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Secukinumab

October 3, 2013 5:10 am / 4 Comments on Secukinumab

Secukinumab is an anti-IL17A drug being investigated for a number of inflammatory conditions. For plaque psoriasis, Novartis is planning to evaluate a dose of 150 mg subcutaneously compared with placebo.

The primary outcome measure of the planned Phase III trial named ERASURE is to evaluate the efficacy in patients with moderate to severe chronic plaque-type psoriasis. Novartis is also planning to evaluate secukinumab dosed at either 150 or 300 mg versus Enbrel (enterecept) 50 mg in a Phase III trial entitled FIXTURE.

Final data collection for the primary outcome measures in both ERASURE and FIXTURE are anticipated in March 2013.

Secukinumab is a human monoclonal antibody designed for the treatments of uveitis,rheumatoid arthritis, and psoriasis. It targets member A from the cytokine family ofinterleukin 17.^[1]^[2]

Secukinumab was developed by Novartis Pharma AG and has completed Phase II clinical trials for plaque psoriasis in 2011.^[3]

CAS registry numbers

875356-43-7 (heavy chain)
875356-44-8 (light chain)

^ “Statement On A Nonproprietary Name Adopted By The USAN Council: Secukinumab”. American Medical Association.
^ Hueber, W.; Patel, D. D.; Dryja, T.; Wright, A. M.; Koroleva, I.; Bruin, G.; Antoni, C.; Draelos, Z.; Gold, M. H.; Psoriasis Study, P.; Durez, P. P.; Tak, J. J.; Gomez-Reino, C. S.; Rheumatoid Arthritis Study, R. Y.; Foster, C. M.; Kim, N. S.; Samson, D. S.; Falk, D.; Chu, Q. D.; Callanan, K.; Nguyen, A.; Uveitis Study, F.; Rose, K.; Haider, A.; Di Padova, F. (2010). “Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis”. Science Translational Medicine 2 (52): 52ra72.doi:10.1126/scitranslmed.3001107. PMID 20926833. edit
^ Papp K.A. et al. ‘Secukinumab efficacy and safety preliminary results from a phase II subcutaneous dose-ranging study in the treatment of moderate-to-severe plaque psoriasis.’ Presented at: 20th Congress of the European Academy of Dermatology and Venereology; 20-24 October, 2011; Lisbon, Portugal.

FDA, EMA Accept Omeros Ophthalmology Product NDA

October 3, 2013 3:21 am / Leave a comment

OMS302

US and European Regulators Accept for Review OMS302 Marketing Applications
— OMS302 Remains on Track for Planned 2014 Commercial Launch —

SEATTLE, Oct. 2, 2013 /PRNewswire/ — Omeros Corporation (NASDAQ: OMER) announced today that the New Drug Application (NDA) for its ophthalmology product, OMS302, has been confirmed for filing by the U.S. Food and Drug Administration (FDA), which means that the application, submitted in July of this year, is sufficiently complete to permit a substantive review. The company also announced that its Marketing Authorization Application (MAA) for OMS302, submitted last month, has been validated by the European Medicines Agency (EMA). Validation of the MAA confirms that the submission package is administratively complete and is ready for formal review by Europe’s Committee for Medicinal Products for Human Use (CHMP).

read all at

http://www.pharmalive.com/fda-ema-accept-omeros-opthamology-product-nda

Isavuconazole – Basilea reports positive results from study

October 2, 2013 1:35 am / 6 Comments on Isavuconazole – Basilea reports positive results from study

Isavuconazole

4-{2-[(1R,2R)-(2,5-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile

[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol;

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol

241479-67-4 CAS

946075-13-4 cas of SULPHATE (USAN) in phase 3Aspergillosis, Infection, candidal, RO-0098557

ROCHE Originator

ChemSpider 2D Image | Isavuconazole | C22H17F2N5OS

30 September 2013

StockMarketWire.com – Basilea Pharmaceutica has revealed positive topline data from the isavuconazole phase 3 invasive aspergillosis study (SECURE). http://www.stockmarketwire.com/article/4677530/Basilea-reports-positive-results-from-study.htmlThe antifungal agent isavuconazole is being co-developed with Astellas Pharma Inc.The randomized, double-blind isavuconazole study (SECURE) achieved its primary objective in demonstrating non-inferiority versus voriconazole for the primary treatment of invasive fungal disease caused by Aspergillus species or certain other filamentous fungi.

This post is updated in sept 2015……..

BAL-4815, 241479-67-4, Bal4815, AC1OCFHQ, UNII-60UTO373KE, , BAL 4815, FT-0670421

Molecular Formula: C₂₂H₁₇F₂N₅OS Molecular Weight: 437.465086

Isavuconazole (BAL4815; trade name Cresemba) is a triazole antifungal drug. Its prodrug, isavuconazonium sulfate (BAL8557), was granted approval by the U.S. Food and Drug Administration (FDA) on March 6, 2015^[1]

During its Phase III drug trials, Astellas partnered with Basilea Pharmaceutica, the developer of the drug, for rights to co-development and marketing of isavuconazole. ^[2]

On May 28, 2013, Basilea Pharmaceutica announced it had been granted orphan drug status by the FDA for treatment of aspergillosis.^[3] Since then, it has also been granted orphan drug status for the treatment of invasive candidiasis.^[4]

Isavuconazonium sulfate (BAL8557)—a prodrug of isavuconazole.

Isavuconazium chloride hydrochloride (BAL-8557), a prodrug of Basilea Pharmaceutica’s BAL-4815 (isavuconazole), is a triazole in phase III clinical trials for the oral and intravenous treatment of severe fungal infections, including candidemia and other invasive Candida infections and invasive aspergillosis in immunocompromised patients. Additional phase III trials are ongoing for the treatment of invasive fungal infections caused by rare fungi. Phase II trials are ongoing for the treatment of candidal esophageal infection. Isavuconazole is water-soluble, highly bioavailable and can be administered in convenient once-daily or once-weekly dosing regimens.Originally developed at Roche, the drug candidate was subsequently acquired by Basilea. In May 2006, isavuconazium received fast track designation from the FDA for the treatment of infections caused by yeasts and molds, including fluconazole-resistant Candida strains, Aspergillus and zygomycetes in patients with weakened immune systems. In 2010, the product was licensed to Astellas Pharma by Basilea Pharmaceutica for codevelopment and copromotion worldwide, including an option for Japan, for the treatment of fungal infection. In 2013, FDA designated isavuconazium as a Qualified Infectious Disease Product (QIDP) designation for the treatment of invasive aspergillosis.

ISAVUCONAZOLE

CLINICAL TRIALS…LINK

PATENTS

US8207352	6-27-2012	Process for the manufacture of enantiomerically pure antifungal azoles as ravuconazole and isavuconazole
US2011281918	11-18-2011	Antifungal Composition
US7803949	9-29-2010	PROCESS FOR PREPARATION OF WATER-SOLUBLE AZOLE PRODRUGS
US7459561	12-3-2008	N-substituted carbamoyloxyalkyl-azolium derivatives
US7189858	3-14-2007	N-phenyl substituted carbamoyloxyalkyl-azolium derivatives
US6812238	11-3-2004	N-substituted carbamoyloxyalkyl-azolium derivatives
US6300353	10-10-2001	Azoles for treatment of fungal infections

Several azoles are currently used for systemic mycoses. However, none of them fulfills the needs of clinical requirement in full extent, particularly with regard 0 to broad antifungal spectrum including aspergillus fumigatus, less drug-drug interaction, and appropriate plasma half-life for once a day treatment. Other clinical requirements which are not fulfilled by the azoles currently used, are efficacy against major systemic mycoses including disseminated aspergillosis, safety, and oral or parenteral formulations. Particularly, demand of a 5 parenteral administration of the azoles is increasing for the treatment of serious systemic mycoses. Most of the azoles on the market as well as under development are highly lipophilic molecules that make the parenteral formulation difficult.

Isavuconazole [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol; formula I, R¹and R³represent fluorine and R²represents hydrogen] as well as Ravuconazole [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol; formula I, R¹and R²represent fluorine and R³represents hydrogen] are useful antifungal drugs as reported in U.S. Pat. No. 5,648,372 from Feb. 1, 1995 or in U.S. Pat. No. 5,792,781 from Sep. 18, 1996 or in U.S. Pat. No. 6,300,353 from Oct. 9, 2001 (WO99/45008).

Since compounds of general formula I contain two adjacent chiral centers, synthesis of enantiomerically pure compound is complex and until now, all patented syntheses are not efficient enough and do not allow cost effective manufacturing on a technical scale:

Thus, U.S. Pat. Nos. 5,648,372 or 5,792,781 describe enantioselective synthesis of compounds of formula I (specifically Ravuconazole) from chiral 3-hydroxy-2-methyl propionic acid in 12 steps with overall yield lower than 5%. In another approach including 13 steps and low overall yield, (R)-lactic acid was used as the starting material (Chem. Pharm. Bull. 46(4), 623 (1998) and ibid. 46(7), 1125 (1998)).

Because both starting materials contain only one chiral center, in a number of inefficient steps, the second, adjacent chiral center has to be created by a diastereoselective reaction (using either Corey or Sharpless epoxidation method) which is not sufficiently selective leading mostly to a mixture of two diastereomers which have to be separated.

The second approach, based on (R)-methyl lactate, was recently very thoroughly optimized by BMS on a multi kilogram scale but it still does not fulfill requirements for cost effective manufacturing process (Organic Process Research & Development 13, 716 (2009)). The overall yield of this optimized 11 steps process is still only 16% (Scheme 1).

The manufacturing process for Isavuconazole is similar: Since Isavuconazole differentiates from Ravuconazole by only another fluorine substitution on the aromatic ring (2,5- instead of 2,4-difluorophenyl), the identical synthesis has been used (U.S. Pat. No. 6,300,353 from Oct. 9, 2001 and Bioorg. & Med. Chem. Lett. 13, 191 (2003)). Consequently, also this manufacturing process, based on (R)-lactic acid, faces the same problems: to many steps, extremely low overall yield and in addition to U.S. Pat. No. 6,300,353 claims even already known step as novel (claim 36).

Recent attempts to improve this concept as reported in WO 2007/062542 (Dec. 1, 2005), using less expensive, natural configured (S)-lactic acid, also failed: As already reported in U.S. Pat. No. 6,133,485 and in US 2003/0236419, the second chiral center was formed from an optically active allyl alcohol prepared in a few steps from (S)-lactic acid.

This allyl alcohol was subjected to Sharpless diastereoselective epoxidation providing first an opposite configured, epimeric epoxy alcohol which had to be then epimerized in an additional inversion step yielding finally the desired epoxy alcohol as the known precursor for Isavuconazole (U.S. Pat. No. 6,300,353). It is obvious that this process using less expensive (S)-lactic acid makes the entire process with an inversion step even more complex than the original approach.

Elegant and more efficient process has been claimed in US 2004/0176432 from Jun. 26, 2001) in which both chiral centers have been formed simultaneously, diastereo- and enantio-selectively pure in one single reaction step using chiral (R)-2-butynol as a chiral precursor in the presence of Pd(II)-catalyst and diethyl zinc (Scheme 2).

Since water soluble, (R)-2-butynol is expensive, recently identical process has been published, in which instead of (R)-2-butynol less water soluble and therefore, less expensive (R)-4-phenyl-3-butyn-2-ol was used (Synthetic Commun. 39, 1611 (2009)). Nevertheless, as incorrectly stated there, this process does not provide better diastereoselectivity than the original process using (R)-2-butynol: On the contrary disadvantage of this process is a very bad atom economy because huge phenyl group of (R)-4-phenyl-3-butyn-2-ol has to be “disposed” in oxidation step by the conversion of triple bond into carboxylic acid function.

All known processes for enantiomerically pure compounds of formula I have definitely too many operation steps and specifically very low overall yield. The chiral starting materials used, either 3-hydroxy-2-methyl propionic acid or (S)- or (R)-methyl lactate, contain only one chiral center and consequently, in number of steps, the second adjacent chiral center has to be ineffectively generated which makes the entire process long and expensive. The only known process, which generates both chiral centers simultaneously, requires again expensive chiral starting material (R)-2-butynol.

ISAVUCONAZOLE

…………………………………………….

US6812238

synthetic scheme A, starting from 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propionyl]morpholine [which can be prepared by a same procedure as described in Chem. Pharm. Bull. 41, 1035, 1993.]. This synthesis route has been described for example in European Patent Application No. 99101360.8.

(a)

………………………………………………………………………

US8207352

Example 1 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol

To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (43.7 g) in acetone (800 ml) a solution of (1R)-10-camphorsulfonic acid (23 g) in methanol (300 ml) was added and the mixture was heated under reflux until a clear solution was obtained. The solution was slowly cooled to rt, seeded with crystals of the title enantiomeric salt and let overnight. The solid was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This crude salt was then taken up in methylenechloride (100 ml) and water (ca. 100 ml) and the mixture was basified with aqueous sodium hydroxide solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride (50 ml) and combined. The organic phases were then washed twice with water (2×50 ml), dried with sodium sulfate, filtrated and the solvent removed under reduced pressure. The crude product was then mixed with isopropanol (ca. 150 ml), heated for 10 min, cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with isopropanol and dried under reduced pressure to provide the enantiomerically pure title compound (17.5 g, 41% yield, 99.1% ee);

m.p. 164-166° C.; [α]=−30° (c=1, methanol, 25° C.);

NMR (CDCl3): 1.23 (3H, d, J=8 Hz), 4.09 (1H, q, J=8 Hz), 4.26 (1H, d, J=14 Hz), 4.92 (1H, d, J=14 Hz), 5.75 (1H, s), 6.75-6.85 (2H, m), 7.45-7.54 (2H, m), 7.62 (1H, s), 7.69 (1H, s), 7.75 (1H, d, J=8 Hz), 7.86 (1H, s), 8.03 (1H, d, J=8 Hz).

The analytical data were identical with published (U.S. Pat. No. 5,648,372 and Chem. Pharm. Bull. 1998, 46, 623-630).

Example 2 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol

Racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (44 g) and (1R)-10-camphorsulfonic acid (20 g) were suspended in methanol (ca. 300 ml), the slurry was stirred intensively, warmed up to ca. 70° C. and a small addition of acetic acid was added to obtain a clear solution. After cooling of the solution to rt and then to 0° C., the mixture was seeded with enantiomerically pure salt and stirred for another 2 hrs. The crystalline solid was collected by filtration, washed with cooled methanol and dried under reduced pressure. The crystals were partitioned between methylenechloride (300 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was washed twice with water (50 ml), dried with magnesium sulphate, filtrated and evaporated under reduced pressure to give the title compound (16.9 g, 38% yield, 95% ee). The analytical data were identical with published (U.S. Pat. No. 5,648,372 or Chem. Pharm. Bull. 1998, 46, 623).

Example 3 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol

To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (10 g) in acetone (ca. 200 ml) a solution of (1R)-10-camphorsulfonic acid (3.9 g) in methanol (50 ml) was added and the mixture was heated shortly under reflux until a clear solution was obtained. The solution was then slowly cooled to rt, seeded with crystals of the desired enantiomeric salt and let overnight. The solid precipitate was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This salt was then taken up in methylenechloride and water and basified with aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride. The organic phases were combined, dried with sodium sulphate, filtrated and the solvent removed under reduced pressure. The crude product was then dissolved in ethanol, the slurry heated for 20 min, small amount of water was added, the solution slowly cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with cold ethanol and dried under reduced pressure to provide the title enantiomerically pure compound (3.9 g, 39% yield, 96% ee). The analytical date were identical with published in U.S. Pat. No. 6,300,353 B1 and WO 99/45008.

Example 4 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol

To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (100 g) in acetone (1000 ml) a solution of (1R)-10-camphorsulfonic acid (47 g) in methanol (500 ml) was added at rt, then slurry was heated under stirring to almost reflux for ca. 30 min, then cooled slowly to rt, seeded with the pure enantiomeric salt and stirred over night. The solid was collected by filtration, washed with methanol/acetone mixture, dried under reduced pressure. The residue was taken up with a solvent mixture of methylenechloride/water and after addition of saturated aqueous sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated, the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 39 g (39% yield, 92% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.

Example 5 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol

A solution of the racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (4.4 g) and (1R)-10-camphorsulfonic acid (2 g) in toluene (40 ml) containing glacial acetic acid (0.6 ml) was warmed up to approximately 70° C., then allowed to cool slowly to 20° C., seeded with the pure enantiomeric salt whereupon the pure enantiomeric salt start to crystallize out. After ca. 2 hrs at this temperature the solid was collected, washed with cold toluene and dried. The crystals were taken with a solvent mixture of methylenechloride/water and after addition of aqueous saturated sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated and the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 2 g (45% yield, 99% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.

…………………………………..

WO 1999045008

US6300353

The following synthetic scheme 1 illustrates the manufacture of one of the compounds of formula I′:

……………………………….

Bioorganic and medicinal chemistry letters, 2003 , vol. 13, 2 p. 191 – 196

http://www.sciencedirect.com/science/article/pii/S0960894X02008922

A highly potent water soluble triazole antifungal prodrug, RO0098557 (1), has been identified from its parent, the novel antifungal agent RO0094815 (2). The prodrug includes a triazolium salt linked to an aminocarboxyl moiety, which undergoes enzymatic activation followed by spontaneous chemical degradation to release 2. Prodrug 1 showed high chemical stability and water solubility and exhibited strong antifungal activity against systemic candidiasis and aspergillosis as well as pulmonary aspergillosis in rats.





Scheme 1. Figure options Figure 1. Structure of RO0098557 and RO0094815. Chemistry Scheme 1. We synthesized a series of new triazolium derivatives of Figure 1, Figure 3 and Scheme 1. CompoundsScheme 1 and Scheme 2, 6, 9, 10 and 11 were first prepared as outlined in Scheme 2 in order to analyze their stability and ability to release Figure 1, Figure 3 and Scheme 1. Next, aromatic analogues 18, 19, 20,21 and Figure 1, Figure 3 and Scheme 3 were synthesized for optimization of 11 to increase its water solubility and conversion rate. Compounds in the second series had sarcosine esters⁶ to make them water soluble, and they were also designed to generate acetaldehyde⁷ instead of formaldehyde for a better safety profile. The synthetic procedures for the second series of the derivatives are outlined in Scheme 3. Scheme 2. (a) ClCOOCH₂Cl, diisopropylethylamine, CH₂Cl₂, rt (quant); (b) Figure 1, Figure 3 and Scheme 1, CH₃CN, 80 °C (60%); (c) (1) ClCOOCH₂Cl, Et₃N, CH₂Cl₂, rt; (2) Ac₂O, pyridine, rt (30%, two steps); (d) (1) NaI, CH₃CN, 50 °C ; (2) Figure 1, Figure 3 and Scheme 1, CH₃CN, 50 °C (88%, two steps); Synthesis of Scheme 1 and Scheme 2: (1) N-3-hydroxypropyl-N-methylamine, ClCOOCH₂Cl, Et₃N, CH₂Cl₂, rt; (2) AcCl, Et₃N, CH₂Cl₂, rt (20%, two steps); (3) Figure 1, Figure 3 and Scheme 1, NaI, CH₃CN, 50 °C (82%); Synthesis of 10: (1) l-prolinol, ClCOOCH₂Cl, Et₃N, CH₂Cl₂, rt; (2) Ac₂O, pyridine, rt (<10%, 2 steps); (3) Figure 1, Figure 3 and Scheme 1, NaI, CH₃CN, 50 °C (92%); Synthesis of 11: (1) 2-hydroxymethyl-N-methylaniline, ClCOOCH₂Cl, diisopropylethylamine, CH₂Cl₂, rt; (2) Ac₂O, diisopropylethylamine, rt (20%, two steps); (3)Figure 1, Figure 3 and Scheme 1, cat. NaI, CH₃CN, reflux (63%). Figure options Scheme 3. (a) (1) oxalyl chloride, DMF, 0 °C; (2) KO^tBu, THF, −5 °C (97%, two steps); (b) CH₃NH₂, MeOH, rt (90%); (c) LiAlH₄, THF, 0 °C (80%); (d) (1) ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (2) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (84%, two steps); (e) (1) Figure 1, Figure 3 and Scheme 1, NaI, CH₃CN, 50 °C; (2) DOWEX-1 Cl⁻ form, aqueous MeOH, rt (65%, two steps); (f) (1) HCl, EtOAc, rt; (2) lyophilization (69%, two steps); Synthesis of 18: (1) (i) (4,5-difluoro-2-methylaminophenyl)methanol, ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (quant, two steps); (2) Figure 1, Figure 3 and Scheme 1, cat. NaI, CH₃CN, 80 °C; (50%,); (3) HCl, EtOAc, rt (90%); Synthesis of 19: (1) (i) 2-fluoro-6-methylaminophenyl)methanol, ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (74%, two steps); (2) Figure 1, Figure 3 and Scheme 1, cat. NaI, CH₃CN, reflux; (3) HCl, EtOAc, rt (29%, two steps); Synthesis of 20: (1) (i) (5-fluoro-2-methylaminophenyl)methanol, ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (91%, two steps); (2) Figure 1, Figure 3 and Scheme 1, cat. NaI, CH₃CN, 70 °C (72%); (3) HCl, EtOAc, rt (88%); Synthesis of 21: (1) (i) (4-chloro-2-methylaminophenyl)methanol, ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (71%, two steps); (2) Figure 1, Figure 3 and Scheme 1, CH₃CN, 65 °C; (3) HCl, EtOAc, rt (65%, two steps).

read more at

Boyd, B.; Castaner, J. BAL-4815/BAL-8557
Drugs Fut 2006, 31(3): 187

Antimicrobial Agents and Chemotherapy, 2008 , vol. 52, 4 p. 1396 – 1400

Ohwada, J.; Tsukazaki, M.; Hayase, T.; Oikawa, N.; Isshiki, Y.; Umeda, I.; Yamazaki, T.; Ichihara, S.; Shimma, N.Development of novel water antifungal, RO0098557
21st Med Chem Symp (November 28-30, Kyoto) 2001, Abst 1P-06

Ohwada, J.; Tsukazaki, M.; Hayase, T.; et al.
RO0098557, a novel water soluble azole prodrug for parenteral and oral administration (I). Design, synthesis, physicochemical properties and bioconversion42nd Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 27-30, San Diego) 2002, Abst F-820

Tasaka et al., Chem. Pharm. Bull. 41(6) pp. 1035-1042 (1993).

Clinical trials

There have been three phase III clinical trials of isavuconazole, ACTIVE, VITAL and SECURE. As of June 2015, SECURE and VITAL have been presented in abstract form and results from ACTIVE have not been released.^[9]

The SECURE trial compared voriconazole and isavuconazole in invasive fungal infections due to aspergillus. Isuvaconazole was found to be non-inferior to voriconazole, anothertriazole antifungal, with all cause mortality at 18.6%, compared to 20.2% in the voriconazole group. It additionally demonstrated a similar side effect profile.^[10]

Data from the VITAL study showed that isavuconazole could be used in treatment of invasive mucormycosis, but did not evaluate its clinical efficacy for this indication.^[11]

The ACTIVE trial is a comparison of isuvaconazole and caspofungin for invasive candida infections and results are anticipated in the second half of 2015.^[12]^[13]

References

[1]
Saboo, Alok. “Basilea Announces Global Partnership With Astellas for Its Antifungal Isavuconazole.” FierceBiotech. N.p., 24 Feb. 2010. Web.
“Basilea reports isavuconazole orphan drug designation by U.S. FDA.” Market Wired. 28 May 2013.
“FDA Grants Orphan Drug Designation to Astellas for Isavuconazole for the Treatment of Invasive Candidiasis.” News Releases. Astellas. 3 Nov 2014.
Cresemba (isovuconazole sulfate) [prescribing information]. Astella Pharma US, Inc. Revised March 2015.
Jump up^ “Aspergillosis.” Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 08 Sept. 2014.
Jump up^ “Astellas Receives FDA Approval for CRESEMBA® (isavuconazonium Sulfate) for the Treatment of Invasive Aspergillosis and Invasive Mucormycosis.” PR Newswire. N.p., 6 Mar. 2015.
Jump up^ “Isavuconazonium.” Micromedex Solutions. Truven Health Analytics, n.d. Web. <www.micromedexsolutions.com>.
Jump up^ Pettit, Natasha N.; Carver, Peggy L. (2015-07-01). “Isavuconazole A New Option for the Management of Invasive Fungal Infections”. Annals of Pharmacotherapy 49 (7): 825–842.doi:10.1177/1060028015581679. ISSN 1060-0280. PMID 25940222.
Mujais, A. “2014: M-1756. A Phase 3 Randomized, Double-Blind, Non-Inferiority Trial Evaluating Isavuconazole (ISA) vs. Voriconazole (VRC) for the Primary Treatment of Invasive Fungal Disease (IFD) Caused by Aspergillus spp. or other Filamentous Fungi (SECURE): Outcomes by Malignancy Status”. http://www.icaaconline.com. Retrieved 2015-06-19.
“Abstract: An Open-Label Phase 3 Study of Isavuconazole (VITAL): Focus on Mucormycosis (IDWeek 2014)”. idsa.confex.com. Retrieved 2015-06-19.
Ltd., Basilea. “Basilea Pharmaceutica – Portfolio – Isavuconazole”. http://www.basilea.com. Retrieved 2015-06-19.
“Isavuconazole (BAL8557) in the Treatment of Candidemia and Other Invasive Candida Infections – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov. Retrieved 2015-06-19.

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US5900486	Sep 9, 1997	May 4, 1999	Hoffmann-La Roche Inc.	N-benzylazolium derivatives
AU4536497A				Title not available
EP0667346A2	Feb 3, 1995	Aug 16, 1995	Eisai Co., Ltd.	Azole antifungal agents, process for the preparation there of and intermediates
WO1992017474A1	Mar 26, 1992	Oct 15, 1992	Pfizer	Triazole antifungal agents

US5648372	Feb 1, 1995	Jul 15, 1997	Eisai Co., Ltd.	Antifungal agents, and compositions
US5686646 *	May 23, 1995	Nov 11, 1997	Schering-Plough Corporation	Chiral hydrazine derivatives
US5746840 *	Mar 28, 1997	May 5, 1998	Janssen Pharmaceutica, N.V.	Process for preparing enantiomerically pure 6-{4-chlorophenyl) (1 H-1,2,4-triazol-1-YL) methyl}-1-methyl-1 H-benzotriazole
US5792781	Sep 18, 1996	Aug 11, 1998	Eisai Co., Ltd.	Antifungal agents, processes for the preparation thereof, and intermediates
US6020497	Oct 9, 1998	Feb 1, 2000	Merck & Co., Inc.	3-substitutes isoxazolidines as chiral auxiliary agents
US6133485	Apr 15, 1998	Oct 17, 2000	Synphar Laboratories, Inc.	Asymmetric synthesis of 2-(2,4-difluorophenyl)-1-heterocycl-1-yl butan-2,3-diols
US6300353	Mar 5, 1999	Oct 9, 2001	Basilea Pharmaceutica Ag, A Swiss Company	Azoles for treatment of fungal infections
US6383233	Mar 7, 1997	May 7, 2002	Reuter Chemicscher Apparatebau Kg	Separation process
US6812238 *	Oct 31, 2000	Nov 2, 2004	Basilea Pharmaceutica Ag	N-substituted carbamoyloxyalkyl-azolium derivatives
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Isavuconazole
Systematic (IUPAC) name


4-{2-[(1R,2R)-(2,5-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile
Clinical data
Trade names	Cresemba (prodrug form)
AHFS/Drugs.com	entry
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only ℞ (Prescription only)
Routes of administration	Oral, intravenous
Identifiers
ATC code	None
PubChem	CID: 6918485
ChemSpider	5293682
UNII	60UTO373KE
ChEBI	CHEBI:85979
ChEMBL	CHEMBL409153
NIAID ChemDB	416566
Chemical data
Formula	C₂₂H₁₇F₂N₅O S
Molecular mass	437.47 g/mol

/////

Vortioxetine ボルチオキセチン臭化水素酸塩 – FDA Approves Brintellix to Treat Major Depressive Disorder

October 1, 2013 3:53 am / 2 Comments on Vortioxetine ボルチオキセチン臭化水素酸塩 – FDA Approves Brintellix to Treat Major Depressive Disorder

Vortioxetine

ボルチオキセチン臭化水素酸塩

1-[2-(2,4-dimethylphenyl)sulfanylphenyl]piperazine

Lu AA21004

VORTIOXETINE; CAS 508233-74-7; 1-(2-((2,4-Dimethylphenyl)thio)phenyl)piperazine; Lu AA21004; UNII-3O2K1S3WQV; C18H22N2S;
Molecular Formula:	C₁₈H₂₂N₂S
Molecular Weight:	298.44568 g/mol

VORTIOXETINE; CAS 508233-74-7;

1-(2-((2,4-Dimethylphenyl)thio)phenyl)piperazine; Lu AA21004; UNII-3O2K1S3WQV; C18H22N2S;

Molecular Formula:

C₁₈H₂₂N₂S

Molecular Weight:

298.44568 g/mol

Vortioxetine Hydrobromide

C18H22N2S.HBr : 379.36
[960203-27-4] HYDROBROMIDE

Vortioxetine is an atypical antipsychotic and antidepressant indicated for the treatment of major depressive disorder (MDD). It is classified as a serotonin modulator and simulator (SMS) as it has a multimodal mechanism of action towards the serotonin neurotransmitter system whereby it simultaneously modulates one or more serotonin receptors and inhibits the reuptake of serotonin. More specifically, vortioxetine acts via the following biological mechanisms: as a serotonin reuptake inhibitor (SRI) through inhibition of the serotonintransporter, as a partial agonist of the 5-HT1B receptor, an agonist of 5-HT1A, and an antagonist of the 5-HT3, 5-HT1D, and 5-HT7 receptors. SMSs were developed because there are many different subtypes of serotonin receptors, however, not all of these receptors appear to be involved in the antidepressant effects of SRIs. Some serotonin receptors seem to play a relatively neutral or insignificant role in the regulation of mood, but others, such as 5-HT1A autoreceptors and 5-HT7 receptors, appear to play an oppositional role in the efficacy of SRIs in treating depression.

Sept. 30, 2013 — The U.S. Food and Drug Administration today approved Brintellix (vortioxetine) to treat adults with major depressive disorder.

Major depressive disorder (MDD),

Commonly referred to as depression, is a mental disorder characterized by mood changes and other symptoms that interfere with a person’s ability to work, sleep, study, eat and enjoy once-pleasurable activities. Episodes of depression often recur throughout a person’s lifetime, although some may experience a single occurrence.

READ ALL AT

http://www.drugs.com/newdrugs/fda-approves-brintellix-major-depressive-disorder-3918.html

Lu AA21004/vortioxetine
The disease: Major depression
The developers: Lundbeck, Takeda

Vortioxetine (vor-tye-OX-e-teen, code name Lu AA21004) is an experimental drug currently under development by Lundbeck and Takeda for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD).Commercial names chosen are Brintellix and Rexulti.

Regulatory approval for the treatment of MDD for the European market has been filed in September 2012, for the United States in October 2012, and filing for Canada should follow. Filing for the Japanese market is expected in 2013.

Depression

In May 22 2011, Lundbeck presented the results of four phase III trials on vortioxetine at the 2011 Annual Meeting of the American Psychiatric Association. A statistically significant effect was shown in two of the studies (one for active treatment using the Hamilton Depression Rating Scale (HAM-D), the second as a maintenance treatment), vortioxetine failed to prove superiority over placebo in a third (again using the HAM-D) and the fourth was nullified by an exceptionally high placebo response (according to the Montgomery-Åsberg Depression Rating Scale (MADRS)).

In July 2011, Lundbeck published the results of a double-blind, randomized, placebo-controlled clinical trial with venlafaxine as an active reference. It was found to be superior to placebo in treating MDD while having fewer side effects than venlafaxine. Similarly, in May 2012, Lundbeck published the results of a double-blind, randomized, placebo-controlled clinical trial with duloxetine evaluating vortioxetine in elderly depressed patients, and it was found superior to placebo, with fewer side effects than duloxetine.

In May 2012, Lundbeck disclosed the results of three phase III clinical trials, showing vortioxetine’s superiority over placebo according to the MADRS.

In August 2012, a randomized, double-blind trial confirms the superiority of vortioxetine over placebo according to all measures, excepted the Sheehan Disability scale.

In September 2012, a randomised, double-blind trial reveals that a dose of 5mg shows superiority over placebo only in patients that suffer from comorbid anxiety.This is consistent with results from another trial published in December 2012, demonstrating that 2.5 mg and 5 mg doses are ineffective.

Anxiety

August 2012, contradictory results of two randomized, double-blind trial were published. While the first demonstrated vortioxetine’s superiority over the placebo, the second showed that the drug had no efficacy, leading the authors to question the designs of the different trials.

United States Patent Number: 7,144,884 , 8,476,279
related to Chinese patent: CN1319958 C , CN1561336 A; CN1319958C, CN1561336A
patent validity: January 9, 2023 (U.S. Patent Number: 7,144,884), October 2, 2022 (U.S. Patent No.: 8,476,279)
peak annual sales (estimated): $ 2 billion
drug companies: Lundbeck (Lundbeck), Takeda (Takeda)

Wal antidepressant drug Paxil (Brintellix, Vortioxetine) for – 1 – Preparation – [2 – (2,4 methyl) phenyl] piperazine process

Method II:

815g of the NaOBut (8,48 mo1), 844 g of piperazine Qin (9,8 mol), 6,6 g of Pd (dba) 2 (11,48 mmol) and 13,6 g of rac-BINAP (21, 84 mmol) was stirred for 50 minutes with 4L ofbenzene. Then, 840 g 2 – bromo – iodobenzene (2,97 mol) and 1.5L of Yue added to the mixture with benzene, and the stirring was continued for 30 minutes. Finally, 390.8g of 2,4 -thiophenol (2,83 mol) was added together with 1.5L toluene. The resulting suspension was heated to reflux and reflux was continued for 5 hours. The reaction mixture was cooled overnight. 2L of water was added and stirred for l hour and then filtered through a filter aid, the resulting mixture. Then, the filtrate was washed with brine 3xlL. Subsequently, the combined aqueous phase extracted with 600ml of benzene. Then, Yue The combined benzene phase was heated to 70 ° C, then adding 329.2ml 48-wt. / HBr (aq.) and 164.6ml water o’s. The mixture was cooled to room temperature overnight. Final product was collected by filtration (l-[2 – (2,4 – di曱group – phenylsulfanyl) – phenyl] – piperazine hydrobromide Qin), and dried under vacuum (60 ⁰ C), to give 895g of product (84% yield).

Method III:

The benzene is placed 500ml three-necked 1L round bottom flask equipped with a mechanical stirrer and add 809mg Pd2dba3 (0.88mmol; 0.5 mol%) and 952 mg DPEPhos (1.77 mmol; 0.5mol-%). The deep red solution was purged with nitrogen for 5 minutes, then add 100g2-bromo-iodobenzene (353 mmol) and 48.9 g 2,4 – bis thiophenol (353 mmol). Add 43.6g KOBut (389 mmol) caused an exothermic reaction, so that the temperature rise of 20 ° C 42 ° C, while forming a non-uniform mixture, and the color changed from deep red to orange / brown. The force of the suspension under nitrogen was heated to port 100 ° C. After only 20 minutes, HPLC showed complete conversion to have l-(2 – bromo – phenylsulfanyl) -2,4 – Yue group – benzene. The mixture was cooled to 40 ° C, was added to 600ml 15-wt% NaCl, and stirred for 5 minutes. The organic phase was separated, and the aqueous phase was washed 2xl00mwith benzene. The combined organic phase was washed with HCl (aq) NaCl and washed with 100ml 2M 100ml 15-wt%, and then Na ₂ S04 dried by activated charcoal (10 g) at reflux for 15 minutes, filtered twice and evaporated to 107.3 g of orange-red oil (103%), the oil was found by HPLC purity of 98%.

To 90 g of the orange-red oil (307 mmol) in 500ml of anhydrous toluene was added 57 g boc-piperazine Qin (307 mmol), degassed with nitrogen for 5 minutes, was added 1.4g Pd2dba3 (1.53 mmol- %; 0.5 mol%) and 2.9g mc-BINAP (4.6 mmol; 1.5 mol-%), degassed and then another 2 minutes, then add 35.4 g of NaOtBu (368 mmol), and heated to 80 ° C for 18 hours. HPLC showed complete conversion to have the reaction mixture was cooled to RT, filtered, and the filter cake was washed with 2 x 100ml of曱benzene. % NaCl, washed twice in Na2S04 dried, added charcoal, refluxed for 30 minutes, filtered twice and evaporated to 140.7 g of a brown oil (4 – – The combined filtrates with 2 x 150ml 15 [2 – (2, 4 – di曱group – phenylsulfanyl) -. phenyl]-BOC-piperazine Qin). The resulting crude oil was dissolved in 300ml MeOH and 200ml 6MHCl (aq.) and refluxed for l hour, after which HPLC showed complete deprotection. After cooling to RT, the vacuum on a rotary evaporator to remove曱alcohol was added 20ml of concentrated NaOH (pH was measured to 13-14), after which the mixture with 1000ml EtOAc – 15 minutes from stirring. The organic phase was collected and dried 300ml 15wtQ /. Saline extraction in Na2S04 dried, and added 46.3 g of fumaric acid in 300mlMeOH (399 mmol) was added. The mixture was heated to reflux, cooled to room temperature and then placed in the tank (-18. C) overnight. The precipitate was collected, washed with 100ml and 100ml of acetone with EtOAc, and dried in vacuo (50 ° C), to give 103.2g of l-[2 – (2,4 – di group – phenylsulfanyl) – phenyl] – piperazine. Qin fumarate (249mmo1), as a white powder, overall yield 81%, determined by LC-MS and the purity was 99% fumarate. Use EtOAc/H20 / concentrated NaOH to the fumarate salt into the free base (l-[2 – (2,4 – dimethyl – phenylsulfanyl) – phenyl] – piperazine Qin), The organic phase was washed with brine, dried over Na ₂ S04 sulfate, filtered and to the filtrate was added 34ml48-wto / o of HBr (aq.), to form a white solid precipitated. The solid was collected, and the solid was washed with 1000ml H20 boiling process, the resultant was cooled to room temperature and purified by forming a slurry. The final product was collected by filtration (l-[2 – (2,4 – digroup – phenylsulfanyl) – phenyl] – piperazine hydrobromide Qin Kr), and dried in vacuo (50 ° C), to produce 83g of white powder (total yield 71%).

Source:

1) Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mørk A, Stensbøl TB “Discovery of 1 -. [2 – (2,4 – dimethylphenylsulfanyl) phenyl] PIPERAZINE (Lu AA21004): a novel multimodal Major Compound for the treatment of depressive disorder. ” Journal of Medicinal Chemistry 54 (9): 3206-21.

2) Thomas Ruhland, Garrick Paul Smith, Benny Bang-Andersen, Ask Puschl, Ejner Knud Moltzen, Kim Andersen,; Phenyl-piperazine derivatives as serotonin reuptake inhibitors; US patent number 7144884 ; also published as CA2462110A1, CA2462110C , CN1319958C, CN1561336A, DE60225162D1, DE60225162T2, DE60233608D1, EP1436271A1, EP1436271B1, EP1749818A2, EP1749818A3, EP1749818B1, US7138407, US7148238, US7683053, US8110567, US8476279, US20050014740, US20060084662, US20060089368, US20070060574, US20110009423, US20120302553, WO2003029232A1; H. Lundbeck A / S;
T · Rouland, G · P · Smith, B · Bang – Anderson, A · Pi Shier, E · K · Moore Cen, K · Anderson; as serotonin reuptake inhibitors phenyl piperazine derivatives matter; CN 1319958 C
T · Rouland, G · P · Smith, B · Bang – Anderson, A · Pi Shier, E · K · Moore Cen, K · Anderson; as serotonin reuptake inhibitors phenyl piperazine derivatives; CN 1561336 A

3) Benny Bang-Andersen; Phenyl-piperazine derivatives as serotonin reuptake inhibitors; US patent number 8476279 B2 ; Also published as CA2462110A1, CA2462110C, CN1319958C, CN1561336A, DE60225162D1, DE60225162T2, DE60233608D1, EP1436271A1, EP1436271B1, EP1749818A2, EP1749818A3, EP1749818B1, US7138407, US7144884, US7148238, US7683053, US8110567, US20050014740, US20060084662, US20060089368, US20070060574, US20110009423, US20120302553, WO2003029232A1; H. Lundbeck A / S;

4) Kim Lasse Christensen; Process for the manufacture of 1 – [2 – (2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine; PCT application, WO2013102573 A1

5) Benny Bang-Andersen, Joergen Brodersen, Andre Faldt, Rene Holm, Morten Joergensen, De Diego Heidi Lopez, Michael J Mealy, Arne Moerk, Nicholas Moore, Lone Munch Ringgaard, Michael Harold Rock, Tine Bryan Stensboel; 1 – [2 – (2, 4-dimethylphenylsulfanyl)-phenyl] piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairment; WO2007144005 A1

Updated oct 2015…………….

Vortioxetine (vor-tye-oks-e-teen, trade name Trintellix) is an atypical antidepressant (a serotonin modulator and stimulator) made by Lundbeck and Takeda.^[1]

Vortioxetine [1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine] is an orally administered small molecule developed as once-daily treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). As a drug, Vortioxetine is a bis-aryl-sulphanyl amine compound that combines serotonin (5-HT) reuptake inhibition with other characteristics, including receptor activity modulation.

Vortioxetine binds to the human serotonin (5-HT) transporter (SERT) with high affinity (K_i = 1.6 nM) and is a potent inhibitor of serotonin reuptake (IC₅₀ = 5.4 nM), whereas its affinity for transporters of noradrenaline (K_i = 113 nM) and dopamine (K_i greater than 1000 nM) is much lower or negligible. The drug also has a broad receptor-binding profile, binding to the 5-HT1A receptor (K_i = 15 nM) where it acts as an agonist, the 5-HT1B receptor (K_i = 33 nM) where it acts as a partial agonist, and the 5-HT1D, 5-HT3 and 5-HT7 receptors (K_i = 54, 3.7 and 19 nM, respectively) where it displays antagonistic properties [1, 2].

Animal and in vitro studies indicate that several neurotransmitter systems may be impacted by vortioxetine, with the drug enhancing levels of 5-HT, noradrenaline, dopamine, acetylcholine and histamine in certain areas of the brain, as well as modulating γ-aminobutyric acid and glutamate neurotransmission. Results from additional animal models suggest vortioxetine may also improve measures of cognitive function, such as memory. In healthy volunteers, single or repeated administration of vortioxetine (10 mg) did not impair cognitive function, psychomotor performance or driving ability in a placebo-controlled study.

In September 2013, Vortioxetine was approved as Brintellix for the once-daily treatment of adults with MDD in the USA and one month later, EMA approved it as it first in line treatment for Europeans with MDD. It is marketed as Trintellix in Canada.

Vortioxetine was discovered by scientists at Lundbeck, where it was known as Lu AA21004. Takeda and Lundbeck entered into a strategic alliance to co-develop and co-commercialise vortioxetine and tedatioxetine in Japan and the USA in September 2007. The two companies will jointly complete product development, which will be funded primarily by Takeda, and the companies will share revenue generated in the USA and Japan.

Vortioxetine is administered orally at a starting dosage of 10 mg/day, with the dosage increased to 20 mg/day, as tolerated; 5 mg/ day may be considered if higher dosages are not tolerated. Dosages greater than 20 mg/day have not been assessed for efficacy or safety in controlled trials.

Medical use

Vortioxetine is used as first-line treatment for major depressive disorder.^[1]^[2]^[3]^[4]^[5]

Pharmacokinetics

Vortioxetine reaches peak plasma concentration (C_max) within 7 to 11 hours post-administration (T_max), and its mean terminal half-life (t½) is ≈ 66 hours. Steady-state plasma concentrations are typically reached within two weeks.^[1] It has no active metabolites (i.e. it is not a prodrug).^[1]

Research

Vortioxetine has been studied in several clinical trials as a potential treatment for general anxiety disorder but results were inconsistent.^[9]^[10]

History

Vortioxetine was discovered by scientists at Lundbeck who reported the rationale and synthesis for the drug (then called Lu AA21004) in a 2011 paper.^[7]^[11]

In 2007, the compound was in Phase II clinical trials, and Lundbeck and Takeda entered into a partnership in which Takeda paid Lundbeck $40 million upfront, with promises of up to $345 million in milestone payments, and Takeda agreed to pay most of the remaining cost of developing the drug. The companies agreed to co-promote the drug in the US and Japan, and that Lundbeck would receive a royalty on all such sales. The deal included another drug candidate, tedatioxetine (Lu AA24530), and could be expanded to include two other Lundbeck compounds.^[12]

Vortioxetine was approved by the U.S. FDA for the treatment of major depressive disorder (MDD) in adults in September, 2013,^[13] and it was approved in Europe later that year.^[14]

Vortioxetine was previously trademarked as Brintellix in the United States, but on May 2, 2016, the US FDA approved a name change to Trintellix in order to avoid confusion with the blood-thinning medication ticagrelor (Brilinta).^[15]

WO2015155153, SYNTHESIS OF VORTIOXETINE VIA (2,4-DIMETHYLPHENYL)(2-IODOPHENYL)SULFANE INTERMEDIATE

LEK PHARMACEUTICALS D.D. [SI/SI]; Verovskova 57 1526 Ljubljana (SI)
Inventors:ZUPANCIC, Borut; (SI)

Vortioxetine is disclosed as Example 1 e in WO 2003/029232 A1 and is described as being prepared analogously to Example 1 . The process used to prepare Example 1 involves the preparation of 1 -(2-((2-(trifluoromethyl)phenyl)thio)phenyl)piperazine on a solid polystyrene support, followed by decomplexation using visible light irradiation, and purification by preparative LC-MS and ion-exchange chromatography. The overall yield for the preparation of vortioxetine is described as 17%.

Several alternative palladium catalyzed processes for the preparation of vortioxetine are described in Examples 17 to 25 of WO 2007/144005 A1 . These processes describe the preparation of vortioxetine from 2,4-dimethylthiophenol and 2-bromoiodobenzene (or 1 ,2-dibromobenzene) starting materials via a 1 -(2-bromo-phenylsulfanyl)-2,4-dimethyl-benzene intermediate. Each of these processes involves the use of a palladium catalyst and a phosphine ligand.

The preparation of vortioxetine is also described by Bang-Andersen et al. in J. Med. Chem. (201 1 ), Vol. 54, 3206-3221 . Here, in a first step, te/t-butyl 4-(2-bromophenyl)piperazine-1 -carboxylate intermediate is prepared from Boc-piperazine and 2-bromoiodobenzene in a palladium catalyzed coupling reaction. te/t-Butyl 4-(2-bromophenyl)piperazine-1 -carboxylate is then reacted with 2,4-dimethylthiophenol, again in the presence of palladium catalyst and a phosphine ligand, to provide Boc-protected vortioxetine. In the final step, vortioxetine is deprotected using hydrochloric acid to give vortioxetine hydrochloride.

WO 2013/102573 A1 describes a reaction between 1 -halogen-2,4-dimethyl-phenyl, 2-halogen-thiophenol and an optionally protected piperazine in the presence of a base and a palladium catalyst consisting of a palladium source and a phosphine ligand.

Each of the above processes has disadvantages. The process described in WO 2003/029232 is low yielding and unsuitable for the large scale production of vortioxetine, whereas the processes described in WO 2007/144005 A1 , WO 2013/102573 A1 and by Bang-Andersen et al. require the use of expensive starting materials, palladium catalyst and phosphine ligand. In addition, the toxicity of palladium is well known, Liu et al. Toxicity of Palladium, Toxicology Letters, 4 (1979) 469-473, and the European Medicines Agency’ s Guideline on the Specification for Residues of Metal Catalysts sets clear limits on the permitted daily exposure to palladium arising from palladium residue within drug substances, http://www.ema.europa.eu. Thus it would be desirable to avoid the use of a palladium catalyst in the synthesis of vortioxetine and the subsequent purification steps required to remove palladium residue from the final pharmaceutical product.

The invention is described below in further detail by embodiments, without being limited thereto.

A general concept of the process of the present invention may be represented in Scheme 1 .

Scheme 1 : General representation of the basic synthetic concept of the present invention.

Scheme 2.

X = NH₂: lb

Scheme 2: Representation of a particular synthetic embodiment of the present invention.

Compound III can also be prepared from 2,4-dimethylbenzenethiol (II) and 1 -fluoro-2-nitrobenzene (l”‘a) or 1 -chloro-2-nitrobenzene (l'”b). In the first step (2,4-dimethylphenyl)(2- nitrophenyl)sulfane (III’) is formed and in the second reaction step nitro group is reduced to ami

Z = F: l”‘a

Z = CI: l”‘b

Scheme 3: Representation of a particular synthetic embodiment of the present invention.

Example 7: Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine vortioxetine, VII)

Mixture of (2,4-dimethylphenyl)(2-iodophenyl)sulfane V (0.34 g, 1 .0 mmol), piperazine VI (0.13 g, 1 .5 mmol), K₃P0₃ (0.42 g, 2.0 mmol), Cul (19 mg, 0.1 mmol), and 2-phenylphenol (68 mg, 0.4 mmol) in dry and degassed DMSO (2 mL) was heated under nitrogen atmosphere at 120°C for 20 h. Water (10 mL) is then added and product is extracted to EtOAc (3 x 10 mL). Combined organic layers were washed with water (3 x 10 mL) and brine (2 x 10 mL) and dried over Na₂S0₄. After evaporation of the solvent crude product is purified by chromatography to afford title compound: H NMR (CDCI₃, 500 MHz) δ 1 .63 (br s, 1 H), 2.33 (s, 3H), 2.37 (s, 3H), 3.02-

3.09 (m, 8H), 6.52 (m, 1 H), 6.87 (m, 1 H), 7.04 (m, 1 H), 7.06-7.10 (m, 2H), 7.16 (m, 1 H), 7.39 (d, J= 7.8 Hz, 1 H); MS (ESI) m/z: 299 [MH]⁺.

Example 8: Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine (vortioxetine, VII)

Mixture of (2,4-dimethylphenyl)(2-iodophenyl)sulfane V (0.34 g, 1 .0 mmol), piperazine VI (0.13 g, 1 .5 mmol), K₃P0₃ (0.42 g, 2.0 mmol), Cul (19 mg, 0.1 mmol), and N,N-diethyl-2-hydroxybenzamide (39 mg, 0.2 mmol) in dry and degassed DMSO (2 mL) was heated under nitrogen atmosphere at 120 ^ for 20 h. Water (10 mL) is then added and product is extracted to EtOAc (3 x 10 mL). Combined organic layers were washed with water (3 x 10 mL) and brine (2 x 10 mL) and dried over Na₂S0₄. After evaporation of the solvent crude product is purified by chromatography to afford title compound: H NMR (CDCI₃, 500 MHz) δ 1 .63 (br s, 1 H), 2.33 (s, 3H), 2.37 (s, 3H), 3.02-3.09 (m, 8H), 6.52 (m, 1 H), 6.87 (m, 1 H), 7.04 (m, 1 H), 7.06-7.10 (m, 2H), 7.16 (m, 1 H), 7.39 (d, J= 7.8 Hz, 1 H); MS (ESI) m/z: 299 [MH]⁺.

Example 9: Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine hydrobromide

(vortioxetine HBr, VII.HBr)

To a solution of vortioxetine VII (1 .80 g, 6.03 mmol) in iPrOAc (20 mL) at room temperature 48% HBr (0.68 mL, 6.03 mmol) was slowly added. Obtained mixture was stirred at room temperature for 1 h, white precipitate was then filtered off, washed with acetone (2 x 20 mL), and dried to afford title compound VII.HBr as a white powder (2.15 g, 94% yield): H NMR (DMSO-d₆, 500 MHz) δ 2.23 (s, 3H), 2.32 (s, 3H), 3.15-3.27 (m, 8H), 6.40 (m, 1 H), 6.96 (m, 1 H), 7.08-7.17 (m, 3H), 7.24 (m, 1 H), 7.32 (d, J= 7.8 Hz, 1 H), 8.85 (br, 2H).

Reference Example 1 : Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine

(vortioxetine, VII)

Mixture of piperazine (1 .0 g, 1 1 .6 mmol), NaOtBu (1 .37 g, 13.8 mmol), Pddba₂ (40 mg, 0.07 mmol), and 1 ,3-bis(2,6-di-i-propylphenyl)imidazolium chloride (24 mg, 0,07 mmol) in dry and degassed toluene (10 mL) is stirred at room temperature for 1 h. (2,4-Dimethylphenyl)(2-iodophenyl)sulfane V (1 .32 g, 3.86 mmol) is then added, reaction mixture is heated to l OO’C and stirred for 24 h. After cooling to room temperature to the reaction mixture water (5 mL) and Celite (0.4 g) is added. After stirring for 20 min salts are filtered off, organic layer is separated, washed with brine (2 x 10 mL), dried over Na₂S0₄ and solvent is evaporated to afford crude product, which is then purified by chromatography to afford title compound as yellowish crystals: H NMR (CDCI₃, 500 MHz) δ 1 .63 (br s, 1 H), 2.33 (s, 3H), 2.37 (s, 3H),

Reference Example 2: Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine

(vortioxetine, VII)

Mixture of piperazine (1 .29 g, 15.0 mmol), NaOtBu (1 .77 g, 17.8 mmol), Pddba2 (52 mg, 0.09 mmol), and rac-BINAP (93 mg, 0,15 mmol) in dry and degassed toluene (10 mL) was stirred at room temperature for 1 h. (2,4-Dimethylphenyl)(2-iodophenyl)sulfane V (1 .70 g, 5.0 mmol) was then added, reaction mixture was heated to 100°C and stirred for 24 h. After cooled to room temperature to the reaction mixture water (5 mL) and Celite (0.4 g) were added. After stirring for 20 min salts were filtered off, organic layer was separated, washed with brine (2 x 10 mL), dried over Na₂S0₄ and solvent was evaporated to afford product as an orange oil (1 .41 g, 95% yield): H NMR (CDCI₃, 500 MHz) δ 1 .63 (br s, 1 H), 2.33 (s, 3H), 2.37 (s, 3H), 3.02-3.09 (m, 8H), 6.52 (m, 1 H), 6.87 (m, 1 H), 7.04 (m, 1 H), 7.06-7.10 (m, 2H), 7.16 (m, 1 H), 7.39 (d, J = 7.8 Hz, 1 H); MS (ESI) m/z: 299 [MH]⁺.

Comparative Example 1 : Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine

(vortioxetine, VII)

Mixture of (2,4-dimethylphenyl)(2-bromohenyl)sulfane V” (0.29 g, 1 .0 mmol), piperazine VI (0.13 g, 1 .5 mmol), K₃P0₃ (0.42 g, 2.0 mmol), Cul (19 mg, 0.1 mmol), and 2-phenylphenol (68 mg, 0.4 mmol) in dry and degassed DMSO (2 mL) was heated under nitrogen atmosphere at 120°C for 20 h. Vortioxetine VII was not formed.

Comparative Example 2: Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine

(vortioxetine, VII)

Mixture of (2,4-dimethylphenyl)(2-bromophenyl)sulfane V (0.29 g, 1 .0 mmol), piperazine VI (0.13 g, 1 .5 mmol), K₃P0₃ (0.42 g, 2.0 mmol), Cul (19 mg, 0.1 mmol), and N,N-diethyl-2-hydroxybenzamide (39 mg, 0.2 mmol) in dry and degassed DMSO (2 mL) was heated under nitrogen atmosphere at 120 ^ for 20 h. Vortioxetine VII was not formed.

Vortioxetine Synthesis

WO2007144005A1: Industrial process

J Med Chem 2011, 54(9), 3206-3221: (also see Ref. 3; it has same details)

Identifications:

PAPER

Discovery of 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): A Novel Multimodal Compound for the Treatment of Major Depressive Disorder

Benny Bang-Andersen*†, Thomas Ruhland†, Morten Jørgensen†, Garrick Smith†, Kristen Frederiksen†, Klaus Gjervig Jensen†, Huailing Zhong‡, Søren Møller Nielsen†, Sandra Hogg†, Arne Mørk†, and Tine Bryan Stensbøl†

^† Neuroscience Drug Discovery Denmark, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark

^‡ Lundbeck Research USA, 215 College Road, Paramus, New Jersey 07652-1431, United States

J. Med. Chem., 2011, 54 (9), pp 3206–3221

DOI: 10.1021/jm101459g

http://pubs.acs.org/doi/abs/10.1021/jm101459g

The synthesis and structure−activity relationship of a novel series of compounds with combined effects on 5-HT_3A and 5-HT_1A receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT_1A (K_i = 15 nM), 5-HT_1B (K_i = 33 nM), 5-HT_3A (K_i = 3.7 nM), 5-HT₇ (K_i = 19 nM), and noradrenergic β₁ (K_i = 46 nM) receptors, and SERT (K_i = 1.6 nM). Compound 5mdisplayed antagonistic properties at 5-HT_3A and 5-HT₇ receptors, partial agonist properties at 5-HT_1B receptors, agonistic properties at 5-HT_1A receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.

1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine Hydrochloride (5m)

ALERT HYDROCHLORIDE DATA

5m was prepared according to general procedure 3 starting from intermediate 12m in a yield of 78%.

¹H NMR (500 MHz, DMSO-d₆) δ 9.39 (s, 2H), 7.33 (d, J = 7.7, 1H), 7.24 (s, 1H), 7.17−7.07 (m, 3H), 6.96 (dd, J = 7.6, 6.0, 1H), 6.41 (d, J = 7.8, 1H), 3.21 (broad s, 8H), 2.31 (s, 3H), 2.24 (s, 3H).

¹³C NMR (126 MHz, DMSO-d₆) δ 148.22, 142.04, 139.68, 136.11, 133.74, 132.14, 128.46, 127.19, 126.40, 126.13, 125.46, 120.64, 48.47 (2C), 43.67 (2C), 21.10, 20.47.

HRMS calcd for C₁₈H₂₂N₂S + H, 299.1576; found, 299.1584.

LC/MS (method 1): t_R = 1.02 min, UV purity 97%, ELS purity 100%.

Anal. (C₁₈H₂₂N₂S·HCl) C, H, N.

References

US Label Last updated July 2014 after review in September, 2014. Versions of label are available at FDA index page Page accessed January 19, 2016
[No authors listed] Vortioxetine. Aust Prescr. 2015 Jun;38(3):101-2. PMID 26648632 Free full text
“Relative efficacy and tolerability of vortioxetine versus selected antidepressants by indirect comparisons of similar clinical studies.”. Curr Med Res Opin 30: 2589–606. Oct 10, 2014. doi:10.1185/03007995.2014.969566. PMID 25249164.
Köhler S, Cierpinsky K, Kronenberg G, Adli M. The serotonergic system in the neurobiology of depression: Relevance for novel antidepressants. J Psychopharmacol. 2016 Jan;30(1):13-22. PMID 26464458
Kelliny M, Croarkin PE, Moore KM, Bobo WV. Profile of vortioxetine in the treatment of major depressive disorder: an overview of the primary and secondary literature. Ther Clin Risk Manag. 2015 Aug 12;11:1193-212. PMID 26316764 Free full text
“Lundbeck’s “Serotonin Modulator and Stimulator” Lu AA21004: How Novel? How Good? – GLG News”.
^ Jump up to:^a ^b ^c Bang-Andersen B, Ruhland T, Jørgensen M, et al. (May 2011). “Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder”. Journal of Medicinal Chemistry 54 (9): 3206–21. doi:10.1021/jm101459g. PMID 21486038.
N. Moore; B. Bang-Andersen; L. Brennum; K. Fredriksen; S. Hogg; A. Mork; T. Stensbol; H. Zhong; C. Sanchez; D. Smith (August 2008). “Lu AA21004: a novel potential treatment for mood disorders”. European Neuropsychopharmacology 18 (Supplement 4): S321.doi:10.1016/S0924-977X(08)70440-1.
Pae CU et al. Vortioxetine, a multimodal antidepressant for generalized anxiety disorder: a systematic review and meta-analysis. J Psychiatr Res. 2015 May;64:88-98. PMID 25851751
Reinhold JA, Rickels K. Pharmacological treatment for generalized anxiety disorder in adults: an update. Expert Opin Pharmacother. 2015;16(11):1669-81. PMID 26159446
Sanchez C, Asin KE, Artigas F Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther. 2015 Jan;145:43-57. PMID 25016186 Free full text
Daniel Beaulieu for First Word Pharma. September 5th, 2007 Lundbeck, Takeda enter strategic alliance for mood disorder, anxiety drugs
FDA approves new drug to treat major depressive disorder, U.S. Food and Drug Administration Press Announcement.
EMA Brintellix page at EMA site Page accessed January 19, 2016
Commissioner, Office of the. “Safety Alerts for Human Medical Products – Brintellix (vortioxetine): Drug Safety Communication – Brand Name Change to Trintellix, to Avoid Confusion With Antiplatelet Drug Brilinta (ticagrelor)”. http://www.fda.gov. Retrieved2016-05-02.

References:

1. Gibb, A.; et. al. Vortioxetine: first global approval. Drugs 2014, 74(1), 135-145.

2. Bang-Andersen, B.; et. al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem 2011, 54(9), 3206-3221.

3. Bang-Andersen, B.; et. al. 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairmentWO2007144005A1

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Vortioxetine
Systematic (IUPAC) name


1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]piperazine
Clinical data
Trade names	Trintellix, Brintellix
License data	EU EMA: Brintellix US FDA: Vortioxetine
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Oral
Legal status
Legal status	℞ (Prescription only)
Pharmacokinetic data
Bioavailability	75% (peak at 7–11 hours)
Protein binding	98%
Metabolism	extensive hepatic, primarilyCYP2D6-mediated oxidation
Biological half-life	66 hours
Excretion	59% in urine, 26% in feces
Identifiers
CAS Number	508233-74-7
ATC code	N06AX26 (WHO)
PubChem	CID 9966051
IUPHAR/BPS	7351
ChemSpider	8141643
KEGG	D10184
ChEBI	CHEBI:76016
Synonyms	Lu AA21004
Chemical data
Formula	C₁₈H₂₂N₂S
Molar mass	298.45 g/mol (379.36 as hydrobromide)

/////////////

CC(C=C(C)C=C1)=C1SC2=C(N3CCNCC3)C=CC=C2

FDA Approves Perjeta for Neoadjuvant Breast Cancer Treatment

October 1, 2013 3:30 am / 2 Comments on FDA Approves Perjeta for Neoadjuvant Breast Cancer Treatment

The structure of HER2 and pertuzumab

pertuzumab

Sept. 30, 2013 — The U.S. Food and Drug Administration today granted accelerated approval to Perjeta (pertuzumab) as part of a complete treatment regimen for patients with early stage breast cancer before surgery (neoadjuvant setting). Perjeta is the first FDA-approved drug for the neoadjuvant treatment of breast cancer.

Perjeta was approved in 2012 for the treatment of patients with advanced or late-stage (metastatic) HER2-positive breast cancer. HER2-positive breast cancers have increased amounts of the HER2 protein that contributes to cancer cell growth and survival

cut paste of my old article

he European Medicines Agency (EMA) has approved Roche’s PERJETA (pertuzumab) for patients with previously untreated HER2-positive metastatic breast cancer (mBC)

MARCH 5, 2013 8:59 AM / 4 COMMENTS /

The structure of HER2 and pertuzumab

march 4, 2013

The European Medicines Agency (EMA) has approved Roche’s PERJETATM (pertuzumab) RG1273 for patients with previously untreated HER2-positive metastatic breast cancer (mBC). PERJETA is approved in combination with Herceptin® (trastuzumab) and docetaxel in adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease\

The European approval comes after the Phase III CLEOPATRA trial showed that the combination of PERJETA, Herceptin and chemotherapy provided patients with a median of 6.1 months longer without their disease worsening or death (progression-free survival, PFS) and provided a 34 percent reduction in the risk of death (overall survival) compared to Herceptin and chemotherapy alone.

Herceptin was the first monoclonal antibody developed for the treatment of HER2-positive breast cancer and has increased survival times for patients so that they are now the same as for patients with HER2-negative breast cancer. Before Herceptin treatment, shorter survival outcomes were expected for patients diagnosed with HER2-positive breast cancer, compared to patients with HER2-negative disease.(1) In the CLEOPATRA study, PERJETA in combination with Herceptin and chemotherapy has shown the extension of survival times for patients with this aggressive disease even further than Herceptin

About PERJETA

PERJETA is designed specifically to prevent the HER2 receptor from pairing (dimerising) with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumour growth and survival. Binding of PERJETA to HER2 may also signal the body’s immune system to destroy the cancer cells. The combination of PERJETA, Herceptin and chemotherapy is thought to provide a more comprehensive blockade of HER signalling pathways.

Pertuzumab (also called 2C4, trade name Perjeta) is a monoclonal antibody. The first of its class in a line of agents called “HER dimerization inhibitors”. By binding to HER2, it inhibits the dimerization of HER2 with other HER receptors, which is hypothesized to result in slowed tumor growth.^[1] Pertuzumab received US FDA approval for the treatment of HER2-positive metastatic breast cancer on June 8, 2012.^[2] Pertuzumab was developed at Genentech and is now owned by Roche which acquired Genentech in 2009.

Clinical trials

Early clinical trials of pertuzumab in prostate, breast, and ovarian cancers have been met with limited success.^[3]

The dosage of pertuzumab used in the pivotal phase III CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial was as follows: IV 840 mg loading dose followed by IV 420 mg every three weeks.^[4]

The pharmacokinetics of intravenous pertuzumab appear to be unaffected by age and no drug-drug interaction has been reported with docetaxel. The pharmacokinetics and pharmacodynamics of pertuzumab were summarized in a Feb 2012 review by Gillian Keating.^[4]

The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects in the randomized, double-blind, multinational, phase III CLEOPATRA trial.^[5]

Intravenous pertuzumab is currently being evaluated in patients with breast cancer in the following trials: MARIANNE (advanced breast cancer), NEOSPHERE (early breast cancer), TRYPHAENA (HER2-positive stage II/III breast cancer) and APHINITY (HER2-positive nonmetastatic breast cancer).^[4]

References

de Bono, Johann S.; Bellmunt, J; Attard, G; Droz, JP; Miller, K; Flechon, A; Sternberg, C; Parker, C et al. (20 January 2007). “Open-Label Phase II Study Evaluating the Efficacy and Safety of Two Doses of Pertuzumab in Castrate Chemotherapy-Naive Patients With Hormone-Refractory Prostate Cancer”. Journal of Clinical Oncology 25 (3): 257–262.doi:10.1200/JCO.2006.07.0888. PMID 17235043.
“FDA Approves Perjeta (Pertuzumab) for People With HER2-Positive Metastatic Breast Cancer” (Press release). Genentech. Retrieved 2012-06-09.
Genentech press release – May 15, 2005
Keating GM. Pertuzumab: in the first-line treatment of HER2-positive metastatic breast cancer. Drugs 2012 Feb 12; 72 (3): 353-60.Link text
Baselga J, Cortés J, Kim SB, and the CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012 Jan 12; 366 (2): 109-19. Link text

About the CLEOPATRA study

CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) is an international, phase III, randomised, double-blind, placebo-controlled study. The study evaluated the efficacy and safety profile of PERJETA combined with Herceptin and docetaxel chemotherapy compared to Herceptin and chemotherapy plus placebo in 808 people with previously untreated HER2-positive mBC or that had returned after prior therapy in the adjuvant (after surgery) or neoadjuvant (before surgery) setting.

In CLEOPATRA, the most common adverse reactions (rate greater than 30 percent) seen with the combination of PERJETA, Herceptin and chemotherapy were diarrhoea, hair loss, low white blood cell count with or without fever, upset stomach, fatigue, rash and peripheral neuropathy (numbness, tingling or damage to the nerves). The most common Grade 3–4 adverse events (rate greater than 2 percent) were low white blood cell count with or without fever, decrease in a certain type of white blood cell, diarrhoea, damage to the nerves, decrease in red blood cell count, weakness and fatigue.

About breast cancer

Breast cancer is the most common cancer among women worldwide.(4) Each year, about 1.4 million new cases of breast cancer are diagnosed worldwide, and over 450,000 women will die of the disease annually.(4) In HER2-positive breast cancer, increased quantities of the human epidermal growth factor receptor 2 (HER2) are present on the surface of the tumour cells. This is known as “HER2 positivity” and affects approximately 15-20 percent of women with breast cancer.(5) HER2-positive cancer is a particularly aggressive form of breast cancer.

Certolizumab pegol – FDA gave green light to UCB’s Cimzia to treat psoriatic arthritis

October 1, 2013 1:12 am / 1 Comment on Certolizumab pegol – FDA gave green light to UCB’s Cimzia to treat psoriatic arthritis

Certolizumab pegol

The US Food and Drug Administration has approved UCB’s Cimzia for the treatment of adults with psoriatic arthritis, the third indication approved by the agency.

The UCB’s biologic drug Cimzia is already on the market for rheumatoid arthritis and Crohn’s disease in both US and Europe. Cimzia, also known as Certolizumab pegol, is a monoclonal antibody directed against tumor necrosis factor alpha. It is a PEGylated Fab’ fragment of a humanized TNF inhibitor monoclonal antibody

read all at http://www.pharmatopics.com/2013/09/fda-gave-green-light-to-ucbs-cimzia-to-treat-psoriatic-arthritis/

Certolizumab pegol (CDP870, tradename Cimzia) is a therapeutic monoclonal antibody to tumor necrosis factor alpha (TNF-α), for the treatment of Crohn’s disease and rheumatoid arthritis, manufactured by UCB.

certolizumab pegol is a monoclonal antibody directed against tumor necrosis factor alpha. More precisely, it is a PEGylated Fab’fragment of a humanized TNF inhibitor monoclonal antibody.

Polyethylene glycol does not cross the placenta, so it should be safe in pregnancy.

Positive results have been demonstrated in two phase III trials (PRECiSE 1 and 2) of certolizumab pegol versus placebo in moderate to severe active Crohn’s disease. In addition, data from both trials suggest it is well tolerated. As yet its efficacy has not been directly compared to other anti-TNF-α agents.

Preliminary results of the RAPID 1 and 2 phase III studies were also reportedly positive.

In 2013, a phase 3 double blind randomized placebo-controlled study found significantly positive result in patient self-reported questionnaires, with rapid improvement of function and pain reduction.

On April 22, 2008, the U.S. Food and Drug Administration (FDA) approved Cimzia for use in the United States for the treatment of Crohn’s disease in people who did not respond sufficiently or adequately to standard therapy.

On June 26, 2009, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) issued a positive opinion recommending that the European Commission grant a marketing authorisation for Cimzia for the treatment of rheumatoid arthritis only – the CHMP refused approval for the treatment of Crohn’s disease. The marketing authorisation was granted to UCB Pharma SA on October 1, 2009.

Daclizumab

September 30, 2013 12:17 pm / 4 Comments on Daclizumab

DACLIZUMAB,

CAS 152923-56-3
Monoclonal antibody
Type	Whole antibody
Source	Humanized (from mouse)
Target	CD25

Daclizumab is a humanized monoclonal antibody indicated in the United States for prophylaxis of acute organ rejection in patients receiving renal transplants.

It was marketed as Zenepax, but discontinued by Roche in 2009 due to diminishing market demand for that indication. Biogen Idec is currently conducting phase III trials for daclizumab in MS. A phase III trial started in March 2010 is being conducted to determine efficacy of preventing MS relapse.

Study dosing of daclizumab is 150 mg subcutaneously once every 4 weeks versus interferon beta-1a (Avonex) 30 mg intramuscularly given once weekly for 96 to 144 weeks.

Daclizumab (Zenapax^®) (molecular wt = 144 kd.) is a humanized monoclonal antibody (IgG1) produced by recombinant DNA technology. It gained FDA approval in Dec 1997. It is known by several other names including HAT (Humanized Anti-Tac), SMART anti-Tac, anti-CD25, and humanized anti-IL2-receptor. It was developed and patented by Protein Design Laboratories (Mountain View, CA) and it is marketed by Hoffman LaRoche (Nutley, NJ ).

Daclizumab is a composite of human (90%) and murine (10%) antibody sequences. In the model below, the murine portions are shown in red and dark blue; the rest of the molecule (gray color) represents the human sequence

The study is aiming for enrollment of 1500 patients and is expected to be complete in January 2014.

more info

Daclizumab (trade name Zenapax) is a therapeutic humanized monoclonal antibody. It is used to prevent rejection in organ transplantation, especially in kidney transplants. The drug is also under investigation for the treatment of multiple sclerosis.

Daclizumab works by binding to CD25, the alpha subunit of the IL-2 receptor of T cells. The drug is marketed in the US, but not in Europe.

Uses

Prevention of organ transplants

Daclizumab is given in multiple doses, the first 1 hour before the transplant operation and 5 further doses given at two week intervals after the transplant. These saturate the receptors and prevent T cell activation and thus prevent formation of antibodiesagainst the transplant.

Like the similar drug basiliximab, daclizumab reduces the incidence and severity of acute rejection in kidney transplantation without increasing the incidence of opportunistic infections.

Daclizumab usage may also be indicated in place of a calcineurin-inhibitor (ciclosporin or tacrolimus) during the early phase after kidney transplantation, when the kidney is recovering and vulnerable to calcineurin-inhibitor toxicity. This has been shown to be beneficial in non-heart beating donor kidney transplantation.

In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) has recommended its use be considered for all kidney transplant recipients.^{[citation needed]}

Multiple sclerosis

In 2006 it began a Phase II clinical trial that finished in 2007 as a possible multiple sclerosis (MS) treatment. Participants were nine patients with multiple sclerosis not controlled with interferon. Daclizumab was effective in reducing lesions and improving clinical scores.^[1] As of June 2013, the drug is in Phase III trials for this indication.^[2]

Autoimmune diseases

Daclizumab has also been used to slow the progression of autoimmune diseases, particularly that of birdshot chorioretinopathy.^[3]

Common side effects with a frequency of at least 10% include sleeplessness, tremor, headache, arterial hypertension, dyspnoea, gastrointestinal side effects and oedema. In rare cases, the drug can cause severe anaphylaxis.^[4]

Daclizumab must not be administered to lactating women.^[4]

History

Daclizumab was developed by PDL Biopharma, building on research at the National Institutes of Health (NIH).^[5] Since December 1997, it is marketed by Hoffmann-La Roche in the US.

In April 2008, Hoffmann-La Roche submitted an application to have its marketing authorisation withdrawn in the EU for commercial reasons. The drug faced diminishing market demand, according to the company. There were no safety concerns with its use. As of January 2009, its marketing authorisation has been withdrawn and the product discontinued completely.^[6]^[7]

Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG (2007). “Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results”.Neurology 69 (8): 785–789. doi:10.1212/01.wnl.0000267662.41734.1f.PMID 17709711.
ClinicalTrials.gov NCT01462318 An Immunogenicity and Pharmacokinetics (PK) Study of DAC HYP Prefilled Syringe in Relapsing Remitting Multiple Sclerosis (RRMS) (OBSERVE)
Sobrin L, Huang JJ, Christen W, Kafkala C, Choopong P, Foster CS (2008). “Daclizumab for treatment of birdshot chorioretinopathy”. Arch Ophthalmol. 126 (2): 186–191. doi:10.1001/archophthalmol.2007.49. PMID 18268208.
“EPAR for Zenapax”. European Medicines Agency. 2007.
Tsurushita, N.; Hinton, P. R.; Kumar, S. (2005). “Design of humanized antibodies: From anti-Tac to Zenapax”. Methods 36 (1): 69–83.doi:10.1016/j.ymeth.2005.01.007. PMID 15848076. edit
British National Formulary, Edition 57
EMEA: Withdrawal of the marketing authorisation in the European Union

VINCRISTINE……..Chemistry, Isolation

September 28, 2013 12:27 pm / 1 Comment on VINCRISTINE……..Chemistry, Isolation

VINCRISTINE

(3aR,3a1R,4R,5S,5aR,10bR)-methyl 4-acetoxy-3a-ethyl-9-((5S,7S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-2,4,5,6,7,8,9,10-octahydro-1H-3,7-methano[1]azacycloundecino[5,4-b]indol-9-yl)-6-formyl-5-hydroxy-8-methoxy-3a,3a1,4,5,5a,6,11,12-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate

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Advanced study of natural sources of anti-cancer from harmoini

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Vincristine (brand name, Oncovin), formally known as leurocristine, sometimes abbreviated “VCR”, is a vinca alkaloid from the Catharanthus roseus (Madagascar periwinkle), formerly Vinca rosea and hence its name. It is amitotic inhibitor, and is used in cancer chemotherapy. Vincristine is created by the coupling of indole alkaloids vindoline and catharanthine in the vinca plant.^[1]

Mechanism

Tubulin is a structural protein that polymerizes to microtubules. The cell cytoskeleton and mitotic spindle, among other things, are made of microtubules. Vincristine binds to tubulin dimers, inhibiting assembly of microtubule structures. Disruption of the microtubules arrests mitosis in metaphase. Therefore, the vinca alkaloids affect all rapidly dividing cell types including cancer cells, but also those of intestinal epithelium and bone marrow.

Uses

Vincristine is delivered via intravenous infusion for use in various types of chemotherapy regimens. Its main uses are in non-Hodgkin’s lymphoma as part of the chemotherapy regimen CHOP, Hodgkin’s lymphoma as part of MOPP, COPP, BEACOPP, or the less popular Stanford V chemotherapy regimen, in acute lymphoblastic leukemia, and in treatment for nephroblastoma (Wilms tumor, a kidney tumor most common in young children). It is also used to induce remission in ALL with Dexamethasone and L-Asparaginase. Vincristine is occasionally used as an immunosuppressant, for example, in treating thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP). It is used in combination with prednisone to treat childhood leukemia.

The main side-effects of vincristine are peripheral neuropathy, hyponatremia, constipation, and hair loss.

Peripheral neuropathy can be severe, and hence a reason to avoid, reduce, or stop the use of vincristine. One of the first symptoms of peripheral neuropathy is foot drop: A person with a family history of foot drop and/or Charcot-Marie-Tooth disease (CMT) should avoid the taking of vincristine.^[2]

Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly dangerous, with a mortality rate approaching 100 percent. The medical literature documents cases of ascending paralysis due to massive encephalopathy and spinal nerve demyelination, accompanied by intractable pain, almost uniformly leading to death; a handful of survivors were left with devastating neurological damage with no hope of recovery. Rescue treatments consist of washout of the cerebrospinal fluid and administration of protective medications.^[3] A significant series of inadvertent intrathecal vincristine administration occurred in China in 2007 when batches of cytarabine andmethotrexate (both often used intrathecally) manufactured by the company Shanghai Hualian were found to be contaminated with vincristine.^[4]

Having been used as a folk remedy for centuries, studies in the 1950s revealed that C. roseus contained 70 alkaloids, many of which are biologically active. While initial studies for its use in diabetes mellitus were disappointing, the discovery that it caused myelosuppression (decreased activity of the bone marrow) led to its study in mice withleukemia, whose lifespan was prolonged by the use of a vinca preparation. Treatment of the ground plant with Skelly-B defatting agent and an acid benzene extract led to a fraction termed “fraction A”. This fraction was further treated withaluminium oxide, chromatography, trichloromethane, benz-dichloromethane, and separation by pH to yield vincristine.^[5]

Vincristine was approved by the United States Food and Drug Administration (FDA) in July 1963 as Oncovin. The drug was initially discovered by a team led by Dr. J.G. Armstrong, then marketed by Eli Lilly and Company.

Like LSD, the microtubule toxin vincristine allegedly causes not-unpleasant visual hallucinations in humans. Other side-effects of vincristine include depression, agitation, and insomnia. Very small doses are needed for the effects of LSD or vincristine, for example, these drugs are active at concentrations of 4.3E-7 M-1 vincristine and 1.0E-8 M-1 LSD.

Many researchers have favored the drug-receptor theory to explain drug-induced hallucinations, usually at the 5-HT2A receptor. In the drug-receptor theory, signal amplification takes place when one molecule of drug binds to a receptor, which activates G-proteins, which affects more proteins, thus signaling cascades explain how a small amount of LSD can lead to widespread changes in the cell.

Van Woerkom suggests instead that LSD binds an element of the cytoskeleton, in a fashion similar to colchicine or vinblastine, which directly bind tubulin. The amount of LSD needed to produce hallucinations is so vanishly small, that it seems hard to believe that a submicromolar dosage of LSD could act on a substrate as vast as the cytoskeleton. However, some microtubule inhibitors such as vincristine are effective at very low dosages. The potency of vincristine may partly explain the success of this drug as a chemotherapeutic drug.

Three generic drug makers supply vincristine in the United States – APP, Mayne, and Sicor (Teva).

^ “Pharmacognosy of Vinca Alkaloids”.
Graf, W. D.; Chance, P. F.; Lensch, M. W.; Eng, L. J.; Lipe, H. P.; Bird, T. D. (1996). “Severe Vincristine Neuropathy in Charcot-Marie-Tooth Disease Type 1A”. Cancer 77 (7): 1356–1362. doi:10.1002/(SICI)1097-0142(19960401)77:7<1356::AID-CNCR20>3.0.CO;2-#. PMID 8608515.
Qweider, M.; Gilsbach, J. M.; Rohde, V. (2007). “Inadvertent Intrathecal Vincristine Administration: A Neurosurgical Emergency. Case Report”. Journal of Neurosurgery: Spine 6 (3): 280–283. doi:10.3171/spi.2007.6.3.280. PMID 17355029.
Jake Hooker and Walt Bogdanich (January 31, 2008). “Tainted Drugs Tied to Maker of Abortion Pill”. New York Times.
Johnson, I. S.; Armstrong, J. G.; Gorman, M.; Burnett, J. P. (1963). “The Vinca Alkaloids: A New Class of Oncolytic Agents” (pdf). Cancer Research 23 (8 Part 1): 1390–1427.PMID 14070392.

External links

Cytostatic Vinca alkaloids rosea L. Catharanthus roseus G.Don) are now well known anticancer and particularly useful. Given the small amount of vincristine in Catharanthus present, quite a number of ways of preparation have been proposed by chemists. Thus FR-A-2296418 describes the synthesis of vincristine by coupling Catha-ranthine and vindoline. Other laboratories have achieved the transformation of vinblastine vincristine oxidation under controlled conditions, very strict.
FR-A-2210393 and US-A-3899493 perform the oxidation by chromic acid at -30, -90 ° C in a mixture of acetic acid-acetone or chloroform-acetic acid at -55 ° C.
In U.S. 4,375,432, chromic compound is also used in acid medium at -65 ° C, -50 ° C in a medium based solvent THF. In addition, EP-A-37289 boasts an oxidation mixture ferrous salt, hydrogen peroxide, perchlorate in acetonitrile. ZA-A-82 08939 discloses a method with chromic acid and an ether-chloroform.
HU-A-23638 offers diterbutylchromate in pelargonic acid, and finally EP-A-117861 gets vinblastinel transformation vincristine oxidant potassium permanganate in acetic acid medium. It is clear that these dimeric alkaloids are a valuable material because of their low levels in vegetable raw materials, and therefore the processes of synthesis or semi-synthesis performance are of extreme interest.

Vincristine is used in cancer chemotherapy, particularly for the treatment of certain acute leukemias.
This alkaloid is obtained mainly by extraction from leaves of Catharanthus Ro-seus (U.S. Patent No. 3,205,220) where it is accompanied by other alkaloids bis-Indo-holic, especially vinblastine.Vinblastine (I, R = CH _3), however, is present at a concentration much higher than that of vincristine and is therefore a precursor of choice for the semisynthesis of the latter.
Several processes of vincristine from vinblastine were disclosed. We note in particular patents or patent applications include:
- a) Belgian Patent 739,337 (Gedeon Richter) which describes a method for the oxidation of vinblastine vincristine in a mixture chromic acid, acetic acid and acetone.
- b) Belgian Patent 823560 (Gedeon Richter) the oxidation is performed with oxygen in the presence of formic acid and of a catalyst based on platinum at room temperature.
- c) European Patent Application 18231 (Gedeon Richter): is carried out by oxidation with chromic acid or an alkali metal dichromate in the presence of acetic anhydride and, optionally, of ethanol and an organic solvent immis target with water.
- d) European Patent Application 37289 (Eli Lil-ly): the oxidation is effected by the perchlorate of iron (II) in the presence of hydrogen peroxide and acetonitrile.
In addition, the European patent application 37. 290 discloses a process for the oxidation of vinblastine base with Na ₂ Cr ₂ O ₇ in the presence of sulfuric acid in tetrahydrofuran. This reaction led to -50 ° C, is achieved with a yield of 80-92% calculated for each estimation.
Observed yields or purity of the products obtained characterizing the processes described above are, however, significant disadvantages.
Frequently a secondary product formed is N-demethyl vinblastine need then reformulate for vincristine.

Thus Potier and Kutney obtained products with the C18’S-C2’R absolute configuration, which is critical for anti-tumor activity, by a coupling reaction of the N.sup.b -oxide of catharanthine, or its derivatives, with vindoline, in the presence of trifluoroacetic anhydride, followed by a reduction reaction. [See Potier et. al. J. Am. Chem. Soc. 98. 7017 (1976) and Kutney et. al. Helv. Chim. Acta, 59, 2858 (1976)].

The Potier and Kutney coupling process has disadvantages. The yields are not satisfactory except for the coupling of catharanthine N-oxide with vindoline and even there the preparative yield is low. While vindoline is the most abundant alkaloid of Vinca rosea and is thus readily available, the other possible components of the Potier-Kutney coupling process (catharanthine, allocatharanthine, voacangine,) are relatively inaccessible, costly, and they do not allow a wide range of structural variation of that component of the coupling process.

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EP 0117861 B1
clips
The process of the present invention produces a simple vincristine, in quantity and purity requiring little or no additional purification by recrystallization or chromatography.
[0009]

The reagent used is oxidation permanganate ion dissolved in toluene or dichloromethane as solvent. An alternative consists in immobilizing the resin on a permanganate anion, for example a polymer such as polystyrene comprising ammonium groups. Solubilization can be achieved by the action of a complexing agent crown ether (“crown-ether”) of potassium permanganate.
[0010]

The permanganate anion can also be solubilized by preparing an ammonium salt or quaternary phosphonium corresponding which is soluble in methylene chloride or toluene. For this purpose, it is preferable to use potassium permanganate benzyltriethylammonium.
[0011]

Obtaining from vincristine vinblastine using a permanganate salt is unexpected since the potassium permanganate used in some acetone oxide derivatives of vinblastine at the portion of the molecule velbanamine (Kutney, Balsevich and Worth, Heterocycles, 11, 69, 1978). The N-methyl group of the vindoline part intact.
[0012]

The formation of N-CHO indoline skeleton on a bis-indole group vinblastine using a permanganate salt has never been reported.
[0013]

According to one embodiment of the method of the present invention, vinblastine, preferably in the form of sulphate, is treated in the presence of an organic acid such as acetic acid, with an excess of potassium permanganate dissolved in dichloromethane or toluene in the presence of “18-crown-6” or ether derivatives dibenzo-or di-cyclohexylcorrespondants. The reaction is conducted at a temperature between -40 ° C and -75 ° C and is preferably followed by thin layer chromatography. The reaction time generally ranges from 5 minutes to 3 hours.
[0014]

Potassium permanganate is preferably dissolved in dichloromethane and the oxidation reaction is then carried out at -70 ° C.
[0015]

The solubility of potassium permanganate is indeed substantially increased in the presence of a macrocyclic polyether as the “18-crown-6” ether (1, 4, 7, 10, 13, 16-hexaoxacy-clooctadécane) or derivative dibenzo – or corresponding dicyclohexyl-hexyl.
[0016]

The reaction mixture is then treated simultaneously by a mild reducing and alkaline. For this purpose, use is preferably an aqueous solution of bisulfite, disulfite or sodium metabisulfite and ammonia.
[0017]

The organic phase was separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phases were concentrated in vacuo to give a residue containing 80-85% of base vincristine, a 90-95% yield.
[0018]

Alternatively, you can proceed with the extraction of the reaction mixture after reduction without conducting a simultaneous alkalinization. The acidic aqueous solution was then extracted with dichloromethane. This route is a novel process for purification of vincristine formed in the reaction medium.
[0019]

According to another embodiment of the present invention, vincristine is obtained by oxidation of vinblastine by reacting a quaternary ammonium permanganate. The ammonium cation is preferably benzyltriethylammonium group or benzyl trimethyl ammonium (see eg Angew. Chem., Intern. Ed. 13, 170, 1974). The reaction is carried out in 2 to 6 hours at -60 ° C in an inert solvent wherein the ammonium salt is soluble, and an acid, preferably an organic acid of low molecular weight. A mixture of dichloromethane and glacial acetic acid can be used. After treatment with a mild reducing agent in aqueous medium, the resulting acidic solution is extracted with dichloromethane, and the organic phase is made alkaline by washing with a basic aqueous solution and concentrated. Vincristine solvate is isolated with a yield higher than 90%.
[0020]

The latest variant of the method of the invention is particularly advantageous in terms of economic and technical.
[0021]

Purification or separation may be effected by crystallization and chromatography using techniques well known this from the crude product of the reaction. The product can also be lyophilized.
[0022]

In most cases, vincristine thus obtained can be converted directly into an addition salt with an organic or inorganic acid, preferably pharmaceutically acceptable. This salt is preferably a sulfate that may arise in a more or less solvated or hydrated.
[0023]

We can also prepare vincristine dissolved in a physiologically acceptable solvent and ready to be injected.
[0024]

In particular, vincristine sulfate is obtained by addition of H ₂ S0 ₄ to a solution of vincristine gross or recrystallized from ethanol, dissolved in a mixture of methylene chloride and anhydrous ethanol, partial removal in vacuo chloride methylene and crystallization.
[0025]

Vincristine sulfate thus obtained has a purity sufficient for use as a medicament, particularly in the form of injectable solutions.

Madagascar Periwinkle: Public Domain Illustration by Sydenham Edwards

The Madagascar periwinkle, an attractive flowering plant, contains the powerful anti-cancer chemicals vinblastine and vincristine. Velvet beans, which are named from the covering of soft hairs on the young plant, contain L-dopa, a very helpful chemical in the treatment of Parkinson’s disease. The Madagascar periwinkle and the velvet bean are just two of the large number of plants that have been found to contain medicinal chemicals. There are almost certainly many more plants that have undiscovered health benefits.

The Madagascar Periwinkle

The Madagascar periwinkle is native to Madagascar and India, but is now grown in many countries as a garden plant. It has also escaped from gardens and grows as a weed. The red, purple, pink or white flowers often have a center which is a different color from the rest of the flower. Madagascar periwinkles may grow up to one meter tall and have glossy green leaves.

The sap of the Madagascar periwinkle, which has a milky appearance and is poisonous, contains vinblastine, vincristine and many other alkaloids. Researchers are discovering that many of these alkaloids are biologically active inside the human body.

Vinblastine and Vincristine

Vinblastine and vincristine have very similar chemical structures, but their effects on the body are not the same. Vinblastine is used to treat specific types of cancer, such as Hodgkin’s disease, breast cancer, testicular cancer and non-small cell lung cancer. Vincristine is used in the treatment of acute lymphoblastic leukemia (ALL) and has provided a great breakthrough in successful treatment of this disease in children. When vincristine is added to the treatment regimen for children suffering from ALL, the survival rate reaches eighty percent. Vincristine is not so impressive in the treatment of ALL in adults.

Cells contain a supporting network of protein tubules, which are known as microtubules. Microtubules also play a vital role in the process of cell division. Before a cell divides, each chromosome in the cell is replicated. The replicated chromosomes are separated from their partners and pulled to opposite ends of the cell by microtubules during a process called mitosis. The cell then divides down the middle.

Vinblastine and vincristine stop microtubule formation during mitosis and therefore prevent cells from reproducing. This effect is strongest in cells that have a high rate of division, such as cancer cells. However, vinblastine and vincristine also affect cells lining the intestine, the cells in the bone marrow that produce blood cells, and the cells in the hair follicles, since these too have a high rate of cell division.

Possible vinblastine or vincristine side effects include constipation, hair loss, a low platelet count, which can cause increased bleeding, a low white blood cell count, which can lead to increased infections, or a low red blood cell count, resulting in anemia. There may occasionally be nerve damage, possibly due to the effect of the medicines on the microctubules in the nerve cells. Vincristine is more likely to cause nerve damage than vinblastine.

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vol. 101 no. 33
> Takeshi Kuboyama, 11966–11970

Total synthesis of (+)-vincristine (2). TFA, trifluoroacetic acid or trifluoroacetyl; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene.

Stereocontrolled total synthesis of (+)-vincristine

vol. 101 no. 33
> Takeshi Kuboyama, 11966–11970

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see docstoc presentation

click below
Vincristine

var docstoc_docid=”51697405″;var docstoc_title=”Vincristine”;var docstoc_urltitle=”Vincristine”;

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isolation

Kumar A, Patil D, Rajamohanan PR, Ahmad A (2013)

Isolation, Purification and Characterization of Vinblastine and Vincristine from Endophytic Fungus Fusarium oxysporumIsolated from Catharanthus roseus. PLoS ONE 8(9): e71805. doi:10.1371/journal.pone.0071805

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0071805

Isolation, purification and characterization of vinblastine and vincristine from the endophytic fungus Fusarium oxysporum

A two stage fermentation procedure was employed for the isolation of vinblastine and vincristine by Fusarium oxysporum. In the first stage, 500 ml Erlenmeyer flasks containing 100 ml medium (MGYP, (0.3%) malt extract, (1.0%) glucose, (0.3%) yeast extract and (0.5%) peptone) were inoculated with 7 days old culture and incubated at 28°C on a rotary shaker (240 rpm) for 4–5 days, which was used as seed culture (I stage). Later, 10 ml seed culture was transferred to 500 ml Erlenmeyer flask containing 100 ml production medium called as vinca medium-1 (Glucose: 3%, Succinic acid: 1%, Sodium benzoate: 100 mg, Peptone: 1%, Magnesium sulphate: 3.6 mg, Biotin: 1 mg, Thiamine: 1 mg, Pyridoxal: 1 mg, Calcium pentothenate: 1 mg, Phosphate buffer: 1 ml (pH 6.8), L-Tryptophan: 0.1%, Geranium oil: 0.05%.) which were incubated at 28°C for 20 days as shake culture (II stage), after which it was harvested and used for further study. Culture filtrates and mycelia were separated with the help of muslin cloth and then lyophilized. Lyophilized culture filtrate was extracted using ethyl acetate as a solvent system. The organic layer was separated from the aqueous layer using separating funnel. The extraction was repeated thrice and the solvent was dried using anhydrous sodium sulphate and concentrated under vacuum using rotavapour at 40°C in order to get crude extract. A small amount of crude extract was dissolved in ethyl acetate and subjected to thin layer chromatography (TLC) on silica gel-G (0.5 mm thickness) using chloroform:methanol (8:2) as a solvent system. The TLC plates were sprayed with ceric ammonium sulphate reagent. Vinca alkaloids spots produced brilliant violet color as well as purple color with above spraying reagent. Purification of fungal vinblastine and vincristine were done by silica gel column chromatography. The crude extract was loaded on silica gel column (60–120 mesh size, 40 cm×2 cm length width) pre-equilibrated with chloroform and eluted with a gradient of chloroform:methanol (100% chloroform, 9:1, 8:2, 7:3, 1:1 and 3:7 and 100% methanol). Fractions containing compounds with Rf values similar to that of the standard vinblastine and vincristine were pooled and subjected to preparative TLC on a 0.5 mm thick (20 cm×20 cm) silica plate and developed in chloroform:methanol (8:2) solvent system. The putative bands of fungal vinblastine and vincristine were scraped and eluted out with methanol. Purity of the isolated compounds was checked on TLC in the solvent systems such as (a) chloroform:methanol (8:2) (b) chloroform:methanol (9:1) and (c) ethyl acetate: acetonitrile (8:2).

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0071805

Purdue Pharma L.P. Receives FDA Approval For 15 mcg/hour Dosage Strength Of Butrans (buprenorphine) Transdermal System CIII

September 25, 2013 3:36 am / 1 Comment on Purdue Pharma L.P. Receives FDA Approval For 15 mcg/hour Dosage Strength Of Butrans (buprenorphine) Transdermal System CIII

buprenorphine

STAMFORD, Conn., Sept. 24, 2013 /PRNewswire/ — Purdue Pharma L.P. announced that the U.S. Food and Drug Administration (FDA) approved a new 15 mcg/hour dosage strength of Butrans® (buprenorphine) Transdermal System CIII, which will provide an additional titration option for healthcare professionals. Four strengths of Butrans will now be available: 5, 10, 15 and 20 mcg/hour. Purdue expects to launch Butrans 15 mcg/hour commercially in the U.S. in October 2013.

read all at

http://www.drugs.com/newdrugs/purdue-pharma-l-p-receives-fda-approval-15-mcg-hour-butrans-buprenorphine-transdermal-ciii-3909.html

Buprenorphine is a semi-synthetic opioid that is used to treat opioid addiction in higher dosages (>2 mg), to control moderate acute pain in non-opioid-tolerant individuals in lower dosages (~200 µg), and to control moderate chronic pain in dosages ranging from 20–70 µg/hour. It is available in a variety of formulations: Subutex, Suboxone, Zubsolv (buprenorphine HCl and naloxone HCl; typically used for opioid addiction), Temgesic (sublingual tablets for moderate to severe pain), Buprenex (solutions for injection often used for acute pain in primary-care settings), Norspan and Butrans (transdermal preparations used for chronic pain).

The treatment of opiate abuse and dependence by substitution of the abused opiate with a safer, longer-acting opioid is often a successful pharmacotherapeutic intervention strategy. Heroin, a widely abused opiate, acts as an agonist for the mu-opioid receptor (MOR). Heroin is often abused using intravenous injection, often resulting in needle-sharing among addicts, which is often responsible for the spread of life-threatening infections such as hepatitis C and HIV/AIDS. Methadone has been used as a substitute MOR agonist. Methadone is orally active, and has sufficient duration of action to enable it to be given as a single daily dose. More recently, buprenorphine 1, 21-(cyclopropyl-7α-[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6,14-endo-ethano-6,7,8,14-tetrahydro-oripavine, a MOR partial agonist, has been used as a pharmacotherapy (see, e.g., U.S. Pat. No. 4,935,428 ). As a partial MOR agonist, it has a lower ceiling to its MOR-mediated effects than a full MOR agonist (e.g., methadone). As a result, buprenorphine has a greater margin of safety than full MOR agonists. In addition, buprenorphine also has a long duration of action. Buprenorphine’s enhanced safety, coupled with its extended duration, enables a relatively long dosing interval, typically every 24 hours, but this can be extended to every 72 hours or more.

Buprenorphine’s favorable safety profile compared to methadone has allowed it to be prescribed by office-based physicians, which has substantially decreased the cost of treatment, and increased the number of addicts in pharmacotherapy treatment.
For the treatment of opiate abuse and dependence, buprenorphine is available as tablets formulated for sublingual administration, and is sold under the trademark Subutex^®. The daily maintenance dose for Subutex^® is in the range 4-16 mg. Subutex^®is readily soluble in aqueous media, making it possible for addicts to misuse the formulation by dissolving the tablets in water, and then injecting the resulting solution. To counter this misuse, buprenorphine has been formulated as a mixture with the MOR antagonist naloxone in a 4:1 ratio (Suboxone^®).
Sublingual administration of buprenorphine has several drawbacks, notably the need to avoid swallowing the tablet because of buprenorphine’s low bioavailability (∼5%) when taken orally. In comparison, buprenorphine’s bioavailability is approximately fifty percent when absorbed sublingually (see, e.g., Jasinski and Preston, Buprenorphine, Ed. A Cowan, JW Lewis, Wiley-Lis, NY pp. 189-211).
Several buprenorphine ester derivatives are described by Stinchcomb et al. in Pharm. Res (1995), 12, 1526-1529. The physiochemical properties of the esters are described, and compared with those of buprenorphine hydrochloride and its free base. Stinchcomb et al. also describe transdermal absorption of these esters in Biol. Pharm. Bull. (1996), 19, 263-267 and Pharm. Res. (1996), 13, 1519-1523. Wang, Published U.S. Patent Application No. 2005/0075361 , also describes some buprenorphine derivatives, which are apparently useful for pain relief when delivered intramuscularly or subcutaneously. EP 1 422 230 discloses buprenorphine monocarboxylic ester derivatives and dibuprenorphine dicarboxylic ester derivatives which exert a longer analgesic effect as compared to buprenorphine hydrochloride.

Buprenorphine hydrochloride was first marketed in the 1980s by Reckitt & Colman (now Reckitt Benckiser) as an analgesic, generally available as Temgesic 0.2 mg sublingual tablets, and as Buprenex in a 0.3 mg/mL injectable formulation. In October 2002, the Food and Drug Administration (FDA) of the United States also approved Suboxone and Subutex, buprenorphine’s high-dose sublingual tablet preparations indicated for detoxification and long-term replacement therapy in opioid dependency, and the drug is now used predominantly for this purpose.

In the European Union, Suboxone and Subutex, buprenorphine’s high-dose sublingual tablet preparations, were approved for opioid addiction treatment in September 2006.^[3] In the Netherlands, buprenorphine is a List II drug of the Opium Law, though special rules and guidelines apply to its prescription and dispensation. In the United States, it was rescheduled to Schedule III drug from Schedule V just before FDA approval of Suboxone and Subutex.^[4] In recent years, buprenorphine has been introduced in most European countries as a transdermal formulation for the treatment of chronic pain.

Commercial preparations

British firm Reckitt & Colman (now Reckitt Benckiser) first marketed buprenorphine under the trade names Temgesic (sublingual/parenteral preparations) and Buprenex (parenteral). Subsequently, two more formulations were released: Subutex (white, oval-shaped, bitter, no active additives) and Suboxone (white color [orange in the U.S.], hexagonal tablet, lemon-lime-flavored, one part naloxone for every four parts buprenorphine). The orange film strips form of Suboxone are lemon flavor. More than 71% of patients gave Suboxone film a favorable taste rating.^[5]

8mg Suboxone film strip

Subutex and Suboxone are available in 2 mg and 8 mg sublingual dosages. (Suboxone Film is also available in doses of 4 mg/1 mg & 12 mg/3 mg buprenorphine/naloxone respectively). On October 8, 2009, Roxane Laboratories of Columbus, Ohio, United States won FDA approval for a generic preparation of Subutex^[6] and as of October 23, 2009, announced that it is ready for distribution nationwide in 2 mg and 8 mg sublingual dosages. The demand for this generic was so high that Roxane did not produce enough to meet market demand, resulting in pharmacies running out and being unable to order more.^[7] Teva Pharmaceutical Laboratories of Tel Aviv, Israel also received approval (as of April 1, 2010) for a generic formulation of Subutex sublingual tablets in 2 mg and 8 mg dosages that are currently available in limited distribution in America as of June 20, 2010. In 2013, Reckitt Benckiser voluntarily discontinued the sale of Suboxone tablets in the United States based on data from Poison control centers that consistently found significantly higher rates (7.8–8.5 times greater) of accidental pediatric exposure with Suboxone tablets as compared with Suboxone Film.^[8]

Since 2001, buprenorphine is also available transdermally as 35, 52.5, and 70 µg/h transdermal patches that deliver the dose over 96 hours. This dosage form is marketed as Transtec in most European countries by Grunenthal (Napp Pharmaceuticals in the UK,^[9]^[10] Norpharma in Denmark) for the treatment of moderate to severe cancer pain and severe non-cancer pain not responding to non-opioids.

Other available buprenorphine formulations include a 5, 10, and 20 µg/h, 7-day patch, marketed as Butrans in the U.S. by Purdue Pharma (and by Napp Pharmaceuticals in the UK) indicated for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time.^[11] A similar transdermal system is marketed by a collaboration between Mundipharma and Grunenthal in Australia under the name Norspan, with indications for moderate chronic pain not responding to non-opioids, dosed in 5, 10, or 20 µg/h patches.^[12]

In India: Addnok 0.4, 2 & 8 Mg Sublingual Tablets by Rusan Pharma Ltd.,^[13] Tidigesic 0.2 mg (slow release) or 0.3 mg/mL injectable by Sun Pharmaceuticals;^[14] Buprigesic (0.3 mg/mL) by Neon Laboratories;^[15] Morgesic (0.3 mg/mL) by Samarth Pharma; Norphin (0.3 mg/mL) Unichem Laboratories.

A novel implantable formulation of buprenorphine (Probuphine), using a polymer matrix sustained-release technology, has been developed to offer treatment for opioid dependence while minimizing risks of patient noncompliance and illicit diversion. FDA requested additional information about Probuphine on April 30, 2013, in a complete response letter to Titan Pharmaceuticals pending NDA.^[16]

In addition to the sublingual tablet, Suboxone is now marketed in the form of a sublingual film, available in the 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, and recently 12 mg/3 mg dosages; the film is not available in Canada or the United Kingdom (where it was discovered). The makers of Suboxone, Reckitt Benckiser, claim that the film has some advantages over the traditional tablet in that it dissolves faster and, unlike the tablet, adheres to the oral mucosa under the tongue, preventing it from being swallowed or falling out; that patients favor its taste over the tablet, stating that “more than 71% of patients scored the taste as neutral or better”; that each film strip is individually wrapped in a compact unit-dose pouch that is child-resistant and easy to carry; and that it is clinically interchangeable with the Suboxone tablet and can also be dosed once daily.^[17] Reckitt Benckiser also states that the film discourages misuse and abuse, as the paper-thin film is more difficult to crush and snort. Also, a ten-digit code is printed on each pouch, which helps facilitate medication counts and, therefore, serves to deter diversion into the illegal drug market. Although Suboxone film may deter snorting the drug it makes injecting the drug much easier as the films are extremely easy to dissolve in water making for easy injection and the fact that the naloxone in suboxone is ineffective at blocking the effects of buprenorphine when injected by addicts not dependent on another opioid.

Physicochemical properties

Buprenorphine is a semi-synthetic derivative of thebaine, one of the most chemically reactive opium alkaloids. Buprenorphine has a molecular weight of 467 and its structure is typically opioid with the inclusion of a C-7 side-chain containing a t-butyl group. This group confers overall lipophilicity on the molecule which has an important influence on its pharmacology.

Opioids exert their pharmacological effects by binding to opioid receptors. The pharmacological effects are determined by the nature of opioid-receptor interaction. Some of these effects such as analgesia, mediated by an agonistic action at the μ-opioid receptor are desirable, whereas others such as nausea, sedation, or constipation can be considered as unwanted adverse effects. Buprenorphine is a μ-opioid receptor agonist with high affinity, but low intrinsic activity. Compared with morphine (a full μ-opioid agonist) buprenorphine is considered a partial μ-opioid agonist displaying high affinity for and slow dissociation from the μ-opioid receptor. A full dose-dependent effect on analgesia has been seen within the clinically relevant dose range (up to 10 mg), but no respiratory depression which levels off at higher doses (Dahan et al. 2005). Clinically, there is also a less marked effect of buprenorphine-binding to μ-opioid receptors on gastrointestinal transit times, and indeed constipation seen in the clinic is remarkably low (Griessinger et al. 2005). Buprenorphine also shows partial agonistic activity at the opioid receptor-like receptor 1 (ORL1)-receptors which are (at least at supraspinal receptors) postulated to induce a pronociceptive effect. A study by Lutfy et al. (2003) reported that co-activation of ORL1-receptors compromises the antinociception induced by activation of the μ-opioid receptor. ORL1-activation has also an effect on hyperalgesia. It might be that buprenorphine’s partial agonism reduces this effect compared with full ORL1-agonists such as morphine or fentanyl. Buprenorphine’s antagonistic action at the δ-receptors which have a marked anti-opioid action and seem to negatively modulate central analgesia seems further to contribute to its clinically seen analgesic effect. Its likewise antagonistic activity at the κ-opioid receptors might explain the fact that it induces much less sedation and psychotomimetic effects than morphine or fentanyl (Lewis 1985; Leander 1988). Animal studies have shown that buprenorphine has a 20–40 times higher potency than morphine (Martin et al. 1976).

The strong binding of buprenorphine to the μ-opioid receptor has several consequences. Initial binding is relatively slow compared with other opioids such as fentanyl (Boas and Villiger 1985). However, the onset of analgesia is not dissimilar, since buprenorphine achieves effective analgesia at relatively low receptor occupancy (5%–10%) (Tyers 1980) and thus relatively low plasma concentrations of buprenorphine are sufficient to provide effective pain relief. The slow dissociation of buprenorphine from the receptor results in a long duration of effect and also confers another advantage in that when the drug is withdrawn an abstinence syndrome is rarely seen because of the long time taken for the drug to come off the receptor (Bickel et al. 1988).

1 Weinberg, D. S.; Inturrisi, C. E.; Reidenberg, B.; Moulin, D. E.; Nip, T. J.; Wallenstein, S.; Houde, R. W.; Foley, K. M. (1988). “Sublingual absorption of selected opioid analgesics”. Clinical pharmacology and therapeutics 44 (3): 335–342. PMID 2458208.
2. Eriksen, J.; Jensen, N. H.; Kamp-Jensen, M.; Bjarnø, H.; Friis, P.; Brewster, D. (1989). “The systemic availability of buprenorphine administered by nasal spray”. The Journal of pharmacy and pharmacology 41 (11): 803–805. PMID 2576057.
3. Suboxone EU Approval
4.DEA Rescheduling
5.What flavor do suboxone come in?. Kgbanswers.com (2012-09-06). Retrieved on 2013-05-19.
6.FDA Approval Letter to Roxane
7.Generic buprenorphine shortage
8.Reckitt Benckiser Announcement of Suboxone tablets withdrawal
9.Napp Pharmaceuticals
10.electronic Medicines Compendium (eMC) of UK medicines, Transtec product characteristics. Medicines.org.uk (2010-10-21). Retrieved on 2013-05-19.
11. “Butrans”, accessed January 23, 2011.
12. “Norspan Buprenorphine Drug/Medicine information”. news-medical.net
13.Addnok information
14. Tidigesic in India
15. Buprigesic in India
16.Probuphine complete response letter
17. Suboxone film patient information
18 Likar, R. (2006). “Transdermal buprenorphine in the management of persistent pain – safety aspects”. Therapeutics and clinical risk management 2 (1): 115–125. PMC 1661652. PMID 18360586.

Buprenorphine acts as a mixed agonist / antagonist and it is an important treatment option for opiate addiction and analgesia.
- Opiate compounds such as (-)-naltrexone, (-)-naloxone, (-)-nalbuphene, (-)-nalmefene, and (-)-buprenorphine have been used for addiction therapy. (-)-Buprenorphine, in particular, is increasingly being used for the treatment of heroin addiction. Recently, the (+)-opiate enantiomers have been shown to have important bioactivities that differ from their (-) counter parts. Because of the exceptional opiate medicinal activity of (-)-buprenorphine, there is great interest in the therapeutic efficacy of (+)-buprenorphine. In order to explore the possible benefits of this compound, there is a need in the art for synthetic routes to produce (+)-buprenorphine or its derivatives in an efficient and cost effective manner that generates a high yield of product having a high degree of purity.
- The following documents disclose processes for the preparation of buprenorphine:
  - D1: WO 2007/081506 A (MALLINCKRODT INC [US]) 19 July 2007 (2007-07-19)
  - D2: J. MARTON ET AL: “Herstellung von 6,14-Ethenomorphinan-Derivaten” LIEBIGS ANNALEN DER CHEMIE, 1993, pages 915-919, XP002519987
  - D1 discloses a process for the preparation of buprenorphine from oripavine.
  - D2 discloses a process
[0002]

The conventional synthetic route used world-wide to prepare buprenorphine utilizes thebaine as the starting material.
[0003]

Through a series of chemical reactions, thebaine is converted into nor-buprenorphine, the immediate precursor to buprenorphine. The final step adds a cyclopropyl methyl group to the nitrogen to form buprenorphine from nor-buprenorphine.
[0004]
An outline of the conventional series of reactions from thebaine to buprenorphine follows:
1. 1. Reaction of thebaine with methyl vinyl ketone to form the 4 + 2 reaction product.
2. 2. Hydrogenation of the carbon-carbon double bond.
3. 3. Addition of a tertiary butyl group via a Grignard Reaction.
4. 4. An N-demethylation, via a two step reaction sequence.
5. 5. An O-demethylation reaction and an N-cyano hydrolysis.
6. 6. Addition of the cyclopropyl methyl group to form buprenorphine.
[0005]

A drawback of this conventional production scheme is that the O-demethylation step is considered a low to moderate yield transformation. There is therefore a need for a norbuprenorphine/buprenorphine production scheme that does not include an O-demethylation step.
[0006]

Processes for preparing Bupremorphine or Bupremorphine derivatives are disclosed in EP1439179 , US5849915 and Chem. Commun., 16, 2002, 1762-1763

[0007]
An aspect of the present invention is to provide a method for producing norbuprenorphine utilizing oripavine as the starting material. The method comprises:
- reacting oripavine according to Formula I with methyl vinyl ketone to form a compound according to Formula II;
- hydrogenating the compound according to Formula II to form a compound according to Formula III;
- adding a t-butyl group to the compound according to Formula III to form a compound according to Formula X; and
- demethylating the nitrogen of the compound according to Formula X to form norbuprenorphine, Formula VIII.
[0008]

Another aspect of the present invention is to provide a method of making buprenorphine utilizing oripavine as the starting material.

[0009]

There is provided a method utilizing oripavine as the preferred starting material for the synthesis of nor-buprenorphine and optionally buprenorphine. Oripavine is a naturally occurring alkaloid of Papaver somniferum. The key difference between the conventional technology and the present use of oripavine as a starting material is that the O-demethylation step, typically a low to moderate yield transformation, is not needed since the oripavine molecule lacks an O-3 methyl group. In a synthesis involving several steps, it is advantageous to have only high yield reactions, in order for the overall transformation to be economical. Since the present oripavine based synthesis does not require the O-3 demethylation step, the overall yield from oripavine provides an improved yield over that traditionally achieved when thebaine is used as the starting material. The conversion route from oripavine to produce buprenorphine is convenient and more straightforward as compared to other synthetic routes.
[0010]

An illustrative embodiment of the steps for converting oripavine into norbuprenorphine, and optionally buprenorphine, is as follows:
[0011]

The sequence outlined above is an illustrative embodiment presented to show the transformations required, but is not limited as to the order in which the transformations may be employed. In an alternative embodiment, the hydrogenation of the Diels-Alder double bond can also be accomplished as part of step 7 when the removal of the Y protecting group is through catalytic hydrogenation.

Step 1:

[0012]

The first step involves reaction of the oripavine with methyl vinyl ketone. This addition reaction may be accomplished by any conventional method known in the art. An illustrative embodiment is a Diels-Alder reaction in which the oripavine and methyl vinyl ketone are dissolved in a solvent and refluxed until the reaction is substantially complete. Illustrative suitable solvents include isopropyl alcohol, methanol, ethanol, toluene and mixtures thereof. The reaction mixture is then filtered to isolate the Diels-Alder adduct solids. Typical reactions result in at least about an 85% yield of at least about 98% purity.

Step 2:

[0013]

The second step involves the hydrogenation of the C-C double bond. In an illustrative embodiment, the Diels-Alder adduct formed in step 1 was charged to a reaction vessel with Pd/ Carbon catalyst, then dissolved in a solvent. A presently preferred solvent is methanol, but any suitable solvent may be used, including methanol, ethanol, isopropyl alcohol, acetic acid and mixtures thereof. The hydrogenation takes place under nitrogen at an elevated pressure and temperature. The temperature and pressure are selected to insure substantial completion of the reaction, as is well known in the art. An illustrative temperature range typical of this reaction is about 50-90°C, with about 60°C being preferred and an illustrative pressure range typical of this reaction is about 20-60 psi, with about 35 psi being preferred. The reaction mixture is filtered to remove the catalyst and the resulting filtrate reduced under vacuum to yield the product according to Formula III.

Step 3:

[0014]

Optional step 3 discloses the addition of a protecting group Y to form a compound according to Formula IV. The preferred method using oripavine as the starting material for norbuprenorphine and then buprenorphine utilizes an O-3 protecting group. However, the reaction can be accomplished without the use of the protection group, although the overall yield may be compromised. Further, the protecting group may be removed simultaneously with another step thereby eliminating one chemical step. Addition of an O-3 protecting group may minimize unwanted chemical reactions involving the unprotected phenol function at the 3-position. Illustrative suitable protecting groups include benzyl, O-t-butyl and silyl groups.
[0015]

In an illustrative embodiment, the reduced Diels-Alder adduct according to Formula III and ground K₂CO₃ are added (K₂CO₃ not soluble) in chloroform and benzyl bromide, heated and refluxed. After cooling to room temperature, the reaction mixture is filtered to remove the K₂CO₃. The filtrate is then reduced under vacuum and azeo dried in toluene.

Step 4:

[0016]

The fourth step utilizes the crude material according to Formula IV, formed in step 3. in a Grignard reaction. Under moisture free conditions and further under an inert atmosphere, t-BuMgCl is added, followed by anhydrous toluene. The solution is distilled until a pot temperature of about 100 °C is achieved, and the compound according the Formula IV is added. The reaction is quenched, and the temperature of the reaction mixture lowered. The organic and aqueous layers are separated, and the organic layer is concentrated under vacuum yielding an oily residue. The oily residue is then purified resulting in a compound according to Formula V, of up to about 93% purity.
[0017]

In an alternate embodiment, the t-butyl group is added using a t-butyl lithium reagent, as is well known in the art.
[0018]

The N-demethylation reaction may be accomplished by any suitable method known in the art. In the illustrative embodiment shown in steps 5 and 6, the methyl group is first converted into a nitrite in step 5, followed by reduction of the nitrile group in step 6.

Step 5:

[0019]

In an illustrative embodiment of step 5, the tertiary alcohol starting material according to Formula V is dissolved in a solvent, flushed with an inert atmosphere, and then K₂CO₃ and cyanogen bromide are added. This reaction mixture is then refluxed until the reaction is substantially complete, cooled to room temperature and filtered to remove the K₂CO₃. The reaction mixture is then extracted and the organic layers reduced and dried under vacuum. The resulting solid is purified yielding up to about 93% clean material after drying.

Step 6:

[0020]

In an illustrative embodiment, potassium hydroxide is dissolved in diethylene glycol and heated. The N-CN compound according to Formula VII is added and the reaction mixture heated until the reaction is substantially complete. After cooling to room temperature, distilled water is added and the resulting solid collected and dried, with up to about 100% yield.
[0021]

The N-demethylation may be accomplished by any method know to those skilled in the art without departing from the instant method.

Step 7:

[0022]

The seventh step involves the removal of the optional protecting group. In the illustrative embodiment, the Y protecting group added in step 3 is removed. In this embodiment, the secondary amine starting material may be catalytically removed by Pd/Carbon in a suitable , solvent. Suitable solvents include methanol, ethanol, isopropyl acetate and mixtures thereof. The resulting filtrate is dried under vacuum to yield norbuprenorphine. In another embodiment, the Y protecting group may be removed with an acid, such as HCl, HOAc, HF or an F anion.

Step 8:

[0023]

Finally the norbuprenorphine is optionally converted to buprenorphine as illustrated in step 8. In an illustrative embodiment, the norbuprenorphine is converted to buprenorphine.
[0024]

In an illustrative embodiment, a mixture of norbuprenorphine, a mild base, and cyclopropylmethyl bromide are heated in an oilbath at about 80-100°C until the reaction is substantially complete. The reaction mixture is then added over 5 minutes to 160ml of water, with mechanical stirring, yielding a gum. The mixture is stirred and filtered, and the filter cake is washed with water. The HPLC will show about 90% by area of desired product, and 0.2-0.5% of an N-butenyl substituted impurity. The resulting product is dried, and then boiled in alcohol, cooled, and filtered to yield buprenorphine.
[0025]

In the alternative, norbuprenorphine can be converted to buprenorphine by reductive amination, or by acylation followed by reduction of the amide.
[0026]

In an alternative embodiment, the hydrogenation step 2 is performed on the crude reaction mixture formed in step 1, thereby providing a one-pot reaction scheme for forming a compound according to Formula III.
[0027]

The oripavine, methyl vinyl ketone and isopropyl alcohol are heated under pressure. Upon cooling, a Pd-C catalyst is added, and the reaction mixture is heated under pressure until the reaction is substantially complete. The product is then solubilized and the catalyst removed by filtration. The filtrate is then concentrated under vacuum.
[0028]

In another alternative embodiment, illustrated below, a method for producing norbuprenorphine, and optionally buprenorphine, from oripavine, without the use of a protecting group on O-3. The individual reactions are as discussed in more detail above.
[0029]
The method comprises:
1. a) reacting the oripavine according to Formula I with methyl vinyl ketone to form a compound according to Formula II;
2. b) hydrogenating the compound according to Formula II to form a compound according to Formula III;
3. c) adding a t-butyl group to the compound according to Formula III to form a compound according to Formula X; and
4. d) demethylating the nitrogen of the compound according to Formula X to form norbuprenorphine, Formula VIII.
………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………….

WO 2009078986 A1

Th invention provides processes and intermediate compounds for producing buprenorphine. In particular, the process encompasses synthetic routes for the production of buprenorphine or derivatives of buprenorphine from norhydromorphone or derivatives of norhydromorphone. While it is envisioned that the synthetic routes described herein may be utilized to produce (+/-)-buprenorphine, in an exemplary aspect of the invention, the process encompasses the production of (+)-buprenorphine or derivatives of (+)-buprenorphine.

For purposes of illustration, Reaction Scheme 1 depicts the production of compound 8 from compound 1 in accordance with one aspect of the present invention:

………………………………………………………………………………………………………………………………………………………

VALSARTAN

September 24, 2013 8:00 am / Leave a comment

VALSARTAN

CAS 137862-53-4

Molecular FormulaC₂₄H₂₉N₅O_{3, A}verage mass435.519 Da

(2S)-3-methyl-2-[N-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)pentanamido]butanoic acid

PAPER

Greening the Valsartan Synthesis: Scale-up of Key Suzuki–Miyaura Coupling over SiliaCat DPP-Pd

Valerica Pandarus †, Delphine Desplantier-Giscard†, Geneviève Gingras , François Béland †*, Rosaria Ciriminna ‡, and Mario Pagliaro ‡*

^† SiliCycle Inc., 2500 Parc-Technologique Blvd, Quebec City, Quebec, Canada G1P 4S6

^‡ Istituto per lo Studio dei Materiali Nanostrutturati, CNR, via U. La Malfa 153, 90146 Palermo, Italy

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/op400118f

Publication Date (Web): June 17, 2013

http://pubs.acs.org/doi/full/10.1021/op400118f

The study of the scale-up of the heterogeneous Suzuki-Miyaura coupling reaction in batch conditions between 2-chlorobenzonitrile and 4-tolylboronic acid, a key step in valsartansynthesis, to produce 4′-methyl-2-biphenylcarbonitrile over the SiliaCat DPP-Pd catalyst in ethanol under reflux allows to identify the optimal reaction conditions.

The catalyst, regardless of limited Pd leaching, is not reusable, and the method can be effectively applied to the high yield synthesis of several coupling products, opening the route to efficient continuous coupling syntheses.

http://pubs.acs.org/doi/full/10.1021/op400118f

ABOUT VALSARTAN

Valsartan (Angiotan or Diovan) is an angiotensin II receptor antagonist (more commonly called an “ARB”, or angiotensin receptor blocker), with particularly high affinity for the type I (AT₁) angiotensin receptor. By blocking the action of angiotensin, valsartan dilates blood vessels and reduces blood pressure.^[1] In the U.S., valsartan is indicated for treatment ofhigh blood pressure, congestive heart failure (CHF), or post-myocardial infarction (MI).^[2] In 2005, Valsartan was prescribed more than 12 million times in the United States^{[citation needed]} and global sales were approximately $6.1 billion in 2010.^[3] The patents for valsartan and valsartan/hydrochlorothiazide expired in September 2012.^[4]^[5]

A study released in 2010, based on 819,491 cases in U.S. Department of Veterans Affairs database from 2002 to 2006, demonstrated a significant reduction in the incidence and progression of Alzheimer’s disease and dementia.^[6] An earlier study released by theJournal of Clinical Investigation in 2007 found some efficacy in the use of valsartan in the treatment and prevention of Alzheimer’s disease (in a mouse model).^[7]

Valsartan, also known as (S)—N-(1-Carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)bi phenyl-4-ylmethyl]-amine, has the following structure:

and is marketed as the free acid under the name DIOVAN. DIOVAN is prescribed as oral tablets in dosages of 40 mg, 80 mg, 160 mg and 320 mg of valsartan.

Valsartan and/or its intermediates are disclosed in various references, including: U.S. Pat. Nos. 5,399,578, 5,965,592, 5,260,325, 6,271,375, WO 02/006253, WO 01/082858, WO 99/67231, WO 97/30036, Peter Bühlmayer, et. al., Bioorgan. & Med. Chem. Let., 4(1) 29–34 (1994), Th. Moenius, et. al., J. Labelled Cpd. Radiopharm., 43(13) 1245–1252 (2000), and Qingzhong Jia, et. al., Zhongguo Yiyao Gongye Zazhi, 32(9) 385–387 (2001).

Valsartan is an orally active specific angiotensin II antagonist acting on the AT1 receptor subtype. Valsartan is prescribed for the treatment of hypertension. U.S. Pat. No. 6,395,728 is directed to use of valsartan for treatment of diabetes related hypertension. U.S. Pat. Nos. 6,465,502 and 6,485,745 are directed to treatment of lung cancer with valsartan. U.S. Pat. No. 6,294,197 is directed to solid oral dosage forms of valsartan.

The synthesis of valsartan is discussed, inter alia, in U.S. Pat. No. 5,399,578. In the synthesis disclosed therein, the final synthetic step (exclusive of work-up and purification) involves the reaction of a cyano group on the biphenyl ring with an azide, for example, tributyl tin azide. The reaction scheme of the ‘578 patent is as follows:

Peter Bühlmayer, et. al., Bioorgan. & Med. Chem. Let., 4(1) 29–34 (1994)

In Moenius, et. al., J. Labelled Cpd. Radiopharm., 43(13) 1245–1252 (2000), various schemes for synthesis of valsartan are provided, with one being:

Another paper, Qingzhong Jia, et. al., Zhongguo Yiyao Gongye Zazhi, 32(9) 385–387 (2001), discloses a synthesis scheme for valsartan as follows:

There is a need in the art for an improved synthetic process for the preparation of valsartan and precursors of valsartan.

DOSE
Oral tablets, containing 40 mg (scored), 80 mg, 160 mg, or 320 mg of valsartan. Usual dosage ranges from 40–320 mg daily.

In some markets available as a hard gelatin capsule, containing 40 mg, 80 mg, or 160 mg of valsartan.

Diovan HCT contains a combination of valsartan and hydrochlorothiazide but, unlike Diovan, is only indicated for hypertension, not for CHF or post-MI. Diovan HCT is available in oral tablets, containing (valsartan/HCTZ mg) 80/12.5, 160/12.5, 160/25, 320/12.5, and 320/25.

Whether angiotensin receptor blockers may or may not increase the risk of myocardial infarction (heart attack) was announced in BMJ^[8] and was debated in 2006 in the medical journal of the American Heart Association.^[9]^[10] To date^[when?], there is no consensus on whether ARBs have a tendency to increase MI, but there is also no substantive evidence to indicate that ARBs are able to reduce MI.

In the VALUE trial, the angiotensin II receptor blocker valsartan produced a statistically significant 19% (p=0.02) relative increase in the prespecified secondary end point of myocardial infarction (fatal and non-fatal) compared with amlodipine.^[11]

The CHARM-alternative trial showed a significant +52% (p=0.025) increase in myocardial infarction with candesartan (versus placebo) despite a reduction in blood pressure.^[12]

Indeed, as a consequence of AT1 blockade, ARBs increase Angiotensin II levels several-fold above baseline by uncoupling a negative-feedback loop. Increased levels of circulating Angiotensin II result in unopposed stimulation of the AT2 receptors, which are, in addition upregulated. Unfortunately, recent data suggest that AT2 receptor stimulation may be less beneficial than previously proposed and may even be harmful under certain circumstances through mediation of growth promotion, fibrosis, and hypertrophy, as well as proatherogenic and proinflammatory effects.^[13]^[14]^[15]

In patients with impaired glucose tolerance, valsartan may decrease the incidence of developing diabetes mellitus type 2.^[16] However, the absolute risk reduction is small (less than 1 percent per year) and diet, exercise or other drugs, may be more protective. In the same study, no reduction in the rate of cardiovascular events (including death) was shown.

Most commonly, headache and dizziness.
Sometimes fatigue^[17]

There is a case report of a stillbirth in which valsartan is implicated.^[18]In the US, UK and Australia, valsartan is marketed by Novartis under the trade name Diovan. In Pakistan, it is marketed by Efroze under the trade name Angiotan. In India, it is marketed by Cipla under the trade name Valtan and by Torrent Pharmaceuticals under the trade name Valzaar. In Egypt and in France, it is marketed by Novartis under the name of Tareg. In Ukraine, it is marketed by Фарма Старт under the trade name Диокор, Диокор Соло

Marks JW (2007-02-15). “Valsartan, Diovan”. MedicineNet. Retrieved 2010-03-04.
“Diovan prescribing information”. Novartis.
J “Novartis Annual Report”. Novartis. 2010. Retrieved June 15, 2011.
Philip Moeller (April 29, 2011). “Blockbuster Drugs That Will Go Generic Soon”. U.S.News & World Report.
Eva Von Schaper (August 5, 2011). “Novartis’s Jimenez Has Blockbuster Plans For Diovan After Patent Expires”. Bloomberg.
Li NC, Lee A, Whitmer RA, et al. (January 2010). “Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis”. BMJ 340: b5465. doi:10.1136/bmj.b5465.PMC 2806632. PMID 20068258.
Wang J, Ho L, Chen L, et al. (November 2007). “Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease” (PDF). J. Clin. Invest. 117 (11): 3393–402. doi:10.1172/JCI31547.PMC 2040315. PMID 17965777. Retrieved 2009-11-11.
Verma S, Strauss M (November 2004). “Angiotensin receptor blockers and myocardial infarction: These drugs may increase myocardial infarction—and patients may need to be told”. BMJ329 (7477): 1248–9. doi:10.1136/bmj.329.7477.1248.PMC 534428. PMID 15564232.
Strauss MH, Hall AS (August 2006). “Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox”. Circulation 114 (8): 838–54.doi:10.1161/CIRCULATIONAHA.105.594986.PMID 16923768.
Tsuyuki RT, McDonald MA (August 2006). “Angiotensin receptor blockers do not increase risk of myocardial infarction”. Circulation 114 (8): 855–60.doi:10.1161/CIRCULATIONAHA.105.594978.PMID 16923769.
Julius S, Kjeldsen SE, Weber M, et al. (June 2004). “Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial”. The Lancet 363 (9426): 2022–31.doi:10.1016/S0140-6736(04)16451-9. PMID 15207952.
Granger CB, McMurray JJ, Yusuf S, et al. (September 2003). “Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial”. The Lancet 362 (9386): 772–6.doi:10.1016/S0140-6736(03)14284-5. PMID 13678870.
Levy BI (September 2005). “How to explain the differences between renin angiotensin system modulators”. Am. J. Hypertens. 18 (9 Pt 2): 134S–141S.doi:10.1016/j.amjhyper.2005.05.005. PMID 16125050.
Levy BI (January 2004). “Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system”. Circulation 109 (1): 8–13.doi:10.1161/01.CIR.0000096609.73772.C5.PMID 14707017.
Reudelhuber TL (December 2005). “The continuing saga of the AT2 receptor: a case of the good, the bad, and the innocuous”. Hypertension 46 (6): 1261–2.doi:10.1161/01.HYP.0000193498.07087.83.PMID 16286568.
McMurray JJ, Holman RR, Haffner SM, et al. (April 2010).“Effect of valsartan on the incidence of diabetes and cardiovascular events” (PDF). The New England Journal of Medicine 362 (16): 1477–90. doi:10.1056/NEJMoa1001121.PMID 20228403.
Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag.ISBN 3-85200-196-X.
Briggs GG, Nageotte MP (2001). “Fatal fetal outcome with the combined use of valsartan and atenolol”. The Annals of Pharmacotherapy 35 (7–8): 859–61. doi:10.1345/aph.1A013.PMID 11485133.

UPDATE……

VALSARTAN

mp 114–118 °C;

¹H NMR (400 MHz, DMSO-d₆): δ 12.6 (brs, 1H), 7.72 (m, 4H), 7.24 (m, 1H), 7.15 (m, 2H), 6.94 (m, 1H), 4.58 (m, 1H), 4.40 (m, 1H), 3.33 (m, 1H), 2.25 (m, 1H), 1.52 (m, 6H), 0.9 (m, 3H), 0.84 (m, 3H), 0.74 (m, 3H);

¹³C NMR (100 MHz, DMSO-d₆): δ 174.0, 172.4, 171.8, 141.7, 138.2, 131.54, 131.1, 131.0, 129.3,128.8, 128.2, 127.4, 126.7, 70.3, 63.4, 49.9, 32.9, 28.05, 27.3, 22.2, 20.6, 14.2;

ESIMS: m/z calcd [M]⁺: 435; found: 436 [M+H]⁺; HRMS (ESI): m/z calcd [M]⁺: 435.5187; found: 435.5125 [M]⁺^{US 7439261 B2}

^{¹H-NMR (CDCl₃) (0.80-1.15 (m, 9H); 1.20-1.50 (m, 2H); 1.60-1.80 (m, 2H); 2.60 (t, 2H); 2.65-2.80 (m, 2H), 3.70 (d, 1H), 4.10 (d, 0.3 H), 4.30 (d, 0.7 H), 4.90 (d, 0.7H), 5.2 (d, 0.3H); 7.00 (d, 0.3H); 7.10-7.20 (m, 4H), 7.40-7.60 (m, 3H), 7.85 (d, 0.7 H).}^{SHORT DESCRIPTION}

Valsartan, N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-valine, is a known anti-hypertensive agent having the following formula (I):

Valsartan and its preparation are disclosed in U.S. Pat. No. 5,399,578, in particular in Example 16. One of the synthetic routes according to U.S. Pat. No. 5,399,578 can be schematically represented as follows:

The synthetic pathway comprises various steps, among which:

- coupling of compound (3) with 2-chlorobenzonitrile to obtain compound (4),
- radicalic bromination of compound (4) to give compound (5),
- transformation of the brominated derivative (5) into the respective aldehyde derivative (6),
- reductive alkylation of compound (6) to obtain intermediate (8),
- acylation of compound (8) to obtain intermediate (9),
- conversion of the cyano group to the tetrazole group to afford intermediate (10),
- deprotection of the carboxylic group by hydrogenolysis to obtain valsartan.

It is marketed as the free acid under the name DIOVAN. DIOVAN is prescribed as oral tablets in dosages of 40 mg, 80 mg, 160 mg and 320 mg ofvalsartan.
[0004]

Valsartan and/or its intermediates are disclosed in various references, including: U.S. Pat. Nos. 5,399,578 ,5,965,592 , 5,260,325 , 6,271,375 , WO 02/006253 , WO 01/082858 , WO 99/67231 , WO 97/30036 , Peter Bühlmayer, et. al., Bioorgan. & Med. Chem. Let., 4(1) 29-34 (1994), Th. Moenius, et. al., J. Labelled Cpd. Radiopharm., 43(13) 1245 – 1252 (2000), and Qingzhong Jia, et. al., Zhongguo Yiyao Gongye Zazhi, 32(9) 385-387 (2001), all of which are incorporated herein by reference.
[0005]

Valsartan is an orally active specific angiotensin II antagonist acting on the AT1 receptor subtype. Valsartan is prescribed for the treatment of hypertension. U.S. Pat. No. 6,395,728 is directed to use of valsartan for treatment of diabetes related hypertension. U.S. Pat. Nos. 6,465,502 and 6,485,745 are directed to treatment of lung cancer with valsartan. U.S. Pat. No. 6,294,197 is directed to solid oral dosage forms of valsartan

GOOD ARTICLES

http://users.uoa.gr/~tmavrom/2009/valsartan2009.pdf

http://www.acgpubs.org/JCM/2009/Volume%203/Issue%201/JCM-0908-14.pdf

https://www.beilstein-journals.org/bjoc/single/printArticle.htm?publicId=1860-5397-6-27 REPORTS

mp 114–118 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 12.6 (brs, 1H), 7.72 (m, 4H), 7.24 (m, 1H), 7.15 (m, 2H), 6.94 (m, 1H), 4.58 (m, 1H), 4.40 (m, 1H), 3.33 (m, 1H), 2.25 (m, 1H), 1.52 (m, 6H), 0.9 (m, 3H), 0.84 (m, 3H), 0.74 (m, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 174.0, 172.4, 171.8, 141.7, 138.2, 131.54, 131.1, 131.0, 129.3,128.8, 128.2, 127.4, 126.7, 70.3, 63.4, 49.9, 32.9, 28.05, 27.3, 22.2, 20.6, 14.2; ESIMS: m/z calcd [M]⁺: 435; found: 436 [M+H]⁺; HRMS (ESI): m/z calcd [M]⁺: 435.5187; found: 435.5125 [M]⁺

Valsartan

Structural formula

UV – Spectrum

The solvent designation schedule	methanol	water	0.1М HCl	0.1M NaOH

Conditions : Concentration – 1 mg / 100 ml
maximum absorption	249 nm	250 nm	248 nm	251 nm
	309	302	289	311
e	13400	13100	12600	13500

IR – spectrum

Wavelength (μm)

Wave number (cm ^-1 )

References

UV and IR Spectra. H.-W. Dibbern, R.M. Muller, E. Wirbitzki, 2002 ECV
NIST/EPA/NIH Mass Spectral Library 2008
Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman. Academic Press, 2000.
Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

^CLIP

^{Scheme 2: (a) Et3N, CH2Cl2, 0 °C, 95%; (b) NaH, THF, 70%; (c) n-BuLi, 25 °C, THF, anhyd ZnCl2, −20 °C, Q-phos, Pd(OAc)2, 75 °C, 2 h, 80%; (d) 3 N NaOH, MeOH, reflux, 90%.}

^{http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-6-27}

^{valsartan 8; mp 114–118 °C; 1H NMR (400 MHz, DMSO-d6): δ 12.6 (brs, 1H), 7.72 (m, 4H), 7.24 (m, 1H), 7.15 (m, 2H), 6.94 (m, 1H), 4.58 (m, 1H), 4.40 (m, 1H), 3.33 (m, 1H), 2.25 (m, 1H), 1.52 (m, 6H), 0.9 (m, 3H), 0.84 (m, 3H), 0.74 (m, 3H); 13C NMR (100 MHz, DMSO-d6): δ 174.0, 172.4, 171.8, 141.7, 138.2, 131.54, 131.1, 131.0, 129.3,128.8, 128.2, 127.4, 126.7, 70.3, 63.4, 49.9, 32.9, 28.05, 27.3, 22.2, 20.6, 14.2; ESIMS: m/z calcd [M]+: 435; found: 436 [M+H]+; HRMS (ESI): m/z calcd [M]+: 435.5187; found: 435.5125 [M]+}

PAPER

An Improved Synthesis of Valsartan

Guo-xi Wang*, Bao-ping Sun, and Cong-hu Peng

Department of Chemical Engineering, Anyang Institute of Technology, Anyang 455000, China

Org. Process Res. Dev., 2011, 15 (5), pp 986–988

DOI: 10.1021/op200032b

Publication Date (Web): July 5, 2011

njuwgx@yahoo.com.cn.

Abstract

Biphenyltetrazole group, an important component of sartans, is usually formed in excellent yield by the reaction of 4′-alkylbiphenyl-2-carbonitrile with excessive organotin azide. However, it is restricted in industrial scale because of the difficult post-treatment. In this article, an improved synthetic method for valsartan and the quantitative recovery of tri-n-butyltin chloride are reported. During this process, the tetrazole–Sn complex and excessive organotin azide were decomposed by HCl to furnish tri–n-butyltin chloride, and then reacted with NaF to lead to filterable polymer tributyltin fluoride which was converted again to tributyltin chloride by HCl in ethyl acetate. This approach is facile for the efficient manufacture of sartans using organotin azide to form the tetrazole group and is valuable for industry readers.

http://pubs.acs.org/doi/suppl/10.1021/op200032b

valsartan (1) (6.5 g, HPLC, 99.7%) as a white crystalline powder with a yield of 72.5% calculated on valstartan benzyl ester (2), mp 113117 C (lit.:14 mp 105115 C, from ethyl acetate). ESI-MS (-p): 434.32. HPLC purity 99.62%, ee =100% (OD-H, mobile phase: n-hexane and isopropyl alcohol in the ratio of 850:150). [R] 20 D = () 67.2 (1% w/v in methanol).

1 H NMR (DMSO-d6) δ: 0.690.94 (m, 9H), 1.101.20 (m, 1H), 1.281.58 (m, 3H), 1.982.10 (m, 1H), 2.172.50 (m, 2H), 4.074.63 (m, 3H), 6.967.21(m, 4H), 7.517.71 (m, 4H), 12.69 (br, 1H), 16.29 (br, 1H).

IR (KBr) νmax/cm1 : 3446(br, w), 3060(w), 2963(s), 2932(m), 2873(m), 2744(w), 2612(w), 1732(s), 1604(s), 1471(s), 1410(m), 1390(w), 1354(w), 1273(w), 1204(m), 1166(m), 1129(w), 1105(w), 1065(w), 1052(w), 1025(w), 996(w), 939(w), 901(w), 852(w), 822(w), 777(w), 760(m), 682(w), 670(w), 624(w), 559(w).

HPLC Conditions for Enantiomer Purity of Valsartan are listed below. Instrument: Water, Breeze 2 Column: Chiralcel OD-H Detection: UV, 220 nm Flow: 0.8 mL/min Injection volume: 10 µL Run time: 30 min Mobile phase: the ratio of n-hexane and isopropyl alcohol is 850:150 Retention time of valsartan: ∼12 min The enantiomeric purity of the crystallized Valsartan prepared in our experiments is nearly 100%. The peak occurred in 4 min can be attributed to the solvent peak in dead time.

Diovan (valsartan) is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the AT₁ receptor subtype.

Valsartan is chemically described as N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4- yl]methyl]-L-valine. Its empirical formula is C₂₄H₂₉N₅O₃, its molecular weight is 435.5, and its structural formula is:

DIOVAN (valsartan) Structural Formula Illustration

Valsartan is a white to practically white fine powder. It is soluble in ethanol and methanol and slightly soluble in water.

Diovan is available as tablets for oral administration, containing 40 mg, 80 mg, 160 mg or 320 mg of valsartan. The inactive ingredients of the tablets are colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides (yellow, black and/or red), magnesium stearate, microcrystalline cellulose, polyethylene glycol 8000, and titanium dioxide.

Valsartan
Systematic (IUPAC) name


(S)-3-methyl-2-(N-{[2′-(2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid
Clinical data
Trade names	Diovan
AHFS/Drugs.com	Monograph
MedlinePlus	a697015
License data	US FDA: Valsartan
Pregnancy category	US: D (Evidence of risk)
Routes of administration	oral
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	25%
Protein binding	95%
Biological half-life	6 hours
Excretion	Renal 30%, biliary 70%
Identifiers
CAS Number	137862-53-4
ATC code	C09CA03 (WHO)
PubChem	CID 60846
IUPHAR/BPS	3937 tritiated: 593
DrugBank	DB00177
ChemSpider	54833
UNII	80M03YXJ7I
KEGG	D00400
ChEBI	CHEBI:9927
ChEMBL	CHEMBL1069
Chemical data
Formula	C₂₄H₂₉N₅O₃
Molar mass	435.519 g/mol
3D model (Jmol)	Interactive image

Valsartan

CAS Registry Number: 137862-53-4

CAS Name: N-(1-Oxopentyl)-N-[[2¢-(1H-tetrazol-5-yl)[1,1¢-biphenyl]-4-yl]methyl]-L-valine

Additional Names: N-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-N-valeryl-L-valine; (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2¢-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]amine

Manufacturers’ Codes: CGP-48933

Trademarks: Diovan (Novartis); Tareg (Novartis)

Molecular Formula: C24H29N5O3

Molecular Weight: 435.52

Percent Composition: C 66.19%, H 6.71%, N 16.08%, O 11.02%

Literature References: Nonpeptide angiotensin II AT1-receptor antagonist. Prepn: P. Bühlmayer et al., EP 443983; eidem, US5399578 (1991, 1995 both to Ciba Geigy); idem et al., Bioorg. Med. Chem. Lett. 4, 29 (1994). Pharmacological profile: L. Criscione et al., Br. J. Pharmacol. 110, 761 (1993). HPLC determn in human plasma: A. Sioufi et al., J. Liq. Chromatogr. 17, 2179 (1994). Clinical pharmacology: P. Müller et al., Eur. J. Clin. Pharmacol. 47, 231 (1994). Clinical comparison with captopril, q.v., in high risk patients following myocardial infarction: M. A. Pfeffer et al., N. Engl. J. Med. 349, 1893 (2003). Review of pharmacology and clinical experience in heart failure: R. Latini et al., Expert Opin. Pharmacother. 5, 181-193 (2004).

Properties: Crystals from diisopropyl ether, mp 116-117°. Partition coefficient (n-octanol/aq phosphate buffer): 0.033. Sol in water at 25°.

Melting point: mp 116-117°

Log P: Partition coefficient (n-octanol/aq phosphate buffer): 0.033

Therap-Cat: Antihypertensive.

Keywords: Angiotensin II Receptor Antagonist; Antihypertensive; Biphenyltetrazole Derivatives.

^////////

CCCCC(=O)N(CC1=CC=C(C=C1)C1=CC=CC=C1C1=NNN=N1)[C@@H](C(C)C)C(O)=O

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and is marketed as the free acid under the name DIOVAN. DIOVAN is prescribed as oral tablets in dosages of 40 mg, 80 mg, 160 mg and 320 mg of valsartan.

DOSE Oral tablets, containing 40 mg (scored), 80 mg, 160 mg, or 320 mg of valsartan. Usual dosage ranges from 40–320 mg daily.

Valsartan

Structural formula

UV – Spectrum

IR – spectrum

References

An Improved Synthesis of Valsartan

Abstract

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DOSE
Oral tablets, containing 40 mg (scored), 80 mg, 160 mg, or 320 mg of valsartan. Usual dosage ranges from 40–320 mg daily.