C.

[00187] In an alternative procedure, the order of addition was changed so that a solution of 17.7 kg L-malic acid dissolved in 129.9 kg water was added to cyclopropane- 1,1- dicarboxylic acid [4-(6,7-dimethoxy-quinoHne-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)- amide (48.7 kg) in methyl ethyl ketone (673.3 kg).

Preparation of Compound 2

[00188] Compound 2 was prepared as provided in Scheme 3 and the accompanying experimental examples. Scheme 3

Toluene

[00189] In Scheme 1, Xb is Br or CI. For the names of the intermediates described within the description of Scheme 1 below, Xb is referred to as halo, wherein this halo group for these intermediates is meant to mean either Br or CI.Preparation of l-[5 methoxy-4 (3-halo propoxy)- 2 nitro-phenyl]- ethanone

[00190] Water (70 L) was charged to the solution of l-[4-(3-halo propoxy)- 3-methoxy phenyl] ethanone (both the bromo and the chloro compound are commercially available). The solution was cooled to approximately 4 °C. Concentrated sulfuric acid (129.5 kg) was added at a rate such that the batch temperature did not exceed approximately 18 °C. The resulting solution was cooled to approximately 5 °C and 70 percent nitric acid (75.8 kg) was added at a rate such that the batch temperature did not exceed approximately 10 °C. Methylene chloride, water and ice were charged to a separate reactor. The acidic reaction mixture was then added into this mixture. The methylene chloride layer was separated and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride layers were washed with aqueous potassium bicarbonate solution and concentrated by vacuum distillation. 1- Butanol was added and the mixture was again concentrated by vacuum distillation. The resulting solution was stirred at approximately 20°C during which time the product crystallized. The solids were collected by filtration, washed with 1-butanol to afford compound the title compound, which was isolated as a solvent wet cake and used directly in the next step. ‘HNMR (400MHz, DMSO-d6): δ 7.69 (s, 1H), 7.24 (s, 1H); 4.23 (m, 2H), 3.94 (s, 3H), 3.78 (0-3.65 (t) (2H), 2.51 (s, 3H), 2.30-2.08 (m, 2H) LC/MS Calcd for [M(CI)+H]+ 288.1, found 288.0; Calcd for [M(Br)+H]+ 332.0, 334.0, found 331.9, 334.0.

Preparation of l-[5-methoxy-4-(3-morpholin-4-yl-propoxy)-2-nitro-phenyl]-ethanone

[00191] The solvent wet cake isolated in the previous step was dissolved in toluene. A solution of sodium iodide (67.9 kg) and potassium carbonate (83.4 kg) was added to this solution, followed by tetrabutylammonium bromide (9.92 kg) and morpholine (83.4 kg). The resulting 2 phase mixture was heated to approximately 85°C for about 9 hours. The mixture was then cooled to ambient temperature. The organic layer was removed. The aqueous layer was back extracted with toluene. The combined toluene layers were washed sequentially with two portions of saturated aqueous sodium thiosulfate followed by two portions of water. The resulting solution of the title compound was used in the next step without further processing. ‘HNMR (400MHz, DMSO-d6): δ 7.64 (s, 1 H), 7.22 (s, 1H), 4.15 (t, 2H), 3.93 (s, 3H), 3.57 (t, 4H), 2.52 (s, 3H), 2.44-2.30 (m, 6H), 1.90 (quin, 2H); LC/MS Calcd for [M+H]+ 339.2, found 339.2.

Preparation of l-[2-amino-5-methoxy-4-(3-morpholin-4-yl- propoxy)-phenyl]-ethanone

[00192] The solution from the previous step was concentrated under reduced pressure to approximately half of the original volume. Ethanol and 10 percent Pd C (50 percent water wet, 5.02 kg) were added; the resulting slurry was heated to approximately 48 °C and an aqueous solution of formic acid (22.0 kg) and potassium formate (37.0 kg) was added. When the addition was complete and the reaction deemed complete by thin layer chromatography (TLC), water was added to dissolve the by-product salts. The mixture was filtered to remove the insoluble catalyst. The filtrate was concentrated under reduced pressure and toluene was added. The mixture was made basic (pH of about 10) by the addition of aqueous potassium carbonate. The toluene layer was separated and the aqueous layer was back extracted with toluene. The combined toluene phases were dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting solution was used in the next step without further processing. ‘HNMR (400MHZ, DMSO-d6): δ 7.1 1 (s, 1H)„ 7.01 (br s, 2H), 6.31 (s, 1H), 3.97 (t, 2H), 3.69 (s, 3H), 3.57 (t, 4H), 2.42 (s, 3H), 2.44-2.30 (m, 6H), 1.91 (quin, 2H LC/MS Calcd for [M+H]+ 309.2, found 309.1.

Preparation of 6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoiin- 4-ol, sodium salt

[00193] A solution of sodium ethoxide (85.0 kg) in ethanol and ethyl formate (70.0 kg) was added to the solution from the previous step. The mixture was warmed to approximately 44 °C for about 3 hours. The reaction mixture was cooled to approximately 25°C. Methyl t- butyl ether (MTBE) was added which caused the product to precipitate. The product was collected by filtration and the cake was washed with MTBE and dried under reduced pressure at ambient temperature. The dried product was milled through a mesh screen to afford 60.2 kg of the title compound. ‘HNMR (400MHz, DMSO-d6): δ 1 1.22 (br s, 1H), 8.61 (d, 1H), 7.55 (s, 1H), 7.54 (s, 1H), 7.17 (d, 1H), 4.29 (t, 2 H), 3.99 (m, 2H), 3.96 (s, 3H), 3.84 (t, 2H), 3.50 (d, 2H), 3.30 (m, 2H), 3.1 1 (m, 2H), 2.35 (m, 2H), LC/MS Calcd for [M+H]+ 319.2, found 319.1.

Preparation of 4-chIor-6-methoxy-7-(3 morpholin-4-yl)-quinoline

[00194] Phosphorous oxychloride (26.32 kg) was added to a solution of 6-methoxy-7-(3- morphoIin-4-yl-propoxy)-quinolin-4-ol (5.00 kg) in acetonitrile that was heated to 50-55 °C. When the addition was complete, the mixture was heated to reflux (approximately 82 °C) and held at that temperature, with stirring for approximately 18 hours at which time it was sampled for in process HPLC analysis. The reaction was considered complete when no more than 5 percent starting material remained. The reaction mixture was then cooled to 20-25 °C and filtered to remove solids. The filtrate was then concentrated to a residue. Acetronitrile was added and the resulting solution was concentrated to a residue. Methylene chloride was added to the residue and the resulting solution was quenched with a mixture of methylene chloride and aqueous ammonium hydroxide. The resulting 2 phase mixture was separated and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride solutions were dried over anhydrous magnesium sulfate, filtered and concentrated to a solid. The solids were dried at 30-40 °C under reduced pressure to afford the title compound (1.480 kg). ‘HNMR (400MHz, DMSO-d6): δ 8.61 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 4.21 (t, 2 H), 3.97 (s, 3H), 3.58 (m, 2H), 2.50-2.30 (m, 6H), 1.97 (quin, 2H) LC MS Calcd for [M+Hf 458.2, found 458.0.

Preparation of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morphoIin-4-yl

propoxy)quinoline

[00195] A solution of 4-chIoro-6-methoxy-7-(3 morpholin-4-yl)-quinoline (2.005 kg, 5.95 mol) and 2 fluoro-4-nitrophenol (1.169 kg, 7.44 mol) in 2,6-Iutidine was heated to 140-145 °C, with stirring, for approximately 2 hours, at which time it was sampled for in process HPLC analysis. The reaction was considered complete when less than 5 percent starting materia! remained. The reaction mixture was then cooled to approximately 75 °C and water was added. Potassium carbonate was added to the mixture, which was then stirred at ambient temperature overnight. The solids that precipitated were collected by filtration, washed with aqueous potassium carbonate, and dried at 55-60 °C under reduced pressure to afford the title compound (1.7 kg). ‘HNMR (400MHz, DMSO-d6): δ 8.54 (d, 1H), 8.44 (dd, 1H), 8.18 (m, 1H), 7.60 (m, 1H), 7.43 (s, 1H), 7.42 (s, 1H), 6.75 (d, 1H), 4.19 (t, 2H), 3.90 (s, 3H), 3.56 (t, 4H), 2.44 (t, 2H), 2.36 (m, 4H), 1.96 (m, 2H). LC/MS Calcd for [M+H]+ 337.1 , 339.1 , found 337.0, 339.0.

Preparation of 3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yIoxy]- phenylamine

[00196] A reactor containing 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morpholin-4- yl propoxy)quinoline (2.5 kg) and 10 percent palladium on carbon (50 percent water wet, 250 g) in a mixture of ethanol and water containing concentrated hydrochloric acid (1.5 L) was pressurized with hydrogen gas (approximately 40 psi). The mixture was stirred at ambient temperature. When the reaction was complete (typically 2 hours), as evidenced by in process HPLC analysis, the hydrogen was vented and the reactor inerted with argon. The reaction mixture was filtered through a bed of Celite® to remove the catalyst. Potassium carbonate was added to the filtrate until the pH of the solution was approximately 10. The resulting suspension was stirred at 20-25 °C for approximately 1 hour. The solids were collected by filtration, washed with water and dried at 50-60 °C under reduced pressure to afford the title compound (1.164 kg)._’H NMR (400MHz, DMSO-d6): δ 8.45 (d, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.08 (t, 1H), 6.55 (dd, 1H), 6.46 (dd, 1H), 6.39 (dd, 1H), 5.51 (br. s, 2H), 4.19 (t, 2H), 3.94 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H). LC/MS Calcd for

[M+H]+ 428.2, found 428.1.

Preparation of l-(4-fluoro-phenylcarbamoyl)-cycIopropanecarboxylic acid

[00197] Triethylamine (7.78 kg) was added to a cooled (approximately 4°C) solution of commercially available cyclopropanel.l-dicarboxylic acid (9.95 kg) in THF, at a rate such that the batch temperature did not exceed 10 °C. The solution was stirred for approximately 30 minutes and then thionyl chloride (9.14 kg) was added, keeping the batch temperature below 10 °C. When the addition was complete, a solution of 4 fluoroaniline (9.4 kg) in THF was added at a rate such that the batch temperature did not exceed 10 °C. The mixture was stirred for approximately 4 hours and then diluted with isopropyl acetate. The diluted solution was washed sequentially with aqueous sodium hydroxide, water, and aqueous sodium chloride. The organic solution was concentrated by vacuum distillation. Heptane was added to the concentrate. The resulting slurry was filtered by centrifugation and the solids were dried at approximately 35 °C under vacuum to afford the title compound (10.2 kg). Ή NMR (400 MHz, DMSO-d6): δ 13.06 (br s, 1H), 10.58 (s, 1H), 7.65-7.60 (m, 2H), 7.18-7.12 (m, 2H), 1.41 (s, 4H), LC/MS Calcd for [M+H]+ 224.1 , found 224.0.

Preparation of l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonylchloride

[00198] Oxalyl chloride (291 mL) was added slowly to a cooled (approximately 5°C) solution of l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid in THF at a rate such that the batch temperature did not exceed 10°C. When the addition was complete, the batch was allowed to warm to ambient temperature and held with stirring for approximately 2 hours, at which time in process HPLC analysis indicated the reaction was complete. The solution was used in the next step without further processing.

Preparation of cyclopropane-l,l-dicarbox lic acid {3-fluoro-4-[6-methoxy-7-(3- morphoIin-4-yl-propoxy)-quinolin-4-ylamino]phenyl}-amide-(4 fluorophenyl)-amide

[00199] The solution from the previous step was added to a mixture of 3-fluoro-4-[6- methoxy-7-(3-mo holin-4-yl-propox )-quinolin-4-ylo y]-phenylamine (1 160 kg) and potassium carbonate (412.25 g) in THF and water at a rate such that the batch temperature was maintained at approximately 15-21 °C. When the addition was complete, the batch was warmed to ambient temperature and held with stirring for approximately 1 hour, at which time in process HPLC analysis indicated the reaction was complete. Aqueous potassium carbonate solution and isopropyl acetate were added to the batch. The resulting 2-phase mixture was stirred and then the phases were allowed to separate. The aqueous phase was back extracted with isopropyl acetate. The combined isopropyl acetate layers were washed with water followed by aqueous sodium chloride and then slurried with a mixture of magnesium sulfate and activated carbon. The slurry was filtered over Celite® and the filtrate was concentrated to an oil at approximately 30°C under vacuum to afford the title compound which was carried into the next step without further processing. Ή NMR (400MHz, DMSO- d6): δ 10.41 (s, 1H), 10.03 (s, 1H), 8.47 (d, 1H), 7.91 (dd, 1H), 7.65 (m, 2H), 7.53 (m, 2H), 7.42 (m, 2H), 7.16 (t, 2H), 6.41 (d, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H), 1.47 (m, 4H). LC MS Calcd for [M+H]+ 633.2, found 633.1.

Preparation of the bisphosphate salt of cyclopropane-l,l-dicarboxylic acid {3-fluoro-4- [6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-ylamino]phenyl}-amide (4-fluoro- phenyl)-amide

[00200] Cyclopropane- 1,1-dicarboxy lie acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl- propoxy)-quinolin-4-ylamino]phenyl}-amide-(4 fluoro phenyl)-amide from the previous step was dissolved in acetone and water. Phosphoric acid (85%, 372.48 g) was added at a rate such that the batch temperature did not exceed 30 °C. The batch was maintained at approximately 15- 30 °C with stirring for 1 hour during which time the product precipitated. The solids were collected by filtration, washed with acetone and dried at approximately 60 °C under vacuum to afford the title compound (1.533 kg). The title compound has a c-Met IC50 value of less than 50 nM. The bisphosphate salt is not shown in scheme 1. Ή NMR (400

MHz, DMSO-d6): (diphosphate) δ 10.41 (s, 1H), 10.02 (s, 1H), 8.48 (d, 1 H), 7.93 (dd, 1H), 7.65 (m, 2H), 7.53 (d, 2H), 7.42 (m, 2H), 7.17 (m, 2H), 6.48 (d, 1H), 5.6 (br s, 6H), 4.24 (t, 2H), 3.95 (s, 3H), 3.69 (bs, 4H), 2.73 (bs, 6H), 2.09 (t, 2H), 1.48 (d, 4H).

Foretinib
Foretinib.svg
Identifiers
CAS number 849217-64-7 Yes
ChemSpider 24608641
UNII 81FH7VK1C4
Jmol-3D images Image 1
Properties
Molecular formula C34H34F2N4O6
Molar mass 632.65 g mol−1
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)

References

  1. Hedgethorne, K., Huang, P.H. (2010). “Foretinib. c-Met and VEGFR-2 inhibitor, Oncolytic”. Drugs Fut 35 (11): 893–901. doi:10.1358/dof.2010.35.11.1529012 (inactive 2014-03-22).
  2. “XL880 (GSK1363089)”. Exelixis, Inc.
  3. “Foretinib”. clinicaltrials.gov.
  4. Qian, F; Engst, S; Yamaguchi, K; Yu, P; Won, KA; Mock, L; Lou, T; Tan, J et al. (2009). “Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases”. Cancer Research 69 (20): 8009–16. doi:10.1158/0008-5472.CAN-08-4889. PMID 19808973.

 

CN102227164A * Sep 25, 2009 Oct 26, 2011 葛兰素史密斯克莱有限责任公司 Preparation of quinolinyloxydiphenylcyclopropanedicarboxamide
CN102977014A * Nov 5, 2012 Mar 20, 2013 沈阳药科大学 New quinoline compounds and uses thereof

Non-Patent Citations
Reference
1 * BAOHUI QI ET AL.: ‘Discovery and optimization of novel 4-Phenoxy-6, 7-disubstituted Quinolines Possessing Semicarbazones as c-Met Kinase Inhibitors.‘ BIOORGANIC & MEDICINAL CHEMISTRY. vol. 21, 19 June 2013, pages 5246 – 5260
2 * BAOHUI QI ET AL.: ‘Synthesis and Biological Evaluation of 4-Phenoxy-6, 7-disubstituted Quinolines Possessing Semicarbazone Scaffolds as Selective c-Met Inhibitors.‘ ARCH. PHARM. CHEM. LIFE SCI. vol. 346, no. 8, 2013, pages 596 – 609

Aplaviroc, AK602, GSK-873140


Aplaviroc.svg

Aplaviroc

4-(4-{[(3R)-1-butyl-3-[(R)-cyclohexylhydroxymethyl]-2,5-dioxo- 1,4,9-triazaspiro[5.5]undecan-9-yl]methyl}phenoxy)benzoic acid

for the treatment of HIV infection

461023-63-2 of hydrochloride

461443-59-4 (free base)

873140
AK-602
GW-873140
ONO-4128

ono…….innovator

Ono Pharmaceutical Co., Ltd.
Base
4-[4-[[(3R)-1-Butyl-3-[(R)-cyclohexylhydroxymethyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl]methyl]phenoxy]benzoic acid
(3R)-1-butyl-2,5-dioxo-3-[(1R)-1-hydroxy-1-cyclohexylmethyl]-9-[4-(4-carboxyphenyloxy)phenylmethyl]-1,4,9-triazaspiro[5.5]undecane
Molecular Formula: C33H43N3O6
Molecular Weight: 577.71
Percent Composition: C 68.61%, H 7.50%, N 7.27%, O 16.62%
References: CCR5 chemokine receptor antagonist; inhibits HIV entry by blocking interaction of viral coat protein gp120 with the receptor. Prepn: H. Habashita et al., WO 02074770 (2002 to Ono); eidem, US 04082584 (2004).
Study of CCR5 binding and mechanism of action: C. Watson et al., Mol. Pharmacol. 67, 1268 (2005).
Antiretroviral activity in immunodeficient mice: H. Nakata et al., J. Virol. 79, 2087 (2005). Clinical pharmacokinetics: K. K. Adkison et al., Antimicrob. Agents Chemother. 49, 2802 (2005).
Derivative Type: Hydrochloride
CAS Registry Number: 461023-63-2
Manufacturers’ Codes: AK-602; GW-873140; ONO-4128
Molecular Formula: C33H43N3O6.HCl
Molecular Weight: 614.17
Percent Composition: C 64.53%, H 7.22%, N 6.84%, O 15.63%, Cl 5.77%
Therap-Cat: Antiviral.

aplaviroc.png

Identifiers
CAS number 461023-63-2 Yes
ATC code None
PubChem CID 3001322
ChemSpider 2272720 Yes
UNII 98B425P30V Yes
KEGG D06557 Yes
ChEMBL CHEMBL1255794
Chemical data
Formula C33H43N3O6 
Mol. mass 577.711 g/mol

 

Aplaviroc (INN, codenamed AK602 and GSK-873140) is a CCR5 entry inhibitor developed for the treatment of HIV infection.[1][2] It is developed by GlaxoSmithKline.

In October 2005, all studies of aplaviroc were discontinued due to liver toxicity concerns.[3][4] Some authors have claimed that evidence of poor efficacy may have contributed to termination of the drug’s development;[5] the ASCENT study, one of the discontinued trials, showed aplaviroc to be under-effective in many patients even at high concentrations.[6]

Aplaviroc hydrochloride, an orally-effective, long-acting chemokine CCR5 receptor antagonist, had been under development by Ono and GlaxoSmithKline for the treatment of HIV infection. In early 2006, the companies discontinued development of the antagonist based on reports of elevated liver function test values from clinical studies.

Originally developed at Ono, aplaviroc was licensed to GlaxoSmithKline in 2003 for development, manufacturing and marketing. GlaxoSmithKline also obtained rights to evaluate the agent in non-HIV conditions worldwide with the exception of Japan, South Korea and Taiwan.

A low-molecular-weight compound, aplaviroc prevents HIV viral infection by blocking the binding of the virus to the CCR5 receptor

……………….

WO 2002074770

0r

http://www.google.com/patents/EP1378510A1?cl=en

Reference example 3(3)

    (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexyl)-1,4,9-triazaspiro[5.5]undecane • hydrochloride

  • [0136]
    Figure 00560002

    TLC:Rf 0.32 (butanol:acetic acid:water = 4:2:1);
    NMR (CD3OD): δ 4.16 (d, J = 2.0 Hz, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 3.52 (m, 1H), 3.37 (m, 1H), 3.28 (m, 1H), 3.22-3.13 (m, 2H), 2.46-1.93 (m, 6H), 1.80-1.64 (m, 5H), 1.48-1.15 (m, 6H), 1.02-0.87 (m, 5H);
    Optical rotation:[α]D +1.22 (c 1.04, methanol, 26°C).

 

Example 9(54)

    (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane • hydrochloride

  • [0359]
    Figure 01740001

    TLC:Rf 0.43(chloroform:methanol = 5:1);
    NMR (CD3OD):δ 8.05 (d, J = 9.0 Hz, 2H), 7.61 (d, J = 9.0 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 4.38 (s, 2H), 4.17 (d, J = 2.1 Hz, 1H), 4.02 (m, 1H), 3.78 (m, 1H), 3.60-3.40 (m, 3H), 3.30-3.10 (m, 2H), 2.56-1.86 (m, 6H), 1.82-1.60 (m, 5H), 1.52-1.16 (m, 6H), 1.06-0.82 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H).

………………….

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-9-265

Owing to the special properties of piperazines (increased solubility and H-bond acceptor capability etc.) it is often considered to be a privileged structure and therefore occurs widely, for instance in GlaxoSmithKlines investigational anti-HIV drug aplaviroc (4.37) which, despite being a promising CCR5 receptor antagonist, was discontinued due to hepatotoxicity concerns. In this compound the spirodiketopiperazine unit (4.35) was designed to mimic a type-1 β-turn (4.36) as present in G-protein coupled receptors (Figure 14) [117].

[1860-5397-9-265-14]
Figure 14: Structural comparison between the core of aplaviroc (4.35) and a type-1 β-turn (4.36).

The synthesis of aplaviroc and its analogues can be accomplished via the use of an Ugi multicomponent reaction (Ugi-MCR) [118]. The procedure involved the condensation of piperidone 4.38 and butylamine (4.39) followed by reaction of the resulting imine with isocyanide 4.41 and interception of the nitrilium intermediate with the amino acid4.40 (Scheme 47) [119]. This sequence was completed by structural rearrangement and acid-mediated ring closure to produce the spirocyclic diketopiperazine 4.43. Following debenzylation this material was subjected to a reductive amination finally affording aplaviroc analogues (Scheme 47).

[1860-5397-9-265-i47]
Scheme 47: Examplary synthesis of an aplaviroc analogue via the Ugi-MCR.
  1. 117         Habashita, H.; Kokubo, M.; Hamano, S.; Hamanaka, N.; Toda, M.; Shibayama, S.; Tada, H.; Sagawa, K.; Fukushima, D.; Maeda, K.; Mitsuya, H. J. Med. Chem. 2006, 49, 4140–4152. doi:10.1021/jm060051s
  2. Dömling, A.; Huang, Y. Synthesis 2008, 2859–2883. doi:10.1055/s-0030-1257906
    ref 118
  3. Nishizawa, R.; Nishiyama, T.; Hisaichi, K.; Matsunaga, N.; Minamoto, C.; Habashita, H.; Takaoka, Y.; Toda, M.; Shibayama, S.; Tada, H.; Sagawa, K.; Fukushima, D.; Maeda, K.; Mitsuya, H.Bioorg. Med. Chem. Lett. 2007, 17, 727–731. doi:10.1016/j.bmcl.2006.10.084
    ref 119
Patent Submitted Granted
Triazaspiro[5.5]undecane derivative and pharmaceutical composition comprising the same as active ingredient [US7262193] 2005-09-29 2007-08-28
Drugs containing triazaspiro[5.5]undecane derivatives as the active ingredient [US7285552] 2004-06-03 2007-10-23
Triazaspiro[5.5]undecane derivatives and drugs containing the same as the active ingredient [US7053090] 2004-04-29 2006-05-30

 

WO1998031364A1 * Jan 20, 1998 Jul 23, 1998 Timothy Harrison 3,3-disubstituted piperidines as modulators of chemokine receptor activity
WO2000014086A1 * Jan 21, 1999 Mar 16, 2000 Kyowa Hakko Kogyo Kk Chemokine receptor antagonists and methods of use therefor
WO2002074769A1 * Mar 18, 2002 Sep 26, 2002 Kenji Maeda Drugs containing triazaspiro[5.5]undecane derivatives as the active ingredient

References

  1.  Maeda, Kenji; Ogata, Hiromi; Harada, Shigeyoshi et al. (2004). “Determination of binding sites of a unique CCR5 inhibitor AK602 / ONO-4128/ GW873140 on human CCR5” (PDF). Conference on Retroviruses and Opportunistic Infections. Archived from the original on November 3, 2005.
  2.  Nakata, Hirotomo; Maeda, Kenji; Miyakawa, Toshikazu et al. (February 2005). “Potent Anti-R5 Human Immunodeficiency Virus Type 1 Effects of a CCR5 Antagonist, AK602/ONO4128/GW873140, in a Novel Human Peripheral Blood Mononuclear Cell Nonobese Diabetic-SCID, Interleukin-2 Receptor γ-Chain-Knocked-Out AIDS Mouse Model”. Journal of Virology 79 (4): 2087–96.doi:10.1128/jvi.79.4.2087-2096.2005.
  3.  “Aplaviroc (GSK-873,140)”. AIDSmeds.com. October 25, 2005. Retrieved September 5, 2008.[dead link]
  4. Nichols WG, Steel HM, Bonny T et al. (March 2008). “Hepatotoxicity Observed in Clinical Trials of Aplaviroc (GW873140)”.Antimicrobial Agents and Chemotherapy 52 (3): 858–65. doi:10.1128/aac.00821-07. PMC 2258506. PMID 18070967.
  5.  Moyle, Graeme (December 19, 2006). “The Last Word on Aplaviroc: A CCR5 Antagonist With Poor Efficacy”. The Body.Archived from the original on 6 October 2008. Retrieved September 5, 2008.
  6.  Currier, Judith; Lazzarin, Adriano; Sloan, Louis et al. (2008). “Antiviral activity and safety of aplaviroc with lamivudine/zidovudine in HIV-infected, therapy-naive patients: the ASCENT (CCR102881) study”. Antiviral Therapy (Lond.) 13 (2): 297–306.PMID 18505181.

Further reading

  • Horster, S; Goebel, FD (April 2006). “Serious doubts on safety and efficacy of CCR5 antagonists: CCR5 antagonists teeter on a knife-edge”. Infection 34 (2): 110–13. doi:10.1007/s15010-006-6206-1. PMID 16703305.

Amprenavir (Agenerase, GlaxoSmithKline) is a protease inhibitor…….


Amprenavir skeletal.svg

AMPRENAVIR

Amprenavir (Agenerase, GlaxoSmithKline) is a protease inhibitor used to treat HIV infection. It was approved by the Food and Drug Administration on April 15, 1999, for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200 mg, delivered in eight very large gel capsules.

Production of amprenavir was discontinued by the manufacturer December 31, 2004; a prodrug version (fosamprenavir) is available.

HIV-1 Protease dimer with Amprenavir (sticks) bound in the active site. PDB entry 3nu3 [1]

 

 

Systematic (IUPAC) name
(3S)-oxolan-3-yl N-[(2S,3R)-3-hydroxy-4-[N-(2-methylpropyl)(4-aminobenzene)sulfonamido]-1-phenylbutan-2-yl]carbamate
Clinical data
Trade names Agenerase
AHFS/Drugs.com monograph
MedlinePlus a699051
Licence data EMA:Link, US FDA:link
Pregnancy cat. C (US)
Routes oral
Pharmacokinetic data
Protein binding 90%
Metabolism hepatic
Half-life 7.1-10.6 hours
Excretion <3% renal
Identifiers
CAS number 161814-49-9 Yes
ATC code J05AE05
PubChem CID 65016
DrugBank DB00701
ChemSpider 58532 Yes
UNII 5S0W860XNR Yes
KEGG D00894 Yes
ChEBI CHEBI:40050 Yes
ChEMBL CHEMBL116 Yes
NIAID ChemDB 006080
Chemical data
Formula C25H35N3O6S 
Mol. mass 505.628 g/mol

Amprenavir (Agenerase, GlaxoSmithKline) is a protease inhibitor used to treat HIV infection. It was approved by the Food and Drug Administration on April 15, 1999, for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200 mg, delivered in eight very large gel capsules.

Production of amprenavir was discontinued by the manufacturer December 31, 2004; a prodrug version (fosamprenavir) is available

………………….

New approaches to the industrial synthesis of HIV protease inhibitors

 

http://pubs.rsc.org/en/content/articlelanding/2004/ob/b404071f/unauth#!divAbstract

Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from L-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to L-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.

Graphical abstract: New approaches to the industrial synthesis of HIV protease inhibitors
…………………………………………………………………

 

AGENERASE (amprenavir) is an inhibitor of the human immunodeficiency virus (HIV) protease. The chemical name of amprenavir is (3S)-tetrahydro-3-furyl N-[(1S,2R)-3-(4-amino-N-isobutylbenzenesulfonamido)-1-benzyl-2-hydroxypropyl]carbamate. Amprenavir is a single stereoisomer with the (3S)(1S,2R) configuration. It has a molecular formula of C25H35N3O6S and a molecular weight of 505.64. It has the following structural formula:

 

AGENERASE® (amprenavir)  Structural Formula Illustration

 

Amprenavir is a white to cream-colored solid with a solubility of approximately 0.04 mg/mL in water at 25°C.

AGENERASE Capsules (amprenavir capsules) are

available for oral administration. Each 50- mg capsule contains the inactive ingredients d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), polyethylene glycol 400 (PEG 400) 246.7 mg, and propylene glycol 19 mg. The capsule shell contains the inactive ingredients d-sorbitol and sorbitans solution, gelatin, glycerin, and titanium dioxide. The soft gelatin capsules are printed with edible red ink. Each 50- mg AGENERASE Capsule contains 36.3 IU vitamin E in the form of TPGS. The total amount of vitamin E in the recommended daily adult dose of AGENERASE is 1,744 IU.

See also

External links

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