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Vinorelbine …For the treatment of non-small-cell lung carcinoma.
4-(acetyloxy)- 6,7-didehydro- 15-((2R,6R,8S)-4-ethyl- 1,3,6,7,8,9-hexahydro- 8-(methoxycarbonyl)- 2,6-methano- 2H-azecino(4,3-b)indol-8-yl)- 3-hydroxy- 16-methoxy- 1-methyl- methyl ester,
3′,4′-Didehydro-4′-deoxy-8′-norvincaleukoblastine
71486-22-1 cas
(2R,3R)-2,3-Dihydroxysuccinic acid – methyl (2ξ,3β,4β,5α,12β,19α)-4-acetoxy-15-[(12S,14R)-16-ethyl-12-(methoxycarbonyl)-1,10-diazatetracyclo[12.3.1.03,11.04,9]octadeca-3(11),4,6, 8,15-pentaen-12-yl]-3-hydroxy-16-methoxy-1-methyl-6,7-didehydroaspidospermidine-3-carboxylate (2:1)
Vinorelbine (trade name Navelbine) is an anti-mitotic chemotherapy drug that is given as a treatment for some types of cancer, including breast cancer and non-small cell lung cancer.
Vinorelbine i.v. is a semi-synthetic derivative of a vinca alkaloid launched in 1989 by Pierre Fabre for the treatment of non-metastatic breast cancer and non-small cell lung cancer (NSCLC). In 2011, a complete response letter was assigned by the FDA for an NDA filed by Adventrx Pharmaceuticals seeking approval for the treatment of non-small cell lung cancer (NSCLC). Pierre Fabre and licensee GlaxoSmithKline had been evaluating the potential of the drug for the treatment of breast cancer, prostate cancer and NSCLC with an oral formulation, but no recent developments have been reported. The evaluation of an injectable emulsion formulation developed by Adventrx Pharmaceuticals is in phase I clinical development for the potential treatment of these indications. Several trials are ongoing to evaluate vinorelbine in combination with other chemotherapy for the treatment of metastatic breast cancer. The University of California, Davis is evaluating vinorelbine in combination with lapatinib for the treatment of solid tumors.
Clinicians sometimes use the abbreviation “NVB” for vinorelbine, although (like many medical abbreviations) it is not a unique identifier.
The antitumor activity is due to inhibition of mitosis through interaction with tubulin.[2] Vinorelbine is the first 5´NOR semi-synthetic vinca alkaloid. It is obtained by semi-synthesis from alkaloids extracted from the rosy periwinkle, Catharanthus roseus. It is marketed in India by Abbott Healthcare under the brand name Navelbine.
History
Vinorelbine was invented by the pharmacist Pierre Potier and his team from the CNRS in France in the 1980s and was licensed to the oncology department of the Pierre Fabre Group. The drug was approved in France in 1989 under the brand name Navelbine for the treatment of non-small celllung cancer. It gained approval to treat metastatic breast cancer in 1991. Vinorelbine received approval by the United States Food and Drug Administration (FDA) in December 1994 sponsored by Burroughs Wellcome Company. Pierre Fabre Group now markets Navelbine in the U.S., where the drug went generic in February 2003.
Vinorelbine interferes with microtubule assembly, particularly that of mitotic microtubules. Like other vinca alkaloids, vinorelbine may also interfere with the metabolism of amino acid, cyclic AMP, and glutathione, the activity of calmodulin-dependent Ca+2 transport ATPase, cellular respiration, and the biosynthesis of lipids and nucleic acid.
Originally developed at Pierre Fabre, vinorelbine i.v. was first licensed to GlaxoSmithKline in the U.S., Canada and Europe and to Kyowa Hakko in Japan. In July 2005, Pierre Fabre licensed the U.S. and Canadian rights to an oral formulation of vinorelbine to Novacea (acquired by Transcept Pharmaceuticals in 2009), while Pierre Fabre will continue to develop and commercialize this formulation in Europe and other countries. In October 2005, SD Pharmaceuticals granted Adventrx an exclusive license to certain rights to the emulsion formulation of the drug. In 2009, the company filed a regulatory application seeking approval for an injectable emulsion for the treatment of patients with stage III or IV NSCLC. Vinorelbine i.v. is currently registered in over 80 countries worldwide. In 2010, this application was withdrawn upon receipt of a refuse to file (FTF) decision from the FDA. The product is available for outlicensing.
In most European countries, vinorelbine is approved to treat non-small cell lung cancer and breast cancer. In the United States it is approved only for non-small cell lung cancer.
NAVELBINE (vinorelbine tartrate) Injection is for intravenous administration. Each vial contains vinorelbine tartrate equivalent to 10 mg (1-mL vial) or 50 mg (5-mL vial) vinorelbine in Water for Injection. No preservatives or other additives are present. The aqueous solution is sterile and nonpyrogenic. Vinorelbine tartrate is a semi-synthetic vinca alkaloid with antitumor activity. The chemical name is 3′,4′-didehydro-4′-deoxy-C’-norvincaleukoblastine [R-(R*,R*)-2, 3-dihydroxybutanedioate (1:2)(salt)]. Vinorelbine tartrate has the following structure:
 |
vinorelbine tartrate is a white to yellow or light brown amorphous powder with the molecular formula C45H54N4O8•2C4H6O6 and molecular weight of 1079.12. The aqueous solubility is > 1,000 mg/mL in distilled water. The pH of NAVELBINE (vinorelbine tartrate) Injection is approximately 3.5.
Uses
As stated above, Vinorelbine is approved for the treatment of non small cell lung cancer and metastatic breast cancer. It is also active inrhabdomyosarcoma.[3]
Oral formulation
An oral formulation has been marketed and registered in most European countries for the same settings. It has similar efficacy as the intravenous formulation, avoids venous toxicities of an infusion and is easier to take.
Side effects
Vinorelbine has a number of side-effects that can limit its use:
Chemotherapy-induced peripheral neuropathy (a progressive, enduring and often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs[4]), lowered resistance to infection, bruising or bleeding, anaemia,constipation, diarrhea, nausea, tiredness and a general feeling of weakness (asthenia), inflammation of the vein into which it was injected (phlebitis). Seldom severe hyponatremia is seen.
Less common effects are hair loss and allergic reaction.
vinorelbine (trade name: Navelbine (Navelbing)) is a novel semi-synthetic vinca alkaloids anticancer drugs, chemical name 3 ‘, 4’ – didehydro-4 ‘- deoxy _8 ‘- vinorelbine, developed by the French PieerFabre company and was listed first in France in 1989, it is mainly through inhibition of centromere tubulin polymerization, to stop cell division in mitotic metaphase, is a cell cycle-specific antineoplastic agents. A change in the structure, it has a strong and specific anti-mitotic properties, and exhibit antineoplastic vinca alkaloids than other low neurotoxicity, characteristics of strong anti-tumor activity.
vinorelbine complex chemical structure, synthesis is difficult, and the difficulty of separating large, making the synthesis of low yield and high cost.Published patent, if the application Patent CN101037446A, CN101284842A, CN1552715A, which are made of boron tetrafluoride shrink ring silver as reagents, but boron tetrafluoride is the price of silver more expensive chemical reagents, increased production costs.
http://www.google.com/patents/EP2135872A1?cl=en
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(1) or a salt thereof to dehydration vinblastine (I) as starting material, the reaction of bromo-condensed ring integrated crude vinorelbine (III):
Example 1
(a) by the dehydration hydrochloride ⑴ vinblastine vinorelbine crude preparation (III)
In a dry round bottom flask, dehydrated hydrochloric vinblastine 20g (laboratory preparation, HPLC purity 92.5%), in the dark and under nitrogen was added IOOOml dry dichloromethane, stirred and dissolved, add 20ml of pyridine , cooled in a dry ice-acetone bath to _50 ° C below bromosuccinimide was added dropwise 6g, trifluoroacetic acid and 13ml of dry methylene IOOOml mixed solution after the addition was complete, stirring below -50 ° C maintaining the reaction 2 hours.After completion of the reaction, adding silver nitrate 12g, 12g and IOOOml ammonium acetate and 800ml of deionized water mixed solution of tetrahydrofuran, stirred rapidly, and gradually heated to 20 ~ 30 ° C, maintaining this temperature, the reaction was stirred for 16 hours. After completion of the reaction, stirring was added dropwise 10% aqueous sodium carbonate aqueous phase PH8 ~ 9, filtered through celite after phase separation, the aqueous phase discarded, and the organic phase was dried, filtered and concentrated to dryness to give crude 14 vinorelbine. 3g (HPLC purity San 85%), 75% yield.
(2) Purification
The above crude product was 14.3g vinorelbine the column of basic alumina with 300 mesh, and with an eluent of 4% methanol – methylene chloride, collecting rich eluate was concentrated to dryness to give product vinorelbine First pure Bin 10. 7g (HPLC purity ^ 97%); then pure product obtained in the beginning of a C18 reversed phase column packing 50μπι, and with an eluent of 40% water – ethanol solution eluted, collected and washed pure deliquored product was extracted with dichloromethane and concentrated to dryness to give 8. lg, and then recrystallized from methanol to obtain pure vinorelbine 6. lg (HPLC purity San 99.5%). Relative to the total dewatering vinblastine hydrochloride 32% yield.
Example 2
(a) by the dehydration hydrochloride ⑴ vinblastine vinorelbine crude preparation (III)
In a dry round bottom flask, dehydrated hydrochloric vinblastine 20g (laboratory preparation, HPLC purity 92.5%), in the dark and under nitrogen was added IOOOml dry dichloromethane, stirred to dissolve, add 2,6 – lutidine 20ml, cooled in a dry ice-acetone bath to _50 ° C or less, is added dropwise bromosuccinimide and 5. 5g, 15ml of trifluoroacetic acid and a mixed solution of dry methylene IOOOml, dropping After stirring below -50 ° C maintaining the reaction 1.5 hours. After completion of the reaction, adding silver nitrate 12g, 12g and IOOOml ammonium acetate and 800ml of deionized water mixed solution of tetrahydrofuran, stirred rapidly, and gradually heated to 20 ~ 30 ° C, maintaining this temperature, the reaction was stirred M hours. After completion of the reaction, stirring was added dropwise 10% aqueous sodium carbonate aqueous phase PH8 ~ 9, filtered through celite and phase separation, the aqueous phase discarded, and the organic phase was dried, filtered and concentrated to dryness to give crude 14 vinorelbine. 7g (HPLC purity> 85%), yield 77.8%.
(2) Purification
The above crude vinorelbine 14. 7g on a column of basic alumina column with 300 mesh, and with an eluent of 4% methanol – methylene chloride, collecting rich eluate was concentrated to dryness to give product vinorelbine early pure llg (HPLC purity ^ 97%); Then get in early on 50 μ m pure product of C18 reverse phase column packing, and then with an eluent of 40% water – ethanol elution fractions containing pure product eluate product is extracted with dichloromethane and concentrated to dryness to give 8. 4g, and then recrystallized from methanol to obtain pure vinorelbine 6. 3g (HPLC purity> 99.5%) relative to the dewatering 0 Vinblastine Hydrochloride total yield of 33.3%.
…………….
Bioorganic and Medicinal Chemistry, 2008 , vol. 16, 11 p. 6269 – 6285
http://www.sciencedirect.com/science/article/pii/S0968089608003532?via=ihub
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Journal of Heterocyclic Chemistry, 1995 , vol. 32, 4 p. 1255 – 1260
http://onlinelibrary.wiley.com/doi/10.1002/jhet.5570320427/abstract
During the development of the bis-indole alkaloid anticancer drug Navelbine® (vinorelbine), several chemical degradants of the drug were isolated and identified. These included 7′-nor-6′,9′-secovinorelbine (7′,8′-bisnor-6′,9′-secoanhydrovinblastine) and 4-deacetyl-8′-vinorelbine (4-deacetyl-8′-noranhydrovinblastine). The elucidation of the structure of 7′-nor-6′,9′-secovinorelbine is described; the assignment of the proton and carbon spectra of both compounds is contrasted to the shift assignments of Navelbine.
References
- Marty M, Fumoleau P, Adenis A, Rousseau Y, Merrouche Y, Robinet G, Senac I, Puozzo C (2001). “Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors”. Ann Oncol 12 (11): 1643–9. doi:10.1023/A:1013180903805. PMID 11822766.
- Jordan, M.A.; Wilson, L. (2004). “Microtubules as a target for anticancer drugs.”. Nature Reviews. Cancer 4 (4): 253–65. doi:10.1038/nrc1317.PMID 15057285.
- Casanova, M; Ferrari, A; Spreafico, F; Terenziani, M; Massimino, M; Luksch, R; Cefalo, G; Polastri, D et al. (2002). “Vinorelbine in previously treated advanced childhood sarcomas: Evidence of activity in rhabdomyosarcoma”. Cancer 94 (12): 3263–8. doi:10.1002/cncr.10600. PMID 12115359.
- del Pino BM. Chemotherapy-induced Peripheral Neuropathy. NCI Cancer Bulletin. Feb 23, 2010;7(4):6.
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