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TROPISETRON
TROPISETRON
89565-68-4
105826-92-4 (HCl)
Novartis (Originator)
Tropisetron (INN) is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy, although it has been used experimentally as an analgesic in cases of fibromyalgia.[1] The drug is available in a 5 mg oral preparation or in 2 mg intravenous form. It is marketed by Novartis in Europe, Australia, New Zealand, Japan, South Korea and the Philippines as Navoban, but is not available in the U.S. It is also available from Novell Pharmaceutical Laboratories and marketed in several Asian countries as Setrovel
Tropisetron is a 5-hydroxytryptamine receptor 3 (5-HT3) antagonist that was launched in 1992 by Novartis for the oral and injection treatment of chemotherapy-induced emesis. The drug has also been approved for the prophylaxis and treatment of post-operative nausea and vomiting, and is available in capsule and ampule formulations. In terms of clinical development, phase III trials were being carried out by the National Institute of Mental Health (NIHM) as an adjunct to risperidone therapy for the treatment of schizophrenia, but no recent development has been reported. Clinical trials for the treatment of fibromyalgia have also been conducted by Novartis, although recent progress reports on this indication have not been made available.
5-HT3 receptors are excitatory ligand-gated cation channel receptors that can be found in the presynaptic vagal afferents, the area postrema and the gastrointestinal tract. Stimulation of these receptors seems to be important in the emetic response and the gag reflex. It has also been shown that tropisetron shows agonistic effects on the 7 nicotinic acetylcholine receptor. This receptor is associated with auditory sensory gating, a neural mechanism believed to have important roles in information processing and cognition, both diminished in people with schizophrenia.
Tropisetron acts as both a selective 5-HT3 receptor antagonist and α7-nicotinic receptor agonist.[2][3]
Tropisetron is a well-tolerated drug with few side effects. Headache, constipation, and dizziness are the most commonly reported side effects associated with its use. Hypotension, transient liver enzyme elevation, immune hypersensitivity syndromes and extrapyramidal side effects have also been associated with its use on at least one occasion.There have been no significant drug interactions reported with this drug’s use. It is broken down by the hepatic cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system.
As a biological stain and as trypanocide.
Tropisetron was originally developed by Novartis, and rights to the drug were subsequently acquired by Asta Medica (now, part of Meda). In December 1997, Novartis and Kyowa Hakko signed an agreement, pursuant to which the companies would copromote the product in Japan. Tropisetron is currently distributed in various countries worldwide, including Belgium, Germany, Italy, Japan, The Netherlands, Sweden and the U.K.
.
- Muller, W.; T. Stratz (2004). “Local treatment of tendinopathies and myofascial pain syndromes with the 5-HT3 receptor antagonist tropisetron”. Scand J Rheumatic Suppl. 119 (119): 44–48.PMID 15515413. Retrieved 2007-05-17.
- Macor JE, Gurley D, Lanthorn T, Loch J, Mack RA, Mullen G, Tran O, Wright N, Gordon JC (February 2001). “The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist”. Bioorganic & Medicinal Chemistry Letters11 (3): 319–21. doi:10.1016/S0960-894X(00)00670-3.PMID 11212100.
- Cui R, Suemaru K, Li B, Kohnomi S, Araki H (May 2009). “Tropisetron attenuates naloxone-induced place aversion in single-dose morphine-treated rats: role of alpha7 nicotinic receptors”.European Journal of Pharmacology 609 (1–3): 74–7.doi:10.1016/j.ejphar.2008.12.051. PMID 19374878.
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Tropisetron hydrochloride (CAS 105826-92-4)
Application: A potent SR-3 antagonist CAS Number: 105826-92-4 Purity: ≥99% Molecular Weight: 320.82 Molecular Formula: C17H20N2O2 HCl - Navoban™ IS THE FORMULATION
Tropisetron hydrochloride is a potent SR (SR-3) antagonist. It is also a selective, partial agonist at AChR α 7 (α7 nicotinic receptors). Tropisetron hydrochloride is an inhibitor of HTR3.
1alphaH,5alphaH-Tropan-3alpha-yl Indole-3-carboxylate, could be produced through many synthetic methods.
Following is one of the synthesis routes: Indole 3-carbonyl chloride (I) is condensed with endo-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (II) in the presence of butyllithium in THF, or Na2CO3 in the same solvent to produce the final product of Tropisetron.
IMPORTANT REFERENCES
Drugs Fut 1986, 11(2): 106
US 4789673
CN 102532128
CN 102887893
WO 2013123426
WO 2007099069
WO 2009033305
WO 2003032897
WO 2004054552
WO 2005105089
WO 2000048597
WO 2000048581
| CN101033225A | 2 Apr 2007 | 12 Sep 2007 | 北京成宇化工有限公司 | Process of preparing troipisetron |
| CN101787021A | 5 Mar 2010 | 28 Jul 2010 | 王明 | High-purified tropisetron hydrochloride compound |
| US4789673 | 10 Nov 1987 | 6 Dec 1988 | Peter Donatsch | Heterocyclic carboxylic acid amides and esters |
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5-HT3 receptor antagonists are a class of compounds which block 5-HT3receptors, and are also sometimes classified as serotonin M receptor antagonists. The 5-HT3 receptor antagonists comprise a defined and recognised class of pharmaceutically active compounds well known in the art and characterised, as their name implies, by their pharmacological activity. Various 5-HT3 receptor antagonist compounds are commercially available and clinically applied, e.g. in the treatment of emesis.
5-HT3 receptor antagonists from various sources have been published for a wide variety of uses, for example for the treatment of visceral pain, migraine, vascular and cluster headache, trigeminal neuralgia, arrhythmia, serotonin-induced gastro-intestinal disorders, including emesis induced by anti-cancer agents, anxiety, stress-related psychiatric disorders, depression, cognitive disorders, social withdrawal, panic attacks, agoraphobia, lung embolism, rhinitis or serotonin-induced nasal disorders, fibromyalgia and local treatment of pain caused by various non-inflammatory or inflammatory conditions. Some have been commercially introduced for the treatment of emesis.
In accordance with the present invention it has now surprisingly been found that 5-HT3 receptor antagonists are useful for the treatment of diseases caused or influenced by activation of thrombocytes.
Thrombocytes play a central role in blood coagulation (clotting) and are therefore also of high importance in the pathogenesis of cardiac infarction and stroke, furthermore also in thrombosis of the veins and inflammatory conditions in the development of atherosclerosis.
Activation of thrombocytes causing blood clotting is based on several mechanisms. It has ■ now been demonstrated that 5-HT3 receptors are present on platelets and that the number of these receptors at the platelet surface is increasing in a dose dependent fashion on addition of ADP (adenosine diphosphate) or TRAP (thrombin receptor activating peptide) known to stimulate thrombocyte activation. The increase of 5-HT3 receptors on addition of compounds inducing aggregation such as ADP and TRAP is proof that such receptors play a role in thrombotic processes. Platelet activity is also important in inflammatory processes in atherosclerotic conditions. Thrombocytes activated by thrombin may, as is already known, induce the production of I L- 1 β , IL-8, MCP (monocyte chemoattractant protein) and other inflammation mediators These are impeded by 5-HT3 receptor antagonists. This demonstrates that 5-HT3 receptor antagonists not only influence blood coagulation but also processes playing a role in the development of atherosclerosis.
Hence, the present invention relates to the use of a 5-HT3 receptor antagonist or of a pharmaceutically acceptable salt of such an antagonist for the manufacture of a pharmaceutical composition for the treatment of a disease caused or influenced by activation of thrombocytes, in particular myocardial infarction, stroke, thrombosis and atherosclerosis.
Any 5-HT3 receptor antagonist can be used in accordance with the invention. Preferred 5-HT3 receptor antagonists which may be employed in accordance with the present invention are ondansetron, 1 ,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1 H-imidazol-1-yl)- methyl]-4H-carbazol-4-one (cf. Merck Index, twelfth edition, item 6979), granisetron, ‘ endo-1-methyl-N-(9-methyl-9-aza-bicyclo[3.3.1]non-3-yl)-1 H-innidazole-3-carboxamide . (cf. loc. cit, item 4557), or dolasetron, 1 H-indole-3-carboxylic acid (2α,6α,8α,9αβ)- octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester, (cf. loc. cit., item 3471). ■•
Particular 5-HT3 receptor antagonists which may be employed in accordance with the ■ present invention are those of the formula 1 as defined in European Patent Publication EP O 189 002 B1, in particular tropisetron, indol-S-yl-carboxylic acid-endo-δ-methyl-δ-aza- bicyclo[3,2,1]-oct-3-yl-ester, (cf. loc. cit., item 9914), ramosetron, 4,5,6,7-tetrahydro-5- [(1-methyl-indol-3-yl)carbonyl]benzimidazole (U.S. Pat. No. 5,344,927), fabesetron, (+)- 10-methyl-7-(5-methyl-1 H-imidazol-4-ylmethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (EP 0 361 317), lintopride, N-(1-ethyl-2-imidazolin-2-y-methyl)-2-methoxy-4-amino-5- chlorobenzamide (Chem. Abstr. No. 107429-63-0), alosetron, 2,3,4,5-tetrahydro-5-methyl- 2-[(5-methyl-1 H-imidazol-4-yl)methyl]-1 H-pyrido[4,3-b]indol-1-one (EP 0 306 323), cilansetron, (-)-(R)-5,6,9,10-tetrahydro-10-[(2-methylimidazol-1-yl)methyl]-4H-pyrido- (3,2,1-jk)carbazol-11(8H)-one, palonosetron, 2-(3S)-1-azabicyclo[2.2.2]oct-3-yl-2,3,3a(S), 4,5,6-hexahydro-1 H-benz(de)isoquinolin-1-one, azasetron, N-(1-azabicyclo[2.2.2]octan-8- yl)-6-chloro-4-methyl-3-oxo-1 ,4-benzoxazine-8-carboxamide, and zatosetron, 5-chloro- 2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-3H-1-benzofuran-7-carboxamide.
5-HT3 receptor antagonists may be employed in accordance with the invention in free or in pharmaceutically acceptable salt form, e.g. as known in the art, for example, in the case of compounds mentioned above in pharmaceutically acceptable acid addition salt form, for example, in the case of ondansetron as the hydrochloride dihydrate, granisetron as the hydrochloride, dolasetron as the mesylate, tropisetron as the monohydrochloride, ramosetron, fabesetron, alosetron and cilansetron as the hydrochlorides, palonosetron as the monohydrochloride, azasetron as the hydrochloride, and zatosetron as the maleate.
References to 5-HT3 receptor antagonists collectively or individually throughout the present specification and claims are accordingly to be understood as embracing both free compounds and such pharmaceutically acceptable salt forms, e.g. as clinically employed, and further also solvates, e.g. hydrates, or specific crystal forms of any of these compounds or salts.
For use in accordance with the present invention tropisetron (especially in the formulation called Navoban™) is most preferred.
tropisetron hydrochloride is a peripheral neurons and central nervous system 5 – hydroxytryptamine 3 (5-ΗΤ3) receptors potent, highly selective competitive antagonist, mainly by selectively blocking peripheral neurons presynaptic 5-ΗΤ3 receptors inhibit vomiting reflex. For the prevention and treatment of child and adult cancer chemotherapy, radiotherapy and post-operative nausea and vomiting caused.
About tropisetron hydrochloride preparation of patent literature, including (for example): US4797406, US 4789673, CN 101033225, CN 101838266, CN 101787021. Tropisetron hydrochloride preparation generally is this: the firstsynthesis of acid chloride intermediates, and then through esterification acidification, refining and other steps, resulting tropisetron hydrochloride.
The preparation method has, in U.S. Patent (US3980668, US4789673, US4797406, US4803199) described with indole-3 – carboxylic acid with oxalyl chloride, treatment with methylene chloride and n-hexane to give 3 – methyl indole chloride, then with tropenol activation in n-butyl lithium produced under tropenol lithium reaction was treated to obtain tropisetron, and the final hydrochloride salt obtained tropisetron hydrochloride
in which the U.S. patent literature US 4797406 and US 4789673 introduces the indole-3 – carboxylic acid with oxalyl chloride to give 3 – indole chloride then with tropenol activation in n-butyl lithium in the reaction system tray alkyl granisetron. This method uses expensive n-butyl lithium and polluting chloride compound, and the multi-step, only about 20% yield.
Chinese patent literature described in CN 101033225 is improved indolesynthesis _3_ chloro acid as raw material of 1,3 – dimethyl-2 – chloro-imidazoline as the condensing agent, an organic base directly under conditions esterified with tropenol obtain the target product. Although this method avoids the acylation step, a condensing agent in preparing dimethyl-2-chloro-1,3 _ – chloro-imidazoline must use highly toxic phosgene, so there is an obvious lack of this route.
In the literature [tropisetron hydrochloride synthesis improvements, Huaihai Institute of Technology, 2003; 12 (4): 4 wide 43; tropisetron hydrochloride Improved synthesis of Hunan Normal University (Medical Sciences), 2006; 3 (4): 29 ^ 30], respectively, 50%, 52.8% obtained in a yield tropisetron hydrochloride, but still use of expensive n-butyl lithium as a condensation reaction activator.
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Example 2:
[0071] The indole-3 – carboxylic acid (20 g, 0. 124mol), benzenesulfonic acid (0. 791g, 0. 005mol), ethyl acetate (230ml), freshly activated 4A molecular sieves (0. 5-1 . Omm) (3 g) was added to a equipped with a thermometer, reflux condenser, 500ml three reaction flask, stir began to heat up, the temperature controlled at 75 ° C _77 ° C, and then began a slow drip Gato Decanter (19. 3 g, 0. 137mol), after the addition was complete the reaction refluxed for 11 hours.
[0072] The reaction was stopped, the organic layer was washed with IOOml a lmol / L of hydrochloric acid, extracting the product three times, the combined aqueous phase was then washed once with 50ml of ethyl acetate. Aqueous phase was 4mol / L sodium hydroxide aqueous solution was adjusted to pH = 9_10, precipitated yellow solid was suction filtered cake was washed with distilled water to neutral, dried under reduced pressure to obtain 33.1 Hector alkoxy granisetron crude. The crude product was dissolved at 60 ° C in 180ml of anhydrous ethanol was slowly added dropwise 12mol / L hydrochloric acid until the pH value 1_2, _5 ° C under crystallization 6 hours, filtered, the filter cake washed with ethanol to white . Drying get tropisetron hydrochloride concept .3 g, yield 71.1% (to indole-3 – carboxylic acid basis), as measured by liquid chromatography purity of 99.56%.
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[0016] (3) tropisetron hydrochloride Preparation:
A solution of indole-3 – carbonyl chloride in THF was slowly added dropwise to sodium tropine THF solution, 35 ° C the reaction was stirred overnight, vacuum distillation recovery THF, and recrystallized from 95% ethanol to give a pale yellow solid adding 70mL ethanol, dissolved by heating, cooling pass into the HCl gas at room temperature, the reaction was stirred for 30min, filtered, tropisetron hydrochloride was crude. Recrystallization from absolute ethanol to give white crystalline product 21. 2g (Liquid chromatographic purity 99.91%), total yield of 53.29%, a melting point of view 3185, the product spectrum consistent with the literature.
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Example 5 tropisetron hydrochloride refined
[0063] (a) The IOOg tropisetron hydrochloride was dissolved in 500ml water, then slowly adding 12% (g / ml) of sodium carbonate solution was stirred until the solution PH 8, resulting tropisetron sedimentation, filtration , 40 ° C under reduced pressure and dried to give tropisetron 84. lg.
[0064] (2) obtained in the above Step Tropisetron 84. Ig dissolved in 400ml ethanol, 5. 2g of activated charcoal, stirred at room temperature for 40 minutes, filtered decarbonization, collecting the filtrate.
[0065] (3) The use of the filtrate obtained in step purified by preparative chromatography separation tropisetron hydrochloride refined products, including the column using a mobile phase as the mobile phase volume accounted for 32% of total current volume of methylene chloride and with 68% aqueous hydrochloric acid to pH 1; stationary phase filler is silica; flow rate of 6. 2ml/min; column temperature: 25 ° C. The filtrate was collected, dried under reduced pressure, to obtain purified tropisetronhydrochloride 91. 7g, yield 91. 7%, HPLC purity of 99.9% method.
[0066] Elemental analysis = C17H21ClN2A
[0067] Theoretical value (%): C: 63. 65, H: 6. 60, N: 8. 73, Cl: 11. 05;
[0068] Found (%): C: 63. 62, H: 6. 64, N: 8. 74, Cl: 11. 06.
[0069] UV (MeOH) Amax: 214 (ε 38,222), 229 (ε 17,438), 282 (ε 13,405).
[0070] IR (KCl) CnT1: 3219,2496 (NH), 3103,748 (Ar CH), 2966,1428 (CH), 1692 (C = 0), 1580,1525 (Ar C = C), 1311, 1128 (CN), 1033 (CO).
[0071] 1HNMR (DMSO-D6) δ: 2. 10 (d, 2H, CH2), 2 · 32 (d, 4H, CH2), 2 · 52 (m, 2H, CH2), 2. 68 (s, 3H, CH3), 3. 88 (s, 2H,-CH), 5. 14 (s, H, CH), 8. 03 (m, H, CH), 8. 08 (d, H, CH), 10. 81 (s, H, HCl), 12. 10 (s, H, NH).
[0072] ESI-MS; EI m / z: 285 (M + H, 100%), 284 (M +, 21. 72%) ”
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Example 1
[0048] equipped with stirrer, thermometer, condenser IOOOml reaction flask, add 80 grams of tropisetron hydrochloride (I Ci refined products) and 560ml of acetone-water (8:2) mixture, start stirring, heating heated to 60 ° C _65 ° C, until all dissolved clear, incubated for 30 minutes, filtered while hot. The filtrate was cooled to room temperature, and then incubated for 2 hours, crystalline precipitation, filtration, drying ie high purity tropisetron hydrochloride crystals, mp: 280.10C -281.1 ° C, purity 99.96% (HPLC normalization method), the solvent residue testing to meet the requirements.
[0049] Elementary analysis:
[0050] Found (calculated value), C: 63.64 (63.57), H: 6.60 (6.62), N: 8.73 (8.72),
[0051] Cl: 11.05 (11.01);
[0052] X-ray diffraction of the crystal shown in Figure 1. Instrument model and measurement conditions: Rigaku D / max 2500 type diffractometer; CuKa 40Kv 100mA; 2 Θ scan range: 0 – 50 °;
[0053] The infrared spectrum of this crystal is shown in Figure 2, as measured by KBr tablet.
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DR ANTHONY MELVIN CRASTO Ph.D
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
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Lorcaserin…Eisai Expands Marketing and Supply Agreement for Anti-obesity Agent Lorcaserin to Include Most Countries Worldwide
(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Eisai Expands Marketing and Supply Agreement for Anti-obesity Agent Lorcaserin to Include Most Countries Worldwide
HATFIELD, England, November 8, 2013 /PRNewswire/ —
Eisai announces today that it has expanded the marketing and supply agreement between its U.S. subsidiary Eisai Inc. and U.S-based Arena Pharmaceuticals Inc.’s Swiss subsidiary, Arena Pharmaceuticals GmbH, for the anti-obesity agent lorcaserin hydrochloride (lorcaserin) (U.S. brand name: BELVIQ®). Whilst the existing agreement granted Eisai Inc. exclusive rights to market and distribute lorcaserin in 21 countries throughout the Americas, the expanded agreement now includes most countries and territories worldwide, most notably, the member states of the European Union, Japan and China (but excludes South Korea, Taiwan, Australia, New Zealand and Israel).http://www.pharmalive.com/eisai-expands-lorcaserin-marketing-and-supply-agreement
Lorcaserin (previously APD-356), a highly selective 5HT2C receptor agonist, is used for the treatment of obesity. It has been shown to reduce body weight and food intake in animal models of obesity…
View original post 4,225 more words
GRANISETRON
GRANISETRON
1-methyl-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-indazole-3-carboxamide
Nausea and Vomiting, Treatment of, Neurologic Drugs, 5-HT3 Antagonists
107007-99-8 hydrochloride
109889-09-0 (free base)
AB-1001
ALM-101
BRL-43694
Inno-P08002
SP-01
SyB D-0701
SyB L-0701
SyB-0701
TRG
Chugai (Proprietary), Roche (Proprietary), GlaxoSmithKline (Originator)
Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect on vomiting due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.
Granisetron hydrochloride is an anti-emetic drug, used for treatment or prophylaxis of emesis and post operative nausea and vomiting. Granisetron hydrochloride is marketed under the trade name Kytril as solution for injection as well as tablets. The chemical name of granisetron is N-(endo-9-methyl-9- azabicyclo[3.3.2]non-3-yl)-l-methylindazole-3-carboxamide and it is represented by the following structural formula :
Granisetron is usually administered as the hydrochloride salt for relieving the symptoms of vomiting and nausea in cancer patients. Recently the U.S. Food and Drug Administration (FDA) has accepted an investigational New Drug (IND) application for transdermal granisetron patch, Sancuso™, for the prevention of chemotherapy-induced nausea and vomiting (CINV). The Sancuso™ Phase I I Istudy is now underway in Europe and in the U.S. Typically, a non-oral form such as transdermal patch uses granisetron base as the active ingredient. The preparation of granisetron base is described in U.S. Patent No. 6,268,498 without referring to the solid state characteristics of granisetron. The preparation of granisetron base is further described in example 3 of U.S. Patent No. 7,071,209 (hereinafter the ‘209 patent), having a melting point of 121-1220C. The ‘209 patent is silent with regard to the solid state of granisetron base as well as to the solid state of the hydrochloride salt,
Granisetron was developed by chemists working at the British drug company Beecham around 1988 and is available as a generic. It is produced byRoche Laboratories under the trade name Kytril. The drug was approved in the United Kingdom in 1991 and in United States in 1994 by the FDA.
A granisetron transdermal patch with the trade name Sancuso was approved by the US FDA on September 12, 2008.[1] Sancuso is manufactured by ProStrakan, Inc., a pharmaceutical company headquartered in Bedminster, NJ, with global headquarters in Scotland.
Granisetron is metabolized slowly by the liver, giving it a longer than average half-life. One dose usually lasts 4 to 9 hours and is usually administered once or twice daily. This drug is removed from the body by the liver and kidneys.
Granisetron hydrochloride is a 5-HT3 antagonist that was launched in 1991 at Roche for the oral treatment of nausea. Preclinical studies demonstrate that, in binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In 2008, FDA approval of a transdermal patch was obtained by ProStrakan for the prophylaxis of chemotherapy-induced nausea/vomiting. Commercial launch took place the same year. This formulation has been filed for approval in the E.U. for the prevention of chemotherapy-induced nausea and vomiting. E.U. approval was obtained in 2012. In 2013, launch took place in United Kingdom. In 2011, Chugai Pharmaceutical received approval in Japan for the prevention of nausea and vomiting associated with antineoplastic agent administration and radiotherapy. Translational Research has developed an intranasal formulation that is in the preclinical phase of development. Acrux has also studied a proprietary metered-dose transdermal system, but progress reports on this formulation are not presently available. Currently marketed formulations include an oral solution, film-coated tablets, injections and sachets. BioDelivery Sciences is developing a formulation of granisetron hydrochloride using its film technology (BioErodable MucoAdhesive) BEMA technology. Almac is developing the compound in phase I clinical studies for the prevention of chemotherapy-induced nausea/vomiting.
It may be used for chemotherapy-induced nausea and vomiting and appears to work about the same as ondansetron.[2]
A number of medications including granisetron appear to be effective in controlling post-operative nausea and vomiting (PONV).[3] It is unclear if it is better than or worse than other agents like droperidol, metoclopramide, ondansetron or cyclizine.[3]
Its efficacy has also been questioned with a research Dr. Yoshitaka Fujii having 12 published papers on this topic in Canadian Journal of Anesthesia retracted. A further five papers in the same journal on the same drug by Dr Fujii are considered indeterminate.
- Is a possible therapy for nausea and vomiting due to acute or chronic medical illness or acute gastroenteritis
- Treatment of cyclic vomiting syndrome although there are no formal trials to confirm efficacy.
Granisetron is a well-tolerated drug with few side effects. Headache, dizziness, and constipation are the most commonly reported side effects associated with its use. There have been no significant drug interactions reported with this drug’s use. It is broken down by the liver‘s cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system.
APF530
A New Drug Application (NDA) for APF530, a sustained-delivery form of Granisetron, was accepted in October 2012.[4] APF530 will be targeted as anantiemetic, towards patients undergoing radiation therapy and chemotherapy. APF530 contains the 5-HT3 antagonist, granisetron, formulated in the Company’s proprietary Biochronomer™ drug delivery system, which allows therapeutic drug levels to be maintained for five days with a single subcutaneous injection.
Originally developed at GlaxoSmithKline, granisetron hydrochloride was divested in September 2000 giving Roche global rights to the drug. Currently, granisetron is being distributed by Roche in France, Italy, South Africa, the U.K. and the U.S. and in Japan by Roche’s subsidiary Chugai. In 2007, a license agreement was signed between LG Life Sciences and ProStrakan in Korea. In 2008, the product was licensed to JapanBridge by ProStrakan for development and marketing in Asia for the prophylaxis of chemotherapy-induced nausea and vomiting. An additional license agreement was made in 2008 granting Paladin rights to granisetron transdermal patches for the treatment of nausea. In 2010, granisetron hydrochloride extended-release transdermal patches were licensed to Kyowa Hakko Kirin by Solasia Pharma in Taiwan, Hong Kong, Singapore and Malaysia for the prevention of chemotherapy-induced nausea and vomiting. Solasia retains full rights in Japan and China.
- Kytril Web site
- Sancuso Web siteKYTRIL Tablets and KYTRIL Oral Solution contain granisetron hydrochloride, an antinauseant and antiemetic agent. Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride with a molecular weight of 348.9 (312.4 free base). Its empirical formula is C18H24N4O•HCl, while its chemical structure is:
granisetron hydrochloride
Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal saline at 20°C.
- PRNewswire. FDA Approves Sancuso, the First and Only Patch for Preventing Nausea and Vomiting in Cancer Patients Undergoing Chemotherapy. September 12, 2008.
- Billio, A; Morello, E; Clarke, MJ (2010 Jan 20). “Serotonin receptor antagonists for highly emetogenic chemotherapy in adults.”. The Cochrane database of systematic reviews (1): CD006272.PMID 20091591.
- Carlisle, JB; Stevenson, CA (2006 Jul 19). “Drugs for preventing postoperative nausea and vomiting.”. The Cochrane database of systematic reviews (3): CD004125. PMID 16856030.
- Drugs.com A.P. Pharma Announces PDUFA Action Date for APF530 New Drug Application Resubmission. October 16, 2012.
- Katzung, Bertram G. Basic and Clinical Pharmacology, 9th ed. (2004). ISBN 0-07-141092-9
- Aapro, M. (2004). “Granisetron: an update on its clinical use in the management of nausea and vomiting”. The oncologist 9 (6): 673–686. doi:10.1634/theoncologist.9-6-673. ISSN 1083-7159. PMID 15561811. edit
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| ES2129349A * | Title not available |
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|---|---|---|---|---|
| WO2008117282A1 * | Mar 24, 2008 | Oct 2, 2008 | Itai Adin | Polymorph of granisetron base and production process therefor |
| EP2323654A1 * | Aug 18, 2009 | May 25, 2011 | ScinoPharm Taiwan, Ltd. | Polymorphic form of granisetron hydrochloride and methods of making the same |
| WO2003080606A1 * | Mar 21, 2003 | Oct 2, 2003 | Barjoan Pere Dalmases | Process for preparing a pharmaceutically active compound (granisetron) |
| WO2007054784A1 * | Nov 8, 2006 | May 18, 2007 | Shanmuga Sundaram Bharan Kumar | An improved process for the preparation of granisetron hydrochloride |
| WO2007088557A1 * | Jan 18, 2007 | Aug 9, 2007 | Prasad Ramanadham Jyothi | Process for highly pure crystalline granisetron base |
| ES2124162A1 * | Title not available |
| WO2007007886A1 * | Jul 10, 2006 | Jan 18, 2007 | Tanabe Seiyaku Co | An oxime derivative and preparations thereof |
| WO2007088557A1 * | Jan 18, 2007 | Aug 9, 2007 | Prasad Ramanadham Jyothi | Process for highly pure crystalline granisetron base |
| WO2008117282A1 * | Mar 24, 2008 | Oct 2, 2008 | Itai Adin | Polymorph of granisetron base and production process therefor |
| WO2008151677A1 | Dec 20, 2007 | Dec 18, 2008 | Inke Sa | Polymorphic form of granisetron base, methods for obtaining it and formulation containing it |
| EP2164848A1 * | Dec 20, 2007 | Mar 24, 2010 | Inke, S.A. | Polymorphic form of granisetron base, methods for obtaining it and formulation containing it |
| EP2323654A1 * | Aug 18, 2009 | May 25, 2011 | ScinoPharm Taiwan, Ltd. | Polymorphic form of granisetron hydrochloride and methods of making the same |
| US8193217 * | Aug 18, 2009 | Jun 5, 2012 | Scinopharm Taiwan Ltd. | Polymorphic form of granisetron hydrochloride and methods of making the same |
| US20100048613 * | Aug 18, 2009 | Feb 25, 2010 | Scinopharm Taiwan Ltd. | Polymorphic form of granisetron hydrochloride and methods of making the same |
| WO2007088557A1 * | Jan 18, 2007 | Aug 9, 2007 | Prasad Ramanadham Jyothi | Process for highly pure crystalline granisetron base |
| WO2008117282A1 * | Mar 24, 2008 | Oct 2, 2008 | Itai Adin | Polymorph of granisetron base and production process therefor |
| WO2008151677A1 | Dec 20, 2007 | Dec 18, 2008 | Inke Sa | Polymorphic form of granisetron base, methods for obtaining it and formulation containing it |
| EP2164848A1 * | Dec 20, 2007 | Mar 24, 2010 | Inke, S.A. | Polymorphic form of granisetron base, methods for obtaining it and formulation containing it |
| EP2323654A1 * | Aug 18, 2009 | May 25, 2011 | ScinoPharm Taiwan, Ltd. | Polymorphic form of granisetron hydrochloride and methods of making the same |
Drugs Fut 1989, 14(9): 875
5-Hydroxytryptamine (5-HT3) receptor antagonists. 1. Indazole and indolizine-3-carboxylic acid derivatives
J Med Chem 1990, 33(7): 1924
WO 2007054784
US 4886808
US 5034398
IN 200901669
……………………………………………………………………………………………………………………………………
Granisetron hydrochloride of formula (I). More particularly this invention relates to the preparation of Granisetron hydrochloride using methyl isobutyl ketone (MIBK) as a single solvent in presence of an organic base such as triethylamine.
(I)
Granisetron hydrochloride which is chemically known as endo-l-methyl-N-(9- methyl-9-azabicyclo[3.3.1]non-3-yl)-lH-indazole-3-carboxamide monohydrochloride is a 5-HT (5 -hydroxy triptamine) antagonist, and has the following structural formula:
(I)
Granisetron hydrochloride is useful as an anti-emetic and marketed as Kytril by Roche.
EP-A-0200444 provides certain 5-HT (5-hydroxytryptamine) antagonists, which are described as possessing a number of therapeutic utilities, inter alia, the prevention of vomiting following the administration of cytotoxic agents. The compound described in Example 6 is endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)- l-methylindazole-3-carboxamide, and this compound has been assigned the INN Granisetron. EP-A-0200444 also discloses that Granisetron can be prepared by reacting l-methylindazole-3-carboxylic acid chloride with endo-3-amino-9-methyl-9-azabicyclo [3.3.1] nonane.
EP 748321 claims a process for preparing Granisetron or a pharmaceutical acceptable salt thereof. The process comprises the condensation of compound of formula (3) and (4) followed by de-protecting the intermediate compound of structure (2) to get the granisetron or optionally forming a pharmaceutically accepted salt of Granisetron. The scheme is presented below in which Q is a leaving group displaceable by a secondary amine wherein R may be represented as benzyl, benzyl substituted with one or more chloro, alkyl or alkoxy group, t-butyl, allyl or a t-butyldimethylsilylgroup.
GRANISETRON
US Pat. No. 6,268,498 discloses an alternative process for preparing
Granisetron, by cyclisation of a previously methylated compound of formula (C), which is shown below. It should be noted that the methylation prior to cyclisation is carried out with sodium hydride and methyl iodide as disclosed in example 1 (b) of said patent. However, the cyclisation conditions applied to that compound of formula (C) may facilitate demethylation of the indazole of the Granisetron so obtained. Thus, for example, in examples 2 and 3 of said patent described the cyclisation reaction, but although in example 2 the reaction leads to Granisetron, in example 3, when the reaction time is increased under the same conditions, quantitatively demethylated Granisetron is provided. The reaction time therefore has a consideration influence on the yield values in the second step of the process that is in the cyclisation, since the Granisetron provided by this process contains as an impurity significant amounts of demethylated Granisetron, which will have to be re-methylated in an additional step.
(C) ES 2,124,162 patent discloses a procedure for the preparation of Granisetron or its pharmaceutically acceptable salts consisting of reaction of l-methylindazole-3- carboxamide of formula (A) with 9-methyl-9-azabicyclononane of formula (B) (L = halogen, OMs, OTs; halogen = esp. Cl, Br; Ms = SO2Me; Ts = SO2C6H4Me4). Thus, l-methylindazole-3-carboxamide in tetrahydrofuran (THF) containing tetramethylethylenediamine is treated with BuLi in hexane followed by addition of endo-3-(mesyloxy)-9-methyl-9-azabicyclo [3.3.1] nonane hydrochloride (L = OMs) to give the title compound i.e. Granisetron The scheme is represented below:
(A) (B) GRANISETRON
As discussed above none of the prior art references disclosed or claimed the use of methyl isobutyl ketone (MIBK) as a single solvent in presence of an organic Λ
4
base such as triethylamine for the preparation of compound of formula (I), hence we focused our research to develop an improved and efficient process for the preparation of the compound of formula (I) in substantial good yield and high purity.
,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
The synthesis of granisetron has been reported: The reaction of 1-methylindazole-3-carboxylic acid (I) with oxalyl chloride and DMF in dichloromethane gives 1-methylindazole-3-carbonyl chloride (II), which is then condensed with endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine (III) by means of triethylamine in dichloromethane.
AU 8656579; EP 0200444; EP 0223385; EP 0498466; ES 8707948; JP 1986275276; JP 1993194508; US 4886808; US 5034398
…………………………………………………………………………………………………….
Example (1) Preparation of Granisetron hydrochloride
10OmL of methyl isobutyl ketone (MIBK), 8.6g of triethylamine and 1Og of 1- methyl indazole-3-carboxylic acid were placed in a 25OmL RBF. The reaction mass was stirred and treated with 7.4g of ethyl chloro formate at O0C to (-) 50C to get a mixed anhydride and then condensed with 8.75g of endo-9-methyl-9-azabicycolo [3.3.1] nonan-3-amine and stirred the reaction mass till the completion of reaction. To the reaction mixture 100 mL of water was added, organic layer separated and distilled to 8 volumes of MIBK, cooled the reaction mass and treated with 10.3g of IPA/HC1 (~ 20%) to get 1Og of Granisetron hydrochloride. Example (2) Preparation of Granisetron base
75OmL of methyl isobutyl ketone, 4Og of triethylamine and 5Og of 1-methyl indazole-3-carboxylic acid were placed in a 2L RBF. The reaction mass was stirred and treated with 34g of ethyl chloro formate at 20°C to 25°C to get a mixed anhydride and then condensed with 48g of endo-9-methyl-9-azabicycolo [3.3.1] nonan-3-amine and stirred the reaction mass till the completion of reaction. To the reaction mixture 500 mL of water was added and the organic layer separated, washed with 5% sodium carbonate
(50OmL) solution and distilled the organic layer to obtain Granisetron freebase with HPLC purity 99.91%.
Example (2 – a ) Preparation of Granisetron hydrochloride
1Og of Granisetron freebase, 10OmL of methanol were placed in 250 mL RBF and heated the reaction mass to 400C to 550C to get a clear solution. The clear solution was filtered and treated with 3.5g of concentrated hydrochloric acid (36%) and diluted the reaction mass with 20OmL of MIBK, heated the reaction mass to 600C to 65°C and distilled the reaction mass up to 10 to 12 Volumes. The reaction mass was cooled and isolated 1Og of Granisetron hydrochloride with HPLC purity 99.91%.
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http://www.google.com/patents/WO1997030049A1?cl=en
Example 3 Preparation of endo-N-(9-methyl-9-azabicyclo[3.3. l]non-3-yl)-indazole-3- carboxamide.
A solution of 2-(N-methylbenzylidenehydrazino)-α-oxophenyl-[endo-N-(9- methyl-9-azabicyclo[3.3.1]non-3-yl)] carboxamide(0.536 g) in methanol (8 ml) was treated with 2N hydrochloric acid (0.4 ml) at room temperature. A rapid colour change from orange to green was observed. The solution was stirred for 24 hours then evaporated to the give the crude endo-N-(9-methyl-9-azabicyclo[3.3.1] non-3-yl)-indazole-3-carboxamide (0.630g).
Example 4 Preparation of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-l-methylindazole- 3-cjχboxamide (granisetron).
Sodium hydride (72 mg, 60% dispersion in oil) was added to a solution of endo- N-(9-methyl-9-azabicyclo[3.3. l]non-3-yl)-indazole-3-carboxamide (0.130g) in dry tetrahydrofuran (3.0 ml) under nitrogen at -50°C. The resultant solution was warmed to room temperature over 20 minutes then cooled to -40°C and treated with methyl iodide (0.015 ml). After 3 hours at room temperature HPLC analysis showed complete conversion to endo-N-(9-methyl-9-azabicyclo[3.3.1] non-3-yl)- l-methy-indazole-3-carboxamide. Water (10 ml) was added and the mixture extracted with ethyl acetate (2x 20 ml). The extracts were dried (MgSO4) ^ evaporated to give endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-l- methylindazole-3-carboxamide 50 mg (41%). MS 313 (M+H)+.
Duchenne Muscular Dystrophy: EspeRare Foundation And Drug Repositioning
This is the fifth Blog Post in a series examining Duchenne Muscular Dystrophy (DMD) in the rare disease and orphan drug space. This Blog Post discusses the EspeRare Foundation and how the organization is using repositioning or repurposing of an old drug to benefit DMD.
Drug repositioning or drug repurposing (DR) is applying existing drugs to new indications or diseases. DR is increasing in importance to many drug development and pharmaceutical companies. Using DR provides several advantages to companies:
• Repositioned drug has already passed toxicity and other tests
• Repositioned drug’s safety profile is already known
• Repositioned drug decreases the development time and cost of developing a drug.
Merck Serono, a division of Merck, announces in April 2013, the launch of the EspeRare Foundation. The EspeRare Foundation is presented to the public and international rare disease community at the IRDiRC (International Rare Diseases Research Consortium) Conference, in April…
View original post 336 more words
MARIZOMIB, Salinosporamide A
MARIZOMIB
http://www.ama-assn.org/resources/doc/usan/marizomib.pdf
THERAPEUTIC CLAIM Antineoplastic
CHEMICAL NAMES
1. 6-Oxa-2-azabicyclo[3.2.0]heptane-3,7-dione, 4-(2-chloroethyl)-1-[(S)-(1S)-2-
cyclohexen-1-ylhydroxymethyl]-5-methyl-, (1R,4R,5S)-
2. (1R,4R,5S)-4-(2-chloroethyl)-1-{(S)-[(1S)-cyclohex-2-en-1-yl]hydroxymethyl}-5-methyl-
6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione
MOLECULAR FORMULA C15H20ClNO4
MOLECULAR WEIGHT 313.8
MANUFACTURER Nereus Pharmaceuticals, Inc.
NOTE….Nereus Pharmaceuticals was acquired by Triphase Research and Development in 2012.
CODE DESIGNATION NPI-0052
CAS REGISTRY NUMBER 437742-34-2
Scripps Institution of Oceanography (Originator)
mp, 168–170° C. (authentic sample: 168–170° C., 169–171° C. in Angew. Chem. Int. Ed., 2003, 42, 355–357); mixture mp, 168–170C.
[α]23 D −73.2 (c 0.49, MeOH), −72.9 (c 0.55, MeOH, in Angew. Chem. Int. Ed., 2003, 42, 355–357);
FTIR (film) νmax: 3406, 2955, 2920, 2844, 1823, 1701, 1257, 1076, 1012, 785, 691 cm−1;
1H NMR (CDCl3, 500 MHz): δ 10.62 (1H, br), 6.42 (1H, d, J=10.5 Hz), 5.88 (1H, m), 4.25 (1H, d, J=9.0 Hz), 4.14 (1H, m), 4.01 (1H, m), 3.17 (1H, t, J=7.0 Hz), 2.85 (1H, m), 2.48 (1H, m), 2.32 (2H, m), 2.07 (3H, s), 1.91 (2H, m), 1.66 (2H, m), 1.38 (1H, m);
13C NMR (CDCl3, 125 MHz): δ 176.92, 169.43, 129.08, 128.69, 86.32, 80.35, 70.98, 46.18, 43.28, 39.31, 29.01, 26.47, 25.35, 21.73, 20.00;
HRMS (ESI) calcd. for (M−H)− C15H19ClNO4 312.1003, found 312.1003.
Marizomib, a highly potent proteasome inhibitor, is in early clinical development at Triphase Research and Development I Corp for the treatment of relapsed or relapsed/refractory multiple myeloma. Phase I clinical trials have also been carried out for the treatment of solid tumors and lymphoma; however, no recent developments have been reported for these studies.
HDAC inhibitors halt tumor cell differentiation and growth, and when combined with marizomib in preclinical in vitro and in vivo studies, show additive and synergistic antitumor activities.
The compound was discovered from a new marine-obligate gram-positive actinomycete (Salinispora tropica). Preclinical studies suggest that this next-generation compound may be superior to other proteasome inhibitors, with broader target inhibition, faster onset and longer duration of action, higher potency, and oral and intravenous availability. By inhibiting proteasomes, marizomib prevents the breakdown of proteins involved in signal transduction, which blocks growth and induces apoptosis in cancer cells.
In 2013, orphan drug designation was assigned in the U.S. for the treatment of multiple myeloma.
The compound was originally developed by Nereus Pharmaceuticals, which was acquired by Triphase Research and Development in 2012.
marizomib is a naturally-occurring salinosporamide, isolated from the marine actinomycete Salinospora tropica, with potential antineoplastic activity. Marizomib irreversibly binds to and inhibits the 20S catalytic core subunit of the proteasome by covalently modifying its active site threonine residues; inhibition of ubiquitin-proteasome mediated proteolysis results in an accumulation of poly-ubiquitinated proteins, which may result in the disruption of cellular processes, cell cycle arrest, the induction of apoptosis, and the inhibition of tumor growth and angiogenesis. This agent more may more potent and selective than the proteasome inhibitor bortezomib
Marizomib (NPI-0052) is an oral, irreversible ββ-lactone derivative that binds selectively to the active proteasomal sites. In vivo studies with marizomib demonstrate reduced tumor growth without significant toxicity in myeloma xenograft models. A phase I trial in refractory and relapsed MM is under way.
Salinosporamide A is a potent proteasome inhibitor used as an anticancer agent that recently entered phase I human clinical trials for the treatment of multiple myeloma only three years after its discovery.[1][2] This novel marine natural product is produced by the recently described obligate marine bacteria Salinispora tropica and Salinispora arenicola, which are found in ocean sediment. Salinosporamide A belongs to a family of compounds, known collectively as salinosporamides, which possess a densely functionalized γ-lactam-β-lactone bicyclic core.
Salinosporamide A was discovered by William Fenical and Paul Jensen from Scripps Institution of Oceanography in La Jolla, CA. In preliminary screening, a high percentage of the organic extracts of cultured Salinospora strains possessed antibiotic and anticancer activities, which suggests that these bacteria are an excellent resource for drug discovery.Salinospora strain CNB-392 was isolated from a heat-treated marine sediment sample and cytotoxicity-guided fractionation of the crude extract led to the isolation of salinosporamide A. Although salinosporamide A shares an identical bicyclic ring structure with omuralide, it is uniquely functionalized. Salinosporamide A displayed potent in vitro cytotoxicity against HCT-116 human colon carcinoma with an IC50 value of 11 ng mL-1. This compound also displayed potent and highly selective activity in the NCI’s 60-cell-line panel with a mean GI50 value (the concentration required to achieve 50% growth inhibition) of less than 10 nM and a greater than 4 log LC50 differential between resistant and susceptible cell lines. The greatest potency was observed against NCI-H226 non-small cell lung cancer, SF-539 CNS cancer, SK-MEL-28 melanoma, and MDA-MB-435 breast cancer (all with LC50 values less than 10 nM). Salinosporamide A was tested for its effects on proteasome function because of its structural relationship to omuralide. When tested against purified 20S proteasome, salinosporamide A inhibited proteasomal chymotrypsin-like proteolytic activity with an IC50 value of 1.3 nM.[3] This compound is approximately 35 times more potent than omuralide which was tested as a positive control in the same assay. Thus, the unique functionalization of the core bicyclic ring structure of salinosporamide A appears to have resulted in a molecule that is a significantly more potent proteasome inhibitor than omuralide.[1]
Salinosporamide A inhibits proteasome activity by covalently modifying the active site threonine residues of the 20S proteasome.
Biosynthesis
Salinosporamide A and B building blocks
Proposed biosynthesis of the nonproteinogenic amino-acid beta-hydroxycyclohex-2′-enylanine (3) (R = H or S~PCP) via a shunt in the phenylalanine biosynthetic pathway
Biosynthesis
It was originally hypothesized that salinosporamide B was a biosynthetic precursor to salinosporamide A due to their structural similarities.
It was thought that the halogenation of the unactivated methyl group was catalyzed by a non-heme iron halogenase.[4][5]Recent work using 13C-labeled feeding experiments reveal distinct biosynthetic origins of salinosporamide A and B.[4][6]
While they share the biosynthetic precursors acetate and presumed β-hydroxycyclohex-2′-enylalanine (3), they differ in the origin of the four-carbon building block that gives rise to their structural differences involving the halogen atom. A hybrid polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) pathway is most likely the biosynthetic mechanism in which acetyl-CoA and butyrate-derived ethylmalonyl-CoA condense to yield the β-ketothioester (4), which then reacts with (3) to generate the linear precursor (5).
The first stereoselective synthesis was reported by Rajender Reddy Leleti and E. J.Corey.[7] Later several routes to the total synthesis of salinosporamide A have been reported.[7][8][9][10]
In vitro studies using purified 20S proteasomes showed that salinosporamide A has lower EC50 for trypsin-like (T-L) activity than does Bortezomib. In vivo animal model studies show marked inhibition of T-L activity in response to salinosporamide A, whereas bortezomib enhances T-L proteasome activity.
Initial results from early-stage clinical trials of salinosporamide A in relapsed/refractory multiple myeloma patients were presented at the 2011 American Society of Hematology annual meeting.[11] Further early-stage trials of the drug in a number of different cancers are ongoing.[12]
- Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W (2003). “Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora”. Angew. Chem. Int. Ed. Engl. 42 (3): 355–7.doi:10.1002/anie.200390115. PMID 12548698.
- Chauhan D, Catley L, Li G et al. (2005). “A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib”. Cancer Cell 8 (5): 407–19.doi:10.1016/j.ccr.2005.10.013. PMID 16286248.
- K. Lloyd, S. Glaser, B. Miller, Nereus Pharmaceuticals Inc.
- Beer LL, Moore BS (2007). “Biosynthetic convergence of salinosporamides A and B in the marine actinomycete Salinispora tropica”. Org. Lett. 9 (5): 845–8.doi:10.1021/ol063102o. PMID 17274624.
- Vaillancourt FH, Yeh E, Vosburg DA, Garneau-Tsodikova S, Walsh CT (2006). “Nature’s inventory of halogenation catalysts: oxidative strategies predominate”. Chem. Rev.106 (8): 3364–78. doi:10.1021/cr050313i.PMID 16895332.
- Tsueng G, McArthur KA, Potts BC, Lam KS (2007). “Unique butyric acid incorporation patterns for salinosporamides A and B reveal distinct biosynthetic origins”. Applied Microbiology and Biotechnology 75 (5): 999–1005. doi:10.1007/s00253-007-0899-7.PMID 17340108.
- Reddy LR, Saravanan P, Corey EJ (2004). “A simple stereocontrolled synthesis of salinosporamide A”. J. Am. Chem. Soc. 126 (20): 6230–1. doi:10.1021/ja048613p.PMID 15149210.
- Ling T, Macherla VR, Manam RR, McArthur KA, Potts BC (2007). “Enantioselective Total Synthesis of (-)-Salinosporamide A (NPI-0052)”.Org. Lett. 9 (12): 2289–92. doi:10.1021/ol0706051. PMID 17497868.
- Ma G, Nguyen H, Romo D (2007). “Concise Total Synthesis of (±)-Salinosporamide A, (±)-Cinnabaramide A, and Derivatives via a Bis-Cyclization Process: Implications for a Biosynthetic Pathway?”. Org. Lett. 9 (11): 2143–6. doi:10.1021/ol070616u. PMC 2518687.PMID 17477539.
- Endo A, Danishefsky SJ (2005). “Total synthesis of salinosporamide A”. J. Am. Chem. Soc. 127 (23): 8298–9.doi:10.1021/ja0522783. PMID 15941259.
- “Marizomib May Be Effective In Relapsed/Refractory Multiple Myeloma (ASH 2011)”. The Myeloma Beacon. 2012-01-23. Retrieved 2012-06-10.
- ClinicalTrials.gov: Marizomib
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IMPORTANT PAPERS
Total synthesis of salinosporamide A
Org Lett 2008, 10(19): 4239
Entry to heterocycles based on indium-catalyzed conia-ene reactions: Asymmetric synthesis of (-)-salinosporamide A
Angew Chem Int Ed 2008, 47(33): 6244
A concise and straightforward total synthesis of (+/-)-salinosporamide A, based on a biosynthesis model
Org Biomol Chem 2008, 6(15): 2782
Formal synthesis of salinosporamide A starting from D-glucose
Synthesis (Stuttgart) 2009, 2009(17): 2983
Stereoselective functionalization of pyrrolidinone moiety towards the synthesis of salinosporamide A
Tetrahedron 2012, 68(32): 6504
………………
Salinosporamide A(1) was recently discovered by Fenical et al. as a bioactive product of a marine microorganism that is widely distributed in ocean sediments. Feeling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.; Jensen, P. R.; Fenical, W., Angew. Chem. Int. Ed., 2003, 42, 355–357.
Structurally Salinosporamide A closely resembles the terrestrial microbial product omuralide (2a) that was synthesized by Corey et al. several years ago and demonstrated to be a potent inhibitor of proteasome function. See, (a) Corey, E. J.; Li, W. D., Z. Chem. Pharm. Bull., 1999, 47, 1–10; (b) Corey, E. J., Reichard, G. A.; Kania, R., Tetrahedron Lett., 1993, 34, 6977–6980; (c) Corey, E. J.; Reichard, G. A., J. Am. Chem. Soc., 1992, 114, 10677–10678; (d) Fenteany, G.; Standaert, R. F.; Reichard, G. A.; Corey, E. J.; Schreiber, S. L., Proc. Natl. Acad. Sci. USA, 1994, 91, 3358–3362.
Omuralide is generated by β-lactonization of the N-acetylcysteine thiolester lactacystin (2b) that was first isolated by the Omura group as a result of microbial screening for nerve growth factor-like activity. See, Omura, S., Fujimoto, T., Otoguro, K., Matsuzaki, K., Moriguchi, R., Tanaka, H., Sasaki, Y., Antibiot., 1991, 44, 113–116; Omura, S., Matsuzaki, K., Fujimoto, T., Kosuge, K., Furuya, T., Fujita, S., Nakagawa, A., J. Antibiot., 1991, 44, 117–118.
Salinosporamide A, the first compound Fenical’s group isolated from Salinospora, not only had a never-before-seen chemical structure 1, but is also a highly selective and potent inhibitor of cancer-cell growth. The compound is an even more effective proteasome inhibitor than omuralide and, in addition, it displays surprisingly high in vitro cytotoxic activity against many tumor cell lines (IC50values of 10 nM or less). Fenical et al. first found the microbe, which they’ve dubbed Salinospora, off the coasts of the Bahamas and in the Red Sea. See,Appl. Environ. Microbiol., 68, 5005 (2002).
Fenical et al. have shown that Salinospora species requires a salt environment to live. Salinospora thrives in hostile ocean-bottom conditions: no light, low temperature, and high pressure. The Fenical group has now identified Salinosporain five oceans, and with 10,000 organisms per cm3 of sediment and several distinct strains in each sample; and according to press reports, they’ve been able to isolate 5,000 strains. See, Chemical & Engineering News, 81, 37 (2003).
A great percentage of the cultures Fenical et al. have tested are said to have shown both anticancer and antibiotic activity. Like omuralide 2a, salinosporamide A inhibits the proteasome, an intracellular enzyme complex that destroys proteins the cell no longer needs. Without the proteasome, proteins would build up and clog cellular machinery. Fast-growing cancer cells make especially heavy use of the proteasome, so thwarting its action is a compelling drug strategy. See, Fenical et al., U.S. Patent Publication No. 2003-0157695A1
PATENTS
WO 2005113558
http://www.google.com/patents/US7183417
Part I. Synthesis of the Salinosporamide A(1)
EXAMPLE 1
(4S, 5R) Methyl 4,5-dihydro-2 (4-methoxyphenyl)-5-methyloxazole-4-carboxylate (4)
A mixture of (2S, 3R)-methyl 2-(4-methoxybenzamido)-3-hydroxybutanoate (3) (35.0 g, 131 mmol) and p-TsOH.H2O (2.5 g, 13.1 mmol) in toluene (400 mL) was heated at reflux for 12 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed in vacuo to give crude oxazoline as yellow oil. Flash column chromatography on silica gel (eluent 15% EtOAc-Hexanes) afforded the pure oxazoline (26.1 g, 80%) as solid.
Rf=0.51 (50% ethyl acetate in hexanes), mp, 86–87° C.; [α]23 D+69.4 (c 2.0, CHCl3); FTIR (film) νmax: 2955, 1750, 1545, 1355, 1187, 1011, 810 cm−1; 1HNMR(CDCl3, 400 MHz): δ 7.87 (2H, d, J=9.2 Hz), 6.84 (2H, d, J=8.8 Hz), 4.90 (1H, m), 4.40 (1H, d, J=7.6 Hz), 3.79 (3H,s), 3.71 (3H, s), 1.49 (3H, d, J=6.0 Hz); 13C NMR (CDCl3, 100 MHz): δ 171.93, 165.54, 162.64, 130.52, 119.80, 113.85, 78.91, 75.16, 55.51, 52.73, 21.14; HRMS (ESI) calcd for C13H16NO4 (M+H)+.250.1079, found 250.1084.
EXAMPLE 2
(4R, 5R)-Methyl 4-{(benzyloxy) methyl)}-4,5-dihydro-2-(4-methoxyphenyl)-5-methyloxazole-4-carboxylate (5)
To a solution of LDA (50 mmol, 1.0 M stock solution in THF) was added HMPA (24 mL, 215 mmol) at −78° C. and then oxazoline 4 (12.45 g, 50 mmol, in 20 mL THF) was added dropwise with stirring at −78° C. for 1 h to allow complete enolate formation. Benzyloxy chloromethyl ether (8.35 mL, 60 mmol) was added at this temperature and after stirring the mixture at −78° C. for 4 h, it was quenched with water (50 mL) and warmed to 23° C. for 30 min. Then the mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:4 then 1:3) to give the benzyl ether 5 (12.7 g, 69%).
Rf=0.59 (50% ethyl acetate in hexanes). [α]23 D−6.3 (c 1.0, CHCl3); FTIR (film) (νmax; 3050, 2975, 1724, 1642, 1607, 1252, 1027, 745, 697 cm−1; 1H NMR (CDCl3, 400 MHz): δ 7.96 (2H, d, J=9.2 Hz), 7.26 (5H, m), 6.90 (2H, J=8.8 Hz), 4.80 (1H, m), 4.61 (2H, s), 3.87 (3H, m), 3.81 (3H, s), 3.73 (3H, s), 1.34 (3H, d, J=6.8 Hz); 13C NMR (CDCl3, 100 MHZ): 6171.23, 165.47, 162.63, 138.25, 130.64, 128.52, 127.87, 127.77, 120.15, 113.87, 81.40, 79.92, 73.91, 73.43, 55.58, 52.45, 16.92; HRMS (ESI) calcd for C21H24O5 (M+H)+370.1654, found 370.1644.
EXAMPLE 3
(2R,3R)-Methyl 2-(4-methoxybenzylamino)-2-((benzyloxy)methyl)-3hydroxybutanoate (6)
To a solution of oxazoline 5 (18.45 g, 50 mmol) in AcOH (25 mL) at 23° C. was added in portions NaCNBH3 (9.3 g, 150 mmol). The reaction mixture was then stirred at 40° C. for 12 h to allow complete consumption of the starting material. The reaction mixture was diluted with water (100 mL), neutralized with solid Na2CO3 and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over NaSO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5) to give the N-PMB amino alcohol 6 (16.78 g, 90%).
Rf=0.50 (50% ethyl acetate in hexanes). [α]23 D−9.1(c 1.0, CHCl3); FTIR (film) νmax; 3354, 2949, 1731, 1511, 1242, 1070, 1030, 820, 736, 697 cm−1; 1H NMR (CDCl3, 400 MHz): δ 7.32 (7H, m), 6.87 (2H, d, J=8.8 Hz), 4.55 (2H, m), 4.10 (1H, q, J=6.4 Hz), 3.85 (2H, dd, J=17.2, 10.0 Hz), 3.81 (3H, s,), 3.77 (3H, s), 3. 69 (2H, dd, J=22.8, 11.6 Hz), 3.22 (2H, bs), 1.16 (3H, d, J=6.0 Hz); 13C NMR (CDCl3, 100 MHz): δ 173.34, 159.03, 137.92, 132.51, 129.78, 128.67, 128.07, 127.98, 114.07, 73.80, 70.55, 69.82, 69.65, 55.51, 55.29, 47.68, 18.15; HRMS (ESI) calcd. for C21H28NO5 (M+H)+ 374.1967, found 374.1974.
EXAMPLE 4
(2R,3R)-Methyl-2-(N-(4-methoxybenzyl)acrylamido)-2-(benzyloxy)methyl)-3-hydroxybutanoate (7)
A solution of amino alcohol 6 (26.2 g, 68.5 mmol) in Et2O (200 mL) was treated with Et3N (14.2 mL, 102.8 mmol) and trimethylchlorosilane (10.4 mL, 82.2 mmol) at 23° C. and stirred for 12 h. After completion, the reaction mixture was diluted with ether (200 mL) and then resulting suspension was filtered through celite. The solvent was removed to furnish the crude product (31.2 g, 99%) in quantitative yield as viscous oil. A solution of this crude trimethylsilyl ether (31.1 g) in CH2Cl2 (200 mL) was charged with diisopropylethylamine (14.2 mL, 81.6 mmol) and then cooled to 0° C. Acryloyl chloride (6.64 mL, 82.2 mmol) was added dropwise with vigorous stirring and the reaction temperature was maintained at 0° C. until completion (1 h). The reaction mixture was then diluted with CH2Cl2 (100 mL) and the organic layer was washed with water and brine. The organic layer was separated and dried over Na2SO4. The solvent was removed to afford the crude acrylamide 7 as a viscous oil. The crude product was then dissolved in Et2O (200 mL) and stirred with 6N HCl (40 mL) at 23° C. for 1 h. The reaction mixture was diluted with water (100 mL) and concentrated to provide crude product. The residue was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5 to 1:1) to give pure amide 7 (28.3 g, 96%) as colorless solid, mp 88–89° C.
Rf=0.40 (50% ethyl acetate in hexanes), [α]23 D−31.1 (c 0.45, CHCl3), FTIR (film) νmax; 3435, 2990, 1725, 1649, 1610, 1512, 1415, 1287, 1242, 1175, 1087, 1029, 732, 698 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.25 (5H, m), 7.15 (2H, d, J=6.0 Hz), 6.85 (2H, d, J=7.5 Hz), 6.38 (2H, d, J=6.0 Hz), 5.55 (1H, t, J=6.0 Hz), 4.81 (2H, s), 4.71 (1H, q, J=6.5 Hz), 4.35 (2H, s), 4.00 (1H, d, J=10.0 Hz), 3.80 (1H, d, J=10.0 Hz), 3.76 (3H, s), 3.75 (3H, s), 3.28 (1H, bs), 1.22 (3H, d, J=6.0 Hz); 13C NMR (CDCl3, 125 MHz): δ 171.87, 168.74, 158.81, 137.73, 131.04, 129.68, 128.58, 128.51, 127.94, 127.72, 127.20, 127.14, 114.21, 73.71, 70.42, 69.76, 67.65, 55.45, 52.52, 49.09, 18.88; HRMS (ESI) calcd. for C24H30NO6 (M+H)+428.2073, found 428.2073.
EXAMPLE 5
(R)-Methyl-2-(N-(4-methoxybenzyl)acrylamido)-2-(benzyloxy)methyl)-3-oxybutanoate (8)
To a solution of amide 7 (10.67 g, 25.0 mmol) in CH2Cl2 (100 mL) was added Dess-Martin periodinane reagent (12.75 g, 30.0 mmol, Aldrich Co.) at 23° C. After stirring for 1 h, the reaction mixture was quenched with aq NaHCO3—Na2S2O3 (1:1, 50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was dried and concentrated in vacuo to afford the crude ketone. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes) to give pure keto amide 8 (10.2 g, 96%).
Rf=0.80 (50% ethyl acetate in hexanes), mp 85 to 86° C.; [α]23 D−12.8 (c 1.45, CHCl3); FTIR (film) νmax: 3030, 2995, 1733, 1717, 1510, 1256, 1178, 1088, 1027, 733, 697 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.30 (2H, d, J=8.0), 7.25 (3H, m), 7.11 (2H, m), 6.88 (2H, d, J=9.0 Hz), 6.38 (2H, m), 5.63 (1H, dd, J=8.5, 3.5 Hz), 4.93 (1H, d, J=18.5 Hz), 4.78 (1H, d, J=18.5, Hz), 4.27 (2H, m), 3.78 (3H, s), 3.76 (3H, s), 2.42 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 198.12, 169.23, 168.62, 158.01, 136.95, 130.64, 130.38, 128.63, 128.13, 127.77, 127.32, 114.33, 77.49, 73.97, 70.66, 55.49, 53.09, 49.03, 28.24; HRMS (ESI) calcd. for C24H28NO6 (M+H)+ 426.1916, found 426.1909.
EXAMPLE 6
(2R,3S)-Methyl-1-(4-methoxybenzyl)-2-((benzyloxy)methyl)-3-hydroxy-3-methyl-4-methylene-5-oxopyrrolidine-2-carboxylate (9+10)
A mixture of keto amide 8 (8.5 g, 20.0 mmol) and quinuclidine (2.22 g, 20.0 mmol) in DME (10 mL) was stirred for 5 h at 23° C. After completion, the reaction mixture was diluted with ethyl acetate (50 mL) washed with 2N HCl, followed by water and dried over Na2SO4. The solvent was removed in vacuo to give the crude adduct (8.03 g, 94.5%, 3:1 ratio of 9 to 10 dr) as a viscous oil. The diastereomeric mixture was separated at the next step, although small amounts of 9 and 10 were purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:10 to 1:2) for analytical purposes.
Major Diastereomer (9).
[α]23 D−37.8 (c 0.51, CHCl3); FTIR (film) vmax: 3450, 3055, 2990, 1733, 1683, 1507, 1107, 1028, 808,734 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.29 (5H, m), 7.15 (2H, d, J=7.5 Hz), 6.74 (2H, d, J=8.5 Hz), 6.13 (1H, s), 5.57 (1H, s), 4.81 (1H, d, J=14.5 Hz), 4.45(1H, d, J=15.0 Hz), 4.20 (1H, d, J=12.0 Hz), 4.10 (1H, d, J=12.0 Hz) 3.75 (3H, s), 3.70 (1H, d, J=10.5 Hz), 3.64 (3H, s), 3.54 (1H, d, J=10.5 Hz), 2.55 (1H, bs, OH), 1.50 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 169.67, 168.42, 158.97, 145.96, 137.57, 130.19, 130.12, 128.53, 127.83, 127.44, 116.79, 113.71, 76.32, 76.00, 73.16, 68.29, 55.45, 52.63, 45.36, 22.64; HRMS (ESI) calcd. for C24H28NO6 (M+H)+ 426.1916, found 426.1915.
Minor Diastereomer (10).
[α]23 D−.50.1 (c 0.40, CHCl3); FTIR (film) νmax: 3450, 3055, 2990, 1733, 1683, 1507, 1107, 1028, 808, 734 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.29 (5H, m), 7.12 (2H, d, J=7.5 Hz), 6.73 (2H, d, J=8.5 Hz), 6.12 (1H, s), 5.57 (1H, s), 4.88 (1H, d, J=15.5 Hz), 4.31 (1H, d, J=15.0 Hz), 4.08 (3H, m), 3.99 (1H, d, J=12.0 Hz) 3.73 (3H, s), 3.62 (3H, s), 3.47 (1H, bs, OH), 3.43 (1H, d, J=10.0 Hz), 1.31 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 169.65, 167.89, 159.13, 147.19, 136.95, 130.29, 129.76, 128.74, 128.19, 127.55, 116.80, 113.82, 76.21, 75.66, 73.27, 68.02, 55.45, 52.52, 45.24, 25.25; HRMS (ESI) calcd. for (M+H)+ C24H28NO6 426.1916, found 426.1915.
EXAMPLE 7
Silylation of 9 and 10 and Purification of 11.
To a solution of lactams 9 and 10 (7.67 g, 18 mmol) in CH2Cl2 (25 ml) was added Et3N (7.54 ml, 54 mmol), and DMAP (2.2 g, 18 mmol) at 0° C., and then bromomethyl-dimethylchlorosilane (5.05 g, 27 mmol) (added dropwise). After stirring the mixture for 30 min at 0° C., it was quenched with aq NaHCO3 and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed in vacuo to give a mixture of the silated derivatives of 9 and 10 (9.83 g, 95%). The diastereomers were purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5 to 1:4) to give pure diastereomer 11 (7.4 g, 72%) and its diastereomer (2.4 g, 22%).
Silyl Ether (11).
Rf=0.80 (30% ethyl acetate in hexanes). [α]23 D−58.9 (c 0.55, CHCl3); FTIR (film) νmax; 3050, 2995, 1738, 1697, 1512, 1405, 1243, 1108, 1003, 809, 732 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.27 (5H, m), 7.05 (2H, d, J=7.0 Hz), 6.71 (2H, d, J=8.5 Hz), 6.18 (1H, s), 5.53 (1H, s), 4.95 (1H, d, J=15.5 Hz), 4.45 (1H, d, J=15.0 Hz), 4.02 (1H, J=12.0 Hz), 3.86 (1H, d, J=11.5 Hz) 3.72 (3H, s), 3.68 (3H, s), 3.65 (1H, d, J=10.5 Hz), 3.30 (1H, d, J=10.0 Hz), 2.34 (2H, d, J=2.0 Hz), 1.58 (3H, s), 0.19 (3H, s), 0.18 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 168.62, 168.12, 158.93, 145.24, 137.53, 130.32, 130.30, 128.49, 127.76,127.22, 117.26, 113.60, 78.55, 78.03, 72.89, 68.45, 55.43, 52.37, 45.74, 21.87, 17.32, −0.72, −0.80; HRMS (ESI) Calcd. for C27H35BrNO6Si (M+H)+ 576.1417, found 576.1407.
EXAMPLE 8
Conversion of (11) to (12).
To a solution of compound 11 (5.67 g 10 mmol) in benzene (250 mL) at 80° C. under nitrogen was added a mixture of tributyltin hydride (4.03 ml, 15 mmol) and AIBN (164 mg, 1 mmol) in 50 ml benzene by syringe pump over 4 h. After the addition was complete, the reaction mixture was stirred for an additional 4 h at 80° C. and the solvent was removed in vacuo. The residue was dissolved in hexanes (20 mL) and washed with saturated NaHCO3 (3×25 mL), water and dried over Na2SO4. The solvent was removed in vacuo to give crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5) to afford the pure 12 (4.42 g, 89%).
Rf=0.80 (30% ethyl acetate in hexanes). [α]23 D−38.8 (c 0.25, CHCl3); FTIR (film) νmax; 3025, 2985, 1756, 1692, 1513, 1247, 1177, 1059, 667 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.28 (5H, m), 7.09 (2H, d, J=7.0 Hz), 6.73 (2H, d, J=9.0 Hz), 4.96(1H, d, J=15.0 Hz), 4.35 (1H, d, J=15.5 Hz), 3.97 (1H, d, J=12.5 Hz), 3.86 (1H, d, J=12.0 Hz), 3.80 (1H, d, J=10.0 Hz), 3.72 (3H, s), 3.65 (3H, s), 3.27 (1H, d, J=10.5 Hz), 2.67 (1H, t, J=4.0 Hz), 2.41 (1H, m), 1.79 (1H, m), 1.46 (3H, s), 0.77 (1H, m), 0.46 (1H, m), 0.10 (3H, s), 0.19 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 175.48, 169.46, 158.76, 137.59, 131.04, 129.90, 128.58, 127.88, 127.52, 113.59, 113.60, 81.05, 78.88, 73.12, 69.03, 55.45, 51.94, 48.81, 45.50, 22.79, 17.06, 7.76, 0.54; HRMS (ESI) calcd. for (M+H)+ C27H36NO6Si 498.2312, found 498.2309.
EXAMPLE 9
Debenzylation of (12).
A solution of 12 (3.98 g, 8 mmol) in EtOH (50 ml) at 23° C. was treated with 10% Pd—C (˜1 g) under an argon atmosphere. The reaction mixture was evacuated and flushed with H2 gas (four times) and then stirred vigorously under an atmosphere of H2 (1 atm, H2 balloon) at 23° C. After 12 h, the reaction mixture was filtered through Celite and concentrated in vacuo to give the crude debenzylation product (3.08 g, 95%) which was used for the next step. A small amount crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:3) for analytical purposes. Rf=0.41 (50% ethyl acetate in hexanes).
mp, 45–47° C.; [α]23 D−30.9 (c 0.55, CHCl3); FTIR (film) νmax: 3432, 3020, 2926, 1735, 1692, 1512, 1244, 1174, 1094, 1024, 870, 795 cm−1; 1H NMR (CDCl3, 400 MHz): δ 7.36 (2H, d, J=8.5 Hz), 6.83 (2H, d, J=8.5 Hz), 5.16 (1H, d, J=15.0 Hz), 4.29 (1H, d, J=15.0 Hz), 3.92 (1H, m), 3.78 (3H, s), 3.68 (3H, s), 3.45 (1H, m), 2.53 (1H, t, J=4.0 Hz), 2.42 (1H, m), 1.82 (1H, m), 1.50 (3H, s), 1.28 (1H, m), 0.75 (1H, m), 0.47 (1H, m), 0.11 (3H, s), 0.02 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 175.82, 169.51, 159.32, 131.00, 129.72, 114.52, 80.79, 80.13, 61.85, 55.48, 51.99, 49.29, 45.06, 23.11, 17.03, 7.44, 0.54; HRMS (ESI) calcd. for C20H30NO6Si (M+H)+ 408.1842, found 408.1846.
EXAMPLE 10
Oxidation to Form Aldehyde (13).
To a solution of the above alcohol from debenzylation of 12 (2.84 g, 7 mmol) in CH2Cl2 (30 mL) was added Dess-Martin reagent (3.57 g, 8.4 mmol) at 23° C. After stirring for 1 h at 23° C., the reaction mixture was quenched with aq NaHCO3—Na2S2O3 (1:1, 50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was dried and concentrated in vacuo to afford the crude aldehyde. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5) to give pure aldehyde 13 (2.68 g, 95%). Rf=0.56 (50% ethyl acetate in hexanes).
mp, 54–56° C.; [α]23 D−16.5 (c 0.60, CHCl3); FTIR (film) νmax: 3015, 2925, 1702 1297, 1247, 1170, 1096, 987, 794 cm−1; 1H NMR (CDCl3, 500 MHz): δ 9.62 (1H, s), 7.07 (2H, d, J=8.0 Hz), 6.73 (2H, d, J=8.5 Hz), 4.49 (1H, quart, J=8.5 Hz), 3.70 (3H, s), 3.67 (3H, s), 2.36 (2H, m), 1.75 (1H, m), 1.37 (3H, s), 0.73 (1H, m), 0.48 (1H, m), 0.07 (3H, s), 0.004 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 197.26, 174.70, 167.36, 158.07, 130.49, 128.96, 113.81, 83.97, 82.36, 55.34, 52.43, 47.74, 46.32, 23.83, 16.90, 7.52, 0.56, 0.45; HRMS (ESD calcd. for C20H28NO6Si (M+H)+ 406.1686, found 406.1692.
EXAMPLE 11
Conversion of (13) to (14).
To a solution of freshly prepared cyclohexenyl zinc chloride (10 mL, 0.5 M solution in THF, 5 mmol) (see Example 15 below) at −78° C. under nitrogen was added a −78° C. solution of aldehyde 13 (1.01 g, in 3 ml of THF, 2.5 mmol). After stirring for 5 h at −78° C. reaction mixture was quenched with water (10 mL) then extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over Na2SO4 and solvent was removed in vacuo to give crude product (20:1 dr). The diastereomers were purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:10 to 1:2 affords the pure major diastereomer 14 (1.0 g, 83%) and a minor diastereomer (50 mg 5%). For 14: Rf=0.56 (50% ethyl acetate in hexanes).
mp, 79–81° C.; [a]23 D−28.5 (c 1.45, CHCl3); FTIR (film) νmax: 3267, 2927, 2894, 2829, 1742, 1667, 1509, 1248, 1164, 1024, 795 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.34 (2H, d, J=8.5 Hz), 6.81 (2H, d, J=9.0 Hz), 5.84 (1H, m), 5.73 (1H, m), 4.88 (1H, d, J=15.5 Hz), 4.39 (1H, d, J=14.5 Hz), 4.11 (1H, t, J=6.5 Hz), 3.77 (3H, s), 3.58 (3H, s), 3.00 (1H, m), 2.95 (1H, d, J=9.0 Hz), 2.83 (1H, t, J=3.5 Hz), 3.36 (1H, m), 2.27 (1H, m), 1.98 (2H, m), 1.74 (3H, m), 1.62 (3H, s), 1.14 (2H, m), 0.59 (1H, m), 0.39 (11H, m), 0.13 (3H, s), 0.03 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 176.80, 170.03, 158.27, 131.86, 131.34, 128.50, 126.15, 113.40, 83.96, 82.45, 77.17, 55.45, 51.46, 48.34, 48.29, 39.08, 28.34, 25.29, 22.45, 21.09, 17.30, 7.75, 0.39, 0.28; HRMS (ESI) calcd. for C26H38NO6Si (M+H)+ 488.2468, found 488.2477.
EXAMPLE 12
Tamao-Fleming Oxidation of (14) to (15).
To a solution of 14 (0.974 g, 2 mmol) in THF (5 mL) and MeOH (5 mL) at 23° C. was added KHCO3 (0.8 g, 8 mmol) and KF (0.348 g, 6 mmol). Hydrogen peroxide (30% in water, 5 mL) was then introduced to this mixture. The reaction mixture was vigorously stirred at 23° C. and additional hydrogen peroxide (2 ml) was added after 12 h. After 18 h, the reaction mixture was quenched carefully with NaHSO3 solution (15 mL). The mixture was extracted with ethyl acetate (3×25 mL) and the combined organic layers were washed with water and dried over Na2SO4. The solvent was removed in vacuo to give the crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate) to give the pure triol 15 (0.82 g, 92%).
Rf=0.15 (in ethyl acetate). mp, 83–84° C.; [α]23 D: +5.2 (c 0.60, CHCl3); FTIR (film) νmax; 3317, 2920, 2827, 1741, 1654, 1502, 1246, 1170, 1018, 802 cm−1; 1HNMR(CDCl3, 500 MHz): δ 7.77 (2H, d, J=8.0 Hz), 6.28 (2H, d, J=8.0 Hz), 5. 76 (1H, m), 5.63 (1H, d, J=10.0 Hz), 4.74 (1H, d, J=15.5 Hz), 4.54 (1H, d, J=15.0 Hz), 4.12 (1H, d, J=2.5 Hz), 3.80 (1H, m), 3.76 (3H, s), 3.72 (1H, m), 3.68 (3H, s), 3.00 (1H, m), 2.60 (1H, br), 2.20 (1H, m), 1.98 (2H, s), 1.87 (1H, m), 1.80 (1H, m), 1.71 (2H, m), 1.61 (3H, s), 1.14 (2H, m); 13C NMR (CDCl3, 125 MHz): δ 178.99, 170.12, 158.27, 131.30, 130.55, 128.13, 126.39, 113.74, 81.93, 80.75, 76.87, 61.61, 55.45, 51.97, 51.32, 48.07, 39.17, 27.71, 27.13, 25.22, 21.35, 21.22; HRMS (ESI) calcd. for C24H34NO7 (M+H)+ 448.2335, found 448.2334.
EXAMPLE 13
Deprotection of (15) to (16).
To a solution of 15 (0.670 g, 1.5 mmol) in acetonitrile (8 mL) at 0° C. was added a pre-cooled solution of ceric ammonium nitrate (CAN) (2.46 g 4.5 mmol in 2 mL H2O). After stirring for 1 h at 0° C. the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated NaCl solution (5 mL) and organic layers was dried over Na2SO4. The solvent was removed in vacuo to give the crude product which was purified by column chromatography (silica gel, ethyl acetate) to give the pure 16 (0.4 g, 83%).
Rf=0.10 (5% MeOH in ethyl acetate). mp, 138 to 140° C.; [α]23 D+14.5 (c 1.05, CHCl3); FTIR (film) νmax 3301, 2949, 2911, 2850, 1723, 1673, 1437, 1371, 1239, 1156, 1008, 689 cm−1; 1H NMR (CDCl3, 600 MHz): δ 8.48 (1H, br), 6.08 (1H, m), 5. 75 (1H, d, J=9.6 Hz), 5.29 (1H, br), 4.13 (1H, d, J=6.6 Hz), 3.83 (3H, m), 3.79 (1H, m), 3.72 (1H, m), 2.84 (1H, d, J=10.2 Hz), 2.20 (1H, m), 2.16 (1H, br), 1.98 (3H, m), 1.77 (3H, m), 1.59 (1H, m), 1.54 (3H, s), 1.25 (1H, m). 13C NMR (CDCl3, 125 MHz): δ 180.84, 172.95, 135.27, 123.75, 82.00, 80.11, 75.56, 62.39, 53.14, 51.78, 38.95, 28.79, 26.48, 25.04, 20.66, 19.99; HRMS (ESI) calcd. (M+H)+ for C16H26NO6 328.1760, found 328.1752.
EXAMPLE 14
Conversion of (16) to Salinosporamide A(1).
A solution of triol ester 16 (0.164 g, 0.5 mmol) in 3 N aq LiOH (3 mL) and THF (1 mL) was stirred at 5° C. for 4 days until hydrolysis was complete. The acid reaction mixture was acidified with phosphoric acid (to pH 3.5). The solvent was removed in vacuo and the residue was extracted with EtOAc, separated, and concentrated in vacuo to give the crude trihydroxy carboxylic acid 16a (not shown). The crude acid was suspended in dry CH2Cl2 (2 mL), treated with pyridine (0.5 mL) and stirred vigorously at 23° C. for 5 min. To this solution was added BOPCl (152 mg, 0.6 mmol) at 23° C. under argon, and stirring was continued for 1 h. The solvent was removed under high vacuum and the residue was suspended in dry CH3CN (1 mL) and treated with pyridine (1 mL). To this solution was added PPh3Cl2 (333 mg, 1.0 mmol) at 23° C. under argon with stirring. After 1 h the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate-CH2Cl2, 1:5) to give the pure β-lactone 1 (100 mg, 64%) as a colorless solid.
Rf=0.55 (50% ethyl acetate in hexane). mp, 168–170° C. (authentic sample: 168–170° C., 169–171° C. in Angew. Chem. Int. Ed., 2003, 42, 355–357); mixture mp, 168–170C. [α]23 D −73.2 (c 0.49, MeOH), −72.9 (c 0.55, MeOH, in Angew. Chem. Int. Ed., 2003, 42, 355–357); FTIR (film) νmax: 3406, 2955, 2920, 2844, 1823, 1701, 1257, 1076, 1012, 785, 691 cm−1; 1H NMR (CDCl3, 500 MHz): δ 10.62 (1H, br), 6.42 (1H, d, J=10.5 Hz), 5.88 (1H, m), 4.25 (1H, d, J=9.0 Hz), 4.14 (1H, m), 4.01 (1H, m), 3.17 (1H, t, J=7.0 Hz), 2.85 (1H, m), 2.48 (1H, m), 2.32 (2H, m), 2.07 (3H, s), 1.91 (2H, m), 1.66 (2H, m), 1.38 (1H, m);13C NMR (CDCl3, 125 MHz): δ 176.92, 169.43, 129.08, 128.69, 86.32, 80.35, 70.98, 46.18, 43.28, 39.31, 29.01, 26.47, 25.35, 21.73, 20.00; HRMS (ESI) calcd. for (M−H)− C15H19ClNO4 312.1003, found 312.1003.
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| Name: | Marizomib | |
| Synonyms: | 6-Oxa-2-azabicyclo[3.2.0]heptane-3,7-dione, 4-(2-chloroethyl)-1-[(S)-(1S)-2-cyclohexen-1-ylhydroxymethyl]-5-methyl-, (1R,4R,5S)-; Other Names: (-)-Salinosporamide A; ML 858; Marizomib; NPI 0052; Salinosporamide A | |
| CAS Registry Number: | 437742-34-2 | |
| Molecular Formula: | C15H20ClNO4 | |
| Molecular Weight: | 313.1 | |
| Molecular Structure: |  |
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 