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Brisbane scientists make cancer treatment breakthrough
BERAPROST….Stable prostacyclin analog.
BERAPROST
https://www.ama-assn.org/resources/doc/usan/beraprost.pdf
2,3,3a,8b-tetrahydro-2-hydroxy-1-(3-hydroxy-4-methyl-1-octen-6-ynyl)-1H-cyclopenta(b)benzofuran-5-butanoic acid
(±)-(IR*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octene-6-inyl]-1H-cyclopenta[b]benzofuran-5-butyric acid
rac-4-{(1R,2R,3aS,8bS)-2-hydroxy-1-[(1E,3S,4RS)-3-hydroxy-4-methyloct-1-en-6-ynyl]-2,3,3a,8b-tetrahydro-1H-cyclopenta[b][1]benzofuran-5-yl}butanoic acid
- Beraprost
- Beraprostum
- Beraprostum [INN-Latin]
- MDL 201229
- MDL-201229
- ML 1229
- ML-1229
- UNII-35E3NJJ4O6
Beraprost is a synthetic analogue of prostacyclin, under clinical trials for the treatment of pulmonary hypertension. It is also being studied for use in avoiding reperfusion injury.
As an analogue of prostacyclin PGI2, beraprost effects vasodilation, which in turn lowers the blood pressure. Beraprost also inhibits plateletaggregation, though the role this phenomenon may play in relation to pulmonary hypertension has yet to be determined.
Beraprost …sodium salt
ML 1129; Procyclin; TRK 100 (CAS 88475-69-8)
| Synonyms |
|
|---|---|
| Formal Name | 2,3,3a,8b-tetrahydro-2-hydroxy-1-(3-hydroxy-4-methyl-1-octen-6-ynyl)-1H-cyclopenta[b]benzofuran-5-butanoic acid, monosodium salt |
| CAS Number | 88475-69-8 |
| Molecular Formula | C24H29O5 · Na |
| Formula Weight | 420.5 |
- Beraprost sodium is a prostacyclin analog and an NOS3 expression enhancer that was first launched in 1992 in Japan pursuant to a collaboration between Astellas Pharma and Toray for the oral treatment of peripheral vascular disease (PVD), including Raynaud’s syndrome and Buerger’s disease. In 2000, the drug was commercialized for the treatment of pulmonary hypertension. Development for the oral treatment of intermittent claudication associated with arteriosclerosis obliterans (ASO) was discontinued at Kaken and United Therapeutics after the product failed to demonstrate statistically significant results in a phase III efficacy trial.
- In terms of clinical development, beraprost sodium is currently in phase II clinical trials at Kaken for the treatment of lumbar spinal canal stenosis and at Astellas Pharma for the oral treatment of primary chronic renal failure. The company is also conducting phase III trials for the treatment of nephrosclerosis. The drug has also been studied through phase II clinical trials at Kaken for the oral treatment of diabetic neuropathy, but recent progress reports for this indication have not been made available.
- Beraprost is an oral form of prostacyclin, a member of the family of lipid molecules known as eicosanoids. Prostacyclin is produced in the endothelial cells from prostaglandin H2 by the action of the enzyme prostacyclin synthase. It has been shown to keep blood vessels dilated and free of platelet aggregation.
- Beraprost sodium was originally developed at Toray in Japan, and rights to the drug were subsequently acquired by Astellas Pharma. A 1972 alliance between Toray and Kaken Pharmaceutical to develop and commercialize prostaglandin led to a later collaboration agreement for the development of beraprost. In 1990, Toray granted the right to market the drug to Sanofi (formerly known as sanofi-aventis), a licensing agreement that was later expanded to include Canada, the U.S., South America, Africa, Southeast Asia, South Asia, Korea and China. In September 1996, Bristol-Myers Squibb entered into separate agreements with Sanofi and Toray to acquire all development and marketing rights to beraprost in the U.S. and Canada. In January 1999, United Therapeutics and Toray agreed to cooperatively test the drug in North America, and in July 2000, a new agreement was signed pursuant to which United Therapeutics gained exclusive North American rights to develop and commercialize sustained-release formulations of beraprost for all vascular and cardiovascular diseases. In 1999, orphan drug designation was received in the U.S. for the treatment of pulmonary arterial hypertension associated with any New York Heart Association classification (Class I, II, III, or IV). In 2011, orphan drug designation was assigned in the U.S. for the treatment of pulmonary arterial hypertension.
-
The compound name of beraprost which is used as an antimetastasis agent of malignant tumors according to the present invention is (±)-(IR*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octene-6-inyl]-1H-cyclopenta[b]benzofuran-5-butyric acid. This compound has the following structure.
Beraprost is described in Japanese Laid-open Patent Application (Kokai) Nos. 58-32277, 57-144276 and 58-124778 and the like as a PGI₂ derivative having a structure in which the exoenol moiety characteristic to beraprost is converted to inter-m-phenylene structure. However, it is not known that beraprost has an activity to inhibit metastasis of malignant tumors.
-
The beraprost which is an effective ingredient of the agent of the present invention includes not only racemic body, but also d-body and l-body. Beraprost can be produced by, for example, the method described in the above-mentioned Japanese Laid-open Patent Application (Kokai) No. 58-124778. The salts of beraprost include any pharmaceutically acceptable salts including alkaline metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; primary, secondary and tertiary amine salts; and basic amino acid salts.
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EXAMPLE 6 Beraprost of the Formula (I)
0.246 g (0.6 mmol) of compound of the general formula (II) obtained in Example 5 is dissolved in 1 ml of methanol and 1 ml of 1 M aqueous sodium hydroxide solution is added dropwise slowly thereto. After stirring for an hour the methanol is distilled off from the reaction mixture in vacuum. The aqueous residue is diluted with 10 ml of water extracted with methyl-tert.butyl-ether and the combined organic phase is washed with saturated NaCl solution, dried on Na2SO4 and evaporated. The residue of evaporation is crystallized from ethylacetate-hexane mixture and the pure above mentioned title compound is obtained as colourless crystals.
Yield: 0.21 g (87%)
TLC-Rf (toluene-dioxan-acetic acid 20:10:1)=0.41
Melting point: 98–112° C.
1H NMR (400 MHz, CDCl3), δH (ppm): 1.00d, 1.03d [3H; J=6.8 Hz; 21-H3]; 1.79m [1H; 16-H]; 1.80t, 1.81t [3H, J=2.5,2.4 Hz; 20-H3]; 2.3–1.9m [5H, 3-H2, 10Hb, 17-H2]; 2.34t [1H; J=7.4 Hz; 2-H2]; 2.43m [1H; 12-H]; 2.64m [3H; 10-Ha, 4-H2]; 3.43t, 3.44t [1H, J=8.7,8.5 Hz; 8-H]; 3.92m [1H; 11-H]; 4.07t, 4.17t [1H, J=7.3,5.6 Hz; 15-H]; 4.3b [2H; OH]; 5.09m [1H, 9-H]; 5.58dd, 5.61dd [1H; J=15.3,6.5 Hz; 14-H]; 5.67dd, 5.68dd [1H; J=15.3,8.0 Hz; 13-H]; 6.77m [1H; 2′-H]; 6.95m [2H; 1′-H,3′-H]13C NMR (100 MHz, CDCl3), δC (ppm): 3.5, 3.6 [C-20]; 14.7, 15.8 [C-21]; 22.3, 22.6 [C-17]; 24.6 [C-2]; 29.1 [C-4]; 33.1 [C-3]; 38.2, 38.3 [C-16]; 41.2 [C-10]; 50.4 [C-8]; 58.8 [C-12]; 75.8, 76.3, 76.4 [C-11, C-15]; 77.2, 77.4 [C-18, C-19]; 84.5, 84.6 [C-9]; 120.6 [C-2′]; 121.9 [C-3′]; 123.2 [C-5]; 129.0 [C-1′]; 129.7 [C-7]; 132.3, 133.0, 133.8, 134.0 [C-13, C-14]; 157.2 [C-6]; 178.3 [C-1].
EXAMPLE 7 Beraprost Sodium Salt (The Sodium Salt of the Compound of Formula (I)
0.199 g of beraprost is dissolved in 2 ml of methanol, 0.5 ml of 1 M aqueous solution of sodium hydroxide is added thereto and after their mixing the solvent is evaporated in vacuum and thus the above title salt is obtained as colourless crystals.
Yield: 0.21 g (100%)
Melting point: >205° C.
1H NMR (400 MHz, DMSO-d6), δH (ppm): 0.90d, 0.92d [3H; J=6.7 Hz; 21-H3]; 1.75–1.55m [7H; 10Hb, 16-H, 3-H2, 20-H3]; 1.89t [2H, J=7.6 Hz; 2-H2]; 1.94m [1H; 17-Hb]; 2.16q [1H, J=8.5 Hz; 12-H]; 2.25m [1H; 17-Ha]; 2.44t [2H; J=7.5 Hz; 4-H2]; 2.50o [1H; 10-Ha]; 3.39t [1H, J=8.5 Hz; 8-H]; 3.72td [1H; J=8.5,6.1 Hz; 11-H]; 3.84t 3.96t [1H, J=6.5,6.0 Hz; 15-H]; 4.85b [2H, OH]; 5.01dt [1H, J=8.5,6.6 Hz; 9-H]; 5.46dd, 5.47dd [1H; J=15.4,6.5 Hz, J=15.4,6.0 Hz; 14-H]; 5.65dd, 5.66dd [1H; J=15.4,8.5 Hz; 13-H]; 6.71m [1H; 2′-H]; 6.92m [2H; 1′-H, 3′-H] During the above thin layer chromatography (TLC) procedures we used plates MERCK Kieselgel 60 F254, thickness of layer is 0.2 mm, length of plates is 5 cm.
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-
Reaction Scheme A.
-
The starting material of bromocarboxylic acid, Compound 1, and the process for the preparation thereof are disclosed in Japanese Patent Application No. 29637/81.
-
Scheme B.
REACTION SCHEME B
-
- REACTION SCHEME C
-
Org Lett 2012, 14(1): 299
EP0024943A1 Sep 2, 1980 Mar 11, 1981 Toray Industries, Inc. 5,6,7-Trinor-4,8-inter-m-phenylene PGI2 derivatives and pharmaceutical compositions containing them EP0084856A1 Jan 19, 1983 Aug 3, 1983 Toray Industries, Inc. 5,6,7-Trinor-4, 8-inter-m-phenylene prostaglandin I2 derivatives JP3069909B Title not available
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Sulfoaildenafil …. An analog of Sildenafil which has been used as an illegal adulterant in some dietary supplements
Sulfoaildenafil
An analog of Sildenafil which has been used as an illegal adulterant in some dietary supplements.
856190-47-1 cas no
5-(5-(((3R,5S)-3,5-Dimethylpiperazin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-7(4H)-thione
-
7H-Pyrazolo(4,3-d)pyrimidine-7-thione, 5-(5-(((3R,5S)-3,5-dimethyl-1-piperazinyl)sulfonyl)-2-ethoxyphenyl)-1,6-dihydro-1-methyl-3-propyl-, rel-
- Sildenafil thione
- Thioaildenafil
- UNII-33DX49E09G
-
-
C23-H32-N6-O3-S2
- 504.6768
-
Sulfoaildenafil (thioaildenafil) is a synthetic chemical compound that is a structural analog of sildenafil (Viagra).[1] It was first reported in 2005,[2] and it is not approved by any health regulation agency. Like sildenafil, sulfoaildenafil is a phosphodiesterase type 5 inhibitor.
Sulfoaildenafil has been found as an adulterant in a variety of supplements which are sold as “natural” or “herbal” sexual enhancement products.[3][4][5][6] A range of designer analogues of USA FDA-approved inhibitors of type-5 cGMP-specific phosphodiesterase (PDE5), such as sildenafil and vardenafil, have been detected in recent years as adulturants in over-the-counter herbal aphrodisiac products and dietary supplements,[7][8][9] in an apparent attempt to circumvent both the legal restrictions on sale of erectile dysfunction drugs, which are prescription-onlymedicines in most Western countries, and the patent protection which prevents sale of these drugs by competitors except under license to their inventors.
Figure 1. Biological pathway of penile erection
These compounds have been demonstrated to display PDE5 inhibitory activity in vitro and presumably have similar effects when consumed, but have undergone no formal testing in either humans or animals, and as such represent a significant health risk to consumers of these products due to their unknown safety profile.[10] Some attempts have been made to ban these drugs as unlicensed medicines, but progress has been slow so far, as even in those jurisdictions which have laws targeting designer drugs, the laws are drafted to ban analogues of illegal drugs of abuse, rather than analogues of prescription medicines. However at least one court case has resulted in a product being taken off the market.[11]
Figure 2. PDE5 domains
In December 2010, the United States Food and Drug Administration (FDA) issued a warning to consumers about such products stating, “The FDA has found many products marketed as dietary supplements for sexual enhancement during the past several years that can be harmful because they contain active ingredients in FDA-approved drugs or variations of these ingredients.”[12]
Figure 3. PDE5 Domains
Volume 50, Issue 2, 8 September 2009, Pages 228–231
Phosphodiesterase type 5 (PDE-5) inhibitors represent a class of drugs used primarily in the treatment of erectile dysfunction. Currently, three PDE-5 inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for use in the United States: sildenafil citrate, tadalafil, and vardenafil hydrochloride trihydrate. A bulk material, labeled as an ingredient for a dietary supplement, was analyzed for the presence of PDE-5 inhibitors. The compound that was detected displayed structural similarities to sildenafil, and was characterized further using LC–MSn, FTICRMS, X-ray crystallography and NMR. The compound was given the name sulfoaildenafil. When compared to sildenafil, sulfoaildenafil contains a sulfur atom substitution for the oxygen atom in the pyrazolopyrimidine portion of the molecule, and a 3,5-dimethyl substitution on the piperazine ring, rather than the 4-methyl moiety. The X-ray crystallographic data indicate that the material in this sample is comprised of two polymorphs, which may affect the chemical and/or biological properties of any product formulated with this compound.
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http://www.theresonance.com/2012/categories/pharmaceutical/adulterated-natural-products
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Herbal Supplement for Erectile Dysfunction Found to Contain Thio Structural Analog of Sildenafil (Viagra)
A herbal supplement marketed to alleviate erectile dysfunction was recently submitted for testing in our laboratory because it was surprisingly effective considering it should only contain the traditional herbals utilized for this problem such as Oyster, 2-Deoxy-D Glucose, Barberry, Snow Lotus, Bombyx Mori L., Ginger Root, Salfron Crocus.
http://process-nmr.com/WordPress/?cat=5
References
- Gratz, SR; Zeller, M; Mincey, DW; Flurer, CL (2009). “Structural characterization of sulfoaildenafil, an analog of sildenafil”. Journal of pharmaceutical and biomedical analysis 50 (2): 228–31. doi:10.1016/j.jpba.2009.04.003. PMID 19427155.
- Li, Shuxin; Ren, Jianping; Zhao, Yanjin; Lv, Qiujun; Guo, Jinhua. Pyrazolopyrimidinethione Derivatives, Salts and Solvates thereof, Preparation Methods and Use thereof. WO 2005058899
- Gryniewicz, CM; Reepmeyer, JC; Kauffman, JF; Buhse, LF (2009). “Detection of undeclared erectile dysfunction drugs and analogues in dietary supplements by ion mobility spectrometry”. Journal of pharmaceutical and biomedical analysis 49 (3): 601–6. doi:10.1016/j.jpba.2008.12.002. PMID 19150190.
- FDA warns consumers to avoid sexual enhancement pills, Sanjay Gupta, CNN, December 13th, 2010
- Reepmeyer JC, d’Avignon DA (January 2009). “Structure elucidation of thioketone analogues of sildenafil detected as adulterants in herbal aphrodisiacs”. Journal of Pharmaceutical and Biomedical Analysis 49 (1): 145–50. doi:10.1016/j.jpba.2008.10.007. PMID 19042103.
- Balayssac S, Trefi S, Gilard V, Malet-Martino M, Martino R, Delsuc MA (November 2008). “2D and 3D DOSY (1)H NMR, a useful tool for analysis of complex mixtures: Application to herbal drugs or dietary supplements for erectile dysfunction”. Journal of Pharmaceutical and Biomedical Analysis 50 (4): 602–12. doi:10.1016/j.jpba.2008.10.034. PMID 19108978.
- Zou P, Oh SS, Hou P, Low MY, Koh HL (February 2006). “Simultaneous determination of synthetic phosphodiesterase-5 inhibitors found in a dietary supplement and pre-mixed bulk powders for dietary supplements using high-performance liquid chromatography with diode array detection and liquid chromatography-electrospray ionization tandem mass spectrometry”. J Chromatogr A 1104 (1-2): 113–22. doi:10.1016/j.chroma.2005.11.103. PMID 16364350.
- Gratz SR, Gamble BM, Flurer RA (2006). “Accurate mass measurement using Fourier transform ion cyclotron resonance mass spectrometry for structure elucidation of designer drug analogs of tadalafil, vardenafil and sildenafil in herbal and pharmaceutical matrices”. Rapid Commun. Mass Spectrom. 20 (15): 2317–27. doi:10.1002/rcm.2594. PMID 16817245.
- Hou P, Zou P, Low MY, Chan E, Koh HL (September 2006). “Structural identification of a new acetildenafil analogue from pre-mixed bulk powder intended as a dietary supplement”. Food Addit Contam 23 (9): 870–5. doi:10.1080/02652030600803856. PMID 16901855.
- Oh, SS; Zou, P; Low, MY; Koh, HL (2006). “Detection of sildenafil analogues in herbal products for erectile dysfunction.”. Journal of toxicology and environmental health. Part A 69 (21): 1951–8.doi:10.1080/15287390600751355. PMID 16982533.
- Venhuis, BJ; Blok-Tip, L; De Kaste, D (2008). “Designer drugs in herbal aphrodisiacs.”. Forensic Science International 177 (2–3): e25–7. doi:10.1016/j.forsciint.2007.11.007. PMID 18178354.
- FDA warns consumers to avoid Man Up Now capsules, United States Food and Drug Administration, Dec. 15, 2010
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%.
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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.
Advanced Nanoparticle System Kills Cancer Cells From Within
The latest cancer targeting nanoparticles being developed in labs around the world are getting ever more complex and are utilizing multiple mechanisms to find and strike their targets. Researchers at North Carolina State University and the University of North Carolina at Chapel Hill just published an article in Nature Communications describing a nanoparticle that delivers its killer payload only when inside cells by homing in on ATP (adenosine triphosphate).
ATP is the famous energy molecule that powers the activity inside of cells, and the new nanoparticle carries DNA strands bound to doxorubicin, an anti-cancer drug, than unfold when high levels of ATP are present. The nanoparticles themselves have a layer of hyaluronic acid (HA) that attracts some types of cancer cells, allowing the nanoparticles to enter and open up, releasing the folded DNA strands.
From study abstract in Nature Communications:
The half-maximal inhibitory concentration of ATP-responsive nanovehicles is 0.24 μM in MDA-MB-231 cells…
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Chemists devise a new way to manufacture peptide drugs, which hold promise for treating many diseases
MIT chemists have devised a way to rapidly combine amino acids into protein fragments known as peptides. Credit: Alexander Vinogradov
Small protein fragments, also called peptides, are promising as drugs because they can be designed for very specific functions inside living cells. Insulin and the HIV drug Fuzeon are some of the earliest successful examples, and peptide drugs are expected to become a $25 billion market by 2018.
However, a major bottleneck has prevented peptide drugs from reaching their full potential: Manufacturing the peptides takes several weeks, making it difficult to obtain large quantities, and to rapidly test their effectiveness.
That bottleneck may soon disappear: A team of MIT chemists and chemical engineers has designed a way to manufacture peptides in mere hours. The new system, described in the March 21st issue of journal ChemBioChem, could have a major impact on peptide drug development, says Bradley Pentelute, an assistant…
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100th approval … Pradaxa® (dabigatran etexilate) now approved in more than 100 countries for stroke prevention in atrial fibrillation
More than 100 countries have now approved Boehringer Ingelheim’s Pradaxa® for the prevention of stroke and systemic embolism for adult patients with the most common sustained heart rhythm condition (non-valvular atrial fibrillation, nvAF).
The 100th approvalwas announced by the Jordan Food and Drug Administration. Further regulatory approvals for Pradaxa® are expected to be received in the near future. The continuous flow of regulatory approvals from health authorities all over the world reaffirms the overarching benefits delivered to patients by the treatment and supports previous announcements by the U.S. Food and Drugs Administation (FDA) and the European Medicines Agency (EMA).Pradaxa®, in addition, offers the most robust clinical data set and the longest real-world experience for stroke prevention in atrial fibrillation (SPAF) compared to any of the novel oral anticoagulants, providing ongoing support for physician use of the novel treatment
Effective Natural Remedies For Kidney Stones
Effective Natural Remedies For Kidney Stones
==> http://www.rapidhomeremedies.com/remedies-to-cure-kidney-stones.html
Facts & Remedies You Should Know to Prevent and Cure Kidney Stones
If you have been diagnosed with kidney stones, you know how painful it is to live with these stones- big or small- in your kidneys. The acute pain in your left or right flanks going towards the lower abdomen and groin area and even towards your back is something that makes you shudder even if thought about. The feeling of nausea and vomiting along with the burning sensation while you pass urine and also the urgency and frequency of urinating, all these has led you to wish that you get rid of kidney stones as soon as possible.
While most kidney stones are small, it doesn’t mean they are harmless bunnies. One little stone in the urinary tract can make you suffer more than you can imagine.http://www.rapidhomeremedies.com/remedies-to-cure-kidney-stones.html
FDA Approves Neuraceq (florbetaben F18 injection) for PET Imaging of Beta-Amyloid Plaques
FLORBETABEN F18
Diagnostic radiopharmaceutical
1. Benzenamine, 4-[(1E)-2-[4-[2-[2-[2-(fluoro-18F)ethoxy]ethoxy]ethoxy]phenyl]
ethenyl]-N-methyl-
2. 4-{(1E)-2-(4-{2-[2-(2-[18F]fluoroethoxy)ethoxy]ethoxy}phenyl)eth- 1-en-1-yl}-N-methylaniline
C21H26[18F]NO3
358.5
Bayer Healthcare
UNII-TLA7312TOI
CAS REGISTRY NUMBER 902143-01-5
https://www.ama-assn.org/resources/doc/usan/florbetaben-f18.pdf
Berlin/Boston, March 20, 2014‒ Piramal Imaging today announced that the U.S. Food and Drug Administration (FDA) has approved Neuraceq. This approval comes only four weeks after receiving marketing authorization for Neuraceq from the European Commission.
Neuraceq is indicated for Positron Emission Tomography (PET) imaging of the brain to estimate beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) and other causes of cognitive decline.
read at
4-[(E)-2-(4-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline has been labeled with [F-18]fluoride and is claimed by patent application WO2006066104 and members of the corresponding patent family.
4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline
The usefulness of this radiotracer for the detection of Αβ plaques have been reported in the literature (W. Zhang et al., Nuclear Medicine and Biology 32 (2005) 799-809; C. Rowe et al., Lancet Neurology 7 (2008) 1 -7).
The synthesis of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)- vinyl]-N-methylaniline has been described before:
a) W. Zhang et al., Nuclear Medicine and Biology 32 (2005) 799-809.
4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline
4 mg precursor 2a (2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]- phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl methanesulfonate) in 0.2 mL
DMSO were reacted with [F-18]fluoride/kryptofix/potassium carbonate complex. The intermediate was deprotected with HCI and neutralized with
NaOH. The mixture was extracted with ethyl acetate. The solvent was dried and evaporated, the residue was dissolved in acetonitrile and purified by semi-preparative HPLC. 20% (decay corrected), 1 1 % (not corrected for decay) 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N- methylaniline were obtained in 90 min.
WO2006066104
4 mg precursor 2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]- phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl methanesulfonate in 0.2 mL DMSO were reacted with [F-18]fluoride/kryptofix/potassium carbonate complex. The intermediates was deprotected with HCI and neutralized with NaOH. The mixture was extracted with ethyl acetate. The solvent was dried and evaporated, the residue was dissolved in acetonitrile and purified by semi- preparative HPLC. 30% (decay corrected), 17% (not corrected for decay) 4- [(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N- methylaniline were obtained in 90 min. to yield N-Boc protected 4-[(E)-2-(4-{2-[2-(2-[F- 18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline. The unreacted perfluorinated precursor was removed using a fluorous phase cartridge.
Deprotection, final purification and formulation to obtain a product, suitable for injection into human is not disclosed. Furthermore, the usefulness (e.g. regarding unwanted F-19/F-18 exchange) of this approach at a higher radioactivity level is not demonstrated. Finally, this method would demand a two-pot setup (first reaction vessel: fluorination, followed by solid-phase- extraction, and deprotection in the second reaction vessel).
However, the focus of the present invention are compounds and methods for an improved “one-pot process” for the manufacturing of 4-[(E)-2-(4-{2-[2-(2- [F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline.
Very recently, further methods have been described:
d) US201001 13763
The mesylate precursor 2a was reacted with [F-18]fluoride species in a solvent mixture consisting of 100 μΙ_ acetonitrile and 500 μΙ_ tertiary alcohol. After fluorination for 10 min at 100-150 °C, the solvent was evaporated. After deprotection (1 N HCI, 5 min, 100-120 °C), the crude product was purified by HPLC (C18 silica, acetonitrile / 0.1 M ammonium formate).
e) H. Wang et al., Nuclear Medicine and Biology 38 (201 1 ) 121 -127
5 mg precursor 2a (2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]- phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl methanesulfonate) in 0.5 ml_
DMSO were reacted with [F-18]fluoride/kryptofix/potassium carbonate complex. The intermediate was deprotected with HCI and neutralized with NaOH. The crude product was diluted with acetonitrile / 0.1 M ammonium dformate (6/4) and purified by semi-preparative HPLC. The product fraction was collected, diluted with water, passed through a C18 cartridge and eluted with ethanol, yielding 17% (not corrected for decay) 4-[(E)-2-(4-{2-[2-(2-[F- 18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline within 50 min. In the paper, the conversion of an unprotected mesylate precursor (is described:
5 mg unprotected mesylate precursor (2-{2-[2-(4-{(E)-2-[4- (methylamino)phenyl]vinyl}phenoxy)ethoxy]-ethoxy}ethyl 4- methanesulfonate) in 0.5 ml_ DMSO were reacted with [F- 18]fluoride/kryptofix/potassium carbonate complex. The crude product was diluted with acetonitrile / 0.1 M ammonium formate (6/4) and purified by semi- preparative HPLC. The product fraction was collected, diluted with water, passed through a C18 cartridge and eluted with ethanol, yielding 23% (not corrected for decay) 4-[(E)-2-(4-{2-[2-(2-[F-
18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline within 30 min. Beside the purification by HPLC, a process based on solid-phase-extraction was investigated, but the purity was inferior to that with HPLC purification. So far, one-pot radiolabelings have been performed using a mesylate precursor. It is know, that for F-18 labeling of stilbenes, mesylates have advantages over corresponding tosylates by providing more clean reactions with less amount of by-products (W. Zhang et al. Journal of Medicinal Chemistry 48 (2005) 5980- 5988), whereas the purification starting from the tosylate precursor was tedious and time consuming resulting in a low yield.
In contrast to this teaching of the prior art, we found advantages of tosylate and further arylsulfonate precursors for 4-[(E)-2-(4-{2-[2-(2-[F- 18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline compared to the corresponding mesylate. Less non-radioactive by-products that eluted close to the retention time of 4-[(E)-2-(4-{2-[2-(2-[F-
18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline were found in the crude products if arylsulfonate precursors were used (Example 2 – Example 6) compared to the crude mixture that was obtained after conversion of the mesylate precursor (Example 1 ).
The favorable by-product profile after radiolabeling of tosylate precursor 2b (Figure 10) compared to the radiolabeling of mesylate precursor 2a (Figure 7) supported an improved cartridge based purification (Example 8, Example 9).
…………………
The term “F-18” means fluorine isotope 18F. The term”F-19″ means fluorine isotope 19F. EXAMPLES
Example 1 Radiolabeling of mesylate precursor 2a
4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline
Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2a (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 1 ). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.
Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 21 % (corrected for decay).
Example 2 Synthesis and radiolabeling of tosylate precursor 2b
4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline
4-Dimethylaminopyridine (26.7 mg) and triethylamine (225 μΙ_) were added to a solution of 1 .0 g terf-butyl {4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate (4) in dichloromethane (12 mL) at 0 °C. A solution of p- toluenesulfonyl chloride (417 mg) in dichloromethane (13.5 mL) was added at 0 °C. The resulting mixture was stirred at room temperature over night. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, 0- 80% ethyl acetate in hexane). 850 mg 2b were obtained as colorless solid.
1 H NMR (300 MHz, CDCI3) δ ppm 1 .46 (s, 9 H), 2.43 (s, 3 H), 3.27 (s, 3 H), 3.59-3.73 (m, 6 H), 3.80- 3.86 (m, 2 H), 4.05-4.19 (m, 2 H), 6.88-7.05 (m, 4 H), 7.21 (d, J = 8.3 Hz, 2 H), 7.32 (d, J = 8.3 Hz, 2 H), 7.39-7-47 (m, 4 H), 7.80 (d, J = 8.3 Hz, 2 H). MS (ESIpos): m/z = 612 (M+H)+
Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2b (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 2). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.
Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 25% (corrected for decay).
Example 3 Synthesis and radiolabeling of 2c (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl
4-bromobenzenesulfonate)
4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline To a stirred solution of 100 mg (0,219 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate
(WO2006/066104) in 2 mL THF was added a solution of 140 mg (0.548 mmol) 4-brombenzene sulfonylchlorid in 3 mL THF drop by drop. The reaction mixture was cooled to 0°C. 156.8 mg (1 .1 mmol) potassium trimethylsilanolat was added. The milky suspension was stirred at 0°C for 2 hours and at 80°C for another 2 hours. The reaction mixture was poured onto ice-cooled water. The aqueous solution was extracted with dichloromethane several times. The combined organic phases were dried with sodium sulphate and concentrated in vacuum. The crude product was purified using silica gel with ethyl acetate/hexane-gradient as mobile phase. The desired product 2c was obtained with 77 mg (0.1 14 mmol, 52.0 % yield).
1 H NMR (300 MHz, CDCI3) δ ppm 1 .39 (s, 10 H) 3.20 (s, 3 H) 3.50 – 3.57 (m, 2 H) 3.57 – 3.61 (m, 2 H) 3.61 – 3.66 (m, 2 H) 3.72 – 3.80 (m, 2 H) 4.02 – 4.10 (m, 2 H) 4.10 – 4.17 (m, 2 H) 6.79 – 6.85 (m, 2 H) 6.91 (d, J=8.10 Hz, 2 H) 7.10 – 7.17 (m, 2 H) 7.32 – 7.41 (m, 5 H) 7.57 – 7.65 (m, 2 H) 7.67 – 7.74 (m, 2 H)
MS (ESIpos): m/z = 676/678 (M+H)+
Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2c (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 3). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.
Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 43% (corrected for decay). Example 4 Synthesis and radiolabeling of 2d (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl
4-(adamantan-1 -yl)benzenesulfonate)
4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline
To a stirred solution of 151 mg (0,330 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate
(WO2006/066104), 4.03 mg (0,033 mmol) DMAP und 36.7 mg (363 mmol) triethylamine in 4 mL dichlormethane was added a solution of 97,4 mg (0,313 mmol) 4-(adamantan-1 -yl)benzene sulfonylchloride in 1 mL dichlormethane at 0°C. The reaction mixture was stirred at 0°C for 1 hour and over night at room temperature. 7.3 mg (0,072 mmol) triethylamin und 19.5 mg (0.062 mmol) 4- (adamantan-l -yl)benzenesulfonyl chloride were added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 days. It was concentrated in vacuum. The crude product was purified using silica gel with ethyl acetate/hexane-gradient as mobile phase. The desired product 2d was obtained with 104 mg (0.142 mmol, 43.4% yield).
1 H NMR (300 MHz, CDCI3) δ ppm 1 .51 (s, 9 H), 1 .62 (s, 1 H), 1 .74 – 1 .91 (m, 6 H), 1 .94 (d, J=3.20 Hz, 6 H), 2.16 (br. s., 3 H), 3.31 (s, 3 H), 3.63 – 3.69 (m, 2 H), 3.69 – 3.73 (m, 2 H), 3.76 (dd, J=5.27, 4.52 Hz, 2 H), 3.89 (d, J=4.90 Hz, 2 H), 4.13 – 4.26 (m, 4 H), 6.95 (d, J=8.85 Hz, 2 H), 7.02 (d, J=8.29 Hz, 2 H), 7.25 (d, J=8.48 Hz, 2 H), 7.40 – 7.52 (m, 4 H), 7.55 (m, J=8.67 Hz, 2 H), 7.89 (m, J=8.67 Hz, 2 H)
MS (ESIpos): m/z = 732 (M+H)+
Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2d (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 4). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.
Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 27% (corrected for decay).
Example 5 Synthesis and radiolabeling of 2e (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl
4-cyanobenzenesulfonate)
4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline
To a stirred solution of 151 mg (0.330 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate
(WO2006/066104), 4.03 mg (0.033 mmol) DMAP und 36.7 mg (0.363 mmol) triethylamine in 4 mL dichlormethane was added a solution of 63.2 mg (0.313 mmol) 4-cyanobenzenesulfonyl chloride in 1 mL dichlormethane at 0°C. The reaction mixture was stirred over night and concentrated in vacuum. The crude product was purified using silica gel with ethyl acetate/hexane-gradient as mobile phase. The desired product 2e was obtained with 118 mg (0.190 mmol, 57.6 % yield).
1 H NMR (400 MHz, CDCI3) δ ppm 1 .47 (s, 9 H) 3.28 (s, 3 H) 3.58 – 3.63 (m, 2 H) 3.63 – 3.68 (m, 2 H) 3.70 – 3.75 (m, 2 H) 3.81 – 3.87 (m, 2 H) 4.1 1 – 4.18 (m, 2 H) 4.24 – 4.30 (m, 2 H) 6.91 (d, J=8.59 Hz, 2 H) 6.99 (dt, 2 H) 7.22 (d, J=8.34 Hz, 2 H) 7.39 – 7.50 (m, 4 H) 7.83 (m, J=8.59 Hz, 2 H) 7.98 – 8.1 1 (m, 2 H)
MS (ESIpos): m/z = 623 (M+H)+
Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2e (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 5). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.
Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 31 % (corrected for decay).
Example 6 Synthesis and radiolabeling of 2f (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl
2-nitrobenzenesulfonate)
4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- eth oxy} phe nyl )vi ny I] -N -methyla n i I i ne
To a stirred solution of 200 mg (0.437 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate
(WO2006/066104), 5.34 mg (0.044 mmol) DMAP und 47.5 mg (0.470 mmol) triethylamine in 4 mL dichlormethane was added a solution of 92 mg (0,415 mmol) 2-nitrobenzenesulfonyl chloride in 1 mL dichlormethane at 0°C. The reaction mixture was stirred over night and concentrated in vacuum. The crude product was purified with ethyl acetate/hexane-gradient as mobile phase using silica gel. The desired product 2f was obtained with 77 mg (0.1 19 mmol, 59.5 % yield). 1 H NMR (400 MHz, CDCI3) δ ppm 1 .39 (s, 9 H) 3.20 (s, 3 H) 3.55 – 3.63 (m, 4 H) 3.59 (m, 4 H) 3.69 – 3.74 (m, 2 H) 3.75 – 3.80 (m, 2 H) 4.06 (dd, J=5.68, 3.92 Hz,
2 H) 4.32 – 4.37 (m, 2 H) 6.80 – 6.84 (m, 2 H) 6.84 – 6.98 (dt, 2 H) 7.14 (d, J=8.59 Hz, 2 H) 7.35 (d, J=3.03 Hz, 2 H) 7.37 (d, J=2.78 Hz, 2 H) 7.62 – 7.74 (m,
3 H) 8.06 – 8.1 1 (m, 1 H)
Cabazitaxel
Cabazitaxel
For treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.
4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate
(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(Acetyloxy)-15-{[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoyl]oxy}-1-hydroxy-9,12-dimethoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-ene-2-yl benzoate
183133-96-2
Cabazitaxel is prepared by semi-synthesis from 10-deacetylbaccatin III (10-DAB) which is extracted from yew tree needles. The chemical name of cabazitaxel is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxy-tax-11-en-2-yl benzoate and is marketed as a 1:1 acetone solvate (propan-2-one),
Cabazitaxel is an anti-neoplastic used with the steroid medicine prednisone. Cabazitaxel is used to treat people with prostate cancer that has progressed despite treatment with docetaxel. Cabazitaxel is prepared by semi-synthesis with a precursor extracted from yew needles (10-deacetylbaccatin III). It was approved by the U.S. Food and Drug Administration (FDA) on June 17, 2010.
Cabazitaxel (previously XRP-6258, trade name Jevtana) is a semi-synthetic derivative of a natural taxoid.[1] It was developed by Sanofi-Aventis and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of hormone-refractory prostate cancer on June 17, 2010. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy.[2]
Nagesh Palepu, “CABAZITAXEL FORMULATIONS AND METHODS OF PREPARING THEREOF.” U.S. Patent US20120065255, issued March 15, 2012.
Cabazitaxel in combination with prednisone is a treatment option for hormone-refractory prostate cancer following docetaxel-based treatment.
Clinical trials
In a phase III trial with 755 men for the treatment of castration-resistant prostate cancer, median survival was 15.1 months for patients receiving cabazitaxel versus 12.7 months for patients receiving mitoxantrone. Cabazitaxel was associated with more grade 3–4 neutropenia (81.7%) than mitoxantrone (58%).[3]
| United States | 5438072 | 2010-06-17 | exp 2013-11-22 |
| United States | 5698582 | 2010-06-17 | 2012-07-03 |
| United States | 5847170 | 2010-06-17 | 2016-03-26 |
| United States | 6331635 | 2010-06-17 | 2016-03-26 |
| United States | 6372780 | 2010-06-17 | 2016-03-26 |
| United States | 6387946 | 2010-06-17 | 2016-03-26 |
| United States | 7241907 | 2010-06-17 | 2025-12-10 |
JEVTANA (cabazitaxel) is an antineoplastic agent belonging to the taxane class. It is prepared by semi-synthesis with a precursor extracted from yew needles.
The chemical name of cabazitaxel is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9oxo-5,20-epoxytax-11-en-2-yl benzoate – propan-2-one(1:1).
Cabazitaxel has the following structural formula:
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Cabazitaxel is a white to almost-white powder with a molecular formula of C45H57NO14•C3H6O and a molecular weight of 894.01 (for the acetone solvate) / 835.93 (for the solvent free). It is lipophilic, practically insoluble in water and soluble in alcohol.
JEVTANA (cabazitaxel) Injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution and is available in single-use vials containing 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 g polysorbate 80. Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80.
DILUENT for JEVTANA is a clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL.
JEVTANA requires two dilutions prior to intravenous infusion. JEVTANA injection should be diluted only with the supplied DILUENT for JEVTANA, followed by dilution in either 0.9% sodium chloride solution or 5% dextrose solution.
The taxane family of terpenes has received much attention in the scientific and medical community, because members of this family have demonstrated broad spectrum of anti-leukemic and tumor-inhibitory activity. A well-known member of this family is paclitaxel (Taxol®).
Paclitaxel (Taxol) Paclitaxel was first isolated from the bark of the pacific yew tree (Taxus brevifolia) in 1971 , and has proved to be a potent natural anti-cancer agent. To date, paclitaxel has been found to have activity against different forms of leukemia and against solid tumors in the breast, ovary, brain, and lung in humans.
As will be appreciated, this beneficial activity has stimulated an intense research effort over recent years with a view to identifying other taxanes having similar or improved properties, and with a view to developing synthetic pathways for making these taxanes, such as paclitaxel.
This research effort led to the discovery of a synthetic analogue of paclitaxel, namely, docetaxel (also known as Taxotere®). As disclosed in U.S. Patent No. 4,814,470, docetaxel has been found to have a very good anti-tumour activity and better bioavailability than paclitaxel. Docetaxel is similar in structure to paclitaxel, having t- butoxycarbonyl instead of benzoyl on the amino group at the 3′ position, and a hydroxy group instead of the acetoxy group at the C-10 position.
As will be appreciated, taxanes are structurally complicated molecules, and the development of commercially viable synthetic methods to make taxanes has been a challenge. A number of semi-synthetic pathways have been developed over the years, which typically begin with the isolation and purification of a naturally occurring starting material, which can be converted to a specific taxane derivative of interest. Cabazitaxel (I) is an anti-tumor drug which belongs to the taxol family. It differs from docetaxel in that it has methoxy groups at positions 7 and 10 of the molecule, as opposed to the hydroxyl groups at equivalent positions in docetaxel. Cabazitaxel is obtained by semi-synthesis from an extract of Chinese yew (Taxus mairei). It is understood that cabazitaxel can be obtained via semi-synthesis from other taxus species including T.candensis, T.baccatta, T.chinensis, T. mairei etc.
Cabazitaxel is a semi-synthetic derivative of the natural taxoid 0-deacetylbaccatin III (10-DAB) with potentially unique antineoplastic activity for a variety of tumors.
Cabazitaxel binds to and stabilizes tubulin, resulting in the inhibition of microtubule depolymerization and cell division, cell cycle arrest in the G2/M phase, and the inhibition of tumor cell proliferation. This drug is a microtubule depolymerization inhibitor, which can penetrate blood brain barrier (BBB).
Cabazitaxel was recently approved by the US Federal Drug Administration (FDA) for the treatment of docetaxel resistant hormone refractory prostate cancer. It has been developed by Sanofi-Aventis under the trade name of Jevtana. The CAS number for the compound is 183133-96-2. A synonym is dimethoxydocetaxel. The compound is also known as RPR-1 16258A; XRP6258; TXD 258; and axoid XRP6258.
The free base form of cabazitaxel has the chemical name
(2aR,4S,4aS,6R,9S, 1 1 S,12S,12aR, 12bS)-12b-acetoxy-9-(((2R,3S)-3-((tert- butoxycarbonyl)amino)-2-hydroxy-3-phenylpropanoyl)oxy)-11-hydroxy-4,6-dimethoxy- 4a,8, 13, 13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9, 10, 11 , 12, 12a, 12b-dodecahydro-1 H- 7, 1 1-methanocyclodeca[3,4]benzo[1 ,2-b]oxet-12-yl benzoate. In a first part of this description, taxel drugs including paclitaxel (taxol), docetaxel (taxotere) and cabazitaxel may be prepared starting from 10-deacetylbaccatin (known as 10-DAB) derived from Taxus plants, via semi-synthesis. Furthermore, the same inventive methodologies can be used to semi-synthesize cabazitaxel starting from 9- dihydro-13-acetylbaccatin III (9-DHB).
Patent numbers CN1213042C, CN152870, CN1179716 and CN1179775 disclose methods to prepare cabazitaxel from 10-DAB (herein compound II).
10-DAB (II)
A typical prior art synthesis route is as follows:
OCOCH3
OCOC6H5
The method above which synthesizes cabazitaxel has many synthetic steps, a very low overall yield and high price.
There is therefore a need in the art to develop new methods to synthesize cabazitaxel and its intermediates to improve the yield of cabazitaxel, simplify the methodology and optimize the synthetic technology.
Cabazitaxel, chemically known as 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate, is represented by formula (I).
It is a microtubule inhibitor, indicated in combination with prednisone for treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen, under the trade name Jevtana®.
Cabazitaxel is known from U.S. Pat. No. 5,847,170. Process for preparation of Cabazitaxel as described in U.S. Pat. No. 5,847,170 involves column chromatography, which is cumbersome tedious and not commercially viable.
The acetone solvate of 4-acetoxy-2α-benzoyloxy-5β-20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxotan-11-en-13α-yl-(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (Form A) is formed by crystallization by using acetone and is characterized by XRD in U.S. Pat. No. 7,241,907.
U.S. 20110144362 describes anhydrous crystalline Forms B to Form F, ethanolates Form B, D, E and F and mono and dihydrate Forms of Cabazitaxel. All the anhydrous crystalline forms are prepared either by acetone solvate or ethanol solvate. Mono and dihydrate forms are formed at ambient temperature in an atmosphere containing 10 and 60% relative humidity, respectively.
Cabazitaxel (also called dimethoxy docetaxel) is a dimethyl derivative of docetaxel, which itself is semi-synthetic, and was originally developed by Rhone-Poulenc Rorer and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of hormone-refractory prostate cancer on Jun. 17, 2010. Cabazitaxel is a microtubule inhibitor. The acetone solvate crystalline form of cabazitaxel and a process for its preparation is disclosed in the U.S. Pat. No. 7,241,907.
U.S. Pat. No. 5,847,170 describes cabazitaxel and its preparation methods. One of the methods described in U.S. Pat. No. 5,847,170 includes a step-wise methylation of 10-DAB (the step-wise methylation method is shown in FIG. 1) to provide the key intermediate (2αR,4S,4αS,6R,9S,11S,12S,12αR,12βS)-12β-acetoxy-9,11-dihydroxy-4,6-dimethoxy-4α,8,13,13-tetramethyl-5-oxo-2α,3,4,4α,5,6,9,10,11,12,12α,12β-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-12-yl benzoate, herein referred to as 7,10-di-O-methyl-10-DAB (XVa). The intermediate XVa is coupled with the 3-phenylisoserine side chain derivative VI to provide XVa′, which is followed by removal of the oxazolidine protecting group from the side chain of XVa′ to give cabazitaxel.
Another method described in U.S. Pat. No. 5,847,170 utilizes methylthiomethyl (MTM) ethers as shown in FIG. 2. MTM ethers can be prepared from alcohols using two common methods. One method comprises deprotonation of an alcohol with a strong base to form an alkoxide followed by alkylation of the alkoxide with a methylthiomethyl halide. This approach is only useful when the alcohol is stable to treatment with a strong base. 10-DAB and some of its derivatives in which C7-OH is not protected displays so instability in the presence of strong bases and epimerization of the C7-OH can occur upon contact of 10-DAB and some of its derivatives in which C7-OH is not protected with strong bases. Another method for the synthesis of MTM ethers from alcohols utilizes Ac2O and DMSO. One disadvantage of this method is that it can also lead to the oxidation of alcohols to aldehydes or ketones. For example when the synthesis of the 10-di-O-MTM derivative of 10-DAB without protecting groups at the C13 hydroxyl group is attempted undesired oxidation of the C13-OH to its corresponding ketone occurs.
U.S. Pat. No. 5,962,705 discloses a method for dialkylation of 10-DAB and its derivatives to furnish 7,10-di-O-alkyl derivatives, as shown in FIG. 3. This has been demonstrated as a one-step, one-pot reaction, however, provides the best isolated yield when potassium hydride is used at −30° C. From an industrial point of view, the use of low reaction temperature is less favorable than using ambient temperature. Furthermore the use of a strong base can cause some epimerization of the C7-OH chiral center with an associated loss of yield. Potassium hydride is a very reactive base and must be treated with great caution.
Accordingly, there is a need for an alternative processes for the preparation of cabazitaxel and its key intermediate, 7,10-di-O-methyl-10-DAB (XVa) that is short in number of synthetic steps and avoids the use of low temperatures and strong bases such as metal hydrides in the C7-O methyl ether formation step. Such a process would also be useful for the preparation of analogues of cabazitaxel wherein the C7-O and C10-O functional groups were substituted with other alkyl groups.
FIG. 1 shows the chemistry employed in the examples of U.S. Pat. No. 5,847,170.
FIG. 2 shows the chemistry employed in the examples of U.S. Pat. No. 5,847,170.
FIG. 3 shows the chemistry employed in the examples of U.S. Pat. No. 5,962,705.
FIG. 4 shows key steps of the general synthetic scheme as per Method A/A′ of the present invention for the synthesis of cabazitaxel and cabazitaxel analogues.
FIG. 5 shows key steps of the general synthetic scheme as per Method B/B′ of the present invention for the synthesis of cabazitaxel and cabazitaxel analogues.
FIG. 6 shows the general scheme for the hydrodesulfurization reaction.
FIG. 7 shows the complete synthetic route of Method A that can be used for conversion of 10-DAB to cabazitaxel.
FIG. 8 shows the complete synthetic route of Method B that can be used for conversion of 10-DAB to cabazitaxel.
FIG. 9 shows the complete synthetic route of Method A′ that can be used for conversion of 10-DAB, via XIV′, to cabazitaxel.
FIG. 10 shows the complete synthetic route of Method B′ that can be used for conversion of 10-DAB, via XVI′, to cabazitaxel.
FIG. 11 shows the synthetic relationship between two methods (A and B) used to convert 7,10-di-O-alkyl-10-DAB (XV) to cabazitaxel.
FIG. 12 shows the synthetic scheme for the preparation of XIVa.
FIG. 13 shows the synthetic scheme for the preparation of XIVb from 10-DAB.
FIG. 14 shows the synthetic scheme for the preparation of XIVb from XIVb′.
FIG. 15 shows the synthetic scheme for the preparation of XIVc.
FIG. 16 shows the synthetic scheme for the preparation of XIVa′ from XIVa.
FIG. 17 shows the synthetic scheme for the preparation of XIVa′ from XX.
FIG. 18 shows the synthetic scheme for the preparation of XIVb′.
FIG. 19 shows the synthetic scheme for the preparation of XIVc′.
FIG. 20 shows the synthetic scheme for the preparation of XVa from XIVa.
FIG. 21 shows the synthetic scheme for the preparation of XVa from XIVb.
FIG. 22 shows the synthetic scheme for the preparation of XVa from XIVc.
FIG. 23 shows the synthetic scheme for the preparation of XVa′ from XIVa.
FIG. 24 shows the synthetic scheme for the preparation of XVa′ from XIVa′.
FIG. 25 shows the synthetic scheme for the preparation of XVa′ from XIVb′.
FIG. 26 shows the synthetic scheme for the preparation of XVa′ from XIVc′.
FIG. 27 shows the synthetic scheme for the preparation of XVa′ from XVa.
FIG. 28 shows the synthesis of cabazitaxel.
FIG. 29 shows the synthesis of XVIIa.
FIG. 30 shows the synthesis of XVIIIa.
FIG. 31 shows the synthesis of XIXa.
FIG. 32 shows the synthesis of XVIa.
FIG. 33 shows the synthesis of XVa from XVIa.
see this at http://www.google.com/patents/US20130116444
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Detailed description
The invention provides a new method for the preparation of cabazitaxel, one embodiment of which can be summarized as follows, showing the preparation of a protected taxane intermediate and its deprotection to taxane compounds:
OH OCOCH3
OCOC6H5
This reaction is also depicted in Figure 1. The reaction of the invention reduces the number of steps and increases yield of cabazitaxel.
The deprotection methods of the invention can also be used for the preparation of paclitaxel (taxol):
The deprotection methods of the invention can also be applied to the preparation of docetaxel:
10-DAB synthetic routes
Example 12
Dissolve 100 g of 2′-THP-cabazitaxel in 1730 ml of HOAc/H20/THF (3:1 :1 ). under N2 atmosphere, increase temperature to 50 degrees C and stir 4 hrs. Then cool to room temperature. Add 2L of ethyl acetate, 2 L of H20, stir, separate layers, wash organic layer with saturated NaHC03 (3 L x 2), saturated NaCI (3 L), dry with Na2S04.
Concentrate to obtain white 77.8 g of cabazitaxel (yield 83%).
MS(m/z) :859(M+Na)„ jHNMR (500MHz) δ 1.21(611, d) , 1.36(911, s) , 1.59(lH, s) , 1.64(lH,s) , 1.79(lH,m) , 1.87 (3H, s) ,2.27 (2H, m) , 2.35(3H,m) ,2.69(lH,m) ,3.30 (3H, s) ,
3.45 (3H, s) , 3.85 (2H, m) , 4.16 (1H, d) , 4.29 (1H, d) , 4.62 (1H, bs) , 4.79 (1H, s) , 5.29 (1H, m),5.42(lH, d),5.62(lH, d),6.21 (1H, t),7.2 ~ 7.4(6H, m) , 7.48 (2H, t),7.59(lH, t) , 8.11 (2H, d) ,
References
- http://www.cancer.gov/drugdictionary/?CdrID=534131
- “Jevtana (cabazitaxel) Injection Approved by U.S. FDA After Priority Review” (Press release). sanofi-aventis. 2010-06-17. Retrieved June 17, 2010.
- “Cabazitaxel Effective for Hormone Refractory Prostate Cancer After Failure of Taxotere”.
- Cabazitaxel – Official web site of manufacturer.
- Cabazitaxel Prescribing Information – Official prescribing information.
- U.S. National Library of Medicine: Drug Information Portal – Cabazitaxel
Patents
Patent :
Patent Number : 5438072
Country : United States
Approved : 2010-06-17
Expires : 2013-11-22
Patent :
Patent Number : 5698582
Country : United States
Approved : 2010-06-17
Expires : 2012-07-03
Patent :
Patent Number : 5847170
Country : United States
Approved : 2010-06-17
Expires : 2016-03-26
Patent :
Patent Number : 6331635
Country : United States
Approved : 2010-06-17
Expires : 2016-03-26
Patent :
Patent Number : 6372780
Country : United States
Approved : 2010-06-17
Expires : 2016-03-26
Patent :
Patent Number : 6387946
Country : United States
Approved : 2010-06-17
Expires : 2016-03-26
Patent :
Patent Number : 7241907
Country : United States
Approved : 2010-06-17
Expires : 2025-12-10
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3-13-2009
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SELF-EMULSIFYING AND SELF-MICROEMULSIFYING FORMULATIONS FOR THE ORAL ADMINISTRATION OF TAXOIDS
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3-32-2005
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Semi-solid formulations for the oral administration of taxoids
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2-4-2005
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Self-emulsifying and self-microemulsifying formulations for the oral administration of taxoids
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6-12-2002
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Use of taxoid derivatives
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DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 