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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 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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DAPAGLIFLOZIN…FDA approves AZ diabetes drug Farxiga


DAPAGLIFLOZIN, BMS-512148

The US Food and Drug Administration has finally approved AstraZeneca’s diabetes drug Farxiga but is insisting on six post-marketing studies, including a cardiovascular outcomes trial.

The approval was expected given that the agency’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1 last month that the benefits of Farxiga (dapagliflozin), already marketed in Europe as Forxiga, outweigh identified risks. The FDA rejected the drug in January 2012 due to concerns about possible liver damage and the potential link with breast and bladder cancer.

READ ABOUT SYNTHESIS AT
 Wish You a Happy Pongal animation

TELMISARTAN ..Actavis’ Generic Version of Micardis Receives FDA Approval


DUBLIN, Jan. 8, 2014 /PRNewswire/ — Actavis plc today announced that it has received approval from the U.S. Food and Drug Administration (FDA) on its Abbreviated New Drug Application (ANDA) for Telmisartan Immediate-Release Tablets, 20 mg, 40 mg and 80 mg, a generic equivalent to Boehringer Ingelheim’s Micardis. Actavis intends to launch the product immediately.

http://www.drugs.com/news/actavis-version-micardis-receives-fda-approval-49915.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+January+8%2C+2014

APREMILAST, … ORALLY ACTIVE PDE4 INHIBITOR


APREMILAST

PDE4 inhibitor

N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide

(+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2- methanesulfonylethyl]-4-acetylaminoisoindolin-l,3-dione,

(S)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
(S)-N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
Molecular Formula: C22H24N2O7S   Molecular Weight: 460.50016

608141-41-9 CAS NO

Celgene (Originator)
CC-10004 (apremilast) is an oral compound that is being studied in multiple Phase III clinical trials for the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases. We successfully completed our early stage studies, demonstrating clinical activity and tolerability and meeting safety endpoints in a placebo controlled proof-of mechanism trial in moderate-to-severe psoriasis and psoriatic arthritis. With the initiation of six multi-center international clinical trials, we are advancing the clinical development of CC-10004.

Celgene's apremilast could be game-changer in PsA

CC-10004, , Apremilast (USAN), SureCN302992, Apremilast (CC-10004), QCR-202,

Apremilast is an orally available small molecule inhibitor of PDE4 being developed byCelgene for ankylosing spondylitispsoriasis, and psoriatic arthritis.[1][2] The drug is currently in phase III trials for the three indications. Apremilast, an anti-inflammatory drug, specifically inhibits phosphodiesterase 4. In general the drug works on an intra-cellular basis to moderate proinflammatory and anti-inflammatory mediator production.

APREMILAST

Apremilast is being tested for its efficacy in treating “psoriasis, psoriatic arthritis and other chronic inflammatory diseases such as ankylosing spondylitis, Behcet’s disease, and rheutmatoid arthritis.

“Apremilast is Celgene’s lead oral phosphodiesterase IV inhibitor and anti-TNF alpha agent in phase III clinical studies at Celgene for the oral treatment of moderate to severe plaque-type psoriasis and for the oral treatment of psoriatic arthritis.

Early clinical development is also ongoing for the treatment of acne, Behcet’s disease, cutaneous sarcoidosis, prurigo nodularis, ankylosing spondylitis, atopic or contact dermatitis and rheumatoid arthritis. No recent development has been reported for research for the treatment of skin inflammation associated with cutaneous lupus erythematosus.

In 2011, Celgene discontinued development of the compound for the management of vision-threatening uveitis refractory to other modes of systemic immunosuppression due to lack of efficacy.

Celgene had been evaluating the potential of the drug for the treatment of asthma; however, no recent development has been reported for this research. The drug candidate is also in phase II clinical development at the William Beaumont Hospital Research Institute for the treatment of chronic prostatitis or chronic pelvic pain syndrome and for the treatment of vulvodynia (vulvar pain).

In 2013, orphan drug designations were assigned to the product in the U.S. and the E.U. for the treatment of Behcet’s disease.

Celgene Corp has been boosted by more impressive late-stage data on apremilast, an oral drug for psoriatic arthritis, this time in previously-untreated patients.

The company is presenting data from the 52-week PALACE 4 Phase III study of apremilast tested in PsA patients who have not taken systemic or biologic disease modifying antirheumatic drugs (DMARDs) at the American College of Rheumatology meeting in San Diego. The results from the 527-patient trial show that at week 16, patients on 20mg of the  first-in-class oral inhibitor of phosphodiesterase 4 (PDE4) achieved an ACR20 (ie a 20% improvement in the condition) response of 29.2% and 32.3% for 30mg aapremilast, compared with 16.9% for those on placebo.

After 52 weeks, 53.4% on the lower dose and 58.7% on 30mg achieved an ACR20 response. ACR50 and 70 was reached by 31.9% and 18.1% of patients, respectively, for apremilast 30mg. The compound was generally well-tolerated and discontinuation rates for diarrhoea and nausea were less than 2% over 52 weeks.

Commenting on the data, Alvin Wells, of the Rheumatology and Immunotherapy Center in Franklin, Wisconsin, noted that apremilast demonstrated long-term safety and tolerability and significant clinical benefit in treatment-naive patients. He added that “these encouraging results suggest that apremilast may have the potential to be used alone and as a first-line therapy”. Celgene is also presenting various pooled data from the first three trials in the PALACE programme which, among other things, shows that apremilast significantly improves swollen and tender joints.

Treatment for PSA, which affects about 30% of the 125 million people worldwide who have psoriasis, currently involves injectable tumour necrosis factor (TNF) inhibitors, notably AbbVie’s Humira (adalimumab) and Pfizer/Amgen’s Enbrel (etanercept), once patients have not responded to DMARDs (at least in the UK). While the biologics are effective, the side effect profile can be a concern, due to the risk of infection and tuberculosis and many observers believe that apremilast will prove popular with patients and doctors due to the fact that it is oral, not injectable.

Apremilast was filed for PsA with the US Food and Drug Administration in the first quarter and will be submitted on both sides of the Atlantic for psoriasis before year-end. The European filing will also be for PsA.

Apremilast impresses for Behcet’s disease

Celgene has also presented promising Phase II data on apremilast as a treatment for the rare inflammatory disorder Behcet’s disease. 71% of patients achieved complete response at week 12 in clearing oral ulcers

APREMILAST

  1.  “Apremilast Palace Program Demonstrates Robust and Consistent Statistically Significant Clinical Benefit Across Three Pivotal Phase III Studies (PALACE-1, 2 & 3) in Psoriatic Arthritis” (Press release). Celgene Corporation. 6 September 2012. Retrieved 2012-09-10.
  2.  “US HOT STOCKS: OCZ, VeriFone, Men’s Wearhouse, AK Steel, Celgene”The Wall Street Journal. 6 September 2012. Retrieved 2012-09-06.
  3. Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor.

    Man HW, Schafer P, Wong LM, Patterson RT, Corral LG, Raymon H, Blease K, Leisten J, Shirley MA, Tang Y, Babusis DM, Chen R, Stirling D, Muller GW.

    J Med Chem. 2009 Mar 26;52(6):1522-4. doi: 10.1021/jm900210d.

  4. Therapeutics: Silencing psoriasis.Crow JM.Nature. 2012 Dec 20;492(7429):S58-9. doi: 10.1038/492S58a. No abstract available.
  5. NMR…http://file.selleckchem.com/downloads/nmr/S803401-Apremilast-HNMR-Selleck.pdf
  6. WO 2003080049
  7. WO 2013126495
  8. WO 2013126360
  9. WO 2003080049
  10. WO 2006065814
  11. US2003/187052 A1 …..MP 144 DEG CENT
  12. US2007/155791
  13. J. Med. Chem.200851 (18), pp 5471–5489
    DOI: 10.1021/jm800582j
  14. J. Med. Chem.201154 (9), pp 3331–3347
    DOI: 10.1021/jm200070e

…………………………………………

INTRODUCTION

2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindoline-l ,3-dione is a PDE4 inhibitor that is currently under investigation as an anti-inflammatory for the treatment of a variety of conditions, including asthma, chronic obstructive pulmonary disease, psoriasis and other allergic, autoimmune and rheumatologic conditions. S-enantiomer form of 2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindoline-l ,3-dione can be prepared by reacting (5)-aminosulfone 1 with intermediate 2.

Figure imgf000003_0001

Existing methods for synthesizing (S)-aminosulfone 1 involve resolution of the corresponding racemic aminosulfone by techniques known in the art. Examples include the formation and crystallization of chiral salts, and the use of chiral high performance liquid chromatography. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). In one example, as depicted in Scheme 1 below, (5)-aminosulfone 1 is prepared by resolution of racemic aminosulfone 3 with N-Ac-L-Leu. Racemic aminosulfone 3 is prepared by converting 3-ethoxy-4-methoxybenzonitrile 4 to enamine intermediate 5 followed by enamine reduction and borate hydrolysis. This process has been reported in U.S. Patent

Application Publication No. 2010/0168475.

Figure imgf000003_0002

CH2CI2, NaOH

Figure imgf000003_0003

Scheme 1

The procedure for preparing an enantiomerically enriched or enantiomerically pure aminosulfone, such as compound 1, may be inefficient because it involves the resolution of racemic aminosulfone 3. Thus, a need exists as to asymmetric synthetic processes for the preparation of an enantiomerically enriched or enantiomerically pure aminosulfone, particularly for manufacturing scale production. Direct catalytic asymmetric hydrogenation of a suitable enamine or ketone intermediate is of particular interest because it eliminates the need for either classic resolution or the use of stoichiometric amount of chiral auxiliary, and thus, may be synthetically efficient and economical.

……………………………………….

SYNTHESIS OF KEY INTERMEDIATE

WO2013126495A2

Example 1

Synthesis of 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine

Figure imgf000058_0001

[00232] A slurry of dimethylsulfone (85 g, 903 mmol) in THF (480 ml) was treated with a

1.6M solution of n-butyllithium in hexane (505 ml, 808 mmol) at 0 – 5 °C. The resulting mixture was agitated for 1 hour then a solution of 3-ethoxy-4-methoxybenzonitrile (80 g, 451 mmol) in THF (240 ml) was added at 0 – 5 °C. The mixture was agitated at 0 – 5 °C for 0.5 hour, warmed to 25 – 30 °C over 0.5 hour and then agitated for 1 hour. Water (1.4 L) was added at 25 – 30 °C and the reaction mass was agitated overnight at room temperature (20 – 30 °C). The solid was filtered and subsequently washed with a 2: 1 mixture of water :THF (200 ml), water (200 ml) and heptane (2 x 200 ml). The solid was dried under reduced pressure at 40 – 45 °C to provide the product as a white solid (102 g, 83% yield); 1H NMR (DMSO-d6) δ 1.34 (t, J=7.0 Hz, 3H), 2.99 (s, 3H), 3.80 (s, 3H), 4.08 (q, J=7.0 Hz, 2H), 5.03 (s, 1H), 6.82 (s, 2H), 7.01 (d, J=8.5 Hz, 1H), 7.09 – 7.22 (m, 2H).

Example 2

Synthesis of (R)- 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine

Figure imgf000059_0001

[00233] A solution of bis(l,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (36 mg, 0.074 mmol) and (i?)-l-[(5)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (40 mg, 0.074 mmol) in 25 mL of 2,2,2-trifluoroethanol was prepared under nitrogen. To this solution was then charged l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (2.0 g, 7.4 mmol). The resulting mixture was heated to 50 °C and hydrogenated under 90 psig hydrogen pressure. After 18 h, the mixture was cooled to ambient temperature and removed from the hydrogenator. The mixture was evaporated and the residue was purified by chromatography on a CI 8 reverse phase column using a water-acetonitrile gradient. The appropriate fractions were pooled and evaporated to -150 mL. To this solution was added brine (20 mL), and the resulting solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgS04) and evaporated to provide the product as a white crystalline solid (1.4 g, 70% yield); achiral HPLC (Hypersil BDS C8, 5.0 μπι, 250 x 4.6 mm, 1.5 mL/min, 278nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 9.11 (99.6%); chiral HPLC (Chiralpak AD-H 5.0 μιη Daicel, 250 x 4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-z-PrOH-diethylamine): 7.32 (97.5%), 8.26 (2.47%); 1H NMR (DMSO-de) δ 1.32 (t, J= 7.0 Hz, 3H), 2.08 (s, 2H), 2.96 (s, 3H), 3.23 (dd, J= 3.6, 14.4 Hz, 1H), 3.41 (dd, J= 9.4, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J= 7.0 Hz, 2H), 4.26 (dd, J= 3.7, 9.3 Hz, 1H), 6.89 (s, 2H), 7.02 (s, 1H); 13C NMR (DMSO-d6) δ 14.77, 41.98, 50.89, 55.54, 62.03, 63.68, 111.48, 111.77, 118.36, 137.30, 147.93, 148.09. Example 3

Synthesis of (6 -l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-Ac-L-Leu salt

Figure imgf000060_0001

[00234] A solution of bis(l,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (17 mg, 0.037 mmol) and (5)-l-[(i?)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (20 mg, 0.037 mmol) in 10 mL of 2,2,2-trifluoroethanol was prepared under nitrogen. To this solution was then charged l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (2.0 g, 7.4 mmol). The resulting mixture was heated to 50 °C and hydrogenated under 90 psig hydrogen pressure. After 18 h, the mixture was cooled to ambient temperature and removed from the hydrogenator. Ecosorb C-941 (200 mg) was added and the mixture was stirred at ambient temperature for 3 h. The mixture was filtered through Celite, and the filter was washed with additional trifluoroethanol (2 mL). Then, the mixture was heated to 55 °C, and a solution of N- acetyl-L-leucine (1.3 g, 7.5 mmol) was added dropwise over the course of 1 h. Stirring proceeded at the same temperature for 1 h following completion of the addition, and then the mixture was cooled to 22 °C over 2 h and stirred at this temperature for 16 h. The crystalline product was filtered, rinsed with methanol (2 x 5 mL), and dried under vacuum at 45 °C to provide the product as a white solid (2.6 g, 80% yield); achiral HPLC (Hypersil BDS Cg, 5.0 μιη, 250 x 4.6 mm, 1.5 mL/min, 278nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 8.57 (99.8%); chiral HPLC (Chiralpak AD-H 5.0 μιη Daicel, 250 x 4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-z-PrOH-diethylamine): 8.35 (99.6%); 1H NMR (DMSO-<¾) δ 0.84 (d, 3H), 0.89 (d, J= 6.6 Hz, 3H), 1.33 (t, J= 7.0 Hz, 3H), 1.41 – 1.52 (m, 2H), 1.62 (dt, J= 6.7, 13.5 Hz, 1H), 1.83 (s, 3H), 2.94 (s, 3H), 3.28 (dd, J= 4.0, 14.4 Hz, 1H), 3.44 (dd, J= 9.1, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J= 6.9 Hz, 2H), 4.18 (q, J= 7.7 Hz, 1H), 4.29 (dd, J= 4.0, 9.1 Hz, 1H), 5.46 (br, 3H), 6.90 (s, 2H), 7.04 (s, 1H), 8.04 (d, J= 7.9 Hz, 1H); Anal. (C20H34N2O7S) C, H, N. Calcd C, 53.79; H, 7.67; N 6.27. Found C, 53.78; H, 7.57; N 6.18.

SUBSEQUENT CONVERSION

S-enantiomer form of 2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindoline-l ,3-dione can be prepared by reacting (5)-aminosulfone 1 with intermediate 2.

Figure imgf000003_0001

……………………………………

APREMILAST

GENERAL SYNTHESIS AND SYNTHESIS OF APREMILAST

WO2012083153A1

Figure imgf000044_0001

Figure imgf000044_0002

Figure imgf000044_0004

(apremilast)

[0145] Preparation of 3-Ethoxy-4-methoxybenzonitrile (Compound 2). 3-Ethoxy-

4-methoxybenzaldehyde (Compound 1, 10.0 gm, 54.9 mmol, Aldrich) and hydroxylamine hydrochloride (4.67 gm, 65.9 mmol, Aldrich) were charged to a 250 mL three-necked flask at room temperature, followed by the addition of anhydrous acetonitrile (50 mL). The reaction mixture was stirred at room temperature for thirty minutes and then heated to reflux (oil bath at 85 °C). After two hours of reflux, the reaction mixture was cooled to room temperature, and added 50 mL of deionized water. The mixture was concentrated under reduced pressure to remove acetonitrile and then transferred to a separatory funnel with an additional 80 mL of deionized water and 80 mL dichloromethane. The aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed successively with water (80 mL) and saturated sodium chloride (80 mL). The organic layer was dried over anhydrous sodium sulfate (approximately 20 gm). The organic layer was filtered and concentrated under reduced pressure to give a yellow oil. Purification by silica gel chromatography (0 to 1 % MeOH/DCM ) afforded 3-Ethoxy-4-methoxybenzonitrile

(Compound 2) as a white solid (7.69 gm, 79 % yield). MS (ESI positive ion) m/z 178.1 (M + 1). HPLC indicated >99% purity by peak area. 1H-NMR (500 MHz, DMSO-c¾: δ ppm 1.32 (t, 3H), 3.83 (s, 3H), 4.05 (q, 2H), 7.10 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 2.0 Hz, 1H).

[0146] Preparation of l-(3-Ethoxy-4-methoxyphenyi)-2-

(niethylsulfonyl)ethanamine (Compound 3). Dimethyl sulfone (2.60 gm, 27.1 mmol, Aldrich) and tetrahydrofuran (10 mL, Aldrich) were charged to a 250 mL three-necked flask at room temperature. The mixture was cooled to 0 – 5 °C, and the solution gradually turned white. n-Butyllithium (10.8 mL, 27.1 mmol, 2.5 M solution in hexanes, Aldrich) was added to the flask at a rate such that the reaction mixture was maintained at 5 – 10 °C. The mixture was stirred at 0 – 5 °C for one hour, turning light-yellow. 3-Ethoxy-4-methoxybenzonitrile (Compound 2, 4.01 gm, 22.5 mmol) in tetrahydrofuran (8 mL) was then charged to the flask at a rate such that the reaction mixture was maintained at 0 – 5 °C. The mixture was stirred at 0 – 5 °C for another 15 minutes. After warming to room temperature, the reaction mixture was stirred for another 1.5 hours and then transferred to a second 250 mL three-necked flask containing a suspension of sodium borohydride (1.13 gm, 29.3 mmol, Aldrich) in

tetrahydrofuran (1 1 mL), maintained at – 5 – 0 °C for 30 minutes. Trifluoroacetic acid (“TFA,” 5.26 mL, 68.3 mmol, Aldrich) was charged to the flask at a rate such that the reaction mixture was maintained at 0 – 5 °C. The mixture was stirred at 0 – 5 °C for 40 minutes and an additional 17 hours at room temperature. The reaction mixture was then charged with 2.7 mL of deionized water over five minutes at room temperature. The mxiture was stirred at room temperature for 15 hours. Aqueous NaOH (10 N, 4.9 mL) was charged to the flask over 15 minutes at 45 °C. The mixture was stirred at 45 °C for two hours, at 60 °C for 1.5 hours, and at room temperature overnight. After approximately 17 hours at room temperature the mixture was cooled to 0 °C for thirty minutes and then concentrated under reduced pressure. The residual material was charged with deionized water (3 mL) and absolute ethanol (3 mL) and stirred at 0 – 5 °C for 2 hours. The mixture was filtered under vacuum, and the filtered solid was washed with cold absolute ethanol (3 x 5 mL), followed by deionized water until the pH of the wash was about 8. The solid was air dried overnight, and then in a vacuum oven at 60 °C for 17 hours to afford Compound 3 as a white solid (4.75 gm, 77 %). MS (ESI positive ion) m/z 274.1 (M + 1). Ή-NMR (500 MHz, DMSO-c¾): δ ppm 1.32 (t, J = 7.0 Hz, 3H), 2.08 (bs, 2H), 2.95 (s, 3H), 3.23 (dd, J = 4.0 Hz, 1H), 3.40 (dd, J = 9.5 Hz, 1H), 3.72 (s, 3H), 4.01 (q, J = 7.0 Hz, 2H), 4.25 (dd, J = 3.5 Hz, 1H), 6.88 (s, 2H), 7.02 (s, 1H).

[0147] Preparation of 4-Nitroisobenzofuran-l,3-dione (Compound 5). Into a 250 mL round bottom flask, fitted with a reflux condenser, was placed 3-nitrophthalic acid (21.0 gm, 99 mmol, Aldrich) and acetic anhydride (18.8 mL, 199 mmol, Aldrich). The solid mixture was heated to 85 °C, under nitrogen, with gradual melting of the solids. The yellow mixture was heated at 85 °C for 15 minutes, and there was noticeable thickening of the mixture. After 15 minutes at 85 °C, the hot mixture was poured into a weighing dish, and allowed to cool. The yellow solid was grinded to a powder and then placed on a cintered funnel, under vacuum. The solid was washed with diethyl ether (3 x 15 mL), under vacuum and allowed to air dry overnight, to afford 4-nitroisobenzofuran-l ,3-dione, Compound 5, as a light-yellow solid (15.8 gm, 82 %). MS (ESI positive ion) m/z 194.0 (M + 1). TLC: Rf = 0.37 (10% MeOH/DCM with 2 drops Acetic acid) Ή-NMR (500 MHz, DMSO-i¾: δ ppm 8.21 (dd, J = 7.5 Hz, 1H), 8.39 (dd, J = 7.5 Hz, 1H), 8.50 (dd, J = 7.5 Hz, 1 H).

[0148] Preparation of 2-(l-(3-Ethoxy-4-methoxyphenyI)-2-

(methylsulfonyl)ethyl)-4-nitroisoindoline-l,3-dione (Compound 6). Into a 2 – 5 mL microwave vial was added 4-nitroisobenzofuran-l ,3-dione (Compound 5, 0.35 gm, 1.82 mmol), the amino-sulfone intermediate (Compound 3, 0.50 gm, 1.82 mmol) and 4.0 mL of glacial acetic acid. The mixture was placed in a microwave at 125 °C for 30 minutes. After 30 minutes the acetic acid was removed under reduced pressure. The yellow oil was taken up in ethyl acetate and applied to a 10 gm snap Biotage samplet. Purification by silica gel chromatography (0 to 20 % Ethyl Acetate/Hexanes) afforded Compound 6 as a light-yellow solid (0.67 gm, 82 %). MS (ESI positive ion) m/z 449.0 (M + 1). TLC: Rf = 0.19

(EtOAc:Hexanes, 1 : 1). HPLC indicated 99% purity by peak area. Ή-NMR (500 MHz, DMSO-c¾: δ ppm 1.32 (t, 3H), 2.99 (s, 3H), 3.73 (s, 3H), 4.02 (m, 2H), 4.21 (dd, J = 5.0 Hz, 1H), 4.29 (dd, J = 10.0 Hz, 1H), 5.81 (dd, J = 5.0 Hz, 1H), 6.93 (d, J – 8.5 Hz, 1H), 7.00 (dd, J = 2.0 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 8.07 (t, J = 15.5 Hz, 1H), 8.19 (dd, J = 8.5 Hz, 1H), 8.30 (dd, J = 9.0 Hz, 1H).

[0149] Preparation of 4-Amino-2-(l-(3-ethoxy-4-methoxyphenyl)-2-

(methylsulfonyl)ethyl)isoindoline-l,3-dione (Compound 7). Compound 6 (0.54 gm, 1.20 mmol) was taken up in ethyl acetate / acetone (1 : 1 , 24 mL) and flowed through the H-cube™ hydrogen reactor using a 10 % Pd/C CatCart™ catalyst cartridge system (ThalesNano, Budapest Hungary). After eluting, the yellow solvent was concentrated under reduced pressure to give Compound 7 as a yellow foam solid (0.48 gm, 95 %). MS (ESI positive ion) m/z 419.1 (M + 1). 1H-NMR (500 MHz, DMSO-<¾): δ ppm 1.31 (t, J = 7.0 Hz, 3H), 2.99 (s, 3H), 3.72 (s, 3H), 4.04 (q, J = 7.0 Hz, 2H), 4.09 (m, 1H), 4.34 (m, 1H), 5.71 (dd, J = 5.5 Hz, 1H), 6.52 (bs, 2H), 6.92-6.98 (m, 3H), 7.06 (bs, 1 H), 7.42 (dd, J = 7.0 Hz, 1H).

[0150] Preparation of N-(2-(l-(3-ethoxy-4-methoxyphenyl)-2-

(methylsuIfonyl)ethyl)-l,3-dioxoisoindolin-4-yl)acetamide (Apremilast, Compound 8).

Into a 2-5 mL microwave vial was placed Compound 7 (0.18 gm, 0.43 mmol), acetic anhydride (0.052 mL, 0.53 mmol) and acetic acid (4 mL). The microwave vial was placed into a Biotage microwave and heated to 125 °C for 30 minutes. The solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (0 to 5% MeOH/DCM) to afford apremilast (Compound 8) as a yellow oil (0.14 gm, 71%). HPLC indicated 94.6% purity by peak area.

1H-NMR (500 MHz, DMSO-c 6): δ ppm 1.31 (t, 3H), 2.18 (s, 3H), 3.01 (s, 3H), 3.73 (s, 3H), 4.01 (t, J = 7.0 Hz, 2H), 4,14 (dd, J = 4.0 Hz, 1H), 4.33 (m, 1H), 5.76 (dd, J = 3.0 Hz, 1H), 6.95 (m, 2H), 7.06 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 7.0 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 8.43 (d, J = 8.5 Hz, 1H), 9.72 (bs, 1H).

……………………..

SYNTHESIS

EP2501382A1

5. EXAMPLES

Certain embodiments provided herein are illustrated by the following non-limiting examples.

5.1 PREPARATION OF (+)-2-[l-(3-ETHOXY-4-METHOXYPHENYL)-2- METHANESULFONYLETHYLJ-4- ACETYL AMINOISOINDOLIN-1,3- DIONE (APREMILAST)

Figure imgf000021_0001

5.1.1 Preparation of 3-aminopthalic acid

10% Pd/C (2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 L) were charged to a 2.5 L Parr hydrogenator under a nitrogen atmosphere. Hydrogen was charged to the reaction vessel for up to 55 psi. The mixture was shaken for 13 hours, maintaining hydrogen pressure between 50 and 55 psi. Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a celite bed and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solid was reslurried in ether and isolated by vacuum filtration. The solid was dried in vacua to a constant weight, affording 54 g (84%> yield) of 3-aminopthalic acid as a yellow product. 1H-NMR (DMSO-d6) δ: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (brs, 2H). 13C-NMR(DMSO-d6) δ: 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.

5.1.2 Preparation of 3-acetamidopthalic anhydride

A I L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to ambient temperature and further to 0-5. degree. C. for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacua at ambient temperature to a constant weight, giving 75 g (61% yield) of 3-acetamidopthalic anhydride as a white product. 1H-NMR (CDCI3) δ: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).

5.1.3 Resolution of 2-(3-ethoxy-4-methoxyphenyl)-l-(methylsulphonyl)- ethyl-2-amine

A 3 L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-l-(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 mL). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30°C. to a constant weight, yielding 49.6 g (90%> recovery) of (S)-2-(3-ethoxy-4- methoxyphenyl)-l-(methylsulphonyl)-eth-2-ylamine-N-acety 1-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2P04 @pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm.times.4.6 mm, 0.5 mL/min., @240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%)

5.1.4 Preparation of (+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2- methanesulfonylethyl] -4-acetylaminoisoindolin- 1 ,3-dione

A 500 mL 3 -necked round bottom flask was equipped with a mechanical stirrer,

thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4- methoxyphenyl)-l-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), 3-acetamidophthalic anhydride (12.1 g, 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50°C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL x

2), saturated aqeous NaHC03 (250 mL.times.2), brine (250 mL.times.2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL.times.2). The product was dried in vacuo at 60°C. to a constant weight, affording 19.4 g (75% yield) of Compound 3 APREMILAST with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2P04 @pH 3.5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm x 4.6 mm, 0.4 mL/min., @240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%).

1H-NMR (CDC13) δ: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H).

13C-NMR(DMSO-d6) δ: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.

…………………………………..

NMR

US20100129363

1H-NMR (CDCl3) δ: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). 13C-NMR (DMSO-d6) δ: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.

…………….

APREMILAST

J. Med. Chem., 2009, 52 (6), pp 1522–1524
DOI: 10.1021/jm900210d

Figure

aReagents and conditions: (a) LiN(SiMe3)2, then Me2SO2/n-BuLi/BF3Et2O, −78 °C; (b) N-Ac-l-leucine, MeOH; (c) HOAc, reflux.

……………………

SARCOIDOSIS

Sarcoidosis is a disease of unknown cause. Sarcoidosis is characterized by the presence of granulomas in one or more organ systems. The most common sites of involvement are the lungs and the lymph nodes in the mediastinum and hilar regions. However, sarcoidosis is a systemic disease and a variety of organ systems or tissues may be the source of primary or concomitant clinical manifestations and morbidity. The clinical course of sarcoidosis is extremely variable, and ranges from a mild or even asymptomatic disease with spontaneous resolution to a chronic progressive disease leading to organ system failure and, in 1-5% of cases, death. See Cecil

Textbook of Medicine, 21st ed. (Goldman, L., Bennett, J. C. eds), W. B. Saunders Company, Philadelphia, 2000, p. 433-436.

While the cause of sarcoidosis is unknown, a substantial body of information suggests that immune mechanisms are important in disease pathogenesis. For example, sarcoidosis is

characterized by enhanced lymphocyte and macrophage activity. See Thomas, P.D. and

Hunninghake, G.W., Am. Rev. Respir. Dis., 1987, 135: 747-760. As sarcoidosis progresses, skin rashes, erythema nodosum and granulomas may form. Granulomas or fibrosis caused by sarcoidosis can occur throughout the body, and may affect the function of vital organs such as the lungs, heart, nervous system, liver or kidneys. In these cases, the sarcoidosis can be fatal. See

http://www.nlm.nih.gov/medlineplus/sarcoidosis.html (accessed November 12, 2009).

Moreover, a variety of exogenous agents, both infectious and non-infectious, have been hypothesized as a possible cause of sarcoidosis. See Vokurka et ah, Am. J. Respir. Crit. Care Med., 1997, 156: 1000-1003; Popper et al, Hum. Pathol, 1997, 28: 796-800; Almenoff et al, Thorax, 1996, 51 : 530-533; Baughman et al., Lancet, 2003, 361 : 1111-1118. These agents include mycobaceria, fungi, spirochetes, and the agent associated with Whipple’s disease. Id.

Sarcoidosis may be acute or chronic. Specific types of sarcoidosis include, but are not limited to, cardiac sarcoidosis, cutaneous sarcoidosis, hepatic sarcoidosis, oral sarcoidosis, pulmonary sarcoidosis, neurosarcoidosis, sinonasal sarcoidosis, Lofgren’s syndrome, lupus pernio, uveitis or chronic cutaneous sarcoidosis.

As the lung is constantly confronted with airborne substances, including pathogens, many researchers have directed their attention to identification of potential causative transmissible agents and their contribution to the mechanism of pulmonary granuloma formation associated with sarcoidosis. See Conron, M. and Du Bois, R.M., Clin. Exp. Allergy, 2001, 31 : 543-554; Agostini et al, Curr. Opin. Pulm. Med. , 2002, 8: 435-440.

Corticosteroid drugs are the primary treatment for the inflammation and granuloma formation associated with sarcoidosis. Rizatto et al. , Respiratory Medicine, 1997, 91 : 449-460. Prednisone is most often prescribed drug for the treatment of sarcoidosis. Additional drugs used to treat sarcoidosis include methotrexate, azathioprine, hydroxychloroquine, cyclophosphamide, minocycline, doxycycline and chloroquin. TNF-a blockers such as thalidomide and infliximab have been reported to be effective in treating patients with sarcoidosis. Baughman et al, Chest, 2002, 122: 227-232; Doty et al, Chest, 2005, 127: 1064-1071. Antibiotics have also been studied for the treatment of sarcoidosis, such as penicillin antibiotics, cephalosporin antibiotics, macrolide antibiotics, lincomycin antibiotics, and tetracycline antibiotics. Specific examples include minocycline hydrochloride, clindamycin, ampicillin, or clarithromycin. See, e.g., U.S. Patent Publication No. 2007/0111956.

There currently lacks a Food and Drug Administration-approved therapeutic agent for the treatment of sarcoidosis, and many patients are unable to tolerate the side effects of the standard corticosteroid therapy. See Doty et al, Chest, 2005, 127: 1064-1071. Furthermore, many cases of sarcoidosis are refractory to standard therapy. Id. Therefore, a demand exists for new methods and compositions that can be used to treat patients with sarcoidosis.

……………..

PATENTS

8-15-2012
PROCESSES FOR THE PREPARATION OF AMINOSULFONE COMPOUNDS
11-4-2011
HETEROCYCLIC COMPOUNDS AS PHOSPHODIESTERASE INHIBITORS
5-27-2011
Nanosuspension of a Poorly Soluble Drug via Microfluidization Process
5-28-2010
METHODS AND COMPOSITIONS USING PDE4 INHIBITORS FOR THE TREATMENT AND MANAGEMENT OF CANCERS

 

 

 

ANTHONY MELVIN CRASTO

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

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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

need help, email or call me

MOBILE-+91 9323115463
web link

I was  paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

 

TEDIGLUTIDE ..Glucagon-like peptide 2 (GLP-2) analog; protects small intestinal stem cells from radiation damage.


File:Teduglutide.png

TEDUGLUTIDE
Glucagon-like peptide 2 (GLP-2) analog; protects small intestinal stem cells from radiation damage.

Gattex (teduglutide) is a recombinant analog of human glucagon-like peptide 2 for the treatment of adults with short bowel syndrome.

  • (Gly2)GLP-2
  • ALX 0600
  • ALX-0600
  • Gattex
  • Gly(2)-GLP-2
  • Teduglutide
  • UNII-7M19191IKG

[Gly2]hGLP-2, [Gly2]-hGLP-2, ALX-0600,

Gattex, Revestive

CAS number 197922-42-2

L-histidylglycyl-L-α-aspartylglycyl-L-seryl-L-phenylalanyl-L-seryl-L-α-aspartyl-L-α-glutamyl-L-methionyl-L-asparaginyl-L-threonyl-L-isoleucyl-L-leucyl-L-α-aspartyl-L-asparaginyl-L-leucyl-L-alanyl-L-alanyl-L-arginyl-L-α-aspartyl-L-phenylalanyl-L-isoleucyl-L-asparaginyl-L-tryptophyl-L-leucyl-L-isoleucyl-L-glutaminyl-L-threonyl-L-lysyl-L-isoleucyl-L-threonyl-L-aspartic acid

Formula C164H252N44O55S 
Mol. mass 3752.082 g/mol

Gattex, ALX-0600, (Gly2)GLP-2, Gly(2)-GLP-2, ALX 0600, [Gly2]GLP-2, Glucagon-like peptide II (2-glycine) (human), UNII-7M19191IKG

LAUNCHED 2013, NPS Pharmaceuticals

APPROVAL FDA

Company: NPS Pharmaceuticals, Inc.
Date of Approval: December 21, 2012 FDA

NDA 203441

POWDER; SUBCUTANEOUS GATTEX

U-1320=TREATMENT OF ADULT PATIENTS WITH SHORT BOWEL SYNDROME WHO ARE DEPENDENT ON PARENTERAL SUPPORT

Patent No Patent Expiry Date Patent use code
5789379 Apr 14, 2015 U-1320
7056886 Sep 18, 2022 U-1320
7847061 Nov 1, 2025 U-1320
Exclusivity Code Exclusivity_Date
ORPHAN DRUG EXCLUSIVITY Dec 21, 2019
NEW CHEMICAL ENTITY Dec 21, 2017

SEE FDA

http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203441Orig1s000lbl.pdf

CLINICAL TRIALS

http://clinicaltrials.gov/search/intervention=Teduglutide+OR+ALX-0600

The active ingredient in GATTEX (teduglutide [rDNA origin]) for injection is teduglutide (rDNA origin), which is a 33 amino acid glucagon-like peptide-2 (GLP-2) analog manufactured using a strain of Escherichia coli modified byrecombinant DNA technology. The chemical name of teduglutide is L-histidyl-L-glycyl-L-aspartyl-L-glycyl-L-seryl-L-phenylalanyl-L-seryl-L-aspartyl-L-glutamyl-L-methionyl-L-asparaginyl-L-threonyl-L-isoleucyl-L-leucyl-L-aspartyl-L-asparaginyl-L-leucyl-L-alanyl-L-alanyl-L-arginyl-L-aspartyl-L-phenylalanyl-L-isoleucyl-L-asparaginyl-L-tryptophanyl-L-leucyl-L-isoleucyl-L-glutaminyl-L-threonyl-L-lysyl-L-isoleucyl-L-threonyl-L-aspartic acid. The structural formula is:

Figure 1: Structural formula of teduglutide

GATTEX (teduglutide) structural formula illustration

Teduglutide has a molecular weight of 3752 Daltons. Teduglutide drug substance is a clear, colorless to light-straw–colored liquid.

Each single-use vial of GATTEX contains 5 mg of teduglutide as a white lyophilized powder for solution for subcutaneous injection. In addition to the active pharmaceutical ingredient (teduglutide), each vial of GATTEX contains 3.88 mg L-histidine, 15 mg mannitol, 0.644 mg monobasic sodium phosphate monohydrate, 3.434 mg dibasic sodium phosphate heptahydrate as excipients. No preservatives are present.

At the time of administration the lyophilized powder is reconstituted with 0.5 mL of Sterile Water for Injection, which is provided in a prefilled syringe. A 10 mg/mL sterile solution is obtained after reconstitution. Up to 0.38 mL of the reconstituted solution which contains 3.8 mg of teduglutide can be withdrawn for subcutaneous injection upon reconstitution.

Teduglutide (brand names Gattex and Revestive) is a 36-membered polypeptide andglucagon-like peptide-2 analog that is used for the treatment of short bowel syndrome. It works by promoting mucosal growth and possibly restoring gastric emptying and secretion.[1] In Europe it is marketed under the brand Revestive by Nycomed. It was approved by the United States under the name Gattex on December 21, 2012.

Teduglutide is a proprietary analogue of glucagon-like peptide 2 (GLP-2) which was approved in the U.S. in December 2012 for the once-daily treatment of short-bowel syndrome in adults who are dependent on parenteral support. Commercial launch took place in 2013.The product was filed for approval in the E.U. in 2011 by Nycomed for this indication. In June 2012, a positive opinion was received in the E.U. and final approval was assigned in September 2012.

At NPS Pharmaceuticals, the compound is in phase III clinical development for this indication in pediatric patients and in phase II clinical studies for the treatment of Crohn’s disease. Preclinical studies are also ongoing at the company for the treatment of chemotherapy-induced enterocolitis and for the prevention and treatment of necrotizing enterocolitis (NEC) in preterm infants.

Teduglutide has been found to induce intestinal hyperplasia, reduce apoptosis and inflammation and improve cell barrier integrity in animal models. In 2001, orphan drug designation was assigned to teduglutide for the treatment of short-bowel syndrome.

In 2007, the compound was licensed to Nycomed for development and commercialization outside the U.S., Canada and Mexico for the treatment of gastrointestinal disorders. In 2012, the product was licensed to Neopharm by NPS Pharmaceuticals in Israel for development and commercialization for the treatment of gastrointestinal disorders.

The estimated prevalence of short bowel syndrome (SBS) patients with non-malignant disease requiring home parenteral nutrition (HPN) is at least 40 per million of the U.S. population. SBS usually results from surgical resection of some or most of the small intestine for conditions such as Crohn’s disease, mesenteric infarction, volvulus, trauma, congenital anomalies, and multiple strictures due to adhesions or radiation. Surgical resection may also include resection of all or part of the colon. SBS patients suffer from malabsorption that may lead to malnutrition, dehydration and weight loss. Some patients can maintain their protein and energy balance through hyperphagia; more rarely they can sustain fluid and electrolyte requirements to become independent from parenteral fluid.

Although long-term parenteral nutrition (PN) is life saving in patients with intestinal failure, it is expensive, impairs quality of life and is associated with serious complications such as catheter sepsis, venous occlusions and liver failure. Treatments that amplify absolute intestinal absorption, and eliminate or minimize the need for PN have great potential significance to SBS patients.

The endogenous meal-stimulated hormone, glucagon-like peptide-2 (GLP-2), raises considerable interest for SBS patients. GLP-2 functions to slow gastric emptying, reduce gastric secretions, increase intestinal blood-flow and stimulate growth of the small and large intestine. In animal studies, GLP-2 administration induces mucosal epithelial proliferation in the stomach and small and large intestine by stimulation of crypt cell proliferation and inhibition of enterocyte apoptosis.

SBS patients with end-jejunostomy and no colon have low basal GLP-2 levels and limited meal-stimulated GLP-2 secretion due to removal of GLP-2 secreting L-cells, which are located primarily in the terminal ileum and colon. This GLP-2 deficiency results in a minimal adaptive response following resection and could explain the gastric hypersecretion, rapid intestinal transit and lack of intestinal adaptation observed in these SBS patients.

Jeppesen et al. (Gastroenterology 2001; 120:806-815) have described positive benefit in an open-label study using pharmacologic doses of native GLP-2 in SBS jejunostomy patients. There was significant improvement in intestinal wet weight absorption and a more modest improvement in energy absorption that led to an increase in body weight, lean body mass and a rise in urinary creatinine excretion.

In contrast, SBS patients with colon-in-continuity have elevated basal endogenous GLP-2 levels resulting in an adaptive response to resection characterized by improved wet weight gain and energy absorption. The potential for added benefit of pharmacologic doses of GLP-2 receptor agonists in these patients is not obvious and has not been studied.

TEDUGLUTIDE

  1.  Jeppesen PB (May 2012). “Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome”Therap Adv Gastroenterol 5 (3): 159–71. doi:10.1177/1756283X11436318PMC 3342570PMID 22570676.
  2. US 2013157954
  3. WO 2006050244
  4. WO 2005021022
  5. US 6586399
  6. WO 2002066062
  7. US 6297214
  8. US 2001021767
  9. WO 2001041779
  10. WO 1999058144
  11. WO 1998052600

Gattex Approved By FDA For Short Bowel Syndrome

Gattex (teduglutide) has been approved by the U.S. Food and Drug Administration to be used in patients that have short bowel syndrome and require parenteral nutrition.

The drug, once it is in the market, will compete against two others that have been approved by the FDA for this type of patient population. Those two medications are Nutrestore (glutamine) and Zorbtive (Somatropin).

Short bowel syndrome comes on following the removal surgically of part of the large or small intestine or part of both. Patients who are affected must have parenteral nutrition due to the poor absorption they have of nutrients and fluids. Teduglutide is injected one time each day and improves the absorption making it less important to have nutrition assistance.

The advisory committee for the FDA voted unanimously in October to recommend the drug’s approval after seeing the results from a pair of clinical trials that showed the advantage teduglutide had over just a placebo in at least a reduction of 20% in the amount of parenteral nutrition at 6 months.

During the first clinical trial, 46% of the patients that took the drug saw a level of reduction, which was compared to only 6% who had taken only a placebo. In the other study, the figure increased to 63%, while the placebo rated was up to 30%

The side effects most common found in those who use teduglutide during the trials included nausea, reactions around the injection site, abdominal pain abdominal distension and headaches.

………..

US5789379 Jun 28, 1996 Aug 4, 1998 1149336 Ontario Inc. Glucagon-like peptide-2 analogs
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US7411039 Oct 14, 2003 Aug 12, 2008 Novo Nordisk A/S GLP-2 compounds, formulations, and uses thereof
EP1231219A1 Apr 11, 1997 Aug 14, 2002 1149336 Ontario Inc. GLucagon-like peptide-2 analogs
WO1997039031A1 Apr 11, 1997 Oct 23, 1997 Allelix Biopharma Glucagon-like peptide-2 analogs
WO1997039091A1 Apr 16, 1997 Oct 23, 1997 Burckett St Laurent James Char Mid-chain branched surfactants
WO2002066511A2 Feb 15, 2002 Aug 29, 2002 Conjuchem Inc Long lasting glucagon-like peptide 2 (glp-2) for the treatment of gastrointestinal diseases and disorders

 

 

ANTHONY MELVIN CRASTO

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

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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

need help, email or call me

MOBILE-+91 9323115463
web link

I was  paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

Palbociclib


PALBOCICLIB

Mechanism of action: selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6
Indication: Estrogen receptor-positive (ER+), HER2-negative (HER2 -) breast cancer
Current Status: Phase III (US, UK, EU), (US Clinical trials numbers NCT01864746,NCT01740427NCT01942135)
Expected Launch Date: 2015
Potential Sales(peak):$5 billion
Company:Pfizer

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

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

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

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

Figure US07345171-20080318-C00002

In standard enzyme assays the compound of Formula 1 exhibits IC50 concentrations for CDK4 and CDK2 inhibition (at 25° C.) of 0.011 μM and >5 μM, respectively. For a discussion of standard CDK4 and CDK2 assays for IC50 determinations, see D. W. Fry et al., J. Biol. Chem. (2001) 16617-16623.

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

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

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

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

Figure US07781583-20100824-C00003

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

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

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Synthesis of Palbociclib Isethionate -CDK4 and 6 dual inhibitor - A highly Anticipated Investigational Breast Cancer Drug from Pfizer 辉瑞乳腺癌试验药物palbociclib的合成

USAN (zz-153)

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

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

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

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

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SYNTHESIS

:WO2008032157

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http://www.google.com/patents/US7781583Figure US07781583-20100824-C00026

Figure US07781583-20100824-C00027

Figure US07781583-20100824-C00034

Figure US07781583-20100824-C00035

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

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

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

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

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

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

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

Figure US07781583-20100824-C00038

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

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

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

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

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

Figure US07781583-20100824-C00039

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

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

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

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

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

Figure US07781583-20100824-C00040

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

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

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

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

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

Figure US07781583-20100824-C00041

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

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

Figure US07781583-20100824-C00042

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

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

EXAMPLES

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

potter at potters wheel animation

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

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

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

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

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

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

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

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

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

US6936612 Jan 16, 2003 Aug 30, 2005 Warner-Lambert Company 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
WO2005005426A1 Jun 28, 2004 Jan 20, 2005 Vladimir Genukh Beylin Isethionate salt of a selective cdk4 inhibitor
US20030229026 * Dec 18, 2000 Dec 11, 2003 Al-Awar Rima Salim Agents and methods for the treatment of proliferative diseases
US20040006074 * Dec 2, 2002 Jan 8, 2004 The Government Of The United States Of America Cyclin dependent kinase (CDK)4 inhibitors and their use for treating cancer
US20040048915 * Sep 24, 2001 Mar 11, 2004 Engler Thomas Albert Methods and compounds for treating proliferative diseases
US20050222163 * Mar 30, 2005 Oct 6, 2005 Pfizer Inc Combinations of signal transduction inhibitors
US20070027147 * Dec 3, 2004 Feb 1, 2007 Takashi Hayama Biarylurea derivatives
WO2008032157A2 * Aug 27, 2007 Mar 20, 2008 David Thomas Erdman Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
WO2010075074A1 Dec 15, 2009 Jul 1, 2010 Eli Lilly And Company Protein kinase inhibitors
WO2012098387A1 Jan 17, 2012 Jul 26, 2012 Centro Nacional De Investigaciones Oncológicas (Cnio) 6, 7-ring-fused triazolo [4, 3 – b] pyridazine derivatives as pim inhibitors
US7781583 Sep 10, 2007 Aug 24, 2010 Pfizer Inc Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d] pryimidin-7-ones
US7855211 Dec 15, 2009 Dec 21, 2010 Eli Lilly And Company Protein kinase inhibitors
US8247408 * Oct 9, 2006 Aug 21, 2012 Exelixis, Inc. Pyridopyrimidinone inhibitors of PI3Kα for the treatment of cancer
US8273755 Feb 9, 2010 Sep 25, 2012 Pfizer Inc 4-methylpyridopyrimidinone compounds

Mona Lisa Painting animation

old info

Date: April 10, 2013

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

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

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

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

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

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

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

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

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

Highlight of recent study using PD-0332991

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

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

Mona Lisa Painting animation

References

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

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

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

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

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

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

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

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

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ANTHONY MELVIN CRASTO

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

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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RAMOSETRON


RAMOSETRON, Antiemetics

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

  C17H17N3O 
  279.33 g/mol

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

YM060

  • Nasea
  • Nor-YM 060
  • Ramosetron
  • UNII-7ZRO0SC54Y

…………………………………………………………………………………..

HYDROCHLORIDE SALT

2D image of a chemical structure

hyrochloride salt, cas no 132907-72-3

C17-H17-N3-O.Cl-H
315.8022
Yamanouchi (Originator)
GASTROINTESTINAL DRUGS, Irritable Bowel Syndrome, Agents for, Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, 5-HT3 Antagonists
Launched-1996 JAPAN

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

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

…………………………………………………………………………………….

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

  1.  Fujii Y, Saitoh Y, Tanaka H, Toyooka H (February 2000). “Ramosetron for preventing postoperative nausea and vomiting in women undergoing gynecological surgery”.Anesth. Analg. 90 (2): 472–5. doi:10.1097/00000539-200002000-00043.PMID 10648342.
  2. http://www.astellas.com/en/corporate/news/detail/astellas-launches-irribow-for.html
  3.  Summary in Japanese. Retrieved on September 4, 2012.
  4.  Abridged prescribing information – Nasea (MIMS Philippines). Retrieved on June 13, 2008.
  5. Synthesis and 5-HT3 antagonistic activities of 4,5,6, 7-tetrahydrobenzimidazole derivatives
    200th ACS Natl Meet (August 26-31, Washington DC) 1990, Abst MEDI 39
1-27-2010
Process for producing ramosetron or its salt
11-20-1996
Intrabuccally dissolving compressed moldings and production process thereof
3-6-1996
5-substituted tetrahydrobenzimidazole compounds
11-15-1995
Intrabuccally disintegrating preparation and production thereof
9-7-1994
Tetrahydrobenzimidazole derivatives and pharmaceutical compositions containing same
6-24-1994
NEW USE OF 5-HT3 RECEPTOR ANTAGONISTS

AU 9048890; EP 0381422; JP 1991223278; US 5344927

CN1696128A Nov 2, 2004 Nov 16, 2005 天津康鸿医药科技发展有限公司 New method for synthesizing Ramosetron Hydrochloride
CN1765896A Oct 28, 2004 May 3, 2006 北京博尔达生物技术开发有限公司 Novel preparation method of ramosetron hydrochloride
US5496942 * 14 Feb 1994 5 Mar 1996 Yamanouchi Pharmaceutical Co., Ltd. 5-substituted tetrahydrobenzimidazole compounds
US5677326 * 30 Sep 1994 14 Oct 1997 Tokyo Tanabe Company Limited Indoline compound and 5-HT.sub.3 receptor antagonist containing the same as active ingredient
US7358270 28 Jan 2005 15 Apr 2008 Astellas Pharma Inc. Treating agent for irritable bowel syndrome
US7683090 18 Oct 2006 23 Mar 2010 Astellas Pharma Inc. Treating agent for irritable bowel syndrome
US7794748 27 Aug 2004 14 Sep 2010 Yamanouchi Pharmaceutical Co., Ltd. Stable oral solid drug composition

WO 2010024306

WO 2013005760

WO 2013100701

WO 2011001954

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

Figure US07652052-20100126-C00002

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

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

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

(Production Method A)

Figure US07652052-20100126-C00003

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

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

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

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

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

(Production Method B)

Figure US07652052-20100126-C00004

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

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

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

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

…………………………………………………………………………..

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

………………………………………………….

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

Figure US06451808-20020917-C00005

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

Figure US06451808-20020917-C00006

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

Figure US06451808-20020917-C00007

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

Figure US06451808-20020917-C00008

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

Figure US06451808-20020917-C00009

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

Figure US06451808-20020917-C00010

Ramosetron

Figure US06451808-20020917-C00011
2D image of a chemical structure
Galdansetron hydrochloride [USAN]
156712-35-5

Biota Reports That Laninamivir Octanoate is Approved for the Prevention of Influenza in Japan


Laninamivir

(4S,5R,6R)-5-acetamido-4-carbamimidamido-6-[(1R,2R)-3-hydroxy-2-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic acid

Formula C13H22N4O7 
Mol. mass 346.33638 g/mol

cas 203120-17-6,

Laninamivir (L174000) prodrug; a novel long-acting neuraminidase inhibitor.

laninamivir octanoate

472.53254, C21H36N4O8,   cas no 203120-46-1, R-125489, CS-8958 

Daiichi Sankyo (Originator)

R-118958 is a potent, long-acting neuraminidase inhibitor (LANI) approved and launched in 2010 in Japan as an inhalable formulation for the treatment of influenza A and influenza B in adults and pediatric patients. In 2013 the product was approved in Japan for the prevention of influenza A and influenza B.

5-(Acetylamino)-4-[(aminoiminomethyl)amino]-2,6-anhydro-3,4,5-trideoxy-7-O-methyl-D-glycero-D-galacto-non-2-enonic Acid 9-Octanoate
(2R,3R,4S)-3-Acetamido-4-guanidino-2-[(1R,2R)-2-hydroxy-1-methoxy-3-(octanoyloxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylic Acid
(4S,5R,6R)-5-Acetamido-4-guanidino-6-[(1R,2R)-2-hydroxy-1-methoxy-3-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-2-carboxylic Acid
CS 8958

ATLANTA, Dec. 20, 2013 (GLOBE NEWSWIRE) — Biota Pharmaceuticals, Inc.
(Nasdaq:BOTA) (“Biota” or the “Company”) today reported that Daiichi Sankyo Company, Limited (“Daiichi Sankyo”) has been granted regulatory approval in Japan to manufacture and market Inavir(R) Dry Powder Inhaler 20mg (generic name laninamivir octanoate) for the prevention of influenza A and B. Inavir(R) was successfully developed and launched by Daiichi Sankyo in Japan for treatment of influenza A and B viruses in October, 2010. Biota is developing laninamivir octanoate outside of Japan for the treatment of influenza, and is currently conducting a large, multi-national Phase 2 trial of laninamivir octanoate in adults infected with influenza. In 2003, the Company and Daiichi Sankyo entered into a collaboration and license agreement to develop long-acting neuraminidase inhibitors, including laninamivir octanoate, and in March 2009, the parties entered into a commercialization agreement, pursuant to which Daiichi Sankyo obtained exclusive marketing rights to laninamivir octanoate in Japan.http://www.pharmalive.com/biota-flu-drug-okd-in-japan

Laninamivir (CS-8958) is a neuraminidase inhibitor which is being researched for the treatment and prophylaxis of Influenzavirus A and Influenzavirus B.[1] It is currently in Phase III clinical trials. [2]

Laninamivir was approved for influenza treatment in Japan in 2010 and is currently marketed under the name “Inavir” by Daiichi Sankyo. Biota Pharmaceuticals [3] and Daiichi Sankyo co-own Laninamivir. On 1st April 2011, BARDA awarded up to an estimated U$231m to Biota Pharmaceuticals (Formerly Biota Holdings Ltd) wholly owned subsidiary, Biota Scientific Management Pty Ltd, for the advanced development of Laninamivir in the US. [4]

patent

8-13-2010
DRUG FOR TREATMENT OF INFLUENZA
WO 2013089168
WO 2008126943

The recent flu scares – first H5N1 bird flu and then H1N1 swine flu – transformed Roche’s neuraminidase inhibitor Tamiflu (oseltamivir) into a household name, along with GSK’s Relenza (zanamivir). Both of these require twice-daily dosing, and the orally available oseltamivir is the first choice, but resistance is starting to appear.

A new neuraminidase inhibitor, laninamivir, is being developed by Daiichi Sankyo.5 When administered as the octanoate prodrug form, it appears that a single dose might be sufficient to treat influenza, weekly doses could be preventative, and it is active against extremely pathogenic H5N1 strains.

Laninamivir octanoate

In a double blind, randomised, placebo-controlled Phase I study in 76 healthy male volunteers, subjects were given inhaled single doses of 5, 10, 20, 40, 80 or 120mg of the prodrug, or twice-daily doses of 20 or 40mg for three days.6 No adverse events were observed, and while the prodrug disappeared from the plasma with a half-life of about two hours, the laninamivir itself was much more slowly eliminated, with a half-life of the order of three days, suggesting the potential for giving long-lasting activity against influenza.

In another Phase I trial, a total of 20 healthy subjects with renal function ranging from normal to severely impaired were given single inhaled 20mg doses of the prodrug.7 The degree of renal impairment did not affect the maximum concentration or the time to achieve it, but the half-life increased as renal function reduced. This indicates that the rate-limiting step for elimination is drug release rate to plasma from tissues rather than renal excretion. It was well tolerated, but systemic exposure increased with increasing renal impairment.

It has also been compared with oseltamivir in patients with influenza. A total of 186 children under 10 who had had febrile influenza symptoms for no longer than 36 hours were randomised to receive 20 or 40mg of laninamivir octanoate as a single inhalation or 2mg/kg oseltamivir orally twice a day for five days.8

The new drug gave a significant reduction, of 61 hours for the 40mg group and 66 for the 20mg group, in median time to illness alleviation compared with oseltamivir in those with oseltamivir-resistant H1N1 influenza A. However, there was no significant difference in the time to alleviation of illness with H3N2 influenza A, or influenza B.

The most common side-effects were gastrointestinal problems.

In a Phase III trial, a total of 1,003 adult patients with febrile influenza symptoms for no more than 36 hours were given similar doses to those in the trial in children.9 Median time to alleviation of illness was 73h for 40mg, 86h for 20mg, and 74h for oseltamivir, and the proportion of patients shedding virus at day 3 was significantly lower in the 40mg group than for those given oseltamivir.

  1.  Yamashita M, Tomozawa T, Kakuta M, Tokumitsu A, Nasu H, Kubo S (January 2009).“CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity”Antimicrobial Agents and Chemotherapy53 (1): 186–92.doi:10.1128/AAC.00333-08PMC2612152PMID18955520.
  2.  Hayden F (January 2009). “Developing new antiviral agents for influenza treatment: what does the future hold?”. Clinical Infectious Diseases. 48. Suppl 1 (S1): S3–13.doi:10.1086/591851PMID19067613.
  3. http://www.biotapharma.com
  4. http://www.biotapharma.com/?page=1021001&subpage=1021019

5. T. Honda et al. Synthesis and in vivo influenza virus-inhibitory effect of ester prodrug of 4-guanidino-7-O-methyl-Neu5Ac2en, Bioorg Med Chem Lett 2009, 19(11): 2938

6. H. Ishizuka et al. J. Clin. Pharmacol. 2010, 50, 1319

7. H. Ishizuka et al. J. Clin. Pharmacol. 2010, epub ahead of print, doi 10.1177/0091270010361914

8. N. Sugaya and Y. Ohashi, Antimicrob. Ag. Chemother. 2010, 54, 2575

9 A. Watanabe et al. Clin. Inf. Dis. 2010, 51, 1167

A new route toward 2-acetamido-4-O-methyl-2-deoxy-D-mannopyranose from a Ferrier derivative of tri-O-acetyl-D-glucal, which contributes to aldolase-catalyzed synthesis of laninamivir (CS-8958)
Tetrahedron 2013, 39(37): 7931

Infection of poultry with H5N1 avian influenza virus has been expanding since 2003 in wide areas including Asia, Europe and Africa. Humans infected with this virus have been found not only in Asia but also in Middle East and Africa. If a new type of H5N1 influenza virus has appeared and its infection has started, it is believed that the infection will rapidly expand to cause a worldwide spread (i.e., influenza pandemic) because most people do not possess immunity against that virus and influenza viruses spread via droplet infection and airborne infection. More than half of human patients infected with H5N1 influenza virus have died so far. Thus, the virus is highly pathogenic. It is known that three influenza pandemics, the Spanish Flu, the Asian Flu and the Hong Kong Flu, occurred in the 20th century. In the Spanish Flu which caused the largest number of patients, it is estimated that about 20-40 million people died in the world and about 0.5 million people in Japan.

According to a report from Japanese Ministry of Health, Labour and Welfare made in November, 2005, if a new type influenza virus has spread, the number of patients who will consult medical doctors in Japan as a result of infection with that virus is estimated about 18-25 million. Further, when the pathogenicity of that new type influenza virus is severe, the number of inpatients is estimated about 0.2 million while the number of dead is estimated about 0.64 million. Therefore, not only health hazard but also significant influences upon social activities are feared.

Thus, a new type influenza can cause a highly severe disease. Early development of effective therapeutics is demanded.

Although it is reported that zanamivir (in particular, zanamivir hydrate) and oseltamivir (in particular, oseltamivir phosphate or oseltamivir carboxylate) which are influenza therapeutics with neuraminidase inhibitory activity show an inhibitory activity against H5N1 influenza virus, compounds with more excellent activity are desired (Non-Patent Document 1 or 2). Further, H5N1 influenza virus strains against which oseltamivir does not show any inhibitory activity (i.e., oseltamivir resistant virus strains) have been reported. Compounds which possess an inhibitory activity against these oseltamivir resistant H5N1 influenza virus strains are desired (Non-Patent Document 1 or 2).

Compounds represented by formula (I) are known to be useful as influenza therapeutics with neuraminidase inhibitory activity (Patent Documents 1 to 3). However, it has not been reported that these compounds have an inhibitory activity against H5N1 influenza virus. Further, the structures of the compounds represented by formula (I) resemble the structure of zanamivir but are completely different from the structure of oseltamivir.

Non-Patent Document 1: Nature, 2005, vol. 437, p. 1108

Non-Patent Document 2: N. Engl. J. Med., 2005, vol. 353, (25):2667-72
Patent Document 1: U.S. Pat. No. 6,340,702 (Japanese Patent No. 3209946)
Patent Document 2: U.S. Pat. No. 6,451,766 (Japanese Patent Publication No. Hei 10-109981)
Patent Document 3: U.S. Pat. No. 6,844,363 (Japanese Patent Publication No. 2002-012590)

Figure US20100204314A1-20100812-C00004

………………………

US20100204314

Preparation Example 1 5-Acetamido-4-guanidino-9-O-octanoyl-2,3,4,5-tetradeoxy-7-O-methyl-D-glycero-D-galacto-non-2-enopyranosoic acid

Figure US20100204314A1-20100812-C00005

(1) Diphenylmethyl 5-acetamido-4-(N,N-bis-t-butyloxycarbonyl)guanidino-9-O-octanoyl-2,3,4,5-tetradeoxy-7-O-methyl-D-glycero-D-galacto-non-2-enopyranosoate (3.46 g, 4.1 mmol) disclosed in Example 35 (i) of U.S. Pat. No. 6,340,702 (Japanese Patent No. 3209946) was dissolved in methylene chloride (27 ml) and trifluoroacetic acid (14 ml). The resultant solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, followed by three cycles of azeotropic distillation to dryness with toluene (5 ml). The resultant oily material was dissolved in ethyl acetate (10 ml). The solution was poured into a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The pH of the resultant solution was adjusted to 8.5 by addition of 20% aqueous solution of sodium carbonate. Then, the solution was stirred at room temperature for 3 hr and its pH was adjusted to 5.0 with hydrochloric acid (3 ml), followed by stirring at room temperature for another 1 hr. The solution was further stirred for 1 hr while ice-cooling. Subsequently, precipitating crystals were suction filtered and vacuum dried for 10 hr at an external temperature of 50° C. The resultant crystals were left in the air for one day to thereby yield the subject compound as a hydrate crystal (0.97 g; yield 51%).

Infrared Absorption Spectrum (KBr) ν max cm−1: 3412, 2929, 2856, 1676, 1401, 1320, 1285, 1205, 1137, 722.

1H Nuclear Magnetic Resonance Spectrum (400 MHz, CD3OD) δ ppm: 5.88 (1H, d, J=2.5 Hz), 4.45 (3H, m), 4.27 (1H, dd, J=10.0 Hz, 10.0 Hz), 4.15 (1H, m), 3.47 (21-1, m), 3.42 (3H, s), 2.37 (2H, t, J=7.4 Hz), 2.10 (3H, s), 1.31 (2H, m), 1.20-1.40 (8H, m), 0.85-0.95 (3H, m).

13C Nuclear Magnetic Resonance Spectrum (100 MHz, CD3OD) δ ppm: 176.5, 173.7, 164.7, 158.9, 146.7, 108.7, 80.1, 78.0, 69.3, 66.8, 61.4, 52.4, 35.1, 32.8, 30.2, 30.1, 26.0, 23.7, 22.8, 14.4.

(2) The subject compound was also obtained by the method described below.

5-Acetamido-4-guanidino-9-O-octanoyl-2,3,4,5-tetradeoxy-7-O-methyl-D-glycero-D-galacto-non-2-enopyranosoic acid trifluoroacetic acid salt (3.0 g, 5.1 mmol) disclosed in Example 35 (ii) of U.S. Pat. No. 6,340,702 (Japanese Patent No. 3209946) was subjected to reversed phase column chromatography [Cosmosil 75C 18PREP (nacalai tesque), 100 g] and eluted with methanol/water (0/1-1/1-2/1). Fractions containing the compound of interest were vacuum concentrated. The precipitating crystals were suction filtered and vacuum dried. The resultant crystals were left in the air for one day to thereby yield the subject compound as a hydrate crystal (1.2 g; yield 49%). The property data of the resultant compound were consistent with those of the compound obtained in (1) above.

Preparation Example 2 5-Acetamido-4-guanidino-2,3,4,5-tetradeoxy-7-O-methyl-D-glycero-D-galacto-non-2-enopyranosoic acid

Figure US20100204314A1-20100812-C00006

5-Acetamido-4-guanidino-2,3,4,5-tetradeoxy-7-O-methyl-D-glycero-D-galacto-non-2-enopyranosoic acid trifluoroacetic acid salt (3.0 g, 5.1 mmol) disclosed in Example 28 (viii) of U.S. Pat. No. 6,340,702 (Japanese Patent No. 3209946) was purified in an ion-exchange resin column [Dowex-50X; (i) water and (ii) 5% aqueous ammonium solution] and further purified by reversed phase column chromatography [Cosmosil 75C 18PREP (nacalai tesque); water]. Fractions containing the compound of interest were vacuum concentrated. The resultant solid was washed with methanol, filtered and dried to thereby yield the subject compound (1.43 g) as a colorless solid.

1H Nuclear Magnetic Resonance Spectrum (400 MHz, CD3OD) δ ppm: 5.64 (1H, d, J=2.0 Hz), 4.43 (2H, m), 4.22 (1H, dd, J=10.0 Hz, 10.0 Hz), 4.00 (1H, m), 3.85 (1H, dd, J=10.0 Hz, 2.4 Hz), 3.68 (1H, dd, J=10.0 Hz, 5.5 Hz), 3.58 (1H, m), 3.43 (3H, s).

………………………….

WO 2013089168

Figure JPOXMLDOC01-appb-C000008

Figure JPOXMLDOC01-appb-C000009

…………………………..

US8455659

Process W is known as a method for manufacturing a compound represented by the formula (Ia), which is embraced in a compound represented by the formula (I) or a pharmacologically acceptable salt thereof, (hereinafter also referred to as “compound (Ia)”; the same shall be applied with respect to other (Patent Document 1). In Process W, n-Hep represents a 1-heptyl group.

Figure US08455659-20130604-C00004
Figure US08455659-20130604-C00005

Process X is known as a method for manufacturing compound (Ib), which is embraced in compound (I) or a pharmacologically acceptable salt thereof (Patent Document 2). Compound (IVk) is a synthetic intermediate in Process W. In Process X, n-Hep represents a 1-heptyl group.

Figure US08455659-20130604-C00006

Process Y is known as a method for manufacturing compound (IIIa), which is a trifluoroacetic acid salt of compound (III) (Non-patent Document 1). The procedures from compound (IVc) to compound (IVe) and from compound (IVf) to compound (IVh) in Process Y are the same as in Process W.

Figure US08455659-20130604-C00007
Figure US08455659-20130604-C00008

Process Z is known as a method for manufacturing compound (IIIa), which is a trifluoroacetic acid salt of compound (III) (Non-patent Document 2). In Process Z, the procedure from compound (IVf) to compound (IVh) is the same as in Process W, and the procedure from compound (IVh) to compound (IIIa) is the same as in Process Y.

Figure US08455659-20130604-C00009
Figure US08455659-20130604-C00010

From the viewpoint of industrial production, the aforementioned Process W, Process Y, or Process Z could be improved in points such as the following:

Want to know everything on vir series

click

http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html

AND

http://medcheminternational.blogspot.in/p/vir-series-hep-c-virus.html

update…………


:ACIE 10.1002/anie.201408138

Scheme zanamivir and Lanimiwei is based on N- acetylneuraminic acid as a starting material, the price is more expensive (ca.13000RMB / kg). Ma recently from Shanghai Institute of Organic Chemistry greatly researcher on ACIE published zanamivir, Lanimiwei and CS-8958 is more simple synthetic route. References: ACIE 10.1002 / anie.201408138

Zosuquidar


LY335979(Zosuquidar)

LY335979, RS-33295-198  (Zosuquidar)

Roche Palo Alto (Originator)

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


LY335979 (Zosuquidar)

M.Wt: 636.99

Formula: C32H31F2N3O2.3HCl

Name: Zosuquidar trihydrochloride

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

CAS : 167465-36-3

167354-41-8 (free base)

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

US5654304WO1994024107A1WO2000075121US6570016

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

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

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

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

Zosuquidar

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

Figure imgf000004_0001

MS-073

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

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

Figure imgf000010_0001

Zosuquidar

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

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

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

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

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

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

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

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

Figure imgf000005_0001

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

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

……………………

 

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

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

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

Figure US06570016-20030527-C00002

Compound II is a mixture of syn isomer (III)

Figure US06570016-20030527-C00003

and anti isomer (IV)

Figure US06570016-20030527-C00004

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

Figure US06570016-20030527-C00005

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

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

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

Figure US06570016-20030527-C00018

Figure US06570016-20030527-C00019

EXAMPLES

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

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

Figure US06570016-20030527-C00022

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

mp 79-81° C.;

[α]25 D−36.4° (c 2.1, EtOH);

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

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

Figure US06570016-20030527-C00023

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

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

Figure US06570016-20030527-C00024

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

mp 149.6° C.

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

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

Figure US06570016-20030527-C00025

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

mp 230.1°-230.6° C.

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

Figure US06570016-20030527-C00026

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

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

Figure US06570016-20030527-C00027

A slurry of (1aα,6β,10bα)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-ol (3.0 g, 11.6 mmol, 1.0 equiv) in heptane (24 mL) was treated with 48% HBr (1.58 mL, 14.0 mmol, 1.2 equiv) and the reaction was heated at reflux with vigorous stirring for 2.5 hr. Solvent was then removed by atmospheric distillation (bp 95-98° C.) until approximately 9 mL of distillate was collected. The reaction was cooled and treated with EtOAc (15 mL), Na2SOand activated charcoal. The mixture was stirred at RT for 15 min and filtered through hyflo. The filter cake was washed with 50:50 EtOAc:heptane and the filtrate was concentrated in vacuo to provide the title product as a crystalline solid.

mp 119° C. (3.46 g corr., 93%);

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

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

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

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

Figure US06570016-20030527-C00028

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

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

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

Figure US06570016-20030527-C00029

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

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

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

Step 6a

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

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

………………………………………

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

REACTION SCHEME 1

Figure imgf000012_0001

FormuIa 1

Formula 1

Figure imgf000012_0002

Formula 2 Formula 2

Figure imgf000013_0001

Formula 3

Formula 3

Figure imgf000013_0002

Formula 4

Figure imgf000013_0003

Formula I

……………………………………….

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

Figure US06521755-20030218-C00028

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

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

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

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

…………………………………………..

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

Figure US06570016-20030527-C00019

Figure US06570016-20030527-C00023

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

……………….

Chemical Shift Data and Peak Assignments for the Crystal Forms.

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

Figure US07282585-20071016-C00001

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

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

Sprout Pharmaceuticals Appeals FDA Decision on NDA for Flibanserin to Treat Hypoactive Sexual Desire Disorder in Premenopausal Women


Flibanserin, girosa
167933-07-5
 cas no

147359-76-0 (monoHCl)

Flibanserin, BIMT-17-BS, BIMT-17
1 – [2 – [4 – [3 – (Trifluoromethyl) phenyl] piperazin-1-yl] ethyl] -2,3-dihydro-1H-benzimidazol-2-one
1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one
C20-H21-F3-N4-O, 390.412, Boehringer Ingelheim (Originator)
  • Bimt 17
  • BIMT 17 BS
  • Bimt-17
  • Flibanserin
  • Girosa
  • UNII-37JK4STR6Z
Boehringer Ingelheim (Originator)
Antidepressants, Disorders of Sexual Function and Reproduction, Treatment of, ENDOCRINE DRUGS, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Treatment of Female Sexual Dysfunction, 5-HT1A Receptor Agonists, 5-HT2A Antagonists
Patents
EP 526434, JP 94509575, US 5576318, WO 9303016.
 WO2010/128516 , US2007/265276
Papers
Pharmaceutical Research, 2002 ,  vol. 19,  3,   pg. 345 – 349
Naunyn-Schmiedeberg’s Archives of Pharmacology, 1995 ,  vol. 352, 3  pg. 283 – 290
Journal of Pharmaceutical and Biomedical Analysis, v.57, 2012 Jan 5, p.104(5)
FLIBANSERIN
…………………….

December 11, 2013 – Sprout Pharmaceuticals today announced that it has received and appealed the Food and Drug Administration’s (FDA) Complete Response Letter (CRL) for flibanserin through the Formal Dispute Resolution process.

Flibanserin is an investigational, once-daily treatment for Hypoactive Sexual Desire Disorder, or HSDD, in premenopausal women. HSDD is the most commonly reported form of female sexual dysfunction

read all here picture    animation

A new drug being developed by Boehringer Ingelheim could give a boost to the sex drive of women with low libido. The drug, known as flibanserin, has been shown in clinical trials to increase their sexual desire when taken once a day at bedtime.

The results from four pivotal Phase III clinical trials on women with hypoactive sexual desire disorder (HSDD) were presented this week at the European Society for Sexual Medicine’s congress in Lyon, France. The trials showed that participants taking flibanserin had a significant improvement in their sexual desire compared to those given a placebo. They also experienced less of the distress associated with sexual dysfunction.

The drug was initially being investigated as a treatment for depression, and acts on the serotonin receptors in the brain – it is both a 5-HT1A receptor agonist and a 5-HT2A receptor antagonist. It is also a partial agonist at the dopamine D4 receptor.

Neurotransmitters such as serotonin are believed to be involved in sexual function, and antidepressants are commonly associated with a loss of libido, so this was an obvious side-effect to look out for during clinical trials in depression. But far from suppressing the libido in women, it appeared to have the opposite effect, so trials in women with HSDD were initiated.

Hormone replacement can improve the libido of women who have had their ovaries removed, but there is no available drug to treat those who have not. There have been accusations that pharma companies invent new diseases like HSDD in order to sell more medicines, but according to Kathleen Segraves, an assistant professor at Case Western Reserve University in the US who has worked in the field of sexual functioning for many years, this is not the case here. HSDD is a very real disorder, she says, and the potential for a treatment for these women is very exciting.

Mona Lisa Painting animation

Flibanserin (code name BIMT-17; proposed trade name Girosa) is a drug that was investigated by Boehringer Ingelheim as a novel, non-hormonal treatment for pre-menopausal women with Hypoactive Sexual Desire Disorder (HSDD).[1][2] Development was terminated in October 2010 following a negative report by the U.S. Food and Drug Administration.[3]

HSDD is the most commonly reported female sexual complaint and characterized by a decrease in sexual desire that causes marked personal distress and/or personal difficulties. According to prevalence studies about 1 in 10 women reported low sexual desire with associated distress, which may be HSDD.[4] The neurobiological pathway of female sexual desire involves interactions among multiple neurotransmitters, sex hormones and various psychosocial factors. Sexual desire is modulated in distinct brain areas by a balance between inhibitory and excitatory neurotransmitters, serotonin acting as an inhibitor while dopamine and norepinephrine act as a stimulator of sexual desire.[5][6]Flibanserin is a 5-HT1A receptor agonist and 5-HT2A receptor antagonist that had initially been investigated as an antidepressant. Preclinical evidence suggested that flibanserin targets these receptors preferentially in selective brain areas and helps to restore a balance between these inhibitory and excitatory effects.[6] HSDD has been recognized as a distinct sexual function disorder for more than 30 years.

The proposed mechanism of action refers back to the Kinsey dual control model. Several sex steroids, neurotransmitters, and hormones have important excitatory or inhibitory effects on the sexual response. Among the neurotransmitters, the excitatory activity is driven by dopamine and norepinephrine, while the inhibitory activity is driven by serotonin. The balance between these systems is relevant for a healthy sexual response. By modulating these neurotransmitters in selective brain areas, flibanserin, a 5-HT1A receptoragonist and 5-HT2A receptor antagonist, is likely to restore the balance between these neurotransmitter systems.[6]

Several large pivotal Phase III studies with Flibanserin were conducted in the USA, Canada and Europe. They involved more than 5,000 pre-menopausal women with generalized acquired Hypoactive Sexual Desire Disorder (HSDD). The results of the Phase III North American Trials demonstrated that

Although the two North American trials that used the flibanserin 100 mg qhs dose showed a statistically significant difference between flibanserin and placebo for the endpoint of [satisfying sexual events], they both failed to demonstrate a statistically significant improvement on the co-primary endpoint of sexual desire. Therefore, neither study met the agreed-upon criteria for success in establishing the efficacy of flibanserin for the treatment of [Hypoactive Sexual Desire Disorder].

These data were first presented on November 16, 2009 at the congress of the European Society for Sexual Medicine in Lyon, France. The women receiving Flibanserin reported that the average number of times they had “satisfying sexual events” rose from 2.8 to 4.5 times a month. However, women receiving placebo reported also an increase of “satisfying sexual events” from 2.7 to 3.7 times a month.

Evaluation of the overall improvement of their condition and whether the benefit was meaningful to the women, showed a significantly higher rate of a meaningful benefit in the flibanserin-treated patient group versus the placebo group.The onset of the Flibanserin effect was seen from the first timepoint measured after 4 weeks of treatment and maintained throughout the treatment period.

The overall incidence of adverse events among women taking flibanserin was low, the majority of adverse events being mild to moderate and resolved during the treatment. The most commonly reported adverse events included dizziness, nausea, fatigue, somnolence and insomnia.

On June 18, 2010, a federal advisory panel to the U.S. Food and Drug Administration (FDA) unanimously voted against recommending approval of Flibanserin.

Earlier in the week, a FDA staff report also recommended non-approval of the drug. While the FDA still might approve Flibanserin, in the past, negative panel votes tended to cause the FDA not to approve.

On October 8, 2010, Boehringer Ingelheim announced that it would discontinue its development of flibanserin in light of the FDA advisory panel’s recommendation.

On June 27, 2013, Sprout Pharmaceuticals confirmed they had resubmitted flibanserin for FDA approval.

Flibanserin, chemically 1 -[2-(4-(3-trifluoromethylphenyl)piperazin-1 – yl)ethyl]-2,3-dihydro-1 H-benzimidazole-2-one was disclosed in form of its hydrochloride in European Patent No. 526,434 (‘434) and has the following chemical structure:

Figure imgf000002_0001

Process for preparation of flibanserin were disclosed in European Patent No. ‘434, U.S. Application Publication No. 2007/0032655 and Drugs of the future 1998, 23(1): 9-16.

According to European Patent No. ‘434 flibanserin is prepared by condensing 1-(2-chloroethyl)-2,3-dihydro-1 H-benzimidazol-one with m- trifluoromethyl phenyl piperazine. According to U.S. Application Publication No. 2007/0032655 flibanserin is prepared by condensing 1-[(3-trifluoromethyl)phenyl]-4-(2- chloroethyl)piperazine with 1 -(2-propenyl)-1 ,3-dihydro-benzimidazol-2H-one.

According to Drugs of the future 1998, 23(1): 9-16 flibanserin is prepared by reacting 1-(2-chloroethyl)-2,3-dihydro-1 H-benzimidazol-one with m- trifluoromethylphenylpiperazine.

…………………

EP0526434A1

1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one

Compound 3

  • Hydrochloride salt (isopropanol) M.p. 230-231°C

Analysis

  • Figure imgb0022

    ¹H NMR (DMSO-d₆/CDCL₃ 5:2) 11.09 (b, 1H), 11.04 (s, 1H), 7.5-6.9 (8H), 4.36 (t, 2H), 4.1-3.1 (10H)

…………………………………

 drawing   animation

The compound 1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1 H- benzimidazol-2-one (flibanserin) is disclosed in form of its hydrochlorid in European Patent Application EP-A-526434 and has the following chemical structure:

Figure imgf000003_0001

Flibanserin shows affinity for the 5-HTιA and 5-HT2-receptor. It is therefore a promising therapeutic agent for the treatment of a variety of diseases, for instance depression, schizophrenia, Parkinson, anxiety, sleep disturbances, sexual and mental disorders and age associated memory impairment.

EXAMPLE……… EP1518858A1

375 kg of 1-[(3-trifluoromethyl)phenyl]-4-(2-cloroethyl)piperazin are charged in a reactor with 2500 kg of water and 200 kg of aqueous Sodium Hydroxide 45%. Under stirring 169.2 kg of 1-(2-propenyl)-1,3-dihydro-benzimidazol-2H-one, 780 kg of isopropanol, 2000 kg of water and 220 kg of aqueous Sodium Hydroxide 45% are added. The reaction mixture is heated to 75-85° C. and 160 kg of concentrated hydrochloric acid and 200 kg of water are added.

The reaction mixture is stirred at constant temperature for about 45 minutes. After distillation of a mixture of water and Isopropanol (about 3000 kg) the remaining residue is cooled to about 65-75° C. and the pH is adjusted to 6.5-7.5 by addition of 125 kg of aqueous Sodium Hydroxide 45%. After cooling to a temperature of 45-50° C., the pH value is adjusted to 8-9 by addition of about 4 kg of aqueous Sodium Hydroxide 45%. Subsequently the mixture is cooled to 30-35° C. and centrifuged. The residue thus obtained is washed with 340 l of water and 126 l of isopropanol and then with water until chlorides elimination.

The wet product is dried under vacuum at a temperature of about 45-55° C. which leads to 358 kg of crude flibanserin polymorph A. The crude product thus obtained is loaded in a reactor with 1750 kg of Acetone and the resulting mixture is heated under stirring until reflux. The obtained solution is filtered and the filtrate is concentrated by distillation. The temperature is maintained for about 1 hour 0-5° C., then the precipitate solid is isolated by filtration and dried at 55° C. for at least 12 hours.

The final yield is 280 kg of pure flibanserin polymorph A.

………………………….

Flibanserin may be prepared by reacting 1-(phenylvinyl)-2,3-dihydro-1H-benzimidazol-2-one (I) with 1,2-dichloroethane (II) in the presence of NaH in warm dimethylformamide. The resulting 1-(2-chloroethyl)-2,3-dihydro-1H-benzimidazol-one (III) is in turn coupled with commercially available m-trifluoromethylphenylpiperazine hydrochloride (IV) in the presence of sodium carbonate and catalytic potassium iodide in refluxing ethanol. The crude flibanserin hydrochloride (V) is then dissolved in aqueous ethanol and the pure base is precipitated upon addition of sodium hydroxide.

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1-(1-phenylvinyl)-1,3-dihydro-2H-benzimidazol-2-one (I)
1,2-dichloroethane (II)
1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazol-2-one (III)
1-[3-(trifluoromethyl)phenyl]piperazine; N-[3-(trifluoromethyl)phenyl]piperazine (IV)
1-(2-[4-[3-(trifluoromethyl)phenyl]piperazino]ethyl)-1,3-dihydro-2H-benzimidazol-2-one (V)

………………………..

WO2010128516A2

A process for the preparation of a compound of formula X or a salt thereof:
Figure imgf000026_0001
wherein R2 is hydrogen or an amino protecting group which comprises reacting the compound of formula VII
Figure imgf000026_0002

wherein R2 is as defined in formula X; with a compound of formula Xl:

Figure imgf000026_0003

According to another aspect of the present invention there is provided a novel compound or a salt thereof selected from the compounds of formula I, IV and VII:

Figure imgf000014_0001
Figure imgf000014_0002

Wherein R is hydrogen or an amino protecting group.

Preferable the amino protecting groups are selected from butyl, 1 ,1- diphenylmethyl, methoxymethyl, benzyloxymethyl, trichloroethoxymethyl, pyrrolidinomethyl, cyanomethyl, pivaloyloxymethyl, allyl, 2-propenyl, t- butyldimethylsilyl, methoxy, thiomethyl, phenylvinyl, 4-methoxyphenyl, benzyl, A- methoxybenzyl, 2,4-dimethoxybenzyl, 2-nitrobenzyl, t-butoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, 4-chlorophenoxycarbonyl, A- nitrophenoxycarbonyl, methoxycarbonyl and ethoxycarbonyl. Still more preferable protecting groups are selected from t- butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, phenylvinyl and 2-propenyl.

R1 is independently selected from chlorine, bromine, iodine, methanesulphonate, trifluoromethanesulphonate, paratoluenesulphonate or benzenesulphonate. Preferable R1 is independently selected from chlorine, bromine or iodine and more preferable R1 is chlorine.

Wherein R2 is hydrogen or an amino protecting group.

The amino protecting group may be any of the groups commonly used to protect the amino function such as alkyl, substituted alkyl, hetero substituted alkyl, substituted or unsubstituted unsaturated alkyl, alkyl substituted hetero atoms, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, alkyoxy carbonyl groups and aryloxy carbonyl groups.

Preferable the amino protecting groups are selected from butyl, 1 ,1 – diphenylmethyl, methoxymethyl, benzyloxymethyl, trichloroethoxymethyl, pyrrolidinomethyl, cyanomethyl, pivaloyloxymethyl, allyl, 2-propenyl, t- butyldimethylsilyl, methoxy, thiomethyl, phenylvinyl, 4-methoxyphenyl, benzyl, A- methoxybenzyl, 2,4-dimethoxybenzyl, 2-nitrobenzyl, t-butoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, 4-chlorophenoxycarbonyl, A- nitrophenoxycarbonyl, methoxycarbonyl and ethoxycarbonyl. Still more preferable protecting groups are selected from t- butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, phenylvinyl and 2-propenyl. The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope and spirit of the invention.

EXAMPLES Example 1

A mixture of sodium hydroxide (47 gm) and i-(α-methylvinyl) benzimidazol-2-one (100 gm) in dimethylformamide (400 ml) was .stirred for 1 hour at room temperature. Dibromoethane (217 gm) was slowly added to the mixture and stirred at 1 hour 30 minutes. The resulting solution after addition water (500 ml) was extracted with ethyl acetate. The combined ethyl acetate extract washed with water. After drying the solvent was removed under vacuum to yield 132 gm of 1 ,3-dihydro-1-(2-bromoethyl)-3-isopropenyl-2H-benzimidazol- 2-one as a yellow oily liquid.

Example 2 A mixture of 1 ,3-dihydro-1-(2-bromoethyl)-3-isopropenyl-2H- benzimidazol-2-one (100 gm), diethanolamine (175 ml), sodium carbonate (40 gm) and potassium iodide (10 gm) was heated to 90 to 95 deg C and stirred for 2 hours. The reaction mass was cooled to room temperature and added water (500 ml). The resulting mixture extracted into ethyl acetate and the organic layer washed with water. After drying the solvent was removed under vacuum to yield 105 gm of 1 ,3-dihydro-1-[2-[N-bis-(2-hydroxyethyl)amino]ethyl]-3-isopropenyl- 2H-benzimidazol-2-one as a thick yellow oily liquid.

Example 3

To the mixture of 1 ,3-dihydro-1-[2-[N-bis-(2-hydroxyethyl)amino]ethyl]-3- isopropenyl-2H-benzimidazol-2-one (100 gm) obtained as in example 2 and chloroform (300 ml), thionyl chloride (95 ml) was slowly added. The mixture was heated to reflux and stirred for 2 hours. The excess thionyl chloride and chloroform was distilled off to yield 98 gm of 1 ,3-dihydro-1-[2-[N-[bis-(2- chloroethyl)amino]ethyl]-3-isopropenyl-2H-benzimidazol-2-one as a brown coloured sticky residue.

Example 4

1 ,3-dihydro-1-[2-[N-[bis-(2-chloroethyl)amino]ethyl]-3-isopropenyl-2H- benzimidazol-2-one (98 gm) obtained as in example 3 was added to water (500 ml) and concentrated hydrochloric acid (200 ml) mixture. The mixture was heated to 60 to 65 deg C and stirred for 1 hour. The contents of the flask cooled to room temperature and pH of the solution adjusted to 9 – 10 with 10% sodium hydroxide solution. The resulting solution extracted with ethyl acetate and washed the organic layer with water. Evaporate the solvent under reduced pressure to yield 82 gm of 1 ,3-dihydro-1-[2-[N-bis-(2-chloroethyl)amino]ethyl]- 2H-benzimidazol-2-one as a dark brown coloured oily liquid

Example 5

A mixture of 1 ,3-dihydro-1-[2-[N-bis-(2-chloroethyl)amino]ethyl]-1,2-H- benzimidazol-2-one (82 gm) obtained as in example 4, xylene (300 ml) and m- trifluoromethyl aniline (58 gm) was refluxed for 64 hours. The reaction mass was cooled to room temperature and filtered to obtain 1-[2-(4-(3- thfluoromethylphenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1 H-benzimidazole-2-one hydrochloride (Flibanserin hydrochloride) as a light brown coloured solid.

The crude flibanserin hydrochloride was purified in isopropyl alcohol to give 85 gm of pure flibanserin hydrochloride as off white solid.

Example 6

Piperazine (12 gm), toluene(60 ml) and tetra butyl ammonium bromide (1 gm) mixture was heated to 60 deg C, added 1 ,3-dihydro-1-(2-bromoethyl)-3- isopropenyl-2H-benzimidazol-2-one (10 gm) and stirred for 4 hours at 90 to 95 deg C. The mixture was cooled to 60 deg C and added water (50 ml). The separated toluene layer distilled under vacuum to give 8.5 gm of 1 ,3-dihydro-1- (2-piperazinyl)ethyl-3-isopropenyl-2H-benzimidazol-2-one as a white solid.

Example 7

To the mixture of concentrated hydrochloric acid (20 ml) and water (100 ml) was added 1 ,3-dihydro-1-(2-piperazinylethyl)-3-isopropenyl-2H- benzimidazol-2-one (10 gm) obtained as in example 6 and heated to 60 to 65 deg C 1 hour. The mixture was cooled to room temperature and pH of the solution was adjusted to 9 – 10 with 10% sodium hydroxide solution, extracted with ethyl acetate and the organic layer was washed with water. After drying the solvent was removed under vacuum to yield 8.5 gm of 1 ,3-dihydro-1-(2- piperazinyl ethyl)-2H-benzimidazol-2-one as a white solid.

Example 8

3-trifluoromethylaniline (40 gm) and hydrobromic acid (85 ml; 48- 50%w/w) mixture was cooled to 0 to 5 deg C. To this mixture added sodium nitrite solution (18.5 gm in 25 ml of water) at 5 to 10 deg C and copper powder (1 gm). The temperature was slowly raised to 50 to 55 deg C and stirred for 30 minutes. Added water (200 ml) to reaction mass and applied steam distillation, collected m-trifluoromethylbromobenzene as oily liquid. The oily liquid washed with sulfuric acid for two times (2 X 10 ml) followed by washed with water (2 X 20 ml) and dried the liquid with sodium sulphate to give 22 gm of m- trifluoromethylbromobenzene.

Example 9

To a mixture of 1 ,3-dihydro-1-(2-piperazinyl ethyl)-2H-benzimidazol-2- one (10 gm) obtained as in example 7, m-trifluoromethylbromobenzene (9 gm) obtained as in example 8, sodium tert-butoxide (5.5 gm), palladium acetate (4.5 mg) and xylene (80 ml) was added tri-tert.-butylphosphine (0.2 ml). The mixture was heated to 120 deg C and stirred for 3 hours. The reaction mass was cooled, added water (100 ml) and extracted with ethyl acetate and the organic layer was washed with water. After drying the solvent was removed under vacuum to yield

10 gm of 1-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1 H- benzimidazole-2-one (Flibanserin).

Example 10

To a mixture of 1 ,3-dihydro-1-[2-[N-bis-(2-hydroxyethyl)amino]ethyl]-3- isopropenyl-2H-benzimidazol-2-one (100 gm) obtained as in example 3, cyclohexane (400 ml) and sodium carbonate (35 gm) was added benzene sulfonyl chloride (116 gm) at room temperature. The mixture was heated to 80 to

85 deg C and stirred for 8 hours . The contents were cooled to room temperature and added water (500 ml). Distilled the organic layer to give 182 gm of 1 ,3-dihydro-1-[2-[N-[bis-(2-benzenesulfonyloxy)- ethyl]amino]ethyl]-3- isopropenyl- 2H-benzimidazol-2-one.

Example 11

1 ,3-dihydro-1 -[2-[N-[bis-(2-benzenesulfonyloxy)- ethyl]amino]ethyl]-3- isopropenyl- 2H-benzitηidazol-2-one (100 gm) obtained as in example 10, dimethylformamide (500 ml) and sodium corbonate (18 gm) was mixed and heated to 70 deg C. To the mixture was added m-trifluoromethyl aniline (27 gm) and heated to 80 to 85 deg C, stirred for 5 hours. The reaction mass was cooled and added water (2000 ml), filtered the solid to yield 1 ,3-dihydro-1-[2-[4-(3- trifluoromethylphenyl)piperazinyl]ethyl]-3-isopropenyl-2H benzimidazol-2-one. Example 12

1 ,3-dihydro-1-[2-[N-[bis-(2-benzenesulfonyloxy)- ethyl]amino]ethyl]-3- isopropenyl- 2H-benzimidazol-2-one (100 gm) obtained as in example 11 added to the mixture of water (500 ml) and concentrated hydrochloric acid (200 ml), heated to 65 deg C and stirred for 1 hour. The reaction mass was cooled to room temperature and pH adjusted to 10 to 10-5 with 10% sodium hydroxide solution. The resulting mixture was extracted with ethyl acetate and the organic

 layer was washed with water. After drying the solvent was removed under vacuum to yield 87 gm of 1-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]- 2,3-dihydro-1 H-benzimidazole -2-one (Flibanserin).

…………………..

Paper

Journal of Pharmaceutical and Biomedical Analysis, v.57, 2012 Jan 5, p.104(5)

Isolation and structural elucidation of flibanserin as an adulterant in a health supplement used for female sexual performance enhancement

Low, Min-Yong et al

http://www.sciencedirect.com/science/article/pii/S0731708511004833

Full-size image (5 K)

This proposed formula and structure was further confirmed by 1H and 13C NMR data which indicated the presence of 20 carbon atoms and 21 protons.

1H NMR

Inline image 6

13C NMR

Inline image 5

1D and 2DNMR data were used to assign the protons and carbon atoms.

Inline image 2

In the1H NMR spectrum , a sharp singlet at 10.00 ppm integrating for one
proton is a typical proton attached to nitrogen. HMBC correlated this proton to C-2, C-4, and C-9 suggesting that it was H-3.

Complex signals were observedbetween 7.00 to 7.31 ppm, integrating for eight protons. A triplet at 7.31 ppm,integrating for a proton has a coupling constant of 8.0 Hz. HMBC correlated thisproton with C-16, C-19, and C-21 suggesting that it was H-20.

A double-doubletsplitting pattern at chemical shift 7.11 ppm, integrating for a proton, has couplingconstants of 6.3 Hz and 1.6 Hz.

HMBC correlated this proton to C-6, C-7, and C-9 showing that it was H-8. Overlapped signals were observed from 7.04 ppm to7.10 ppm, integrating for five protons. A double-doublet splitting pattern at 7.01ppm with coupling constant 8.0 Hz and 2.0 Hz, integrating for a proton was
observed.

HMBC correlated this proton to C-17 suggesting that it was either H-19or H-21. Four triplet signals were also observed from 2.73 ppm to 4.08 ppm,integrating for a total of twelve protons.

Two of these triplet signals at 2.74 ppmand 3.22 ppm integrated for four protons each, suggesting overlapping signals ofmethylene protons. This was further confirmed by 13C and DEPT NMR.

13C and DEPT NMR data showed the signals of four methylene, eight methineand six quaternary carbon atoms. The DEPT signals at 53.1 ppm and 48.6 ppmhave intensities which were double of those from the rest of the methylene carbonsignals, suggesting two methylene carbon atoms each contributing to the signal at 53.1 ppm and 48.6 ppm.

DEPT

Inline image 4

HMQC results further indicated that these two methylene carbon signals at 53.1 ppm and 48.6 ppm were correlated to the protons signal at 2.73 ppm and 4.08 ppm respectively, which corresponded to four protons each. The finding confirmed overlapping methylene carbon signals (at 53.1 ppm and 48.6 ppm) and methylene proton signals (at 2.73 ppm and 4.08 ppm). Hence, the unknown compound has six methylene carbon atoms with a total of twelve methylene protons.

The chemical shifts of the twelve methylene protons suggested that they were attached to relatively electronegative atoms. It was speculated that the six methylene groups were attached to the nitrogen atoms and the electron withdrawing effect of these electronegative nitrogen atoms resulted in the deshielding of the protons. HMBC and COSY correlations were used to assign the rest of the protons

The 13C NMR data  showed that there were two quaternary carbon at
155.6 ppm and 151.3 ppm. The carbon with chemical shift 155.6 ppm was C-2. Inthe structure of imidazolone, carbonyl carbon C-2 was attached to two nitrogenatoms which helped to withdraw electrons from oxygen to C-2. Hence, C-2 wasless deshielded as compared to a normal carbonyl carbon which has chemical shiftabove 170 ppm.

Eight methine carbons and two quaternary carbons with chemicalshifts above 108 ppm suggested the presence of two aromatic rings. Thequaternary carbon with chemical shift 125.4 ppm was C-22 which was attached tothree fluorine atoms. Due to the strong electron withdrawing effect of the fluorineatoms, C-22 was highly deshielded and had a high chemical shift.

The IR spectrum of the isolated compound showed absorption bands of amide (νC=O 1685 cm-1, νN-H (stretch) 3180 cm-1, νN-H (bending) 1610 cm-1), alkyl fluoride (νC-F1077 cm-1, 1112 cm-1, 1158 cm-1), aromatic ring (ν Ar-H 3028 cm-1, 3078 cm-1 andνC=C 1401 cm-1, 1446 cm-1, 1453 cm-1, 1468 cm-1, 1487 cm-1) and alkane (νC-H2891 cm-1, 2930 cm-1 2948 cm-).

Inline image 1

COSY

Inline image 3

……………………………….

US5576318, 1996

1 H NMR (DMSO-d6 /CDCL3 5:2) 11.09 (b, 1H), 11.04 (s, 1H), 7.5-6.9 (SH), 4.36 (t, 2H), 4.1-3.1 (10 H)

,,,,,,,,,,,,,,,,,,

  1.  Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S (summer 2002). “Pharmacology of flibanserin”. CNS Drug Rev. 8 (2): 117–142. doi:10.1111/j.1527-3458.2002.tb00219.xPMID 12177684.
  2.  Jolly E, Clayton A, Thorp J, Lewis-D’Agostino D, Wunderlich G, Lesko L (April 2008). “Design of Phase III pivotal trials of flibanserin in female Hypoactive Sexual Desire Disorder (HSDD)”. Sexologies 17 (Suppl 1): S133–4. doi:10.1016/S1158-1360(08)72886-X.
  3.  Spiegel online: Pharmakonzern stoppt Lustpille für die Frau, 8 October 2010 (in German)
  4.  Nygaard I (November 2008). “Sexual dysfunction prevalence rates: marketing or real?”. Obstet Gynecol 112 (5): 968–9.doi:10.1097/01.AOG.0000335775.68187.b2PMID 18978094.
  5.  Clayton AH (July 2010). “The pathophysiology of hypoactive sexual desire disorder in women”Int J Gynaecol Obstet 110 (1): 7–11.doi:10.1016/j.ijgo.2010.02.014PMID 20434725.
  6.  Pfaus JG (June 2009). “Pathways of sexual desire”. J Sex Med 6 (6): 1506–33. doi:10.1111/j.1743-6109.2009.01309.x.PMID 19453889.
EP0200322A1 * Mar 18, 1986 Nov 5, 1986 H. Lundbeck A/S Heterocyclic compounds
BE904945A1 * Title not available
GB2023594A * Title not available
US3472854 * May 29, 1967 Oct 14, 1969 Sterling Drug Inc 1-((benzimidazolyl)-lower-alkyl)-4-substituted-piperazines
US4954503 * Sep 11, 1989 Sep 4, 1990 Hoechst-Roussel Pharmaceuticals, Inc. 3-(1-substituted-4-piperazinyl)-1H-indazoles

Rilpivirine


Rilpivirine

500287-72-9  cas no

4-{[4-({4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile

Rilpivirine (TMC278, trade name Edurant) is a pharmaceutical drug, developed byTibotec, for the treatment of HIV infection.[1][2] It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reducedside-effect profile compared with older NNRTIs, such as efavirenz.[3][4]

Rilpivirine entered phase III clinical trials in April 2008,[5][6] and was approved for use in the United States in May 2011.[7] A fixed-dose drug combining rilpivirine with emtricitabine andtenofovir, was approved by the U.S. Food and Drug Administration in August 2011 under the brand name Complera.[8]

Like etravirine, a second-generation NNRTI approved in 2008, rilpivirine is a diarylpyrimidine(DAPY). Rilpivirine in combination with emtricitabine and tenofovir has been shown to have higher rates of virologic failure than Atripla in patients with baseline HIV viral loads greater than 100,000 copies.

  1.  “TMC278 – A new NNRTI”. Tibotec. Retrieved 2010-03-07.
  2.  Stellbrink HJ (2007). “Antiviral drugs in the treatment of AIDS: what is in the pipeline ?”.Eur. J. Med. Res. 12 (9): 483–95. PMID 17933730.
  3.  Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, de Béthune MP, Peeters M, Woodfall B (2006). “Short-term antiviral activity of TMC278–a novel NNRTI–in treatment-naive HIV-1-infected subjects”AIDS 20 (13): 1721–6.doi:10.1097/01.aids.0000242818.65215.bdPMID 16931936.
  4.  Pozniak A, Morales-Ramirez J, Mohap L et al. 48-Week Primary Analysis of Trial TMC278-C204: TMC278 Demonstrates Potent and Sustained Efficacy in ART-naïve Patients. Oral abstract 144LB.
  5.  ClinicalTrials.gov A Clinical Trial in Treatment naïve HIV-1 Patients Comparing TMC278 to Efavirenz in Combination With Tenofovir + Emtricitabine
  6.  ClinicalTrials.gov A Clinical Trial in Treatment naïve HIV-Subjects Patients Comparing TMC278 to Efavirenz in Combination With 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
  7.  “FDA approves new HIV treatment”. FDA. Retrieved 2011-05-20.
  8.  “Approval of Complera: emtricitabine/rilpivirine/tenofovir DF fixed dose combination”. FDA. August 10, 2011.

FORMULATION

EDURANT (rilpivirine, Janssen Therapeutics) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). EDURANT is available as a white to off-white, film-coated, round, biconvex, 6.4 mm tablet for oral administration. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine.

The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C22H18N6 • HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:

EDURANT (rilpivirine) Structural Formula Illustration

Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range.

Each EDURANT tablet also contains the inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin.

…………………………….

papers

Sun, et al.: J. Med. Chem., 41, 4648 (1998),

Kashiwada, et al.: Bioorg. Med. Chem. Lett., 11, 183 (2001)

Journal of Medicinal Chemistry, 2005 ,  vol. 48,  6  , pg. 2072 – 2079

………………………………………………

patents

WO201356003, WO200635067,

WO2013038425 

The following PCT Publications describe the synthesis of Rilpivirine:

WO03016306, WO2005021001, WO2006024667, WO2006024668, W02994916581, WO2009007441, WO2006125809, and WO2005123662. [0006] Crystalline Rilpivirine base Forms I and II are described in the US Patent

Publication: US2010189796. Crystalline Rilpivirine HC1, Forms A, B, C, and D, are described in the US Patent Publications: US2009/012108, and US2011/0008434. Rilpivirine fumarate and a synthesis thereof are disclosed in WO2006024667.

country……………….patent……………approved……………expiry

United States 6838464 2011-05-20 2021-02-26
United States 7067522 2011-05-20 2019-12-20
United States 7125879 2011-05-20 2014-04-14
United States 7638522 2011-05-20 2014-04-14
United States 8080551 2011-05-20 2023-04-11
United States 8101629 2011-05-20 2022-08-09
Rilpivirine and its hydrochloride salt were disclosed in U.S. patent no. 7,125,879.Process for the preparation of rilpivirine was disclosed in U.S. patent no. 7,399,856 (‘856 patent). According to the ‘856 patent, rilpivirine can be prepared by reacting the (E)-3-(4-amino-3,5-dimethylphenyI)acrylonitrile hydrochloride of formula II with 4-(4-chloropyrimidin-2-ylamino)benzonitrile of formula III-a in the presence of potassium carbonate and acetonitrile under reflux for 69 hours. The synthetic procedure is illustrated in scheme I, below:

Figure imgf000003_0001

Scheme 1 Process for the preparation of rilpivirine was disclosed in U.S. patent no.

7,705,148 (Ί48 patent). According to the Ί48 patent, rilpivirine can be prepared by reacting the 4-[[4-[[4-bromo-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile with acrylonitrile in the presence of palladium acetate, Ν,Ν-diethylethanamine and tris(2-methylphenyl)phosphine in acetonitrile. According to the Ί48 patent, rilpivirine can be prepared by reacting the compound of formula IV with 4-(4-chloropyrimidin-2-ylamino)benzonitrile formula Ill-a in the presence of hydrochloric acid and n-propanol to obtain a compound of formula Vll, and then the compound was treated with acetonitrile and potassium carbonate under reflux for 69 hours. The synthetic procedure is illustrated in scheme II, below:

Figure imgf000004_0001

Rilpivirine

Scheme II

U.S. patent no. 7,563,922 disclosed a process for the preparation of (E)-3-(4- amino-3,5-dimethylphenyl)acrylonitrile hydrochloride. According to the patent, (E)-3-(4- amino-3,5-dimethylphenyl)acrylonitrile hydrochloride can be prepared by reacting the 4- iodo-2,6-dimethyl-benzenamine in Ν,Ν-dimethylacetamide with acrylonitrile in the presence of sodium acetate and toluene, and then the solid thus obtained was reacted with hydrochloric acid in 2-propanol in the presence of ethanol and diisopropyl ether.

U.S. patent no. 7,956,063 described a polymorphic Form A, Form B, Form C and Form D of rilpivirine hydrochloride.

An unpublished application, IN 1415/CHE/201 1 assigned to Hetero Research

Foundation discloses a process for the preparation of rilpivirine. According to the application, rilpivirine can be prepared by reacting the 4-(4-chloropyrimidin-2- ylamino)benzonitrile with (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride in the presence of p-toluene sulfonic acid monohydrate and 1 ,4-dioxane. It has been found that the rilpivirine produced according to the prior art procedures results in low yields.

 

The synthesis is as follows:

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Rilpivirine, which is chemically known as 4-{[4-({4-[(lE)-2-cyanoethenyl]-2,6- dimethylphenyl} amino) pyrimidin-2-yl]amino}benzonitrile, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and exhibits human immunodeficiency virus (HIV) replication inhibiting properties. Rilpivirine is used as its hydrochloride salt in the anti-HIV formulations.

Figure imgf000002_0001

Conventionally, various processes followed for the synthesis of Rilpivirine hydrochloride (I), generally involve preparation of the key intermediate, (E)-4-(2- cyanoemenyl)-2,6-dimethylphenylamine hydrochloride of formula (II).

Figure imgf000003_0001

(E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II)

WO 03/016306 first disclosed the synthesis of Rilpivirine involving different routes for synthesis of 4-(2-cyanoethenyl)-2,6-dimethylphenylamine. The first route involved protection of the amino group of 4-bromo-2,6-dimemylphenylarnine by converting to Ν,Ν-dimethylmethanimidamide, followed by formylation involving n- butyl lithium and dimethylformamide. The resulting formyl derivative was treated with diethyl(cyanomethyl) phosphonate to give the cyanoethenyl compound which was deprotected using zinc chloride to yield the cyanoethenylphenylamine intermediate having an undisclosed E/Z ratio. This route involved an elaborate sequence of synthesis comprising protection of amine by its conversion into imide, use of a highly moisture sensitive and pyrophoric base such as butyl lithium and a low yielding formylation reaction. All these factors made the process highly unviable on industrial scale.

The second route disclosed in WO 03/016306 employed 4-iodo-2,6- dimethylphenylamine as a starting material for synthesis of cyanoemenylphenylamine intermediate, which involved reaction of the dimethylphenylamine derivative with acrylonitrile for atleast 12 hours at 130 C in presence of sodium acetate and a heterogeneous catalyst such as palladium on carbon. Isolation of the desired compound involved solvent treatment with multiple solvents followed by evaporation. This route also does not give any details of the E/Z ratio of the unsaturated intermediate product. Although this route avoids use of phosphine ligands but lengthy reaction time and problem of availability of pure halo-phenylamine derivatives coupled with moderate yields hampers the commercial usefulness of this route.

The third route disclosed in WO 03/016306 involved reaction of 4-bromo-2,6- dimethylphenylamine with acrylamide in presence of palladium acetate, tris(2- methylphenyl)phosphine and N,N-diethylethanamine. The resulting amide was dehydrated using phosphoryl chloride to give 4-(2-cyanoethenyi)-2,6- dimethylphenylamine in a moderate yield of 67% without mentioning the E/Z ratio. Although the E/Z isomer ratio for the cyanoethenyl derivative obtained from these routes is not specifically disclosed in the patent, however, reproducibility of the abovementioned reactions were found to provide an E/Z ratio between 70/30 and 80/20. Various other methods have also been reported in the literature for introduction of the ‘ cyanoethenyl group in Rilpivirine. The Journal of Medicinal Chemistry (2005), 48, 2072-79 discloses Wittig or Wadsworth-Emmons reaction of the corresponding aldehyde with cyanomethyl triphenylphosphonium chloride to provide a product having an E/Z isomer ratio of 80/20. An alternate method of Heck reaction comprising reaction of aryl bromide with acrylonitrile in presence of tri-o- tolylphosphine and palladium acetate gave the same compound with a higher E/Z isomer ratio of 90/10. The method required further purification in view of the presence of a significant proportion of the Z isomer in the unsaturated intermediate. A similar method was disclosed in Organic Process Research and Development (2008), 12, 530-536. However, the E/Z ratio of 4-(2-cyanoethenyl)-2,6- dimethylphenylamine was found to be 80/20, which was found to improve to 98/2 (E/Z) after the compound was converted to its hydrochloride salt utilizing ethanol and isopropanol mixture.

It would be evident from the foregoing that prior art methods are associated with the following drawbacks:

a) High proportion of Z isomer, which requires elaborate purification by utilizing column chromatographic techniques, crystallization, or successive treatment with multiple solvents, which decreases the overall yield,

b) Introduction of cyanoethenyl group to the formylated benzenamine derivatives involves a moisture sensitive reagent like n-butyl lithium, which is not preferred on industrial scale. Further, the method utilizes cyanomethyl phosphonate esters and is silent about the proportion of the Z isomer and the higher percentage of impurities which requires elaborate purification and ultimately lowers the yield,

c) Prior art routes involve use of phosphine ligands which are expensive, environmentally toxic for large scale operations,

d) Prior art methods utilize phase transfer catalysts such as tetrabutyl ammonium bromide in stoichiometric amounts and the reactions are carried out at very high temperatures of upto 140-150°C.

Thus, there is a need to develop an improved, convenient and cost effective process for preparation of (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride of formula (II) having Z-isomer less than 0.5%, without involving any purification and does not involve use of phosphine reagent and which subsequently provides Rilpivirine hydrochloride (I) conforming to regulatory specifications.

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http://www.google.com/patents/EP2643294A2?cl=en

The present inventors have developed a process for stereoselective synthesis of the key Rilpivirine intermediate, (E)-4-(2-cyanoethenyl)-2,6-dimemylphenylarnine hydrochloride (II), comprising diazotization of 2,6-dimethyl-4-amino-l- carboxybenzyl phenylamine followed by treatment with alkali tetrafluoroborate to provide the tetrafluoroborate salt of the diazonium ion which is followed by reaction with acrylonitrile in presence of palladium (II) acetate and subsequent deprotection of the amino group with an acid followed by treatment with hydrochloric acid to give the desired E isomer of compound (II) having Z isomer content less than 0.5% and with a yield of 75-80%. The compound (II) was subsequently converted to Rilpivirine hydrochloride of formula (I) with Z isomer content less than 0.1%.

Figure imgf000008_0001

Figure imgf000008_0002

Figure imgf000011_0001

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Figure

Chemical structures of selected NNRTIs

 

 

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http://pubs.acs.org/doi/full/10.1021/jm040840e

J. Med. Chem., 2005, 48 (6), pp 1901–1909
DOI: 10.1021/jm040840e
R278474, rilpivirine is the E-isomer of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, which can be synthesized in six high-yield reaction steps.60 The end product contains minimal amounts (less than 0.5%) of the Z-isomer.
R278474 is a slightly yellow crystalline powder with molecular mass of 366.4 Da and a melting point of 242 °C. It is practically insoluble in water (20 ng/mL at pH 7.0), moderately soluble in poly(ethylene glycol) (PEG 400, 40 mg/mL), and readily soluble in dimethyl sulfoxide (>50 mg/mL). The compound is ionizable in aqueous solution (pKa = 5.6) and is very lipophilic (log P = 4.8 at pH 8.0). For comparison, the pKa value for TMC120 is 5.8 and the corresponding log P value amounts to 5.3.
Under daylight and in weak acid solution a conversion of 8% of the E-isomer of R278474 into the Z-isomer has been observed.
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