Oncolytic Drugs …Preparation of (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide)

cancer Comments Off

Jan 212014

Patents– EP2111401B1

1036712-77-2 cas NO

see also WO 2008079968 BAYER

VEGFR-2 (FLK-1/KDR) Inhibitors
Bcr-Abl Kinase Inhibitors
HGFR (MET; c-Met) Inhibitors

Inhibitors of protein kinases, such as wild-type and mutations of Bcr-Abl, Flk1, c-Met, expected to be useful for the treatment of hyperproliferative and/or angiogenesis disorders such as cancer. A representative compound suppressed Flk-1, c-Met and wild type and T135I mutant Bcr-Abl enzymes with IC50 values below 1 mcM. Compound also inhibited the proliferation of K562 (IC50 = 1.58 nM) and BAF3 cells expressing wild-type and T315I, E255K, M351T and Y253F mutant Brc-Abl enzymes (IC50 = 3.84, 34.1, 503, 811 and 564 nM, respectively).

Example 1HYDROXY METHYL PHENYL PYRAZOLYL UREA (4-{4-[({3-tert-Butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide)

HYDROXY METHYL PHENYL PYRAZOLYL UREAStep 1. Preparation of ethyl 3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzoate

Sulfuric acid (concentrated, 15.7 mL, 295.7 mmol) was carefully added drop-wise to cold EtOH (600 mL) with stirring. To this, 3-hydrazinobenzoic acid (45 g, 295.7 mmol) and 4,4-dimethyl-3-oxopentanenitrile (40.7 g, 325.3 mmol) were added and then the mixture was heated at 90°C for 48 h. Most of the solvent was evaporated at reduced pressure, and the residual mixture was diluted with ethyl acetate. The resulting mixture was washed with ice cold 2M NaOH followed by brine, and dried (Na₂SO₄). The solution was filtered through a bed of silica gel, washing with more ethyl acetate. Evaporation of ethyl acetate and treatment of the residue with dichloromethane/hexanes gave the product as an off-white crystalline solid (61 g, 71%). MS mlz 288.2 (M+H)⁺; calcd. mass 287. Retention time (LC-MS): 2.99 min. ¹H-NMR (DMSO-d₆): δ 8.16 (m 1H); 7.88 (m, 2H); 7.60 (t, 1H); 5.40 (s, 1H); 5.32 (s, 2H); 4.36 (q, 2H); 1.34 (t, 3H); 1.21 (s, 9H).

Step 2. Preparation of ethyl 3-{3-tert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazol-1-yl}-benzoate

To a mixture of ethyl 3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzoate (60 g, 208.8 mmol) and K₂CO₃ (86.6 g, 626.4 mmol) in THF (1400 mL) was added phenyl chloroformate (98.1 g, 626.4 mmol). The reaction was stirred at room temperature overnight. The solid was removed by filtration and most of the solvent was evaporated under reduced pressure. The residual mixture was dissolved in EtOAc and washed with brine, then water. The organic layer was then dried and concentrated. The crude product was purified by recrystallization from CH₂Cl₂/hexanes to give the desired product as a white powder (78.5 g, 92%). MS m/z 408.1 (M+H)⁺; calcd. mass 407. Retention time (LC-MS): 3.92 min. ¹H-NMR (DMSO-d₆): δ 10.19 (s, broad, 1H); 8.11 (m 1H); 7.97 (d, J = 7.6 Hz, 1H); 7.86 (m, 1H); 7.71 (t, 1H); 7.38 (m, 2H); 7.24 (m, 1H); 7.08 (m, 1H); 6.40 (s, 1H); 4.38 (q, 2H); 1.32 (t, 3H); 1.29 (s, 9H).

Step 3. Preparation of ethyl 3-(3-tert-butyl-5-{[(2-fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]-oxy}phenyl)carbamoyl]amino}-1H-pyrazol-1-yl)benzoate

A solution of ethyl 3-{3-tert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazol-1-yl}benzoate (9.36 g, 22.0 mmol), 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide (5.0 g, 19.1 mmol; prepared as described in Dumas et al., PCT Int. Appl. WO 2004078748 (2004 )) and triethyl amine (3.87 g, 38.3 mmol) in anhydrous THF (100 mL) was stirred at room temperature overnight. The crude product was purified by column chromatography (CH₂Cl₂ plus 1% to 3% of 2M NH₃ in MeOH), followed by recrystallization from EtOAc/hexanes to give the desired product as an off-white crystalline solid (6.32 g, 57%). MS m/z 575.1 (M+H)⁺; calcd. mass 574. Retention time (LC-MS): 3.75 min.¹H-NMR (DMSO-d₆): δ 8.97 (m, 1H); 8.89 (m, 1H); 8.80 (m, 1H); 8.52 (d, J = 5.6 Hz, 1H); 8.16 (t, 1H); 8.06 (m, 1H); 7.99 (m, 1H); 7.85 (m, 1H); 7.71 (t, 1H); 7.39 (m, 1H); 7.33 (m, 1H); 7.17 (m, 1H); 7.06 (m, 1H); 6.42 (s, 1H); 4.36 (q, 2H); 2.78 (d, J = 5.2 Hz, 3H); 1.31 (m, 12H).

Step 4. Preparation of (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide)

To a well-stirred cooled solution of 4-(4-{3-[5-tert-butyl-2-(3-ethoxycarbonyl-phenyl)-2H-pyrazol-3-yl]-ureido}-3-fluoro-phenoxy)-pyridine-2-carboxylic acid methylamide (56 mg, 0.1 mmol) in ethanol (10 mL), NaBH₄ (50 mg) was added in portions. After 14 h, ice water (10 mL) was carefully added to the reaction mixture. Then, most of the ethanol was evaporated under reduced pressure. The residual mixture was treated with saturated aqueous ammonium chloride solution (10 mL) and extracted three times with dichloromethane (50, 25, and 25 mL). The combined dichloromethane extract was dried (sodium sulfate) and the solvent was evaporated. The crude product was purified by preparative thin layer chromatography on silica gel using 3-5% 2M ammonia in methanol in dichloromethane as the eluent to yield the desired product as a white powder (31 mg, 58%).
For a larger scale synthesis, the following similar procedure was followed: To a solution of ethyl 3-(3-tert-butyl-5-{[(2-fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]oxy}phenyl)carbamoyl]-amino}-1H-pyrazol-1-yl)benzoate (11.2 g, 19.5 mmol) in EtOH was added NaBH₄ stepwise as a solid. The reaction was then stirred at room temperature overnight, and then quenched by gradual addition of aqueous NH₄Cl. The mixture was diluted with EtOAc, washed with aq. NH₄Cl, followed by brine. The organic layer was then dried and concentrated. The crude product was then purified by column chromatography on silica gel (CH₂Cl₂ plus 1 to 5% of 2M NH₃ in MeOH), followed by recrystallization from dichloromethane/hexanes to give the desired product as a white crystalline solid (8.0 g, 77%). Mp 160 ºC; after further recrystallization, desired product was obtained with mp 196 ºC.
MS m/z 533.3 (M+H)⁺; calcd. mass 532. Retention time (LC-MS): 3.13 min.
¹H-NMR (DMSO-d₆): δ 9.02 (s, broad, 1H); 8.87 (s, 1H); 8.81 (m, 1H); 8.52 (d, J= 5.2 Hz, 1H); 8.21 (t, 1H); 7.51 (m, 2H); 7.39 (m, 3H); 7.32 (m, 1H); 7.17 (m, 1H); 7.06 (m, 1H); 6.40 (s, 1H); 5.36 (t, 1H); 4.59 (d, J = 5.6 Hz, 2H); 2.78 (d, J = 4.8 Hz, 3H); 1.27 (s, 9H).
Elemental Analysis: C 62.92%; H 5.43%; N 15.70%; calcd. C 63.15%; H 5.49%; N 15.78%.

Linsitinib

cancer, Uncategorized Comments Off

Dec 302013

linsitinib

OSI 906

ASP7487

3-[8-Amino-1-(2-phenyl-7-quinolyl)imidazo[1,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol

CAS: 867160-71-2

Chemical Formula: C26H23N5O

Molecular Weight: 421.5

Elemental Analysis: C, 74.09; H, 5.50; N, 16.62; O, 3.80

PHASE 2

Linsitinib (OSI-906) is an orally bioavailable small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) with potential antineoplastic activity. OSI-906 selectively inhibits IGF-1R, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell apoptosis. Overexpressed in a variety of human cancers, IGFR-1 stimulates cell proliferation, enables oncogenic transformation, and suppresses apoptosis

Linsitinib (OSI-906) was developed through drug-discovery efforts focused on identifying a potent and selective, small-molecule inhibitor of the IGF-1R signaling axis. The lead optimization phase utilized IR and IGF-1R co-crystal structures, with lead compounds from the imidazopyrazine series, to afford a structure-based design-driven component, which complemented ongoing empirical medicinal chemistry efforts. These combined approaches improved metabolic and pharmacokinetic liabilities of earlier lead compounds and ultimately led to the discovery of OSI-906. OSI-906 was synthesized from an advanced imidazopyrazine intermediate in two linear steps. OSI-906 potently inhibits ligand-dependent auto-phosphorylation of both human IGF-1R and IR in cells, while displaying a high degree of selectivity versus a wide panel of protein kinases.

Moreover, OSI-906, through its inhibition of both IGF-1R and IR, prevents ligand-induced activation of downstream pathways including pAKT, pERK1/2 and p-p70S6K and, therefore, inhibits proliferation in a variety of tumor cell lines. Robust anti-tumor activity was achieved in an IGF-1R-driven LISN xenograft model following once-daily oral administration of OSI-906. The anti-tumor activity obtained in this study correlated well with the degree and duration of inhibition of tumor IGF-1R phosphorylation achieved in vivo by OSI-906. OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-1R/IR kinase inhibitor with demonstrated in vivo efficacy in tumor models. It is currently being evaluated in clinical trials.

Furthermore, the exceptional selectivity profile of OSI-906 in conjunction with its ability to inhibit both IGF-1R and IR provides the unique opportunity to fully target the IGF-1R/IR axis. (source: Future Medicinal Chemistry September 2009, Vol. 1, No. 6, Pages 1153-1171. )

Linsitinib is an experimental drug candidate for the treatment of various types of cancer. It is an inhibitor of the insulin receptor and of the insulin-like growth factor 1 receptor (IGF-1R).^[1] This prevents tumor cell proliferation and induces tumor cell apoptosis.^[2]

The development of target-based anti-cancer therapies has become the focus of a large number of pharmaceutical research and development programs. Various strategies of intervention include targeting protein tyrosine kinases, including receptor tyrosine kinases believed to drive or mediate tumor growth.

Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase that plays a key role in tumor cell proliferation and apoptosis inhibition, and has become an attractive cancer therapy target. IGF-1R is involved in the establishment and maintenance of cellular transformation, is frequently overexpressed by human tumors, and activation or overexpression thereof mediates aspects of the malignant phenotype. IGF-1R activation increases invasion and metastasis propensity.

Inhibition of receptor activation has been an attractive method having the potential to block IGF-mediated signal transduction. Anti-IGF-1R antibodies to block the extracellular ligand-binding portion of the receptor and small molecules to target the enzyme activity of the tyrosine kinase domain have been developed. See Expert Opin. Ther. Patents, 17(1):25-35 (2007); Expert Opin. Ther. Targets, 12(5):589-603 (2008); and Am J. Transl. Res., 1:101-114 (2009).

US 2006/0235031 (published Oct. 19, 2006) describes a class of bicyclic ring substituted protein kinase inhibitors, including Example 31 thereof, which corresponds to the dual IR/IGF-1R inhibitor known as OSI-906. As of 2011, OSI-906 is in clinical development in various cancers and tumor types. The preparation and characterization of OSI-906, which can be named as cis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol, is described in the aforementioned US 2006/0235031.

OSI-906 is a potent, selective, and orally bioavailable dual IGF-1R/IR kinase inhibitor with favorable drug-like properties. The selectivity profile of OSI-906 in conjunction with its ability to inhibit both IGF-1R and IR affords the special opportunity to fully target the IGF-1R/IR axis. See Future Med. Chem., 1(6), 1153-1171, (2009).

It is desirable to develop novel processes to prepare imidazopyrazine compounds, namely OSI-906, which may be practical, economical, efficient, reproducible, large scale, and meet regulatory requirements.

Linsitinib was discovered by OSI Pharmaceuticals and is currently in Phase III clinical trials for adrenocortical carcinoma and Phase II clinical trials for lung and ovarian cancers.^[3]^[4]

Mulvihill, MJ; Cooke, A; Rosenfeld-Franklin, M; Buck, E; Foreman, K; Landfair, D; O’Connor, M; Pirritt, C et al. (2009). “Discovery of OSI-906: A selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor”. Future medicinal chemistry 1 (6): 1153–71. doi:10.4155/fmc.09.89.PMID 21425998.
“Linsitinib”. NCI Drug Dictionary. National Cancer Institute. Retrieved October 16, 2012.
“OSI Pharmaceuticals, LLC”. Astellas Pharma. Retrieved October 16, 2012.
“Linsitinib”. National Institutes of Health’s clinicaltrials.gov. Retrieved October 16, 2012.

OSI-906: A novel, potent, and selective first-in-class small molecule insulin-like growth factor 1 receptor (IGF-1R) inhibitor in phase I clinical trials
238th ACS Natl Meet (August 16-20, Washington) 2009, Abst MEDI 152

………………………………………………………

US20130123501

EXAMPLES1

cis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol (OSI-906) (Compound 1)

A vessel was charged with DMF (79 kg), cis-3-(8-amino-1-bromo-imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (16.725 kg), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (22.4 kg), triphenylphosphine (0.586 kg), cesium carbonate (36.7 kg) and water (20.1 kg). The reaction mixture was degassed and heated to 95-105° C. and a solution of palladium acetate (0.125 kg) in DMF (9.8 kg) was added and rinsed in with DMF (5.9 kg). After the reaction was complete, water (154 kg) was added keeping the temperature above 70° C. The resultant slurry was cooled and the solid was collected by filtration. After washing with a mixture of DMF (9.4 kg) and water (23.4 kg) and then water (67 kg) the solid was suspended in water (167 kg) at 50° C. and the pH of the mixture was adjusted to 2.9 with 6N hydrochloric acid (10.9 kg). The resultant yellow slurry was filtered to remove the major impurities and the cake was washed with water (67 kg). The acid solution was stirred at 50-55° C. and polymer bound trimercaptotriazine resin (MP-TMT) (4.9 kg) was added. The mixture was stirred for 23 hours, the resin was removed by filtration and the cake was washed with water (58 kg).

The resultant acid solution was diluted with 2-propanol (82 kg), the temperature was adjusted to 35-45° C. and the pH was adjusted to 5.0 by the addition of 1N sodium hydroxide solution. The mixture was cooled, the yellow product was collected by filtration and was washed with water (33 kg). The solid was re-suspended in water (157 kg) stirred, filtered and washed with water (125 kg). The solid was dried under vacuum at 45-55° C. (the resulting material was a hemihydrate of OSI-906 designated Form C) and was then stirred in refluxing 2-propanol (157 kg) for 3 hours. The mixture was cooled and the solid was isolated by filtration. After washing with 2-propanol (26.7 kg), the product was dried at 45-55° C. under vacuum to yield 15.6 kg (65% yield) of OSI-906. The resulting material was an anhydrous crystalline form of OSI-906 designated Form A.

Example 2cis-3-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol

THF (87 kg) and 3M methyl magnesium chloride (83.6 kg) were charged to a vessel. The contents were cooled to −65 to −55° C. and 3-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (33.0 kg) in THF (253 kg) was added, maintaining the temperature at −65° C. to −45° C.

The charged vessel was rinsed with THF (41 kg) and the reaction mixture was stirred at −65 to −45° C. until reaction completion. Preferably, the level of iron present in the reaction is about 100 ppm or less, or about 20 ppm or less. These conditions are suitable to achieve the desired stereoselectivity. A 5% ammonium chloride solution (462 kg) was added slowly while maintaining the temperature below 10° C. The aqueous layer was then separated, the pH was adjusted to pH 7-8 by the addition of 6N hydrochloric acid and the mixture was extracted with methyl t-butyl ether (2×145 kg). The combined organic extracts were washed sequentially with 1N sodium hydroxide solution (330 kg) and 20% sodium chloride solution (2×330 kg). THF (767 kg) was then added and the solution was distilled to a residual volume of 165 L. Toluene (567 kg) was added and again the mixture was distilled to a volume of 165 L. The mixture was heated to 85-90° C. until complete dissolution was achieved and then cooled to 20-30° C. to crystallize the product. The solids were collected by filtration, washed with toluene (2×41 kg) and dried at 50-60° C. under vacuum. Yield was 78%. ¹H NMR (300 MHz, DMSO-d₆) δ 8.3 (d, 1H), 7.4 (d, 1H), 5.2 (s, 1H), 3.5 (m, 1H), 2.4 (m, 4H), 1.4 (s, 3H).

Example 3cis-3-(8-amino-1-bromo-imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol

Cis-3-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (27.1 kg), isopropanol (65 kg) and 30% ammonia solution (165 kg) were charged to a suitable vessel. The vessel was sealed and the mixture was heated and stirred for 18 hours at 75 to 85° C. and then cooled. The vessel was vented to a scrubber and water (22 kg) was added. The mixture was concentrated under vacuum to a residual volume of 73-89 L and was then cooled to <5° C. The product was collected by filtration and washed with water (2×108 kg). The product was dried at 40-50° C. under vacuum. Yield was 88%. ¹H NMR (300 MHz, DMSO-d₆) δ 7.5 (d, 1H), 7.0 (d, 1H), 6.6 (br s, 2H), 5.2 (s, 1H), 3.4 (m, 1H), 2.4 (m, 4H), 1.4 (s, 3H).

Example 4cis-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-7-ium chloride

This material was prepared by heating OSI-906 with an equivalent of hydrochloric acid in water and then allowing the solution to cool. The solid was filtered from the cooled mixture and dried. The XRPD and DSC suggest a semi-crystalline material. The DSC, XRPD, and ¹H NMR (300 MHz, DMSO-d₆) of the sample were recorded and are reproduced in FIGS. 1, 2, and 3, respectively.

…………………………………………………………

PATENTS

WO 2010107968

WO 2010129740

WO 2011109572

WO 2011112666

WO 2011163430

WO 2012016095

WO 2012129145

WO 2012149014

WO 2013152252

…………………………………………………………….

WO2011163430A1

The present invention provides for methods of preparing OSI-906 Forms A-G illustrated in Scheme 1 .

…………………………………………………….

PROSTRATE CANCER

cancer Comments Off

Sep 302013

http://www.intechopen.com/books/advances-in-prostate-cancer

Advances in Prostate Cancer

Edited by Gerhard Hamilton, ISBN 978-953-51-0932-7, Hard cover, 690 pages, Publisher: InTech, Chapters published January 16, 2013 under CC BY 3.0 license
DOI: 10.5772/45948

Prostate cancer is one of the most common types of cancer in men and its treatment was constricted to surgery for confined state and androgen ablation for advanced disease until new options have become available. The present book covers a broad range of novel aspects of prostate cancer diagnosis, treatment and patient care, as well as new research on relevant cell biology. In detail, this special volume focusses on supportive modalities for prostate cancer patients, appropriate selection of novel therapeutic regimens, including inhibitors of steroidal synthesis, cytotoxic agents, as well as intermittent androgen suppression and the roles of prostate cancer stem cells and inflammatory processes.

Chapter 1 Epidemiology of Prostate Cancerby Martin Dörr, Anne Schlesinger-Raab and Jutta Engel
Chapter 2 Is There an Infectious Agent Behind Prostate Cancer?by Ugo Rovigatti
Chapter 3 Psychological and Social Factors influencing Patients’ Treatment Selection for Localised Prostate Cancerby Luke A Robles, Shihning Chou, Owen J Cole, Akhlil Hamid, Amanda Griffiths and Kavita Vedhara
Chapter 4 The Role of Physiotherapy in the Pre and Post Treatment Interventions in Prostate Cancer Patientsby Mario Bernardo Filho and Mauro Luis Barbosa Júnior
Chapter 5 Abdominoperineal Resection: Consideration and Limitations of Prostate Cancer Screening and Prostate Biopsyby Zachary Klaassen, Ray S. King, Kelvin A. Moses, Rabii Madi and Martha K. Terris
Chapter 6 Radiation Therapy for Prostate Cancerby Shinji Kariya
Chapter 7 High-Dose-Rate Interstitial Brachytherapy as Monotherapy in One Fraction for the Treatment of Favorable Stage Prostate Cancerby Pedro J. Prada
Chapter 8 Testosterone Measurement and Prostate Cancerby Tine Hajdinjak
Chapter 9 Describing Prostate Cancer Dynamics: Second Look at PSA- Doubling Time and PSA-Specific Growth Rateby Glenn Tisman
Chapter 10 Rational Categorization of the Pipeline of New Treatments for Advanced Cancer – Prostate Cancer as an Exampleby Sarah M. Rudman, Peter G. Harper and Christopher J. Sweeney
Chapter 11 Novel Therapeutic Settings in the Treatment of Castration- Resistant Prostate Cancerby Miguel Álvarez Múgica, Jesús M. Fernández Gómez, Antonio Jalón Monzón, Erasmo Miguelez García and Francisco Valle González
Chapter 12 Steroidal CYP17 Inhibitors for Prostate Cancer Treatment: From Concept to Clinicby Jorge A. R. Salvador, Vânia M. Moreira and Samuel M. Silvestre
Chapter 13 Intermittent Androgen Suppression Therapy for Prostate Cancer Patients: An Updateby Gerhard Hamilton and Gerhard Theyer
Chapter 14 Stem Cells and Prostate Cancerby Vildan Bozok Çetintaş, Burçin Tezcanlı Kaymaz and Buket Kosova
Chapter 15 Salinomycin-Induced Apoptosis in Human Prostate Cancer Cellsby Hak-Jong Choi, Kwang-Youn Kim, Sun-Nyoung Yu, Sang-Hun Kim, Sung-Sik Chun, Hak-Sun Yu, Yeong-Min Park and Soon-Cheol Ahn
Chapter 16 Natural Compounds, Antioxidant and Antiandrogens in the Prevention of Prostate Cancer: In vivo Evidences from Murine Models and Human Clinical Studiesby Rossano Lattanzio, Alessia Lamolinara, Mauro Piantelli and Manuela Iezzi
Chapter 17 Prostate Cancer, Inflammation and Antioxidantsby Marika Crohns, Tuomas Westermarck and Faik Atroshi
Chapter 18 Inflammatory Microenvironment in Prostate Carcinogenesisby Geraldine Gueron, Javier Cotignola and Elba Vazquez
Chapter 19 Expression and Function of Stromal Androgen Receptor in Prostate Cancerby Mandeep Singh, Garrett Daniels, Yirong Li and Pen g Lee
Chapter 20 Prostate Cancer Progression to Androgen Independent Disease: The Role of the PI3K/AKT Pathwayby Jacqueline R Ha, Yu Hao D Huang, Amit Persad and Sujata Persad
Chapter 21 Non-Androgen Regulated Transcription Factors as Novel Potential Targets for Prostate Cancer Therapyby J. Nathan Davis, Adam H. Greer, Thomas Yong and Shari Meyers
Chapter 22 Trithorax Genes in Prostate Cancerby Pier-Luc Clermont, Francesco Crea and Cheryl D. Helgason
Chapter 23 The Function of YY1 and Its Oncogenic Role in Prostate Cancerby Daniel B. Stovall and Guangchao Sui
Chapter 24 The Role of PARP Activation in Prostate Cancerby Luis A. Espinoza
Chapter 25 Integrins in Prostate Cancer Invasion and Metastasisby Paulynn Chin Suyin, Joanne Louise Dickinson and Adele Frances Holloway
Chapter 26 The Role of E-Cadherin-Catenin Complex in Prostate Cancer Progressionby Anuradha K. Murali and James S. Norris

http://www.intechopen.com/books/advances-in-prostate-cancer

The Potential of Triterpenoids in the Treatment of Melanoma

cancer Comments Off

Sep 292013

READ THIS FANTASTIC CHAPTER

By J. Sarek, M. Kvasnica, M. Vlk, M. Urban, P. Dzubak and M. Hajduch
DOI: 10.5772/19582

http://www.intechopen.com/books/research-on-melanoma-a-glimpse-into-current-directions-and-future-trends/the-potential-of-triterpenoids-in-the-treatment-of-melanoma

The Potential of Triterpenoids in the Treatment of Melanoma

J. Sarek^1,², M. Kvasnica³, M. Vlk^2,⁴, M. Urban⁵, P. Dzubak⁶ and M. Hajduch⁶

^[1] Dept. of Org. Chem., IMTM, Faculty of Sciences, Palacky University, Olomouc, Czech Republic

^[2] Betulinines – Chemical group, Stribrna Skalice, Czech Republic

^[3] IOCB, Academy of Sciences, Prague, Czech Republic

^[4] Dept. of Nuclear Chemistry, Faculty of Nuclear Sciences and Physical Engineering, CTU, Prague, Czech Republic

^[5] Dept. of Chem. and Bioch., Univ. of Colorado at Boulder, Colorado, USA

^[6] Lab. of Exp. Medicine, IMTM, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic

http://www.intechopen.com/books/research-on-melanoma-a-glimpse-into-current-directions-and-future-trends/the-potential-of-triterpenoids-in-the-treatment-of-melanoma

ALL THE THUMBNAILS FOR READER

The first generic version of the oral chemotherapy drug Xeloda (capecitabine) has been approved by the U.S. Food and Drug Administration to treat cancers of the colon/rectum or breast

cancer Comments Off

Sep 172013

capecitabine

154361-50-9

R-340, Ro-09-1978, Xeloda

pentyl [1-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1H-pyrimidin-4-yl]carbamate

MONDAY Sept. 16, 2013 — The first generic version of the oral chemotherapy drug Xeloda (capecitabine) has been approved by the U.S. Food and Drug Administration to treat cancers of the colon/rectum or breast, the agency said Monday in a news release.

This year, an estimated 142,820 people will be diagnosed with cancer of the colon/rectum, and 50,830 are predicted to die from the disease, the FDA said, citing the U.S. National Cancer Institute. An estimated 232,340 women will be diagnosed with cancer of the breast this year, and some 39,620 will die from it.

The most common side effects of the drug are diarrhea, vomiting; pain, redness, swelling or sores in the mouth; fever and infection, the FDA said.

The agency stressed that approved generics have the same high quality and strength as their brand-name counterparts.

License to produce the generic drug was given to Israel-based Teva Pharmaceuticals. The brand name drug is produced by the Swiss pharma firm Roche.

Capecitabine (INN) /k eɪ p ˈ s aɪ t ə b iː n / (Xeloda, Roche) is an orally-administeredchemotherapeutic agent used in the treatment of metastatic breast andcolorectal cancers. Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5′-deoxy-5-fluorocytidine (5′-DFCR) and 5′-deoxy-5-fluorouridine (5′-DFUR), to form 5-fluorouracil

Indications

Capecitabine is FDA-approved for:

Adjuvant in colorectal cancer Stage III Dukes’ C – used as first-line monotherapy.
Metastatic colorectal cancer – used as first-line monotherapy, if appropriate.
Metastatic breast cancer – used in combination with docetaxel, after failure of anthracycline-based treatment. Also as monotherapy, if the patient has failed paclitaxel-based treatment, and if anthracycline-based treatment has either failed or cannot be continued for other reasons (i.e., the patient has already received the maximum lifetime dose of an anthracycline).

In the UK, capecitabine is approved by the National Institute for Health and Clinical Excellence (NICE) for colon and colorectal cancer, and locally advanced or metastatic breast cancer.^[1] On March 29, 2007, the European Commission approved Capecitabine, in combination with platinum-based therapy (with or without epirubicin), for the first-line treatment of advanced stomach cancer.

Capecitabine is a cancer chemotherapeutic agent that interferes with the growth of cancer cells and slows their distribution in the body. Capecitabine is used to treat breast cancer and colon or rectum cancer that has spread to other parts of the body.

Formulation

Capecitabine (as brand-name Xeloda) is available in light peach 150 mg tablets and peach 500 mg tablets.

Lacy, Charles F; Armstrong, Lora L; Goldman, Morton P; Lance, Leonard L (2004). Lexi-Comp’s Drug Information Handbook (12th Edition). Lexi-Comp Inc. ISBN 1-59195-083-X
Fischer, David S; Knobf, M Tish; Durivage, Henry J; Beaulieu, Nancy J (2003). The Cancer Chemotherapy Handbook (6th Edition). Mosby. ISBN 0-323-01890-4
Thomson Centerwatch: Drugs Approved by the FDA (Xeloda) Retrieved 6/05
Mercier C, Ciccolini J (2007). “Severe or lethal toxicities upon capecitabine intake: is DPYD genetic polymorphism the ideal culprit?”. Trends in pharmacological sciences 28 (12): 597–598.doi:10.1016/j.tips.2007.09.009. PMID 18001850.

“Subtopics”. Nice.org.uk. Retrieved 2012-08-15.
Fingerprints May Vanish With Cancer Drug – US News and World Report
Cancer Drug Erases Man’s Fingerprints – CNN
“Stritch School of Medicine”. Stritch.luc.edu. Retrieved 2012-08-15.

Xeloda.com (patient information, tools, and resources)
OralChemo Advisor (patient information)

WO2009066892A1

Capecitabine is an orally-administered anticancer agent widely used in the treatment of metastatic breast and colorectal cancers. Capecitabine is a ribofuranose-based nucleoside, and has the sterochemical structure of a ribofuranose having an β-oriented 5-fluorocytosine moiety at C-I position.

US Patent Nos. 5,472,949 and 5,453,497 disclose a method for preparing capecitabine by glycosylating tri-O-acetyl-5-deoxy-β-D-ribofuranose of formula I using 5-fluorocytosine to obtain cytidine of formula II; and carbamoylating and hydrolyzing the resulting compound, as shown in Reaction Scheme 1 :

Reaction Scheme 1

The compound of formula I employed as an intermediate in Reaction

Scheme 1 is the isomer having a β-oriented acetyl group at the 1 -position, for the reason that 5-fluorocytosine is more reactive toward the β-isomer than the α-isomer in the glycosylation reaction due to the occurrence of a significant neighboring group participation effect which takes place when the protecting group of the 2-hydroxy group is acyl.

Accordingly, β-oriented tri-O-acetyl-5-deoxy-β-D-ribofuranose (formula

I) has been regarded in the conventional art to the essential intermediate for the preparation of capecitabine. However, such a reaction gives a mixture of β- and α-isomers from which cytidine (formula II) must be isolated by an uneconomical step.

Meanwhile, US Patent No. 4,340,729 teaches a method for obtaining capecitabine by the procedure shown in Reaction Scheme 2, which comprises hydrolyzing 1-methyl-acetonide of formula III to obtain a triol of formula IV; acetylating the compound of formula IV using anhydrous acetic anhydride in pyridine to obtain a β-/α-anomeric mixture of tri-O-acetyl-5-deoxy-D-ribofuranose of formula V; conducting vacuum distillation to purify the β-/α-anomeric mixture; and isolating the β-anomer of formula I therefrom:

Reaction Scheme 2

III IV

However, the above method is also hampered by the requirement to perform an uneconomical and complicated recrystallization steps for isolating the β-anomer from the mixture of β-/α-anomers of formula V, which leads to a low yield of only about 35% to 40% (Guangyi Wang et al., J. Med. Chem., 2000, vol. 43, 2566-2574; Pothukuchi Sairam et al., Carbohydrate Research, 2003, vol. 338, 303-306; Xiangshu Fei et al., Nuclear Medicine and Biology, 2004, vol. 31, 1033-1041; and Henry M. Kissman et al., J. Am. Chem. Soc, 1957, vol. 79, 5534-5540).

Further, US Patent No. 5,476,932 discloses a method for preparing capecitabine by subjecting 5′-deoxy-5-fluorocytidine of formula VI to a reaction with pentylchloroformate to obtain the compound of formula VII having the amino group and the 2-,3-hydroxy groups protected with C₅Hi₁CO₂ groups; and removing the hydroxy-protecting groups from the resulting compound, as shown in Reaction Scheme 3 :

Reaction Scheme 3

Vl VII 1

However, this method suffers from a high manufacturing cost and also requires several complicated steps for preparing the 5′-deoxy-5-fluorocytidine of formula VI: protecting the 2-,3-hydroxy groups; conducting a reaction thereof with 5-fluorocytosine; and deprotecting the 2-,3-hydroxy groups.

Accordingly, the present inventors have endeavored to develop an efficient method for preparing capecitabine, and have unexpectedly found an efficient, novel method for preparing highly pure capecitabine using a trialkyl carbonate intermediate, which does not require the uneconomical β-anomer isolation steps.

synthesis

WO2010065586A2

more info and description

Aspects of the present invention relate to capecitabine and processes for the preparation thereof.

The drug compound having the adopted name “capecitabine” has a chemical name 5′-deoxy-5-fluoro-N-[(pentyloxy) carbonyl] cytidine and has structural formula I.

OH OH I

This compound is a fluoropyrimidine carbamate with antineoplastic activity. The commercial product XELODA™ tablets from Roche Pharmaceuticals contains either 150 or 500 mg of capecitabine as the active ingredient.

U.S. Patent No. 4,966,891 describes capecitabine generically and a process for the preparation thereof. It also describes pharmaceutical compositions, and methods of treating of sarcoma and fibrosarcoma. This patent also discloses the use of ethyl acetate for recrystallization of capecitabine. The overall process is summarized in Scheme I.

Scheme I

U.S. Patent No. 5,453,497 discloses a process for producing capecitabine that comprises: coupling of th-O-acetyl-5-deoxy-β-D-hbofuranose with 5- fluorocytosine to obtain 2′,3′-di-O-acetyl-5′-deoxy-5-fluorocytidine; acylating a 2′, 3′- di-O-acetyl-5′-deoxy-5-fluorocytidine with n-pentyl chloroformate to form 5′-deoxy- 2′,3′-di-O-alkylcarbonyl-5-fluoro-N-alkyloxycarbonyl cytidine, and deacylating the 2′ and 3′ positions of the carbohydrate moiety to form capecitabine. The overall process is summarized in Scheme II.

Capecitabine

Scheme Il

The preparation of capecitabine is also disclosed by N. Shimma et al., “The Design and Synthesis of a New Tumor-Selective Fluoropyrimidine Carbamate, Capecitabine,” Bioorganic & Medicinal Chemistry, Vol. 8, pp. 1697-1706 (2000). U.S. Patent No. 7,365,188 discloses a process for the production of capecitabine, comprising reacting 5-fluorocytosine with a first silylating agent in the presence of an acid catalyst under conditions sufficient to produce a first silylated compound; reacting the first silylated compound with 2,3-diprotected-5- deoxy-furanoside to produce a coupled product; reacting the coupled product with a second silylating agent to produce a second silylated product; acylating the second silylated product to produce an acylated product; and selectively removing the silyl moiety and hydroxyl protecting groups to produce capecitabine. The overall process is summarized in Scheme III. te

R: hydrocarbyl

Scheme III

Further, this patent discloses crystallization of capecitabine, using a solvent mixture of ethyl acetate and n-heptane. International Application Publication No. WO 2005/080351 A1 describes a process for the preparation of capecitabine that involves the refluxing N₄– pentyloxycarbonyl-5-fluorocytosine with trimethylsiloxane, hexamethyl disilazanyl, or sodium iodide with trimethyl chlorosilane in anhydrous acetonitrile, dichloromethane, or toluene, and 5-deoxy-1 ,2,3-tri-O-acetyl-D-ribofuranose, followed by hydrolysis using ammonia/methanol to give capecitabine. The overall process is summarized in Scheme IV.

Scheme IV

International Application Publication No. WO 2007/009303 A1 discloses a method of synthesis for capecitabine, comprising reacting 5′-deoxy-5- fluorocytidine using double (trichloromethyl) carbonate in an inert organic solvent and organic alkali to introduce a protective lactone ring to the hydroxyl of the saccharide moiety; reacting the obtained compound with chloroformate in organic alkali; followed by selective hydrolysis of the sugar component hydrolytic group using an inorganic base to give capecitabine. The overall process is summarized in Scheme V.

Scheme V

Even though all the above documents collectively disclose various processes for the preparation of capecitabine, removal of process-related impurities in the final product has not been adequately addressed. Impurities in any active pharmaceutical ingredient (API) are undesirable, and, in extreme cases, might even be harmful to a patient. Furthermore, the existence of undesired as well as unknown impurities reduces the bioavailability of the API in pharmaceutical products and often decreases the stability and shelf life of a pharmaceutical dosage form.

nmr

¹H NMR(CD₃OD) δ 0.91(3H₅ t), 1.36~1.40(4H, m), 1.41(3H, d), 1.68~1.73(2H, m), 3.72(1H, dd), 4.08(1H, dd), 4.13~4.21(3H, m), 5.7O(1H, s), 7.96(1H, d)

The acetylation of 5′-deoxy-5-fluorocytidine (I) with acetic anhydride in dry pyridine gives 2′,3′-di-O-acetyl-5′-deoxy-5-fluorocytidine (II), which is condensed with pentyl chloroformate (III) by means of pyridine in dichromethane yielding 2′,3′-di-O-acetyl-5′-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine (IV). Finally, this compound is deacetylated with NaOH in dichloromethane/water. The diacetylated cytidine (II) can also be obtained by condensation of 5-fluorocytosine (V) with 1,2,3-tri-O-acetyl-5-deoxy-beta-D-ribofuranose (VI) by means of trimethylchlorosilane in acetonitrile or HMDS and SnCl4 in dichloromethane..
- EP 602454, JP 94211891, US 5472949.
  - Capecitabine. Drugs Fut 1996, 21, 4, 358,
    - Bioorg Med Chem Lett2000,8,(7):1697,

Drug in Focus: Abiraterone Acetate (Zytiga) New drug for the treatment of advanced prostate cancer

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Sep 112013

Abiraterone Acetate (Zytiga)

When prostate cancer spreads to another location in the body, it is considered to have metastasised, and surgery to remove the prostate and pelvic lymph nodes cannot eliminate the cancer. As a result, most men with metastatic prostate cancer (PCa) receive hormonal therapy which is also known as androgen ablation or androgen-deprivation therapy (ADT). ADT is used to reduce the levels of circulating androgens (male hormones) in the body (a process known as castration) or to keep them from reaching PCa cells. After sometime, however, the PCa no longer responds to hormone therapy, including LHRH analogues and anti-androgens, andis considered to be castration-resistant. At this stage, so-called metastatic castration-resistant PCa (mCRPC) becomes increasingly difficult to treat……………full article

READ ALL AT

http://www.medicalgrapevineasia.com/mg/2013/07/09/drug-in-focus-abiraterone-acetate-zytiga/

Dr Tan Yew Oo, Medical Oncologist and Hematologist in private practice at Gleneagles Hospital, to tell us more about AA.

Dr Tan Yew Oo is currently a Consultant Medical Oncologist and Hematologist in private practice at Gleneagles Hospital, Singapore. After graduating with MBBS from University of Singapore in 1971, he did his postgraduate training in Internal Medicine, Hematology and Medical Oncology in the United States and Canada. Upon his return to Singapore, he joined the Faculty of Medicine of the National University of Singapore in 1978 as Lecturer. He rapidly rose to be Chief of Medicine at National University Hospital (NUH) and Head, Division of Hematology-Oncology at NUH in 1988 and Professor of Medicine in 1991. He resigned and went into private practice since 1993. Dr Tan has been active in post-graduate education and has published many papers and has been an invited speaker for numerous meetings. He has participated in several international phase III clinical trials using novel drugs, and he has special interests in multiple myeloma, breast, thoracic and GI/GU oncology.

Chemical synthesis of Abiraterone acetate

The following synthetic route of Abiraterone acetate was from J Med Chem. 1995 Jun 23;38(13):2463-71. Novel steroidal inhibitors of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer. Potter GA, Barrie SE, Jarman M, Rowlands MG. Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, U.K.

CAS#: 154229-18-2.

Synonym: CB 7630；CB-7630.

Chemical Formula: C26H33NO2
Exact Mass: 391.25113
Molecular Weight: 391.54
Elemental Analysis: C, 79.76; H, 8.50; N, 3.58; O, 8.17

IUPAC: [(3S,10R,13S)-10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl] acetate.

ZYTIGA™ (abiraterone acetate) received FDA Approval in May 2011 for Treatment of Metastatic Prostate Cancer After Priority Review; First Once-Daily, Oral Treatment for Metastatic Prostate Cancer Inhibits Androgen Production. ZYTIGA^™ (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

According to Wikipedia, Abiraterone (tradename Zytiga) is a drug currently under investigation for use in castration-resistant prostate cancer (formerly hormone-resistant or hormone-refractory prostate cancer) (prostate cancer not responding to androgen deprivation or treatment with antiandrogens). After an expedited six-month review, the drug has been approved for use by the Food and Drug Administration (FDA). This drug was initially discovered in the Cancer Research UK Centre for Cancer Therapeutics at the Institute of Cancer Research in London. Rights for commercialization of the drug were assigned to BTG plc, a UK company that manages commercialization activity in pharmaceuticals. BTG then licensed the product to Cougar Biotechnology which began development of the commercial product. In 2009, Cougar was acquired by Johnson & Johnson which is currently conducting clinical trials on abiraterone. http://en.wikipedia.org/wiki/Abiraterone).

Abiraterone acetate is an FDA approved drug, and is an orally active acetate ester of the steroidal compound abiraterone with antiandrogen activity. Abiraterone acetate was approved by the U.S. Food and Drug Administration (FDA) in April 2011. Abiraterone inhibits the enzymatic activity of steroid 17alpha-monooxygenase (17alpha-hydrolase/C17,20 lyase complex), a member of the cytochrome p450 family that catalyzes the 17alpha-hydroxylation of steroid intermediates involved in testosterone synthesis. Administration of this agent may suppress testosterone production by both the testes and the adrenals to castrate-range levels. Check for active clinical trials or closed clinical trials using this agent.

Current developer: Cougar Biotechnology Inc, and Johnson & Johnson。

Bladder Cancer Drug Pipeline Update 2013

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Aug 302013

Bladder Cancer Drug Pipeline Update 2013
Sacramento Bee
Pipeline Breakdown According to Number of Drugs Marketed# 10 Pre-registration# 1 Phase III# 4 Phase II# 45 Phase I# 26 Preclinical# 29 Suspended# 3 Ceased# 30 Note: You are able to sort and find drugs according to developmental stage from …http://www.sacbee.com/2013/08/29/5691549/bladder-cancer-drug-pipeline-update.html

Roche’s breast cancer drug patent partly annulled by Indian government

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Aug 062013

Roche’s breast cancer drug patent partly annulled by Indian government
Patents granted to pharmaceutical giant Roche Holding for the breast cancer drug Herceptin (trastuzumab) have been partially voided by the Indian government.

read all at

http://www.pharmaceutical-technology.com/news/newsroches-breast-cancer-drug-patent-partly-annulled-by-indian-government?WT.mc_id=DN_News

and

http://newdrugapprovals.wordpress.com/2013/02/23/fda-approves-kadcyla-ado-trastuzumab-emtansine-a-new-therapy-for-patients-with-her2-positive-late-stage-metastatic-breast-cancer/

New Compound May Be Future Of Breast Cancer Treatment

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Jul 142013

Image Credit: Photos.com

Rebekah Eliason for redOrbit.com – Your Universe Online

Scientists from Melbourne, Australia recently discovered compounds currently being researched to treat leukemia may also be effective in treating the most common form of breast cancer.

Researchers found a group of anti-cancer compounds known as BH3-mimetics are effective for treating estrogen receptor-positive (ER-positive) forms of breast cancers when used with tamoxifen, a drug currently used to treat breast cancer. Breast cancer is comprised of roughly 70 percent ER-positive types.

http://www.redorbit.com/news/health/1112893311/compound-bh3-mimetics-future-of-breast-cancer-treatment-070913/