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Palbociclib

January 5, 2014 3:20 am / 2 Comments on Palbociclib

PALBOCICLIB

Mechanism of action: selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6
Indication: Estrogen receptor-positive (ER+), HER2-negative (HER2 -) breast cancer
Current Status: Phase III (US, UK, EU), (US Clinical trials numbers NCT01864746,NCT01740427, NCT01942135)
Expected Launch Date: 2015
Potential Sales(peak):$5 billion
Company:Pfizer

CHEMICAL NAMES
1. Pyrido[2,3-d]pyrimidin-7(8H)-one, 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-
piperazinyl)-2-pyridinyl]amino]-
2. 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-
yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one
MOLECULAR FORMULA C24H29N7O2
MOLECULAR WEIGHT 447.5
TRADEMARK None as yet
SPONSOR Pfizer Inc.
CODE DESIGNATION PD-0332991
CAS#: 571190-30-2 (PD0332991); 827022-32-2 (PD0332991 HCl salt) 827022-33-3 (palbociclib isethionate)

http://www.ama-assn.org/resources/doc/usan/palbociclib.pdf FOR STRUCTURE AND DETAILS

recent studies have identified a number of selective CDK4 inhibitors that, as discussed above, may prove useful in treating cancer—either as anti-cancer agents or as chemoprotective agents—and in treating cardiovascular disorders, such as restenosis and atherosclerosis, diseases caused by infectious agents, and autoimmune disorders, including rheumatoid arthritis. For a disclosure of these selective CDK4 inhibitors, see commonly assigned International Patent Application PCT/IB03/00059, filed Jan. 10, 2003 (the ‘059 application), which is herein incorporated by reference in its entirety for all purposes.

The ‘059 application discloses a particularly potent and selective CDK4 inhibitor, 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one:

In standard enzyme assays the compound of Formula 1 exhibits IC₅₀concentrations for CDK4 and CDK2 inhibition (at 25° C.) of 0.011 μM and >5 μM, respectively. For a discussion of standard CDK4 and CDK2 assays for IC₅₀determinations, see D. W. Fry et al., J. Biol. Chem. (2001) 16617-16623.

Though the compound of Formula 1 is a potent and selective CDK4 inhibitor, its use in pharmaceutical products presents challenges. For example, the free base has poor water solubility (9 μg/mL) and exhibits low bioavailability in animal studies. A di-HCl salt of the compound of Formula 1 appears to exhibit adequate water solubility. However, moisture uptake studies reveal that, even at low relative humidity (10% RH), the di-HCl salt absorbs water in an amount greater than about 2% of its mass, making it unsuitable for use in a solid drug product. A mono-HCl salt of the compound of Formula 1 is marginally hygroscopic, absorbing more than 2% of its mass at a relative humidity above 80%. However, the process for preparing the mono-HCl salt yields partially crystalline drug substance, indicating potential problems with process scale-up. Other salt forms of the compound of Formula 1 are thus needed.

Pfizer’s breast cancer drug Palbociclib (PD-0332991), a first in the class oral inhibitor of cyclin-dependent kinases (CDK) 4 and 6, is widely seen by investors as Pfizer’s most valuable compound in late-stage development. The FDA awarded Palbociclib “breakthrough therapy designation” in April 2013 based on the preliminary phase 2 data showing palbociclib, combined with Novartis’ drug,Femara (Letrozole), stopped breast tumors progression for more than two years as compared with 7.5 months with letrozole alone. The phase 3 trial started in February 2013 and estimated final completion date is March 2016. Leerink Swann analyst Seamus Fernandez forecasts palbociclib could become a $5 billion drug, with potential for $3 billion in first-line metastatic breast cancer alone.

Palbociclib, also known as PD0332991, is an orally available pyridopyrimidine-derived cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic activity. PD-0332991 selectively inhibits cyclin-dependent kinases (particularly Cdk4/cyclin D1 kinase), which may inhibit retinoblastoma (Rb) protein phosphorylation; inhibition of Rb phosphorylation prevents Rb-positive tumor cells from entering the S phase of the cell cycle (arrest in the G1 phase), resulting in suppression of DNA replication and decreased tumor cell proliferation. PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC50 = 0.011 μmol/L) and Cdk6 (IC50 = 0.016 μmol/L), having no activity against a panel of 36 additional protein kinases.

6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride (also referred to as “Compound 1”),

as well as its intermediates. Compound 1 is described in U.S. Pat. No. 6,936,612, the disclosure of which is hereby incorporated in its entirety. This compound is a protein kinase inhibitor and represents a synthetic, small molecule inhibitor capable of modulating cell cycle control.

A method of preparing Compound 1 is disclosed as Example 36 of U.S. patent application Ser. No. 6,936,612. Methods of preparing the isethionate salt forms of Compound 1 are disclosed in Examples 1-13 of WO 2005/005426. These methods are for synthesis of small quantities of the salt forms of Compound 1 and are not designed for commercial scale-up. Therefore, a preparation of the salt forms for CDK inhibitor 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride which is cost-efficient, scaleable and productive is highly desirable.

USAN (zz-153)

PALBOCICLIB ISETHIONATE
THERAPEUTIC CLAIM Antineoplastic
CHEMICAL NAMES
1. Ethanesulfonic acid, 2-hydroxy-, compd. with 6-acetyl-8-cyclopentyl-5-methyl-
2-[[5-(1-piperazinyl)-2-pyridinyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one (1:1)

2. 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-
yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one mono(2-hydroxyethanesulfonate)

MOLECULAR FORMULA C24H29N7O2 . C2H6O4S
MOLECULAR WEIGHT 573.7
SPONSOR Pfizer, Inc.
CODE DESIGNATIONS PD 0332991-0054, PF-00080665-73
CAS REGISTRY NUMBER 827022-33-3

PD 0332991-0054
PF-00080665-73
UNII-W1NYL2IRDR

SYNTHESIS

：WO2008032157

……………………………….

http://www.google.com/patents/US7781583

COMPARATIVE EXAMPLE 1A Preparation of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester

A suspension of 6-bromo-8-cyclopentyl-2-methansulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (10.00 g, 0.027 mol, prepared as in Example 6 of WO 01/707041, which is incorporated herein by reference) and 10.37 g (0.0373 mol) of 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester in toluene (100 mL) was heated under nitrogen in an oil bath for 7 hours. Thin layer chromatography (SiO₂, 10% MeOH/DCM) indicated the presence of both starting materials. The suspension was heated under reflux for an additional 18 hours. The resulting suspension was cooled to RT and filtered to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93 g, 38%). Melting point>250° C. MS (APCI) M⁺+1: calc’d, 584.2, found, 584.2.

COMPARATIVE EXAMPLE 1B Preparation of 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester

A suspension of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93 g, 0.010 mol, prepared as in Example 1A), tetrakis(triphenylphosphine)palladium(0) (1.40 g, 0.00121 mol), and tributyl(1-ethoxyvinyl)tin (5.32 mL, 0.0157 mol) in toluene (30 mL) was heated under reflux for 3.5 hours. The mixture was cooled and filtered to give a solid. Purification of the solid by silica gel chromatography using a gradient of 5%-66% ethyl acetate/hexane over 15 minutes gave 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow foam (4.50 g, 78%). MS (APCI) M⁺+1: calc’d 576.2, found, 576.3.

COMPARATIVE EXAMPLE 1C Preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride

Hydrogen chloride gas was bubbled into an ice-bath cooled solution of 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (4.50 g, 0.00783 mol, prepared as in 2005-0059670A1) in DCM (100 mL). The resulting suspension was stoppered and stirred at RT overnight, then diluted with diethyl ether (200 mL). The solid was collected by filtration, washed with diethyl ether, and dried to give the hydrochloride salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (4.01 g, 92%). Melting point 200° C. HPLC, C18 reverse phase, 10%-95% gradient of 0.1% TFA/CH₃CN in 0.1% TFA/H₂O during 22 minutes: 99.0% at 11.04 minutes. MS (APCI) M⁺+1: calc’d, 448.2, found, 448.3. Anal. calc’d for C₂₄H₂₉N₇O₂.2.4H₂O.1.85 HCl: C, 51.64; H, 6.44; N, 17.56, Cl (total), 11.75. Found: C, 51.31; H, 6.41; N, 17.20; Cl (total), 12.11.

EXAMPLE 2 Preparation of 4-(6-Nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester

EXAMPLE 2A Preparation of 4-(6-Nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester

To 1.0 kg (5 mol) 5-bromo-2-nitropyridine was added 1.2 kg (6.4 mol) boc piperazine (tert-Butyl piperazine-1-carboxylate) in 2.6 L DMSO and 0.5 kg triethylamine under nitrogen. The mixture was heated to 65-70° C. and held for 30 hours after which some solids precipitated. Water was added and the reaction cooled to 25° C. over 2 hrs. The resulting slurry was filtered, washed and dried at 45° C. to give 1.2 kg (79% crude yield) of canary yellow solid intermediate (2A), which was used without further purification in the subsequent step.

EXAMPLE 2 Preparation of 4-(6-Nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2)

60.0 g of 20% Pd(OH)₂/C, 1213.1 g (3.9 moles) of intermediate 2a, and isopropanol were charged and stirred in a Parr reactor, then purged under gas, followed by removal of the catalyst under pressure. The filtrates were concentrated in vacuo at ˜20° C. leaving 917 g of dry brown powder (crude yield ˜84%).

EXAMPLE 3 Preparation of 2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

EXAMPLE 3A Preparation of 5-bromo-2-chloro-4-cyclopentyl-aminopyrimidine

To 1 g (0.004 mol) of 5-bromo-2,4-dichloropyrimidine in ethanol was added 1.5 kg (0.018 mol) cyclopentylamine under nitrogen. The mixture was stirred at 25° C. for 2 hrs. Water was added to precipitate the product, and the solid was recrystallized using hexane 4:1 to give a white crystalline product (3A).

EXAMPLE 3 Preparation of 2-Chloro-8-Cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

41.5 g (0.15 mol) of 5-bromo-2-chloro-4-cyclopentylaminopyrimidine 3a and 32.3 g (0.375 mol) of crotonic acid were mixed in 100 L of THF and 105 ml (1.6 mol) diisopropyl ethylamine under nitrogen. The slurry was stirred, evacuated and refilled with nitrogen three times, after which 860 mg (0.0022 mol) palladium dichloride dibenzonitrile complex and 685 mg (0.0022 mol) tri-ortho-tolylphosphine were added and the resulting slurry degassed an additional three times. The mixture was then heated and stirred at 70° C. for 16 hrs, after which 35 ml acetic anhydride was added and the mixture stirred for an additional 1.5 hrs. The mixture was cooled and diluted with 100 ml MTBE and then extracted with 1NHCl, then aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered, concentrated in vacuo, and recrystallized from IPA to yield 31.2 g (68%) of crude product (3).

EXAMPLE 4 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester

EXAMPLE 4A Preparation of 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine-7-one

10 g (0.04 mol) of intermediate 3 and 13 g (0.16 mol) of sodium acetate were mixed with 50 ml of glacial acetic acid and 12 g (0.08 mol) bromine under nitrogen. The solution was heated to 50° C. and stirred for 35 hrs, then cooled to room temperature. Sodium bisulfite solids were added until the bromine color disappeared, then quenched, filtered and washed to provide a solid which was subsequently dissolved in 500 ml hot IPA, filtered hot, and cooled. The resulting crystals were further filtered, and dried in vacuo at 65° C. to yield 8 g (61%) of crude product (4A).

EXAMPLE 4 Preparation of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester

3.78 g (2.10 equiv; 13.6 mmoles) of intermediate 1, 25 ml toluene and lithium bis(trimethylsilyl)amide in 1 M THF (13.6 mmoles; 13.6 mL; 12.1 g) were mixed for 10 min under nitrogen to form a dark solution. In a separate beaker the intermediate 4a (1.00 equiv, 6.47 mmoles; 2.50 g) was slurried in toluene then added to the mixture containing 1 and stirred for 30 min, after which the combined mixture was quenched with 25 ml 1 M sodium bicarbonate and then filtered. Alternatively, the combined mixture can be quenched with ammonium chloride. The filter cake was washed with toluene, then acetone, then water and dried at 60° C. to give 3.5 g (92%) of a grey-yellow solid 4.

EXAMPLE 5 Preparation of 4-{6-[6-(1-butoxy-vinyl)-8-cycloentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester

768 g (1.3 mol) of intermediate 4, was mixed with 395 g (3.9 mol) of butyl vinyl ether, 4.7 L of n-butanol, and 275 ml (1.6 mol) diisopropyl ethylamine under nitrogen. The slurry was stirred and placed under ca. 50 tore vacuum and then refilled with nitrogen; this was repeated 2 more times. To this degassed solution was added 22 g (0.03 mol) Bis-(diphenylphosphinoferrocene)palladium dichloride dichloromethane complex and the resulting slurry was degassed an additional three times as described above. The mixture was then heated and stirred at 95° C. for 20 hrs. The resulting thin red slurry was diluted with 4 L branched octane’s and cooled to about 5° C. after which 1 L saturated aq. potassium carbonate was added and the mixture was filtered and rinsed with 500 ml branched octanes. After drying for 16 hrs at 45° C., 664 g (83%) of gray-solid product (5) was obtained. In addition, column chromatography can be used to further purify the crude product.

EXAMPLE 6 Preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one

11.6 g (1.00 eq, 19.2 mmol) of intermediate 5, water (10.1 equiv; 193 mmoles; 3.48 mL; 3.48 g) and methanol (3.62 moles; 146 mL; 116 g) were combined and heated to 55-60° C. Isethionic acid was added slowly until a clear solution was obtained; 3.3 g isethionic acid solution was necessary to reach this end point. The resulting clear orange solution was filtered through paper and rinsed through with 20 ml methanol, after which the filtrate was reheated to 55-60° C. and the remaining isethionic acid was added (a total of 9.93 g was added). The reaction mixture precipitated and thickened for 6 hours, after which it was cooled and held at 30-35° C. while triethylamine (2.92 g; 28.8 mmoles) was added slowly as a 10% solution in methanol over 12 hrs. About halfway through the addition of triethylamine, desired polymorphic seeds were added to help formation of the desired polymorph. The resulting slurry was cooled and held at 5° C. for 15 minutes and the crystals were filtered and washed with methanol. The solid product was dried in vacuo at 55° C. to obtain 11 g of yellow crystals of the title compound.

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http://www.google.com/patents/US7345171

EXAMPLES

The following examples are intended to be illustrative and non-limiting, and represent specific embodiments of the present invention.

Example 1 Preparation of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester

Example 2 Preparation of 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2.3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester

A suspension of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93 g, 0.010 mol, prepared as in Example 1), tetrakis(triphenylphosphine)palladium(0) (1.40 g, 0.00121 mol), and tributyl(1-ethoxyvinyl)tin (5.32 mL, 0.0157 mol) in toluene (30 mL) was heated under reflux for 3.5 hours. The mixture was cooled and filtered to give a solid. Purification of the solid by silica gel chromatography using a gradient of 5%-66% ethyl acetate/hexane over 15 minutes gave 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow foam (4.50 g, 78%). MS (APCI) M⁺+1: calc’d 576.2, found, 576.3.

Example 3 Preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride

Hydrogen chloride gas was bubbled into an ice-bath cooled solution of 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (4.50 g, 0.00783 mol, prepared as in Example 2) in DCM (100 mL). The resulting suspension was stoppered and stirred at RT overnight, then diluted with diethyl ether (200 mL). The solid was collected by filtration, washed with diethyl ether, and dried to give the hydrochloride salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (4.01 g, 92%). Melting point 200° C. HPLC, C18 reverse phase, 10%-95% gradient of 0.1% TFA/CH₃CN in 0.1% TFA/H₂O during 22 minutes: 99.0% at 11.04 minutes. MS (APCI) M⁺+1: calc’d, 448.2, found, 448.3. Anal. calc’d for C₂₄H₂₉N₇O₂.2.4H₂O.1.85 HCl: C, 51.64; H, 6.44; N, 17.56, Cl (total), 11.75. Found: C, 51.31; H, 6.41; N, 17.20; Cl (total), 12.11.

Example 4 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2.3-d]pyrimidin-7-one (Form B)

To a slurry of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (7.0 g, 15.64 mmol, prepared as in Example 3 following contact with NaOH) dispersed in 250 mL of water was added drop-wise 30 mL of a 0.52 M solution of isethionic acid in MeOH (15.64 mmol) to a pH of 5.2. The solution was filtered through a glass filter (fine) and the clear solution was freeze-dried to give 9.4 g of the amorphous salt. The amorphous salt (3.16 g) was mixed with 25 mL of MeOH and after almost complete dissolution a new precipitate formed. Another 25 mL of MeOH was added and the mixture was stirred at 46° C. to 49° C. for four hours. The mixture was slowly cooled to 32° C. and put in a cold room (+4° C.) overnight. A sample was taken for PXRD, which indicated formation of Form B. The mixture was filtered and the precipitate was dried overnight at 50° C. in a vacuum oven. This furnished 2.92 g of the mono-isethionate salt of the compound of Formula 1 in 92% yield. HPLC-99.25%, PXRD-Form B, CHNS, H-NMR were consistent with the structure.

Example 5 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2.3-d]pyrimidin-7-one (Form B)

MeOH (100 mL) was placed in a 250 mL flask equipped with a mechanical stirrer, thermocouple/controller, condenser, and heating mantle and preheated to 35° C. An amorphous isethionate salt (2 g, prepared as in Example 4) was slowly added in three even portions with a 25 min to 30 min interval between the additions. The reaction mixture was stirred overnight at 35° C. and subsequently cooled. A sample was filtered and examined by PXRD. It was pure Form B. The whole reaction mixture was then used as Form B seeds in a larger scale experiment.

Example 6 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Form B)

MeOH (50 mL) was placed in a 250 mL flask equipped with a magnetic stirrer, condenser, thermocouple/controller, and heating mantle, and preheated to 40° C. An amorphous isethionate salt (1 g, prepared as in Example 4) was slowly added in three even portions with 30 min interval between the portions and then stirred overnight at 40° C. The reaction was monitored by in-situ Raman spectroscopy. The sample was taken, filtered and analyzed by PXRD. It was pure Form B by PXRD and Raman spectroscopy. The mixture was cooled to 25° C. at a rate of 3° C./h, cooled to −10° C., filtered, and vacuum dried to furnish 0.85 g of the Form B crystalline product.

Example 7 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Form B)

The free base (Formula 1, 0.895 mg, 2 mmol) was mixed with 10 mL of MeOH and seeded with 33 mg of a mono-isethionate salt of the compound of Formula 1 (Form B). Then 5.6 mL of a 0.375 M solution of isethionic acid in MeOH (2.1 mmol) was added in 10 even portions over 75 min time period. The mixture was stirred for an additional hour and a sample was taken for PXRD analysis. It confirmed formation of crystalline Form B. The mixture was stirred at RT overnight and another PXRD was taken. There was no change in the crystal form. The mixture was cooled in a refrigerator at −8° C. overnight, filtered, and dried at 50° C. in a vacuum oven to give 1.053 g (91.8% of theory) of the above-named compound (Form B). HPLC—99.8%, CHNS, H-NMR, IR are consistent with the structure, PXRD-Form B.

Example 8 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2.3-d]pyrimidin-7-one (Form A)

An amorphous isethionate salt (47 mg, prepared as in Example 4) was mixed with 4 mL of EtOH in a 15 mL flask equipped with a magnetic stirrer, thermocouple and condenser. The mixture was heated to reflux, which resulted in the formation of a nearly clear solution. After refluxing for 10-15 min, the mixture became cloudy. It was slowly cooled to 50° C. and was seeded at 69° C. with Form A. The mixture was held at 50° C. for 5 h and was allowed to cool to RT overnight. The mixture was subsequently cooled to 1° C. with an ice bath, held for 1.5 h, filtered, washed with 0.5 mL of cold EtOH, air-dried, and then dried in a vacuum oven at 70° C. overnight to furnished 38.2 mg of a fine crystalline material. The crystalline material was found to be mono-isethionate salt Form A by PXRD. H-NMR was consistent for the mono-isethionate salt and indicated the presence of residual EtOH ca. 5.9 mol % or 0.6 wt %.

Example 9 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Form D)

An amorphous isethionate salt (9.0 g, prepared as in Example 4) was mixed with 300 mL of MeOH, stirred and heated to 63.8° C. (at reflux). To the slightly cloudy mixture was added two 50-mL portions of MeOH. The hot mixture was filtered into a 2-L flask equipped with a mechanical stirrer. The mixture was briefly heated to reflux and then cooled to 60° C. IPA (100 mL) was added to the mixture. The mixture was again heated to 60° C. and an additional 110 mL of IPA was added. A precipitate started to form at 59.7° C. The mixture was reheated to 67.5° C., cooled to 50° C., and held overnight. A sample was taken the next morning for PXRD analysis. The mixture was cooled to 25° C. at a rate of 3° C./h and another PXRD sample was taken when the mixture reached 28° C. The mixture was allowed to cool to RT overnight. A precipitate was collected and dried in a vacuum oven at 65° C. and 30 Torr. The procedure produced 7.45 g (82.8% yield) of the crystalline compound (Form D by PXRD analysis). Previously analyzed samples were also Form D. HPLC showed 98.82% purity and CHNS microanalysis was within +/−0.4%. A slurry of isethionate salt Form A, B, and D in MeOH yielded substantially pure Form B in less than three days.

Example 10 Preparation of isethionic acid (2-hydroxy-ethanesulfonic acid)

A 5-L, four-necked, round-bottomed flask, equipped with mechanical stirrer, thermocouple, gas sparger, and an atmosphere vent through a water trap was charged with 748 g (5.05 mol) of sodium isethionate (ALDRICH), and 4 L of IPA. The slurry was stirred at RT. An ice bath was used to keep the internal temperature below 50° C. as 925 g (25.4 mol) of hydrogen chloride gas (ALDRICH) was sparged into the system at a rate such that it dissolved as fast as it was added (as noted by lack of bubbling through the water trap). Sufficient HCl gas was added until the system was saturated (as noted by the start of bubbling through the water trap). During the addition of HCl, the temperature rose to 45° C. The slurry was cooled to RT and filtered over a coarse-fritted filter. The cake was washed with 100 mL of IPA and the cloudy filtrate was filtered through a 10-20μ filter. The resulting clear, colorless filtrate was concentrated under reduced pressure on a rotary evaporator, while keeping the bath temperature below 50° C. The resulting 1.07 kg of clear, light yellow oil was diluted with 50 mL of tap water and 400 mL of toluene and concentrated under reduced pressure on a rotary evaporator for three days, while keeping the bath temperature below 50° C. The resulting 800 g of clear, light yellow oil was diluted with 500 mL of toluene and 250 mL of IPA and concentrated under reduced pressure on a rotary evaporator for 11 days, keeping the bath temperature below 50° C. The resulting 713 g of clear, light yellow oil was titrated at 81 wt % (580 g, 91.1% yield) containing 7.9 wt % water and 7.5 wt % IPA.

Example 11 Preparation of 4-{6-[6-(1-butoxy-vinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester

A 5-L, three-necked, round-bottomed flask, equipped with a mechanical stirrer, a thermocouple, and a nitrogen inlet/outlet vented through a silicone oil bubbler was placed under a nitrogen atmosphere and charged with 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (300 g, 0.51 mol, prepared as in Example 2), butyl vinyl ether (154 g, 1.54 mol, ALDRICH), n-butanol (1.5 L, ALDRICH), and diisopropyl ethylamine (107 mL, 0.62 mol, ALDRICH). The slurry was placed under approximately 50 Torr vacuum and then refilled with nitrogen 3 times. To this was added 8.3 g (0.01 mol) bis-(diphenylphosphinoferrocene) palladium dichloride dichloromethane (JOHNSON MATTHEY, Lot 077598001) and the resulting slurry was purged an additional three times as described above. The mixture was then heated to 95° C. and stirred for 20 h. The resulting thin red slurry was diluted with 2 L of heptane and cooled to approximately 5° C. At this temperature, 400 mL saturated aqueous potassium carbonate was added and the mixture was filtered and rinsed with 250 mL of heptane. After drying in an oven for 16 h at 45° C., 231.7 g (75% yield) of the title compound was obtained as a yellow solid.

Example 12 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-Pyrido[2,3-d]pyrimidin-7-one (Form B)

A 22-L, three-necked, round-bottomed flask, equipped with a mechanical stirrer, a thermocouple, and a nitrogen inlet/outlet vented through a silicone oil bubbler was placed under a nitrogen atmosphere and charged with 4-{6-[6-(1-butoxy-vinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (725 g, 1.20 mol, prepared as in Example 11) and MeOH (14 L). The slurry was stirred at RT as it was charged with a solution of isethionic acid (530 g, 4.20 mol, prepared as in Example 10), MeOH (1.5 L), and water (70 mL, 3.89 mol). The resulting slurry was heated to 55° C. over 30 minutes and then stirred at 55° C. for 30 minutes. A solution of 175 g (1.73 mol) of Et₃N (ALDRICH) in 200 mL of MeOH was charged to the slurry as it was cooled to 30° C. The slurry was held at 30° C. as a solution of 128 g (1.26 mol) of Et₃N in 2 L of MeOH was added dropwise over 6 hours. The resulting slurry was sampled to determine crystal form (Form B). The slurry was cooled and held at 5° C. for 15 minutes and was subsequently filtered through a coarse-fritted filter. The resulting filter cake was washed with multiple washes of 200 mL of cold MeOH. The solid product was dried at 55° C. under vacuum to yield 710 g (91% yield) of the title compound as yellow crystals.

1)Peter L. Toogood, Patricia J. Harvey, Joseph T. Repine, Derek J. Sheehan, Scott N. VanderWel, Hairong Zhou, Paul R. Keller, Dennis J. McNamara, Debra Sherry, Tong Zhu, Joanne Brodfuehrer, Chung Choi, Mark R. Barvian, and David W. Fry;Discovery of a Potent and Selective Inhibitor of Cyclin-Dependent Kinase 4/6; Journal of Medicinal Chemistry, 2005, 48(7),2388-2406;

2)Scott N. VanderWel, Patricia J. Harvey, Dennis J. McNamara, Joseph T. Repine, Paul R. Keller, John Quin III, R. John Booth, William L. Elliott, Ellen M. Dobrusin, David W. Fry, and Peter L. Toogood; Pyrido[2,3-d]pyrimidin-7-ones as Specific Inhibitors of Cyclin-Dependent Kinase 4; Journal of Medicinal Chemistry,2005,48(7),2371-2387;

3)Erdman, David Thomas et al;Preparation of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones;PCT Int. Appl., WO2008032157

4)Sharpless, Norman E. et al;Hematopoietic protection against chemotherapeutic compounds using selective cyclin-dependent kinase 4/6 inhibitors;PCT Int. Appl., WO2010039997

5)Dirocco, Derek Paul et al;Protection of renal tissues from schema through inhibition of the proliferative kinases CDK4 and CDK6;PCT Int. Appl., WO2012068381

6)Logan, Joshua E.et al.;PD- 0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity; Anticancer Research (2013), 33(8), 2997-3004.

7)Phase III Study Evaluating Palbociclib (PD-0332991), a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor in Patients With Hormone-receptor-positive, HER2-normal Primary Breast Cancer With High Relapse Risk After Neoadjuvant Chemotherapy “PENELOPEB”;ClinicalTrials.gov number:NCT01864746;currently recruiting participants(as of January 2, 2013)

8)A Randomized, Multicenter, Double-Blind Phase 3 Study Of PD-0332991 (Oral CDK 4/6 Inhibitor) Plus Letrozole Versus Placebo Plus Letrozole For The Treatment Of Postmenopausal Women With ER (+), HER2 (-) Breast Cancer Who Have Not Received Any Prior Systemic Anti Cancer Treatment For Advanced Disease;ClinicalTrials.gov number:NCT01740427;currently recruiting participants(as of January 2, 2013)

9)Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Of Fulvestrant (Faslodex®) With Or Without PD-0332991 (Palbociclib) +/- Goserelin In Women With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer Whose Disease Progressed After Prior Endocrine Therapy;ClinicalTrials.gov number:NCT01942135;currently recruiting participants(as of January 2, 2013)

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WO2005005426A1	Jun 28, 2004	Jan 20, 2005	Vladimir Genukh Beylin	Isethionate salt of a selective cdk4 inhibitor

US20030229026 *	Dec 18, 2000	Dec 11, 2003	Al-Awar Rima Salim	Agents and methods for the treatment of proliferative diseases
US20040006074 *	Dec 2, 2002	Jan 8, 2004	The Government Of The United States Of America	Cyclin dependent kinase (CDK)4 inhibitors and their use for treating cancer
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US20050222163 *	Mar 30, 2005	Oct 6, 2005	Pfizer Inc	Combinations of signal transduction inhibitors
US20070027147 *	Dec 3, 2004	Feb 1, 2007	Takashi Hayama	Biarylurea derivatives

WO2008032157A2 *	Aug 27, 2007	Mar 20, 2008	David Thomas Erdman	Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
WO2010075074A1	Dec 15, 2009	Jul 1, 2010	Eli Lilly And Company	Protein kinase inhibitors
WO2012098387A1	Jan 17, 2012	Jul 26, 2012	Centro Nacional De Investigaciones Oncológicas (Cnio)	6, 7-ring-fused triazolo [4, 3 – b] pyridazine derivatives as pim inhibitors
US7781583	Sep 10, 2007	Aug 24, 2010	Pfizer Inc	Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d] pryimidin-7-ones
US7855211	Dec 15, 2009	Dec 21, 2010	Eli Lilly And Company	Protein kinase inhibitors
US8247408 *	Oct 9, 2006	Aug 21, 2012	Exelixis, Inc.	Pyridopyrimidinone inhibitors of PI3Kα for the treatment of cancer
US8273755	Feb 9, 2010	Sep 25, 2012	Pfizer Inc	4-methylpyridopyrimidinone compounds

old info

Date: April 10, 2013

Pfizer Inc. said that its experimental pill for advanced, often deadly breast cancer has been designated as a breakthrough therapy by the Food and Drug Administration.

The breakthrough designation, created under legislation enacted last summer to fund and improve operations of the FDA, is meant to speed up development and review of experimental treatments that are seen as big advances over existing therapies for serious diseases. Pfizer is working with the agency to determine exactly what research results it will need to apply for approval of the drug.

Palbociclib is being evaluated as an initial treatment for the biggest subgroup of postmenopausal women whose breast cancer is locally advanced or has spread elsewhere in the body. About 60% of women with such advanced breast cancer have tumors classified as ER+, or estrogen-receptor positive, but HER2-, or lacking an excess of the growth-promoting protein HER2.

Estrogen-receptor positive tumors have proteins inside and on the surface of their cells to which the estrogen hormone can attach and then fuel growth of cells. These tumors tend to grow slowly and can be fought with drugs that block estrogen’s effects.

Meanwhile, about 80% of breast cancer tumor cells are HER2 negative. That means that unlike HER2 positive tumors, they don’t produce too much of the HER2 protein, which makes tumors grow and spread more aggressively than in other breast cancer types.

New York-based Pfizer is currently running a late-stage study of palbociclib at multiple centers, comparing its effects when used in combination with letrozole with the effects of letrozole alone.

Letrozole, sold under the brand name Femara for about the past 15 years, is a pill that works by inhibiting aromatase. That’s an enzyme in the adrenal glands that makes estrogen.

According to Pfizer, palbociclib targets enzymes called cyclin dependent kinases 4 and 6. By inhibiting those enzymes, the drug has been shown in laboratory studies to block cell growth and suppress copying of the DNA of the cancer cells.

Pfizer, which has made research on cancer medicines a priority in recent years, also is testing palbociclib as a treatment for other cancers.

Highlight of recent study using PD-0332991

Phase I study of PD-0332991: Forty-one patients were enrolled. DLTs were observed in five patients (12%) overall; at the 75, 125, and 150 mg once daily dose levels. The MTD and recommended phase II dose of PD 0332991 was 125 mg once daily. Neutropenia was the only dose-limiting effect. After cycle 1, grade 3 neutropenia, anemia, and leukopenia occurred in five (12%), three (7%), and one (2%) patient(s), respectively. The most common non-hematologic adverse events included fatigue, nausea, and diarrhea. Thirty-seven patients were evaluable for tumor response; 10 (27%) had stable disease for ≥4 cycles of whom six derived prolonged benefit (≥10 cycles). PD 0332991 was slowly absorbed (median T(max), 5.5 hours), and slowly eliminated (mean half-life was 25.9 hours) with a large volume of distribution (mean, 2,793 L). The area under the concentration-time curve increased linearly with dose. Using an E(max) model, neutropenia was shown to be proportional to exposure. CONCLUSIONS:
PD 0332991 warrants phase II testing at 125 mg once daily, at which dose neutropenia was the sole significant toxicity. (Source: Clin Cancer Res; 18(2); 568-76.)

Phase I study of PD-0332991 in 3-week cycles (Schedule 2/1): Six patients had DLTs (18%; four receiving 200 mg QD; two receiving 225 mg QD); the MTD was 200 mg QD. Treatment-related, non-haematological adverse events occurred in 29 patients (88%) during cycle 1 and 27 patients (82%) thereafter. Adverse events were generally mild-moderate. Of 31 evaluable patients, one with testicular cancer achieved a partial response; nine had stable disease (≥10 cycles in three cases). PD 0332991 was slowly absorbed (mean T(max) 4.2 h) and eliminated (mean half-life 26.7 h). Volume of distribution was large (mean 3241 l) with dose-proportional exposure. Using a maximum effective concentration model, neutropenia was proportional to exposure. CONCLUSION: PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study. (source: Br J Cancer. 2011 Jun 7;104(12):1862-8)

References

1: Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, Shaik MN, Wilner KD, O’Dwyer PJ, Schwartz GK. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res. 2012 Jan 15;18(2):568-76. doi: 10.1158/1078-0432.CCR-11-0509. Epub 2011 Nov 16. PubMed PMID: 22090362.

2: Smith D, Tella M, Rahavendran SV, Shen Z. Quantitative analysis of PD 0332991 in mouse plasma using automated micro-sample processing and microbore liquid chromatography coupled with tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Oct 1;879(27):2860-5. doi: 10.1016/j.jchromb.2011.08.009. Epub 2011 Aug 16. PubMed PMID: 21889427.

3: Katsumi Y, Iehara T, Miyachi M, Yagyu S, Tsubai-Shimizu S, Kikuchi K, Tamura S, Kuwahara Y, Tsuchiya K, Kuroda H, Sugimoto T, Houghton PJ, Hosoi H. Sensitivity of malignant rhabdoid tumor cell lines to PD 0332991 is inversely correlated with p16 expression. Biochem Biophys Res Commun. 2011 Sep 16;413(1):62-8. doi: 10.1016/j.bbrc.2011.08.047. Epub 2011 Aug 17. PubMed PMID: 21871868; PubMed Central PMCID: PMC3214763.

4: Schwartz GK, LoRusso PM, Dickson MA, Randolph SS, Shaik MN, Wilner KD, Courtney R, O’Dwyer PJ. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer. 2011 Jun 7;104(12):1862-8. doi: 10.1038/bjc.2011.177. Epub 2011 May 24. PubMed PMID: 21610706; PubMed Central PMCID: PMC3111206.

5: Nguyen L, Zhong WZ, Painter CL, Zhang C, Rahavendran SV, Shen Z. Quantitative analysis of PD 0332991 in xenograft mouse tumor tissue by a 96-well supported liquid extraction format and liquid chromatography/mass spectrometry. J Pharm Biomed Anal. 2010 Nov 2;53(3):228-34. doi: 10.1016/j.jpba.2010.02.031. Epub 2010 Feb 26. PubMed PMID: 20236782.

6: Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77. doi: 10.1186/bcr2419. PubMed PMID: 19874578; PubMed Central PMCID: PMC2790859.

7: Menu E, Garcia J, Huang X, Di Liberto M, Toogood PL, Chen I, Vanderkerken K, Chen-Kiang S. A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model. Cancer Res. 2008 Jul 15;68(14):5519-23. doi: 10.1158/0008-5472.CAN-07-6404. PubMed PMID: 18632601.

8: Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004 Nov;3(11):1427-38. PubMed PMID: 15542782.

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TEDIZOLID (torezolid)

January 4, 2014 1:58 am / 2 Comments on TEDIZOLID (torezolid)

TEDIZOLID PHOSPHATE

[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxo-5-oxazolidinyl]methyl]phosphate,

DA 7157

THERAPEUTIC CLAIM Treatment of complicated skin and skin structure infections
CHEMICAL NAMES
1. 2-Oxazolidinone, 3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5- [(phosphonooxy)methyl]-, (5R)-
2. [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxooxazolidin-5- yl]methyl hydrogen phosphate

http://www.ama-assn.org/resources/doc/usan/tedizolid-phosphate.pdf

MOLECULAR FORMULA C17H16FN6O6P

MOLECULAR WEIGHT 450.3
TRADEMARK None as yet
SPONSOR Trius Therapeutics
CODE DESIGNATION TR-701 FA
CAS REGISTRY NUMBER 856867-55-5
Note: This adoption statement supersedes the USAN torezolid phosphate (N09/81), which is hereby rescinded and replaced by the USAN tedizolid phosphate (N10/118).\

……………………………..

Tedizolid, 856866-72-3

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one

(5R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone,

TR 700

Molecular Formula: C17H15FN6O3
Average mass: 370.337799

Torezolid (also known as TR-701 and now tedizolid[1]) is an oxazolidinone drug being developed by Trius Therapeutics (originator Dong-A Pharmaceuticals) for complicated skin and skin-structure infections (cSSSI), including those caused by Methicillin-resistantStaphylococcus aureus (MRSA).[2]

As of July 2012, tedizolid had completed one phase III trial, with another one under way. [3]Both trials compare a six-day regimen of tedizolid 200mg once-daily against a ten-day regimen of Zyvox (linezolid) 600mg twice-daily.

The prodrug of tedizolid is called “TR-701″, while the active ingredient is called “TR-700″.[4][5]

Trius Therapeutics will soon be reporting data from its second phase III trial (ESTABLILSH-2) and the recently announced publication of the data from its first phase III trial (ESTABLISH-1) in the Journal of the American Medical Association (JAMA)

“Trius grows as lead antibiotic moves forward”. 31 Oct 2011.
“Trius Completes Enrollment In Phase 2 Clinical Trial Evaluating Torezolid (TR-701) In Patients With Complicated Skin And Skin Structure Infections”. Jan 2009.
http://clinicaltrials.gov/ct2/results?flds=Xf&flds=a&flds=b&term=tedizolid&phase=2&fund=2&show_flds=Y
PMID 19528279 In vitro activity of TR-700, the active ingredient of the antibacterial prodrug TR-701, a novel oxazolidinone antibacterial agent.
PMID 19218276 TR-700 in vitro activity against and resistance mutation frequencies among Gram-positive pathogens.

…………………………………………………….

Emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in treating bacterial infections. One way forward to treat bacterial infections, and especially those caused by resistant bacteria, is to develop newer antibacterial agents that can overcome the bacterial resistance. Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1154.) have reviewed novel approaches to developing new antibiotics. However, the development of new antibacterial agents is a challenging task. For example, Gwynn et al. (Annals of the New York Academy of Sciences, 2010, 1213: 5-19) have reviewed the challenges in the discovery of antibacterial agents.

Several antibacterial agents have been described in the prior art (for example, see PCT International Application Nos. PCT/US2010/060923, PCT/EP2010/067647, PCT/US2010/052109, PCT/US2010/048109, PCT/GB2009/050609, PCT/EP2009/056178 and PCT/US2009/041200). However, there remains a need for potent antibacterial agents for preventing and/or treating bacterial infections, including those caused by bacteria that are resistant to known antibacterial agents.

Various oxazolidinone-containing compounds have been disclosed for use asantibiotics. For example, oxazolidinone-containing compounds have been described in U.S. patent application Ser. No. 10/596,412 (filed Dec. 17, 2004), and WO 04/048350, WO 03/022824 and WO 01/94342, which are incorporated herein by reference.

U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009) and U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010), which are assigned to the same assignee as in the present application, disclose phosphate dimer impurities made during the process of making of the compounds disclosed therein. Surprisingly, it has been found that compounds containing at least two phosphates binding two oxazolidinone-containing moieties, such as dimers of oxazolidinone-containing compounds have antibacterial activity similar to their dihydrogen monophosphate analog

active drug of Formula I is (5R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone, i.e.,

These active compounds have been disclosed in WO 05/058886 and US Patent Publication No. 20070155798, while processes for making these and related compounds have been disclosed in U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009), and a crystalline form of the phosphate ester and related salts of the above compound has been disclosed in U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010).

US Patent Publication No. 20070155798, recently disclosed a series of potently anti-bacterial oxazolidinones including

wherein R═H, PO(OH)₂, and PO(ONa)₂.

Cubist Announces Submission of New Drug Application for Investigational Antibiotic Tedizolid for Treatment of Serious Skin Infections

LEXINGTON, Mass.–(BUSINESS WIRE)– Cubist Pharmaceuticals, Inc. today announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of its investigational antibiotic tedizolid phosphate (TR-701). Cubist is seeking approval of tedizolid phosphate for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Tedizolid phosphate is a once daily oxazolidinone being developed for both intravenous (I.V.) and oral administration for the treatment of serious Gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA).

http://www.drugs.com/nda/tedizolid_131023.html

…………………………………………………………..

Efficacy of DA-7218, a new oxazolidinone prodrug, in the treatment of experimental actinomycetoma produced by Nocardia brasiliensis.

Espinoza-González NA, Welsh O, de Torres NW, Cavazos-Rocha N, Ocampo-Candiani J, Said-Fernandez S, Lozano-Garza G, Choi SH, Vera-Cabrera L.

Molecules. 2008 Jan 11;13(1):31-40.

…………………………………………..

imp patents

US2010305069	12-3-2010	OXAZOLIDINONE CONTAINING DIMER COMPOUNDS, COMPOSITIONS AND METHODS TO MAKE AND USE
US7816379	10-20-2010	Oxazolidinone derivatives
US2009192197	7-31-2009	NOVEL OXAZOLIDINONE DERIVATIVES

…………………………………………..

TEDIZOLID disodium salt

59 nos in

http://www.google.com/patents/US20130102523

38 nos

Tedizolid (formerly known as torezolid or TR-700) is the active hydroxymethyl oxazolidinone having the following formula:

Pharmaceutical prodrugs such as tedizolid phosphate (also referred to as TR-701, torezolid phosphate, and TR-701 “free acid” or FA) have the following formula:

The disodium salt of tedizolid phosphate, has the following structure:

…………………………………………………………………………………………………………………………………………………………….

US20100305069

Example 1 Preparation of the Phosphate Monohydrogen Diester, Formula III
In this and the following Examples, “Formula III” refers to a compound wherein Z is
Figure US20100305069A1-20101202-C00024
and M=OH.
A 1-L, three-neck round-bottom flask equipped with a magnetic stirrer, nitrogen inlet/outlet and thermocouple was charged with the compound of Formula Ia below (16.0 g, 0.0499 mol], THF (320 mL, 20 vol) and Et3N (21.9 g, 0.216 mol, 5.0 equiv.).
Figure US20100305069A1-20101202-C00025
POCl3 (3.31 g, 0.0216 mol, 0.5 equiv.) was added dropwise via syringe over 5 minutes. The reaction temperature was maintained below 25° C. The batch was aged for 16 hours at room temperature at which point HPLC analysis (XBridge, C18) indicated that the reaction was complete. The reaction vessel was then immersed in an ice-water bath and a 500-mL addition funnel charged with 320 mL of H2O was attached to the reaction vessel. When the temperature of the reaction reached 2.7° C., H2O was added drop wise over 30 minutes. The temperature of the reaction was maintained below 10° C. Upon completion of the H2O addition, the ice-water bath was removed and the batch was aged for 3 hours. The solution was transferred to a 2-L round-bottom flask and concentrated under reduced pressure on a rotary evaporator. After removal of most of the THF from the solution, the aqueous mixture was extracted with 5 1-L portions of CH2Cl2:MeOH (9:1). The CH2Cl2 layers were combined and concentrated to a dark oil. This crude material was purified on 200 g of silica gel, eluting with 10% MeOH/CH2Cl2 to 20% 2 N NH3 in MeOH/CH2Cl2. Fractions containing mostly the bis-ester (as judged by TLC Rf=0.3 eluting with 20% 2 N NH3 in MeOH/CH2Cl2) were combined and concentrated under reduced pressure on a rotary evaporator, during which time a white precipitate was observed. The flask containing the slurry was removed from the rotary evaporator and equipped with a magnetic stir bar and allowed to stir while cooling to room temperature over 3 hours, during which time the slurry thickened. The solid was filtered and dried in a vacuum oven at 45° C. for 16 hours to give 3.55 g of bis-ester as an off-white solid (20% yield). HPLC analysis (Method A): 99.0% (AUC), tR=16.3 min. This reaction was repeated and the combined lots of the compound of Formula III (6.7 g) were slurried in 100 mL of MeOH (15 vol). The slurry was heated to 40° C. for 30 minutes and then allowed to cool to room temperature over 1 hour. The off-white solid was filtered and dried in a vacuum oven at 40° C. for 16 hours to give 6.15 g of the compound of Formula III (92% yield). The 1H NMR analysis of the product was consistent with the assigned structure. HPLC analysis (Method A): 99.0% (AUC), tR=16.3 min.

Example 2 Preparation of the Diphosphate Dihydrogen Diester, Formula IV
In Examples 2-5, “Formula IV” refers to a compound wherein Z is
Figure US20100305069A1-20101202-C00026
n=0 and M=O-imidazolium salt.

A 250-mL 3-neck round-bottom flask equipped with a magnetic stirrer, nitrogen inlet/outlet and thermocouple was charged with the compound of Formula IIa below (5.0 g, 11.1 mmol), carbonyldiimidazole (890 mg, 5.55 mmol, 0.5 equiv.) and DMF (100 mL, 20 vol).
Figure US20100305069A1-20101202-C00027
The suspension was heated to 50° C. and held at that temperature for 4 hours at which point HPLC analysis (XBridge, C18) indicated that the reaction was complete. The reaction was filtered at 50° C. and dried in a vacuum oven at 50° C. for 24 hours to give 5.15 g of the imidazolium salt (i.e., the compound of Formula IV) as an off-white solid (98% yield). The 1H NMR analysis of the product was consistent with the assigned structure. HPLC analysis (Method A): 94.5% (AUC), tR=14.6 min.
TABLE 1
Method A (Waters XBridge C18 Column)
Time (min) Flow (mL/min) % A % B
0.0 1.0 98.0 2.0
15.0 1.0 5.0 95.0
25.0 1.0 5.0 95.0
27.0 1.0 98.0 2.0
30.0 1.0 98.0 2.0
A = 87% 25 mM ammonium bicarbonate solution in water/13% Acetonitrile
B = Acetonitrile
Wavelength = 300 nm

disodium salt is TR 701

……………………………………

US8580767

Various oxazolidinone-containing compounds have been disclosed for use as antibiotics. For example, oxazolidinone-containing compounds have been described in U.S. patent application Ser. No. 10/596,412 (filed Dec. 17, 2004), and WO 04/048350, WO 03/022824 and WO 01/94342, which are incorporated herein by reference.

………………………………………………………………………………………………………………………..

SYNTHESIS

US20070155798

DESCRIPTION OF COMPDS

10,

(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on (compound 10)

………………………………………………………………………………………………………………………….

Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoromethyl oxazolidin-2-on (compound 18)

………………………………………………………………………………………………………………………………………………………….

(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methoxymethyl oxazolidin-2-on (compound 33)

…………………………………………………………………………………………………………………………………………..

(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl disodiumphosphate (compound 59)

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

mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72)

COMPLETE SYNTHESIS

Example 5

Preparation of 2-cyano-5-bromopyridine

In 1 L of dimethylformamide was dissolved 100 g of 2,5-dibromopyridine, 32 g of cupper cyanide and 17.8 g of sodium cyanide were added to the solution at room temperature and the solution was stirred at the temperature of 150° C. for 7 hours for reaction. After being cooled to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated in vacuo. The title compound 54 g was obtained. Yield 70%.

¹HNMR(CDCl₃) δ 8.76(s,1H), 7.98(dd,1H), 7.58(dd,1H)

Example 6

Preparation of 2-(tetrazol-5-yl)-5-bromopyridine

10 g of 2-cyano-5-bromopyridine prepared in the Preparation example 5 was dissolved in 100 ml of dimethylformamide, 5.33 g of sodiumazide, and 4.4 g of ammonium chloride were added to the solution at room temperature, and the solution was stirred at the temperature of 110° C. for 3 hours for reaction. The reaction mixture was added with water and then was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated and concentrated in vacuo thereby to obtain 10.5 g of the title compound. Yield 85%.

Preparation Example 7 Preparation of 2-(1-methyltetrazol-5-yl)-5-bromopyridine and 2-(2-methyltetrazol-5-yl)-5-bromopyridine

10.5 g of 2-(tetrazol-5-yl)-5-bromopyridine prepared in the Preparation example 6 was dissolved in 100 ml of dimethylformamide. And then 6.5 g of sodium hydroxide was added to the solution and 9.3 g of iodomethane was slowly added to the solution at the temperature of 0° C. The solution was stirred for 6 hours at room temperature, added with water, extracted with ethyl acetate. And then the organic layer was washed with brine, dehydrated, filtrated, concentrated in vacuo and purified by column chromatography to obtain 4 g of 2-(1-methyltetrazol-5-yl)-5-bromopyridine and 5 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine.

1) 2-(1-methyltetrazol-5-yl)-5-bromopyridine

¹HNMR(CDCl₃) δ 8.77(t,1H), 8.23(dd,1H), 8.04(dd,1H), 4.46(s,3H)

2) 2-(2-methyltetrazol-5-yl)-5-bromopyridine

¹HNMR(CDCl₃) δ 8.80(t,1H), 8.13(dd,1H), 7.98(dd,1H), 4.42(s,3H)

Example 1

Preparation of N-Carbobenzyloxy-3-fluoroaniline

3-fluoroaniline 100 g was dissolved in 1 L of tetrahydrofuran (THF) and the solution was added with 150 g (1.8 mol) of sodium bicarbonate (NaHCO₃). After being cooled to 0° C., the solution was slowly added with 154 ml of N-carbobenzyloxy chloride (CbzCl) for reaction. While the temperature was maintained at 0° C., the reaction mixture was let to react for 2 hours with stirring. Afterwards, the reaction was extracted with 0.5 L of ethyl acetate. The organic layer, after being separated, was washed with brine, dried over anhydrous magnesium sulfate (MgSO₄) and concentrated in vacuo. The residue was washed twice with n-hexane to afford the title compound as white crystal. 132 g. Yield 85%.

Example 2

Preparation of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

132 g of N-carbobenzyloxy-3-fluoroaniline 132 g prepared in the Preparation example 1 was dissolved in 1.3 L of tetrahydrofuran and the solution was cooled to −78° C. 370 ml of n-buthyllitium (n-BuLi, 1.6M/n-hexane) was slowly added to the solution in a nitrogen atmosphere, followed by stirring for 10 min. And 84 ml of (R)-(−)-glycidylbuthylate was slowly added to the reaction mixture, stirred at the same temperature for 2 hours and allowed to react for 24 hours at room temperature. After completion of the reaction, the solution was added with ammonium chloride (HH₄Cl) solution and extracted with 0.5 L of ethyl acetate at room temperature. The organic layer, thus separated, was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate and washed with n-hexane to give white crystals, which were purified to the title compound. 80 g. Yield 70%.

¹H NMR (DMSO-d₆) δ 7.85(t,1H), 7.58(dd,1H), 7.23(dd,1H), 4.69(m,1H), 4.02 (t,1H), 3.80(dd,1H), 3.60(br dd,2H).

Example 3

Preparation of (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

In 300 ml of acetonitryl was dissolved 30 g of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 2, and 46 g of trifluoroacetic acid silver salt (CF₃COOAg) and 43 g of iodide were added to the solution. After being stirred for one day at room temperature, the solution was added with water and was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine and dehydrated. And then the residue was filtered, concentrated in vacuo and dried thereby to form the title compound 44 g. Yield 94%.

¹H NMR (DMSO-d₆) δ 7.77(t,1H), 7.56(dd,1H), 7.20(dd,1H), 5.20(m,1H), 4.70 (m,1H), 4.07(t,1H), 3.80(m,1H), 3.67(m,2H), 3.56(m,3H)

Example 4

Preparation of (R)-3-(4-tributhylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

In 660 ml of 1,4-dioxan was dissolved 50 g of (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 3, 52 g of hexabutylditin ((Bu₃Sn)₂) and 9.3 g of dichlorobistriphenylphosphinpalladium were added into the solution, and stirred for 2 hours. The solution was filtered using celite and concentrated in vacuo. The residue was purified by column chromatography and 45 g of the title compound was formed.

¹H NMR (DMSO-d₆) δ 7.74(m,3H), 5.20(t,1H), 4.71(m,1H), 4.08(t,1H), 3.82(dd,1H), 3.68(m,1H), 3.52(m,1H), 1.48(m, 6H), 1.24(m, 6H), 1.06(m,6H), 0.83(t,9H)

COMPD 10

Example 1 Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on (compound 10)

In 150 ml of 1-methyl-2-pyrrolidone was dissolved 37 g of (R)-3-(4-tributhylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol. The solution was added with 19.7 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 10.44 g of lithium chloride and 2.9 g of dichlorobistriphenylphospine palladium(II) at room temperature and then stirred at the temperature of 120° C. for 4 hours. The reaction mixture was added with water and then extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated, concentrated in vacuo and purified by column chromatography to provide 8 g of the title compound. Yield 26%.

¹H NMR (DMSO-d₆) δ 8.90(s,1H), 8.18(m,2H), 7.70(m,2H), 7.49(dd,1H), 5.25(t,1H), 4.74(m,1H), 4.46(s,3H), 4.14(t,1H), 3.88(dd,1H), 3.68(m,1H), 3.58 (m,1H)

COMPD 18

Example 28 Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoromethyl oxazolidin-2-on (compound 18)

In 5 ml of methylenchloride was dissolved 100 mg of the compound 10. The solution was added with 43 mg of diethylaminosulfurtrifloride (DAST) and 0.078 ml of triethylamine and then stirred for 24 hours. After being concentrating, the reaction mixture was purified by column chromatography to obtain the title compound 75 mg. Yield 75%.

¹H NMR (DMSO-d₆) δ 8.91(s,1H), 8.19(m,2H), 7.74(t,1H), 7.66(dd,1H) 7.49 (dd,1H), 5.06(m,1H), 4.89(m,2H), 4.46(s,3H), 4.23(t,1H), 3.95(dd,1H)

COMPD 33

Example 37 Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methoxymethyl oxazolidin-2-on (compound 33)

In 10 ml of methanol was dissolved 400 mg of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyl oxazolidin-2-on prepared in the secondary step of the Example 24. The solution was added with 90 mg of sodium methoxide at room temperature and then stirred for one day at room temperature. The solution was extracted with ethyl acetate and the organic layer, thus separated, was washed with water and brine. The organic layer was dehydrated, filtered, concentrated in vacuo and purified by column chromatography to provide the title compound 200 mg. Yield 58%.

¹H NMR(CDCl₃) δ 8.90(s,1H), 8.29(d,1H), 8.04(d,1H), 7.61(dd,1H), 7.58 (t,1H), 7.38(dd,1H), 4.80(m,1H), 4.45(s,3H), 4.08(t,1H), 3.96(dd,1H), 3.67 (m,2H), 3.43(s,3H)

COMPD 59

Example 58 Preparation of mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72) and (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl disodiumphosphate (compound 59)

1. The Primary Step

In 10 ml of mixture solvent (tetrahydrofuran:methylenchloride=1:1) was dissolved 1 g of compound 10. The solution was added with 0.6 g of tetrazole and 2.3 g of di-tetrabutyl diisoprophylphosphoamidite and stirred for 15 hours at room temperature. The reaction mixture was refrigerated to −78° C., added with 0.7 g of metachloroperbenzoic acid and stirred for 2 hours. After being cooling to −78° C., the reaction mixture was added with metachloroperbenzoic acid (0.7 g). When the reaction mixture was stirred for 2 hours, the temperature of the reaction mixture was raised to room temperature. The reaction mixture was then added with ethyl acetate. The organic layer, thus separated, was washed with sodium bisulfate, sodium bicarbonate and brine, dehydrated, filtered and concentrated in vacuo, followed by purification with column chromatography thereby to provide (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl phosphoric acid ditetrabuthylester (0.71 g, 71%).

¹H NMR (DMSO-d₆) δ 8.90(s,1H), 8.18(m,2H), 7.74(t,1H), 7.68 (dd,1H), 7.49(dd,1H), 4.98(m,1H), 4.46(s,3H), 4.23(t,1H), 4.18(m,1H), 4.09(m,1H), 3.89 (dd,1H), 1.39(s,9H), 1.38(s,9H)

The crystal prepared the above method was dissolved in a mixture of methanol and chloroform. And then the solution added with 3.4 ml of sodium methoxide (0.3M methanol solution) at the room temperature and stirred for 10 hours. The reaction mixture was concentrated to prepare the residue. The residue was crystallized and filtered thereby to obtain the title compound (compound 59) 300 mg.

¹H NMR (D₂O) δ 8.27(s,1H), 7.56(dd,2H), 7.06(m,2H), 6.90(m,1H), 4.79 (m,1H), 4.63(s,3H), 3.90(m,4H)

COMPD 72

The Secondary Step

In 30 ml of methylenchloride was dissolved the compound (0.7 g) in the Primary Step. The solution was added with 15 ml of trifluoroacetic acid and then stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo to prepare the residue. The residue was crystallized with ethanol and ethyl ether to obtain mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72) 400 mg.

¹H NMR (DMSO-d₆) δ 8.92(s,1H), 8.20(m,2H), 7.74(t,1H), 7.66(dd,1H), 7.500(dd,1H), 4.95 (m,1H), 4.46(s,3H), 4.21(t,1H), 4.05(m,2H), 3.91(dd,1H)

US20070155798

………………………………………………………

IMPURITIES

US8426389

Organic Impurities in TR-701 FA Drug Substance
Impurity
‘Name’	Structure and Chemical Name

Rx600013 ‘Des-methyl TR- 701’
	dihydrogen ((5R)-3-{3-fluoro-4-[6-(2H-1,2,3,4-tetrazol-5-
	yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-yl)methyl
	phosphate

Rx600024 ‘Pyrophosphate’
	trihydrogen ((5R)-3-{3-fluoro-4-[6-(1-methyl-1H-1,2,3,4-
	tetraazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-
	yl)methyl pyrophosphate

Rx600014 ‘Ring opened’
	dihydrogen 3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetraazol-5-
	yl)-3-pyridinyl]aniline}-2-hydroxypropyl phosphate

Rx600023 ‘Me-isomer’
	dihydrogen ((5R)-3-{3-fluoro-4-[6-(1-methyl-1H-1,2,3,4-
	tetraazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-
	yl)methyl phosphate

Rx600025 ‘Overalkylated- phosphorylated impurity’
	(R)-1-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-
	yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methoxy)-3-
	hydroxypropan-2-yl dihydrogen phosphate;
	(R)-3-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-
	yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methoxy)-2-
	hydroxypropyl dihydrogen phosphate

Rx600020 ‘Dimer impurity’
	dihydrogen bis-O-O′-[(5R)-3-{3-fluoro-4-[6-(2-methyl-
	2H-1,2,3,4-tetrazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-
	oxazolidin-5-yl]methyl pyrophosphate

Rx600026 “Chloro”
	(R)-5-(chloromethyl)-3-(3-fluoro-4-(6-(2-methyl-2H-
	tetrazol-5-yl)pyridin-3-yl)phenyl)oxazolidin-2-one

Rx600001 TR-700
	5R)-3-{3-Fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-
	pyridin-3-yl]-phenyl}-5-hydroxymethyl-1,3-oxazolidin-2-one

Rx600022 ‘Bis phosphate’
	hydrogen bis-O-O′-[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-
	tetrazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl
	phosphate

Rx600042
	3-{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
	yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}-2-hydroxypropyl
	[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
	yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl hydrogen phosphate

Rx600043
	2-{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
	yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}-1-hydroxyethyl
	[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
	yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl hydrogen phosphate

……………………………………………..

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WO2003072575A1	25 Feb 2003	4 Sep 2003	Astrazeneca Ab	3-cyclyl-5-(nitrogen-containing 5-membered ring) methyl-oxazolidinone derivatives and their use as antibacterial agents
WO2003072576A2	25 Feb 2003	4 Sep 2003	Astrazeneca Ab	Oxazolidinone derivatives, processes for their preparation, and pharmaceutical compositions containing them
WO2004048350A2	24 Nov 2003	10 Jun 2004	Astrazeneca Ab	Oxazolidinones as antibacterial agents
WO2004083205A1	16 Mar 2004	30 Sep 2004	Astrazeneca Ab	Antibacterial 1, 3- oxazolidin -2- one derivatives
WO2005005398A2	29 Jun 2004	20 Jan 2005	Yasumichi Fukuda	Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof
WO2005051933A1	23 Nov 2004	9 Jun 2005	Vijay Kumar Kaul	An improved process for the synthesis of 4-(4-benzyloxy-carbonylamino-2-fluorophenyl)-piperazine-1-carboxylic acid tert-butyl ester, a key intermediate for oxazolidinone antimicrobials and compounds prepared thereby
WO2005058886A1	17 Dec 2004	30 Jun 2005	Dong A Pharm Co Ltd	Novel oxazolidinone derivatives
WO2005116017A1	24 May 2005	8 Dec 2005	Astrazeneca Ab	Process for the preparation of aryl substituted oxazolidinones as intermediates for antibacterial agents
WO2006038100A1	6 Oct 2005	13 Apr 2006	Ranbaxy Lab Ltd	Oxazolidinone derivatives as antimicrobials
WO2007023507A2	19 Jun 2006	1 Mar 2007	Milind D Sindkhedkar	Oxazolidinones bearing antimicrobial activity composition and methods of preparation
WO2007138381A2	13 Oct 2006	6 Dec 2007	Delorme Daniel	Phosphonated oxazolidinones and uses thereof for the prevention and treatment of bone and joint infections
WO2010042887A2	9 Oct 2009	15 Apr 2010	Trius Therapeutics	Methods for preparing oxazolidinones and compositions containing them
WO2010091131A1	3 Feb 2010	12 Aug 2010	Trius Therapeutics	Crystalline form of r)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate
WO2010138649A1	27 May 2010	2 Dec 2010	Trius Therapeutics, Inc.	Oxazolidinone containing dimer compounds, compositions and methods to make and use

……………………………………………………………………………………….

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

need help, email or call me

amcrasto@gmail.com

MOBILE-+91 9323115463

web link

http://about.me/amcrasto
http://anthonymelvincrasto.brandyourself.com/

I was paralysed in dec2007

RAMOSETRON

December 30, 2013 7:22 am / 1 Comment on RAMOSETRON

RAMOSETRON, Antiemetics

Ramosetron (INN),(1-methylindol-3-yl)-[(5R)-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl]methanone, 132036-88-5 cas no

	C₁₇H₁₇N₃O
	279.33 g/mol

(1-methyl-1H-indol-3-yl)[(5R)-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl]methanone

YM060

Nasea
Nor-YM 060
Ramosetron
UNII-7ZRO0SC54Y

…………………………………………………………………………………..

HYDROCHLORIDE SALT

hyrochloride salt, cas no 132907-72-3

C17-H17-N3-O.Cl-H

315.8022

Yamanouchi (Originator)

GASTROINTESTINAL DRUGS, Irritable Bowel Syndrome, Agents for, Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, 5-HT3 Antagonists

Launched-1996 JAPAN

US7652052

(−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride (yield 78.8%, 99.5% e.e.). FAB-MS (m/z): 280 [M+H⁺]

¹H NMR (DMSO-d₆, 30° C.): δ ppm (TMS internal standard): 1.82-1.95 (1H, m), 2.12-2.22 (1H, m), 2.66-2.94 (4H, m), 3.63-3.72 (1H, m), 3.88 (3H, s), 7.24 (1H, t, J=8.0 Hz), 7.30 (1H, t, J=8.0 Hz), 7.56 (1H, d, J=8.0 Hz), 8.22 (1H, d, J=8.0 Hz), 8.53 (1H, s), 8.90 (1H, s), 14.42 (1H, br)

…………………………………………………………………………………….

Ramosetron (INN) is a serotonin 5-HT₃ receptor antagonist for the treatment of nausea and vomiting.^[1] Ramosetron is also indicated for a treatment of “diarrhea-predominant irritable bowel syndrome in males”.^[2] In India it is marketed under the brand name of“IBset”.
It is only licensed for use in Japan and selected Southeast Asian countries.　In Japan it is sold under the tradename Iribo (イリボー). ^[3] Elsewhere it is commonly sold under the tradename Nasea and in India as Nozia (300 mcg/ml Inj. & 100 mcg Tab.) ^[4]

Fujii Y, Saitoh Y, Tanaka H, Toyooka H (February 2000). “Ramosetron for preventing postoperative nausea and vomiting in women undergoing gynecological surgery”.Anesth. Analg. 90 (2): 472–5. doi:10.1097/00000539-200002000-00043.PMID 10648342.
http://www.astellas.com/en/corporate/news/detail/astellas-launches-irribow-for.html
Summary in Japanese. Retrieved on September 4, 2012.
Abridged prescribing information – Nasea (MIMS Philippines). Retrieved on June 13, 2008.
Synthesis and 5-HT3 antagonistic activities of 4,5,6, 7-tetrahydrobenzimidazole derivatives
200th ACS Natl Meet (August 26-31, Washington DC) 1990, Abst MEDI 39

US7652052	1-27-2010	Process for producing ramosetron or its salt
US5576014	11-20-1996	Intrabuccally dissolving compressed moldings and production process thereof
US5496942	3-6-1996	5-substituted tetrahydrobenzimidazole compounds
US5466464	11-15-1995	Intrabuccally disintegrating preparation and production thereof
US5344927	9-7-1994	Tetrahydrobenzimidazole derivatives and pharmaceutical compositions containing same
WO9413284	6-24-1994	NEW USE OF 5-HT3 RECEPTOR ANTAGONISTS

AU 9048890; EP 0381422; JP 1991223278; US 5344927

CN1696128A	Nov 2, 2004	Nov 16, 2005	天津康鸿医药科技发展有限公司	New method for synthesizing Ramosetron Hydrochloride
CN1765896A	Oct 28, 2004	May 3, 2006	北京博尔达生物技术开发有限公司	Novel preparation method of ramosetron hydrochloride

US5496942 *	14 Feb 1994	5 Mar 1996	Yamanouchi Pharmaceutical Co., Ltd.	5-substituted tetrahydrobenzimidazole compounds
US5677326 *	30 Sep 1994	14 Oct 1997	Tokyo Tanabe Company Limited	Indoline compound and 5-HT.sub.3 receptor antagonist containing the same as active ingredient
US7358270	28 Jan 2005	15 Apr 2008	Astellas Pharma Inc.	Treating agent for irritable bowel syndrome
US7683090	18 Oct 2006	23 Mar 2010	Astellas Pharma Inc.	Treating agent for irritable bowel syndrome
US7794748	27 Aug 2004	14 Sep 2010	Yamanouchi Pharmaceutical Co., Ltd.	Stable oral solid drug composition

WO 2010024306

WO 2013005760

WO 2013100701

WO 2011001954

The chemical name of ramosetron is (−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole, and it has the structure represented by the formula (II).

It is known that ramosetron or a salt thereof has a potent 5-HT₃receptor antagonism (Patent Reference 1, Non-patent references 1 and 2), and it is on the market as a preventive or therapeutic agent for digestive symptoms (nausea, emesis) caused by administration of an anti-malignant tumor agent (cisplatin or the like). In addition, a possibility has been reported that ramosetron or a salt thereof may be useful as an agent for treating diarrheal-type irritable bowel syndrome or an agent for improving diarrheal symptoms of irritable bowel syndrome (Patent Reference 1), and its clinical trials are now in progress as an agent for treating diarrheal-type irritable bowel syndrome or an agent for improving diarrheal symptoms of irritable bowel syndrome.

As a process for producing ramosetron or a salt thereof, the following production methods are known.

Patent Reference 1 describes a production method shown by the following Production method A, namely a method for producing a tetrahydrobenzimidazole derivative (V) by allowing a heterocyclic compound (III) to react with a carboxylic acid represented by a formula (IV) or its reactive derivative.

(Production Method A)

(In the formula, X²is a single bond and binds to a carbon atom on the heterocyclic ring represented by Het.)

As an illustrative production method of ramosetron, Patent Reference 1 describes a production method (Production method A-1) in which racemic ramosetron are obtained by using 1-methyl-1H-indole as the compound (III), and N,N-diethyl-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide or N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine, which are acid amides, as the reactive derivative of compound (IV), and allowing them to undergo treatment with phosphorus oxychloride (Vilsmeyer reaction), and then their optical resolution is carried out by fractional crystallization using (+)-dibenzoyltartaric acid.

In addition, the Patent Reference 1 exemplifies an acid halide as one of the reactive derivatives of the compound (IV), and also describes another production method of the compound (V) (Production method A-2) in which the heterocyclic compound (III) is condensed with an acid halide of the compound (IV) by the Friedel-Crafts acylation reaction using a Lewis acid as the catalyst. However, illustrative production example of ramosetron by the Friedel-Crafts acylation reaction is not described therein.

Also, a method similar to the Production example A-1 is described in Non-patent References 1 and 2 as a production method of ramosetron.

In addition, Non-patent Reference 3 describes a method for producing ramosetron labeled with ¹¹C, represented by a Production method B. However, it discloses only the methylation step, and does not disclose a production method of nor-YM060 as the starting material.

(Production Method B)

(In the formula, nor-YM060 means (R)-5-[(1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole which was provided by the present applicant, DMF means dimethylformamide.)

Non-patent Reference 1: Chemical & Pharmaceutical Bulletin, 1996, vol. 44, no. 9, p. 1707-1716
Non-patent Reference 2: Drugs of the Future, 1992, vol. 17, no. 1, p. 28-29
Non-patent Reference 3: Applied Radiation and Isotopes, 1995, vol. 46, no. 9, p. 907-910
Patent Reference 1: JP-B-6-25153

LIU Qing-wen, XU Hao, TIAN Hua, ZHENG Liang-yu, ZHANG Suo-qin
Chemoenzymatic Synthesis of Ramosetron Hydrochloride

2012 Vol. 28 (1): 70-72 [Abstract] ( 1143 ) [HTML 1KB] [PDF 206KB] ( 1052 )
doi:http://www.cjcu.jlu.edu.cn/hxyj/EN/abstract/abstract13356.shtml

…………………………………………………………………………..

The Vilsmeier-type reaction of 1-methylindole (I) with 5 – (1-pyrrolidinocarbonyl) -4,5,6,7-1 H-tetrahydrobenzimidazole hydrochloride (II) and phosphorous oxychloride in 1,2-dichloroethane gives (-5? -. [(1-methyl-3-indolyl) carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazol e (III) Optical resolution of (III) with (+)-dibenzoyltartaric acid (DIBTA) in DMF -H2O, followed by exchange of the salt affords YM060.

………………………………………………….

Ondansetron: 1,2,3 ,9-Tetrahydro-9-methyl-3-[(2-methyl1-H-imidazole-1-yl)methyl]-4H-carbazol-4-one

Granisetron: Endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide

Tropisetron: Endo-1H-indole-3-carbocylic acid8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester

Dolasetron: 1H-Indole-3 -carboxylic acid (2a, 6a, 8a, 9up)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl Ester

Azasetron: (±)-N-Azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide

Alosetron: 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl- 1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one

Ramosetron

Galdansetron hydrochloride [USAN]
156712-35-5

Zosuquidar

December 24, 2013 3:50 am / Leave a comment

LY335979, RS-33295-198 (Zosuquidar)

Roche Palo Alto (Originator)

LY335979 (Zosuquidar) is a selective Pgp (P-glycoprotein) inhibitor with a Ki of 59 nM. LY335979 significantly enhanced the survival of mice implanted with Pgp-expressing murine leukemia (P388/ADR) when administered in combination with either daunorubicin, doxorubicin or etoposide.

LY335979 (Zosuquidar)

M.Wt: 636.99

Formula: C₃₂H₃₁F₂N₃O₂.3HCl

Name: Zosuquidar trihydrochloride

Elemental Analysis: C, 60.34; H, 5.38; Cl, 16.70; F, 5.97; N, 6.60; O, 5.02

CAS : 167465-36-3

167354-41-8 (free base)

Roche Bioscience (Originator), Eli Lilly and Company (Licensee).

US5654304, WO1994024107A1, WO2000075121, US6570016

Drug Des Discov 1992, 9(1): 69, Bioorg Med Chem Lett 1995, 5(21): 2473, Drugs Fut 2003, 28(2): 125

Zosuquidar is currently under development. It is now in “Phase 3” of clinical tests in the United States. Its action mechanism consists of the inhibition of P-glycoproteins; other drugs with this mechanism include tariquidar and laniquidar. P-glycoproteins are proteins which convert the energy derived from the hydrolysis of ATP to structural changes in protein molecules, in order to perform coupling, thus discharging medicine from cells. If P-glycoprotein coded with the MDR1 gene manifests itself in cancer cells, it discharges much of the antineoplastic drugs from the cells, making cancer cells medicine tolerant, and rendering antineoplastic drugs ineffective. This protein also manifests itself in normal organs not affected by the cancer (such as the liver, small intestine, and skin cells in blood vessels of the brain), and participates in the transportation of medicine. The compound Zosuquidar inhibits this P-glycoprotein, causing the cancer cells to lose their medicine tolerance, and making antineoplastic drugs effective

Clinicial trials: Clinical report published in 2010 showed that zosuquidar did not improve outcome in older acute myeloid leukemia, in part, because of the presence P-gp independent mechanisms of resistance. (Blood. 2010 Nov 18;116(20):4077-85.)

Zosuquidar is a potent P-glycoprotein inhibitor, which binds with high affinity to P-glycoprotein and inhibits P-glycoprotein-mediated multidrug resistance (MDR). P-glycoprotein, encoded by the MDR-1 gene, is a member of the ATP-binding cassette superfamily of transmembrane transporters and prevents the intracellular accumulation of many natural product-derived cytotoxic agents

Zosuquidar

U.S. Patent No. 5,112,817 to Fukazawa et al. discloses certain quinoline derivatives useful as anticancer drug potentiators for the treatment of multidrug resistance. One of the initially promising active agents there-disclosed is MS-073, which has the following structure:

MS-073

U.S. Pat. Nos. 5,643,909 and 5,654,304 disclose a series of 10,11- methanobenzosuberane derivatives useful in enhancing the efficacy of existing cancer chemotherapeutics and for treating multidrug resistance. One such derivative having good activity, oral bioavailability, and stability, is zosuquidar, a compound of formula (2R)-anti-5-

3 – [4-( 10, 11 -difluoromethanodibenzosuber-5-yl)piperazin- 1 -yl]-2-hydroxypropoxy) quinoline.

Zosuquidar

Given the limitations of previous generations of MDR modulators, three preclinical critical success factors were identified and met for zosuquidar: 1) it is a potent inhibitor of P-glycoprotein; 2) it is selective for P-glycoprotein; and 3) no pharmacokinetic interaction with co-administered chemotherapy is observed.

Zosuquidar is extremely potent in vitro (Kj = 59 nM) and is among the most active modulators of P-gp-associated resistance described to date. Zosuquidar has also demonstrated good in vivo activity in preclinical animal studies. In addition, the compound does not appear to be a substrate for P-gp efflux, resulting in a relatively long duration of reversal activity in resistant cells even after the modulator has been withdrawn.

Another significant attribute of zosuquidar as an MDR modulator is the minimal pharmacokinetic (PK) interactions with several oncolytics tested in preclinical models. Such minimal PK interaction permits normal doses of oncolytics to be administered and also a more straightforward interpretation of the clinical results.

Zosuquidar is generally administered in the form of the trihydrochloride salt. Conventional zosuquidar trihydrochloride formulations include those containing zosuquidar (50 mg as free base), glycine (15 mg), and mannitol (200 mg) dissolved in enough water for injection, to yield a free base concentration of 5 mg/mL. The formulation is filled into vials and lyophilized to give a vial containing 50 mg of free base. For such formulations, a 30 mL vial size is necessary to contain 50 mg of thezosuquidar formulation. For a typical >200 mg dose of zosuquidar, multiple 50 mg vials are needed to contain the formulation, greatly increasing manufacturing costs and reducing convenience for the end user {e.g., a pharmacist). Modified Cyclodextrins

Cyclodextrins are cyclic oligomers of glucose; these compounds form inclusion complexes with any drug whose molecule can fit into the lipophile-seeking cavities of the cyclodextrin molecule. See U.S. Pat. No. 4,727,064 for a description of various cyclodextrin derivatives. Cyclodextrins of preferred embodiments can include α-, β-, and χ-cyclodextrins. The α-cyclodextrins include six glucopyranose units, the β- cyclodextrins include seven glucopyranose units, and the χ-cyclodextrins include eight glucopyranose units. The β -cyclodextrins are generally preferred as having a suitable cavity size for zosuquidar. Cyclodextrin can be in any suitable form, including amorphous and crystalline forms, with the amorphous form generally preferred. Cyclodextrins suitable for use in the formulations of preferred embodiments include the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl, and maltotrosyl derivatives of β- cyclodextrin, carboxyamidomethyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, and diethylamino-β-cyclodextrin.

Pharmaceutical complexes including various cyclodextrins and cyclodextrin derivatives are disclosed in the following United States patents: U.S. Pat. No. 4,024,223; U.S. Pat. No. 4,228,160; U.S. Pat. No. 4,232,009; U.S. Pat. No. 4,351,846; U.S. Pat. No. 4,352,793; U.S. Pat. No. 4,383,992; U.S. Pat. No. 4,407,795; U.S. Pat. No. 4,424,209; U.S. Pat. No. 4,425,336; U.S. Pat. No. 4,438,106; U.S. Pat. No. 4,474,881; U.S. Pat. No. 4,478,995; U.S. Pat. No. 4,479,944; U.S. Pat. No. 4,479,966; U.S. Pat. No. 4,497,803; U.S. Pat. No. 4,499,085; U.S. Pat. No. 4,524,068; U.S. Pat. No. 4,555,504; U.S. Pat. No. 4,565,807; U.S. Pat. No. 4,575,548; U.S. Pat. No. 4,598,070; U.S. Pat. No. 4,603,123; U.S. Pat. No. 4,608,366; U.S. Pat. No. 4,659,696; U.S. Pat. No. 4,623,641; U.S. Pat No. 4,663,316; U.S. Pat. No. 4,675,395; U.S. Pat. No. 4,728,509; U.S. Pat. No. 4,728,510; and U.S. Pat. No. 4,751,095.

Chemically modified and substituted α-, β-, and χ-cyclodextrins are generally preferred over unmodified α-, β-, and χ-cyclodextrins due to improved toxicity and solubility properties. The degree of substitution of the hydroxy 1 groups of the glucopyranose units of the cyclodextrin ring can affect solubility. In general, a higher average degree of substitution of substituent groups in the cyclodextrin molecule yields a cyclodextrin of higher solubility.

Examples for Pgp inhibitors are cyclosporine A, valpodar, elacridar, tariquidar, zosuquidar, laniquidar, biricodar, S-9788, MS-209, BIBW-22 (BIBW-22-BS) , toremifene, verapamil, dexverapamil , quinine, quinidine, trans- flupentixol, chinchonine and others (J. Roberts, C. Jarry (2003) : J. Med. Chem. 46, 4805 – 4817) . The list of inhibitors of P-glycoprotein is increasing (e.g. Wang et al . (2002) : Bioorg. Med. Chem. Lett. 12, 571 – 574) .

Figure 2: Structures of BIBW-22, MS-209 and S-9788


US6087365	7-12-2000	10,11-methanodibenzosuberane derivatives
US7282585	10-17-2007	Salt and crystalline forms of (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline
US7582762	9-2-2009	Salt and crystalline forms of (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-YL)piperazin-1-YL]-2-hydroxypropoxy}quinoline

……………………

U.S. Pat. Nos. 5,643,909 and 5,654,304, incorporated herein by reference, disclose a series of 10,11-methanobenzosuberane derivatives useful in enhancing the efficacy of existing cancer chemotherapeutics and for treating multidrug resistance. (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride disclosed therein, is currently under development as a pharmaceutical agent.

U.S. pat. No. 5,654,304 (‘304), incorporated by reference herein, discloses a series of 10,11-(optionally substituted)methanodibenzosuberane derivatives useful in enhancing, the efficacy of existing cancer chemotherapeutics and for treating multidrug resistance. (2R)-anti-5-{3-[4-(10,11-Difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinolone trihydrochloride is disclosed in ‘304 and is currently under development as a pharmaceutical agent. WO00/75121 discloses Form I, a crystalline form of (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinolone trihydrochloride.

The art disclosed in U.S. Pat. No. 5,776,939, and U.S. Pat. No. 5,643,909 both incorporated herein by reference, and PCT Patent Applications (Publication numbers WO 94/24107 and 98/22112) teach the use of 1-formylpiperazine to introduce the piperazine group of the compound of formula II

Compound II is a mixture of syn isomer (III)

and anti isomer (IV)

The process as disclosed in U.S. Pat. Nos. 5,643,909 and 5,654,304 (represented by scheme A, below) involves (a) chromatographic separation(s) of the formyl piperazine compound; and (b) deformylation of the formyl piperazine compound to provide compound IV.https://www.google.co.in/patents/US6570016?cl=en

The process of the present invention uses piperazine to react with the (1aα,6α,10bα)-6-halo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cycloheptene compound or derivative, instead of formylpiperazine.

The process of the present invention is advantageous because piperazine is readily available in commercial quantities whereas 1-formylpiperazine, which was utilized in the process disclosed in U.S. Pat. No. 5,643,909 is often not readily available in commercial quantities. Additionally piperazine enjoys a significant cost advantage over 1-formylpiperazine.

The use of piperazine instead of 1-formylpiperazine is a significant advancement over the prior art because it obviates the need to deformylate or hydrolyze off the formyl group (step 6, scheme A), thereby providing fewer operational steps. U.S. Pat. No. 5,643,909 teaches the separation of the 1-formylpiperazine compounds by chromatography or repeated crystallization. The present invention obviates the need for chromatographic separations of the formylpiperazine diastereomeric addition compounds (see step 4, scheme A)

EXAMPLES

The following examples and preparations are illustrative only and are not intended to limit the scope of the invention in any way.

Preparation 1 R-1-(5-Quinolinyloxy)-2,3-epoxypropane

A mixture of 5-hydroxyquinoline (5.60 g, 38.6 mmol), R-glycidyl nosylate (10.0 g, 38.6 mmol), powdered potassium carbonate (11.7 g, 84.9 mmol), and N,N-dimethylformamide (100 mL) was stirred at ambient temperature until HPLC analysis (40% acetonitrile/60% of a 0.5% aqueous ammonium acetate solution, 1 mL/min, wavelength=230 nm, Zorbax RX-C8 25 cm×4.6 mm column) indicated complete disappearance of glycidyl nosylate (approximately 6 hours). The reaction mixture was filtered through paper and the filter cake was washed with 200 mL of a 3:1 mixture of MTBE and methylene chloride. The filtrate was washed with 200 mL of water and the aqueous layer was extracted four times with 100 mL of 3:1 MTBE/methylene chloride. The combined organic layers were dried over 30 grams of magnesium sulfate and the dried solution was then stirred with 50 grams of basic alumina for 30 minutes. The alumina was removed by filtration and the filter cake was washed with 200 mL of 3:1 MTBE/methylene chloride. The filtrate was concentrated to a volume of 100 mL, 300 mL of MTBE were added, and the solution was again concentrated to 80 mL. After heating to 50° C., the solution was treated with 160 mL of heptane dropwise over 15 minutes, allowed to cool to 40° C., and seeded, causing the formation of a crystalline precipitate. The mixture was stirred for two hours at ambient temperature and then at 0-5° C. for an additional 2 hours. The crystals were filtered, washed with cold heptane, and dried to provide 5.68 g (73.2%) of (2R)-1-(5-quinolinyloxy)-2,3-epoxypropane as white needles.

mp 79-81° C.;

[α]²⁵ _D−36.4° (c 2.1, EtOH);

¹H NMR (500 MHz, CDCl₃)δ 2.83 (dd, J=4.8, 2.7 Hz, 1H), 2.97 (m, 1H), 3.48 (m, 1H), 4.10 (dd, J=11.0, 6.0 Hz, 1H), 4.43 (dd, J=11.0, 2.7 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 7.38 (dd, J=8.5 Hz, 4.1 Hz, 1H), 7.59 (m, 1H), 7.71 (d, J=8.5 Hz, 1H), 8.61 (m, 1H), 8.90 (m, 1H).

Example 1 (2R)-Anti-1-[4-(10,11-difluoromethano-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperazin-1-yl]-3-qunolin-5-yloxy)-propan-2-ol Trihydrochloride

Preparation of the above compound is exemplified in the following preparative steps.

Step 1 1,1-Difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6 (1H)-one

A solution of sodium chlorodifluoroacetate (350 g) in diglyme (1400 mL) was added dropwise over 4 to 8 hours, preferably over 6 hours, to a solution of 5H-dibenzo[a,d]cyclo-hepten-5-one (25 g) in diglyme (500 mL), with stirring, and under nitrogen, maintaining the reaction temperature at 160°-165° C. The cooled reaction mixture was poured into water (1.8 L) and extracted with ether (1.8 L). The organic phase was washed with water, dried over sodium sulfate (Na₂SO₄), and evaporated. The residue was recrystallized from ethanol, then from acetone/hexane to give 14 g of 1,1-difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6(1H)-one.

mp 149.6° C.

Flash chromatography of the combined mother liquors on silica gel, eluting with 20% acetone/hexane, gave an additional 6.5 g of the target compound.

Step 2 (1aα,6β,10bα)-1,1-Difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol

A solution of 1,1-difluoro-1a,10b-dihydro-dibenzo[a,e]cyclopropa[c]cyclohepten-6(1H)-one (20.4 g) in tetrahydrofuran/methanol (1:2, 900 mL) was cooled in an ice bath. Sodium borohydride (12 g) was added in portions. The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 2 hours, then poured into water. The product was filtered off, washed with water, and dried to give 20 g of (1aα,6β,10bα)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol (ii).

mp 230.1°-230.6° C.

Step 2A Combined Steps 1 and 2 Procedure (1aα,6β,10bα)-1,1-Difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol

To a solution of 103.1 g (0.500 mol) of 5H-dibenzo[a,d]cyclohepten-5-one (2) in 515 mL of triethylene glycol dimethyl ether heated to between 180° C. and 210° C. was added over 7 hours, 293.3 g (2.15 mol) of chlorodifluoroacetic acid lithium salt (as a 53% by weight solution in ethylene glycol dimethyl ether). The ethylene glycol dimethyl ether was allowed to distill from the reaction as the salt addition proceeded. The GC analysis of an aliquot indicated that all of the 5H-dibenzo[a,d]cyclohepten-5-one had been consumed. The reaction was cooled to ambient temperature and then combined with 400 mL of ethyl acetate and 75 g of diatomaceous earth. The solids were removed by filtration and washed with 300 mL of ethyl acetate. The washes and filtrate were combined and the ethyl acetate was removed by concentration under vacuum leaving 635 g of dark liquid. The dark liquid was cooled to 18° C. and to this was added, over 15 minutes, 6.62 g (0.175 mol) of sodium borohydride (as a 12% by wt solution in 14 M NaOH). After stirring for 2 h the reaction was quenched by careful addition of 900 mL of a 1:3.5:4.5 solution of conc. HCl-methanol-water. The suspension was stirred for 30 min and the crude product was collected by filtration, washed with 600 mL of 1:1 methanol-water and dried to 126.4 g of dark brown solid. The crude product was slurried in 600 mL of methylene chloride, filtered, washed twice with 150 mL portions of methylene chloride, and dried to 91.6 g (71%) of (1aα,6β,10bα)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-ol. Gas Chromatography (GC) Conditions; Column: JW Scientific DB-1, Initial Temperature 150° C. for 5 min, 10° C./min ramp, Final temp 250° C. for 5 min. t_R: intermediate, 11.5 min; reaction product (alcohol), 11.9 min; starting material, 12.3 minutes.

Step 3 Preparation of (1aα,6α,10b)-6-bromo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa-[c]cycloheptene

A slurry of (1aα,6β,10bα)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-ol (3.0 g, 11.6 mmol, 1.0 equiv) in heptane (24 mL) was treated with 48% HBr (1.58 mL, 14.0 mmol, 1.2 equiv) and the reaction was heated at reflux with vigorous stirring for 2.5 hr. Solvent was then removed by atmospheric distillation (bp 95-98° C.) until approximately 9 mL of distillate was collected. The reaction was cooled and treated with EtOAc (15 mL), Na₂SO₄and activated charcoal. The mixture was stirred at RT for 15 min and filtered through hyflo. The filter cake was washed with 50:50 EtOAc:heptane and the filtrate was concentrated in vacuo to provide the title product as a crystalline solid.

mp 119° C. (3.46 g corr., 93%);

¹H NMR (500 MHz CDCl₃) δ 7.20-7.41 (8H, m), 5.81 (1H, s), 3.41 (2H, d, J 12.5 Hz);

¹³CNMR (126 MHz CDCl₃) δ 141.3, 141.2, 133.5, 130.1, 129.8, 128.3, 128.2, 112.9, 110.6, 110.5, 108.3, 53.6, 30.2, 30.1, 30.0.

Anal. Calcd. For C₁₆H₁₁BrF₂: C, 59.84; H, 3.45. Found: C, 60.13; H, 3.50.

Step 3A Preparation of (1aα,6α,10bα)-6-Bromo-1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene

To a stirred suspension of (1aα,6β,10bα)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-ol, (18.4 g, 71.2 mmol) in 151 mL of methylene chloride which had been cooled to 10-17° C. was added phosphorous tribromide (9.6 g, 35.6 mmol) dropwise over 15 minutes. The cooling bath was removed and the reaction was stirred for 2 hours at ambient temperature. Analysis by gas chromatography indicated complete consumption of starting material. Cold water (92 mL) and activated carbon (1.84 g) were added and the resulting mixture was stirred for 30 minutes. The activated carbon was removed by filtration through Hyflo brand filter aid and the two phases were separated. The organic phase was washed with water (184 mL×2), brine (184 ml), dried over magnesium sulfate and concentrated to dryness under vacuum, affording 21.7 g (94.8%) of (1aα,6α,10bα)-6-bromo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene.

¹H NMR (CDCl₃, 300 MHz) δ 3.36 (s, 1H), 3.40 (s, 1H), 5.77 (s, 1H), 7.16-7.38 (m, 8H).

Steps 4 and 5 (1aα,6α,10bα)-1-(1,1-Difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl)-piperazine, Hydrobromide Salt

To a solution of 237.5 g (0.739 mol) of (1aα,6α,10bα)-6-bromo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]-cyclopropa[c]cycloheptene in 3.56 L of acetonitrile was added 207.7 g (2.41 mol) of piperazine and the mixture was heated to reflux for 2 hours, at which time analysis by gas chromatography showed complete consumption of (1aα,6α,10bα)-6-bromo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene (iii) and formation of a mixture of syn and anti piperazine compounds (III and IV) in an anti-syn ratio of 55:45. The reaction was cooled to about 7° C. and stirred for 30 minutes at that temperature. The reaction mixture was filtered to remove the precipitated syn-isomer (III) and the filter cake was washed with 250 mL of acetonitrile. The combined filtrate and wash were concentrated under vacuum to 262.4 grams of a foam which was dissolved in 450 mL of acetonitrile with heating. The solution was cooled to about 12° C. in an ice bath and stirred for 1 hour at that temperature. The precipitated syn-piperazine compound of formula (III) was filtered and washed with 125 ml of acetonitrile. The combined filtrate and wash were concentrated under vacuum to 194.1 g and dissolved in 1.19 L of ethyl acetate. The organic solution was washed sequentially with 500 mL portions of 1N sodium hydroxide, water, and saturated sodium chloride. The ethyl acetate solution was dried over sodium sulfate and concentrated to give 137.0 grams of residue which was dissolved in 1.37 L of methylene chloride and seeded with (1aα,6α,10bα)-1-(1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-yl)-piperazine, hydrobromide salt, followed by the addition of 70.8 grams of 48% aqueous hydrobromic acid. The mixture was stirred for about 45 minutes, causing the anti-isomer to crystallize as its hydrobromide salt. The crystals were filtered, washed with methylene chloride, and dried to provide purified hydrobromide salt of compound (IVa), shown by HPLC to have an anti-syn ratio of 99.3:0.7. Treatment of the isolated hydrobromide salt of compound (IVa) with aqueous sodium hydroxide, extraction into methylene chloride, separation of the aqueous layer and concentration to dryness gave 80.1 grams (33.2% yield based on starting material) of (1aα,6α,10bα)-1-(1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-yl)-piperazine as the free base. Acidification of a solution of the free base in 800 mL of methylene chloride by addition of 41.2 g of 48% hydrobromic acid as described above afforded 96.4 g of pure hydrobromide salt (title compound) with an anti-syn ratio of 99.8:0.2 (HPLC), mp 282-284° C. ¹H NMR (DMSO-d₆) δ 2.41 (m, 4H), 3.11 (m, 4H), 3.48 (d, J=12.4 Hz, 2H), 4.13 (s, 1H), 7.2 (m, 8H), 8.65 (bs, 2H). ¹³C NMR (DMSO-d₆) δ 28.0, 42.9, 48.0, 75.1, 108.5, 112.9, 117.3, 127.5, 128.0, 128.6, 129.6, 132.4, 141.3. IR: (KBr) 3019, 2481, 1587, 1497, 1298 cm⁻¹. Anal. Calcd for C₂₀H₂₁BrF₂N₂: C, 58.98; H, 5.20; N, 6.88. Found: C, 58.75; H, 5.29; N, 7.05.

Step 6 Preparation of (2R)-Anti-1-[4-(10,11-difluoromethano-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperazin-1-yl]-3-quinolin-5-yloxy)propan-2-ol Trihydrochloride

A suspension of (1aα,6α,10bα)-1-(1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-yl)-piperazine, hydrochloride compound of formula IVa (5.41 g, 14.9 mmol) and powdered sodium carbonate (3.16 g, 29.8 mmol) in 54 mL of 3A ethanol was stirred at ambient temperature for 1 hour. R-1-(5-quinolinyloxy)-2,3-epoxypropane (3.00 g, 14.9 mmol) was added in one portion and the reaction mixture was heated to 65° C. for 19 hours. HPLC analysis (Gradient system with solvent A (acetonitrile) and solvent B (0.02M sodium monophosphate buffer containing 0.1% triethylamine adjusted to pH 3.5 with phosphoric acid) as follows: 0-12 min, 30% solvent A/70% solvent B; 12-30 min, linear gradient from 30% to 55% solvent A/70% to 45% solvent B; 30-35 min, 55% solvent A/45% solvent B, 1 mL/min, 1=240 nm, Synchropak SCD-100 25 cm×4.6 mm column) indicated the total consumption of the piperazinyl compound of formula (IV). The mixture was allowed to cool to room temperature, filtered through a plug of silica gel, and eluted with an additional 90 mL of ethanol. The eluent was concentrated to a volume of approximately 60 mL and heated to 65° C. with stirring. A solution of HCl in ethanol (16.1 g at 0.135 g/g of solution, 59.6 mmol) was added dropwise over 10 minutes and the resultant product solution was seeded, causing the trihydrochloride salt to precipitate. The mixture was allowed to cool to ambient temperature and stirred slowly (less than 100 RPM) for 2 hours. The precipitate was filtered, washed with ethanol, and dried in vacuo at 50° C. to give the crude trihydrochloride salt which was further purified by recrystallization from methanol/ethyl acetate to provide 7.45 g (78.4%) of (2R)-anti-1-[4-(10,11-difluoromethano-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperazin-1-yl]-3-quinolin-5-yloxy)-propan-2-ol trihydrochloride.

Step 6a

The syn isomer compound of formula (III) isolated as described supra (combined steps 4 and 5), can be utilized to produce the corresponding syn-5-{3-[4-(10,11-difluoromethano-dibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (XII) essentially as shown below for the free base of the anti isomer (IVa)in step 6.

https://www.google.co.in/patents/US6570016?cl=en

………………………………………

http://www.google.it/patents/WO1994024107A1?cl=en

REACTION SCHEME 1

FormuIa 1

Formula 1

Formula 2 Formula 2

Formula 3

Formula 4

Formula I

……………………………………….

http://www.google.com/patents/WO2000075121A3

¹HNMR (500 MHz DMSO-d₆) δ9.41 (2H, br. s), 7.17-7.31 (8H, m), 4.17 (1H, s), 3.52 (2H, d, J=12.4 Hz), 3.11 (4H, br. s), 2.48-2.51 (4H, m)

¹³CNMR (126 MHz DMSO-d₆) δ142.3, 133.4, 130.5, 129.6, 129.0, 128.4, 115.9, 113.6, 111.3, 76.2, 49.0, 43.6, 29.2, 29.1, 29.0; FD MS: m/e 326 (M+).

Anal. Calcd. For C₂₀H₂₁ClF₂N₂: C, 66.20; H, 5.83; N, 7.72.

Found: C, 66.08; H, 5.90; N, 7.72.

…………………………………………..

http://www.google.com/patents/US6570016?cl=fr

(2R)-Anti-1-[4-(10,11-difluoromethano-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperazin-1-yl]-3-qunolin-5-yloxy)-propan-2-ol Trihydrochloride

……………….

Chemical Shift Data and Peak Assignments for the Crystal Forms.

https://www.google.co.in/patents/US7282585?pg=PA1&dq=US+7282585&hl=en&sa=X&ei=zN64UsC2FIaSrgfS8YGIBQ&ved=0CDcQ6AEwAA

Form II has a solid-state ¹³C NMR spectrum comprised of isotropic peaks at the following chemical shifts: 29.9, 50.1, 55.3, 62.0, 66.5, 72.0, 75.8, 104.8, 107.5, 108.2, 109.1, 110.2, 112.0, 118.4, 119.5, 120.1, 123.1, 128.7, 131.1, 133.0, 134.8, 136.4, 136.9, 139.9, 140.0, 142.3, 144.5, 146.6, 149.0, 144.2, 153.0 and 153.6 ppm.

Form III has a solid-state ¹³C NMR spectrum comprised of isotropic peaks at the following chemical shifts: 30.3, 50.4, 59.1, 63.2, 72.8, 77.2, 109.1, 110.2, 112.2, 112.8, 118.7, 119.5, 119.9, 121.0, 122.2, 123.0, 128.9, 130.6, 132.7, 134.0, 136.4, 140.0, 141.0, 141.8, 142.5, 143.3, 146.1, 153.1, 153.8 and 154.7 ppm.

Bayer, Onyx win early FDA OK for Nexavar (sorafenib) in thyroid cancer

November 25, 2013 3:57 am / 4 Comments on Bayer, Onyx win early FDA OK for Nexavar (sorafenib) in thyroid cancer

The U.S. Food and Drug Administration said on Friday it has expanded the approved use of the cancer drug Nexavar to include late-stage differentiated thyroid cancer.

Differentiated thyroid cancer is the most common type of thyroid cancer, the FDA said. The National Cancer Institute estimates that 60,220 people in the United States will be diagnosed with it and 1,850 will die from the disease in 2013.

The drug, made by Germany’s Bayer AG and Onyx Pharmaceuticals, is already approved to treat advanced kidney cancer and liver cancer that cannot be surgically removed. Onyx was acquired by Amgen Inc earlier this year.

READ ABOUT SORAFENIB IN MY EARLIER BLOGPOST

https://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/

Daiichi Sankyo anticoagulant edoxaban succeeds in Phase III

November 21, 2013 3:59 am / 1 Comment on Daiichi Sankyo anticoagulant edoxaban succeeds in Phase III

Edoxaban, DU-176b

Daiichi Sankyo, APPROVED IN JAPAN as tosylate monohydrate salt in 2011 for the prevention of venous embolism in patients undergoing total hip replacement surgery

for synthesis see….http://www.sciencedirect.com/science/article/pii/S0968089613002642 Bioorganic & Medicinal Chemistry 21 (2013) 2795–2825, see s[pecific page 2808 for description ie 14/31 of pdf

WO 2010071121, http://www.google.com/patents/WO2010071121A1

WO 2007032498

N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide

NOV20, 2013

Daiichi Sankyo will file edoxaban on both sides of the Atlantic shortly after the bloodthinner proved as effective and safer than warfarin in a Phase III trial of patients with atrial fibrillation.

The company has presented data on edoxaban, a once-daily oral factor Xa inhibitor, at the American Heart Association meeting in Dallas, from a study involving 21,105 patients across 46 countries. The drug, evaluated in 60mg and 30mg doses, met its primary endpoint of non-inferiority compared to warfarin for the prevention of stroke or systemic embolic events in patients with non-valvular AF.http://www.pharmatimes.com/Article/13-11-20/Daiichi_Sankyo_anticoagulant_edoxaban_succeeds_in_Phase_III.aspx

Edoxaban (INN, codenamed DU-176b, trade name Lixiana) is an anticoagulant drug which acts as a direct factor Xa inhibitor. It is being developed by Daiichi Sankyo. It was approved in July 2011 in Japan for prevention of venous thromboembolisms (VTE) following lower-limb orthopedic surgery.^[1]

In animal studies, edoxaban is potent, selective for factor Xa and has good oral bioavailability.^[2]

Daichi Sankyo’s edoxaban tosilate is an orally administered
coagulation factor Xa inhibitor that was approved and launched
in Japan for the preventive treatment of venous thromboembolic
events (VTE) in patients undergoing total knee arthroplasty, total
hip arthroplasty, or hip fracture surgery. Edoxaban has been
shown to have a rapid onset of anticoagulant effect due to short
Tmax (1–2 h) after dosing and sustained for up to 24 h post-dose.
Marketed under the brand name Lixiana, it is currently in phase
III studies in the US for the prevention of stroke and systemic embolic
events in patients with atrial fibrillation (AF) and venous
thromboembolism (VTE).

Several Phase II clinical trials have been conducted, for example for thromboprophylaxis after total hip replacement^[3] (phase III early results compare well to enoxaparin^[4]), and for stroke prevention in patients with atrial fibrillation^[5]^[6].Those papers follow similar recent major trials showing similar results for the other new factor Xa inhibitors, rivaroxaban and apixaban.

A large phase III trial showed that edoxaban was non inferior to warfarin in preventing recurrent venous thromboembolic events with fewer episodes of major bleeding.^[7]

“First market approval in Japan for LIXIANA (Edoxaban)”. Press Release. Daiichi Sankyo Europe GmbH. 2011-04-22.
Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, Morishima Y, Shibano T (September 2008). “DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles”. J. Thromb. Haemost. 6 (9): 1542–9. doi:10.1111/j.1538-7836.2008.03064.x. PMID 18624979.
Raskob, G.; Cohen, A. T.; Eriksson, B. I.; Puskas, D.; Shi, M.; Bocanegra, T.; Weitz, J. I. (2010). “Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement”. Thrombosis and Haemostasis 104 (3): 642–649. doi:10.1160/TH10-02-0142.PMID 20589317. edit
“Phase III Trial Finds Edoxaban Outclasses Enoxaparin in Preventing Venous Thromboembolic Events”. 8 Dec 2010.
Weitz JI, Connolly SJ, Patel I, Salazar D, Rohatagi S, Mendell J, Kastrissios H, Jin J, Kunitada S (September 2010). “Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation”. Thromb. Haemost. 104 (3): 633–41. doi:10.1160/TH10-01-0066.
Edoxaban versus Warfarin in Patients with Atrial Fibrillation Robert P. Giugliano, M.D., Christian T. Ruff, M.D., M.P.H., Eugene Braunwald, M.D., Sabina A. Murphy, M.P.H., Stephen D. Wiviott, M.D., Jonathan L. Halperin, M.D., Albert L. Waldo, M.D., Michael D. Ezekowitz, M.D., D.Phil., Jeffrey I. Weitz, M.D., Jindřich Špinar, M.D., Witold Ruzyllo, M.D., Mikhail Ruda, M.D., Yukihiro Koretsune, M.D., Joshua Betcher, Ph.D., Minggao Shi, Ph.D., Laura T. Grip, A.B., Shirali P. Patel, B.S., Indravadan Patel, M.D., James J. Hanyok, Pharm.D., Michele Mercuri, M.D., and Elliott M. Antman, M.D. for the ENGAGE AF-TIMI 48 InvestigatorsDOI: 10.1056/NEJMoa1310907
“Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism”. N. Engl. J. Med. August 2013. doi:10.1056/NEJMoa1306638. PMID 23991658.
WO 03/000657 pamphlet WO 03/000680 pamphlet WO 03/016302 pamphlet WO 04/058715 pamphlet WO 05/047296 pamphlet WO 07/032498 pamphlet WO 08/129846 pamphlet WO 08/156159 pamphlet
J Am Chem Soc 1978, 100(16): 5199

Drug formulation , lixiana, edoxaban tosylate monohydrate, CAS 912273-65-5, C24 H30 Cl N7 O4 S . C7 H8 O3 S . H2 O, 738.274

N¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonic acid monohydrate represented by the following formula (A) (hereinafter, also referred to as compound A) :
is known as a compound that exhibits an inhibitory effect on activated blood coagulation factor X (FXa), and is useful as a preventive and/or therapeutic drug for thrombotic diseases (Patent Literature 1 to 8).
For example, a method comprising mixing the free form of compound A represented by the following formula (B) (hereinafter, also referred to as compound B):
with p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate, followed by crystallization from aqueous ethanol, is known as a method for obtaining compound A (Patent Literature 1 to 8). These literature documents do not make any mention about adding p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate in a stepwise manner in the step of obtaining compound A from compound B.

Citation ListPatent Literature

- Patent Literature 1: International Publication No. WO 03/000657
- Patent Literature 2: International Publication No. WO 03/000680
- Patent Literature 3: International Publication No. WO 03/016302
- Patent Literature 4: International Publication No. WO 04/058715
- Patent Literature 5: International Publication No. WO 05/047296
- Patent Literature 6: International Publication No. WO 07/032498
- Patent Literature 7: International Publication No. WO 08/129846
- Patent Literature 8: International Publication No. WO 08/156159

SIMILAR

OTHER SALTS

Edoxaban hydrochloride
CAS Number: 480448-29-1
Molecular Formula: C₂₄H₃₀ClN₇O₄S · HCl
Molecular Weight: 584.52 g.mol^-1

Edoxaban is reported to be a member of the so-called “Xaban-group” and as such to be a low molecular inhibitor of the enzyme factor Xa, participating in the blood coagulation system. Therefore, edoxaban is classified as an antithrombotic drug and its possible medical indications are reported to be treatment of thrombosis and thrombosis prophylaxis after orthopaedic operations, such as total hip replacement, as well as for stroke prevention in patients with atrial fibrillation, the prophylaxis of the acute coronary syndrome and the prophylaxis after thrombosis and pulmonary embolism.

The IUPAC name for edoxaban is N’-(5-chloropyridin-2-yl)-N-[(15,2^,4S)-4- (dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[l ,3]thiazolo[5,4-c]pyridine-2- carbonyl)amino]cyclohexyl]oxamide. The chemical structure of edoxaban is shown in the formula (1) below:

formula ( 1 ) While Edoxaban is reported to be soluble in strongly acidic aqueous solutions, its solubility is considered to be very low in neutral or alkaline aqueous media. EP 2 140 867 A 1 claims an edoxaban-containing pharmaceutical composition comprising a water-swelling additive and/or a sugar alcohol. Further, it is alleged that compositions comprising lactose or cornstarch do not have good dissolution properties. The claimed pharmaceutical compositions in EP 2 140 867 Al are considered to show good dissolution properties in a neutral aqueous medium as well. Tablets comprising said composition were produced by wet granulation. However, it turned out that prior art pharmaceutical formulations comprising edoxaban being suitable for oral administration are still improvable with regards to dissolution rate and bioavailability. Further, stability and content uniformity of the known formulations could be improved. Further, due to the intolerance of many people to sugar alcohol(s), such as sorbitol, the use of sugar alcohol(s) should be avoided.

Quetiapine

November 11, 2013 9:43 am / 3 Comments on Quetiapine

Quetiapine, astrazeneca

111974-69-7 cas

US 5,948,437*PED, NDA 022047 Appr may 17 2007 sustained release formulation

NDA 020639 approved 26.9.1997

patent approved expiry

United States	5948437	1997-11-28	2017-11-28
United States	4879288	1994-09-26	2011-09-26
Canada	2251944	2007-04-10	2017-05-27

United States

4879288

1994-09-26

2011-09-26

Quetiapine (/k w ɨ ˈ t aɪ .ə p iː n / kwi-ty-ə-peen) (branded as Seroquel, Xeroquel, Ketipinor) is a short-acting atypical antipsychotic approved for the treatment of schizophrenia, bipolar disorder, and along with an antidepressant to treat major depressive disorder.

Annual sales are approximately $5.7 billion worldwide, with $2.9 billion in the United States. The U.S. patent, which expiredv in 2011, received a pediatric exclusivity extension which pushed its expiration to March 26, 2012.The patent has already expired in Canada. Quetiapine was developed by AstraZeneca from 1992-1996 as an improvement from first generation antipsychotics. It was first approved by the FDA in 1997. There are now several generic versions of quetiapine, such as Quepin, Syquel and Ketipinor

Seroquel (quetiapine) is a psychotropic medication that is used to treat schizophrenia in adults and children who are at least 13 years old. Seroquel is also used in the treatment of major depression and bipolar disorder. Side effects of Seroquel may include mood or behavior changes, constipation, drowsiness, headache, and trouble sleeping. Older adults with dementia may have a slightly increased risk of death when taking this medication.

Dosing preparations are 25, 50, 100, 200, 300, and 400 mg tablets. Seroquel may interact with a number of other drugs, including, but not limited to, antidepressant medications, antifungal drugs, steroids, cimetidine (Tagamet), thioridazine (Mellaril), and lorazepam (Ativan). During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor. Seroquel passes into breast milk and may have undesirable effects on a nursing infant.

Quetiapine fumarate is a psychotropic agent belonging to a chemical class of dibenzothiazepine derivatives, designated chemically as 2-[2-(4-dibenzo [b,f] [l,4]thiazepin -1 l-yl-l-piperazinyl)ethoxy]-ethanol fumarate (2: l )(salt). Its molecular formula is C42H5oN₆0₄S₂*C₄H₄0₄ having a molecular weight of 883.1 1. The structural formula is:

Quetiapine is marketed as immediate release as well as extended release tablets in United States under the trade name Seroquel® and Seroquel XR® by AstraZeneca.

Quetiapine was first described in a patent publication EP 240228 (US 4879288 ). It is prepared starting from dibenzo[b,f][1,4]thiazepin-11-[10H]one of formula II

which is first halogenated with phosphorous oxychloride, then isolated and condensed with 1-(2-hydroxyethoxy) ethyl piperazine to obtainquetiapine. After purification by flash chromatography the yield was 77.7 %. As an alternative to halogenation a process via a thioether in the first step is presented.
In the process claimed in EP 282236 the piperazine ring is first condensed with 11-chloro-dibenzo[b,f][1,4] thiazepine and thereafterquetiapine is obtained by its reaction with haloethoxy ethanol. The base is further converted to the hemifumarate salt, which was isolated in 78 % yield.
WO 2006/117700 describes a process of EP ‘228 improved by the destruction of phosphorous oxychloride in situ to decrease the amount of hazardous waste. Phosphorous oxychloride is used only about 1 equivalent to the compound of formula II whereas in the process of EP 240228 it was used in about 15 equivalents.
A reaction of 11-chlorodibenzo[b,f][1,4]thiazepine with a piperazine moiety in the presence of a halide is the improvement described inWO 2006/113425 . The process is said to yield quetiapine in high purity.
In WO 2006/094549 there is described a process which avoids the halogenation step and the use of hazardous phosphorous halogenating agents by the reaction of 10H-dibenzo[b,f][1,4] thiazepin-11-one directly with a piperazine derivative. This is achieved by performing the reaction in the presence of titanium alkoxide. Yields of 50 – 75 % as a fumarate salt are reported. Expensive titanium alkoxide is used from about 2 to 3 fold excess to starting compound of formula II.
Also the process of US 2006/0063927 avoids the use of phosphorous compounds in halogenation by using oxalyl chloride as a halogenating agent. The imino chloride is obtained in 66 % yield. The reaction of 11-chloro-dibenzo[b,f][1,4] thiazepine with 1-(2-hydroxyethoxy)ethylpiperazine is performed either in the presence of a base in an organic solvent or in a two-phase system. However, the reagent used, oxalyl chloride is poisonous and requires special attention.
A one-pot process for the preparation of quetiapine is described inWO 2007/020011 . Phosphorous oxychloride is used in halogenation step about one equivalent to 10H-dibenzo[b,f][1,4] thiazepin-11-one.
WO 2007/004234 describes a process comprising the reaction of chloro ethoxy ethanol with piperazinyl-dibenzo[b,f][1,4] thiazepine dihydrocloride, which is obtained by halogenating the dibenzo[b,f][1,4] thiazepin-11-[10H]one, reacting the imino chloride obtained with piperazine, and treating the obtained compound with an alcoholic solution of hydrogen chloride.
All processes described above use dibenzo[b,f][1,4] thiazepin-11-[10H]one as a starting material. Its preparation requires several steps, and in most cases it has to be even halogenated to the imino chloride before the piperazine moiety can be condensed with it. Halogenating reagents, e.g. phosphorous oxychloride have been used in excess and their removal from the reaction mixture requires evaporation of large amounts.
A different approach using protected intermediates is used e.g. in routes described in WO 2005/014590 , WO 2005/028457 , WO 2005/028458and WO 2005/028459 . In some cases the reactions may be performed in one pot fashion and no extra purification steps are needed to get a pure product in high yield. However, protection and deprotection steps used lengthen the processes and shorter processes for the preparation of quetiapine are still needed.
Similar compounds are prepared in US 3, 539,573

U.S. Patent 4,879,288 discloses 1 l-[4-[2-(2-hydroxyethoxy) ethyl] -1 – piperazinyl] dibenzo [b, f] [1 , 4] thiazepine as an antipsychotic drug of dibenzothiazepine class suitable for treatment of various psychotic disorders.

US patent 5,948,437 discloses sustained release formulations of quetiapine using gelling agents such as hydroxypropyl methylcellulose and its derivatives that create a gel structure after contact with water. US patent 4,547,57 1 describes process for the preparation of carboxymethyl ethyl cellulose (CMEC) polymer.

WO 2004012699 discloses modified release dosage forms prepared by using dual – retard— technique comprising micro matrix particles containing quetiapine and hydrophobic release controlling agents, which are coated with hydrophobic release controlling agents.

WO 2005041935 discloses matrix composition comprising quetiapine and a wax material.

WO 2007086079 discloses sustained release compositions of quetiapinecomprising a channelizer and a rate controlling polymer.

WO 2008060228 discloses extended release compositions comprisingquetiapine, hydroxypropyl methyl cellulose and sodium citrate dihydrate.

WO 20091 13051 discloses sustained release compositions containingquetiapine and one or more non-gelling and/or waxy excipients.

WO 2010001413 discloses sustained release dosage forms comprisingquetiapine or its pharmaceutically acceptable salts and one or more non-gellable release controlling polymers.

WO 2010028794 discloses a matrix formulation in the form of a retard tablet comprising quetiapine, at least one matrix-forming, water-insoluble, non-swellable auxiliary agent, and at least one water-soluble binding agent.

The synthesis of quetiapine begins with a dibenzothiazepinone. The lactam is first treated with phosphoryl chloride to produce a dibenzothiazepine. A nucleophilic substitutionis used to introduce the sidechain.U.S. Patent 4,879,288.

Atypical antipsychotic quetiapine (Quetiapine, drugs used its fumarate) for the treatment of schizophrenia (schizophrenia) and dry depressive disorder (bipolar disorder), trade name Seroquel, produced by AstraZeneca. Star molecule drugs, the global sales of about $ 6 billion.

Quetiapine synthesis o-nitro-chlorobenzene ( 1 ) starting a thiophenol occurred and SNAr reaction, hydrogenation of nitro group to an amino group after reaction with phosgene isocyanate 2 , 2 ring closure in hot sulfuric acid to obtain 3 , 3 with phosphorus oxychloride isomerization chlorinated4 , 4 and 5 SNAr reaction occurs fumarate salt formation with quetiapine fumarate.

The route of the compound 4 is not stable enough, then there are improved route. 6 and the reaction of phenyl chloroformate 7

Quetiapine fumarate, Bis [2-(2-[4-(dibenzo[b,f][1,4]thiazepin-11-yl]ethoxy)ethanol] fumarate (IUPAC)2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol-(E)-2-butanedioate (2:1) salt), [ICI 204,636], is a novel dibenzothiazepine antipsychotic developed by Zeneca. It is marketed under the trade name ‘Seroquel’Seroquel. Quetiapine is well tolerated and clinically effective in the treatment of schizophrenia.

The initial hope of investigators was that quetiapine would have antipsychotic potential and that it might share some of the properties of clozapine without its toxicity to white blood cells.

The effective dosage range is usually 300-450 mg/day split into two doses. The dose is titrated upwards from 25 mg twice dailybd from day one to 300mg/daya fuller dosage on day 4. Elderly patients or patients with liver problems should be started on lower doses. It is both superior to placebo and, and comparable to haloperidol in reducing positive symptoms at doses ranging from 150 to 750 mg/day and is an effective treatment for in reducing negative symptoms at a dose of 300 mg/day.

Somnolence is the most common adverse event. Abnormalities of the QTqt interval on ECG appear very infrequently and there is no need for a baseline ECG or blood pressure monitoring as used to be the case with ssertindole. There is no need for haematological monitoring as with clozapine. Quetiapine, across the full dosage range, is associated with no greater extrapyramidal symptoms than placeboThere is a reduced potential for extrapyramidal symptoms compared with conventional antipsychotics.

Quetiapine’s general efficacy and side effect profile suggest that, unless there are unforeseen post-marketing complications, quetiapine deserves a major place in the initial and long term management of schizophreniform disorders.

Quetiapine fumarate, Bis [2-(2-[4-(dibenzo[b,f][1,4]thiazepin-11-yl]ethoxy)ethanol] fumarate (IUPAC) 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol-(E)-2-butanedioate (2:1) salt), [ICI 204,636], is a novel dibenzothiazepine antipsychotic developed by Zeneca Pharmaceuticals. It is marketed under the trade name ‘Seroquel’. Quetiapine is well tolerated and clinically effective in the treatment of schizophrenia.

BAYER 2013 AND BEYOND

October 25, 2013 12:06 pm / 4 Comments on BAYER 2013 AND BEYOND

http://www.bayer.com/

Bayer

With 11 treatments in Phase I trials, 8 in Phase II, and 13 in Phase III, Bayer has a strong pipeline.

By far the most interest currently, given that the latest reports came out October 21st, is riociguat (BAY 63-2521),

which has had good news from its ongoing Phase III clinical trials of the treatment for pulmonary arterial hypertension, also known as PAH. PAH is a progressive condition that overburdens the heart.

Trials indicate subjects had improved heart function and could better tolerate physical exercise. Patients on riociguat improved their walking distance by 36 meters on average, while those on placebo showed no improvement.

Professor Hossein Ardeschir Ghofrani of University Hospital Giessen, the principal investigator, was quite pleased with the results and explained the value of the measurement. “The six-minute walk distance test is a well-validated clinical measure in patients with PAH, and therefore, the results of the PATENT-1 trial are encouraging. . .These data from the PATENT study suggest that riociguat may be a potential treatment option both for patients who have never been treated for PAH as well as for those who have received prior treatment.”

Hossein A. Ghofrani
Associate Professor of Internal Medicine,
MD (University of Giessen) 1995 Research interests: pulmonary hypertension, ischaemia-reperfusion, experimental therapeutics, clinical trials

http://www.uni-giessen.de/cms/fbz/fb11/forschung/graduierte/mbml/faculty

Although Bayer put forth no sales estimate for the treatment, analysts predicted 2017 sales from riociguat of $480 million

BAYER PIPELINE AS ON OCT 25 2013

phase 1

Project	Indication
CDK-Inhibitor (BAY 1000394)	Cancer
Mesothelin-ADC (BAY 94-9343)	Cancer
PSMA Bi TE Antibody (BAY 2010112)	Cancer
PI3K-Inhibitor (BAY 1082439)	Cancer
FGFR2 Antibody (BAY 1179470)	Cancer
HIF-PH (BAY 85-3934)	Anemia
Partial Adenosine A1 Agonist(BAY 1067197)	Heart Failure
Vasopressin Receptor Antagonist(BAY 86-8050)	Heart Failure
sGC Stimulator (BAY 1021189)	Heart Failure
S-PRAnt (BAY 1002670)	Symptomatic uterine fibroids
BAY 1026153	Endometriosis

phase2

Project	Indication
PI3K-Inhibitor (BAY 80-6946)	Cancer
Regorafenib	Cancer
Refametinib (MEK-Inhibitor)	Cancer
Radium-223-Dichloride	Cancer
Sorafenib	Additional Indications
MR-Antagonist (BAY 94-8862)	Congestive Heart Failure (CHF)
MR-Antagonist (BAY 94-8862)	Diabetic Nephopathy
Riociguat (sGC Stimulator)	Pulmonary Hypertension
Neutrophil Elastase Inhibitor(BAY 85-8501)	Bronchiectasis

phase 3

Project	Indication
Sorafenib	Breast Cancer
Sorafenib	Adjuvant HCC
Sorafenib	Adjuvant RCC
Regorafenib	HCC 2nd line
Rivaroxaban	Major Adverse Cardiac Events
Rivaroxaban	CHF and CAD
peg rFVIII(BAY 94-9027)	Hemophilia
Aflibercept	Myopic choroidal neovascularization (mCNV)
Aflibercept	Diabetic Macular Edema (DME)
LCS 16	Contraception
Vaginorm	Vulvovaginal atrophy (VVA)
Sodium Deoxycholate	Submental fat removal
Cipro DPI	Lung infection
Tedizolid	Skin and Lung Infections
Amikacin Inhale	Gram-negative pneumonia

Information for Download from bayer

From molecules to medicine – A journey through research and development (PDF, 3 MB)

Sorafenib tosylate

https://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/

TEDIZOLID PHOSPHATE

https://newdrugapprovals.wordpress.com/2013/10/24/cubist-pharmaceuticals-inc-announced-that-it-has-submitted-a-nda-to-the-u-s-fda-for-approval-of-its-investigational-antibiotic-tedizolid-phosphate-tr-701/

Bayer Accelerates Clinical Development of Promising New Drug Candidates

Five new molecular entities projected to enter Phase III by 2015 / Addressing unmet medical needs in the areas of oncology, cardiology, and women’s health / Initiation of further studies with recently launched products planned to add new treatment options

Leverkusen, October 8, 2013 – Following the recent commercial introduction of five new drugs to address the medical needs of patients with various diseases, Bayer is now accelerating the development of further five promising drug candidates which are currently undergoing phase I and II clinical studies. The company today announced that it plans to progress these five new highly innovative drug candidates in the areas of oncology, cardiology, and women’s health into phase III clinical studies by 2015.

“Our Pharma research and development has done a tremendous job of bringing five new products to the market offering physicians and patients new treatment alternatives for serious diseases”, said Bayer CEO Dr. Marijn Dekkers. “Following our mission statement ‘Science For A Better Life’, the five chosen further drug candidates all have the potential to impact the way diseases are treated for the benefit of patients.”

Bayer CEO Dr. Marijn Dekkers
“Our research and development activities are strongly focused on areas where treatment options are not available today or where true breakthrough innovations are missing”, said Prof. Andreas Busch, member of the Bayer HealthCare Executive Committee and Head of Global Drug Discovery at Bayer HealthCare. “Our drug development pipeline holds a number of promising candidates which we want to bring to patients who need them urgently”, said Kemal Malik, member of the Bayer HealthCare Executive Committee, Chief Medical Officer and Head of Pharmaceutical Development at Bayer HealthCare. “Furthermore we are continuing to expand the range of indications for all our recently launched products Xarelto, Stivarga, Xofigo, Riociguat as well as Eylea and further refine the profile of these drugs in specific patient populations.”

Cl 223Ra Cl

Xofigo

https://newdrugapprovals.wordpress.com/2013/09/21/xofigo-injection-recommended-for-approval-in-eu/

The five mid-stage candidates have been selected for accelerated development based on positive “proof-of-concept” data from early clinical studies. Three of them are development compounds in the area of cardiology or the cardio-renal syndrome: Finerenone (BAY 94-8862) is a next generation oral, non-steroidal Mineralocorticoid Receptor antagonist which blocks the deleterious effects of aldosterone. Currently available steroidal MR antagonists have proven to be effective in reducing cardiovascular mortality in patients with heart failure but have significant side effects that limit their utilization. Finerenone is currently in clinical Phase IIb development for the treatment of worsening chronic heart failure, as well as diabetic nephropathy.

Finerenone (BAY 94-8862)

https://newdrugapprovals.wordpress.com/2013/10/09/finerenone-bay-94-8862-bayers-next-generation-oral-non-steroidal-mineralocorticoid-receptor-antagonist-which-blocks-the-deleterious-effects-of-aldosterone/

The second drug candidate in the area of cardiology is an oral soluble guanylate cyclase (sGC) stimulator (BAY 1021189). The start of a Phase IIb study in patients with worsening chronic heart failure is expected later this year.

For the cardio-renal syndrome, a Phase IIb program with the investigational new drug Molidustat (BAY 85-3934) is under initiation in patients with anemia associated with chronic kidney disease and/or end-stage renal disease. Molidustat is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO.

Molidustat (BAY 85-3934)

https://newdrugapprovals.wordpress.com/2013/10/09/molidustat-bay-85-3934-bayers-drug-under-initiation-in-patients-with-anemia-associated-with-chronic-kidney-disease-andor-end-stage-renal-disease/

In oncology, Copanlisib (BAY 80-6946), a novel, oral phosphatidylinositol-3 kinases (PI3K) inhibitor, was selected for accelerated development. Copanlisib demonstrated a broad anti-tumor spectrum in preclinical tumor models and promising early clinical signals in a Phase I study in patients with follicular lymphoma. A Phase II study in patients with Non-Hodgkin’s lymphoma is currently ongoing.

Bayer has also made good progress in the development of new treatment options for patients with gynecological diseases: sPRM (BAY 1002670) is a novel oral progesterone receptor modulator that holds the promises of long-term treatment of patients with symptomatic uterine fibroids. Based on promising early clinical data the initiation of a Phase III study is planned for mid-2014.

Initiation of further studies with recently launched products
Bayer has successfully launched five new pharmaceutical products, namely Xarelto™, Stivarga™, Xofigo™, Eylea™, and Riociguat, which has very recently been approved in Canada under the trade name Adempas™.

https://newdrugapprovals.wordpress.com/2013/05/27/xarelto-approved-for-secondary-prevention-in-acute-coronary-syndrome-patients-in-europe/

Regorafenib, stivarga

https://newdrugapprovals.wordpress.com/2013/08/31/bayers-stivarga-regorafenib-tablets-approved-in-europe/

Bayer’s Eylea (aflibercept),

https://newdrugapprovals.wordpress.com/2013/06/01/lucentis-rival-one-step-away-from-nhs-approval/

Xarelto has been approved globally for five indications across seven distinct areas of use, allowing doctors to treat patients in a greater variety of venous and arterial thromboembolic conditions than any other novel oral anticoagulant. The company continues to study the use of Xarelto for the treatment of further cardiovascular diseases. Ongoing clinical Phase III studies include COMPASS and COMMANDER-HF. The COMPASS study will assess the potential use of Xarelto in combination with aspirin, or as a single treatment to prevent major adverse cardiac events (MACE) in nearly 20,000 patients with atherosclerosis related to coronary or peripheral artery disease. The COMMANDER-HF study will evaluate the potential added benefit of Xarelto in combination with single or dual-antiplatelet therapy to help reduce the risk of death, heart attack and stroke in approximately 5,000 patients with chronic heart failure and coronary artery disease, following hospitalization for exacerbation of their heart failure.
In order to answer medically relevant questions for specific patient populations Bayer has initiated a range of additional Xarelto studies in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention with stent placement (PIONEER-AF-PCI), cardioversion (X-VERT) or an AF ablation procedure (VENTURE-AF).
As an extension to the Xarelto clinical trial programme, a number of real-world studies are designed to observe and further evaluate Xarelto in everyday clinical practice. These include the XAMOS study of more than 17,000 orthopaedic surgery patients, which confirmed the clinical value of oral, once-daily Xarelto in routine clinical practice in adults following orthopaedic surgery of the hip or knee. XANTUS is designed to collate data on real-world protection with Xarelto in over 6,000 adult patients in Europe with non-valvular AF at risk of stroke while XANAP is designed to collate data on real-world protection with Xarelto in over 5,000 adult patients in Europe and Asia with non-valvular AF at risk of stroke. XALIA will generate information from over 4,800 patients treated for an acute DVT with either Xarelto or standard of care.

In the area of oncology, Stivarga has been approved in 42 countries for use against metastatic colorectal cancer that is refractory to standard therapies, and additionally for gastrointestinal stromal tumor (GIST) in the US and Japan. Bayer is now planning to assess Stivarga in earlier stages of colorectal cancer as well as other cancer types. A Phase III trial in patients with colorectal cancer after resection of liver metastases is currently under initiation. Based on early clinical data Bayer has also initiated a Phase III study in liver cancer in patients who have progressed on sorafenib treatment.

Furthermore, the anti-cancer drug Xofigo (radium 223 dichloride) is a first-in-class alpha-pharmaceutical which is designed for use in prostate cancer patients with ‘bone metastases’ (secondary cancers in the bone) to treat the cancer in the bone and to help extend their lives. Xofigo is approved in the US for the treatment of patients with advanced castrate-resistant prostate cancer with symptomatic bone metastases. In addition, the European CHMP recently gave a positive opinion for radium 223 dichloride for the same use. The decision of the European Commission on the approval is expected in the fourth quarter of 2013.
Based on the excellent Phase III results for Xofigo in patients with castration resistant prostate cancer and symptomatic bone metastases Bayer is looking to expand the use of Xofigo to earlier stages of the disease, and plans to initiate a Phase III study in combination with the novel anti-hormonal agent abiraterone. In addition, early stage signal-generating studies in other cancer forms where bone metastases are important causes of morbidity and mortality are planned.

In the area of pulmonary hypertension Adempas (Riociguat) is the first member of a novel class of compounds – so-called ‘soluble guanylate cyclase (sGC) stimulators’ – being investigated as a new and specific approach to treating different types of pulmonary hypertension (PH). Adempas has the potential to overcome a number of limitations of currently approved treatments for pulmonary arterial hypertension (PAH) and addresses the unmet medical need in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It was approved for the treatment of CTEPH in Canada in September 2013, making it the world’s first drug approved in this deadly disease.
Riociguat has already shown promise as a potential treatment option beyond these two PH indications. An early clinical study was conducted in PH-ILD (interstitial lung disease), a disease characterized by lung tissue scarring (fibrosis) or lung inflammation which can lead to pulmonary hypertension, and, based on positive data, the decision was taken to initiate Phase IIb studies in PH-IIP (idiopathic pulmonary fibrosis), a subgroup of PH-ILD. Moreover, scientific evidence was demonstrated in preclinical models that the activity may even go beyond vascular relaxation. To prove the hypothesis Bayer is initiating clinical studies in the indication of systemic sclerosis (SSc), an orphan chronic autoimmune disease of the connective tissue affecting several organs and associated with high morbidity and mortality. If successful, Riociguat has the potential to become the first approved treatment for this devastating disease.

In the area of ophthalmology, Eylea (aflibercept solution for injection) is already approved in Europe and several additional countries for the treatment of neovascular (wet) age-related macular degeneration and for macular edema following central retinal vein occlusion. In September, Bayer HealthCare and Regeneron Pharmaceuticals presented data of the two phase III clinical trials VIVID-DME and VISTA-DME of VEGF Trap-Eye for the treatment of diabetic macular edema (DME) at the annual meeting of the Retina Society in Los Angeles and at the EURetina Congress in Hamburg, Germany. Both trials achieved the primary endpoint of significantly greater improvements in best-corrected visual acuity from baseline compared to laser photocoagulation at 52 weeks. Bayer plans to submit an application for marketing approval for the treatment of DME in Europe in 2013.

About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 54,900 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at www.healthcare.bayer.com.

Positive Review For Gilead’s Hep C Drug Sofosbuvir

October 24, 2013 7:20 am / 1 Comment on Positive Review For Gilead’s Hep C Drug Sofosbuvir

Sofosbuvir

Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate

http://www.ama-assn.org/resources/doc/usan/sofosbuvir.pdf –for cas no

The U.S. Food and Drug Administration (FDA) has issued a positive review for a highly anticipated hepatitis C drug from Gilead Sciences, saying the pill cures more patients in less time than currently available treatments.

The agency posted its review of Gilead’s sofosbuvir online ahead of a meeting Friday where government experts will vote on whether to recommend the drug’s approval.

http://www.dddmag.com/news/2013/10/positive-review-gileads-hep-c-drug?et_cid=3555713&et_rid=523035093&type=headline

old article cut paste

Jun. 7, 2013– Gilead Sciences, Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted priority review to the company’s New Drug Application (NDA) for sofosbuvir, a once-daily oral nucleotide analogue inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. The FDA grants priority review status to drug candidates that may offer major advances in treatment over existing options. Gilead filed the NDA for sofosbuvir on April 8, 2013, and FDA has set a target review date under the Prescription Drug User Fee Act (PDUFA) of December 8, 2013.

The data submitted in this NDA support the use of sofosbuvir and ribavirin (RBV) as an all-oral therapy for patients with genotype 2 and 3 HCV infection, and for sofosbuvir in combination with RBV and pegylated interferon (peg-IFN) for treatment-naïve patients with genotype 1, 4, 5 and 6 HCV infection.

Sofosbuvir is an investigational product and its safety and efficacy have not yet been established.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

Sofosbuvir (formerly PSI-7977 or GS-7977) is an experimental drug candidate for the treatment of hepatitis C.^[1] It was discovered at Pharmasset and then acquired for development by Gilead Sciences. It is currently in Phase III clinical trials.^[2]

Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-monophosphate.^[3]

Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) polymerase.^[4] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.

Sofosbuvir is being studied in combination with pegylated interferon and ribavirin, with ribavirin alone, and with other direct-acting antiviral agents.^[5] It has shown excellent clinical efficacy when used either with pegylated interferon/ribavirin or in interferon-free combinations. In particular, combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or GS-5885, have shown sustained virological response rates of up to 100% in people infected with HCV.^[6]

Data from the ELECTRON trial showed that a dual interferon-free regimen of sofosbuvir plus ribavirin produced a 24-week post-treatment sustained virological response (SVR24) rate of 100% for previously untreated patients with HCV genotypes 2 or 3.^[7]^[8]

Data presented at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013 showed that a triple regimen of sofosbuvir, ledipasvir (formerly GS-5885), and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100% for both treatment-naive patients and prior non-responders with HCV genotype 1.^[9]Gilead has developed a sofosbuvir + ledipasvir coformulation that is being tested with and without ribavirin.

Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S. et al. (2010). “Discovery of a β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus”. Journal of Medicinal Chemistry 53 (19): 7202–7218. doi:10.1021/jm100863x. PMID 20845908. edit
“PSI-7977″. Gilead Sciences.
Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C. et al. (2010). “Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977″. Journal of Biological Chemistry 285 (45): 34337–34347.doi:10.1074/jbc.M110.161802. PMC 2966047. PMID 20801890. edit
Alejandro Soza (November 11, 2012). “Sofosbuvir”. Hepaton.
Tom Murphy (November 21, 2011). “Gilead Sciences to buy Pharmasset for $11 billion”. Bloomberg Businessweek.
http://www.gilead.com/pr_1757156
AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C. Gane, E et al. New England Journal of Medicine 368:3444. January 3, 2013.
CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.

ACIPHEX, RABEPRAZOLE SODIUM, patent exp 8 th Nov 2013

October 24, 2013 3:47 am / 2 Comments on ACIPHEX, RABEPRAZOLE SODIUM, patent exp 8 th Nov 2013

AS SODIUM SALT

Bottle of rabeprazole 20 mg tablets

ACIPHEX, RABEPRAZOLE SODIUM

Drug Patent Expiration and Exclusivity

US 5045552 – Uspto – United States Patent and Trademark Office

Active Ingredient	Form	Dosage		Drug Type	Application	Product
RABEPRAZOLE SODIUM	TABLET, DELAYED RELEASE; ORAL	10MG Federal Register determination that product was not discontinued or withdrawn for safety or efficacy reasons		DISCN	020973	001
RABEPRAZOLE SODIUM	TABLET, DELAYED RELEASE; ORAL	20MG		RX	020973	002

EISAI INC’s ACIPHEX.

Patent		Expiration
US 5045552*PED		2013-11-8
US 5045552	Pyridine derivatives having anti-ulcerative activity Pyridine derivatives useful for preventing or treating peptic ulcers, pharmaceutical preparations and methods of treating peptic ulcers are described.	2013-5-8(expired)

Exclusivity

Exclusivity is marketing rights granted by the FDA to the EISAI INC.

	Bosmolisib – N… on Bosmolisib
	Cenacitinib –… on Cenacitinib
	Emestedastat –… on Emestedastat
	Enrupatinib –… on Enrupatinib
	Evetifator – N… on Evetifator

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ACIPHEX, RABEPRAZOLE SODIUM

Drug Patent Expiration and Exclusivity

EISAI INC’s ACIPHEX.

Exclusivity

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