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US FDA grants breakthrough therapy designation to Boehringer Ingelheim’s volasertib to treat patients with AML

September 20, 2013 3:43 am / 3 Comments on US FDA grants breakthrough therapy designation to Boehringer Ingelheim’s volasertib to treat patients with AML

Volasertib

755038-65-4

CHEMICAL NAMES
1. Benzamide, N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-
ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-
methoxy-
2. N-{trans-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-4-{[(7R)-7-ethyl-5-methyl-8-
(1-methylethyl)-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxybenzamide

CODE DESIGNATION BI 6727

Ingelheim, Germany
Thursday, September 19, 2013, 16:00 Hrs [IST]

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to Boehringer Ingelheim’s volasertib, a selective and potent polo-like kinase (Plk) inhibitor, for the treatment of patients with acute myeloid leukaemia (AML), a type of blood cancer.

http://www.pharmabiz.com/NewsDetails.aspx?aid=77733&sid=2

Volasertib (also known as BI 6727) is a small molecule inhibitor of the PLK1 (polo-like kinase 1) protein being developed byBoehringer Ingelheim for use as an anti-cancer agent. Volasertib is the second in a novel class of drugs called dihydropteridinone derivatives.^[1]

Mechanism of action

Volasertib is a novel small-molecule targeted therapy that blocks cell division by competitively binding to the ATP-binding pocket of the PLK1 protein. PLK1 proteins are found in the nuclei of all dividing cells and control multiple stages of the cell cycle and cell division.^[2] ^[3] ^[4] The levels of the PLK1 protein are tightly controlled and are raised in normal cells that are dividing. Raised levels of the PLK1 protein are also found in many cancers including; breast, non-small cell lung, colorectal, prostate, pancreatic, papillary thyroid, ovarian, head and neck and Non-Hodgkin’s Lymphoma.^[5] ^[3] ^[6] ^[4] ^[7] ^[8] Raised levels of PLK1 increase the probability of improper segregation of chromosomes which is a critical stage in the development of many cancers. Raised levels of PLK1 have been associated with a poorer prognosis and overall survival in some cancers^[4]^[9] ^[10] In addition to its role in cell division, there is evidence that PLK1 also interacts with components of other pathways involved in cancer development including the K-Ras oncogene and the retinoblastoma and p53 tumour suppressors^[11] These observations have led to PLK1 being recognised as an important target in the treatment of cancer.

Volasertib can be taken either orally or via intravenous infusion, once circulating in the blood stream it is distributed throughout the body, crosses the cell membrane and enters the nucleus of cells where it binds to its target; PLK1. Volasertib inhibits PLK1 preventing its roles in the cell-cycle and cell division which leads to cell arrest and programmed cell death.^[2] Volasertib binds to and inhibits PLK1 at nanomolar doses however, it has also been shown to inhibit other PLK family members; PLK2 and PLK3 at higher; micromolar doses. The roles of PLK2 and PLK3 are less well understood; however they are known to be active during the cell cycle and cell division.^[12]

Volasertib inhibits PLK1 in both cancer and normal cells; however it only causes irreversible inhibition and cell death in cancer cells, because inhibition of PLK1 in cancer cells arrests the cell cycle at a different point to normal, non-cancer cells. In cancer cells PLK1 inhibition results in G2/M cell cycle arrest followed by programmed cell death, however, in normal cells inhibition of PLK1 only causes temporary, reversible G1 and G2 arrest without programmed cell death.^[13] This specificity for cancer cells improves the efficacy of the drug and minimizes the drug related toxicity.

Clinical uses

Volasertib is currently undergoing investigation in phase 1 and 2 trials and has yet to be licensed by the FDA. Volasertib may be effective in several malignancies evidenced by the fact that its target PLK1 is overexpressed in up to 80% of malignancies, where it has been associated with a poorer treatment outcome and reduced overall survival.^[1]^[4]^[9]Further phase 1 and 2 trials are active, investigating the effects of Volasertib both as a single agent and in combination with other agents in solid tumours and haematological malignancies including; ovarian cancer, urothelial cancer and acute myeloid leukaemia.^[14]

Studies

Preclinical studies on volasertib have demonstrated that it is highly effective at binding to and blocking PLK1 function and causing programmed cell death in colon and non-small cell lung cancer cells both in vitro and in vivo. Volasertib can also cause cell death in cancer cells that have are no longer sensitive to existing anti-mitotic drugs such as vinca alkaloids and taxanes.^[13] This suggests that volasertib may be effective when used as a second line treatment in patients who have developed resistance to vinca alkaloid and taxane chemotherapeutics.

A first in man trial of volasertib in 65 patients with solid cancers reported that the drug is safe to administer to patients and is stable in the bloodstream. This study also reported favourable anti-cancer activity of the drug; three patients achieved a partial response, 48% of patients achieved stable disease and 6 patients achieved progression free survival of greater than 6 months.^[15] A further phase 1 trial of volasertib in combination with cytarabine in patients with relapsed / refractory acute myeloid leukaemiareported that 5 of 28 patients underwent a complete response, 2 achieved a partial response and a further 6 patients no worsening of their disease.^[16]

Schoffski, P. (2009). “Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology”. Oncologist 14 (6): 559–70. ISSN (Electronic) 1083-7159 (Linking) 1549-490X (Electronic) 1083-7159 (Linking).
Barr, F. A.; H. H. Sillje, E. A. Nigg (2004). “Polo-like kinases and the orchestration of cell division”. Nat Rev Mol Cell Biol 5 (6): 429–40. ISSN (Print) 1471-0072 (Linking) 1471-0072 (Print) 1471-0072 (Linking).
Garland, L. L.; C. Taylor, D. L. Pilkington, J. L. Cohen, D. D. Von Hoff (2006). “A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors”. Clin Cancer Res 12 (17): 5182–9. ISSN (Print) 1078-0432 (Linking) 1078-0432 (Print) 1078-0432 (Linking).
Santamaria, A.; R. Neef, U. Eberspacher, K. Eis, M. Husemann, D. Mumberg, S. Prechtl, V. Schulze, G. Siemeister, L. Wortmann, F. A. Barr, E. A. Nigg (2007). “Use of the novel Plk1 inhibitor ZK-thiazolidinone to elucidate functions of Plk1 in early and late stages of mitosis”. Mol Biol Cell 18 (10): 4024–36. ISSN (Print) 1059-1524 (Linking) 1059-1524 (Print) 1059-1524 (Linking).
Fisher, R.A.H.; D.K. Ferris (2002). “The functions of Polo-like kinases and their relevance to human disease.”. Curr Med Chem 2: 125–134.
Holtrich, U.; G. Wolf, A. Brauninger, T. Karn, B. Bohme, H. Rubsamen-Waigmann, K. Strebhardt (1994). “Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors”. Proc Natl Acad Sci U S A 91 (5): 1736–40. doi:10.1073/pnas.91.5.1736. ISSN (Print) 0027-8424 (Linking) 0027-8424 (Print) 0027-8424 (Linking). PMC 43238. PMID 8127874.
Steegmaier, M.; M. Hoffmann, A. Baum, P. Lenart, M. Petronczki, M. Krssak, U. Gurtler, P. Garin-Chesa, S. Lieb, J. Quant, M. Grauert, G. R. Adolf, N. Kraut, J. M. Peters, W. J. Rettig (2007). “BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo”. Curr Biol 17 (4): 316–22. doi:10.1016/j.cub.2006.12.037. ISSN (Print) 0960-9822 (Linking) 0960-9822 (Print) 0960-9822 (Linking). PMID 17291758.
Winkles, J. A.; G. F. Alberts (2005). “Differential regulation of polo-like kinase 1, 2, 3, and 4 gene expression in mammalian cells and tissues”. Oncogene 24 (2): 260–6.doi:10.1038/sj.onc.1208219. ISSN (Print) 0950-9232 (Linking) 0950-9232 (Print) 0950-9232 (Linking). PMID 15640841.
Eckerdt, F.; J. Yuan, K. Strebhardt (2005). “Polo-like kinases and oncogenesis”. Oncogene 24 (2): 267–76. doi:10.1038/sj.onc.1208273. ISSN (Print) 0950-9232 (Linking) 0950-9232 (Print) 0950-9232 (Linking). PMID 15640842.
Weichert, W.; A. Ullrich, M. Schmidt, V. Gekeler, A. Noske, S. Niesporek, A. C. Buckendahl, M. Dietel, C. Denkert (2006). “Expression patterns of polo-like kinase 1 in human gastric cancer”. Cancer Sci 97 (4): 271–6. ISSN (Print) 1347-9032 (Linking) 1347-9032 (Print) 1347-9032 (Linking).
Liu, X.; R. L. Erikson (2003). “Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells”. Proc Natl Acad Sci U S A 100 (10): 5789–94. doi:10.1073/pnas.1031523100.ISSN (Print) 0027-8424 (Linking) 0027-8424 (Print) 0027-8424 (Linking). PMC 156279. PMID 12732729.
Schmit, T. L.; N. Ahmad (2007). “Regulation of mitosis via mitotic kinases: new opportunities for cancer management”. Mol Cancer Ther 6 (7): 1920–31. ISSN (Print) 1535-7163 (Linking) 1535-7163 (Print) 1535-7163 (Linking).
Rudolph, D.; M. Steegmaier, M. Hoffmann, M. Grauert, A. Baum, J. Quant, C. Haslinger, P. Garin-Chesa, G. R. Adolf (2009). “BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity”. Clin Cancer Res 15 (9): 3094–102. ISSN (Print) 1078-0432 (Linking) 1078-0432 (Print) 1078-0432 (Linking).
ClinicalTrials.gov (2011). “Clinical Trials.gov Search of: Volasertib”. Missing or empty |url= (help)
Gil, T.; P. Schöffski, A. Awada, H. Dumez, S. Bartholomeus, J. Selleslach, M. Taton, H. Fritsch, P. Glomb, Munzert G.M. (2010). “Final analysis of a phase I single dose-escalation study of the novel polo-like kinase 1 inhibitor BI 6727 in patients with advanced solid tumors”. J Clin Oncol 28.
Bug, G.; R. F. Schlenk, C. Müller-Tidow, M. Lübbert, A. Krämer, F. Fleischer, T. Taube, O. G. Ottmann, H. Doehner (2010). “Phase I/II Study of BI 6727 (volasertib), An Intravenous Polo-Like Kinase-1 (Plk1) Inhibitor, In Patients with Acute Myeloid Leukemia (AML): Results of the Dose Finding for BI 6727 In Combination with Low-Dose Cytarabine”. 52nd ASH Annual Meeting and Exposition. Orange County Convention Centre, Florida: American Society of Haematology.

VOLASERTIB TRIHYDROCHLORIDE

CHEMICAL NAMES
1. Benzamide, N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-
ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-
methoxy-, hydrochloride (1:3)
2. N-{trans-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-4-{[(7R)-7-ethyl-5-methyl-8-
(1-methylethyl)-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxybenzamide
trihydrochloride

MOLECULAR FORMULA C34H50N8O3 . 3 HCl
MOLECULAR WEIGHT 728.2

SPONSOR Boehringer Ingelheim Pharmaceuticals, Inc.
CODE DESIGNATION BI 6727 CL3
CAS REGISTRY NUMBER 946161-17-7

Volasertib is a highly potent and selective inhibitor of the serine-threonine Polo like kinase 1 (Plk1), a key regulator of cell-cycle progression. Volasertib is a dihydropteridinone derivative with distinct pharmacokinetic (PK) properties. The problem underlying this invention was to develop improved dosage schedules for combination therapy of advanced and/or metastatic solid tumours.

Volasertib (I) is known as the compound N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-methoxy-benzamide,

This compound is disclosed in WO 04/076454. Furthermore, trihydrochloride salt forms and hydrates thereof are known from WO 07/090844. They possess properties which make those forms especially suitable for pharmaceutical use. The above mentioned patent applications further disclose the use of this compound or its monoethanesulfonate salt for the preparation of pharmaceutical compositions intended especially for the treatment of diseases characterized by excessive or abnormal cell proliferation.

U.S. 8,188,086

Several dihydropteridione derivatives effectively prevent cell proliferation. G. Linz and co-inventors report a comprehensive method for preparing pharmacologically active crystalline and anhydrous forms of compound 1 (Figure 1) that are suitable for drug formulations.

The inventors list several criteria for the properties of 1 and its manufacturing procedure:

favorable bulk characteristics such as drying times, filterability, solubility in biologically acceptable solvents, and thermal stability;
purity of the pharmaceutical composition;
low hygroscopicity;
no or low tendency toward polymorphism; and
scalability to a convenient commercial process.

They describe their finding that the tri-HCl salt of 1 satisfies these criteria as “surprising”.

Free base 1 is prepared by condensing cyclopropylmethylpiperazine derivative 2 with pteridinone 3 in the presence of p-toluenesulfonic acid (TsOH), as shown in Figure 1. After the reaction is complete, the crude free base 1 is recovered as a viscous oil. It is then treated with HCl in an organic solvent to form 1·3HCl, isolated in 91% yield. Alternatively, the free base is not isolated; instead, concd HCl is added to the reaction mixture, followed by acetone. The crude salt is recovered in 92% yield.

The salt is purified by crystallization from refluxing EtOH, adding water, and cooling to precipitate the crystals. The inventors do not report the purity of this or any other reaction product.

The inventors obtained a hydrated form of the tri-HCl salt by dissolving the free base in EtOH at room temperature, followed by adding concd HCl and cooling to 2 °C. An anhydrous form can be recovered by drying the hydrate at 130 °C. The solubility of the hydrated salt in aqueous and organic media is reported, as are X-ray diffraction data for the hydrated form. The hydrated salt has good solid-state stability.

The patent also contains the syntheses of reactants 2 and 3 (Figures 2 and 3). The preparation of 2 begins with the formation of amide 7. Acid 4 is treated with SOCl₂–DMF to form acid chloride 5; the crude product is added to a suspension of chiral difunctionalized cyclohexane 6 in THF and aq K₂CO₃ to produce 7. The crude product is recovered in 98% yield and oxidized to 8 with RuCl₃ and N-methylmorpholine N-oxide (NMMO) in 91% yield.

Amide 8 reacts with cyclopropylmethylpiperazine 9 in the presence of methanesulfonic acid (MsOH). The solvent is evaporated, and the reaction mixture is treated with NaBH₄. After further workup, product 10 is isolated in 46% yield. The nitro group is then hydrogenated over Raney Ni to give 2 in 90% yield. An alternative method for preparing10 is also described.

To prepare 3, readily available amino acid 11 is esterified and alkylated to form 12. In a multistep, one-pot procedure, 11 is first treated with HC(OMe)₃ and SOCl₂. Further reaction with NaBH(OAc)₃, acetone, and NH₄OH produces 12 as its HCl salt in 90% yield. The salt is treated with aq NaOH to form the free base, which reacts with pyrimidine 13 in the presence of NaHCO₃ to form 14 in 79% isolated yield.

The pteridinone system is formed by hydrogenating 14 over a Pt/C catalyst in the presence of V(acac)₃. Precursor 15 is recovered in 90% yield and methylated with (MeO)₂CO and K₂CO₃ to give 3 in 82% isolated yield.

The inventors succeeded in developing a route for making a crystalline salt that is suitable for preparing pharmaceutical formulations. The many synthetic steps, however, use a large number of solvents that are frequently evaporated to dryness. [This observation implies that the processes have a significant environmental burden. —Ed.] (Boehringer Ingelheim International [Ingelheim am Rhein, Germany]. US Patent U.S. 8,188,086,

FDA accepts new drug application for investigational compound Epanova for the treatment of severe hypertriglyceridaemia

September 19, 2013 1:18 am / 3 Comments on FDA accepts new drug application for investigational compound Epanova for the treatment of severe hypertriglyceridaemia

LONDON, Sept. 18, 2013 – AstraZeneca today announced that the US Food and Drug Administration (FDA) has accepted for review a New Drug Application (NDA) for EpanovaTM, an investigational compound for the treatment for patients with severe hypertriglyceridaemia (triglyceride levels greater than or equal to 500mg/dL). The NDA submission for Epanova was filed by Omthera Pharmaceuticals, now a wholly-owned subsidiary of AstraZeneca, as a 505(b)(1) application in July 2013. The Prescription Drug User Fee Act (PDUFA) goal date for the FDA is 5 May 2014.http://www.pharmalive.com/fda-accepts-astrazeneca-nda-for-epanova

Genzyme’s multiple sclerosis treatment approved by European Commission

September 18, 2013 3:36 am / Leave a comment

Alemtuzumab
Sanofi and its subsidiary Genzyme have been given marketing approval by the European Commission for Lemtrada (alemtuzumab), a treatment for multiple sclerosis. read all at

click on title below

Genzyme’s multiple sclerosis treatment approved by European Commission

http://www.pharmaceutical-technology.com/news/newsgenzymes-multiple-sclerosis-treatment-approved-by-european-commission?WT.mc_id=DN_News

Generic versions of high cholesterol drug Lovaza can be developed, rules judge

September 17, 2013 7:45 am / 2 Comments on Generic versions of high cholesterol drug Lovaza can be developed, rules judge

LOVAZA, a lipid-regulating agent, is supplied as a liquid-filled gel capsule for oral administration. Each 1-gram capsule of LOVAZA (omega-3-acid ethyl esters) contains at least 900 mg of the ethyl esters of omega-3 fatty acids. These are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA – approximately 465 mg) and docosahexaenoic acid (DHA – approximately 375 mg).

The structural formula of EPA ethyl ester is:

The empirical formula of EPA ethyl ester is C22H34O2, and the molecular weight of EPA ethyl ester is 330.51.

The structural formula of DHA ethyl ester is:

The empirical formula of DHA ethyl ester is C24H36O2, and the molecular weight of DHA ethyl ester is 356.55.

LOVAZA capsules also contain the following inactive ingredients: 4 mg α-tocopherol (in a carrier of partially hydrogenated vegetable oils including soybean oil), and gelatin, glycerol, and purified water (components of the capsule shell).

Lovaza

A US appeals court ruled on this week that drug companies can develop generic versions of fish oil-derived, high-cholesterol drug Lovaza.

read all at

http://www.pharmaceutical-technology.com/news/newsgeneric-versions-high-cholesterol-drug-lovaza-developed-rules-judge?WT.mc_id=DN_News

Lovaza is a brand name prescription drug. The capsule sold by GlaxoSmithKline but developed by Reliant Pharmaceuticals, contains esterified fish oils and is approved by the U.S. Food and Drug Administration to lower very high triglyceride levels. It is metabolized intoOmega-3 fatty acids. It is a dietary supplement that has been purified, chemically altered, branded, and been put through the approval process of the U.S. Food and Drug Administration (FDA); in these respects it is considered a pharmaceutical. Due to the esterification process during manufacturing there is no risk of contamination^{[citation needed]} by methyl mercury, arsenic,^[1] or other pollutants that are often seen in the world’s oceans. Each 1-gram capsule is 38% DHA, 47% EPA, and 17% other fish oils in the form of the ethyl ester.

Lovaza is named Omacor in Europe (and this name was once used in the US).^[2]

Effectiveness

Lovaza is approved in the U.S. for treatment of patients with very high triglycerides (hypertriglyceridemia).^[3]

In the European markets and other major markets outside the US Lovaza is known as Omacor, and is indicated for:

Hypertriglyceridemia. Used as monotherapy, or in combination with a statin for patients with mixed dyslipidemia.
Secondary prevention after myocardial infarction (heart attack)

in addition to other standard therapy (e.g. statins, antiplatelets medicinal products, beta-blockers, and ACE-I).

Lovaza has been demonstrated to reduce triglycerides in patients with high or very high triglycerides. ^[3]

Lovaza has also been demonstrated to reduce VLDL-cholesterol and non-HDL-cholesterol, and increase HDL-cholesterol. But, it can raise LDL-cholesterol up to 45%.^[4] The LDL raising activity correlates with a reduction in ApoB levels, though. Lovaza, through the stimulation of Lipoprotein Lipase, seems to stimulate the production of less atherogenic LDL species. In some patients, it can elevatealanine transaminase levels, so liver enzymes should be checked, periodically.^[4]

Effects on significant patient outcomes such as acute myocardial infarction, stroke, cardiovascular and all-cause mortality have been studied in patients who have suffered a myocardial infarction (this is in the US; however, data from GISSI-P showed a combined end-point of all-cause death, non-fatal MI, and non-fatal stroke was significantly reduced by 15%). Lovaza has not been shown to lower the rates of all cause mortality and cardiovascular mortality, or the combination of mortality and non-fatal cardiovascular events.^[3]

GlaxoSmithKline‘s patent expired in September 2012. Generic versions may be made available at that time. Other DHA/EPA products containing similar amounts of Omega-3 fatty acids are currently sold over the counter in the United States as dietary supplements.

Competitors

In July 2012, Amarin Corporation received U.S. FDA marketing approval for Vascepa, also referred to as AMR-101.^[5] Vascepa will undoubtedly become a major competitor for Lovaza.^[6] In clinicial trials, Vascepa was shown to lower triglycerides; while Lovaza also lowers the triglyceride concentration, Vascepa also lowers LDL-C; Lovaza does not. Lovaza was approved to treat people with very high triglyceride levels (>500 mg/dl), Vascepa is also approved for this market; however the company has also demonstrated that the drug can impact levels in people with high triglyceride (> 200 mg/dl and < 500 mg/dl) levels and will file an sNDA for this indication late in 2012.^[7]

In 2011, Ariix started selling an almost identical FDA-Certified Omega3 Ethyl Ester 1000 mg capsule ‘OmegaQ’ fish oil through direct marketing and online auto-ship at a discounted price, creating another major competitor for Lovaza and Amarin’s Vascepa. One capsule contains 295 mg EPA, and 235 mg DHA, but it is unique in that it is combined with 20 mg of the coenzyme CoQ-10, with reported ‘anti-aging’ effects on the cell’s telomeres, which are still under study.

Forms of Lovaza

Lovaza is available as 1-gram soft-gelatin capsules.^[8]

Active Ingredient: Omega-3-acid ethyl esters

Inactive Ingredients: Gelatin, glycerol, purified water, alpha-tocopherol (in soybean oil)

References

External links

Official website

Paclitaxel Against Cancer: A Short Review

September 16, 2013 12:11 pm / Leave a comment

Priyadarshini K^1* and ²Department of Biotechnology, Loyola Academy Degree & PG College, Secunderabad, IndiaKeerthi Aparajitha U²

http://www.omicsonline.org/paclitaxel-against-cancer-a-short-review-2161-0444.1000130.php?aid=9996

Corresponding Author :

Priyadarshini K
Department of Biotechnology
JSS College for Arts Commerce & Science
Mysore, India
E-mail: prits_bhargav88@yahoo.com

Received November 16, 2012; Accepted November 28, 2012; Published November 30, 2012

Citation: Priyadarshini K, Keerthi Aparajitha U (2012) Paclitaxel Against Cancer: A Short Review. Med chem 2:139-141. doi:10.4172/2161-0444.1000130

Copyright: © 2012 Priyadarshini K, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Cancer is a life threatening condition. Though it has been immensely studied in the field of medical research, not all attempts have been fruitful. More than half the people diagnosed with cancer receive chemotherapy. One such effective discovery leads to Paclitaxel, a Pacific Yew tree isolate. This review makes attempt at understanding a few advancements in cancer treatment using Paclitaxel since its discovery. We await the discovery of many such compounds which make an impact in cancer treatment. This review tried to discuss the various research using Paclitaxel and its efficacy against various types of cancers and stresses on the need for the research in the field of Cancer Chemotherapy.

Eisai Co. Ltd. announced that Halaven (eribulin mesylate), an anti-cancer agent, has now been launched in Russia

September 16, 2013 4:12 am / 3 Comments on Eisai Co. Ltd. announced that Halaven (eribulin mesylate), an anti-cancer agent, has now been launched in Russia

Eribulin

Eribulin mesylate

Eisai R&D Management Co., Ltd.

13/9/2013

Halaven is a novel anticancer agent discovered and developed in-house by Eisai and is currently approved in more than 50 countries, including Japan, the United States and in Europe. In Russia, Halaven was approved in July 2012 for the treatment of locally advanced or metastatic breast cancer previously treated with at least two chemotherapy regimens including an anthracycline and a taxane. Approximately 50,000 women in Russia are newly diagnosed with breast cancer each year, with this type of cancer being the leading cause of death in women aged 45 to 55 years. read all at…………………….

http://www.dddmag.com/news/2013/09/eisai-launches-halaven-cancer-drug-russia

Eribulin mesylate (Halaven; Eisai) — a synthetic analogue of the marine natural product halichondrin B that interferes with microtubule dynamics — was approved in November 2010 by the US Food and Drug Administration for the treatment of metastatic breast cancer.

Family members of the product patent, WO9965894, have SPC protection in the EU until 2024 and one of its Orange Book listed filings, US8097648, has US154 extension till January 2021.

The drug also has NCE exclusivity till November 2015.

Halichondrin B, a large polyether macrolide, was isolated 25 years ago from the marine sponge Halichondria okadai

Eribulin is an anticancer drug marketed by Eisai Co. under the trade name Halaven. Eribulin mesylate was approved by the U.S. Food and Drug Administration on November 15, 2010, to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease, including both anthracycline– and taxane-based chemotherapies.^[1] It was approved by Health Canada on December 14, 2011 for treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. ^[2]

Eribulin is also being investigated by Eisai Co. for use in a variety of other solid tumors, including non-small cell lung cancer, prostate cancer and sarcoma.^[3]

Eribulin has been previously known as E7389 and ER-086526, and also carries the US NCI designation NSC-707389.

Eribulin mesylate is an analogue of halichondrin B, which in 1986 was isolated from the marine sponge Halichondria okadai toxic Pacific.Halichondrin B has a significant anti-tumor activity. The Eribulin synthetically obtained has a simpler but still complex molecular structure.Taxanes such as to inhibit the spindle apparatus of the cell, but it is engaged in other ways.

Patent Data

Appl No	Prod No	Patent No	Patent Expiration	Drug Substance Claim	Drug Product Claim	Patent Use Code
N201532	001	6214865	Jul 20, 2023	Y
N201532	001	6469182	Jun 16, 2019			U – 1096
N201532	001	7470720	Jun 16, 2019		Y
N201532	001	8097648	Jan 22, 2021			U – 1096

Exclusivity Data

Appl No	Prod No	Exclusivity Code	Exclusivity Expiration
N201532	001	NCE	Nov 15, 2015

The substance inhibits the polymerization of tubulin into microtubules and encapsulates tubulin molecules in non-productive aggregates from. The lack of training of the spindle apparatus blocks the mitosis and ultimately induces apoptosis of the cell. Eribulin differs from known microtubule inhibitors such as taxanes and vinca alkaloids by the binding site on microtubules, also it does not affect the shortening. This explains the effectiveness of the new cytostatic agent in taxane-resistant tumor cell lines with specific tubulin mutations.

Structure and mechanism

Structurally, eribulin is a fully synthetic macrocyclic ketone analogue of the marine sponge natural product halichondrin B,^[4]^[5] the latter being a potent naturally-occurring mitotic inhibitor with a unique mechanism of action found in the Halichondria genus of sponges.^[6]^[7] Eribulin is a mechanistically-unique inhibitor of microtubule dynamics,^[8]^[9] binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules.^[10] Eribulin exerts its anticancer effects by triggering apoptosis of cancer cells following prolonged and irreversible mitotic blockade.^[11]^[12]

A new synthetic route to E7389 was published in 2009.^[13]

References

^“FDA approves new treatment option for late-stage breast cancer” (Press release). USFDA. 2010-11-15. Retrieved November 15, 2010.
^Notice of Decision for HALAVEN
^http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389
^ Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA (February 2001). “In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B”. Cancer Res.61 (3): 1013–21. PMID 11221827.
^ Yu MJ, Kishi Y, Littlefield BA (2005). “Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B”. In Newman DJ, Kingston DGI, Cragg, GM. Anticancer agents from natural products. Washington, DC: Taylor & Francis. ISBN 0-8493-1863-7.
^ Hirata Y, Uemura D (1986). “Halichondrins – antitumor polyether macrolides from a marine sponge”. Pure Appl. Chem.58 (5): 701–710. doi:10.1351/pac198658050701.
^ Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E (August 1991). “Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data”. J. Biol. Chem.266 (24): 15882–9. PMID 1874739.
Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L (July 2005). “The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth”. Mol. Cancer Ther.4 (7): 1086–95. doi:10.1158/1535-7163.MCT-04-0345. PMID 16020666.
Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA (July 2008). “Inhibition of Centromere Dynamics by Eribulin (E7389) during Mitotic Metaphase”. Mol. Cancer Ther.7 (7): 2003–11. doi:10.1158/1535-7163.MCT-08-0095. PMC 2562299. PMID 18645010.
Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA (February 2010). “Eribulin Binds at Microtubule Ends to a Single Site on Tubulin to Suppress Dynamic Instability”. Biochemistry49 (6): 1331–7. doi:10.1021/bi901810u. PMC 2846717. PMID 20030375.
Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, Littlefield BA (August 2004). “Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389”. Cancer Res.64 (16): 5760–6. doi:10.1158/0008-5472.CAN-04-1169. PMID 15313917.
^ Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, Zhu X, Lewis BM, Kishi Y, Yu MJ, Littlefield BA (January 2011). “Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions”. Cancer Res.71 (2): 496–505. doi:10.1158/0008-5472.CAN-10-1874. PMID 21127197.
^ Kim DS, Dong CG, Kim JT, Guo H, Huang J, Tiseni PS, Kishi Y (November 2009). “New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach”. J. Am. Chem. Soc.131 (43): 15636–41. doi:10.1021/ja9058475. PMID 19807076.

HALAVEN (eribulin mesylate) Injection is a non-taxane microtubule dynamics inhibitor. Eribulin mesylate is a synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria okadai. The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-7,9-ethano12,15-methano-9H,15H-furo[3,2-i]furo[2′,3′:5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, 2[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt).

It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C₄₀H₅₉NO₁₁ •CH₄O₃S. Eribulin mesylate has the following structural formula:

HALAVEN® (eribulin mesylate) Structural Formula Illustration

HALAVEN is a clear, colorless, sterile solution for intravenous administration. Each vial contains 1 mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95).

complete syn is available here

http://www.sciencedirect.com/science/article/pii/S0968089611010674

http://www.drugdevelopment-technology.com/projects/halaven-cancer/halaven-cancer1.html

Nitrogen: dark blue, oxygen: red, hydrogen: light blue
graphics: Wurglics, Frankfurt am Main

……………….

Macrocyclization process for preparing a macrocyclic intermediate of halichondrin B analogs, in particular eribulin, from a non-macrocyclic compound, using a carbon-carbon bond-forming reaction.

http://www.pnas.org/content/108/17/6699/F1.expansion.html

http://www.nature.com/nrd/journal/v8/n1/fig_tab/nrd2487_F6.html

UPDATED

WO 2015066729

Eisai has developed and launched eribulin mesylate for treating breast cancer. Follows on from WO2014208774, claiming use of a combination comprising eribulin mesylate and lenvatinib mesylate, for treating cancer.

Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin B

By: Fang, Francis G.; Kim, Dae-Shik; Choi, Hyeong-Wook; Chase, Charles E.; Lee, Jaemoon

Assignee: Eisai R&D Management Co., Ltd., Japan

The invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Horner-Wadsworth-Emmons olefination), Dieckmann reaction, catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate. The invention also provides compds. useful as intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof and methods for prepg. the same.

WO2012129100A1 *	Mar 16, 2012	Sep 27, 2012	Eisai R&D Management Co., Ltd.	Methods and compositions for predicting response to eribulin
WO2012166899A2 *	May 31, 2012	Dec 6, 2012	Eisai R&D Management Co., Ltd.	Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
CA2828946A1 *	Apr 16, 2012	Oct 26, 2012	Eisai R&D Management Co., Ltd.	Therapeutic agent for tumor
US7982060 *	Jun 3, 2005	Jul 19, 2011	Eisai R&D Management Co., Ltd.	Intermediates for the preparation of analogs of Halichondrin B

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.

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How Long Is A Drug Patent Good For?

September 15, 2013 3:22 am / 7 Comments on How Long Is A Drug Patent Good For?

Patents are good for 20 years after the invention of a drug–not after the drug comes to market. It can easily take eight years for the pharmaceutical companies to gather enough data to get approval for their new invention from the U.S. Food and Drug Administration. Meanwhile the FDA can send the drug company back for more clinical studies (experiments using humans as subjects to test the drugs’ efficacy and side effects) and more data, and all the while the patent clock is ticking.

That’s why the name of the game for pharmaceutical companies is working to extend those patents for a top-selling drug

read all at

How Long Is A Drug Patent Good For? – Drugsdb.com http://www.drugsdb.com/blog/how-long-is-a-drug-patent-good-for.html#ixzz2evb9L5rn

FDA grants Arzerra ‘breakthrough’ designation for use with chlorambucil in CLL

September 15, 2013 2:57 am / 3 Comments on FDA grants Arzerra ‘breakthrough’ designation for use with chlorambucil in CLL

The FDA today granted “breakthrough therapy” designation to ofatumumab for treatment of patients with chronic lymphocytic leukemia.

The designation applies to use of ofatumumab (Arzerra, GlaxoSmithKline) in combination with chlorambucil in patients with untreated CLL who unsuitable for fludarabine-based therapy.

Ofatumumab is a human monoclonal antibody that targets an epitope on the CD20 molecule encompassing parts of the small and large extracellular loops.

read all at

http://www.healio.com/hematology-oncology/hematologic-malignancies/news/online/%7b7ad941c8-330f-45db-a359-381088d89808%7d/fda-grants-arzerra-breakthrough-designation-for-use-with-chlorambucil-in-cll

MACITENTAN , 马昔腾坦 , ماسيتانتان , Мацитентан , マシテンタン

September 15, 2013 1:40 am / 4 Comments on MACITENTAN , 马昔腾坦 , ماسيتانتان , Мацитентан , マシテンタン

MACITENTAN

N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide,

N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl] -N’-propylsulfamide

CAS NO 441798-33-0

ACT-064992, Opsumit,UNII-Z9K9Y9WMVL
Mechanism of Action: Endothelin receptor antagonist (ERA)
Date of Approval: October 18, 2013(US)
Indication: Pulmonary Hypertension (PAH)
Company: Actelion Pharmaceuticals Ltd
PCT patent application: WO2002053557

FDA N204410, MACITENTANTABLET; ORAL10MG, OPSUMIT, ACTELION PHARMS LTD

Macitentan is achiral

Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive.

Mp 135–136 °C;………….J. Med. Chem., 2012, 55 (17), pp 7849–7861, DOI: 10.1021/jm3009103/CN 104447572

R_f (silica gel, heptane:ethyl acetate 1:1) 0.44.

LC-MS: t_R = 0.79 min, [M + H]⁺ = 588.86 (major isotope).

HR-LC-MS: t_R = 1.96 min; (m + H)/z = 586.9711, found = 586.9714.

¹H NMR (CDCl₃): δ 8.51 (s, 2 H), 8.49 (s, 1 H), 7.58–7.63 (m, 2 H), 7.16–7.21 (m, 2 H), 6.88 (s, 1 H), 5.61 (t, J = 6.2 Hz, 1 H), 4.72–4.76 (m, 2 H), 4.62–4.66 (m, 2 H), 2.99 (q, J = 6.8 Hz, 2 H), 1.61 (h, J = 7.3 Hz, 2 H), 0.97 (t, J = 7.4 Hz, 3 H)……………..J. Med. Chem., 2012, 55 (17), pp 7849–7861,DOI: 10.1021/jm3009103

¹³C NMR (CDCl₃): δ 11.6, 22.7, 46.1, 65.3, 65.9, 104.8, 112.4, 123.7, 128.0, 131.7, 133.0, 155.7, 156.4, 159.7, 163.5, 166.3…………….J. Med. Chem., 2012, 55 (17), pp 7849–7861,DOI: 10.1021/jm3009103

Macitentan (Opsumit® )is a novel dual endothelin receptor antagonist that resulted from a tailored drug discovery process. Macitentan has a number of potentially key beneficial characteristics – i.e., increased in vivo preclinical efficacy vs. existing ERAs resulting from sustained receptor binding and tissue penetration properties. A clinical pharmacology program indicated a low propensity of macitentan for drug-drug interactions.

Macitentan (ACT-064992) is a tissue-targeting dual ET(A)/ET(B) endothelin (ET) receptor antagonist designed for tissue targeting. Macitentan inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ET(A) receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ET(B) receptors). In diabetic rats, chronic administration of macitentan decreased blood pressure and proteinuria and prevented end-organ damage. Treatment with macitentan enhanced the cytotoxicity mediated by paclitaxel as measured by the degree of apoptosis in tumor cells and tumor-associated endothelial cells. A Phase III clinical trial of macitentan was successfully completed in 2012.

Macitentan is an investigational drug being studied for the treatment of pulmonary arterial hypertension. It acts as a dualendothelin receptor antagonist and is being developed by Actelion.^[1] A Phase III clinical trial was successfully completed in 2012.^[2]

on 22 October 2012 – Actelion (SIX: ATLN) announced that it has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) seeking approval for macitentan (Opsumit®) for the treatment of patients with pulmonary arterial hypertension

Actelion’s experimental lung drug macitentan prolonged overall survival by more than a third according to detailed study data, which the company hopes will convince investors it has a viable follow-up product to secure its commercial future.

Europe’s largest standalone biotech company wants the drug, which treats pulmonary arterial hypertension — a disease that causes high blood pressure in the arteries of the lungs — to replace blockbuster Tracleer.

Tracleer currently makes up 87 percent of sales but loses patent protection in 2015 and has also seen its market share eroded by Gilead’s Letairis.

Pharmacokinetics

Macitentan has an active metabolite, ACT-132577, which is an oxidative depropylation product. Both macitentan and ACT-132577 are mainly excreted in form of hydrolysis products via urine (about 2/3 of all metabolites) and faeces (1/3).^[3]

Co-administration of ciclosporin has only a slight effect on the concentrations of macitentan and its active metabolite, whilerifampicin decreases the area under the curve (AUC) of the drug’s blood plasma concentration by 79%, and ketoconazoleapproximately doubles it. This corresponds to the finding that macitentan is mainly metabolised via the liver enzyme CYP3A4.^[4]

SYNTHESIS

The synthesis begins with the reaction of chlorosulfonyl isocyanate (1) (dissolved in dichloromethane at 0 ° C) with one equivalent of tert-butanol. This produces a by BOC protected Aminosulfonylchlorid (2). With one equivalent of n-propylamine (dissolved in 3 eq. Of triethylamine, dichloromethane, at 0 ° C, RT 16 h) is produced by a hydrochloric acid elimination BOC-protected sulfamide (3). This is dissolved in 5 M HCl and dioxane (4-8 h), the BOC protecting group is cleaved. The sulfamide formed (4) is potassium tert-butoxide-(dissolved in MeOH, 3h) is converted to the potassium salt (5). Tert-butoxide potassium acts as a very strong base for deprotonation. This sulfamide potassium salt reacts with the nucleophilic substituents on the heteroaromatic Dichlorpyrimidinderivat (6) (dissolved in dimethyl sulfoxide, at room temperature, RT 42-72 h) under KCl-cleavage to a Monochlorpyrimidin intermediate (7). By treatment with ethylene glycol (dissolved in dimethyl ether, potassium-tert-butoxide,), the ethylene glycol side chain is generated (8). With 2-chloro-5-bromo-pyrimidine (dissolved in tetrahydrofuran, close, at 60-75 ° C) is formed under elimination of HCl in an S _N 1 reaction Macitentan (9)…………Journal of Medicinal Chemistry 55, 2012 S. 7849-7861, doi : 10.1021 / jm3009103 .

Synthesis of Macitentan

…………………………………………….

SYNTHESIS

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………………………….

SYNTHESIS

(WO2006/051502A2, JMC2012, 7849). Chlorosulfonyl isocyanate ( 1 ) reaction with tert-butyl alcohol 2 , which is then reacted with n-propylamine 3 . 3 de-boc protected through the acid after reaction with potassium t-butoxide 4 . Another compound 5 with NaH after acidic protons off with dimethyl carbonate ( 6 ) to obtain 7 . 7 and formamidine hydrochloride ( 8 ) to ring chlorinated later POCl3 9 . 9 and 4 SNAr reaction occurs 10 . 10under basic conditions with ethylene glycol SNAr reaction occurs again in alkaline conditions with11 SNAr reaction occurs MACITENTAN.

………………………

http://www.google.com/patents/WO2014155304A1?cl=en

LC-MS (Agilent MS detector G1956B with Agilent 1200 Binary Pump and DAD).

Parameters of the LC-MS method:

Injection volume: 2 |jL

Column: Kinetex C18, 2.6 μιη, 2.1 x 50 mm

Column flow rate: 1 mL/min

Eluents: Eluent A: water + 0.08% TFA

Eluent B: MeCN + 0.012% TFA

Gradient: 2.0 min 95% B

2.8 min 95% B

3.0 min 5% B

Temperature: 40°C Detector wavelength 210 nm

Preparation B: N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]- 4-pyrimidinyl] -N’-propylsulfamide (macitentan):

N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane- 1-sulfamide (200 g; 0.46 mol; see Example 2 or 3) and 5-bromo-2-chloropyrimidine (117 g; 0.60 mol; 1.3 eq) were dissolved in toluene (3 L) and DMF (400 mL). The reaction mixture was warmed up to 50°C and toluene (approx. 400 mL) was distilled our under reduced pressure. The mixture was cooled to 0 °C and tBuOK (156 g, 3 eq, 1.38 mol) was added portionwise. It was stirred at 20 °C for 1 h. Water (1 L) was added and the pH of the solution was adjusted to 3-5 using 33% aq. HC1. The mixture was heated to 50°C and the layers were separated. The org. phase was treated with charcoal at 50°C and filtered over Celite. The filter cake was rinsed with toluene. At 50°C, water (1 L) was added to the org. layer. The layers were separated. The org. layer was concentrated under reduced pressure to a total volume of 1 L and cooled to 0°C. The solid obtained was filtered off. It was rinsed with toluene and MeOH. The crude material was suspended in EA (1 L) and heated to 50°C. 300 mL of EA were distilled out and MeOH (400 mL) was added. The suspension was cooled down to 0°C. The solid was filtered off, rinsed with MeOH and dried under reduced pressure to afford the title compound as a white solid (225 g; 83% yield).

……………………

PAPER

http://pubs.acs.org/doi/abs/10.1021/jm3009103

J. Med. Chem., 2012, 55 (17), pp 7849–7861

DOI: 10.1021/jm3009103

Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ET_A with significant affinity for the ET_B receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension

N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (17)

………………………….. to give 17 (11.99 g, 88%) as a white powder;

mp 135–136 °C; R_f (silica gel, heptane:ethyl acetate 1:1) 0.44.

LC-MS: t_R = 0.79 min, [M + H]⁺ = 588.86 (major isotope).

HR-LC-MS: t_R = 1.96 min; (m + H)/z = 586.9711, found = 586.9714.

¹³C NMR (CDCl₃): δ 11.6, 22.7, 46.1, 65.3, 65.9, 104.8, 112.4, 123.7, 128.0, 131.7, 133.0, 155.7, 156.4, 159.7, 163.5, 166.3.

……………

WO 2015004265 click

Example 3 : N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)pr opane- 1- sulfamide (reaction in and work-up with MIBK):

EG (124 mL, 3.7 mol, 6.0 eq.) was added to a warm (40-50°C) suspension of the compound of Preparation A (150 g, 0.37 mol) in MIBK (600 mL). Solid KOtBu (114 g, 1.11 mol, 3.0 eq.) was added portionwise so that IT < 60°C. The mixture was stirred for

2- 3 h at 100-105°C. After completion of the reaction (LC-MS control), it was cooled to 50 °C. A 40%) aq. solution of citric acid monohydrate (300 mL) was added until pH 4 was reached. The layers were separated. The org. phase was washed with water (450 mL) and the layers were separated. Water (450 mL) was added and the mixture was warmed to 50°C. It was stirred at 50°C for 5 min. The layers were separated. The org. phase was concentrated under vacuum at 50°C until 200 mL of MIBK were removed. Hept (800 mL) was added dropwise at 70-75°C until turbidity was observed. The mixture was seeded with an analytically pure sample of N-(5-(4-bromophenyl)-6-(2 hydroxy ethoxy)pyrimidin-4-yl)propane-l-sulfamide and stirred at 60-65°C for 30 min. It was allowed to cool to 5°C within 5 h. It was filtered off, rinsed with a cold MIBK/Hept mixture (300 mL, 1 : 1) and dried under vacuum at 50°C to yield the title compound as a white solid (121 g; 76% yield).

The product had NMR data equivalent to those reported in Bolli et al, J. Med. Chem. (2012), 55, 7849-7861. [M+H]⁺ = 430 and 432. LC-MS: t_R = 1.46 min; purity: 98.4% a/a. Residual ethylene glycol (GC-FID): 530 ppm.

…….

CN 104447572 click

(l) Martin H. Bolli et al. Reported the synthesis of Marcy cefotetan follows:

[0008] The method W 5- (4- desert phenyl) -4,6-dichloro-chewing clever as a starting material, N- propyl amine Lai ugly bell in DMS0 as a reaction solvent, an alcohol bell as t a base under substitution reaction conditions, the reaction temperature needs of 24-7 to give

The intermediate compound 15, compound 15 in hexylene glycol dimethyl off as the reaction solvent, a tertiary alcohol under conditions with a strong base clock as hexanediol substitution reaction, l〇 (TC Reaction of 18-2 to give compound 17, Compound 17 was then reacted with 5-chloro-chewing desert -2 clever substitution reaction at tetraammine Qiao Nan as a reaction solvent, ammoniated axis as the alkali conditions, the reaction to give the final product of Marcy cefotetan The route every step the higher the yield, the experimental use of N- propyl amine Lai ugly bell hygroscopic, unstable and a long time before the two-step reaction, the reaction at the second step requires l〇 (TC high temperature 18-2 technology is not suitable for industrial production.

[0009] International Patent W02002 / 053557 discloses some preparation methods and other Massey cefotetan column derivative method at each step of the preparation of the reaction times are longer, some reactions up to 4 days, and the resulting intermediate are purified by column chromatography method is not suitable for industrial production.

A method for preparing Marcy cefotetan, comprising the steps of: (1) the compound of formula II with N- cyclopropyl sulfonamide compound of formula III 5- (4- bromophenyl) -4, 6- dichloropyrimidine substitution reaction is converted to the formula IV:

Compound (2) in the presence of a strong base of formula IV with a compound of formula V glycol substitution reaction to give a compound of formula VI:

Compound (3) a strong base of formula VI in the presence of a substitution reaction conditions to give a compound of formula I with a compound of formula W occurs:

, The resulting compound of formula I as Marcy cefotetan.

[00 pairs (3) N- [5- (4- desert) -6-mouth – [(5-desert -2- chew clever-yl) oxy] hexyl oxy] -4-chewing clever yl] -N ‘- Lai ugly propyl amine (Formula I) Synthesis

[0036] Weigh 20gN-5- (4- desert) -6- (2-2- light hexyl group -) 4- chew clever group -N ‘- Lai ugly propyl amine, 200ml dried DMS0 added to 1L H jar, add 20g of alcohol t-clock was added in portions, then add 17. 7g5- desert – dichloro chew clever, 30-4 (TC reduction reaction, the reaction and the reaction solution. a 10% sample skillfully acid to adjust PH value 3 to 4, the reaction mixture was added to 1000ml water, olive mix, suction. suction Massey cefotetan get wet crude product 42g, 450ml of methanol was added at room temperature and then beating 20min, filtration and dried 45C to give white solid was dried under vacuum to give 23.2 Marcy cefotetan yield;.. 85%

[0037] The compound (Formula I) relating to the physical and chemical properties, spectroscopic data are as follows:

[0038] branded point; 135-136 ° C; we NMR (300MHz, DMS0) 5 (egg m):… 9 8 (s, lH), 8 7 (s, 2H), 8 5 (s, l H,) 7. 5 (s, 2H), 7. 2 (s, IH), 7. 1 (s, 2H,) 4. 7 (s, 2H), 4. 6 (s, 2H,) 2. 8 (s, 2H,), 1. 5 (m, 2H,), 0. 81 (m, 3H), MS Qiaoqiao m / z 589 ([M + Tin +).

…………

see

WO 2002053557

http://www.google.com/patents/WO2002053557A1?cl=en

………..

NMR spectroscopy

Assignment of the signals mentioned in the text of the H-NMR spectrum of the drug Macitentan

¹ H-NMR

Solvent: CDCl ₃

δ 8.51 (s, 2H, CH) ¹¹ , 8.49 (s, 1 H, CH) ¹⁰ , 7.58 to 7.63 (m, 2H, CH) ⁹ , 7.16 to 7.21 ( m, 2H, CH) ⁸ , 6.88 (s, 1H, NH) ⁷ , 5.61 (t, J = 6.2 Hz, 1H, NH) ⁶ , 4.72 to 4.76 (m, 2H , CH ₂ ) ⁵ , 4.62 to 4.66 (m, 2H, CH ₂ ) ⁴ , 2.99 (q, J = 6.8 Hz, 2H, CH ₂ ) ³ , 1.61 (h, J = 7.3 Hz, 2H, CH₂ ) ² , 0.97 (t, J = 7.4 Hz, 3H, CH ₃ ) ¹ . ^{[Journal of Medicinal Chemistry 55, 2012 S. 7849-7861, doi : 10.1021 / jm3009103 .]}

……………………………………………………………………………………

Gatfield, John; Grandjean, Celia Mueller; Bur, Daniel; Bolli, Martin H.; Nayler, Oliver (2014): Proton assignment in macitentan as used in NMR interpretation.Figure_9.tif. PLOS ONE. 10.1371/journal.pone.0107809.g009.

¹³ C-NMR

Solvent: CDCl ₃

δ 11.6, 22.7, 46.1, 65.3, 65.9, 104.8, 112.4, 123.7, 128.0, 131.7, 133.0, 155.7, 156 , 4, 159.7, 163.5, 166.3. ^{[ Journal of Medicinal Chemistry 55, 2012 S. 7849-7861, doi : 10.1021 / jm3009103 . ]}

NMR PREDICT BY ME

1H NMR PREDICT

13C NMR PREDICT BY ME

COSY PREDICT BY ME, WORLDDRUGTRACKER ON A WHEELCHOPPER SCALING NEW HEIGHTS

REFERENCES

Bolli, M. H.; Boss, C.; Binkert, C.; Buchmann, S.; Bur, D.; Hess, P.; Iglarz, M.; Meyer, S.; Rein, J.; Rey, M.; Treiber, A.; Clozel, M.; Fischli, W.; Weller, T. (2012). “The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist”. Journal of Medicinal Chemistry 55 (17): 7849–7861. doi:10.1021/jm3009103. PMID 22862294.
“Macitentan”. Actelion. Retrieved 22 August 2012.
Bruderer, S.; Hopfgartner, G. R.; Seiberling, M.; Wank, J.; Sidharta, P. N.; Treiber, A.; Dingemanse, J. (2012). “Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans”. Xenobiotica 42 (9): 901–910.doi:10.3109/00498254.2012.664665. PMID 22458347.
Bruderer, S.; Äänismaa, P. I.; Homery, M. C.; Häusler, S.; Landskroner, K.; Sidharta, P. N.; Treiber, A.; Dingemanse, J. (2011).“Effect of Cyclosporine and Rifampin on the Pharmacokinetics of Macitentan, a Tissue-Targeting Dual Endothelin Receptor Antagonist”. The AAPS Journal 14 (1): 68–78. doi:10.1208/s12248-011-9316-3. PMC 3282010. PMID 22189899.
Bolli, M. H.; Boss, C.; Binkert, C.; Buchmann, S.; Bur, D.; Hess, P.; Iglarz, M.; Meyer, S.; Rein, J.; Rey, M.; Treiber, A.; Clozel, M.; Fischli, W.; Weller, T. (2012). “The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist“. Journal of Medicinal Chemistry, 2012, 55 (17): 7849–7861
Martin Bolli, Christoph Boss, Martine Clozel, Walter Fischli, Thomas Weller, Novel sulfamides and their use as endothelin receptor antagonists, WO2002053557 A1, CA2431675A1, CA2431675C, CN1524079A, CN100432070C, DE60118782D1, DE60118782T2, EP1345920A1, EP1345920B1, EP1693372A1, US7094781, US7285549, US20040077670, US20060178365,
Martin Bolli, Christoph Boss, Martine Clozel, Walter Fischli, Thomas Weller, Sulfamides as endothelin receptor antagonists for the treatment of cardiovascular diseases, WO2006051502
Martine Clozel, Therapeutic compositions containing macitentan,WO2010018549 A2, CA2731370A1, CN102099026A, CN102099026B, EP2315587A2, US20110136818(WO2006/051502A2, JMC2012, 7849). Chlorosulfonyl isocyanate ( 1 ) reaction with tert-butyl alcohol 2 , which is then reacted with n-propylamine 3 . 3 de-boc protected through the acid after reaction with potassium t-butoxide 4 . Another compound 5 with NaH after acidic protons off with dimethyl carbonate ( 6 ) to obtain 7 . 7 and formamidine hydrochloride ( 8 ) to ring chlorinated later POCl3 9 . 9 and 4 SNAr reaction occurs 10 . 10under basic conditions with ethylene glycol SNAr reaction occurs again in alkaline conditions with11 SNAr reaction occurs MAXI cefotetan.

External links

Actelion home page

Actelion Ltd

Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion’s first drug Tracleer®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium – the single layer of cells separating every blood vessel from the blood stream. Actelion’s over 2,400 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SIX Swiss Exchange (ticker symbol: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMI®).

Macitentan
Systematic (IUPAC) name

N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide
Clinical data
Trade names	Opsumit
Pregnancy category	US: X (Contraindicated)
Legal status	US: ℞-only FDA approved drug
Routes of administration	Oral
Pharmacokinetic data
Metabolism	Hydrolysis, oxidation (CYP3A4)
Excretion	2/3 urine, 1/3 faeces
Identifiers
CAS Registry Number	441798-33-0
ATC code	C02KX04
PubChem	CID: 16004692
ChemSpider	13134960
ChEBI	CHEBI:76607
Synonyms	ACT-064992
Chemical data
Formula	C₁₉H₂₀Br₂N₆O₄S
Molecular mass	588.273 g/mol

Patent	Submitted	Granted
Sulfamides and their use as endothelin receptor antagonists [US7094781]	2004-04-22	2006-08-22
Sulfamides and their use as endothelin receptor antagonists [US7285549]	2006-08-10	2007-10-23
Stable Pharmaceutical Compositions Comprising a Pyrimidine – Sulfamide [US2008233188]	2008-09-25
Combination Comprising Paclitaxel for Treating Ovarian Cancer [US2010311774]	2010-12-09
Stable pharmaceutical compositions comprising a pyrimidine-sulfamide [US2010004274]	2010-01-07
SULFONYLUREA MODULATORS OF ENDOTHELIN RECEPTOR [US2011082151]	2011-04-07
ENDOTHELIN RECEPTOR ANTAGONISTS FOR EARLY STAGE IDIOPATHIC PULMONARY FIBROSIS [US2010022568]	2007-04-12	2010-01-28
THERAPEUTIC COMPOSITIONS CONTAINING MACITENTAN [US2011136818]	2011-06-09
Therapeutic Compositions Comprising a Specific Endothelin Receptor Antagonist and a PDE5 Inhibitor [US2009318459]	2009-12-24

Patent and Exclusivity

Patent Data

Appl No	Prod No	Patent No	Patent Expiration	Drug Substance Claim	Drug Product Claim	Patent Use Code
N204410	001	US7094781	Oct 12, 2022	Y	Y
N204410	001	US8268847	Apr 18, 2029			U – 1446
N204410	001	US8367685	Oct 4, 2028		Y	U – 1445

Exclusivity Data

Appl No	Prod No	Exclusivity Code	Exclusivity Expiration
N204410	001	ODE	Oct 18, 2020
N204410	001	NCE	Oct 18, 2018

U1446 METHOD OF TREATING PULMONARY HYPERTENSION COMPRISING ADMINISTERING MACITENTAN IN COMBINATION WITH A COMPOUND HAVING PHOSPHODIESTERASE-5 INHIBITORY PROPERTIES

U1445 METHOD OF TREATING PULMONARY ARTERIAL HYPERTENSION BY ADMINISTERING A PHARMACEUTICAL COMPOSITION COMPRISING MACITENTAN AND A POLYSORBATE, WHERIN THE POLYSORBATE REPRESENTS 0.1 TO 1% OF THE WEIGHT OF SAID PHARMACEUTICAL COMPOSITION

OPSUMIT (macitentan) is an endothelin receptor antagonist. The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide. It has a molecular formula of C₁₉H₂₀Br₂N₆O₄S and a molecular weight of 588.27. Macitentan is achiral and has the following structural formula:

OPSUMIT® (macitentan) Structural Formula Illustration

Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive.

OPSUMIT is available as a 10 mg film-coated tablet for once daily oral administration. The tablets include the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A. The tablets are film-coated with a coating material containing polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum.

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BENAZEPRIL HYDROCHLORIDE SYNTHESIS AND REVIEW

September 14, 2013 4:00 am / 5 Comments on BENAZEPRIL HYDROCHLORIDE SYNTHESIS AND REVIEW

BENAZEPRIL HYDROCHLORIDE, CAS NO 86541-74-4

Benazepril, brand name Lotensin (Novartis), is a medication used to treat high blood pressure (hypertension), congestive heart failure, and chronic renal failure. Upon cleavage of its ester group by the liver, benazepril is converted into its active form benazeprilat, a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor.

Dosage forms

Benazepril is available as oral tablets, in 5-, 10-, 20-, and 40-mg doses.

Benazepril is also available in combination with hydrochlorothiazide, under the trade name Lotensin HCT, and with amlodipine(trade name Lotrel).

Side effects

Most commonly, headaches and cough can occur with its use. Anaphylaxis, angioedema and hyperkalemia, the elevation of potassium levels, can also occur.

Benazepril may cause harm to the fetus during pregnancy.

According to coverage of the study on WebMD:

“

ACE inhibitors can pose a potential threat to kidneys as well. The key question was whether damaged kidneys would worsen if patients took ACE inhibitors. In a nutshell, concerns centered on blood levels of potassium andcreatinine, waste products that are excreted by the kidneys. Testing creatinine levels in the blood is used as a way to monitor kidney function (…) kidney problems worsened more slowly in those taking Lotensin. Overall, there were no major differences in side effects between patients taking Lotensin or the placebo.^[2]

”

This study marks the first indication that benazepril, and perhaps other ACE inhibitors, may actually be beneficial in the treatment of hypertension in patients with kidney disease.

The Benazepril hydrochloride, with the CAS registry number 86541-74-4, is also known as (3S)-3-(((1S)-1-Carboxy-3-phenylpropyl)amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid, 3-ethyl ester, monohydrochloride; Benazepril HCl; Cibacen; Cibacen CHF; Labopol. It belongs to the product categories of Intermediates & Fine Chemicals; Pharmaceuticals; Amines; Aromatics; Heterocycles. This chemical’s molecular formula is C₂₄H₂₉ClN₂O₅ and molecular weight is 460.96. What’s more, its IUPAC name 2-[(3S)-3-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid hydrochloride. In addition, Benazepril hydrochloride (CAS 86541-74-4) is crystalline solid which is soluble in DMSO. It is used in high blood pressure and congestive heart failure. When you are using this chemical, you should not breathe dust and avoid contact with skin and eyes.

Veterinary use

Under the brand names Fortekor (Novartis) and VetACE (Jurox Animal Health), benazepril hydrochloride is used to treat congestive heart failure in dogs and chronic renal failure in dogs and cats.

^ Hou F, Zhang X, Zhang G, Xie D, Chen P, Zhang W, Jiang J, Liang M, Wang G, Liu Z, Geng R (2006). “Efficacy and safety of benazepril for advanced chronic renal insufficiency”. N Engl J Med 354 (2): 131–40. doi:10.1056/NEJMoa053107. PMID 16407508.
^ ^a ^b Hitti, Miranda; Chang, Louise (January 11, 2006). “Drug May Treat Advanced Kidney Disease”. WebMD. Retrieved 2006-09-07.

Prescribing Information for Lotensin

	Benazepril hydrochloride, TWT-8154, CGS-14824A, Cibacene, Briem, Cibacen, Lotensin
	1-Carboxymethyl-3(S)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one monohydrochloride; 3(S)-[1(S)-Ethoxycarbonyl-3-phenylpropylamino]-2-oxo-2,3,4,5-tetrahydro-1-benzazepine-1-acetic acid monohydrochloride
【CAS】	86541-74-4, 86541-75-5 (free base)
MF	C24-H28-N2-O5.Cl-H
MW	460.9551rot–[Alpha] 20 D -141.0 °. (C = 0.9, ethanol)
	Cardiovascular Drugs, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors
	Launched-1990
	Novartis (Originator), Pierre Fabre (Licensee), Andrx (Generic), Eon Labs (Generic), KV Pharmaceutical (Generic), Mylan (Generic)

Above Preparation of Benazepril hydrochloride (CAS 86541-74-4): The reaction of 2(R)-hydroxy-4-phenyl butyric acid ethyl ester (I) with trifluoromethanesulfonic anhydride in dichloromethane gives the corresponding triflate (II), which is then condensed with the amino benzazepinone (III) by means of NMM in the same solvent to provide the target benazepril.

ABOVE SCHEME-EP 1891014 B1

BACKGROUND

Benazepril (CAS REGISTRY No. 86541-75-5) first disclosed inUS 4,410,520 is one of the well-known ACE inhibitors and is used for the treatment of hypertension.
Chemically, Benazepril, is (3S)-1-(carboxymethyl-[[(1(S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one.
Benazepril is administered orally in the form of hydrochloride salt (CAS REGISTRY No. 86541-74-4) represented by formula (I).
The preparation of benazepril disclosed in US 4,410,520 , J. Med. Chem. 1985, 28, 1511-1516, and Helvetica Chimica Acta (1988) 71, 337-342, as given in scheme 1, involves reductive amination of ethyl 2-oxo-4-phenyl butyrate (IV) with sodium salt of (3S)-3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1 H-benzazepin-2-one (III).
In example 12 of US 4,410,520 , the crude benazepril (II) obtained in a diastereomeric ratio of SS: SR=70:30 was dissolved in dichloromethane and treated with HCl gas to obtain benazepril hydrochloride. The benazepril hydrochloride of formula (I) obtained as a foam was crystallized from methyl ethyl ketone to obtain in a SS: SR=95:5 diastereomeric ratio. Benazepril hydrochloride was further purified by recrystallization from a mixture of 3-pentanone/methanol (10:1), melting point: 188-190 °C.
Alternatively, in example 27 of US 4,410,520 , benazepril hydrochloride was purified by refluxing in chloroform, filtering, and washing first with chloroform and then with diethyl ether. The melting point of benazepril hydrochloride obtained as per this example is 184-186 °C.
An alternative process disclosed in US 4,785,089 involves nucleophilic substitution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepine-2-one (V), using the chiral substrate ethyl (2R)-2-(4-nitrobenzenesulfonyl)-4-phenyl butyrate (VI) in presence of N-methylmorpholine (scheme 2). The benazepril t-butyl ester (IIa) obtained in a diastereomeric ratio of SS: SR=96:4 was hydrolyzed to benazepril (II) and converted to hydrochloride salt by treating with HCl gas in ethyl acetate. The crystalline suspension of benazepril hydrochloride in ethyl acetate was diluted with acetone and filtered to obtain in a diastereomeric ratio of SS: SR=99.1:0.9. Further purification by refluxing in ethyl acetate afforded benazepril hydrochloride in a diastereomeric ratio of SS: SR=99.7:0.3, melting point of 181 °C.
The above documents do not disclose the crystalline form of benazepril hydrochloride obtained by following the purification processes disclosed in the examples.
The Merck Index., 12^th edition reports benazepril hydrochloride crystals obtained from 3-pentanone+methanol (10:1), melting point 188-190 °C
The crystallization methods taught in the prior art does not consistently produce a constant diastereomeric composition of SS:SR diastereomer. This is evident from the variation in the melting points of the benazepril hydrochloride reported in three different working examples, which varies between 181 to 190°C.
The variation in diastereomeric composition of a pharmaceutical substance is not desirable as it would affect its efficacy. Hence there is a need for a crystallization process that consistently produce a constant diastereomeric composition of SS diastereomer in greater than 99.8%.
Coming to the crystalline form, it is well known in the art that the solid form of a pharmaceutical substance affect the dissolution rate, solubility and bioavailability. The solid form may be controlled by process employed for the manufacture of the pharmaceutical substance. In particular the process of purification of the solid substance by crystallization is used to control the solid form (Organic Process Research & Development, 2003, 7, 958-1027).
It has been found that the crystalline form of benazepril hydrochloride obtained from processes of prior art documents is designated as crystalline Form A as evident from the following documents.
In a monograph published by Al-badar et al in Profiles of Drug Substances, Excipients, and Related Methodology, Vol. 31, 2004, p117-161; benazepril hydrochloride prepared by the process disclosed in US 4,410,520 , and J. Med. Chem. 1985, 28, 1511-1516, has been characterized by powder X-ray diffraction pattern having 2θ peaks at 6.6, 9.9, 11.9, 13.7, 14.0, 14.9, 15.3, 16.4, 17.3, 18.9, 19.6, 20.2, 20.9, 21.5, 22.2, 25.2, 25.5, 26.4, 26.6, 27.1, 27.9, 29.8, 30.4, 31.0, 32.6, 33.3, 33.8, 34.4, 35.5, 38.2, 39.9, 43.9, 48.9.
The major peaks are at 6.6, 9.9, 11.9, 13.7, 14.9, 16.4, 17.3, 18.9, 19.6, 20.2, 20.9, 21.5, 25.2, 25.5, 26.4, 26.6, 27.9, 31.0, and 32.6.
WO 2004/013105 A1 also discloses that by following the processes of the prior art mentioned above, crystalline benazepril hydrochloride is isolated in a form designated as Form A having a powder X-ray diffraction pattern with 2θ values at 6.7, 10.1, 12.0, 13.8, 15.1, 16.4, 17.4, 19.0, 19.6, 20.2, 20.9, 21.0, 25.3, 25.5, 26.4, 26.6, 27.6, 28.0, 31.0, 32.7.
WO 2004/013105 A1 discloses that benazepril hydrochloride Form A may be prepared from a concentrated solution of the benazepril hydrochloride in a solvent selected from C₁-C₁₀ alcohol, N,N-dimethylformamide, N-methylpyrrolidone by adding an anti-solvent selected from C₄-C₁₂ alkane or C₁-C₁₀ acetate, preferably, hexane or ethyl acetate.
WO 2004/013105 A1 in Example 5 describes a process of making crystalline form A of benazepril hydrochloride by passing HCl gas into a solution of benazepril free base in diethyl ether and filtering the resulting suspension.
Similarly, in Example 6, the benazepril hydrochloride was dissolved in water free ethanol and the resulting solution was added to heptane at 20° C to obtain the crystalline Form A.
Further, WO 2004/013105 A1 , mentions a list of solvents and anti-solvents that can be used to make benazepril hydrochloride crystalline Form A. However, there is no enabling disclosure and the document is silent on the diastereomeric purity of the crystalline form A obtainable by the process disclosed.
The processes of crystallization and/or recrystallization disclosed in the prior art do not consistently produce benazepril hydrochloride with constant diasteromeric content as evident from the variation in the melting point of the crystalline benazepril hydrochloride obtained from crystallization from various solvents.

SYNTHETIC SCHEMES

	Benzazepin-2-ones, process for their preparation, pharmaceutical preparations containing these compounds and the compounds for therapeutical use
	Watthey, J.W.H. (Novartis AG)
	EP 0072352; GB 2103614; JP 8338260

The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I) with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (II), which is treated with sodium acetate and reduced with H2 over Pd/C in acetic acid yielding 3-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The reaction of (III) with sodium azide in DMSO affords 3-azido-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is condensed with benzyl bromoacetate (V) by means of NaH in DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI) with Raney-Ni in ethanol-water yields 3-amino-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol affording 3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VIII). Finally, this compound is condensed with ethyl 3-benzylpyruvate (IX) by means of sodium cyanoborohydride in methanol acetic acid.


	Process for the preparation of benazepril
	Kumar, Y.; De, S.; Thaper, R.K.; Kumar, D.S.M. (Ranbaxy Laboratories Ltd.)
	WO 0276375

The reaction of 2(R)-hydroxy-4-phenyl butyric acid ethyl ester (I) with trifluoromethanesulfonic anhydride in dichloromethane gives the corresponding triflate (II), which is then condensed with the amino benzazepinone (III) by means of NMM in the same solvent to provide the target benazepril.


	CGS-14824 A
	Casta馿r, J.; Serradell, M.N.
	Drugs Fut 1984,9(5),317

The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I) with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (II), which is treated with sodium acetate and reduced with H2 over Pd/C in acetic acid yielding 3-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The reaction of (III) with sodium azide in DMSO affords 3-azido-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is condensed with benzyl bromoacetate (V) by means of NaH in DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI) with Raney-Ni in ethanol-water yields 3-amino-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol affording 3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VIII). Finally, this compound is condensed with ethyl 3-benzylpyruvate (IX) by means of sodium cyanoborohydride in methanol acetic acid.


	Synthesis of 14C-labeled 3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid hydrochloride ([14C]CGS 14824A)
	Chaudhuri, N.K.; Patera, R.; Markus, B.; Sung, M.-S.
	J Label Compd Radiopharm 1987,24(10),1177-84

A new synthesis of CGS-14824A is given: The reaction of 3-bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1-tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII). The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N-alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4-phenylbutyrate (XIII) by means of sodium cyanoborohydride.

US 6548665 B2– above

see translated vesrsion————-First, 2,3,4,5 – tetrahydro-1H-[1] azepin-2 phenyl – one (2) Preparation of
the dry reaction flask, add α- tetralone 20g (0.137mol), stacked acid 7.36g (0.171mol) and chloroform 140ml, was stirred at 40 ℃ in 1h concentrated sulfuric acid was slowly added dropwise 36ml, acid layer was separated and poured into 900ml water to give a creamy solid. Recrystallization with hot water to give white crystals (2) 15.5g (70%), mp141 ℃. (Acidic filtrate and after a small amount of product can be obtained.)
Second, 3,3 – dichloro-2, 3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (3) of the prepared
in a dry reaction flask, (2) 48.3g (0.3mol) and xylene solution of 1300ml, phosphorus pentachloride 188g (0.9mol), stirred and gradually heated to at 0.5h 90 ℃, (Caution! When phosphorus pentachloride dissolved hydrogen chloride gas had severe.) 90 ℃ the reaction was continued for 0.5h, filtered to remove a small amount of suspended solids, solvent recovery under reduced pressure, to the residue was added saturated sodium bicarbonate solution, 100ml, stirred until a solid precipitate complete, filtered and the cake washed with ethanol (100ml × 2), diethyl ether (50ml) and dried to give (3) 69.0g (90%), mp185 ~ 187 ℃.
III.3 – chloro-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (4) Preparation of
the reaction flask (3) 10g (0.087mol), Sodium acetate 77g (0.11mol), acetic acid 460ml and 5% Pd-C 0.86g, under atmospheric pressure at room temperature to a hydrogen-absorbing up total of 950ml (about 0.5h). Filtration, recycling the catalyst recovered solvent, the residue was dried under reduced pressure, and then added 900ml of 10% sodium bicarbonate solution and dichloromethane 300ml, stirring, standing, the organic layer was separated and the aqueous layer extracted with dichloromethane (300ml × 3) extracted organic layers were combined, dried over anhydrous sodium sulfate, the solvent recovered under reduced pressure. Diethyl ether was added to the cured 350ml, and mashed, filtered and dried to give (4) 8.19g (95%), mp163 ~ 167 ℃.
4 (3) – azido-2, 3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (5) Preparation of
the dry reaction flask (4) 15.9g ( 0.08mol), sodium azide 6.4g (0.10mol) and 320ml solution of dimethyl sulfate, the reaction was stirred at 80 ℃ 3h, cooled to room temperature, poured into ice-water (1L) to precipitate a pale yellow solid , filtered and dried under reduced pressure at 75 ℃ to give (5) 14.7g (90%), mp142 ~ 145 ℃.
V.3 – azido-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (6) Preparation of
the dry reaction flask, (5) 3.0g (0.015mol), tetrabutylammonium bromide, 0.5g (0.0015 mol), powdered potassium hydroxide 1.1g (0.016mol) and 30ml of tetrahydrofuran solution of ethyl bromoacetate was added 1.9ml ( 0.016mol), stirred rapidly at room temperature for 1.5h (nitrogen). Water was added: dichloromethane (50:100 ml), stirred, allowed to stand, the organic layer separated. Washed with water, dried over anhydrous sodium sulfate, the solvent recovered under reduced pressure to give a pale yellow oil (6) 4.1g (96%) (can be used directly in the next step).
VI.3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (7) Preparation of
the dry reaction flask, (6 ) 20.0g (0.070mol), ethanol 100ml, 10% Pd-C 1.0g stirring, at room temperature, 303.9kPa hydrogenated under a hydrogen pressure 1.5h, intermittent deflated to remove the generated nitrogen gas, after the reaction was collected by filtration Pd / C, recovery of solvents under reduced pressure to give a yellow oil, add ether l00ml, mashed, filtered and dried to give a white solid (7) 17.0g (93%) mp101 ~ 102 ℃.
Seven, (3S) -3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (8) Preparation of
the reaction flask, adding (7) 25.1g (0.096mol), L – tartaric acid 14.4g (0.096mol) and hot ethanol 200ml, stirring to dissolve, cooled at room temperature overnight, filtered and dried under reduced pressure to give a white powder 30.7g, with ethanol Recrystallization twice (each 200ml), to give (8) tartaric acid salt of 13.6g (34%), mp168 ~ 169 ℃, with 10% ammonium hydroxide, to give a white solid (8) 8.0g (95%) mp104 ~ 106 ℃.
Eight, (3S) -3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (9) Preparation of
the reaction flask, (8) 4.0g (0.056mol) and 150ml of methanol solution of sodium hydroxide 2.1g (0.056moI) and a solution of 5ml of water, stirred at room temperature for 2h, the solvent recovered under reduced pressure, the residue was dried and diethyl ether was added 100ml, trace broken, filtered, and dried to give (9) 12.9g (89%) (used directly in the next step).
IX benazepril (1) Synthesis of
the reaction flask (9) 12.9g (0.050mol), 2 – oxo-4 – phenylbutyrate 31.0g (0.15mol), acetic acid and 100ml methanol 75ml, the reaction was stirred at room temperature for 1h (nitrogen). Of sodium borohydride cyanide was slowly added dropwise 3.8g (0.062mol) and 30ml of methanol solution of (4h was completed within), stirred overnight, heat. Concentrated hydrochloric acid 10ml, 1h stirring at room temperature, the solvent was recovered under reduced pressure, water was added to the residue and diethyl ether 400ml l00ml, dissolved with concentrated ammonium hydroxide and the pH adjusted to 9.3, the organic layer was separated and the aqueous layer acidified with concentrated hydrochloric to pH 4.3, extracted with ethyl acetate (100ml × 3) extracted organic layers were combined, dried over anhydrous magnesium sulfate, the solvent recovered under reduced pressure, to the residue was added methylene chloride (150ml) to dissolve. And pass into dry hydrogen chloride after 5min recovered solvent under reduced pressure, to the residue was added hot ethyl ketone 100ml, stirring to dissolve, cooled and precipitated solid was filtered to give crude product (1). A 3 – amyl ketone / methanol (volume ratio 10:1) (110ml) was recrystallized (1) 5.8 g, mp 188 ~ 190 ℃, [alpha] _D²⁰ -141.0 (C = 0.9, C ₂ H ₅ OH )
[Spectral Data] (free base) ^[2]
MS: m / Z (%) 424 (M ⁺ , 2), 351 (100), 190 (22), 91 (65)
] [other synthetic routes
described in the reference literature.

[References]
[1] Briggs LH et al. J Chem Soc, 1937, 456
[2] Watthey WH et al. J Med Clmm, 1985, 28:1511
[3] EP 1986, 206933 (CA, 1987, 107: 77434e)
[4] EP 1983, 72352 (CA, 1983, 99:53621 d)
[5] package insert: Lotensin
[6] property protection case I: Lotensin
[7] property protection case II: Lotensin
[8] Drug Monograph information: BENAZEPRIL

more info

Benazepril M.p. 148.5°.

Proprietary names. Briem; Cibace; Cibacen; Cibacene; Labopal; Lotensin; Tensanil; Zinandril.

C₂₄H₂₈N₂O₅,HCl=461.0

CAS—86541–74–4

A white to off–white crystalline powder. It is soluble in water, ethanol and methanol.

Partition Coefficient.

Log P(octanol/water), 3.50.

Gas Chromatography.

System GP—RI 3030 (benazepril-ME); RI 2985 (M (benazeprilate)-ME3).

Column: 3% OV-101 on Gaschrom Q, 80–100 mesh (Ciba-Geigy), pyrex glass (1.5 m × 2 mm i.d.). Column and injector port temperature: 275°. Carrier gas: helium, flow rate 30 mL/min. MS detection (EI, SIM). Retention times: benazepril (methyl ester derivative) 2.55 min; benazeprilat (derivative) 2.3 min. [G. Kaiser et al.,J. Chromatogr.,1987, 419, 123–133].

High Performance Liquid Chromatography.

System HAA—retention time 17.0 min.

Column: C₁₈ (RP-BDS, 5 μm packing, 250 × 3 mm i.d.). Mobile phase: sodium dihydrogen phosphate (0.025 M, pH 4.8):acetonitrile (55:45). 0.4 mL/min flow rate. UV detection (λ=250 nm). Retention time: benazepril hydrochloride, 4.95 min. [I. E. Panderi and M. Parissi-Polou,J. Pharm. Biomed. Anal.,1999, 21, 1017–1024].

Column: Hypersil ODS (5 μm, 250 × 4.5 mm). Mobile phase: sodium heptanesulfonate (20 mM, pH 2.5):acetonitrile (5% THF) (52:48 v/v), 1.0 mL/min flow rate. UV detection (λ=215 nm). Retention time: 15 min. [D. Bonazzi et al.,J. Pharm. Biomed. Anal.,1997, 16, 431–438].

Ultraviolet Spectrum.

Aqueous acid (0.2 M NH₂SO₄)—237 nm; basic—241 nm; aqueous acid (0.1 M hydrochloric acid)—237.2 nm (hydrochloride salt).

Reference(s):
Clarke’s Analysis of Drugs and Poisons
Watthey, J.W.H. et al.: J. Med. Chem. (JMCMAR) 28, 1511 (1985).
US 4 410 520 (Ciba-Geigy; 18.10.1983; prior. 11.8.1981, 9.11.1981, 19.7.1982).
EP 72 352 (Ciba-Geigy; appl. 5.8.1982; USA-prior. 11.8.1981, 9.11.1981).

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