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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Foretinib (Exelixis, GlaxoSmithKline, XL-880)


Foretinib.svg

Foretinib (Exelixis, GlaxoSmithKline) (XL-880)

CAS No.:849217-64-7, 937176-80-2
Formula:C34H34F2N4O6
M.Wt:632.24

GSK1363089, XL880

1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Foretinib is an experimental drug candidate for the treatment of cancer.[1] It was discovered by Exelixis and is under development by GlaxoSmithKline.[2] It is currently in Phase II clinical trials.[3] As of December 2012 no phase III trials are registered.[3]

Foretinib is an inhibitor of the kinase enzymes c-Met and vascular endothelial growth factor receptor 2 (VEGFR-2).[4]

Foretinib is an orally bioavailable small molecule with potential antineoplastic activity. MET/VEGFR2 inhibitor GSK1363089 binds to and selectively inhibits hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor 2 (VEGFR2), which may result in the inhibition of tumor angiogenesis, tumor cell proliferation and metastasis. The proto-oncogene c-MET has been found to be over-expressed in a variety of cancers. VEGFR2 is found on endothelial and hematopoietic cells and mediates the development of the vasculature and hematopoietic cells through VEGF signaling.

Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met and KDR with IC50 of 0.4 nM and 0.9 nM. Less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

 

Foretinib.png

 

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Patent Submitted Granted
Preparation of a Quinolinyloxydiphenylcyclopropanedicarboxamide [US2010081805] 2010-04-01
C-Met Modulators and Method of Use [US2012022065] 2012-01-26
C-Met Modulators and Method of Use [US2011077233] 2011-03-31
c-Met modulators and methods of use [US7579473] 2009-07-02 2009-08-25
c-MET MODULATORS AND METHODS OF USE [US8067436] 2009-04-23 2011-11-29
C-MET MODULATORS AND METHOD OF USE [US8178532] 2007-09-27 2012-05-15
Method of Treating Cancer using a cMet and AXL Inhibitor and an ErbB Inhibitor [US2009274693] 2009-11-05
c-MET MODULATORS AND METHOD OF USE [US2007244116] 2007-10-18
c-Met modulators and methods of use [US2007054928] 2007-03-08

………………………………….

http://www.google.com/patents/WO2014067417A1?cl=en

Foretinib (GSK1363089, XL880) quinoline compounds are, an oral c-Met and VEGFR / KDR kinase inhibitor of c-Met kinase and KDR kinase IC 5Q Wo port respectively 0.4 0.8 nM, the current has entered Phase II clinical study (WO2010036831Al). Clinical studies have shown that, Foretinib variety of people, such as human lung cancer cells, human gastric cancer cells and other tumor cell lines showed a significant inhibitory effect, an IC 50 value of 0.004 g / mL.

Figure imgf000004_0001

 

 

 

……………………………

http://www.google.com/patents/WO2014145693A1?cl=en

Accordingly, small-molecule compounds that specifically inhibit, regulate, and/or modulate the signal transduction of kinases, particularly including Ret, c-Met, and VEGFR2 described above, are particularly desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis. One such small-molecule is XL880, known variously as N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-(4-fluorophenyl)cyclopropane-l,l- dicarboxamide and alternatively as foretimb. Foretimb has the chemical structure:

[0007] WO 2005/030140 describes the synthesis of foretinib (Example 44) and also discloses the therapeutic activity of this molecule to inhibit, regulate, and/or modulate the signal transduction of kinases (Assays, Table 4, entry 312). Example 44 begins at paragraph [0349] in WO 2005/030140.

Figure imgf000034_0001

 

 

Figure imgf000032_0001

……………………………………

 

WO 2012044577 A1…….Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases

Figure imgf000020_0003
Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)
Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)WO 2012044577 A1…….Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases
 http://www.google.com/patents/WO2012044577A1?cl=en

In another embodiment, the compound of Formula I is Compound 1 :
Figure imgf000005_0001
Compound 1
or a pharmaceutically acceptable salt thereof. Compound I is known as N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N’-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide. WO 2005/030140 describes the synthesis of N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy }phenyl)-N’-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide (Example 12, 37, 38, and 48) and also discloses the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 289). Example 48 is on paragraph [0353] in WO 2005/030140.
[0013] In another embodiment, the compound of Formula I is Compound 2:
Figure imgf000005_0002
Compound 2
Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)
or a pharmaceutically acceptable salt thereof. Compound 2 is known as is N-[3-fluoro-4- ({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-(4- fluorophenyl)cyc!opropane- 1,1 -dicarboxamide. WO 2005-030140 describes the synthesis of Compound (I) (Examples 25, 30, 36, 42, 43 and 44) and also discloses the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 312). Compound 2 has been measured to have a c-Met IC50 value of about 0.6 nanomolar (nM). PC1YUS09/064341, which claims priority to U.S. provisional application 61/199,088, filed November 13, 2008, describes a scaled-up synthesis of Compound I.

Scheme 2

Preparation of 4-Chloro-6,7-dimethoxy-quinoIine

[00173] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg) and the filter bed was washed with DCM (1 18.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound. (35.6 kg).

Preparation of -(6, 7 -Dimethoxy-quinoline- -yloxy)-phenylamine

[00174] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 °C. This mixture was then heated to 100- 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 °C and water (pre-cooled, 2-7 °C, 587 L) charged at a rate to maintain 15-30 °C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4- yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7- dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 21 1.4 kg) and DMA (108.8 kg) for approximately lhour and then cooled to 0-5 °C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 °C to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg). Alternative Preparation of 4-(6, 7-Dimethoxy-quinoIine-4-yloxy)-phenylamine

[00175] 4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-aminophenoI (30.8 kg) and sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35 weight percent in THF) were charged to a reactor, followed by N(N-dimethylacetamide (DMA, 293.3 kg). This mixture was then heated to 105-1 15 °C for approximately 9 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-25 °C and water (315 kg) was added over a two hour period while maintaining the temperature between 20-30 °C. The reaction mixture was then agitated for an additional hour at 20-25 °C. The crude product was collected by filtration and washed with a mixture of 88kg water and 82.1 kg DMA, followed by 175 kg water. The product was dried on a filter drier for 53 hours. The LOD showed less than 1 percent w/w.

[00176] In an alternative procedure, 1.6 equivalents of sodium tert-pentoxide were used and the reaction temperature was increased from 1 10-120 °C. In addition , the cool down temperature was increased to 35-40 °C and the starting temperature of the water addition was adjusted to 35-40 °C, with an allowed exotherm to 45 °C.

Preparation of l-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid

[00177] Triethylamine (19.5 kg) was added to a cooled (approximately 5 °C) solution of cyclopropane-l,l-dicarboxylic acid (24.7 kg) in THF (89.6 kg) at a rate such that the batch temperature did not exceed 5 °C. The solution was stirred for approximately 1.3 hours, and then thionyl chloride (23.1 kg) was added, keeping the batch temperature below 10 °C. When the addition was complete, the solution was stirred for approximately 4 hours keeping temperature below 10 °C. A solution of 4-fluoroaniline (18.0 kg) in THF (33.1 kg) was then added at a rate such that the batch temperature did not exceed 10 °C. The mixture was stirred for approximately 10 hours after which the reaction was deemed complete. The reaction mixture was then diluted with isopropyl acetate (218.1 kg). This solution was washed sequentially with aqueous sodium hydroxide (10.4 kg, 50 percent dissolved in 1 19 L of water) further diluted with water (415 L), then with water (100 L) and finally with aqueous sodium chloride (20.0 kg dissolved in 100 L of water). The organic solution was concentrated by vacuum distillation (100 L residual volume) below 40 °C followed by the addition of n- heptane (171.4 kg), which resulted in the precipitation of solid. The solid was recovered by filtration and washed with n-heptane ( 102.4 kg), resulting in wet, crude l-(4-fluoro- phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg). The crude, l-(4-fluoro- phenylcarbamoy -cyclopropanecarboxylic acid was dissolved in methanol (139.7 kg) at approximately 25 °C followed by the addition of water (320 L) resulting in slurry which was recovered by filtration, washed sequentially with water (20 L) and n-heptane (103.1 kg) and then dried on the filter at approximately 25 °C under nitrogen to afford the title compound (25.4 kg).

Preparation of l-(4-Fluoro-phenyIcarbamoyl)-cyclopropanecarbonyl chloride

[00178] Oxalyl chloride ( 12.6 kg) was added to a solution of I -(4-fluoro- phenylcarbamoyD-cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and N, N-dimethylformamide (DMF; 0.23 kg) at a rate such that the batch temperature did not exceed 25 °C. This solution was used in the next step without further processing.

Alternative Preparation of l-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride

[00179] A reactor was charged with l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarboxylic acid (35 kg), 344 g DMF, and 175kg THF. The reaction mixture was adjusted to 12-17 °C and then to the reaction mixture was charged 19.9 kg of oxalyl chloride over a period of 1 hour. The reaction mixture was left stirring at 12-17 °C for 3 to 8 hours. This solution was used in the next step without further processing.

Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4- yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide

[00180] The solution from the previous step containing l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 °C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20-25 °C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 °C and then at approximately 45 °C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD). Alternative Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy- quinoIine-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide

[00181] A reactor was charged with 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (35.7 kg, 1 equivalent), followed by 412.9 kg THF. To the reaction mixture was charged a solution of 48.3 K2C03 in 169 kg water. The acid chloride solution of described in the

Alternative Preparation of l-(4-Fluoro-phenylcarbamoyl)-cvclopropanecarbonyl chloride above was transferred to the reactor containing 4-(6,7-dimethoxy-quinoline-4-yloxy)- phenylamine while maintaining the temperature between 20-30 °C over a minimum of two hours. The reaction mixture was stirred at 20-25 °C for a minimum of three hours. The reaction temperature was then adjusted to 30-25 °C and the mixture was agitated. The agitation was stopped and the phases of the mixture were allowed to separate. The lower aqueous phase was removed and discarded. To the remaining upper organic phase was added 804 kg water. The reaction was left stirring at 15-25 °C for a minimum of 16 hours.

[00182] The product precipitated. The product was filtered and washed with a mixture of 179 kg water and 157.9 kg THF in two portions. The crude product was dried under a vacuum for at least two hours. The dried product was then taken up in 285.1 kg THF. The resulting suspension was transferred to reaction vessel and agitated until the suspension became a clear (dissolved) solution, which required heating to 30-35 °C for approximately 30 minutes. 456 kg water was then added to the solution, as well as 20 kg SDAG-1 ethanol (ethanol denatured with methanol over two hours. The mixture was agitated at 15-25 °C fir at least 16 hours. The product was filtered and washed with a mixture of 143 kg water and 126.7 THF in two portions. The product was dried at a maximum temperature set point of 40 °C.

[00183] In an alternative procedure, the reaction temperature during acid chloride formation was adjusted to 10-15 °C. The recrystallization temperature was changed from 15-25 °C to 45-50 °C for 1 hour and then cooled to 15-25 °C over 2 hours.

Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4- yloxy)-phenyl]-amide (4-fluoro-phenyI)-amide, malate salt

[00184] Cyclopropane- 1 , 1 -dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyI)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor and the mixture was heated to reflux (approximately 74 °C) for approximately 2 hours. The reactor temperature was reduced to 50 to 55 °C and the reactor contents were filtered. These sequential steps described above were repeated two more times starting with similar amounts of starting material (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1 133.2 kg) (approximate residual volume 71 1 L; KF < 0.5 % w/w) at approximately 74 °C. The temperature of the reactor contents was reduced to 20 to 25 °C and held for approximately 4 hours resulting in solid precipitate which was filtered, washed with MEK (448 kg) and dried under vacuum at 50 °C to afford the title compound (45.5 kg).

Alternative Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yIoxy)-phenyl]-amide (4-fluoro-phenyI)-amide, (L) malate salt

[00185] Cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyI)-amide (47.9 kg), L-malic acid (17.2), 658.2 kg methyl ethyl ketone, and 129.1 kg water (37.3 kg) were charged to a reactor and the mixture was heated 50-55 °C for approximately 1-3 hours, and then at 55-60 °C for an addition al 4-5 hours. The mixture was clarified by filtration through a 1 μπι cartridge. The reactor temperature was adjusted to 20-25 °C and vacuum distilled with a vacuum at 150-200 mm Hg with a maximum jacket temperature of 55 °C to the volume range of 558-731 L.

[00186] The vacuum distillation was performed two more times with the charge of 380 kg and 380.2 kg methyl ethyl ketone, respectively. After the third distillation, the volume of the batch was adjusted to 18 v/w of cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyI)-amide by charging 159.9 kg methyl ethyl ketone to give a total volume of 880L. An addition al vacuum distillation was carried out by adjusting 245.7 methyl ethyl ketone. The reaction mixture was left with moderate agitation at 20-25 °C for at least 24 hours. The product was filtered and washed with 415.1 kg methyl ethyl ketone in three portions. The product was dried under a vacuum with the jacket temperature set point at 45 °C.

[00187] In an alternative procedure, the order of addition was changed so that a solution of 17.7 kg L-malic acid dissolved in 129.9 kg water was added to cyclopropane- 1,1- dicarboxylic acid [4-(6,7-dimethoxy-quinoHne-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)- amide (48.7 kg) in methyl ethyl ketone (673.3 kg).

Preparation of Compound 2

[00188] Compound 2 was prepared as provided in Scheme 3 and the accompanying experimental examples. Scheme 3

Toluene

[00189] In Scheme 1, Xb is Br or CI. For the names of the intermediates described within the description of Scheme 1 below, Xb is referred to as halo, wherein this halo group for these intermediates is meant to mean either Br or CI.Preparation of l-[5 methoxy-4 (3-halo propoxy)- 2 nitro-phenyl]- ethanone

[00190] Water (70 L) was charged to the solution of l-[4-(3-halo propoxy)- 3-methoxy phenyl] ethanone (both the bromo and the chloro compound are commercially available). The solution was cooled to approximately 4 °C. Concentrated sulfuric acid (129.5 kg) was added at a rate such that the batch temperature did not exceed approximately 18 °C. The resulting solution was cooled to approximately 5 °C and 70 percent nitric acid (75.8 kg) was added at a rate such that the batch temperature did not exceed approximately 10 °C. Methylene chloride, water and ice were charged to a separate reactor. The acidic reaction mixture was then added into this mixture. The methylene chloride layer was separated and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride layers were washed with aqueous potassium bicarbonate solution and concentrated by vacuum distillation. 1- Butanol was added and the mixture was again concentrated by vacuum distillation. The resulting solution was stirred at approximately 20°C during which time the product crystallized. The solids were collected by filtration, washed with 1-butanol to afford compound the title compound, which was isolated as a solvent wet cake and used directly in the next step. ‘HNMR (400MHz, DMSO-d6): δ 7.69 (s, 1H), 7.24 (s, 1H); 4.23 (m, 2H), 3.94 (s, 3H), 3.78 (0-3.65 (t) (2H), 2.51 (s, 3H), 2.30-2.08 (m, 2H) LC/MS Calcd for [M(CI)+H]+ 288.1, found 288.0; Calcd for [M(Br)+H]+ 332.0, 334.0, found 331.9, 334.0.

Preparation of l-[5-methoxy-4-(3-morpholin-4-yl-propoxy)-2-nitro-phenyl]-ethanone

[00191] The solvent wet cake isolated in the previous step was dissolved in toluene. A solution of sodium iodide (67.9 kg) and potassium carbonate (83.4 kg) was added to this solution, followed by tetrabutylammonium bromide (9.92 kg) and morpholine (83.4 kg). The resulting 2 phase mixture was heated to approximately 85°C for about 9 hours. The mixture was then cooled to ambient temperature. The organic layer was removed. The aqueous layer was back extracted with toluene. The combined toluene layers were washed sequentially with two portions of saturated aqueous sodium thiosulfate followed by two portions of water. The resulting solution of the title compound was used in the next step without further processing. ‘HNMR (400MHz, DMSO-d6): δ 7.64 (s, 1 H), 7.22 (s, 1H), 4.15 (t, 2H), 3.93 (s, 3H), 3.57 (t, 4H), 2.52 (s, 3H), 2.44-2.30 (m, 6H), 1.90 (quin, 2H); LC/MS Calcd for [M+H]+ 339.2, found 339.2.

Preparation of l-[2-amino-5-methoxy-4-(3-morpholin-4-yl- propoxy)-phenyl]-ethanone

[00192] The solution from the previous step was concentrated under reduced pressure to approximately half of the original volume. Ethanol and 10 percent Pd C (50 percent water wet, 5.02 kg) were added; the resulting slurry was heated to approximately 48 °C and an aqueous solution of formic acid (22.0 kg) and potassium formate (37.0 kg) was added. When the addition was complete and the reaction deemed complete by thin layer chromatography (TLC), water was added to dissolve the by-product salts. The mixture was filtered to remove the insoluble catalyst. The filtrate was concentrated under reduced pressure and toluene was added. The mixture was made basic (pH of about 10) by the addition of aqueous potassium carbonate. The toluene layer was separated and the aqueous layer was back extracted with toluene. The combined toluene phases were dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting solution was used in the next step without further processing. ‘HNMR (400MHZ, DMSO-d6): δ 7.1 1 (s, 1H)„ 7.01 (br s, 2H), 6.31 (s, 1H), 3.97 (t, 2H), 3.69 (s, 3H), 3.57 (t, 4H), 2.42 (s, 3H), 2.44-2.30 (m, 6H), 1.91 (quin, 2H LC/MS Calcd for [M+H]+ 309.2, found 309.1.

Preparation of 6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoiin- 4-ol, sodium salt

[00193] A solution of sodium ethoxide (85.0 kg) in ethanol and ethyl formate (70.0 kg) was added to the solution from the previous step. The mixture was warmed to approximately 44 °C for about 3 hours. The reaction mixture was cooled to approximately 25°C. Methyl t- butyl ether (MTBE) was added which caused the product to precipitate. The product was collected by filtration and the cake was washed with MTBE and dried under reduced pressure at ambient temperature. The dried product was milled through a mesh screen to afford 60.2 kg of the title compound. ‘HNMR (400MHz, DMSO-d6): δ 1 1.22 (br s, 1H), 8.61 (d, 1H), 7.55 (s, 1H), 7.54 (s, 1H), 7.17 (d, 1H), 4.29 (t, 2 H), 3.99 (m, 2H), 3.96 (s, 3H), 3.84 (t, 2H), 3.50 (d, 2H), 3.30 (m, 2H), 3.1 1 (m, 2H), 2.35 (m, 2H), LC/MS Calcd for [M+H]+ 319.2, found 319.1.

Preparation of 4-chIor-6-methoxy-7-(3 morpholin-4-yl)-quinoline

[00194] Phosphorous oxychloride (26.32 kg) was added to a solution of 6-methoxy-7-(3- morphoIin-4-yl-propoxy)-quinolin-4-ol (5.00 kg) in acetonitrile that was heated to 50-55 °C. When the addition was complete, the mixture was heated to reflux (approximately 82 °C) and held at that temperature, with stirring for approximately 18 hours at which time it was sampled for in process HPLC analysis. The reaction was considered complete when no more than 5 percent starting material remained. The reaction mixture was then cooled to 20-25 °C and filtered to remove solids. The filtrate was then concentrated to a residue. Acetronitrile was added and the resulting solution was concentrated to a residue. Methylene chloride was added to the residue and the resulting solution was quenched with a mixture of methylene chloride and aqueous ammonium hydroxide. The resulting 2 phase mixture was separated and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride solutions were dried over anhydrous magnesium sulfate, filtered and concentrated to a solid. The solids were dried at 30-40 °C under reduced pressure to afford the title compound (1.480 kg). ‘HNMR (400MHz, DMSO-d6): δ 8.61 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 4.21 (t, 2 H), 3.97 (s, 3H), 3.58 (m, 2H), 2.50-2.30 (m, 6H), 1.97 (quin, 2H) LC MS Calcd for [M+Hf 458.2, found 458.0.

Preparation of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morphoIin-4-yl

propoxy)quinoline

[00195] A solution of 4-chIoro-6-methoxy-7-(3 morpholin-4-yl)-quinoline (2.005 kg, 5.95 mol) and 2 fluoro-4-nitrophenol (1.169 kg, 7.44 mol) in 2,6-Iutidine was heated to 140-145 °C, with stirring, for approximately 2 hours, at which time it was sampled for in process HPLC analysis. The reaction was considered complete when less than 5 percent starting materia! remained. The reaction mixture was then cooled to approximately 75 °C and water was added. Potassium carbonate was added to the mixture, which was then stirred at ambient temperature overnight. The solids that precipitated were collected by filtration, washed with aqueous potassium carbonate, and dried at 55-60 °C under reduced pressure to afford the title compound (1.7 kg). ‘HNMR (400MHz, DMSO-d6): δ 8.54 (d, 1H), 8.44 (dd, 1H), 8.18 (m, 1H), 7.60 (m, 1H), 7.43 (s, 1H), 7.42 (s, 1H), 6.75 (d, 1H), 4.19 (t, 2H), 3.90 (s, 3H), 3.56 (t, 4H), 2.44 (t, 2H), 2.36 (m, 4H), 1.96 (m, 2H). LC/MS Calcd for [M+H]+ 337.1 , 339.1 , found 337.0, 339.0.

Preparation of 3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yIoxy]- phenylamine

[00196] A reactor containing 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morpholin-4- yl propoxy)quinoline (2.5 kg) and 10 percent palladium on carbon (50 percent water wet, 250 g) in a mixture of ethanol and water containing concentrated hydrochloric acid (1.5 L) was pressurized with hydrogen gas (approximately 40 psi). The mixture was stirred at ambient temperature. When the reaction was complete (typically 2 hours), as evidenced by in process HPLC analysis, the hydrogen was vented and the reactor inerted with argon. The reaction mixture was filtered through a bed of Celite® to remove the catalyst. Potassium carbonate was added to the filtrate until the pH of the solution was approximately 10. The resulting suspension was stirred at 20-25 °C for approximately 1 hour. The solids were collected by filtration, washed with water and dried at 50-60 °C under reduced pressure to afford the title compound (1.164 kg)._’H NMR (400MHz, DMSO-d6): δ 8.45 (d, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.08 (t, 1H), 6.55 (dd, 1H), 6.46 (dd, 1H), 6.39 (dd, 1H), 5.51 (br. s, 2H), 4.19 (t, 2H), 3.94 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H). LC/MS Calcd for

[M+H]+ 428.2, found 428.1.

Preparation of l-(4-fluoro-phenylcarbamoyl)-cycIopropanecarboxylic acid

[00197] Triethylamine (7.78 kg) was added to a cooled (approximately 4°C) solution of commercially available cyclopropanel.l-dicarboxylic acid (9.95 kg) in THF, at a rate such that the batch temperature did not exceed 10 °C. The solution was stirred for approximately 30 minutes and then thionyl chloride (9.14 kg) was added, keeping the batch temperature below 10 °C. When the addition was complete, a solution of 4 fluoroaniline (9.4 kg) in THF was added at a rate such that the batch temperature did not exceed 10 °C. The mixture was stirred for approximately 4 hours and then diluted with isopropyl acetate. The diluted solution was washed sequentially with aqueous sodium hydroxide, water, and aqueous sodium chloride. The organic solution was concentrated by vacuum distillation. Heptane was added to the concentrate. The resulting slurry was filtered by centrifugation and the solids were dried at approximately 35 °C under vacuum to afford the title compound (10.2 kg). Ή NMR (400 MHz, DMSO-d6): δ 13.06 (br s, 1H), 10.58 (s, 1H), 7.65-7.60 (m, 2H), 7.18-7.12 (m, 2H), 1.41 (s, 4H), LC/MS Calcd for [M+H]+ 224.1 , found 224.0.

Preparation of l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonylchloride

[00198] Oxalyl chloride (291 mL) was added slowly to a cooled (approximately 5°C) solution of l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid in THF at a rate such that the batch temperature did not exceed 10°C. When the addition was complete, the batch was allowed to warm to ambient temperature and held with stirring for approximately 2 hours, at which time in process HPLC analysis indicated the reaction was complete. The solution was used in the next step without further processing.

Preparation of cyclopropane-l,l-dicarbox lic acid {3-fluoro-4-[6-methoxy-7-(3- morphoIin-4-yl-propoxy)-quinolin-4-ylamino]phenyl}-amide-(4 fluorophenyl)-amide

[00199] The solution from the previous step was added to a mixture of 3-fluoro-4-[6- methoxy-7-(3-mo holin-4-yl-propox )-quinolin-4-ylo y]-phenylamine (1 160 kg) and potassium carbonate (412.25 g) in THF and water at a rate such that the batch temperature was maintained at approximately 15-21 °C. When the addition was complete, the batch was warmed to ambient temperature and held with stirring for approximately 1 hour, at which time in process HPLC analysis indicated the reaction was complete. Aqueous potassium carbonate solution and isopropyl acetate were added to the batch. The resulting 2-phase mixture was stirred and then the phases were allowed to separate. The aqueous phase was back extracted with isopropyl acetate. The combined isopropyl acetate layers were washed with water followed by aqueous sodium chloride and then slurried with a mixture of magnesium sulfate and activated carbon. The slurry was filtered over Celite® and the filtrate was concentrated to an oil at approximately 30°C under vacuum to afford the title compound which was carried into the next step without further processing. Ή NMR (400MHz, DMSO- d6): δ 10.41 (s, 1H), 10.03 (s, 1H), 8.47 (d, 1H), 7.91 (dd, 1H), 7.65 (m, 2H), 7.53 (m, 2H), 7.42 (m, 2H), 7.16 (t, 2H), 6.41 (d, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H), 1.47 (m, 4H). LC MS Calcd for [M+H]+ 633.2, found 633.1.

Preparation of the bisphosphate salt of cyclopropane-l,l-dicarboxylic acid {3-fluoro-4- [6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-ylamino]phenyl}-amide (4-fluoro- phenyl)-amide

[00200] Cyclopropane- 1,1-dicarboxy lie acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl- propoxy)-quinolin-4-ylamino]phenyl}-amide-(4 fluoro phenyl)-amide from the previous step was dissolved in acetone and water. Phosphoric acid (85%, 372.48 g) was added at a rate such that the batch temperature did not exceed 30 °C. The batch was maintained at approximately 15- 30 °C with stirring for 1 hour during which time the product precipitated. The solids were collected by filtration, washed with acetone and dried at approximately 60 °C under vacuum to afford the title compound (1.533 kg). The title compound has a c-Met IC50 value of less than 50 nM. The bisphosphate salt is not shown in scheme 1. Ή NMR (400

MHz, DMSO-d6): (diphosphate) δ 10.41 (s, 1H), 10.02 (s, 1H), 8.48 (d, 1 H), 7.93 (dd, 1H), 7.65 (m, 2H), 7.53 (d, 2H), 7.42 (m, 2H), 7.17 (m, 2H), 6.48 (d, 1H), 5.6 (br s, 6H), 4.24 (t, 2H), 3.95 (s, 3H), 3.69 (bs, 4H), 2.73 (bs, 6H), 2.09 (t, 2H), 1.48 (d, 4H).

Foretinib
Foretinib.svg
Identifiers
CAS number 849217-64-7 Yes
ChemSpider 24608641
UNII 81FH7VK1C4
Jmol-3D images Image 1
Properties
Molecular formula C34H34F2N4O6
Molar mass 632.65 g mol−1
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)

References

  1. Hedgethorne, K., Huang, P.H. (2010). “Foretinib. c-Met and VEGFR-2 inhibitor, Oncolytic”. Drugs Fut 35 (11): 893–901. doi:10.1358/dof.2010.35.11.1529012 (inactive 2014-03-22).
  2. “XL880 (GSK1363089)”. Exelixis, Inc.
  3. “Foretinib”. clinicaltrials.gov.
  4. Qian, F; Engst, S; Yamaguchi, K; Yu, P; Won, KA; Mock, L; Lou, T; Tan, J et al. (2009). “Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases”. Cancer Research 69 (20): 8009–16. doi:10.1158/0008-5472.CAN-08-4889. PMID 19808973.

 

CN102227164A * Sep 25, 2009 Oct 26, 2011 葛兰素史密斯克莱有限责任公司 Preparation of quinolinyloxydiphenylcyclopropanedicarboxamide
CN102977014A * Nov 5, 2012 Mar 20, 2013 沈阳药科大学 New quinoline compounds and uses thereof

Non-Patent Citations
Reference
1 * BAOHUI QI ET AL.: ‘Discovery and optimization of novel 4-Phenoxy-6, 7-disubstituted Quinolines Possessing Semicarbazones as c-Met Kinase Inhibitors.‘ BIOORGANIC & MEDICINAL CHEMISTRY. vol. 21, 19 June 2013, pages 5246 – 5260
2 * BAOHUI QI ET AL.: ‘Synthesis and Biological Evaluation of 4-Phenoxy-6, 7-disubstituted Quinolines Possessing Semicarbazone Scaffolds as Selective c-Met Inhibitors.‘ ARCH. PHARM. CHEM. LIFE SCI. vol. 346, no. 8, 2013, pages 596 – 609
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Bafetinib


Structure of Bafetinib

Bafetinib

4-[[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-N-[4-methyl-3-[(4-pyrimidin-5-ylpyrimidin-2-yl)amino]phenyl]-3-(trifluoromethyl)benzamide, cas 859212-16-1

4-[(S)-3-(dimethylamino)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

859212-07-0 (hydrochloride)

  1. bafetinib
  2. INNO-406
  3. NS-187

Bafetinib , previously as INNO-406 , NS-187 and CNS-9 refers is an experimental drug from the substance group ofbenzamides , who as Tyrosinkinasehemmstoff to be used. [2] It was originally developed by the Japanese company Nippon Shinyaku and 2006 Innovive Pharmaceuticals licensed. [3] Innovive was established in June 2008 by the CytRx Corp. adopted. [4]

Bafetinib, also known as INNO-406,  is an orally bioavailable 2-phenylaminopyrimidine derivative with potential antineoplastic activity. Bafetinib specifically binds to and inhibits the Bcr/Abl fusion protein tyrosine kinase, an abnormal enzyme produced by Philadelphia chromosomal translocation associated with chronic myeloid leukemia (CML). This agent also inhibits the Src-family member Lyn tyrosine kinase, upregulated in imatinib-resistant CML cells and in a variety of solid cancer cell types. The inhibitory effect of bafetinib on these specific tyrosine kinases may decrease cellular proliferation and induce apoptosis in tumor cells that overexpress these kinases. CML patients may be refractory to imatinib, which sometimes results from point mutations occurring in the kinase domain of the Bcr/Abl fusion product. Due to its dual inhibitory activity, the use of bafetinib has been shown to overcome this particular drug resistance.

INNO-406 (formerly NS-187) is a potent, orally available, rationally designed, dual Bcr-Abl and Lyn kinase inhibitor that is currently in early clinical studies at CytRx Oncology for the treatment of B-cell chronic lymphocytic leukemia, metastatic prostate cancer and glioblastoma multiforme. CytRx is also conducting phase I clinical studies for the treatment of recurrent high-grade glioma or metastatic disease to the brain that has progressed after treatment with whole brain radiation therapy or stereotactic radiosurgery.

The company is developing INNO-406 in preclinical studies for the prevention of bone loss in multiple myeloma patients. Nippon Shinyaku is also evaluating the compound for the treatment of chronic myeloid leukemia. The compound had been under evaluation for the treatment of certain forms of acute myeloid leukemia (AML) that are refractory or intolerant of other approved treatments; however, no recent development has been reported for this indication.

Based on its mechanisms of action, INNO-406 is expected to be effective in treating Gleevec-resistant CML and may delay or even prevent the onset of resistance in treatment naive CML patients. The ability of INNO-406 to specifically target the Bcr-Abl and Lyn kinases may result in a better side effect profile than compounds that target multiple kinases such as a pan-Src inhibitor.

In 2005, the compound was licensed to Innovive Pharmaceuticals (acquired by CytRx Oncology in 2008) by Nippon Shinyaku on a worldwide basis, with the exception of Japan, for the treatment of CML. Orphan drug designation was assigned to the compound for the treatment of CML in the U.S in 2007 and in the E.U. in 2010.

Pharmacology

Bafetinib is an inhibitor of tyrosine kinases . It affects the formation of the fusion protein Bcr-Abl , as well as that of theenzyme Lyn kinase and should in mice ten times stronger effect than the imported Tyrosinkinasehemmstoff imatinib .[5]

Patent Submitted Granted
Amide Derivative and Medicine [US7728131] 2008-11-27 2010-06-01

Clinical Development 

Bafetinib currently has no indication for an authorization as medicines .

The drug is intended for the treatment of chronic lymphocytic leukemia are developed (CLL). For this indication is Bafetinib is in the development phase II (June 2011). [6]

Bafetinib is also in phase II for the treatment of hormone-refractory prostate cancer . [7]

The US regulatory authority FDA had Bafetinib end of 2006, the status of a drug orphan (orphan drug) awarded. [8]This status could allow an accelerated development and approval.

N-[3-([5,5′-Bipyrimidin]-2-ylamino)-4-methylphenyl]-4-[[(3S)-3-(dimethyl-amino)-1-pyrrolidinyl]methyl]-3-(trifluoromethyl)benzamide

CAS No .:         887650-05-7

MW:  576.62

Formula: C 30 H 31 F 3 N 8 O

Synonym:        INNO-406, NS-187

Synthesis of Bafetinib

Analytical Chemistry Insights 2007:2 93–106
U.S. Patent 7,728,131
Reference Example 31
4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamideStep 1

4-(bromomethyl)-3-trifluoromethylbenzoic acidTo 60.0 g of 4-methyl-3-trifluoromethylbenzoic acid was added 600 ml of isopropyl acetate. Under stirring at room temperature, a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water were added in turn. The mixture was gradually heated from 30° C. up to 50° C. at intervals of 10° C. and stirred until the color of the reaction solution disappeared. The aqueous layer was separated to remove, and to the organic layer were added a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water, and then the mixture was gradually heated up to 60° C. as above. After separation, to the organic layer were further added a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water, and the mixture was gradually heated as above and heated to the temperature the mixture was finally refluxed. After the completion of the reaction, the reaction solution was separated, the organic layer was washed twice with a 5% aqueous sodium thiosulfate solution and twice with 15% saline, dried over anhydrous magnesium sulfate, and, then the solvent was distilled off under reduced pressure. To the residue was added 120 ml of n-heptane, the mixture was stirred, and then the crystals were collected by filtration to obtain 50.0 g of the objective compound as colorless crystals.

Melting point: 140-143° C.

Step 2

4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide7.69 g of 4-(bromomethyl)-3-trifluoromethylbenzoic acid obtained in the step 1 was suspended in 154 ml of anhydrous dichloromethane. Under ice-cool stirring, 6.59 ml of oxalyl chloride and 0.1 ml of anhydrous N,N-dimethylformamide were added dropwise. Under ice cooling, the mixture was further stirred for 3 hours, and then the reaction solution was concentrated under reduced pressure. To the residue was added 70 ml of anhydrous 1,4-dioxane, and then 7.00 g of 4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (Reference Example 18) and 4.18 g of potassium carbonate were added in turn, followed by stirring at room temperature for 18 hours. To the reaction solution was added 175 ml of water, and the mixture was violently stirred for one hour. Then, the deposit was collected by filtration and washed in turn with water, a small amount of acetonitrile, ethyl acetate and diisopropyl ether to obtain 8.10 g of the objective compound as pale yellow crystals.

Melting point: 198-202° C. (with decomposition)

Example 47
4-[(S)-3-(dimethylamino)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

To a solution of 6.00 g of 4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide (Reference Example 31) in 60 ml of anhydrous N,N-dimethylformamide were added 1.51 g of (S)-(−)-3-(dimethylamino)pyrrolidine and 1.83 g of potassium carbonate, followed by stirring at room temperature for 14 hours. To the reaction solution were added water and an aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.57 g of pale yellow crystals.

Melting point: 179-183° C. (with decomposition)

……………………………..
Bioorg Med Chem Lett 2006, 16(5): 1421

A series of 3-substituted benzamide derivatives of STI-571 (imatinib mesylate) was prepared and evaluated for antiproliferative activity against the Bcr-Abl-positive leukemia cell line K562. Several 3-halogenated and 3-trifluoromethylated compounds, including NS-187, showed excellent potency.

Full-size image (6 K)

 

Full-size image (12 K)Bafetinib

Figure 1.

Chemical structures of STI-571 and NS-187 (9b).

 

Full-size image (32 K)

Scheme 2.

Reagents and conditions: (a) NaBrO3, NaHSO3, EtOAc; (b) (COCl)2, cat. DMF, CH2Cl2, rt; (c) 7, K2CO3, dioxane, rt; (d) cyclic amines, K2CO3, DMF, rt.

 

………………………………

Bioorganic and Medicinal Chemistry Letters, 2007 ,  vol. 17,  10  pg. 2712 – 2717

 

CHEMBL206834.pngBafetinib

References 

  1.  This substance has not yet been rated on their dangerousness either in terms of which a reliable and quotable source for this purpose has not been found.
  2.  A. Quintas-Cardama include: Flying under the radar: the new wave of BCR-ABL inhibitors. In: Nature Reviews Drug Discovery 6/2007, pp 834-848, PMID 17853901 .
  3. Nippon Shinyaku. press release dated January 5, 2006 (s.) , accessed on 25 February 2011th
  4.  Drugs.com: Signs Definitive Agreement Cytrx Corporation to Acquire Innovive Pharmaceuticals, Inc. Retrieved June 17, 2011
  5. H. Naito include: In vivo antiproliferative effect of NS-187, a dual Bcr-Abl / Lyn tyrosine kinase inhibitor, on leukemic cells harbourage ring-Abl kinase domain mutations.In: . Leukemia Research 30/2006, pp 1443-1446, PMID 16546254 .
  6.  ClinicalTrials.gov: Study of Bafetinib as Treatment for relapsed or Refractory Chronic Lymphocytic Leukemia B-Cell (B-CLL). Retrieved on June 17, 2011th
  7. ClinicalTrials.gov: Study of Bafetinib (INNO-406) as Treatment for Patients With Hormone-Refractory Prostate Cancer (PROACT). Retrieved on June 17, 2011th
  8.  Food and Drug Administration: Database summary of 27 December of 2006. Accessed on 16 September, 2009.

Literature 

External links 

References

1: Peter B, Hadzijusufovic E, Blatt K, Gleixner KV, Pickl WF, Thaiwong T, Yuzbasiyan-Gurkan V, Willmann M, Valent P. KIT polymorphisms and mutations determine responses of neoplastic mast cells to bafetinib (INNO-406). Exp Hematol. 2010 Sep;38(9):782-91. doi: 10.1016/j.exphem.2010.05.004. Epub 2010 May 26. PubMed PMID: 20685234.

2: Kantarjian H, le Coutre P, Cortes J, Pinilla-Ibarz J, Nagler A, Hochhaus A, Kimura S, Ottmann O. Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance. Cancer. 2010 Jun 1;116(11):2665-72. doi: 10.1002/cncr.25079. PubMed PMID: 20310049; PubMed Central PMCID: PMC2876208.

3: Rix U, Remsing Rix LL, Terker AS, Fernbach NV, Hantschel O, Planyavsky M, Breitwieser FP, Herrmann H, Colinge J, Bennett KL, Augustin M, Till JH, Heinrich MC, Valent P, Superti-Furga G. A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. Leukemia. 2010 Jan;24(1):44-50. doi: 10.1038/leu.2009.228. Epub 2009 Nov 5. PubMed PMID: 19890374.

4: Kamitsuji Y, Kuroda J, Kimura S, Toyokuni S, Watanabe K, Ashihara E, Tanaka H, Yui Y, Watanabe M, Matsubara H, Mizushima Y, Hiraumi Y, Kawata E, Yoshikawa T, Maekawa T, Nakahata T, Adachi S. The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Cell Death Differ. 2008 Nov;15(11):1712-22. doi: 10.1038/cdd.2008.107. Epub 2008 Jul 11. PubMed PMID: 18617896.

5: Morinaga K, Yamauchi T, Kimura S, Maekawa T, Ueda T. Overcoming imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification. Int J Cancer. 2008 Jun 1;122(11):2621-7. doi: 10.1002/ijc.23435. PubMed PMID: 18338755.

6: Deguchi Y, Kimura S, Ashihara E, Niwa T, Hodohara K, Fujiyama Y, Maekawa T. Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines. Leuk Res. 2008 Jun;32(6):980-3. doi: 10.1016/j.leukres.2007.11.008. Epub 2008 Jan 8. PubMed PMID: 18191450.

7: Pan J, Quintás-Cardama A, Manshouri T, Cortes J, Kantarjian H, Verstovsek S. Sensitivity of human cells bearing oncogenic mutant kit isoforms to the novel tyrosine kinase inhibitor INNO-406. Cancer Sci. 2007 Aug;98(8):1223-5. Epub 2007 May 22. PubMed PMID: 17517053.

8: Kuroda J, Kimura S, Strasser A, Andreeff M, O’Reilly LA, Ashihara E, Kamitsuji Y, Yokota A, Kawata E, Takeuchi M, Tanaka R, Tabe Y, Taniwaki M, Maekawa T. Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia. Cell Death Differ. 2007 Sep;14(9):1667-77. Epub 2007 May 18. PubMed PMID: 17510658.

9: Maekawa T. [Innovation of clinical trials for anti-cancer drugs in Japan–proposals from academia with special reference to the development of novel Bcr-Abl/Lyn tyrosine kinase inhibitor INNO-406 (NS-187) for imatinib-resistant chronic myelogenous leukemia]. Gan To Kagaku Ryoho. 2007 Feb;34(2):301-4. Japanese. PubMed PMID: 17301549.

10: Niwa T, Asaki T, Kimura S. NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. Anal Chem Insights. 2007 Nov 14;2:93-106. PubMed PMID: 19662183; PubMed Central PMCID: PMC2716809.

11: Yokota A, Kimura S, Masuda S, Ashihara E, Kuroda J, Sato K, Kamitsuji Y, Kawata E, Deguchi Y, Urasaki Y, Terui Y, Ruthardt M, Ueda T, Hatake K, Inui K, Maekawa T. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. Blood. 2007 Jan 1;109(1):306-14. Epub 2006 Sep 5. PubMed PMID: 16954504.

Bafetinib

Bafetinib in its binding site

Brivanib alaninate ブリバニブアラニンエステル


Brivanib alaninate.svgBMS-582664,  brivanib alaninate

((S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-
methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate

Brivanib alaninate  is a new oncology therapy with potential applications against a wide variety of tumor types and several stages of disease progression

A prodrug of BMS-540215.

  • BMS-540215
  • BMS540215
  • Brivanib
  • UNII-DDU33B674I

BMS 540215, 649735-46-6

(S)-(R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-yl 2-aminopropanoate
Clinical data
Legal status
  • Investigational new drug
Routes Oral
Identifiers
CAS number 649735-63-7
ATC code None
PubChem CID 11154925
ChemSpider 9330033
ChEMBL CHEMBL270995
Chemical data
Formula C22H24FN5O4 
Mol. mass 441.5 g/mol

C22H24FN5O4 : 441.46
[649735-63-7]

Brivanib alaninate (INN/USAN) also known as BMS-582664 is an investigational, anti-tumorigenic drug for oral administration. The drug is being developed by Bristol-Myers Squibb for the treatment of hepatocellular carcinoma or HCC (also called malignant hepatoma), the most common type of liver cancer. Hepatocellular carcinoma [1] is a primary cancer of the liver and is more common in men than in women. The disease occurs mostly in people who have scarring of the liver (cirrhosis) or after infection with hepatitis B or hepatitis C. Symptoms include pain and swelling in the abdomen, weight loss, weakness, loss of appetite and nausea. Hepatocellular carcinoma is a severe and life-threatening disease that is associated with poor overall survival. [2] While the choice of treatment depends mainly on how advanced the disease is, the only proven therapies to cure the cancer is surgery to remove the tumor and liver transplantation, but these therapies can only be carried out in very few patients. Other treatments includechemotherapy and immunotherapy. Radiofrequency ablation and ethanol injection are also used to remove small tumors.[3]

As a result of poor liver function, metastases, or both, only 10% to 20% of patients undergo surgery. In patients having surgery, the 5-year survival rate is only 25% to 50%. Several chemotherapeutic agents have been evaluated for the treatment of hepatocellular carcinoma. Doxorubicin (trade name Adriamycin; also known as hydroxydaunorubicin), the most widely used agent in HCC, has shown a 4% to 10.5% response rate in patients with HCC.

Studies have shown that the overall response (OR) rate, but not overall survival (OS), doubles when doxorubicin was given in combination with cisplatin, IFN, and 5-fluorouracil. The multitargeted tyrosine kinase inhibitor sorafenib (trade name Nexavar), which inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, raf, c-kit, and flt-3, has been shown to inhibit HCC-induced proliferation and angiogenesis.

Sorafenib has also been shown to provide a significant improvement in OS in patients with HCC. Based on these results, researchers concluded that this class of agents may be effective in the treatment of HCC. Brivanib alaninate also inhibits VEGFR and fibroblast growth factorreceptors (FGFR), which is known to play a major role in the etiopathogenesis of HCC. To date, brivanib alaninate has been investigated in 29 studies, including more than 4,000 patients around the world.

 Brivanib alaninate.png
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/op500126u
Abstract Image

This manuscript describes the control strategy for the commercial process to manufacture brivanib alaninate. The active pharmaceutical ingredient is a prodrug which is susceptible to hydrolysis. In addition to controlling hydrolysis, a robust strategy was required in order to control input and process-related impurities. Three significant aspects of control include understanding of the reaction parameters in order to minimize the regioisomer during the alkylation with (R)-propylene oxide, development of a design space through statistical models to control impurity formation, and the use of in situ FT-IR to monitor the hydrogenolysis of the Cbz protecting group.

(S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2-f][1,2,4]triazin-6-yloxy)propan-2-yl)-2-aminopropanonate (1)

Brivanib alaninate.svg

1H NMR (400 MHz, CDCl3) 8.31 (1 H, s), 7.83 (1 H, s), 7.25 (1 H, s), 7.00 (1 H, d, J= 8.6 Hz), 6.95 (1 H, dd, J = 15.4, 8.6 Hz), 6.28 (1 H, s), 5.36–5.30 (1 H, m), 4.08–4.00 (2 H, m), 3.57 (1 H, dd, J = 14.0, 6.9 Hz), 2.47 (3 H, s), 2.40 (3 H, s), 1.66 (3 H, s), 1.38 (3 H, d, J = 6.4 Hz), 1.35 (3 H, d, J = 7.1 Hz).

(S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2-f][1,2,4]triazin-6-yloxy)propan-2-yl)-2-(benzyloxycarbonylamino)propanonate

1H NMR (400 MHz, CDCl3) 8.17 (1 H, br s), 7.84 (1 H, s), 7.41 (1 H, s), 7.35–7.28 (5 H, m), 7.03 (1 H, d, J = 8.6 Hz), 6.95 (1 H, t, J = 7.7 Hz), 6.30 (1 H, s), 5.36–5.32 (2 H, m), 5.11 (2 H, br s), 4.43–4.40 (1 H, m), 4.02–3.99 (2 H, m), 2.46 (3 H, s), 2.41 (3 H, s), 1.44 (3 H, d, J = 7.2 Hz), 1.38 (3 H, d, J = 7.2 Hz).

Ongoing clinical development program

To further investigate the benefits of brivanib in patients with advanced HCC, a broad-spectrum, global, phase III clinical development plan called the Brivanib studies in HCC patients at RISK (BRISK), has been initiated. Clinical benefits seen with brivanib in the first-line setting, and following the failure of sorafenib therapy, highlight the potential to improve the clinical course of patients with advanced HCC. Brivanib may provide a novel therapeutic option to a growing number of patients for whom no other treatment choice exists.

Regulatory status

On 27 October 2011, orphan designation (EU/3/11/918) was granted by the European Commission to Bristol-Myers Squibb for brivanib alaninate for the treatment of hepatocellular carcinoma.[11] Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorization. As a consequence, demonstration of quality, safety and efficacy is necessary before a product can be granted a marketing authorization. At the time of the orphan designation, several medicines were authorized in the EU for the treatment of hepatocellular carcinoma.

Submission and application

At the time of submission of the application for orphan designation, clinical trials with brivanib alaninate in patients with hepatocellular carcinoma were ongoing. As part of the submission process, Bristol-Myers Squibb has provided sufficient information to show that brivanib alaninate might be of significant benefit for patients with hepatocellular carcinoma because it could provide an alternative for patients who cannot take or for whom existing treatments do not work. Early studies show that it might improve the treatment of patients with this condition, particularly if used when existing treatment had failed. However, this assumption needs to be confirmed at the time of EU marketing authorization, in order to maintain the orphan status.

Synthesis of Brivanib

Route 1

Route 2
…………………………….

[(1R), 2S]-2-Aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester, has the structure of formula I:

Figure US07932383-20110426-C00001

and is referred to herein as “Compound I”. Compound I, compositions comprising Compound I, and methods of using Compound I are disclosed in U.S. Pat. No. 6,869,952 B2, which is assigned to the present assignee and is incorporated herein by reference in its entirety.Compound I, a prodrug, is suitable for inhibiting tyrosine kinase activity of growth factor receptors such as VEGFR-2 and FGFR-1 and is useful in the treatment of cancer. Compound I is also useful in the treatment of diseases, other than cancer, which are associated with signal transduction pathways operating through growth factors and anti-angiogenesis receptors such as VEGFR-2.

Typically, in the preparation of a pharmaceutical composition, a form of the active ingredient having desired properties such as dissolution rate, solubility, bioavailability, and/or storage stability is sought. For example, a form of the active ingredient, which has the desired solubility and bioavailability, has sufficient stability that it does not convert during manufacture or storage of the pharmaceutical composition to a different form having different solubility and/or bioavailibility. A form of Compound I is desired having properties and stability that allow the preparation of pharmaceutical compositions suitable for the treatment of diseases such as cancer.

…………………………………..

 http://www.google.com/patents/US6869952

EXAMPLE 81

Figure US06869952-20050322-C00100

[(1R), 2S]-2-Aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester

Step A

A mixture of Example 15 (60 mg, 0.0.16 mmol), N-Cbz-L-alanine (89 mg, 0.4 mmol), HATU (253 mg, 0.4 mmol), DIPEA (103 mg, 0.8 mmol), and DMAP (5 mg) in DMF (1 mL) was stirred overnight. The volatiles were removed in vacuo, and the residue was purified by preparative HPLC to afford homochiral 2-benzyloxyearbonylamino-propionic acid [2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]]-l-methylethyl ester as a white solid (77 mg, 84% yield).

Step B

A mixture of the compound from step A above (60 mg, 0.11 mmol), Pd/C (6 mg), and ammonium formate (200 mg) in DMF (1.5 mL) were stirred at RT for 30 min. The mixture was diluted with ethyl acetate, and then filtered through a pad of Celite®. The filtrate was washed with water, dried over Na2SO4, and concentrated. The product was mixed with 1 N aqueous HCl and lyophilized to afford the title compound as a white solid (53 mg, 99% yield). MS: (M+H)+=442. 1HNMR (CD3OD): δ 1.45 (d, 3H, J=6.60 Hz), 1.56 (d, 3H, J=7.47 Hz), 2.44 (s, 3H), 2.46 (s, 3H), 4.13 (q, 1H), 4.18 (d, 2H, J=3.96 Hz), 5.45 (m 1H); 6.23 (s, 1H); 6.90 (dd, 1H); 7.10 (d, 1H); 7.66 (s, 1H), 7.75 (s, 1H).

…………………………

Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215)
J Med Chem 2008, 51(6): 1976

http://pubs.acs.org/doi/abs/10.1021/jm7013309

Abstract Image

A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.

(R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (1)

A mixture of 6 (7.5 g, 24 mmol), R-(+)-propylene oxide (120 mmol), LiCl (3.02 g, 72 mmol), and NEt3 (300 μL) in EtOH (50 mL)………………………………………..o afford 1 (7.2 g, 81% yield) as an off-white solid. MS (ESI+) m/z 371.2 (M + H)+. 1H NMR (500 MHz, CD3OD) δ 7.72 (s, 1H), 7.61 (s, 1H), 7.10 (d, 1H, J = 8.80 Hz), 6.90 (t, 1H, J = 7.15 Hz), 6.23 (s, 1H), 4.12–4.20 (m, 1H), 3.92 (d, 2H, J = 6.55 Hz), 2.48 (s, 3H), 2.43 (s, 3H), 1.29 (d, 3H, J = 6.6 Hz). Mp 208–210 °C. Anal. (C19H19FN4O3): C, H, N, F.

 (S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-
yloxy)propan-2-yl) 2-aminopropanoate (8)
1H NMR (500 MHz, CD3OD): 7.75 (s, 1H), 7.66 (s, 1H), 7.10 (d, 1H, J= 10.95 Hz), 6.90 (t, 1H,
J=9.60 Hz), 6.23 (s, 1H), 5.45 (m 1H), 4.18 (d, 2H, J= 3.96 Hz), 4.13 (q, 1H), 2.46 (s, 3H), 2.44 (s,3H), 1.56 (d, 3H, J=7.47 Hz), 1.45 (d, 3H, J=6.60 Hz). LC/MS(ESI+) m/z 442.1 (M+H)+.
M.p. 136-142 oC. Elemental analysis: (C22H24FN5O4:1H2O:1.09HCl): Calc’d: C, 52.95; H, 5.47; N,14.03; F, 3.81; Cl, 7.74. Found: C, 53.16; H, 5.35; N, 14.07; F, 3.72; Cl, 7.74HRMS (calc’d for C22H24FN5O4 M+H+): 442.1891, found: 442.1897.

……………………..

Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor
J Med Chem 2006, 49(7): 2143

http://pubs.acs.org/doi/abs/10.1021/jm051106d

Abstract Image

A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure−activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The l-alanine prodrug of12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.

 Preparation of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (12).
A mixture of 7 (650 mg, 2.08 mmol), (R)-(+)-propylene oxide (595 mg, 10.4 mmol), and
triethylamine (30 µl) in ethanol (8 mL) was heated at 70 °C in a sealed tube. After 2 h, the solvent was removed in vacuo and the product was purified by flash column chromatography (silica gel, 20% EtOAc/ CH2Cl2) to afford a solid, which was triturated with 50% Et2O in CH2Cl2 to give 12 (410 mg,53% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.41 (s, 1H), 7.11 (d, 1H,J = 11 Hz), 7.02 (t, 1H, J = 8.8 Hz), 6.39 (s, 1H), 4.20-4.30 (m, 1H), 3.8-4.00 (m, 2H), 2.51 (s, 3H),2.45 (s, 3H), 1.31 (d, 3H, J = 8.2 Hz). 13C NMR (125 MHz, DMSO-d6) δ 8.36, 13.3, 20.0, 64.5, 76.36,95.1, 100.0, 105.75, 106.66, 110.17, 115.47, 117.66, 117.8, 129.83, 136.34, 137.64, 144.13, 144.6,146.53, 148.15, 160.71. LC/MS (ESI) m/z 371 ((M+H)+. HPLC Method / tR / purity: method A/ 3.95min/ 99%. HRMS for C19H20FN4O3, calcd: 371.1519, found: 371.1522. Anal. (Calcd. ForC19H19FN4O3): theoretical %C 61.61, %H 5.17, %N 15.13, %F 5.13; found %C 61.35, %H 5.06, %N 14.99, %F 4.88.

…….

References

  1.  National Cancer Institute Dictionary of Cancer Terms
  2.  National Cancer Institute Adult Primary Liver Cancer Treatment (PDQ®)
  3.  National Cancer Institute Adult Primary Liver Cancer Treatment (PDQ®)/Treatment Option Overview
  4.  Huynh, H.; Ngo, V. C.; Fargnoli, J.; Ayers, M.; Soo, K. C.; Koong, H. N.; Thng, C. H.; Ong, H. S. et al. (2008). “Brivanib Alaninate, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Tyrosine Kinases, Induces Growth Inhibition in Mouse Models of Human Hepatocellular Carcinoma”. Clinical Cancer Research 14 (19): 6146–53. doi:10.1158/1078-0432.CCR-08-0509. PMID 18829493.
  5.  Cai, Zhen-wei; Zhang, Yongzheng; Borzilleri, Robert M.; Qian, Ligang; Barbosa, Stephanie; Wei, Donna; Zheng, Xiaoping; Wu, Lawrence et al. (2008). “Discovery of Brivanib Alaninate ((S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), A Novel Prodrug of Dual Vascular Endothelial Growth Factor Receptor-2 and Fibroblast Growth Factor Receptor-1 Kinase Inhibitor (BMS-540215)”. Journal of Medicinal Chemistry 51 (6): 1976–80. doi:10.1021/jm7013309. PMID 18288793.
  6.  Ayers, M.; Fargnoli, J.; Lewin, A.; Wu, Q.; Platero, J. S. (2007). “Discovery and Validation of Biomarkers that Respond to Treatment with Brivanib Alaninate, a Small-Molecule VEGFR-2/FGFR-1 Antagonist”. Cancer Research 67 (14): 6899–906. doi:10.1158/0008-5472.CAN-06-4555. PMID 17638901.
  7.  Bhide, Rajeev S.; Cai, Zhen-Wei; Zhang, Yong-Zheng; Qian, Ligang; Wei, Donna; Barbosa, Stephanie; Lombardo, Louis J.; Borzilleri, Robert M. et al. (2006). “Discovery and Preclinical Studies of (R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in Vivo Active Potent VEGFR-2 Inhibitor”. Journal of Medicinal Chemistry 49 (7): 2143–6. doi:10.1021/jm051106d. PMID 16570908.
  8.  ClinicalTrials.gov NCT00640471 Cetuximab With or Without Brivanib in Treating Patients With K-Ras Wild Type Tumours and Metastatic Colorectal Cancer
  9.  Allen, E.; Walters, I. B.; Hanahan, D. (2011). “Brivanib, a Dual FGF/VEGF Inhibitor, is Active Both First and Second Line against Mouse Pancreatic Neuroendocrine Tumors Developing Adaptive/Evasive Resistance to VEGF Inhibition”. Clinical Cancer Research 17 (16): 5299–310. doi:10.1158/1078-0432.CCR-10-2847. PMC 3156934. PMID 21622725.
  10.  Finn, R. S.; Kang, Y.-K.; Mulcahy, M.; Polite, B. N.; Lim, H. Y.; Walters, I.; Baudelet, C.; Manekas, D.; Park, J.-W. (2012). “Phase II, Open-label Study of Brivanib as Second-line Therapy in Patients with Advanced Hepatocellular Carcinoma”. Clinical Cancer Research 18 (7): 2090–8. doi:10.1158/1078-0432.CCR-11-1991. PMID 22238246.
  11.  orphan designation

External links

US6869952 * Jul 18, 2003 Mar 22, 2005 Bristol Myers Squibb Company Such as 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-pyrrolo(2,1-f)(1,2,4)triazin-6-ol; for treament of cancer
US6982265 May 18, 2000 Jan 3, 2006 Bristol Myers Squibb Company Pyrrolotriazine inhibitors of kinases
US7671199 * Apr 20, 2007 Mar 2, 2010 Britsol-Myers Squibb Company dual inhibitor of VEGFR and FGFR tyrosine kinases; cancer
WO2006030941A1 Sep 13, 2005 Mar 23, 2006 Eisai Co Ltd Simultaneous use of sulfonamide-containing compound and angiogenesis inhibitor
WO2006124689A2 May 12, 2006 Nov 23, 2006 Squibb Bristol Myers Co Combination therapy
NON-PATENT CITATIONS
Reference
1 Bennett, J.C. et al., eds., Cecil Textbook of Medicine, 20th Edition, vol. 1, W.B. Saunders Company, publ., pp. 1004-1010 (1996).
2 Fabbro, D. et al., “Protein kinases as targets for anticancer agents: from inhibitors to useful drugs“, Pharmacology & Therapeutics, vol. 93, pp. 79-98 (2002).
3 Gautschi, O. et al., “Aurora Kinases as Anticancer Drug Targets“, Clin. Cancer Res., vol. 14, No. 6, pp. 1639-1648 (2008).
4 Huynh, H. et al., “Brivanib Alaninate, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Tyrosine Kinases, Induces Growth Inhibition in Mouse Models of Human Hepatocellular Carcinoma“, Clin. Cancer Res., vol. 14, No. 19, pp. 6146-6153 (2008).
5 Mass, R.D. , “The HER Receptor Family: a Rich Target for Therapeutic Development“, Int, J. Radiation Oncology Biol. Phys., vol. 58, No. 3, pp. 932-940 (2004).
6 Mountzios, G. et al., “Aurora kinases as targets for cancer therapy“, Cancer Treatment Reviews, vol. 34, pp. 175-182 (2008).
7 National Cancer Institute, http://www.cancer.gov, Brivanib Active Trial Listing (ID#: 5552473) (Dec. 15, 2008).

 

hplc

HPLC methods
Method A :A linear gradient program using 10% methanol, 90% water, 0.2% H3PO4 (solvent A) and
90% methanol, 10% water, 0.2% H3PO4 (solvent B); t = 0 min, 0% B, t = 4 min, 100% B was
employed on a YMC S5 Combiscreen 4.6 × 50 mm column. Flow rate was 4 mL/min and UV detection
was set to 220 nm. The LC column was maintained at ambient temperature.
Method B: A linear gradient program using 10% methanol, 90% water, 0.2% H3PO4 (solvent A) and
90% methanol, 10% water, 0.2% H3PO4 (solvent B); t = 0 min, 0% B, t = 4 min, 100% B was
employed on a YMC ODS 4.6 x 50 mm column. Flow rate was 4 mL/min and UV detection was set to
220 nm. The LC column was maintained at ambient temperature.
Method C: A linear gradient program using 10% methanol, 90% water, 0.1% trifluoroacetic acid (TFA)
(solvent A) and 90% methanol, 10% water, 0.1% TFA (solvent B); t = 0 min, 0% B, t = 4 min, 100% B
was employed on a Chromolith SpeedROD, 4.6 × 50 mm column. Flow rate was 4 mL/min and UV
detection was set to 254 nm. The LC column was maintained at ambient temperature.
Method D: A linear gradient program using 10% methanol, 90% water, 0.1% TFA (solvent A) and 90%
methanol, 10% water, 0.1% TFA (solvent B); t = 0 min, 0% B, t = 2 min, 100% B was employed on a
Waters Xterra 5 m, 4.6 mm × 30 mm column. Flow rate was 4 mL/min and UV detection was set to
220 nm. The LC column was maintained at ambient temperature.

 

http://www.google.com/patents/EP2364699A1?cl=en

  • (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2-f][1,2,4]triazin-6-yloxy)propan-2-ol (hereinafter also referred to as “BMS-540215”; Proceedings of the American Association for Cancer Research., 46, (Abstract 3033), 2005) (see Formula (XXXIII)):
    Figure imgb0052

    and

  • (28) (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2-f][1,2,4]triazin-6-yloxy)propan-2-ol) 2-aminopropanonate (hereinafter also referred to as “BMS-582664”; Proceedings of the American Association for Cancer Research., 46, (Abstract 3033), 2005) (see Formula (XXXIV)):
    Figure imgb0053

Radius Announces Positive Phase 3 Top-Line Results for Its Investigational Drug Abaloparatide-SC in Postmenopausal Women With Severe Osteoporosis


Chemical structure for Abaloparatide

Abaloparatide

WALTHAM, Mass., Dec. 21, 2014 (GLOBE NEWSWIRE) — Radius Health, Inc. today announced positive top-line 18-month fracture results from the Company’s Phase 3 clinical trial (ACTIVE) evaluating the investigational drug abaloparatide-SC for potential use in the reduction of fractures in postmenopausal osteoporosis.

https://in.finance.yahoo.com/news/radius-announces-positive-phase-3-042531179.html

Chemical structure for Abaloparatide

Abaloparatide
BA058
BIM-44058
UNII-AVK0I6HY2U

BA058; BIM-44058; CAS  247062-33-5

MW 3960.5896, MF C174 H300 N56 O49

NAME………C2.29-methyl(22-L-glutamic acid(F>E),23-L-leucine(F>L),25-L-glutamic acid(H>E),26-L-lysine(H>K),28-L-leucine(I>L),30-L-lysine(E>K),31-L-leucine(I>L))human parathyroid hormone-related protein-(1-34)-proteinamide
L-Alaninamide, L-alanyl-L-valyl-L-seryl-L-alpha-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-alpha-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-alpha-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-alpha-glutamyl-L-leucyl-L-leucyl-L-alpha-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-

L-​Alaninamide, L-​alanyl-​L-​valyl-​L-​seryl-​L-​α-​glutamyl-​L-​histidyl-​L-​glutaminyl-​L-​leucyl-​L-​leucyl-​L-​histidyl-​L-​α-​aspartyl-​L-​lysylglycyl-​L-​lysyl-​L-​seryl-​L-​isoleucyl-​L-​glutaminyl-​L-​α-​aspartyl-​L-​leucyl-​L-​arginyl-​L-​arginyl-​L-​arginyl-​L-​α-​glutamyl-​L-​leucyl-​L-​leucyl-​L-​α-​glutamyl-​L-​lysyl-​L-​leucyl-​L-​leucyl-​2-​methylalanyl-​L-​lysyl-​L-​leucyl-​L-​histidyl-​L-​threonyl-

 

CLINICAL……….https://clinicaltrials.gov/search/intervention=Abaloparatide%20OR%20BA058%20OR%20BIM-44058

BIM-44058 is a 34 amino acid analog of native human PTHrP currently in phase III clinical trials at Radius Health for the treatment of postmenopausal osteoporosis. Radius is also developing a microneedle transdermal patch using a 3M drug delivery system in phase II clinical trials. The drug candidate was originally developed at Biomeasure (a subsidiary of Ipsen), and was subsequently licensed to Radius and Teijin Pharma.

………………………….

PATENT

http://www.google.com/patents/EP2206725A1?cl=en

  1. A peptide of the formula:

    [Glu22, 25, Leu23, 28, 31, Lys26, Aib29, Nle30]hPTHrP(1-34)NH2;
    [Glu22, 25, Leu23, 28, 30, 31, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, 25,29, Leu23, 28, 30, 31, Lys26]hpTHrP(1-34)NH2; [Glu22, 25, 29, Leu23, 28, 31, Lys26, Nle30]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11, 23, 28, 31, His14, Cha15, Glu22, 25, Lys26, 30, Aib29]hPTHrP (1-34)NH2; [Cha22, Leu23, 28, 31, Glu25, 29, Lys26, Nle30]hPTHrP(1-34)NH2; [Cha7, 11, 15]hPTHrP(1-34)NH2; [Cha7, 8, 15]hPTHrP(1-34)NH2; [Glu22, Leu23, 28, Aib25, 29, Lys26]hpTHrP(1-34)NH2; [Aib29]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Lys26, Aib29, 30]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Aib26, 29, Lys30] hPTHrP(1-34)NH2; or [Leu27, Aib29]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.

…………………

SEE……http://www.google.com.ar/patents/US8148333?cl=en

………………..

SEE…………http://www.google.im/patents/US20090227498?cl=pt

EP5026436A Title not available
US3773919 Oct 8, 1970 Nov 20, 1973 Du Pont Polylactide-drug mixtures
US4767628 Jun 29, 1987 Aug 30, 1988 Imperial Chemical Industries Plc Polylactone and acid stable polypeptide
WO1994001460A1 * Jul 13, 1993 Jan 20, 1994 Syntex Inc Analogs of pth and pthrp, their synthesis and use for the treatment of osteoporosis
WO1994015587A2 Jan 5, 1994 Jul 21, 1994 Steven A Jackson Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides
WO1997002834A1 * Jul 3, 1996 Jan 30, 1997 Biomeasure Inc Analogs of parathyroid hormone
WO1997002834A1 * 3 Jul 1996 30 Jan 1997 Biomeasure Inc Analogs of parathyroid hormone
WO2008063279A2 * 3 Oct 2007 29 May 2008 Radius Health Inc A stable composition comprising a bone anabolic protein, namely a pthrp analogue, and uses thereof
US5695955 * 23 May 1995 9 Dec 1997 Syntex (U.S.A.) Inc. Gene expressing a nucleotide sequence encoding a polypeptide for treating bone disorder
US20030166836 * 6 Nov 2002 4 Sep 2003 Societe De Conseils De Recherches Et D’application Scientefiques, S.A.S., A France Corporation Analogs of parathyroid hormone
US20050282749 * 14 Jan 2005 22 Dec 2005 Henriksen Dennis B Glucagon-like peptide-1 (GLP-1); immunotherapy; for treatment of obesity

Automation of Process Control within the Pharmaceutical Industry


Valve Systems for Pharmaceutical Applications logo

Automation of Process Control within the Pharmaceutical Industry

While most pharmaceutical businesses have adopted process automation in one format or another, the technology has evolved considerably over the past few years, leading to improvements in design, efficiency and reliability.

One of the major drivers for businesses to increase levels of automation is legislation, but the need to compete in the market place and reduce production costs has also played a significant part.

Within the pharmaceutical industry, the key to finding the best automation solution is a thorough analysis of each individual part of the plant or installation.

By carrying out an in-depth analysis of the application, it can be determined if a centralized control system using non-intelligent nodes, will deliver the required performance, or if the sheer size of the system means that the control has to be decentralised using a fieldbus system working with field controls, intelligent valves and actuators.

Download to find out more.

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  • Automation of Process Control within the Pharmaceutical Industry 
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http://www.pharmaceutical-technology.com/downloads/whitepapers/process_automation/automation_process_control-pharma/?WT.mc_id=WN_WP

Elemental Impurity Analysis in Pharmaceuticals.free download from Butterworth labs


 

Contract Analytical Chemistry Services and Quality Control Testing logo

Elemental Impurity Analysis in Pharmaceuticals

A method to identify the presence of heavy metals in pharmaceuticals was introduced in the United States Pharmacopeia more than 100 years ago.

Pharmaceutical companies are still using essentially the same method, known as the USP Heavy Metals Limit Test.

This paper will provide an overview of current method limitations, considerations for the new methodology and risk-based assessments being carried out by manufacturers.

Boswellia serrata, -The cure for osteoarthritis in ayurveda, Shallaki,


Boswellia serrata (Salai) in Kinnarsani WS, AP W2 IMG 5840.jpg

in Kinnerasani Wildlife Sanctuary,Andhra Pradesh, India.

Boswellia serrata, -The cure for osteoarthritis in ayurveda, Shallaki,

Shallaki-Boswellia serrata

In degenerative and inflammatory pathologies invoving joints, there is no other drug as useful as Guggulu. Many international companies today use shallaki for the manufacture of drugs, ayurvedic and allopathic alike.

Family : Berseraceae

Scientific name : Boswellia serrata

Nomenclature in other languages :

Sanskrit : Shallaki, Susrava, Gajabhakshya

Hindi : Salei

Gujarathi : Dhoopa

Bengali : Salei

Tamil : Olibana

English : Indian Olibanum

Distribution : Gujarat, Rajasthan, Bihar are most commonly the residence of this plant.

Botanical description : It’s a resinous tree that grows to a height of 12m. A tree of moderate height , its bark are grey in colour. Upon time the bark sheds off like scales of a snake. The younger branches and leaflets of this tree are very smooth. The leaves which are compound(pinnate) in nature are 20-37 cm long. The leaflets are 2-5cm long and 1-2.5cm wide. The leaflets are oval shaped. The leaves contains 8 pairs or more of the leaflets . The margins of leaflets are serrated. Flowers are many and the inflorescence is terminal raceme, with it seen in the axilla of the leaf and stem. The petals and sepals are hairy and five in number. The stamen are 10 in number, they are diercted inwards. The fruits are seen in 3-4 numbers and are seen as drupes along with cones. The flowering season in April-May.

C hemical constituents and action

The bark contains carbohydrates, glycosides, beta-sitosterol. The resin contains ditrepene alcohol. This is knownn by the name sitosterol. In addition to that 11-keto-b-boswellic acid also has been extracted from the resin.

Ayurvedic Pharmacoepia

Rasa : kashaya, tikta, madhura

Guna : laghu, rooksha

Veerya : sheeta

Vipaka : katu

Medicinal properties :

Alleiviates vata kapha disorders. Also cures chronic skin lesions of all kinds infective and inflammatory, ulcers, wounds, piles, diseases of mouth, diarhhoea, hepatic disorders etc.

Useful parts : Bark, Resin

Therapeutic uses :

-1gm of resin taken in tablet form daily three times cures rheumatic, neurologic complaints and rheumatic fever.

-for gangrenes in diabetes the resin of this palnt may be applied externally and it taken internally as pills regularly

-the resin of this plant when chewed cures bad odour of mouth and mouth ulcers.

Medical uses

In Ayurvedic medicine Indian frankincense (Boswellia serrata) has been used for hundreds of years for treating arthritis.

Extracts of Boswellia serrata have been clinically studied for osteoarthritis and joint function, particularly for osteoarthritis of the knee, with the research showing a slight improvement of both pain and function compared to a placebo. Positive effects of Boswellia in some chronic inflammatory diseases including rheumatoid arthritis, bronchial asthma, osteoarthritis, ulcerative colitis and Crohn’s disease have been reported. A Boswellia extract marketed under the name Wokvel has undergone human efficacy, comparative, pharmacokinetic studies. Some see Boswellia serrata as a promising alternative to NSAIDs, warranting further investigation in pharmacological studies and clinical trials.

Topical application

Boswellia serrata has been recently developed for topical use in a patent-pending formula in Sano Relief Gel. Boswellia serrata is used in the manufacture of the supposed anti-wrinkle agent “Boswelox”,which has been criticised as being ineffective.

Potential for anti-cancer activity

Boswellic acid, an extract from Boswellia serrata, has been studied for anti-neoplastic activity, especially in experimental primary and secondary brain tumors, indicating potential efficacy from in vitro and limited clinical research. Boswellic acid is also undergoing an early-stage clinical trial at the Cleveland Clinic.

Active constituents

Boswellic acid and other pentacyclic triterpene acids are present. Beta-boswellic acid is the major constituent.

Mechanism of action

Animal studies performed in India show ingestion of a defatted alcoholic extract of Boswellia decreased polymorphonuclear leukocyte infiltration and migration, decreased primary antibody synthesis and almost totally inhibited the classical complement pathway.

Properties

Shallaki has potent analgesic and anti-inflammatory effects that can reduce the pain and inflammation of joints.

Frankincense ‘can ease arthritis’ researches have suggested

Extracts from Boswellia serrata, a similar species to the variety famous for its role in the Christian nativity, were tested on dozens of patients.

Those who received it reported better movement and less pain and stiffness.

The herb has been used for thousands of years in Indian Ayurvedic medicine, reports the journal Arthritis Research and Therapy.
Osteoarthritis is the most common form of the condition, and normally affects the weight bearing joints such as hands, wrists, feet and spine.

Current treatments carry a great many adverse effects, and scientists have been hunting for an alternative.

The investigation into the properties of Boswellia serrata was led by Dr Siba Raychaudhuri at the University of California, Davis.

Eventually they tested an extract of the plant enriched with the chemical – AKBA – thought to be its active ingredient.

Some of the 70 patients with severe arthritis in their knees recruited into the trial were given a low-dose capsule, some a higher dose capsule, and the remainder were given a dummy pill with no active ingredients.

In as little as seven days, patients taking the frankincense drug reported improvements in their pain and stiffness levels compared with the placebo group, and these continued until the 90-day mark, when the study ended.

Alternative therapies

Tests of the fluid within affected joints also revealed falls in levels of enzymes linked to the condition.

Dr Raychaudhuri said: “We have shown that B. serrata enriched with AKBA can be an effective treatment for osteoarthritis of the knee.”

However, UK experts urged caution. Professor Philip Conaghan, from Leeds University, and a spokesman for the Arthritis Research Campaign, said: “Certainly osteoarthritis is in need of new safe analgesics, although many effective therapies that reduce pain such as muscle strengthening exercises, shock-absorbing footwear and weight loss have very few bad side-effects.

“This report on treating knee pain with a chemical derivative of B. serrata is interesting but the patient numbers are small, there were some problems with the reported trial design and we need more information on its medium to long-term safety.”

Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data.

Non-steroidal anti-inflammatory drug (NSAID) intake is associated with high prevalence of gastrointestinal or cardiovascular adverse effects. All efforts to develop NSAIDs that spare the gastrointestinal tract and the cardiovasculature are still far from achieving a breakthrough. In the last two decades, preparations of the gum resin of Boswellia serrata (a traditional ayurvedic medicine) and of other Boswellia species have experienced increasing popularity in Western countries. Animal studies and pilot clinical trials support the potential of B. serrata gum resin extract (BSE) for the treatment of a variety of inflammatory diseases like inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and asthma. Moreover, in 2002 the European Medicines Agency classified BSE as an ‘orphan drug’ for the treatment of peritumoral brain oedema. Compared to NSAIDs, it is expected that the administration of BSE is associated with better tolerability, which needs to be confirmed in further clinical trials. Until recently, the pharmacological effects of BSE were mainly attributed to suppression of leukotriene formation via inhibition of 5-lipoxygenase (5-LO) by two boswellic acids, 11-keto-β-boswellic acid (KBA) and acetyl-11-keto-β-boswellic acid (AKBA). These two boswellic acids have also been chosen in the monograph of Indian frankincense in European Pharmacopoiea 6.0 as markers to ensure the quality of the air-dried gum resin exudate of B. serrata. Furthermore, several dietary supplements advertise the enriched content of KBA and AKBA. However, boswellic acids failed to inhibit leukotriene formation in human whole blood, and pharmacokinetic data revealed very low concentrations of AKBA and KBA in plasma, being far below the effective concentrations for bioactivity in vitro. Moreover, permeability studies suggest poor absorption of AKBA following oral administration. In view of these results, the previously assumed mode of action – that is, 5-LO inhibition – is questionable. On the other hand, 100-fold higher plasma concentrations have been determined for β-boswellic acid, which inhibits microsomal prostaglandin E synthase-1 and the serine protease cathepsin G. Thus, these two enzymes might be reasonable molecular targets related to the anti-inflammatory properties of BSE. In view of the results of clinical trials and the experimental data from in vitro studies of BSE, and the available pharmacokinetic and metabolic data on boswellic acids, this review presents different perspectives and gives a differentiated insight into the possible mechanisms of action of BSE in humans. It underlines BSE as a promising alternative to NSAIDs, which warrants investigation in further pharmacological studies and clinical trials.

Reference :

http://www.ncbi.nlm.nih.gov/pubmed/21553931

http://en.wikipedia.org/wiki/Boswellia_serrata

http://news.bbc.co.uk/2/hi/health/7535733.stm

Olaparib オラパリブ 奥拉帕尼 (AZD-2281, trade name Lynparza) AZ’ first-in-class PARP inhibitor wins EU nod


Olaparib.png

Olaparib

オラパリブ

奥拉帕尼

Women suffering from advanced relapsed BRCA-mutated ovarian cancer could gain access to a new treatment option after European regulators waved through AstraZeneca’s Lynparza (olaparib).

The European Commission has approved the first-in-class PARP inhibitor for the maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete response or partial response to platinum-based chemotherapy.

read at……http://www.pharmatimes.com/Article/14-12-18/AZ_first-in-class_PARP_inhibitor_Lynparza_wins_EU_nod.aspx


Olaparib.png
4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one, cas  763113-22-0

Kudos Pharmaceuticals Limited

Olaparib, AZD2281,  AZD2281

KU-0059436
KU-59436

Olaparib (AZD-2281, trade name Lynparza) is an experimental chemotherapeutic agent, developed by KuDOS Pharmaceuticalsand later by AstraZeneca, that is currently undergoing clinical trials. It is an inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair.[1] It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast and prostate cancers.

Olaparib is an oral poly-ADP-ribose polymerase (PARP) enzyme inhibitor developed by AstraZeneca. The product is awaiting registration in the E.U. and US as a maintenance treatment of patients with BRCA mutated platinum-sensitive relapsed serous ovarian cancer. In 2014, positive opinion was received in the E.U. recommending Lynparza approval for the maintanance treatment of BRCA mutated platinum-sensitive relapsed serous ovarian cancer.

An oral poly (ADP ribose) polymerase (PARP) inhibitor being investigated by British drug company AstraZeneca, is seeking approval from the U.S. Food and Drug Administration (FDA) for the treatment of BRCA mutated platinum-sensitive relapsed ovarian cancer. AstraZeneca filed the US regulatory submission for olaparib in February 2014.  Olaparib, one of several cancer drugs AstraZeneca flagged as having strong potential in its defense of a $118 billion take-over bid by Pfizer,was accepted for priority review on April 30, 2014  by the U.S.  Food and Drug Administration (FDA). The NDA filing was based on Phase II study 19 data, a randomized, double-blind, placebo-controlled, Phase II study.

On June 25, 2014, FDA Oncologic Drugs Advisory Committee (ODAC), an advisory panel to the U.S. Food and Drug Administration (FDA),  voted 11 to two against the accelerated approval of the PARP inhibitor olaparib as a maintenance therapy for women with platinum-sensitive relapsed ovarian cancer who have the germline BRCA (gBRCA) mutation, and who are in complete or partial response to platinum-based chemotherapy. By voting no, the committee recommended waiting for results from the larger confirmatory phase III SOLO-2 trial, which began enrolling in September 2013. According to clincialtrials.gov, the SOLO-2 study (NCT01874353) is slated to wrap in July 2015.

In terms of clinical development, phase III trials are ongoing at AstraZeneca for the treatment of gastric cancer and metastatic breast cancer. Olaparib is also in phase II clinical studies for several indications, including breast cancer, pancreatic cancer and castration-resistant prostate cancer. In March 2014, a phase II was also initiated in GB for the treatment of patients with stage IIIB or stage IV NSCLC that is not amenable to curative therapy. A phase I clinical trial for the treatment of melanoma has been completed. Phase II clinical trials are ongoing at General Hospital Corp. for the treatment of sarcoma. The drug had been in phase II clinical trials for the treatment of colorectal cancer; however no recent developments have been reported.

Discovered by KuDOS Pharmaceuticals, has experienced several twists and turns during its clinical development. Promising results for the drug were reported at the 2011 ASCO Annual Meeting, based on impressive early phase II results, only to have clinical development discontinued later that year after disappointing phase II trial results in a more generalized group of ovarian cancer patients. However, a re-analysis of the data in BRCA-positive patients – coupled with a reformulation of the drug – convinced the British drugmaker to think again and keep it going. AstraZeneca initiates Phase III clinical studies (SOLO 1 and SOLO 2) for olaparib in the U.S. in September 2013. AstraZeneca has filed Marketing Authorisation Application (MAA) for olaparib in EU in September 2013 based on Phase II study 19 data. The U.S. Food and Drug Administration has already granted olaparib orphan drug status for ovarian cancer and will hold an advisory panel hearing on the company’s application on June 25, 2014.

In 2013, orphan drug designation in the U.S. was assigned to the compound for the treatment of ovarian cancer. The compound was originally developed by Kudos Pharmaceuticals, which was acquired by AstraZeneca in 2006.

Early Phase I trials were promising, and olaparib underwent Phase II trials. However, in December 2011, AstraZeneca announced following interim analysis of a phase-II study which indicated that the previously reported progression free survival benefit was unlikely to translate into an overall survival benefit, that it would not progress into Phase III development for the maintenance treatment of serous ovarian cancer,[2] and took a charge of $285 million. The decision to discontinue development of the drug was reversed in 2013,[3] with AstraZeneca posting a new Phase III trial of Olaparib for patients with BRCA mutated ovarian cancer in April 2013.[4]

Mechanism of action

Olaparib acts as an inhibitor of the enzyme Poly ADP ribose polymerase (PARP) and is one of the first PARP inhibitors. Patients with BRCA1/2 mutations may be genetically predisposed to developing some forms of cancer, and are often resistant to other forms of cancer treatment, but this also sometimes gives their cancers a unique vulnerability, as the cancer cells have increased reliance on PARP to repair their DNA and enable them to continue dividing. This means that drugs which selectively inhibit PARP may be of significant benefit in patients whose cancers are susceptible to this treatment.[5][6][7][8][9][10]

Trial results

Phase I clinical trials, in patients with BRCA-mutated tumors including ovarian cancer, were encouraging.[11] In one of these studies, it was given to 19 patients with inherited forms of advanced breast, ovarian and prostate cancers caused by mutations of the BRCA1 and BRCA2 genes. In 12 of the patients, none of whom had responded to other therapies, tumours shrank or stabilised.[12] One of the first patients to be given the treatment (who had castration-resistant prostate cancer) was as of July 2009 still in remission after two years.

In 2009 Phase II clinical trials examining the efficacy of Olaparib in treating breast, ovarian and colorectal cancer were initiated.[13][14] A phase II trial that included 63 cases of ovarian cancer concluded that olaparib is promising for women with ovarian cancer. [7 responses in 17 patients with BRCA1 or BRCA2 mutations and 11 responses in the 46 who did not have these mutations.][15]

Side effects

Olaparib is generally well tolerated, the side effects consist mainly of fatigue, somnolence, nausea, loss of appetite and thrombocytopenia.

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Synthesis of Investigational Ovarian Cancer Drug Olaparib_PAPP Inhibitor_AstraZeneca 阿斯利康卵巢癌试验药物奥拉帕尼的化学合成

…………….

LOU Xi-yu, YANG Xuan, DING Yi-li, WANG Jian-jun, YAN Qing-yan, HUANG Xian-gui, GUO Yang-hui, WANG Xiang-jing, XIANG Wen-sheng
Synthesis of Olaparib Derivatives and Their Antitumor Activities
2013 Vol. 29 (2): 231-235 [摘要] ( 390 ) [HTML 1KB] [PDF 0KB] ( 22 )
doi: 10.1007/s40242-013-2448-5

……………………….

…………………

4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1
J Med Chem 2008, 51(20): 6581

…………………………..

http://www.google.co.in/patents/WO2004080976A1?cl=en

Synthesis of Key Intermediates

3- (4-0x0-3 , 4-dihydrophthalazin-l -ylmethyl) benzoic a cid (A)

Figure imgf000046_0001

A mixture of 27% sodium methoxide solution in methanol (400 g, 2 mol) and methanol (150 ml) was added dropwise between ambient temperature and 30°C over 15 minutes to a stirred mixture of phthalide (67 g, 0.5 mol), 3-formylbenzonitrile (65.5 g, 0.5 mol) and ethyl propionate (250 ml) , the mixture was stirred at ambient temperature for 40 minutes and at reflux temperature for 1 hour, then it was allowed to cool to ambient temperature. The resulting red solid was collected by filtration, washed with ethyl acetate (2 x 50 ml) and dissolved in water (1800 ml) . The solution was acidified by the addition of acetic acid (60 ml) and the resulting red solid was collected by filtration, washed with water (2 x 200 ml) and dried in vacuo to give 3- (1,3- dioxoindan-2-yl) benzonitrile (83.2 g) as a dark red solid, m.pt. 179- 182°C, m/z (M+H)+‘ 248, which was used without further purification.

3- (1, 3-Dioxoindan-2-yl) benzonitrile (74.18 g, 0.3 mol) was added in portions to a solution of sodium hydroxide (36 g, 0.9 mol) in water (580 ml), the resulting dark red suspension was stirred at reflux temperature for 5 hours, then it was cooled to ambient temperature and washed with ethyl acetate (3 x 300 ml) . The aqueous solution was acidified by the dropwise addition of concentrated hydrochloric acid (110 ml), the mixture was stirred at ambient temperature for 1 hour, then the resulting solid was collected by filtration, washed with water (2 x 200 ml) and dried in vacuo to give a 1:1 mixture of 3- (1,3- dioxoindan-2-yl)benzoic acid, (M+H)+” 267, and 2- [2- (3- carboxyphenyl) acetyl] benzoic acid, (M+H)+‘ 285, (69.32 g) , which was used without further purification.

The mixture obtained in the previous step (52.8 g) was added to a solution of triethylamine (37.55 g, 0.372 mol) in industrial methylated spirit (500 ml) and the resulting cloudy solution was filtered through a pad of filter-aid to give a clear solution. Hydrazine monohydrate (9.3 g, 0.186 mol) was added in one portion at ambient temperature, the stirred mixture was heated under reflux for 1 hour, then it was concentrated in vacuo to approximately 250 ml and added to a solution of sodium acetate (41 g, 0.5 mol) in water (500 ml) . The mixture was brought to pH 7 by the dropwise addition of concentrated hydrochloric acid, then it was stirred at ambient temperature for 3 hours. The resulting solid was collected by filtration, washed with water (50 ml) and dried in va cuo to give a white solid (15.62 g) . The combined filtrate and washings were acidified to pH 6 by the addition of hydrochloric acid, then the mixture was stirred at ambient temperature for 3 hours. The resulting solid was collected by filtration, washed with water (50 ml) and dried in va cuo to give a second crop of off-white solid (17.57 g) . The combined filtrate and washings from the second crop were readjusted to pH 6 and treated as before to give a third crop of pale orange solid (6.66 g) . The three crops were combined to give essentially pure 3- (4-oxo-3, 4-dihydrophthalazin-l-ylmethyl) benzoic acid (A), (M+H)+‘ 281, δH 4.4 (2H, s), 7.2-7.4 (IH, m) , 7.5-7.6 (IH, ) , 7.7-8.0 (5H, m) , 8.1- 8.2 (IH, m) , 12.6 (IH, s)

b . 2-Fluoro-5- (4-oxo-3 , 4-dihydro-phthalazin -l -ylmethyl) benzoi c a cid (B)

Figure imgf000048_0001

Dimethyl phosphite (22.0 g, 0.2 mol) was added drop-wise to a solution of sodium methoxide (43.0 g) in methanol (100 ml) at 0°C. 2- Carboxybenzaldehyde (21.0 g, 0.1 mol) was then added portion-wise to the reaction mixture as a slurry in methanol (40 ml), with the temperature kept below 5°C. The resulting pale yellow solution was warmed to 20°C over 1 hour. Methanesulphonic acid (21.2 g, 0.22 mol) was added to the reaction drop-wise and the resulting white suspension was evaporated in va cuo . The white residue was quenched with water and extracted into chloroform (3 x 100 ml) . The combined organic extracts were washed with water (2 x 100 ml) , dried over MgS04, and evaporated in va cuo to yield (3-oxo-l, 3-dihydro-isobenzofuran-l-yl) phosphonic acid dimethyl ester as a white solid (32.0 g, 95 %, 95 % purity) . This was then used without further purification in the next stage.

To a mixture of (3-oxo-l, 3-dihydro-isobenzofuran-l-yl) phosphonic acid dimethyl ester (35.0 g, 0.14 mol) in tetrahydrofuran (200 ml) and 2- fluoro-5-formylbenzonitrile (20.9 g, 0.14 mol) in tetrahydrofuran (130 ml) was added triethylamine (14 ml, 0.14 mol) drop-wise over 25 min, with the temperature kept below 15°C. The reaction mixture was warmed slowly to 20°C over 1 hour and concentrated in vacuo . The white residue was slurried in water (250 ml) for 30 minutes, filtered, washed with water, hexane and ether, and dried to yield 2-fluoro-5- (3- oxo-3H-isobenzofuran-l-ylidenemethyl) benzonitrile as a 50:50 mixture of E and Z isomers (37.2 g, 96 %); m/z [M+l]+ 266 (98 % purity) To a suspension of 2-fluoro-5- (3-oxo-3H-isobenzofuran-l- ylidenemethyl) benzonitrile in water (200 ml) was added aqueous sodium hydroxide (26.1 g in 50 ml water) solution and the reaction mixture was heated under nitrogen to 90 °C for 30 minutes. The reaction mixture was partially cooled to 70°C, and hydrazine hydrate (100 ml) was added and stirred for 18 hours at 70°C. The reaction was cooled to room temperature and acidified with 2M HC1 to pH 4. The mixture was stirred for 10 min and filtered. The resulting solid was washed with water, hexane, ether, ethyl acetate and dried to yield 2-fluoro-5- (4-oxo-3, 4- dihydrophthalazin-l-ylmethyl)benzoic acid as a pale pink powder (30.0 g, 77 %) . m/z [M+l]+ 299 (96 % purity), δH 4.4 (2H, s) , 7.2-7.3 (IH, m) , 7.5-7.6 (IH, m) , 7.8-8.0 (4H, m) , 8.2-8.3 (IH, m) , 12.6 (IH, s).

c . 1 – [3- (4-Oxo-S , 4-dihydrophthalazin-l -ylmethyl) benzoyl]piperidine-4- carboxylic a cid (C)

Figure imgf000049_0001undesried????????

(A) (C)

3- (4-Oxo-3, 4-dihydrophthalazin-l-ylmethyl)benzoic acid (A) (7.0 g, 0.25 mol), ethyl isonipecotate (5 ml, 0.32 mol), 2- (lH-benzotriazol-1-yl) – 1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HBTU) (12.3 g, 0.32 mol) and N, N, -diisopropylethylamine (10.0 ml, 0.55 mol) were added to dimethylacetamide (40 ml) and stirred for 18 h. Water (100 ml) was added to the reaction mixture and the product was extracted into dichloromethane (4 x 50 ml) . The combined organic layers were washed with water (3 x 100 ml), dried over MgS0, filtered and evaporated in va cuo to yield an oil. To a solution of the oil in tetrahydrofuran (100 ml) was added 10 % aqueous sodium hydroxide solution (20 ml) and the reaction was stirred for 18 hours. The reaction was concentrated, washed with ethyl acetate (2 x 30 ml) and acidified with 2M HCl to pH 2. The aqueous layer was extracted with dichloromethane (2 x 100 ml), then the extracts were dried over MgS04, filtered and evaporated to yield 1- [3- (4-oxo-3, 4-dihydrophthalazin-l-ylmethyl)benzoyl]piperidine- 4-carboxylic acid (C) as a yellow solid (7.0 g, 65 %), m/z [M+l]+ 392

(96 % purity), δH 1.3-1.8 (5H, m) , 2.8-3.1 (4H, m) , .4 (2H, s), 7.2- 7.3 (IH, m) , 7.3-7.4 (IH, ) , 7.7-8.0 (5H, m) , 8.2-E 3 (IH, m) , 12.6 (IH, s) .

d . 1 – [2-Fluoro-5- (4 -oxo-3 , 4-dihydrophthala zin-l – ylmethyl) benzoyl]piperidine-4~carboxylic a cid (D)

Figure imgf000050_0001

(B) (D)

2-Fluoro-5- ( -oxo-3, 4-dihydrophthalazin-l-ylmethyl) benzoic acid (B) (3.1 g, 0.14 mol), ethyl isonipecotate (1.7 ml, 0.11 mol), 2-(lH- benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (HBTU) (5.1 g, 0.13 mol) and N,N, -diisopropylethylamine (10.0 ml, 0.55 mol) were added to dimethylacetamide (15 ml) and stirred for 18 hours. Water (100 ml) was added to the reaction mixture and the product was extracted into dichloromethane (4 x 50 ml) . The combined organic layers were, filtered, washed with water (3 x 100 ml), dried over MgS04, filtered and evaporated in vacuo to yield an orange oil. The oil was purified by flash chromatography (ethyl acetate) to yield l-[2- fluoro-5- (4-oxo-3, 4-dihydrophthalazin-l-ylmethyl) benzoyl] piperidine-4- carboxylic acid as the methyl ester (1.5 g, 33 %, 96 % purity) . To a solution of the methyl ester in tetrahydrofuran: water (2:1, 40 ml) was added sodium hydroxide (0.3 g, 0.075 mol) and the reaction was stirred for 18 h. The reaction was concentrated, washed with ethyl acetate (2 x 20 ml) and acidified with 2M HC1 to pH 2. The aqueous layer was extracted with dichloromethane (2 x 20 ml) , and the combined extracts were dried over MgS04 and evaporated to yield 1- [3- ( 4-oxo-3, 4- dihydrophthalazin-1-ylmethyl) benzoyl] piperidine- -carboxylic acid (D) as a yellow solid (0.6 g, 65 %), m/z [M+l]+ 392 (96 % purity) Example 1 – Synthesis of Key Compounds

a. Synthesis of 4- [3- (piperazine-1-carfoonyl)benzyl] -2H-phthalasin-l- one (1)

Figure imgf000051_0001undesired????????

(A) (1)

3- (4-0xo-3, 4-dihydrophthalazin-l-ylmethyl) benzoic acid (A) (5.0g, 0.17mol), tert-butyl 1-piperazinecarboxylate (3.9 g, 0.21 mol), 2-(lH- benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (HBTU) (8.6 g, 0.22 mol) and N, , -diisopropylethylamine (6.7 ml, 0.38 mol) were added to dimethylacetamide (40 ml) and stirred for 18 hours. Water (100 ml) was added and the reaction mixture was heated to 100°C for 1 hour. The suspension was cooled to room temperature, filtered and dried to yield a white solid. The solid was dissolved in a solution of 6M HC1 and ethanol (2:1, 50 ml) and stirred for 1 hour. The reaction was concentrated, basified with ammonia to pH 9, and the product was extracted into dichloromethane (2 x 50 ml). The combined organic layers were washed with water (2 x 50 ml), dried over MgS04, and evaporated in va cuo to yield 4- [3- (piperazine-1-carbonyl) benzyl] – 2H-phthalazin-l-one (1) as a yellow crystalline solid (4.0 g, 77 %); m/z [M+l]+ 349 (97 % purity), δH 2.6-3.8 (8H, ) , 4.4 (2H, s), 7.2-7.5 (4H, m) , 7.7-8.0 (3H, m) , 8.2-8.3 (IH, m) , 12.6 (IH, s)

b . Synthesis of 4 – [4-Fluoro-3- (piperazine-1 -carbonyl) benzyl ] -2H- phthala zin ~l -one (2)

Figure imgf000051_0002desired……

(β) (2)

The synthesis was carried out according to the method described in (a) above using 2-fluoro-5- (4-oxo-3, -dihydrophthalazin-l-ylmethyl) benzoic acid (B) to yield 4- [4-fluoro-3- (piperazine-1-carbonyl) benzyl] -2H- phthalazin-1-one (2) as a white crystalline solid (4.8 g, 76 %); m/z [M+l]+ 367 (97 % purity), δH 2.6-3.8 (8H, m) , 4.4 (2H, s), 7.2-7.5 (3H, m) , 7.7-8.0 (3H, m) , 8.2-8.3 (IH, m) , 12.6 (IH, s) .

…………………………..

US 8183369

http://www.google.co.in/patents/US8183369

4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (compound A) disclosed in WO 2004/080976:

Figure US08183369-20120522-C00001

is of particular interest.

A crystalline form of compound A (Form A) is disclosed in co-pending applications, which claim priority from U.S. 60/829,694, filed 17 Oct. 2006, entitled “Phthalazinone Derivative”, including U.S. Ser. No. 11/873,671 and WO 2008/047082.

Form A

Figure US08183369-20120522-C00002

References(a) 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (Compound A)

2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(15.23 g, 51.07 mmol) was suspended with stirring under nitrogen in acetonitrile (96 ml). Diisopropylethylamine (19.6 ml, 112.3 mmol) was added followed by 1-cyclopropylcarbonylpiperazine (I)(9.45 g, 61.28 mmol) and acetonitrile (1 ml). The reaction mixture was cooled to 18° C. 0-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (25.18 g, 66.39 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to 3° C. and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3° C.) acetonitrile (20 ml) before being dried in vacuo at up to 40° C. to give the title compound as a pale yellow solid (20.21 g).

Mass Spectrum: MH+ 435

1H NMR (400 MHz, DMSO-d6) δ: 0.70 (m, 4H), 1.88 (br s, 1H), 3.20 (br s, 2H), 3.56 (m, 6H), 4.31 (s, 2H), 7.17 (t, 1H), 7.34 (dd, 1H), 7.41 (m, 1H), 7.77 (dt, 1H), 7.83 (dt, 1H), 7.92 (d, 1H), 8.25 (dd, 1H), 12.53 (s, 1H).

………………………..

http://www.google.co.in/patents/US8247416

4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (compound A) disclosed in WO 2004/080976:

Figure US08247416-20120821-C00001

is of particular interest.

In WO 2004/080976, compound A was synthesised as one of a number of library compounds from 4-[4-fluoro-3-(piperazine-1-carbonyl)-benzyl]-2H-phthalazin-1-one (compound B):

Figure US08247416-20120821-C00002

by the addition of cyclopropanecarbonyl chloride:

Figure US08247416-20120821-C00003

to a solution of (B) in dichloromethane, followed by Hünig’s base (N,N-diisopropylethyl amine). This reaction is carried out with stirring at room temperature for 16 hours, and the resulting compound being purified by preparative HPLC.

The piperazine derivative (B) was prepared by deprotecting 4-[2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (compound C):

Figure US08247416-20120821-C00004

by the use of 6M HCl and ethanol for 1 hour, followed by basification with ammonia to pH 9, and extraction into dichloromethane.

The Boc-protected piperazine derivative (C) was prepared from 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoic acid (compound D):

Figure US08247416-20120821-C00005

by the addition of piperazine-1-carboxylic acid tert-butyl ester:

Figure US08247416-20120821-C00006

2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and N,N,-diisopropylethylamine in dimethylacetamide, followed by stirring for 18 hours.

In WO 2004/080976, the following route to compound D is disclosed:

Figure US08247416-20120821-C00007

The method of synthesising compound D may further comprise the step of:

(c) synthesising 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (ED):

Figure US08247416-20120821-C00008

from compound E by reaction with hydrazine hydrate; and

(d) synthesising compound D from compound ED by reaction with sodium hydroxide.

Step (c) may be achieved by using between 1.1 and 1.3 equivalents of hydrazine hydrate in tetrahydrofuran followed by neutralisation of the excess hydrazine hydrate using acetic acid.

A sixth aspect of the present invention provides the compound ED:

Figure US08247416-20120821-C00009

and its use in the synthesis of compound D.

EXAMPLES

Example 1Synthesis of Compound A

Figure US08247416-20120821-C00010

Starting material (D) was synthesised by the method disclosed in WO 2004/080976

Methods

Preparative HPLC

Samples were purified with a Waters mass-directed purification system utilising a Waters 600 LC pump, Waters Xterra C18 column (5 μm 19 mm×50 mm) and Micromass ZQ mass spectrometer, operating in positive ion electrospray ionisation mode. Mobile phases A (0.1% formic acid in water) and B (0.1% formic acid in acetonitrile) were used in a gradient; 5% B to 100% over 7 min, held for 3 min, at a flow rate of 20 ml/min.

Analytical HPLC-MS

Analytical HPLC was carried out with a Spectra System P4000 pump and Jones Genesis C18 column (4 μm, 50 mm×4.6 mm). Mobile phases A (0.1% formic acid in water) and B (acetonitrile) were used in a gradient of 5% B for 1 min rising to 98% B after 5 min, held for 3 min at a flow rate of 2 ml/min. Detection was by a TSP UV 6000LP detector at 254 nm UV and range 210-600 nm PDA. The Mass spectrometer was a Finnigan LCQ operating in positive ion electrospray mode.

(a) 4-[2-Fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (C)

To a stirred solution of the starting material D (850 g) in dimethylacetamide (DMA) (3561 ml) at room temperature under nitrogen was added HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (1402 g) in one portion. Hünig’s base (iPr2NEt, 1096 ml) was then added with the temperature kept between 15 to 25° C. followed by a solution of 1-Boc-piperazine (637 g) in DMA (1428 ml) with the temperature kept between 15 to 25° C.

The solution was stirred at room temperature for 2 hours and sampled for completion (HPLC). Upon completion the solution was added to vigorously stirred water (17085 ml) with the temperature kept between 15 to 25° C. and the solid filtered off, washing with water (2×7131 ml), hexane (2×7131 ml) and methyl tert-butyl ether (MTBE) (2×3561 ml). The solid was then dried overnight and then sampled for water content and chemical purity.

This reaction was then repeated, see table:

Purity Water Content
Batch Yield (g) (HPLC Area %) (K.F.) Corrected yield
1 1571.3 86.80 24.3 1032.5 g (78%)
2 2781.6 85.00 40.3 1411.5 g (106%)
a. Greater than 100% yield attributed to non-representative sampling

(b) 4-[4-Fluoro-3-(piperazine-1-carbonyl)-benzyl]-2H-phthalazin-1-one (B)

To a stirred solution of industrial methylated spirits (IMS) (2200 ml) and concentrated HCl (4400 ml) was added compound C (2780.2 g) in portions at room temperature under nitrogen, the foaming was controlled by the addition rate. The solution was then stirred at 15 to 25° C. for 30 minutes and sampled for completion (HPLC).

Upon completion the solution was evaporated to remove any IMS and the aqueous extracted with CH2Cl2 (2×3500 ml) before the pH was adjusted to >8 using concentrated ammonia. The resultant slurry was then diluted with water (10000 ml) and extracted with CH2Cl2 (4×3500 ml), washed with water (2×2000 ml), dried over MgSO4 (250 g) and evaporated. The crude product was then slurried in CH2Cl2 (3500 ml) and added to MTBE (5000 ml). The resultant suspension was filtered and dried at 50° C. overnight yielding 611.0 g (58.5% yield) of material with a purity of 94.12%

(c) 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (A)

To a stirred suspension of compound B (1290 g) in CH2Cl2 (15480 ml) under nitrogen was added a pre-mixed solution of triethylamine (470 ml) and cyclopropane carbonyl chloride (306 ml) in CH2Cl2 (1290 ml) dropwise with the temperature kept below 20° C. The solution was then stirred at 10-15° C. for 15 minutes and sampled for completion. The reaction mixture was found to contain only 1.18% of starting material B and so the reaction was deemed complete and the batch was then worked-up.

The reaction mixture was washed with water (7595 ml), 5% citric acid solution (7595 ml), 5% sodium carbonate solution (7595 ml) and water (7595 ml). The organic layer was then dried over magnesium sulfate (500 g).

The CH2Cl2 containing product layer was then isolated, filtered through Celite and charged to a 251 vessel. CH2Cl2 (8445 ml) was then distilled out at atmospheric pressure and ethanol (10000 ml) added. Distillation was then continued with every 4000 ml of distillate that was removed being replaced with ethanol (4000 ml) until the head temperature reached 73.7° C. The reaction volume was then reduced (to 7730 ml) by which time the head temperature had reached 78.9° C. and the solution was allowed to cool to 8° C. overnight. The solid was then filtered off, washed with ethanol (1290 ml) and dried at 70° C. overnight. Yield=1377.3 g (90%). HPLC purity (99.34% [area %]). Contained 4.93% ethanol and 0.45% CH2Cl2 by GC.

(d) Water Treatment of Compound A

A suspension of compound A (1377.0 g), as produced by the method of Example 1, in water (13770 ml) was heated to reflux for 4 hours, cooled to room temperature and filtered. The solid was washed with water (2754 ml) and dried at 70° C. overnight. Yield=1274.8 g (92.6%). HPLC purity (99.49% [area %]). Contained 0.01% ethanol and 0.01% CH2Cl2 by GC.

1H NMR spectrum of compound A (DMSO-d6) following the water treatment is shown in FIG. 1.

The powder XRD pattern of Compound A following the water treatment is shown in FIG. 2, which shows the compound is as Form A.

Example 2

Alternative Synthesis of Compound A Using 1-(cyclopropylcarbonyl) piperazine

Figure US08247416-20120821-C00011

Methods (also for Examples 3 & 4)

NMR

1H NMR spectra were recorded using Bruker DPX 400 spectrometer at 400 MHz. Chemical shifts were reported in parts per million (ppm) on the δ scale relative to tetramethylsilane internal standard. Unless stated otherwise all samples were dissolved in DMSO-d6.

Mass Spectra

Mass spectra were recorded on an Agilent XCT ion trap mass spectrometer using tandem mass spectrometry (MS/MS) for structural confirmation. The instrument was operated in a positive ion elctrospray mode.

(a) 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (Compound A)

2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(15.23 g, 51.07 mmol) was suspended with stirring under nitrogen in acetonitrile (96 ml). Diisopropylethylamine (19.6 ml, 112.3 mmol) was added followed by 1-cyclopropylcarbonylpiperazine (1)(9.45 g, 61.28 mmol) and acetonitrile (1 ml). The reaction mixture was cooled to 18° C. O-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (25.18 g, 66.39 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to 3° C. and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3° C.) acetonitrile (20 ml) before being dried in vacuo at up to 40° C. to give the title compound as a pale yellow solid (20.21 g).

Mass Spectrum: MH+435

1H NMR (400 MHz. DMSO-d6) δ: 0.70 (m, 4H), 1.88 (br s, 1H), 3.20 (br s, 2H), 3.56 (m, 6H), 4.31 (s, 2H), 7.17 (t, 1H), 7.34 (dd, 1H), 7.41 (m, 1H), 7.77 (dt, 1H), 7.83 (dt, 1H), 7.92 (d, 1H), 8.25 (dd, 1H), 12.53 (s, 1H).

Example 3Alternative Synthesis of Compound A Using 1-(cyclopropylcarbonyl) piperazine HCl salt

Figure US08247416-20120821-C00012

(a) 1-(Cyclopropylcarbonyl)piperazine HCl salt (I′)

Acetic acid (700 ml) was treated with piperazine (50.00 g, 0.581 mol) portionwise over 15 minutes with stirring under nitrogen The reaction mixture was warmed to 40° C. and maintained at this temperature until a complete solution was obtained. Cyclopropanecarbonyl chloride 59.2 ml, 0.638 mol) was added over 15 minutes. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate distilled under reduced pressure until ˜430 ml of distillates had been collected. Toluene (550 ml) was charged to the reaction mixture and reduced pressure distillation continued until a further 400 ml of distillates were collected. A further charge of toluene (550 ml) was added and reduced pressure distillation continued until 350 ml of distillates were collected. The resulting slurry was diluted with toluene (200 ml) and stirred overnight. Further toluene (500 ml) was added in order to mobilise the slurry. The slurry was filtered, washed with toluene (100 ml) and dried in vacuo at 40° C. to give the title compound as an off white solid (86.78 g).

Mass Spectrum: MH+155

1H NMR (400 MHz. D2O) δ: 0.92 (m, 4H), 1.98 (m, 1H), 3.29 (m, 2H), 3.38 (m, 2H), 3.84 (m, 2H), 4.08 (m, 2H).

(b) Compound A

2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(0.95 g, 3.19 mmol) was suspended with stirring under nitrogen in acetonitrile (4 ml). 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (1.45 g, 3.83 mmol) was added followed by 1-cyclopropylcarbonylpiperazine HCl salt (I′)(0.73 g, 3.83 mmol). Diisopropylethylamine (1.39 ml, 7.98 mmol) was added over 3 minutes and the reaction mixture was stirred for overnight at room temperature. The reaction mixture was cooled to 5° C. and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3° C.) acetonitrile (2 ml) before being dried in vacuo at up to 40° C. to give the title compound as a pale yellow solid (0.93 g).

  1.  “Olaparib, a PARP Inhibitor”. Health and Life.
  2.  “AZ updates on olaparib and TC5214”. 20 December 2011.
  3.  http://uk.reuters.com/article/2013/09/04/astrazeneca-cancer-idUKL6N0H00KN20130904
  4.  http://www.clinicaltrials.gov/ct2/show/NCT01844986
  5.  New cancer drug ‘shows promise’ BBC News 24 June 2009
  6.  Olaparib for the treatment of ovarian cancer.
  7.  Vasiliou S, Castaner R, Bolos J. Olaparib. Drugs of the Future. 2009; 34(2): 101.
  8.  Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM, Matthews IT, Moore S, O’Connor MJ, Smith GC, Martin NM (October 2008). “4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1”. Journal of Medicinal Chemistry 51 (20): 6581–91. doi:10.1021/jm8001263. PMID 18800822.
  9.  Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O’Connor MJ, Martin NM, Borst P, Jonkers J (November 2008). “High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs”. Proceedings of the National Academy of Sciences of the United States of America 105 (44): 17079–84. doi:10.1073/pnas.0806092105. PMC 2579381. PMID 18971340.
  10.  Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, Douglas-Jones A, Smith GC, Martin NM, O’Connor M, Clarke AR (May 2009). “Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin”. Cancer Research 69 (9): 3850–5. doi:10.1158/0008-5472.CAN-08-2388. PMID 19383921.
  11. http://www.ncri.org.uk/ncriconference/archive/2007/abstracts/pdf/LB57.pdf “A Phase I trial of AZD2281 (KU-0059436), a PARP inhibitor with single agent anticancer activity in patients with BRCA deficient tumours, particularly ovarian cancer”
  12.  Fong PC, Boss DS, Yap TA, et al. (July 2009). “Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers”. N. Engl. J. Med. 361 (2): 123–34.doi:10.1056/NEJMoa0900212. PMID 19553641.
  13.  http://www.cancercompass.com/cancer-news/1,15869,00.htm “Phase II Trials Investigating Oral PARP Inhibitor, Olaparib, In BRCA-Deficient Advanced Breast And Ovarian Cancer” June 2009
  14.  http://clinicaltrials.gov/ct2/show/NCT00912743 Efficacy and Safety of Olaparib in Pretreated Patients With Measurable Colorectal Cancer, Stratified by Microsatellite Instability (MSI) Status
  15.  “Olaparib Looks Promising in Treatment of Non-BRCA Ovarian Cancer”. 26 Aug 2011.
Patent Submitted Granted
Phthalazinone Derivatives [US2012010204] 2012-01-12
PARP1 TARGETED THERAPY [US2012035244] 2012-02-09
Phthalazinone derivatives [US7449464] 2005-03-17 2008-11-11
4- [3- (4-CYCLOPROPANECARBONYL-PIPERAZINE-I-CARBONYL) -4 -FLUORO-BENZYL] -2H-PHTHALAZ IN-1-ONE [US8183369] 2010-11-11 2012-05-22
PHTHALAZINONE DERIVATIVES [US7692006] 2008-06-19 2010-04-06
PHTHALAZINONE DERIVATIVES [US7981889] 2008-08-21 2011-07-19
PHARMACEUTICAL FORMULATION 514 [US2010098763] 2010-04-22
PHTHALAZINONE DERIVATIVE [US8247416] 2009-10-29 2012-08-21
WO2002036576A1 * 25 Oct 2001 10 May 2002 Kudos Pharm Ltd Phthalazinone derivatives
WO2002090334A1 * 30 Apr 2002 14 Nov 2002 Kudos Pharm Ltd Isoquinolinone derivatives as parp inhibitors
WO2003093261A1 * 29 Apr 2003 13 Nov 2003 Kudos Pharm Ltd Phthalazinone derivatives

extras…………..

Olaparib
Olaparib.png
Systematic (IUPAC) name
4-[(3-[(4-cyclopropylcarbonyl)piperazin-4-yl]carbonyl) -4-fluorophenyl]methyl(2H)phthalazin-1-one
Clinical data
Trade names Lynparza
Legal status
  • Investigational
Routes Oral
Identifiers
CAS number 763113-22-0 
ATC code None
PubChem CID 23725625
ChemSpider 23343272 Yes
UNII WOH1JD9AR8 Yes
ChEMBL CHEMBL521686 Yes
Chemical data
Formula C24H23FN4O3 
Mol. mass 435.08 g/mol
Research Area
Cancer
Biological Activity
Description Olaparib (AZD2281, KU0059436) is a selective inhibitor of PARP1 and PARP2 with IC50 of 5 nM and 1 nM, respectively.
Targets PARP1 PARP2
IC50 5 nM 1 nM [1]
In Vitro Olaparib would act against BRCA1 or BRCA2 mutations. AZD2281 is not sensitive to tankyrase-1 (IC50 >1 μM). Olaparib could ablate the PARP-1 activity at concentrations of 30-100 nM in SW620 cells. Olaparib is hypersensitive to BRCA1-deficient cell lines (MDA-MB-463 and HCC1937), compared with BRCA1- and BRCA2-proficient cell lines (Hs578T, MDA-MB-231, and T47D). [1] Olaparib is strongly sensitive to KB2P cells due to suppression of base excision repair by PARP inhibition, which may result in the conversion of single-strand breaks to double-strand breaks during DNA replication, thus activating BRCA2-dependent recombination pathways. [2]
In Vivo Combining with temozolomide, Olaparib (10 mg/kg, p.o.) significantly suppresses tumor growth in SW620 xenografts. [1] Olaparib shows great response to Brca1-/-;p53-/- mammary tumors (50 mg/kg i.p. per day), while no responses to HR-deficient Ecad-/-;p53-/- mammary tumors. Olaparib even does not show dose-limiting toxicity in tumor-bearing mice. [3] Olaparib has been used to treat with BRCA mutated tumors, such as ovarian, breast and prostate cancers. Moreover, Olaparib shows selectively inhibition to ATM (Ataxia Telangiectasia Mutated)-deficient tumor cells, which indicates to be a potential agent for treating ATM mutant lymphoid tumors. [4]
Clinical Trials Combining with cediranib, Olaparib is currently in Phase I/II study for treatment of recurrent papillary-serous ovarian, fallopian tube or peritoneal cancer or treatment of recurrent triple-negative breast cancer.
Features Olaparib is one of the first PARP inhibitors.
Protocol
Kinase Assay [1]
FlashPlate assay (96-well screening assay) To columns 1 through 10, 1 μL of Olaparib (in DMSO) is added, and 1 μL DMSO only is added to the positive (POS) and negative (NEG) control wells (columns 11 and 12, respectively) of a pretreated FlashPlate. PARP-1 is diluted 1:40 in buffer (buffer B: 10% glycerol (v/v), 25 mM HEPES, 12.5 mM MgCl2,50 mM KCl, 1 mM DTT, 0.01% NP-40 (v/v), pH 7.6) and 40 μL added to all 96 wells (final PARP-1 concentration in the assay is ~1 ng/μL). The plate is sealed and shaken at RT for 15 min. Following this, 10 μL of positive reaction mix (0.2 ng/μL of double-stranded oligonucleotide [M3/M4] DNA per well, 5 μM of NAD+ final assay concentration, and 0.075 μCi 3H-NAD+ per well) is added to the appropriate wells (columns 1-11). The negative reaction mix, lacking the DNA oligonucleotide, is added to column 12 (with the mean negative control value used as the background). The plate is resealed and shaken for a further 60 min at RT to allow the reaction to continue. Then, 50 μL of ice-cold acetic acid (30%) is added to each well to stop the reaction, and the plate is sealed and shaken for a further 60 min at RT. Tritiated signal bound to the FlashPlate is then determined in counts per minute (CPM) using the TopCount plate reader.
In vitro isolated enzyme assay PARP-2 activity inhibition uses a variation of the PARP-1 assay in which PARP-2 protein (recombinant) is bound down by a PARP-2 specific antibody in a 96-well white-walled plate. PARP-2 activity is measured following 3H-NAD+ DNA additions. After washing, scintillant is added to measure 3H-incorporated ribosylations. For tankyrase-1, a α-Screen assay is developed in which HIS-tagged recombinant TANK-1 protein is incubated with biotinylated NAD+in a 384-well ProxiPlate assay. Alpha beads are added to bind the HIS and biotin tags to create proximity signal, whereas the inhibition of TANK-1 activity is directly proportional to the loss of this signal.
Cell Assay [1]
Cell lines Breast cancer cell lines including SW620 colon, A2780 ovarian, HCC1937, Hs578T, MDA-MB-231, MDA-MB-436, and T47D
Concentrations 1-300 nM
Incubation Time 7-14 days
Method The cytotoxicity of Olaparib is measured by clonogenic assay. Olaparib is dissolved in DMSO and diluted by culture media before use. The cells are seeded in six well plates and left to attach overnight. Then Olaparib is added at various concentrations and the cells are incubated for 7-14 days. After that the surviving colonies are counted for calculating the IC50.
Animal Study [3]
Animal Models Brca1-/-;p53-/- mammary tumors are generated in K14cre;Brca1F/F;p53F/F mice.
Formulation 50 mg/mL stocks in DMSO with 10% 2-hydroxyl-propyl-β-cyclodextrine/PBS
Doses 50 mg/kg
Administration Administered via i.p. injection at 10 μL/g of body weight
References
[1] Menear KA, et al. J Med Chem, 2008, 51(20), 6581-6591.
[2] Evers B, et al, Clin Cancer Res, 2008, 14(12), 3916-3925.
[3] Rottenberg S, et al, Proc Natl Acad Sci U S A, 2008, 105(44), 17079-17084.
[4] Weston VJ, et al, Blood, 2010, 116(22), 4578-4587.

 nmr

H-NMR spectral analysis
olaparib NMR spectra analysis, Chemical CAS NO. 763113-22-0 NMR spectral analysis, olaparib H-NMR spectrum
CAS NO. 763113-22-0, olaparib H-NMR spectral analysis
C-NMR spectral analysis
olaparib NMR spectra analysis, Chemical CAS NO. 763113-22-0 NMR spectral analysis, olaparib C-NMR spectrum
CAS NO. 763113-22-0, olaparib C-NMR spectral analysis

Butoconazole


Butoconazole.svg

1-(4-(4-chlorophenyl)-2-(2,6-dichlorophenylthio)-n-butyl)-1H-imidazole

64872-77-1  NITRATE ,

64872-76-0 (free base)

Butoconazole nitrate, RS-35887-00-10-3, RS-35887, Gynomyk, Gynazole-1, Femstat

1-[4-(4-Chlorophenyl)-2-[(2,6-dichlorophenyl)thio]butyl]-1H-imidazole
Molecular Formula: C19H17Cl3N2S
Molecular Weight: 411.78
Percent Composition: C 55.42%, H 4.16%, Cl 25.83%, N 6.80%, S 7.79%
Properties: Crystals from cyclohexane, mp 68-70.5°.
Melting point: mp 68-70.5°
Derivative Type: Nitrate
CAS Registry Number: 64872-77-1
Manufacturers’ Codes: RS-35887
Trademarks: Femstat (Syntex); Gynomyk (Cassenne)
Molecular Formula: C19H17Cl3N2S.HNO3
Molecular Weight: 474.79
Percent Composition: C 48.06%, H 3.82%, Cl 22.40%, N 8.85%, S 6.75%, O 10.11%
Properties: Colorless blades from acetone/ethyl acetate, mp 162-163°. LD50 in mice, male, female rats (mg/kg): >3200, >3200, 1720 orally; >1600, 940, 940 i.p. (Walker).
Melting point: mp 162-163°
Toxicity data: LD50 in mice, male, female rats (mg/kg): >3200, >3200, 1720 orally; >1600, 940, 940 i.p. (Walker)
Therap-Cat: Antifungal (topical).

 

 Butoconazole (trade names Gynazole-1, Mycelex-3) is an imidazole antifungal used in gynecology. It is administered as a vaginal cream.[1][2]
For the local treatment of vulvovaginal candidiasis (infections caused by Candida)

Brief background information

Salt ATC Formula MM CAS
G01AF15 C 19 H 17 Cl 3 N 2 S 411.78 g / mol 64872-76-0
mononitrate G01AF15 C 19 H 17 Cl 3 N 2 S ⋅ HNO 3 474.80 g / mol 64872-77-1

No Exclusivity found

Drug Name Femstat 3 (from Drugs@FDA)
Active Ingredient Butoconazole nitrate
Dosage Form Cream
Route Vaginal
Strength 2%
Market Status Over the Counter
Company Bayer
Patent No Patent Expiry
5993856 Nov 17, 2017

Laszlo Czibula, Laszlo Dobay, Eva Werkne Papp, Judit Nagyne Bagdy, Ferenc Sebok, “High Purity Butoconazole Nitrate with Specified Particle Size and a Process for the Preparation Thereof.” U.S. Patent US20080221190, issued September 11, 2008.

Butoconazole
Butoconazole.svg
Systematic (IUPAC) name
1-[4-(4-Chlorophenyl)-2-(2,6-dichlorophenyl)sulfanylbutyl]imidazole
Clinical data
Trade names Gynazole-1, Mycelex-3
AHFS/Drugs.com monograph
MedlinePlus a682012
Pregnancy cat.
Legal status
Routes Vaginal cream
Identifiers
CAS number 67085-13-6 Yes
ATC code G01AF15
PubChem CID 47472
DrugBank DB00639
ChemSpider 43192 Yes
UNII 0Q771797PH Yes
KEGG D00880 
ChEBI CHEBI:3240 Yes
ChEMBL CHEMBL1295 Yes
Chemical data
Formula C19H17Cl3N2S 
Mol. mass 411.776 g/mol

Use

  • an antifungal agent for topical use

Classes substance

  • Eter chlorothiophenol
    • Imidazoles

Synthesis pathway

Synthesis of a)

Trade names

Country Trade name Manufacturer
France Ginomik Cassenne
USA Femstat Syntex
Ukraine Gіnofort BAT “Gideon Rіhter” Ugorschina

Formulations

  • 2% vaginal cream

Reference for syn

 

  1. Synthesis of a)
    • Walker, KAM et al .: J. Med. Chem. (JMCMAR) 21, 840 (1978).
    • US 4,078,071 (Syntex; USA-prior. 28.7.1975).
    • DOS 2,800,755

 

 

………………………

Patent

 http://www.google.com/patents/EP1709005A1?cl=en

Butoconazole nitrate (chemical name: l-[4-(4-chlorophenyl)-2-(2,6-dichloro- -phenylthio)-n-butyl]-imidazol nitrate) is a compound of the formula (I),

Figure imgf000003_0001

(I)

it belongs among the aryl-ethylimidazole compounds, has fungicidal activity and may be used for the treatment of vaginal infections caused primarily by Candida albicans. Azoles exert their antifungal effect via modifying the ergosterol synthesis of fungus cells; more particularly, imidazoles inhibit the 14α-demethylase enzyme, thereby bringing about an increased level of 14α-methyl sterols which, in turn, causes an alteration of cell membrane permeability leading to the destruction of the fungus cells (Tetrahedron: Asymmetry Vol 4, No. 7, pp. 1521-1526, 1993). The first process for the preparation of the butoconazole nitrate is a multistep synthesis disclosed in the US 4,078,071 patent specification. Here two reaction routes are given for the preparation of the key intermediate of the formula (TV) (l-[4-(4-chlorophenyl)-2-hydroxy-n- -butyl] -imidazole) .

Figure imgf000004_0001

(IN)

According to one of them first an epoxy compound is prepared from an aromatic aldehyde or from an olefinic compound having a terminal double bond; then the epoxy compound is reacted with imidazole to yield the key intermediate. The aromatic aldehyde (VIII)

Figure imgf000004_0002

(VIII)

is treated with expensive and hazardous reagents (trimethylsulfoxonium iodide and sodium hydride) in dry dimethyl sulfoxide and the epoxide formed in the reaction is isolated after a complicated work-up. The epoxide so obtained is converted to the imidazole derivate in a time consuming reaction in the presence of dimethylformamide, then the key intermediate of the formula (IN) (l-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) is isolated and purified in an additional step. From the compounds having terminal double bond (Nil)

Figure imgf000004_0003

(Nil) the epoxide is obtained via a highly explosive peracidic oxidation step and the epoxide is then converted into (l-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IV) in a manner described above. In the other reaction route a poisoning aromatic α-halo-keto compound is used as starting material which is reacted with imidazole to give the corresponding keto-imidazole which, in turn, is reduced with a complex metal hydride – a reagent with potential hazards – to yield the key intermediate (IN). The reaction mixture is worked up in an involved manner. The synthesis way described in J. Med. Chem., 1978, Vol. 21, No. 8, pp 840-843 is as follows: l-chloro-4-chlorophenyl-2-butanol (II)

Figure imgf000005_0001

(II) is treated with the imidazole (III)

Figure imgf000005_0002

(HI)

in the presence of sodium hydride reagent in dimethylformamide solvent. This substitution reaction takes a long time and gives the (l-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]- imidazole) (IN) with a poor yield (51.7 %). In the next step of the butoconazole nitrate synthesis

(l-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IN) is treated with thionyl chloride (which is at once a reagent and a solvent) at 65-70 °C to yield l-[4-(4-chlorophenyl)-2-chloro- -n-butyl] -imidazole of the formula (N).

Figure imgf000006_0001

(V)

The reaction mixture is then evaporated to dryness. The removal of the excess thionyl chloride, a highly corrosive substance, requires special equipment; the same applies to waste treatment, an operation which also involves an environmental risk. The residue is dissolved in dichloromethane, the solution is made alkaline by adding aqueous potassium carbonate solution. Phases are separated, the organic layer is washed with water, dried on magnesium sulphate and evaporated to give l-[4-(4-chlorophenyl)-2-chloro-n-butyl]-imidazole (N), as a gum. Said gum is dissolved in acetone and reacted with 2,6-dichlorothiophenol in the presence of potassium carbonate with a long reaction time. After the reaction has been finished, the inorganic salts are removed by filtration, the solvent is evaporated, and the residue is partitioned between water and ether. Butoconazole nitrate is precipitated with nitric acid from the ethereal layer. The end-product crystals in white plates from a mixture of acetone and ethyl acetate (yield: 84 %). Our aim was to provide a process by which the active agent can be prepared in high purity via reaction steps producing good yields and besides that said steps require neither solvents that are highly flammable and explosive (ether), carcinogenic (dimethylformamide) or corrosive (thionylchloride), nor reagents (e. g. sodium hydride) that are highly flammable or explosive. We have surprisingly found that when the starting material l-chloro-4-chlorophenyl-2-

-butanol (II) is reacted with the imidazole (III) in a mixture of toluene and aqueous sodium hydroxide solution in the presence of a phase transfer catalyst, the

(l-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IN) key intermediate is obtained with short reaction time and excellent yield (95 %). Next we studied alternative solvents to replace the thionyl chloride in solvent function in the reaction step converting (l-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IN) into (l-[4-(4-chlorophenyl)-2-chloro-n-butyl]-imidazole) (N). In the inert solvents which could be taken into account such as dichloromethane, toluene, chlorobenzene and dimethylformamide, the chlorinating reaction yielded a sticky reaction mixture which couldn’t be processed. We have surprisingly found, however that when (l-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IN) is dissolved in 1 ,2-dichloroethane and reacted with approximately equimolar amount of thionyl chloride reagent in the presence of catalytic amount of dimethylformamide at 30-35 °C temperature, a crystal suspension is obtained which is easy-to-stir during the whole reaction time, resulting in that chlorination proceeds completely giving l-[4-(4-chlorophenyl)-2-chloro-n-butyl]-imidazole (N) in quantitative yield. Being the compound sufficiently pure, it is not isolated, but separated by extraction and reacted directly with 2,6-dichlorothiophenol in methyl isobutyl ketone to give 1 -[4-(4-chlorophenyl)-2-(2,6-dichlorophenylthio)-n-butyl]-imidazole (VI) (butoconazole).

Figure imgf000007_0001

(NI)

Example 1. Preparation of (1 4-(4-chlorophenyl)-2-hvdroxy-n-butyll-imidazole) (IV) To a solution of 56.7 g (0.26 mol) of l-chloro-4-chloroρhenyl-2-butanol (J. of Medicinal Chemistry, 1978. Nol. 21. No. 8. p. 842) in 200 ml of toluene 36.2 g (0.9 mol) of sodium hydroxide dissolved in 100 ml of water, 6.4 g (0.028 mol) of benzyltriethyammomum chloride and 35.2 g (0.51 mol) of imidazole (III) are added. The reaction mixture is heated at 93-95 °C for one hour then the temperature is returned to about 60 °C, the phases are separated and to the organic layer water (100 ml) is added. The mixture is first stirred at 22-25 °C for 1 hour then at 0-5 °C for two hours. The crystals are separated by filtration, washed with water (2 x 35 ml) of 0-5 °C to yield 74 g of wet (l-[4-(4-chloroρhenyl)-2-hydroxy-n-butyl]-imidazole) which is dried at maximum 50 °C in vacuo to give 61.6 g (95 %) of the product. Recrystallization from ethyl acetate gives 52.4 g (85 %) of dry product melting at 104-106 °C.

 

Example 2. Preparation of l-[4-(4-chlorophenvπ-2-(2,6-(McMorophenyl o)-n-butyl1-ϊmidazole nitrate (I) 25 g (0.1 mol) of l-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole (IN) is suspended in 1,2-dichloroethane (125 ml), to this suspension dimethylformamide (1 ml) and thionyl chloride (13.6 g; 0.11 mol) are added at 30-32 °C and the reaction mixture is kept at 35-38 °C for 1.5 hour under stirring. After the chlorination has been finished the homogenous solution is cooled to 15-18 °C, the excess of thionyl choride is decomposed with water (10 ml) then again water (80 ml) is added to the solution. After stirring at 20-22 °C for 0.5 hour the phases are separated and the organic layer is extracted with water (30 ml). To the aqueous solution methyl isobutyl ketone (250 ml) is added and the pH of the mixture is adjusted to 8.5 – 9 with 15 g (0.14 mol) of sodium carbonate dissolved in water (70 ml). The mixture is stirred at 22-25 °C for 0.5 hour, phases are separated, from the organic layer an 50 ml portion is distilled off to remove water and to the remaining solution 26.8 g (0.15 mol) of 2,6-dichloro-thiophenol and 40 g (0.29 mol) of dry potassium carbonate are added. The suspension is stirred at 105 – 108 °C under nitrogen for 3-4 hours. After the reaction has been finished the inorganic salts are removed by filtration at 22-25 °C, the filtrate is washed and clarified with activated carbon and the pH of the clear solution is adjusted to 3 – 3.5 by adding about 8 – 9 ml of 65 % nitric acid. The solution is stirred at the same temperature for 1 hour then the temperature is lowered to 8 – 12 °C. The crystals obtained are filtered and washed to give 48 g of wet l-[4-(4-chlorophenyl)-2-(2,6-dichlorophenylthio)-n-butyl]- -imidazole nitrate corresponding to 42.6 g (90 %) of dry product.

HPLC

Details of the HPLC method: Type of the apparatus: Spectra System/TSP (manufacturer: Thermo Separation Products, USA) Column: LiChrospher RP-18, 250×4.0 mm ID., 5 μm (Merck, Germany, Cat. No. : 1.50983) Mobile phase: methanol : buffer = 8:2 Bujfer: 2.18 g KH2PO4 + 4.18 g K2HPO4-3H2O dissolved in 1000 ml of distilled water; MeOH (HPLC Gradient grade, Merck, Germany, Cat. No.: 1.06007.2500) KH2PO4 (p.a., Merck, Germany, Cat. No.: 1.04877.1000) K2HPO4-3H2O (p.a., Merck, Germany, Cat. No.: 1.05099.1000) Flow rate: 1.0 ml/min Temperature: 40 °C Detection: UN 229 nm Solvent for sampling: eluent Sample concentration: 1.0 mg/ml Injected volume: 10 μl Duration of analysis: 40 min Evaluation: area normalization method. Approximative retention time: 11.9 min B. Particle size: Particle size was determined by sieve analysis using an Alpine sieve operated by a jet of air.

……………………..

WALKER K A M ET AL: “1-[4-(4-Chlorophenyl)-2-(2,6-dichloro phenylthio)-n-butyl]-1H-imidazole nitrate, a new potent antifungal agent” JOURNAL OF MEDICINAL CHEMISTRY, vol. 21, no. 8, August 1978 (1978-08), pages 840-843,

http://pubs.acs.org/doi/pdf/10.1021/jm00206a028

1- [4-(4-chlorophenyl)-2-(2,6-dichlorophenylthio)-n-b~-
tyll-lH-imidazole nitrate (I).

I as colorless blades
(9.6 g, 84%): mp 162-163 “C (foaming). Anal. (C19H18C13N303S)
C, H, N. The free base prepared by neutralization of a suspension
of 1 in ether with aqueous potassium carbonate and recrystallization
from cyclohexane had mp 68-70.5 “C (foaming).

……………….

FULL SYNTHESIS

SEE

http://www.chemdrug.com/databases/8_0_yyfgohllmfsvfvsx.html

The chlorohydrin (II) is obtained by the reaction of p-chlorobenzylmagnesium chloride (I) with epichlorohydrin (A) in ether. This is then converted to the crystalline alcohol (III) by reaction with sodium imidazole (B) in DMF. On treatment with thionyl chloride is converted to the corresponding chloro compound (IV). When (IV) is reacted with 2,6-dichloro thiophenol (C) in the presence of anhydrous potassium carbonate in acetone, the free base of butoconazole is formed. Neutralization of the free base (V) with nitric acid gives butoconazole.

References

  1. Seidman, L. S.; Skokos, C. K. (2005). “An evaluation of butoconazole nitrate 2% site release vaginal cream (Gynazole-1) compared to fluconazole 150 mg tablets (Diflucan) in the time to relief of symptoms in patients with vulvovaginal candidiasis”. Infectious diseases in obstetrics and gynecology 13 (4): 197–206. doi:10.1080/10647440500240615. PMC 1784583. PMID 16338779. edit
  2.  Butoconazole monograph

Literature References:

Imidazole derivative with antifungal properties. Prepn: K. A. M. Walker, US 4078071 (1978 to Syntex).

 

Prepn, toxicity, activity vs Candida albicans in mice: K. A. M. Walker et al., J. Med. Chem. 21, 840 (1978).

 

In vitro comparison with other antifungal agents: F. C. Odds et al., J. Antimicrob. Chemother. 14, 105 (1984).

 

Clinical trials in treatment of vulvovaginal candidiasis: W. Droegemueller et al., Obstet. Gynecol. 64, 530 (1984); J. B. Jacobson et al., Acta Obstet. Gynecol. Scand. 64, 241 (1985).

 

Comparison with miconazole, q.v.: C. S. Bradbeer et al., Genitourin. Med. 61, 270 (1985).

FDA issues Guidance for a clear Identification of pharmaceutical Companies


DRUG REGULATORY AFFAIRS INTERNATIONAL

 

FDA issues Guidance for a clear Identification of pharmaceutical Companies

In November the US FDA has issued a Guidance for a clear identification of pharmaceutical companies. The authority now definitely prefers the DUNS system. Get more information.

see………..http://www.gmp-compliance.org/enews_4590_FDA-issues-Guidance-for-a-clear-Identification-of-pharmaceutical-Companies_9187,Z-CAUR_n.html

In our GMP News from September 2013 you learned about a draft of a FDA Guidance for Industry entitled “Specification of the Unique Facility Identifier (UFI) System for Drug Establishment Registration”. This document’s goal was to clearly identify pharmaceutical sites. The draft comprised (manageable) five pages – including the cover page. And in terms of volume this didn’t change. However, some of the alternatives still mentioned in the draft, are not stated any longer – as one can find out when contacting the authority in these cases. The method now wanted is a registration by a D-U-N-S- (Data Universal Numbering System) number. This number – which is a 9-digit code – is…

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