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Phase 3 Amicus in collaboration with GlaxoSmithKline (GSK) is developing the investigational pharmacological chaperone migalastat HCl for the treatment of Fabry disease
CAS Number:75172-81-5-
3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride (1:1), (2R,3S,4R,5S)-
- Molecular Structure:
- Formula:C6H14ClNO4
- Molecular Weight:199.63
- Synonyms:3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride, (2R,3S,4R,5S)- (9CI);3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride, [2R-(2a,3a,4a,5b)]-;Migalastat hydrochloride;Galactostatin hydrochloride;(2S,3R,4S,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol hydrochloride;
- Melting Point:260 °C
- Boiling Point:382.7 °C at 760 mmHg
- Flash Point:185.2 °C
end feb 2013
About Amicus Therapeutics
Amicus Therapeutics is a biopharmaceutical company at the forefront of therapies for rare and orphan diseases. The Company is developing orally-administered, small molecule drugs called pharmacological chaperones, a novel, first-in-class approach to treating a broad range of human genetic diseases. Amicus’ late-stage programs for lysosomal storage disorders include migalastat HCl monotherapy in Phase 3 for Fabry disease; migalastat HCl co-administered with enzyme replacement therapy (ERT) in Phase 2 for Fabry disease; and AT2220 co-administered with ERT in Phase 2 for Pompe disease.
About Migalastat HCl
Amicus in collaboration with GlaxoSmithKline (GSK) is developing the investigational pharmacological chaperone migalastat HCl for the treatment of Fabry disease. Amicus has commercial rights to all Fabry products in the United States and GSK has commercial rights to all of these products in the rest of world.
As a monotherapy, migalastat HCl is designed to bind to and stabilize, or “chaperone” a patient’s own alpha-galactosidase A (alpha-Gal A) enzyme in patients with genetic mutations that are amenable to this chaperone in a cell-based assay. Migalastat HCl monotherapy is in Phase 3 development (Study 011 and Study 012) for Fabry patients with genetic mutations that are amenable to this chaperone monotherapy in a cell-based assay. Study 011 is a placebo-controlled study intended primarily to support U.S. registration, and Study 012 compares migalastat HCl to ERT to primarily support global registration.
For patients currently receiving ERT for Fabry disease, migalastat HCl in combination with ERT may improve ERT outcomes by keeping the infused alpha-Gal A enzyme in its properly folded and active form thereby allowing more active enzyme to reach tissues.2 Migalastat HCl co-administered with ERT is in Phase 2 (Study 013) and migalastat HCl co-formulated with JCR Pharmaceutical Co. Ltd’s proprietary investigational ERT (JR-051, recombinant human alpha-Gal A enzyme) is in preclinical development.
About Fabry Disease
Fabry disease is an inherited lysosomal storage disorder caused by deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A). The role of alpha-Gal A within the body is to break down specific lipids in lysosomes, including globotriaosylceramide (GL-3, also known as Gb3). Lipids that can be degraded by the action of α-Gal are called “substrates” of the enzyme. Reduced or absent levels of alpha-Gal A activity leads to the accumulation of GL-3 in the affected tissues, including the kidneys, heart, central nervous system, and skin. This accumulation of GL-3 is believed to cause the various symptoms of Fabry disease, including pain, kidney failure, and increased risk of heart attack and stroke.
It is currently estimated that Fabry disease affects approximately 5,000 to 10,000 people worldwide. However, several literature reports suggest that Fabry disease may be significantly under diagnosed, and the prevalence of the disease may be much higher.
2. Benjamin, et al., Molecular Therapy: April 2012, Vol. 20, No. 4, pp. 717–726.
http://clinicaltrials.gov/show/NCT01458119
http://www.docstoc.com/docs/129812511/migalastat-hcl
| Chemical Name: | DEOXYGALACTONOJIRIMYCIN, HYDROCHLORIDE |
| Synonyms: | DGJ;Amigal;Unii-cly7m0xd20;GALACTOSTATIN HCL;DGJ, HYDROCHLORIDE;Migalastat hydrochloride;Galactostatin hydrochloride;DEOXYGALACTONOJIRIMYCIN HCL;1-DEOXYGALACTONOJIRIMYCIN HCL;1,5-dideoxy-1,5-imino-d-galactitol |
Lumacaftor, VX-809 an experimental drug for the treatment of Late-Stage cystic fibrosis, being developed by Vertex Pharmaceuticals
3-{6-{[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino}-3-methylpyridin-2-yl}benzoic acid
26,FEB 2013
syn at >>>>>>>https://newdrugapprovals.org/2013/07/28/3274/
Vertex Pharmaceuticals announced Tuesday night the design of two phase III studies for its combination therapy to treat the most common form of cystic fibrosis. The studies will each run for six months, so results could be ready as early as the end of 2013 or during first half of 2014.
The studies announced Tuesday will evaluate the two different doses of an experimental medicine VX-809 in combination with Kalydeco. Each study will enroll 500 cystic fibrosis patients randomized to either the VX-809/Kalydeco arms or a placebo for six months of treatment. The studies’ primary endpoint will be the relative improvement in lung function of VX-809/Kalydeco compared to placebo.
Last fall, Vertex presented data from a phase II study demonstrating that a 600 mg dose of VX-809 and Kalydeco worked synergistically to improve lung function in cystic fibrosis patients with the F508del mutation compared to placebo. This same dose combination will be tested in the phase III study along with a higher 800 mg (actually, 400 mg given twice a day) dose of VX-809 plus Kalydeco.
Vertex also announced new data from this phase II study on Tuesday night showing similar lung function improvements between the 800 mg and 600 mg doses of VX-809. For this reason, the higher dose was included in the phase III studies.
Along with the two phase III studies in adult patients, Vertex will also conduct a six-month study of the combination therapy in pediatric patients ages 6 to 11. This study, along with the data from the adult studies, may be used to expand the combination therapy’s approval into younger patients.
In January, FDA anointed Kalydeco and VX-809 with Breakthrough Therapy Designation as part of the agency’s efforts to accelerate the development and approval of drugs for serious and life-threatening disease. Vertex did not say whether Breakthrough Designation played a specific role in the VX-809/Kalydeco phase III program but the relatively short six-month duration of the studies plus the ability to test the combination in children at the same time does accelerate the development of the combination therapy. If the data from the studies are positive, the drugs could be approved sooner than expected and for more patients.
Lumacaftor (USAN, codenamed VX-809) is an experimental drug for the treatment of cystic fibrosis, being developed by Vertex Pharmaceuticals. The drug is designed to be effective in patients that have the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein that causes the disease. F508del, meaning that the amino acid phenylalanine in position 508 is missing, is found in about 60% of cystic fibrosis patients.[1]
Interim results from a Phase II clinical trial indicate that patients with the most common form of genetic mutation causing cystic fibrosis homozygous F508del had an 8.5% increase in lung function (FEV1) after 56 days on a combination of lumacaftor and ivacaftor (Kalydeco).[2]
- Merk; Schubert-Zsilavecz. (in German)Pharmazeutische Zeitung 156 (37): 24–27.
- Vertex Pharmaceuticals. May 29,2012.
- syn at >>>>>>>https://newdrugapprovals.org/2013/07/28/3274/
- syn at >>>>>>>https://newdrugapprovals.org/2013/07/28/3274/
Pfizer Gains China Approval of Kinase-Specific Lung Cancer Drug, Xalkori (crizotinib)
Xalkori, crizotinib,
(PF-02341066)
3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
Crizotinib; 877399-52-5; Xalkori; PF-2341066; PF-02341066; (R)-crizotinib; 877399-52-5
| Molecular Formula: | C21H22Cl2FN5O |
|---|---|
| Molecular Weight: | 450.336683 g/mol |
Crizotinib an inhibitor of receptor tyrosine kinase for the treatment of non-small cell lung cancer (NSCLC). Verification of the presence of ALK fusion gene is done by Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit. This verification is used to select for patients suitable for treatment. FDA approved in August 26, 2011.
Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients
Feb 25, 2013
Pfizer has been granted China approval for Xalkori (crizotinib), an innovative treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive. The ALK-positive variation, which comprises between 3% and 5% of all NSCLC tumors, must be proved by a biomarker test. Pfizer said China’s approval came just eleven months after it submitted a new drug application to the SFDA for Xalkori
Crizotinib (trade name Xalkori,[1] Pfizer), is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and some other countries, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.[2]
- FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. U.S. Food and Drug Administration.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.htm
- ClinicalTrials.gov NCT00932451 An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene
Crizotinib the core structure is a substituted pyridine, the 3 – position of the ether as a chiral center adjacent, so with Mitsunobu reaction to complete, as is a typical Mitsunobu SN2 reaction, the reaction chiral center occurs in reverse, so easy to control, no racemization occurs. Pyridine substituted at position 5 by Suzuki reaction constructed.
Compound 1 The activation of the hydroxyl groups of methanesulfonyl chloride, and then with a 4 – iodopyrazole reaction 2 , 2 to 4 Suzuki reaction conversion can be used, but will generate a large quantity of the reaction product of their coupling, the first 2 converted to a Grignard reagent, and then with a boronic acid ester of 3 reaction 4 .
……………………
http://www.specchemonline.com/articles/view/biocatalyst-breakthroughs#.VTcW9yxabEs
http://www.google.com/patents/WO2014020467A2?cl=en
(R)-3-[l-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(l-piperidin-4-yl-lH-py- razol-4-yl)-pyridin-2-ylamine, also known as Crizotinib, is represented by the Formula (I):
Formula (I)
Crizotinib is a potent small-molecule inhibitor of c-Met/HGFR (hepatocyte growth factor receptor) kinase and ALK (anaplastic lymphoma kinase) activity. Enantiomerically pure compound of formula I was first disclosed in US Patent No. 7,858,643. Additionally, the racemate of compound of formula I was disclosed in U.S. patent application 2006/0128724, both of these references discloses similar methods for the synthesis of Compound of Formula I.
Conventionally, the compounds of formula I are prepared by reacting Bis(pinacolato)diboron with protected 5-bromo-3-[l-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine in the presence of Pd catalyst. The obtained product after deprotection is reacted with N- protected 4-(4-bromo-pyrazol-l-yl)-piperidine in the presence of Pd Catalyst. The obtained product is filtered through celite pad and purified by Column Chromatography. The final product of formula I was obtained by deprotection of the purified compound by using HCl/dioxane. US Patent No. 7,858,643 provides enantiomerically pure aminoheteroaryl compounds, particularly aminopyridines and aminopyrazines, having protein tyrosine kinase activity. More particularly, US 7,858,643 describes process for the preparation of 3-[(lR)-l-(2,6- dichloro-3-fluorophenyl)ethoxy]-5-(l-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine. The Scheme is summarized below in Scheme- 1 :
Scheme-1
wherein, “Boc” means tert-butoxycarbonyl; and a) (Boc)2, DMF, Dimethylaminopyridine b) Pd(dppf)Cl2, KOAc, Dichloromethane; c) HC1, Dioxane, Dichloromethane; d) Pd(PPh3)2Cl2, Na2C03, DME/H20; e) 4M HCl/Dioxane, Dichloromethane
A similar process has been disclosed in the U.S. patent application 2006/0128724 for the preparation of Crizotinib. J. Jean Cui et. al. in J. Med. Chem. 2011, 54, 6342-6363, also provides a similar process for the preparation of Crizotinib and its derivatives.
However, above mentioned synthetic process requires stringent operational conditions such as filtration at several steps through celite pad. Also column chromatography is required at various steps which is not only tedious but also results in significant yield loss. Another disadvantage of above process involves extensive use of palladium catalysts, hence metal scavengers are required to remove palladium content from the desired product at various steps which makes this process inefficient for commercial scale.
Yet another disadvantage of above process is the cost of Bis(pinacolato)diboron. This reagent is used in excess in the reaction mixture resulting in considerable cost, especially during large-scale syntheses.
US Patent No. 7,825,137 also discloses a process for the preparation of Crizotinib where Boc protected 4-(4-iodo-pyrazol-l-yl)-piperidine is first reacted with Bis(pinacolato)diboron in the presence of Pd catalyst. The reaction mixture is filtered through a bed of celite and the obtained filtrate is concentrated and purified by silica gel chromatography to give to form tert-butyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]piperidine-l- carboxylate. To this compound, 5-bromo-3-[l-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]- pyridin-2-ylamine is added in the presence of a Pd catalyst. The reaction mixture is stirred for 16h at 87°C. The reaction mixture is filtered through celite pad and the concentrated filtrate is purified on silica gel column to obtain (4-{6-amino-5-[(R)-l-(2,6-dichloro-3-fluoro- phenyl)-ethoxy]-pyri- din-3-yl}-pyrazol-l-yl)-piperidine-l-carboxylic acid tert-butyl ester of 95% purity. To the solution of resulting compound in dichloromethane 4N HCl/Dioxane is added and thereby getting the reaction suspension is filtered in Buchner funnel lined with filter paper. The obtained solid is dissolved in HPLC water and pH is adjusted to 10 with the addition of Na2C03 Compound is extracted using dichloroform and is purified on a silica gel column by eluting with CH2Cl2 MeOH/NEt3 system to obtain Crizotinib. The scheme is summarized below in scheme 2:
Formula (i) Formula (ii)
Formula (iii) Formula (ii) ula (iv)
Formula (v) Formula (I)
Scheme-2
Preparation of Crizotinib:
To a stirred solution of Tert-butyl 4-(4-{ 6-amino-5-[(li?)-l-(2,6-dichloro-3- fluorophenyl)ethoxy]pyridin-3 -yl } – lH-pyrazol- 1 -yl)piperidine- 1 -carboxylate (material obtained in Example 3) (l.Og, 0.00181 moles) in dichloromethane (-13 ml) at 0°C was added 4.0 M dioxane HQ (6.7 ml, 0.0272 moles). Reaction mixture was stirred at room temperature for 4h. After the completion of reaction monitored by TLC, solid was filtered and washed with dichloromethane (10 ml). The obtained solid was dissolved in water (20 ml); aqueous layer was extracted with dichloromethane (10×2). The pH of aqueous layer was adjusted to 9-10 with Na2C03 and compound was extracted with dichloromethane (10 x 3), combined organic layers were washed with water (20 ml), evaporated under vacuum to get solid product. The solid was stirred with ether (10 ml), filtered off, washed well with ether, dried under vacuum to get Crizotinib.
Yield: 0.45g (55 %)
HPLC Purity: 99.35 %
1HNMR (400 MHz, CDC13) δ: 7.76 (d, J = 1.6 Hz, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.30 (dd, J = 9.2 Hz), 7.0 (m, 1H), 6.86 (d, J = 1.6 Hz, 1H), 6.09 ( q, J= 6.8 Hz, 1H), 4.75 (brs, 1H), 4.19 (m, 1H), 3.25 (m, 2H), 2.76 (m, 2H), 2.16 (m, 2H), 1.92 (m, 2H), 1.85 (d, J= 6.8 Hz, 3H), 1.67 (brs, 1H)
…………………………
http://www.sciencedirect.com/science/article/pii/S0040403914000872
Abstract
A novel approach for the synthesis of Crizotinib (1) is described. In addition, new efficient procedures have been developed for the preparation of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (2) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (4), the key intermediates required for the synthesis of Crizotinib.
Graphical abstract
- …………………
- http://www.sciencedirect.com/science/article/pii/S0040403911021745
-
Abstract
4-(4-Iodo-1H-pyrazol-1-yl)piperidine is a key intermediate in the synthesis of Crizotinib. We report a robust three-step synthesis that has successfully delivered multi-kilogram quantities of the key intermediate. The process includes nucleophilic aromatic substitution of 4-chloropyridine with pyrazole, followed by hydrogenation of the pyridine moiety and subsequent iodination of the pyrazole which all required optimization to ensure successful scale-up.
Graphical abstract
……………………
Org. Process Res. Dev., 2011, 15 (5), pp 1018–1026
DOI: 10.1021/op200131n
A robust six-step process for the synthesis of crizotinib, a novel c-Met/ALK inhibitor currently in phase III clinical trials, has been developed and used to deliver over 100 kg of API. The process includes a Mitsunobu reaction, a chemoselective reduction of an arylnitro group, and a Suzuki coupling, all of which required optimization to ensure successful scale-up. Conducting the Mitsunobu reaction in toluene and then crystallizing the product from ethanol efficiently purged the reaction byproduct. A chemoselective arylnitro reduction and subsequent bromination reaction afforded the key intermediate 6. A highly selective Suzuki reaction between 6 and pinacol boronate 8, followed by Boc deprotection, completed the synthesis of crizotinib 1.
3-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine 1
crizotinib1 (20.7 kg, 80%) as a white solid.
Mp 192 °C;
1H NMR (400 MHz, CDCl3) δ: 7.78 (d, J = 1.8 Hz, 1H), 7.58 (s, 1H), 7.52 (s, 1H), 7.31 (dd, J = 9.0, 4.9 Hz, 1H), 7.06 (m, 1H), 6.89 (d, J = 1.7 Hz, 1H), 6.09 (q, 1H), 4.79 (br s, 2H), 4.21 (m, 1H), 3.26 (m, 2H), 2.78 (m, 2H), 2.17 (m, 2H), 1.90 (m, 2H), 1.87 (d, J = 6.7 Hz, 3H), 1.63 (br s, 1H).
13C NMR (100.6 MHz, CDCl3) δ: 157.5 (d, J = 250.7 Hz), 148.9, 139.8, 137.0, 135.7, 135.6, 129.9, 129.0 (d, J = 3.7 Hz), 122.4, 122.1 (d, J = 19.0 Hz), 119.9, 119.3, 116.7 (d, J = 23.3 Hz), 115.0, 72.4, 59.9, 45.7, 34.0, 18.9.
LC-MS: found m/z 450.0, 451.0, 452.0, 453.0, 454.0, 455.0.
Anal. Calcd for C21H22Cl2FN5O: C, 56.01; H, 4.92; N, 15.55. Found: C, 56.08; H, 4.94; N, 15.80.
Cui, J. J.; Botrous, I.; Shen, H.; Tran-Dube, M. B.; Nambu, M. D.; Kung, P.-P.; Funk, L. A.; Jia, L.; Meng, J. J.; Pairish, M. A.; McTigue, M.; Grodsky, N.; Ryan, K.; Alton, G.; Yamazaki, S.; Zou, H.; Christensen, J. G.; Mroczkowski, B.Abstracts of Papers; 235th ACS National Meeting, New Orleans, LA, United States, April 6–10, 2008.
Cui, J. J.; Funk, L. A.; Jia, L.; Kung, P.-P.; Meng, J. J.; Nambu, M. D.; Pairish, M. A.; Shen, H.; Tran-Dube, M. B. U.S. Pat. Appl. U. S. 2006/0046991 A1, 2006.
Cosy predict above
1H NMR PREDICT
![3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine NMR spectra analysis, Chemical CAS NO. 877399-52-5 NMR spectral analysis, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine H-NMR spectrum](https://i0.wp.com/pic11.molbase.net/nmr/nmr_image/2014-07-29/000/437/336/877399-52-5-1h.png)
13C NMR PREDICT
![3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine NMR spectra analysis, Chemical CAS NO. 877399-52-5 NMR spectral analysis, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine C-NMR spectrum](https://i0.wp.com/pic11.molbase.net/nmr/nmr_image/2014-07-29/000/437/336/877399-52-5-13c.png)
| WO2006021881A2 * | 15 Aug 2005 | 2 Mar 2006 | Pfizer | Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors |
| WO2006021884A2 * | 15 Aug 2005 | 2 Mar 2006 | Pfizer | Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors |
| WO2013181251A1 * | 29 May 2013 | 5 Dec 2013 | Ratiopharm Gmbh | Crizotinib hydrochloride salt in crystalline |
| EP2620140A1 * | 26 Jan 2012 | 31 Jul 2013 | ratiopharm GmbH | Crizotinib containing compositions |
-
WO2010048131A1 * Oct 20, 2009 Apr 29, 2010 Vertex Pharmaceuticals Incorporated C-met protein kinase inhibitors WO2011042389A2 * Oct 4, 2010 Apr 14, 2011 Bayer Cropscience Ag Phenylpyri(mi)dinylazoles US7825137 Nov 23, 2006 Nov 2, 2010 Pfizer Inc. Method of treating abnormal cell growth US7858643 Aug 26, 2005 Dec 28, 2010 Agouron Pharmaceuticals, Inc. Crizotinib, a c-Met protein kinase inhibitor anticancer agent; 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine is crizotinib US20060128724 Aug 26, 2005 Jun 15, 2006 Agouron Pharmaceuticals, Inc. Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors 1 J. JEAN CUI J. MED. CHEM. vol. 54, 2011, pages 6342 – 6363 2 ORG. PROCESS RES. DEV. vol. 15, 2011, pages 1018 – 1026 3 * PIETER D. DE KONING ET AL: “Fit-for-Purpose Development of the Enabling Route to Crizotinib (PF-02341066)“, ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 15, no. 5, 16 September 2011 (2011-09-16), pages 1018-1026, XP055078841, ISSN: 1083-6160, DOI: 10.1021/op200131n
Pernix Therapeutics Holdings, Inc., a specialty pharmaceutical company, today announced that its subsidiary, Hawthorn Pharmaceuticals, Inc., has received FDA approval of a NDA for Vituz Oral Solution (hydrocodone bitartrate and chlorpheniramine maleate).
Hydrocodone bitartrate is morphinan-6-one, 4,5-epoxy-3-methoxy-17-methyl-, (5α)-, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1), hydrate (2:5); also known as 4,5α-Epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5); a fine white crystal or crystalline powder, which is derived from the opium alkaloid, thebaine; and may be represented by the following structural formula:
 |
Hydrocodone Bitartrate
C18H21N03•C4H606•2.5 H20
Molecular weight = 494.5
Chlorpheniramine maleate is 2-pyridinepropanamine, γ-(4-chlorophenyl)-N,N-dimethyl-, (Z)-2-butenedioate (1:1) and has the following chemical structure:
 |
Chlorpheniramine Maleate
C16H19C1N2•C4H404
Molecular weight = 390.86
Feb 28, 2013 – Pernix Therapeutics Holdings, Inc., a specialty pharmaceutical company, today announced that its subsidiary, Hawthorn Pharmaceuticals, Inc., has received U.S. Food and Drug Administration (FDA) approval of a new drug application (NDA) for Vituz Oral Solution (hydrocodone bitartrate and chlorpheniramine maleate). Vituz is indicated for the relief of cough and symptoms associated with upper respiratory allergies or a common cold in adults 18 years of age and older.
Cooper Collins, President and CEO of Pernix, said, “Vituz broadens our cough and cold product line and is our first NDA approved by the FDA, since we closed the acquisition of Hawthorn and Cypress at the end of December 2012. We look forward to the launch of this new treatment option for cough and cold symptoms, which is expected prior to the fall of this year.”
Phase 3 FDA -Acorafloxacin (Avarofloxacin) Granted QIDP and Fast Track Designation
Avarofloxacin Granted QIDP and Fast Track Designation
JNJ-Q2, JNJ-32729463-AAA
CAS NO 878592-87-1 of base
7-[3-[2-Amino-1(E)-fluoroethylidene]piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Furiex Pharmaceuticals Inc. announced that the FDA has granted Qualified Infectious Disease Product (QIDP) and Fast Track designation for avarofloxacin (JNJ-Q2). Avarofloxacin is a Phase 3-ready broad-spectrum fluoroquinolone antibiotic for the treatment of acute bacterial skin and skin-structure (ABSSSI) infections, community-acquired pneumonia and has proven to be effective in treating methicillin-resistant Staphylococcus aureus (MRSA) infections.
Avarofloxacin is an investigational novel fluoroquinolone antibiotic that has been shown to be effective in a Phase 2 study of ABSSSI infections. In this study, avarofloxacin demonstrated favorable efficacy for both early clinical response endpoints as well as all clinical cure endpoints for the intent to treat population.
Avarofloxacin has a low tendency for development of drug resistance and exhibits a broad range of antibacterial activities in vitro, including MRSA, fluoroquinolone-resistant Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug resistant strains), gram positive, gram negative, atypical respiratory pathogens (such as legionella and mycoplasma) and anaerobic bacteria, which are often associated with abscesses of the skin and other organs.
The availability of IV and oral formulations for avarofloxacin differentiates it from a number of other products for MRSA infections which are only available for intravenous administration.
For more information call (919) 456-7800or visit http://www.furiex.com/
About Methicillin-Resistant Staphylococcus aureus (MRSA)
MRSA is a strain of the bacteria Staphylococcus aureus (staph) which commonly causes skin and soft tissue infections and is resistant to many antibiotics. Although MRSA had previously been primarily a hospital-acquired pathogen, its incidence has been rising in the community, and it has become the most frequent cause of skin and soft tissue infections presenting to emergency departments in the United States. There are a limited number of antibiotics approved to treat MRSA, and their frequent usage has led to emergence of multi-drug resistant bacteria. Thus, we believe there is significant unmet medical need for new antibiotics such as avarofloxacin that provide flexible (hospital and outpatient) treatment options for MRSA.
WO-2006/101603 describes 7-amino alkylidenyl- heterocyclic quinolones as antimicrobial compounds and the synthesis of 7-[(3E)-3-(2-amino-l-fluoroethylidene)-l- piperidinyl]- 1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid is disclosed as compound (303) in Table 1 on page 20. This compound is conveniently referred to as compound ‘A’ hereafter.
compound ‘A’
7-[(3E)-3-(2-amino-1 -fluoroethylidene)-1 -piperidinyl]-1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid
The in vitro antibacterial properties of compound ‘A’ are described by Morrow B.J. et al. in Antimicrobial Agents and Chemotherapy, vol. 54, pp. 1995 – 1964 (2010).
WO-2008/005670 discloses one-pot methods for the production of substituted allylic alcohols as well as extractive methods for the separation of certain isomeric alcohol products which are useful for preparing quinolones such as the antimicrobial compound 7-[(3E)-3-(2-amino- 1 -fluoroethylidene)- 1 -piperidinyl]- 1 -cyclopropyl-6-fluoro- 1 ,4- dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid (i.e. compound ‘Α’). An important intermediate in the overall synthesis route of said antimicrobial compound ‘A’ is 2-[(2E)-2-fluoro-2-(3-piperidinylidene)ethyl]-lH-isoindole-l,3(2H)- dione and its hydrochloric acid salt thereof : compound (1 )
2-[(2E)-2-fluoro-2-(3-piperidinylidene)ethyl]-1 H-isoindole-1 ,3(2H)-dione compound (1 ) .HCI
Compound (1) introduces the desired E- stereochemistry into the overall synthesis route for the antimicrobial compound ‘Α’.
WO-2008/005670 discloses a synthesis route for compound (1) on page 38 as depicted below :
– highly enriched (E)
(Step 3a) O
The detailed reaction procedure for compound (1) is disclosed in WO-2008/005670 in Example 1 on pages 37 to 44 affording compound (1) in Method A with a E:Z ratio of 97:3 in an approximate overall yield of 18 % in Method A (step 1 for the first 3 heptane layers has a yield of 34 % with a ratio E:Z of 71 :29, step 2a has a yield of 53.4% with a ratio E:Z of 97:3, and step 3 has quantitave yield), or affording compound (1) in Method B with an approximate overall yield of 15% with a ratio E:Z of 94.4 : 5.6. WO-2008/005670 discloses a synthesis route for the hydrochloric acid addition salt of compound (1) on page 15 in Scheme 2 as depicted below :
into n-butanol,
1 ) 5/6 N HCl in IPA
2) heat to distill
3) add IPA
enriched E-isomer
compound (1 ) .HCl
The detailed reaction procedure to prepare the HCl salt of compound (1) is disclosed in WO-2008/005670 in Example 4 on pages 49 to 52 affording >95% of desired E-isomer with an overall yield of 18 – 22% starting from N-boc-3-piperidone.
The reaction procedures described in WO-2008/005670 for the preparation of compound (1) or its HCl salt are characterized by lack of selectivity of the Wadsworth- Emmons-Horner reaction which produces the undesired Z-isomer in large quantities. This undesired Z-isomer requires additional time consuming separation steps.
Hence there is a need for a more efficient and less waste-producing procedure for the preparation of compound (1) or its HCl salt. WO-2010/056633 discloses a synthesis scheme XIV on page 87 to prepare tert-butyl 4- (2-ethoxy-2-oxoethylidene)piperidinyl-l-carboxylate and a synthesis scheme XXVI on page 111 to prepare (l-benzyl-piperidin-4-ylidene)bromoacetic acid ethyl ester.
In a first embodiment the present invention relates to an improved process for preparing compounds of formula (III) having an improved ratio of the desired (E)-isomer over the undesired (Z)-isomer.
(I)
In a further embodiment the compound (E)-(III) is then converted in to compound (1) or its hydrochloric acid addition salt thereof.
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WO 2008005670
http://www.google.com/patents/WO2008005670A2?cl=en
Scheme 1
3 eq NaBH4 OH
30 – 4O0C
2a 2b 2a
2b shows the preparation of alcohol 2
Scheme 2
1 ) HCI (5 eq )
aqueous layer to enriched E isomer pH 9-10 then extract into n-Butanol, discard aqueous layer
Preparation of
7-[3-(2-Amino-l-fluoroethylidene)piperidin-l-yl]-l-cyclopropyl- 6-fluoro-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (10) and its HCl salt (12)
7-[3-(2-Amino-1-fluoro-ethyhdene)-piperidin-1-yl]-1-cyclopropyl–fluoro-8-mΘthoxy-4-oxo-1 ,4-dιhydro-quιnolιne-3-carboxylιc acid (10)
Step 1: Preparation of 3-(l-fluoro-2-hydroxyethylidene)piperidine-l-carboxylic acid tert-butyl ester (2a)
A 22-L 4-neck round bottom flask, equipped with a thermocouple controller, overhead mechanical stirrer, condenser, nitrogen inlet adapter, and stopper, was charged with N-Boc-3-piperidone (663.36 g, 3.34 mol), 2-methoxyethanol (6.0 L) and 2-fluorotriethylphosphonoacetate (843.54 g, 3.49 mol). The mixture was stirred to obtain a homogeneous solution and then CS2CO3 was added in portions over 1.5 h. After the CS2CO3 addition was complete, NaBH4 was added in portions over 6 h; during most of this addition the reaction temperature was maintained between 35 0C to 40 0C. After the addition was complete, the reaction was allowed to stir overnight after which time HPLC analysis indicated that the reaction was complete. This run was combined with two additional runs of equal size and transferred to a stirred 100-L Hastalloy® reactor containing water (90 L). The aqueous mixture was extracted with heptane (4 x 20 L) followed by extraction with MTBE (methyl tert-butyl ether) (20 L). The first three heptane extracts provided 842 g of the allylic alcohol as 71:29 (E: Z) mixture (HPLC and NMR). The product mixture from the first three heptane extractions was carried on to the next step without any additional purification. The fourth heptane extract gave 114 g of product that was a 67:33 mixture of is: Z alcohols (NMR). MTBE extraction and concentration gave 1.1 Kg of product as a 33:67 mixture of E:Z alcohols (HPLC). The total overall yield for both isomers was 2.06 Kg (83%). 1H NMR of 2a (400 MHz, CDCl3): £ 1.45 (s, 9 H), 1.52 (m, 2 H), 2.40 (m, 2 H), 3.45 (m, 2 H), 3.90 (s, 2 H), 4.25 (d, 2 H). 1H NMR of 2b (400 MHz, CDCl3): δ 1.46 (s, 9 H), 1.65 (m, 2 H), 2.27 (m, 2 H), 3.45 (m, 2 H), 4.1 (s, 2 H), 4.25 (d, 2 H).
Step 2, Method A: Preparation of 3-is-[2-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-l- fluoroethylidene]-piperidine-l-carboxylic acid tert-butyl ester (3-ϋ)
A 22-L 4-neck round bottom flask, equipped with a thermocouple controller, overhead mechanical stirrer, condenser, pressure-equalizing addition funnel, nitrogen inlet adapter, and stopper, was charged with E:Z alcohol mixture 2a and 2b (377.5 g, 1.296 mol corrected), 2-MeTHF (3.31 L), phthalimide (232.8 g, 1.581 mol), and Ph3P (411.3 g, 1.568 mol). The white suspension was stirred under N2 and cooled to -12 0C in an acetone/Dry-Ice bath, DIAD (309 mL, 1.49 mol) was added via the addition funnel over a 36-min period, while the reaction temperature was maintained at -15 0C to -10 0C. After the addition, the reaction was warmed to 20 0C in a water bath and stirred for 2 h. The reaction was cooled to 0 0C in an ice/water bath and quenched with cold 1.0 M HCl (950 mL). The aqueous phase was separated and EtOAc (1.70 L) was added to the organic phase. This phase was washed with cold 1.0 M HCl (0.95 L) (the aqueous phase was pH < 2) and then separated. The organic phase was next washed with cold 4 NNaOH (1.70 L), the alkaline aqueous phase (pH > 13) was separated and the EtOAc layer washed with brine (1.70 L). Concentration of the organic phase at 60 0C under house vacuum (-120 mm Hg) afforded 1,442.0 g of crude 3. This run was repeated on the same scale to provide an additional 1,431.0 g of crude material for a combined yield of 2,873 g (159%). HPLC analysis (area%) indicated crude 3 was a mixture of 3-E (29.4%), 3-Z (10.4 %), Ph3PO (51.0 %), and phthalimide (1.1 %). This was purified by recrystallization as described in step 2a.
Step 2a, Method A: Purification of 3-is-[2-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-l- fluoroethylidene]-piperidine-l-carboxylic acid tert-butyl ester
A 22-L 4-neck round bottom flask equipped with a thermocouple controller, overhead mechanical stirrer, condenser, pressure-equalizing addition funnel, nitrogen inlet adapter and stopper was charged with the combined crude 3 (2,873 g) and MeOH (9.0 L). The solution was stirred under nitrogen and heated to 65 0C, while hot (60 0C) D.I. water (7.8 L) was added over a 15-min period. The solution was stirred at 65 0C for 5 min, and then the heating mantle was replaced with a water bath, and the mixture was gradually cooled to 0 0C over a 4-h period, and continued stirring for 1 h at 0 0C. The off-white solid was collected by filtration, and dried by air-suction at 60 0C for 20 h, this provided 1,172.6 g of a mixture of 3-E and 3-Z.
The partially purified product above was recrystallized a second time in the same manner using hot MeOH (7.2 L) and hot water (5.0 L) except that the water was added over a 10-min period to afford 515.6 g (53.4%) of 3-E as a 97:3 mixture of E:Z geometric isomers. This material was used in the next step without additional purification. . 1H NMR of 3-E (400 MHz, CDCl3): δ 1.48 (s, 9 H), 1.52-1.66 (m, 2 H), 2.28-2.38 (m, 2 H), 3.40-3.51 (m, 2 H), 4.18 (s, 2 H), 4.55 (d, J= 21.0 Hz, 2 H), 7.68- 7.77 (m, 2 H), 7.80-7.89 (m, 2 H). MS: 397 (M+Na)+, 771 (2M+Na)+.
3 -E-[2-( 1 ,3 -dioxo- 1 ,3-dihydroisoindol-2-yl)- 1 -fluoroethylidene]-piperidine- 1 – carboxylic acid tert-butyl ester was also prepared with Method B below: Step 2, Method B: Preparation of 3-£-[2-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-l- fluoroethylidene]-piperidine-l-carboxylic acid tert-butyl ester (3-E)
Preparation of the methanesulfonate and chloride derivatives
2a
A 12-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with 2a (297.0 g, 1.21 mol) and CH2Cl2 (3.9 L). The solution was cooled to 0 0C under N2 and EtsN (320 mL, 2.30 mol) was added via the addition funnel over a 10- min period. This was followed by methanesulfonyl chloride (115 mL, 1.49 mol) added over a 60-min period then the reaction was stirred for an additional 60-min at 0 0C. The mixture was poured into a mixture of deionized water (4.4 L) and saturated NaHCθ3 (0.78 L), the layers were separated, the aqueous layer was extracted with CH2Cl2 (2 x 2 L). All the CH2Cl2 layers were combined and washed with saturated NaHCθ3 (2 L). The CH2Cl2 was removed under vacuum at 40 0C to afford a mixture of the mesylate and chloride (342.3 g). This mixture was taken on to the next step without any purification.
Conversion of the methanesulfonate/chloride to phthalimide 3
A 5-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with the mixture of the mesylate and chloride from above (342.2 g, 1.21 mol) and DMF (2.0 L) followed by potassium phthalimide (224.9 g, 1.21 mol). The mixture was stirred at 60 0C for 1-h then at 20 0C for 18 h. The mixture was poured into ice- water, allowed to stand for 30-min and filtered. The liquors from the filtration were allowed to stand at 0 0C over the weekend and filtered again. The combined solids were dissolved in acetone (4 L) and concentrated on the rotary evaporator, this process was repeated a second time to give the phthalimide derivative 3 as a mixture oiEIZ (79/31) isomers (263.2 g, 58.1 %).
Step 2a, Method B: Purification of 3-£-[2-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-l- fluoroethylidene]-piperidine-l-carboxylic acid tert-butyl ester
A 12-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with the crude phthalimide derivative 3 (263.1 g) and MeOH (2.74 L). The mixture was heated to 66 – 68 0C while water (2.1 L) was added over 20-min, the mixture was stirred at 68 0C for 5-min, then gradually cooled to 20 0C for 18-h. While the crystallization mixture was cooling it was seeded at 60 0C, 56 0C and 530C. This crystallization gave a white solid that was filtered and dried under vacuum at 50 0C to afford 3-E (118.8 g, 45.2%) as a mixture containing 94.4% E and 5.6% Z isomers (NMR analysis).
Step 3: Preparation of 2-[2-fluoro-2-(3-piperidinylidene)ethyl]-lH-isoindole-l,3)- dione (4)
A 12-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with 3-E (578.0 g, 1.544 mol) and CH2Cl2 (4.5 L). The solution was stirred at 200C under N2 and TFA (476 mL, 6.18 mol) was added via the addition funnel over a 10-min period. The mixture was gently heated to 38 0C and stirred for 3 h. The solvent was removed under vacuum to give the TFA salt of 4 (962.6 g). This material was dissolved in CH2Cl2 (4.0 L) and washed with 2.5 NNa2CO3 (4.6 L)-followed by saturated NaHCO3 (4.6 L). The organic phase was dried (MgSO4), filtered, and condensed in vacuo. The off-white solid was dried at 40 0C under vacuum (20 mm Hg) for 20 h to afford 464.3 g of the free base of 4 as slightly yellowish foamy substance. 1H NMR of 4 TFA salt (400 MHz, CDCl3): δ 1.87-1.98 (m, 2 H), 2.42-2.55 (m, 2 H), 3.38-3.50 (m, 2 H), 4.08-4.18 (br s, 2 H), 4.50 (d, J= 21.0 Hz, 2 H), 7.69-7.78 (m, 2 H), 7.79-7.87 (m, 2 H), 7.98-8.23 (br s, 1 H), 12.48 (s, 1 H). MS: 275 (MH)+, 549 (2M+H)+.
Step 4: Preparation of l-Cyclopropyl-ό^-difluoro-S-methoxy^-oxo-l^- dihydroquinoline-3-carboxylic acid difluoroborate ester (6)
A 22-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, pressure equalizing addition funnel, and a nitrogen inlet adapter was charged with quinoline-3-carboxylic acid 5 (450.0 g, 1.524 mol), THF (5.40 L) and K2CO3 (247.2 g, 1.753 mol). This suspension was first stirred at 20 0C under N2 for 5 min, and BF3 »Et20 (259 mL, 2.04 mol) was added dropwise via the addition funnel to the stirred mixture over a 5-min period. After the addition, the mixture was heated to reflux (66 0C) for 6 h. The reaction was cooled to 10 0C, diluted with Et2O (9.0 L) and stirred for 10 min. The solid was filtered and washed with Et2O (200 mL x 2) and then dried at 50 0C under house vacuum (-160 mm Hg) for 20 h to afford 771.O g of crude difluoroborate ester 6. After this, the crude material was suspended in MeCN (8.0 L) and stirred at 20 0C for 20 min; the solid was collected by filtration. The filter cake was re-suspended and stirred in MeCN four more times (2.0 L x 4), and all filtrates were combined and concentrated at 60 0C under hi-vac (~10 mmHg). The resulting off- white solid was dried at 50 0C under house vacuum (-160 mmHg) for 20 h to afford 508.66 g (97.2% isolated yield, HPLC = 99.2% by area) of pure difluoroborate ester 6. 1H NMR of 6 (400 MHz, CD3CN): «51.17-1.28 (m, 2 H), 1.29-1.40 (m, 2 H), 4.19 (s, 3 H), 4.40-4.52 (m, 1 H), 8.16 (dd, J= 6.9, 7.0 Hz, 1 H), 9.17 (s, 1 H). MS: 344 (MH)+, 667 (2M-F)+.
Step 5: Preparation of intermediate 8
A 5-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, pressure-equalizing addition funnel and a nitrogen inlet adapter was charged with difluoroborate ester 6 (320.0 g, 0.933 mol), DMF (1.10 L) and piperidine 4 (289.0 g, 1.053 mole). This suspension was stirred at 20 0C under N2 for 5 min, EtsN (299 mL, 2.15 mol) was added to the stirred mixture via the addition funnel over an additional 5-min period. After this addition, the mixture was heated to 60 0C and stirred for 3 h, to give crude intermediate 7. HPLC analysis (area%) indicated crude 7 is a mixture of 7 (40.5%), 8 (1.7 %), 6 (24.1%), and the rest of unknowns (33.7%). MS: 598 (MH)+. The coupled crude product 7 was carried on to the next step without isolation.
Removal of the Fluoroborate Ester The above stirred reaction mixture containing 7 was treated in the same flask with EtOH (6.80 L) and Et3N (299 mL, 2.147 mol) under N2 at 60 0C. The amber solution was heated to reflux at 72 0C for 2 h and cooled to 20 0C. The reaction mixture was poured into a rapidly stirred 22-L 4-neck round bottom flask containing a 1 : 1 (v/v) ice-water mixture (8.0 L) over a 10-min period; stirring was continued for -10 min. Cold 1 NHCl (4.0 L) was added to the solution over 20 min to adjust the pH from 9-10 to 3; stirring was continued for an additional 20 min at 0 0C. The yellow solid was isolated by filtration and dried in a filter funnel by air-suction using house vacuum (-160 mm Hg) at 20 0C for 20 h to afford 1,889.0 g of crude 8 as a damp solid (HPLC = 33.6%, area%).
Purification of Intermediate 8
To a 22-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with crude 8 (1889.0 g), MeCN (3.6 L) and EtOH (3.2 L). The suspension was heated to reflux (76 0C), while D.I. H2O (500 mL) was added over 10 min. The solution was stirred at 76 0C for 5 min, and then gradually cooled to 10 0C over 1 h; stirred for an additional hour. The yellow solid was collected by filtration, dried in a vacuum oven under house vacuum (-160 mm Hg) at 60 0C for 20 h to afford 229. Ig (45%) of 8, which was used in next step without further purification. 1H ΝMR of 8 (400 MHz, DMSO-d6): £ 1.02-1.10 (m, 2 H), 1.11-1.19 (m, 2 H), 1.67-1.79 (m, 2 H), 2.34-2.45 (m, 2 H), 3.38-3.49 (m, 2 H), 3.78 (s, 3 H), 4.10 (s, 2 H), 4.15-4.26 (m, 1 H), 4.54 (d, J= 21.0 Hz, 1 H), 7.72 (d, J= 9.1 Hz, 1 H), 7.81 (s, 4 H), 8.71 (s, I H), 14.98 (s, 1 H). MS: 550 (MH)+.
Step 6: Preparation of 7-[3-(2-amino-l-fluoro-ethylidene)-piperidin-l-yl]-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (10)
8 10 A
22-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, pressure-equalizing addition funnel and a nitrogen inlet adapter was charged with 8 (253.6 g, 0.462 mol) and MeOH (5.10 L). This suspension was stirred at 20 0C under N2 and H2NNH2 (86.9 mL, 2.796 mol) was added over a 5-min period. The yellow suspension was heated to 65 0C and refluxed for 1 h. The reaction was cooled to 60 0C and MeCN (3.84 L) was added. The mixture was heated to reflux for 5 min, and then cooled to 20 0C in a water bath. The light-yellow solid was collected by filtration and the filter cake was washed with MeCN (150 mL x 2). The combined filtrate was concentrated at 60 0C affording 322.0 g of crude product 10. This product was recrystallized from a mixture of MeOH (1.0 L) and water (1.195 L) to give 176.6 g (91.2%) of pure product 10 as a light yellow solid.
BASE FORM
1H NMR of 10 (400 MHz, DMSO- d6): £ 1.0-1.09 (m, 2 H), 1.10-1.19 (m, 2 H), 1.66-1.78 (m, 2 H), 2.30-2.41 (m, 2 H), 3.17 (s, 2 H), 3.35 (s, 1 H), 3.36-3. 47 (m, 2 H), 3.74 (s, 3 H), 3.89 (s, 2 H), 4.13-4.22 (m, 1 H), 5.35-6.18 (br, 2 H), 7.74 (d, J= 8.9 Hz, 1 H), 8.69 (s, 1 H).
MS: 420 (MH)+.
Example 3
Preparation of7-[3-(2-Amino-l-fluoro-ethylidene)-piperidin-l-yl]-l-cyclopropyl-
6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid hydrogen chloride salt (12)
7-[3-(2-amino-l-fluoro-ethylidene)-piperidin-l-yl]-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (10) was prepared as described in Step 6 of Example 1.
A 5-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with compound 10 (176.0 g, 0.4196 mol) and EtOH (2.40 L). The suspension was stirred under N2 and cooled to 10 0C with an ice/water bath. A solution of HCl in EtOH (1.25 M, 350 mL) was added via the addition funnel over a 20-min period. After the addition, the reaction was stirred at 10 0C for 5 min. The water bath was replaced with a heating mantle and the solution was heated to 76 0C and stirred for 5 min. The heating mantle was replaced with the water bath, the solution was cooled to 0 0C over 1 h and stirred at this temperature for an additional 1 h. The solid was collected by filtration, washed with ice-cold EtOH (100 mL x 2) and dried at 60 0C under vacuum (~4 mmHg) for 60 h. There was obtained 88.9 g (82%) of HCl salt 12 as an off-white to very light-yellow solid.
HCl SALT
1H NMR of HCl salt 12 (400 MHz, CD3CO2D): £ 1.10-1.19 (m, 2 H), 1.29-1.38 (m, 2 H), 1.81-1.93 (m, 2 H), 2.51-2.60 (m, 2 H), 3.48- 3.60 (m, 2 H), 3.86 (s, 3 H), 4.08 (s, 2 H), 4.18 (s, 1 H), 4.19-4.30 (m, 2 H), 7.92 (d, J= 8.6 Hz, 1 H), 8.98 (s, 1 H) 11.65 (s, 1 H).
MS: 420 (MH)+
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http://www.google.com/patents/WO2013045599A1?cl=en
Experiment 6
(VI) compound (1 ) .HCI
Compound (1) .HCI salt from Compound (Via) :
9.8 ml (90.6 mmol) of 1-chloroethyl chloro formate are added slowly to a solution of 30 g (82.3 mmol) of compound (E)-(Va) in 165 ml of toluene kept at 0°C. The reaction mixture is stirred 1 hour at room temperature than 1 hour at 80°C and filtered. 24 ml of ethanol and 15.35 ml (90.6 mmol) of 6M HCI solution in isopropanol are added to the filtrate and the resulting mixture is refluxed for 4 hours then cooled to 0°C. The precipitate is filtered, washed with 16 ml of acetone and 16 ml of toluene and dried under vacuum to give 21.94 g of compound (1) . HCI salt. Yield: 86%>.
NMR and MS data are identical to those of the literature.
-
Avarofloxacin nonproprietary drug name
http://www.ama-assn.org/resources/doc/usan/avarofloxacin.pdf
November 28, 2012. N12/130. STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. USAN (ZZ-145). AVAROFLOXACIN.
- [PDF]
Avarofloxacin hydrochloride nonproprietary drug name
http://www.ama-assn.org/resources/doc/usan/avarofloxacin-hydrochloride.pdf
WO2006101603A1 Feb 2, 2006 Sep 28, 2006 Janssen Pharmaceutica Nv 7-amino alkylidenyl-heterocyclic quinolones and naphthyridones WO2008005670A2 Jun 14, 2007 Jan 10, 2008 Janssen Pharmaceutica Nv One-pot condensation reduction methods for preparing substituted allylic alcohols WO2010056633A2 Nov 10, 2009 May 20, 2010 Janssen Pharmaceutica Nv 7-amino alkylidenyl-heterocyclic quinolones and naphthyridones
Phase3 Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy
Chemical structure of ganetespib and its co-crystal structure with Hsp90 N-terminal.
A, chemical structure of ganetespib.
B, crystallographic complex of ganetespib in the Hsp90 N-terminal.
C, hydrogen bond interactions between ganetespib with amino acid residues in the Hsp90 N-terminal ATP-binding pocket.
Synta Pharmaceuticals has opened a ClinicalTrials.gov listing for their much discussed GALAXY-2 phase 3 trial of their HSP90 inhibitor ganetespib in second-line non-small cell lung cancer (NSCLC), in combination with docetaxel. For the moment at least, the phase 2b GALAXY-1 trial is still listed as enrolling patients, but that would be expected to complete soon.
http://clinicaltrials.gov/ct2/show/NCT01798485
- CAS Number:
- 888216-25-9
-
3H-1,2,4-Triazol-3-one, 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-2,4-dihydro-4-(1-methyl-1H-indol-5-yl)-
- Ganetespib
- Molecular Structure:
![Molecular Structure of 888216-25-9 (3H-1,2,4-Triazol-3-one, 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-2,4-dihydro-4-(1-methyl-1H-indol-5-yl)-)](https://i0.wp.com/www.lookchem.com/300w/2012-2/e100939d-148c-4f54-9b7c-83632fb0d675.gif)
- Formula: C20H20N4O3
![Molecular Structure of 888216-25-9 (3H-1,2,4-Triazol-3-one, 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-2,4-dihydro-4-(1-methyl-1H-indol-5-yl)-)](http://www.lookchem.com/300w/2012-2/e100939d-148c-4f54-9b7c-83632fb0d675.gif)
Hsp90, a chaperone essential for the folding of JAK2, is the target of Synta Pharmaceuticals’ ganetespib.
HSP70i, A genetically modified protein, on Experimental Vitiligo Treatment, Shows Promise in Mice
WEDNESDAY Feb. 27, 2013 — A genetically modified protein could provide the first effective treatment for the skin condition vitiligo, a new study in mice suggests.
People with vitiligo have white patches on the face, hands and other parts of the body. Vitiligo is an autoimmune disorder in which the immune system becomes overactive and kills the pigment cells that give skin its color.
Researchers at the Loyola University Chicago Stritch School of Medicine developed a genetically modified protein that reversed vitiligo in mice and had similar effects on human skin tissue samples. Findings from animal studies do not always hold up in human trials, however.
A protein called HSP70i plays a major role in the autoimmune response that causes vitiligo. The researchers genetically modified an amino acid in the protein in order to create a mutant version of HSP70i. This version replaces normal HSP70i and reverses the autoimmune response that causes vitiligo, the study authors explained in a Loyola news release.
When the mutant HSP70i was given to mice with vitiligo, their salt-and-pepper fur turned black, giving them a normal appearance. The mutant protein had a similar effect on human skin samples, according to the study, published in the current issue of the journal Science Translational Medicine.
Researcher I. Caroline Le Poole, a professor in Loyola’s Oncology Institute, and colleagues are seeking approval and funding to conduct a clinical trial of the modified protein in humans.
About 1 million Americans have vitiligo, which affects about one in 200 people worldwide. There are no long-term effective treatments for the condition. Current options include steroid creams, light therapy and skin grafts, but none of them can prevent vitiligo from progressing.
More information
The U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases has more about vitiligo.
AstraZeneca ready to file constipation drug naloxegol
4,5α-epoxy-6α-[(3,6,9,12,15,18,21-heptaoxadocosan-1-yl)oxy]-17-(prop-2-en-1-yl)morphinan-3,14-diol
Naloxegol (INN; NKTR-118), or PEGylated naloxol,[1] is a peripherally-selective opioid antagonist under development by AstraZeneca (licensed from Nektar) for the treatment of opioid-induced constipation.[2]
- Roland Seifert; Thomas Wieland; Raimund Mannhold; Hugo Kubinyi, Gerd Folkers (17 July 2006). G Protein-Coupled Receptors as Drug Targets: Analysis of Activation and Constitutive Activity. John Wiley & Sons. p. 227. ISBN 978-3-527-60695-5. Retrieved 14 May 2012.
- “Nektar | R&D Pipeline | Products in Development | CNS/Pain | Oral Naloxegol (NKTR-118) and Oral NKTR-119”. Retrieved 2012-05-14.
phase3
AstraZeneca has presented positive data from a late-stage trial of naloxegol in patients with non-cancer related pain and opioid-induced constipation.
In the fourth trial in a Phase III development programme designed to evaluate long-term safety and adverse event profile , 534 patients received naloxegol once-daily for up to 52 weeks, while 270 were on usual care (laxatives) for OIC. The most commonly-reported AEs occurring more frequently on naloxegol than on usual care included abdominal pain, diarrhoea, nausea and headache but the trial reported no imbalances in serious adverse events.
Briggs Morrison, head of the global medicines development at AstraZeneca, said “these high-level results are similar to the safety results seen in the Phase III studies previously reported and provide further confidence in the data we’ve seen to date for naloxegol”. The programme is now complete and filings in the USA and Europe are planned for the third quarter.
Globally, some 40–50% (28-35 million) of patients taking opioids for long-term pain develop constipation and about 40–50% (11-18 million) of those OIC sufferers achieve the desired outcomes with current options, ie laxatives.
The actual timing of the submissions depend in part on a meeting with the US Food and Drug Administration as naloxegol is currently considered a Schedule II controlled substance across the Atlantic based on its “structural relatedness” to noroxymorphone. AstraZeneca says it has conducted the studies necessary to evaluate the abuse potential and dependence-producing properties of naloxegol and a petition to de-control the drug was submitted in March 2012.
Naloxegol, a peripherally-acting mu-opioid receptor antagonist and formerly known as NKTR-118, was licensed from Nektar Therapeutics in September 2009.
FDA Approves Osphena,Ospemifene for Postmenopausal Women Experiencing Dyspareunia
Ospemifene
CAS Number: 128607-22-7
Molecular Formula: C24H23ClO2
Molecular Weight: 378.89 g.mol-1
February 26, 2013 — The U.S. Food and Drug Administration today approved Osphena (ospemifene) to treat women experiencing moderate to severe dyspareunia (pain during sexual intercourse), a symptom of vulvar and vaginal atrophy due to menopause.
Dyspareunia is a condition associated with declining levels of estrogen hormones during menopause. Less estrogen can make vaginal tissues thinner, drier and more fragile, resulting in pain during sexual intercourse.
Osphena, a pill taken with food once daily, acts like estrogen on vaginal tissues to make them thicker and less fragile, resulting in a reduction in the amount of pain women experience with sexual intercourse.
“Dyspareunia is among the problems most frequently reported by postmenopausal women,” said Victoria Kusiak, M.D., deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Osphena provides an additional treatment option for women seeking relief.”
Osphena’s safety and effectiveness were established in three clinical studies of 1,889 postmenopausal women with symptoms of vulvar and vaginal atrophy. Women were randomly assigned to receive Osphena or a placebo. After 12 weeks of treatment, results from the first two trials showed a statistically significant improvement of dyspareunia in Osphena-treated women compared with women receiving placebo. Results from the third study support Osphena’s long-term safety in treating dyspareunia.
Common side effects reported during clinical trials included hot flush/flashes, vaginal discharge, muscle spasms, genital discharge and excessive sweating.
Osphena is marketed by Florham Park, N.J.-based Shionogi, Inc.
Ospemifene, FC-1271a
2-[4-[4-Chloro-1,2-diphenyl-1(Z)-butenyl]phenoxy]ethanol
Orion Corp. (Originator), Hormos (Codevelopment)
Bone Diseases, Treatment of, ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Hormone Replacement Therapy, METABOLIC DRUGS, Treatment of Osteoporosis, Treatment of Postmenopausal Syndrome , Selective Estrogen Receptor Modulators (SERM)
- Shionogi Files a New Drug Application for Ospemifene Oral Tablets 60mg for the Treatment of Vulvar and Vaginal Atrophy – May 9, 2012
credit chemdrug
The condensation of desoxybenzoin (I) with 2-(benzyloxy)ethyl bromide (II) by means of aqueous 48% NaOH containing triethylbenzylammonium chloride (TEBAC) gives 4-(benzyloxy)-1,2-diphenyl-1-butanone (III), which by reaction with the Grignard reagent (IV) – prepared from 4-(tetrahydropyranyloxy)phenyl bromide (V) and Mg in THF – yields the triphenylbutanol derivative (VI). Elimination of the THP-protecting group of compound (VI) by means of H2SO4 in ethanol/water at room temperature affords the triphenylbutanol derivative (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to provide the butane-1,4-diol derivative (VIII). Cyclization of the butane-1,4-diol (VIII) by means of H2SO4 in hot ethanol/water gives 2-(4-hydroxyphenyl)-2,3-diphenyltetrahydrofuran (IX), which is treated with 48% HBr in refluxing AcOH to yield a mixture of (E)- and (Z)-4-(4-hydroxyphenyl)-3,4-diphenyl-3-buten-1-ol (X), which is separated by chemical work up. The phenolic OH group of the desired (Z)-isomer (X) is condensed with 2-(benzyloxy)ethyl bromide (II) by means of NaOH and tetrabutylammonium bromide in refluxing toluene/ water to afford the benzyloxyethyl ether (XII). Reaction of the aliphatic OH group of ether (XII) with PPh3 and CCl4 in acetonitrile provides the corresponding chloro derivative (XIII), which is finally debenzylated with H2 over Pd/C in ethyl acetate/ethanol.
Sorbera, L.A.; Castar, J.; Bay
Ospemifene. Drugs Fut 2004, 29, 1, 38
Immune begins Phase II study of ulcerative colitis drug, Bertilimumab
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Human |
| Target | CCL11 (eotaxin-1) |
phase 2 NCT01671956; C2a/BRT/UC-01
A Randomized, Double-Blind, Placebo-Controlled Study Designed to Evaluate the Safety, Clinical Efficacy, and Pharmacokinetic Profile of Bertilimumab in Subjects With Active Moderate to Severe Ulcerative Colitis
25 February 2013
Immune Pharmaceuticals has started Phase II study of its bertilimumab (iCo-008 or CAT-213) drug, designed for the treatment of moderate-to-severe ulcerative colitis.
Bertilimumab is a human immunoglobulin monoclonal antibody which targets eotaxin-1, a member of the chemokine family of proteins regulating eosinophilic inflammation.
The double-blind, parallel group, randomized, placebo-controlled 90 patients-based study is designed to demonstrate the safety, clinical efficacy, and pharmacokinetic profile of bertilimumab in subjects with active moderate-to-severe ulcerative colitis.
60 patients in the study will be treated with bertilimumab 7mg/kg, while 30 patients with placebo every two weeks at days 0, 14, and 28, according to the company.
In addition, the patients will be evaluated for clinical response after six weeks to determine the decrease if any in the full Mayo Clinic Ulcerative Colitis Score.
Secondary and exploratory end points of the study include clinical remission defined as symptom free, fecal calprotectin, a recognized marker of gastro-intestinal inflammation, histopathology improvement and degree of mucosal injury.
The company, which is expecting to follow-up the patients for up to day 90, said the patient enrollment and clinical results are likely to be completed in 2014.
The company has also announced that bertilimumab will be the lead clinical stage development drug for the combined company following completion of the proposed merger with EpiCept in the second quarter of 2013.
Bertilimumab is a human monoclonal antibody that binds to eotaxin-1, an important regulator of overall eosinophil function.
patent WO00166754
It was discovered by Cambridge Antibody Technology using their phage displaytechnology.[1] Named CAT-213 during early discovery and development by CAT, it was to be used to treat severe allergic disorders.[2]
In January 2007, CAT licensed the drug for treatment of allergy disorders to iCo Therapeutics Inc.[3] iCo Therapeutics Inc. is a Vancouver-based reprofiling company focused on redosing or reformulating drugs with clinical history for new or expanded indications – a so-called ‘search and development company’.[4]
iCo Therapeutics Inc. renamed the drug from CAT-213 to iCo-008 and, at that stage, planned to initiate a Phase II clinical trial in patients with vernal keratoconjunctivitis.[5]
In March 2008, iCo announced iCo-008 had been in 126 patients in Phase I and II clinical trials. The drug substance had been manufactured by Lonza, in its cGMP facilities inSlough, UK. Subsequently iCo moved the drug substance to a fill-finish site for the final stage of manufacturing. iCo reported that the iCo-008 drug product was within specifications and contained a high antibody yield.[6]
In June 2011, IMMUNE Pharmaceuticals[7] (Herzliya, Israel) in-licensed Bertilimumab from iCo for non-ophthalmic indications. [8]IMMUNE is initiating Phase II clinical trials of Bertilimumab in inflammatory bowel disease (ulcerative colitis & Crohn’s disease) in 2012 and 2013.
- http://jpet.aspetjournals.org/cgi/content/abstract/319/3/1395
- Bertilimumab Cambridge Antibody Technology Group. 5. November 2004. pp. 1213–8. PMID 15573873.
- http://www.icotherapeutics.com/site/investor-relations/cambridge_antibody_tech_licenses_monoclonal_antibody_treatment_allergy/
- http://www.icotherapeutics.com/site/corporate_overview/overview/
- http://www.icotherapeutics.com/site/pipeline/ico008/
- http://www.icotherapeutics.com/site/investor-relations/ico_therapeutics_provides_ico_008_phase_ii_clinical_update/
- http://immunepharmaceuticals.com/
- http://immunepharmaceuticals.com/index.php?option=com_content&view=article&id=32&Itemid=20
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DR ANTHONY MELVIN CRASTO Ph.D , Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues,
Currently he is working with GLENMARK- GENERICS LTD, Research centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India.
Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now Sanofi Aventis, & Searle India ltd, now Rpg lifesciences, etc. He has worked in Basic research, Neutraceuticals, Natural products, Flavors, Fragrances, Pheromones, Vet Drugs, Drugs, formulation, GMP etc. He has total 25 yrs exp in this field, he is now helping millions, has million hits on google on all organic chemistry websites.
His New Drug Approvals , Green Chemistry International, Eurekamoments in Organic Chemistry , Organic Chemistry by Dr Anthony, WIX BLOG , are some most read chemistry blogs
He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 25 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide .
He has good proficiency in Technology Transfer, Spectroscopy , Stereochemistry , Synthesis, Reactions in Org Chem , Polymorphism, Pharmaceuticals , Medicinal chemistry , Organic chemistry literature , Patent related site , Green chemistry , Reagents , R & D , Molecules , Heterocyclic chem , Sourcing etc
He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com
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