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APREMILAST, … ORALLY ACTIVE PDE4 INHIBITOR

January 8, 2014 8:11 am / 4 Comments on 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.

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

Apremilast
CC 10004
CC-10004
CC10004
UNII-UP7QBP99PN
CLINICAL TRIALS….http://clinicaltrials.gov/search/intervention=Apremilast+OR+CC-10004

Apremilast is an orally available small molecule inhibitor of PDE4 being developed byCelgene for ankylosing spondylitis, psoriasis, 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

“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.
“US HOT STOCKS: OCZ, VeriFone, Men’s Wearhouse, AK Steel, Celgene”. The Wall Street Journal. 6 September 2012. Retrieved 2012-09-06.
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.
Therapeutics: Silencing psoriasis.Crow JM.Nature. 2012 Dec 20;492(7429):S58-9. doi: 10.1038/492S58a. No abstract available.
NMR…http://file.selleckchem.com/downloads/nmr/S803401-Apremilast-HNMR-Selleck.pdf
WO 2003080049
WO 2013126495
WO 2013126360
WO 2003080049
WO 2006065814
US2003/187052 A1 …..MP 144 DEG CENT
US2007/155791
J. Med. Chem., 2008, 51 (18), pp 5471–5489

DOI: 10.1021/jm800582j
J. Med. Chem., 2011, 54 (9), pp 3331–3347

DOI: 10.1021/jm200070e

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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.

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.

CH₂CI₂, NaOH

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.

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SYNTHESIS OF KEY INTERMEDIATE

WO2013126495A2

Example 1

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

[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

[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

[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.

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APREMILAST

GENERAL SYNTHESIS AND SYNTHESIS OF APREMILAST

WO2012083153A1

(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).

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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)

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

^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

US8242310	8-15-2012	PROCESSES FOR THE PREPARATION OF AMINOSULFONE COMPOUNDS
US2011269753	11-4-2011	HETEROCYCLIC COMPOUNDS AS PHOSPHODIESTERASE INHIBITORS
US2011124702	5-27-2011	Nanosuspension of a Poorly Soluble Drug via Microfluidization Process
US2010129363	5-28-2010	METHODS AND COMPOSITIONS USING PDE4 INHIBITORS FOR THE TREATMENT AND MANAGEMENT OF CANCERS

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

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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

need help, email or call me

amcrasto@gmail.com

MOBILE-+91 9323115463

web link

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

I was paralysed in dec2007, 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.

January 8, 2014 5:14 am / Leave a comment

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

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

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:10.1177/1756283X11436318. PMC 3342570. PMID 22570676.
US 2013157954
WO 2006050244
WO 2005021022
US 6586399
WO 2002066062
US 6297214
US 2001021767
WO 2001041779
WO 1999058144
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.

………..

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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

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

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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

need help, email or call me

amcrasto@gmail.com

MOBILE-+91 9323115463

web link

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

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

CASOPITANT

January 7, 2014 10:23 am / 1 Comment on CASOPITANT

CASOPITANT

READ ALL AT

http://worlddrugtracker.blogspot.in/2014/01/casopitant.html

AZASETRON..a selective 5-HT3 receptor antagonist

January 7, 2014 10:07 am / 5 Comments on AZASETRON..a selective 5-HT3 receptor antagonist

AZASETRON, NAZASETRON

N-(1-azabicyclo[2.2.2]octan-8-yl)-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide

6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide

123039-99-6 , 123040-69-7 (free base)

141922-90-9 HYD SALT

Y-25130 (hydrochloride)LAUNCHED 1994 AS HCL SALT FORM SEROTONE

a selective 5-HT3 receptor antagonist , ANTIEMETIC

UNII-77HC7URR9Z

Mitsubishi Tanabe Pharma, JAPAN TOBACCO (Originator)

FOR..Nausea and Vomiting, Treatment of
Prokinetic Agents

Azasetron is an antiemetic which acts as a 5-HT₃ receptor antagonist.

Chemical and Pharmaceutical Bulletin, 1992 , vol. 40, 3 p. 624 – 630, ENTRY 15 , MP 305 OF HCL SALT

Biological and Pharmaceutical Bulletin, 2006 , vol. 29, 9 p. 1931 – 1935, AS MERCK 903

US 4892872…

CN 101786963…

WO 1996001630..

WO 2006006595..

WO 2007134077..

CN 102526740, CN 102451166, US 4892872, JP 2008297277

US5773436 A1, WO2006/119295 A2, EP1336602 A1, US4892872 A1,

US2003/18008 A1, US2002/147197 A1, US4892872

AZASETRON

The nitration of 5-chloro-2-hydroxybenzoic acid methyl ester (I) with nitric acid in sulfuric acid gives 5-chloro-2-hydroxy-3-nitrobenzoic acid methyl ester (II), which is reduced with Fe and NH4Cl in water yielding 3-amino-5-chloro-2-hydroxybenzoic acid methyl ester (III). The cyclization of (III) with chloroacetyl chloride (IV) by means of NaHCO3 in CHCl3 – water affords 6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid methyl ester (V), which is methylated with methyl iodide and K2CO3 in DMF affording the corresponding 4-methyl derivative (VI). Hydrolysis of (VI) with ethanolic NaOH gives the corresponding acid (VII), which by treatment with refluxing SOCl2 is converted into its acyl chloride (VIII). Finally, this compound is condensed with 3-aminoquinuclidine (IX) by means of N-methylmorpholine (NMM) in CHCl3.

………………

SYNTHESIS

CN101786963B

Azasetron hydrochloride (Azasetron hydrochloride) is a secondary cancer drugs, mainly synthetic route is as follows

[0003]

[0004] In EP 0313393; JP 1989207290; JP 1990005415; US 4892872; Eur.Pat.Appl., 313393,, Chem pharm Bull, 1992,40 (3) :624-630 reported the synthesis of intermediates III is with ammonium chloride, iron as the reducing agent, the nitro substrate was dissolved in toluene and added dropwise to a reduction of the media inside, the study found that this approach has a number of disadvantages, notably the reaction can not be completely, while post-processing is very troublesome, purity of the product obtained is poor, and difficult purification. Although the “Chinese Medicinal Chemistry” magazine, 10 (2) ,138-140; 2000, the author hydrochloride instead of ammonium chloride, but still need the nitro group was dissolved in toluene was added dropwise, in fact, the nitro compound in toluene the solubility is limited, and in the process will precipitate dropwise addition, there are also incomplete reaction, impurities, and complicated post-treatment problems.

[0005] In the “China Pharmaceutical Industry” magazine 34 (3) ,214-215; 2003 in order to restore hydrosulfite as reductant,

Azasetron preparation of intermediates, the steps are as follows:

[0015] (I) A mixture of 3 – nitro-5 – chloro-salicylate added glacial acetic acid was stirred for 30-40 minutes, add water, temperature 30 ~ 100 ° C, adding iron powder, 2.5-3 hour plus finished, the addition was completed, at a temperature of 30 ~ 100 ° C the reaction for 5 to 10 hours; give 3 – amino-5-chloro-salicylate mixture;

[0016] The mass ratio of the added material is 3 – nitro-5 – chloro-salicylate: acetic acid: water: iron = 1: 5 ~ 10: 5 ~ 10: 0.5 ~ I;

[0017] (2) obtained in the step ⑴ added to a mixture of glacial acetic acid, glacial acetic acid added in the amount of step ⑴ same amount of glacial acetic acid, 70 ° C was stirred for 30-35 minutes, filtered through celite to remove the iron sludge to obtain filter cake; this procedure to that step (I) the resulting product was dissolved in glacial acetic acid solvent sufficient, in order to facilitate post-processing; while removing impurities.

[0018] (3) The filter cake was washed with an organic solvent, the combined filtrate and stirred for 10-15 minutes, allowed to stand for 30-35 minutes, the organic layer was separated; aqueous phase was extracted once again with an organic solvent, the combined organic solution was washed three times , mention made three – amino -5 chloro methyl salicylate (intermediate III) sulphate solution.

[0019] (4) of step (3) of 3 – amino-5-chloro-salicylate was added a saturated NaHCO3 solution, saturated NaHCO3 solution and the amount of acetic acid in step ⑴ same volume, cooling to _1 ° C ~ 0 ° C, control the temperature -1 ° C_5 ° C was added dropwise acetyl chloride, drop Bi. Reaction 2-3 hours. To give 3 – (2 – chloro-acetylamino)-5-chloro-mixed solution of methyl salicylate;

[0020] The amount of chloroacetyl chloride is added in step ⑴ source material 3 – nitro-5 – chloro molar ratio of methyl salicylate

I: 0.9-0.95.

[0021] (5) obtained in the step ⑷ 3 – (2 – chloro-acetylamino) methyl salicylate _5 chloride mixture was heated to 30-40 ° C, stirred for 1-1.5 hours; organic layer was separated, water phase extracted once again with an organic solvent, the combined organic layer was washed with water three times, separated and the organic layer is directly subjected to atmospheric distillation, the organic solvent is distilled off, distillation was complete, methanol or ethanol as the crystallization solvent, 80 ° C under stirring for 2.5 hours under reflux , to give 3 – (2 – chloro-acetylamino) _5 chlorine in alcohol solution of methyl salicylate. This step is intended to 3 – (2 – chloro-acetylamino)-5-chloro methyl salicylate purification.

[0022] (6) in the step (5) cooling to room temperature, an alcoholic solution, crystallization, centrifugation, and washed with ethanol crystal; 80 ° C drying in needle-like crystals 3 – (2 – chloro-acetylamino) _5 Chlorine methyl salicylate (intermediate IV).

……………………………………………………

USEFUL PATENTS

US5773436	6-31-1998	Use of serotonin antagonists for treating fibromyalgia
WO9744026	11-28-1997	COMPOSITIONS COMPRISING CONJUGATES OF CIS-DOCOSAHEXAENOIC ACID AND TAXOTERE
WO9744063	11-28-1997	DHA-PHARMACEUTICAL AGENT CONJUGATES DHA-PHARMACEUTICAL AGENT CONJUGATES
WO9744336	11-28-1997	CONJUGATES OF CIS-DOCOSAHEXAENOIC ACID AND PACLITAXEL
WO9710823	3-28-1997	5-HT3 RECEPTOR ANTAGONISTS FOR DYSKINESIA
US5603943	2-19-1997	Nasally administrable compositions
WO9601630	1-26-1996	PREVENTIVE OR REMEDY FOR IRRITABLE BOWEL SYNDROME OR DIARRHEA
EP0313393	3-17-1994	Benzoxazine compounds and pharmaceutical use thereof.
US4892872	1-10-1990	Benzoxazine compounds and pharmaceutical use thereof


WO9964046	12-17-1999	MULTIVALENT AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS AND ANTAGONISTS OF THE 5-HT3 RECEPTORS MULTIVALENT AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS AND ANTAGONISTS OF THE 5-HT>3< RECEPTORS MULTIVALENT AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS AND ANTAGONISTS OF THE 5-HT3 RECEPTORS
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WO9847481	10-30-1998	USE OF 5HT3 ANTAGONISTS FOR PROMOTING INTESTINAL LAVAGE
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US2009197823	8-7-2009	ALISKIREN MODULATION OF NEUROGENESIS
EP0975327	7-3-2003	USE OF 5HT3 ANTAGONISTS FOR PROMOTING INTESTINAL LAVAGE
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EP1054998	11-30-2000	TRANSGLUTAMINASE LINKAGE OF AGENTS TO TISSUE


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WO0053231	9-15-2000	FATTY ACID-ANTICANCER CONJUGATES AND USES THEREOF FATTY ACID-ANTICANCER CONJUGATES AND USES THEREOF
EP1019360	7-20-2000	$g(b)2-ADRENERGIC RECEPTOR AGONISTS $g(b)2-ADRENERGIC RECEPTOR AGONISTS
WO0039283	7-7-2000	USE OF CD40 ENGAGEMENT TO ALTER T CELL RECEPTOR USAGE USE OF CD40 ENGAGEMENT TO ALTER T CELL RECEPTOR USAGE USE OF CD40 ENGAGEMENT TO ALTER T CELL RECEPTOR USAGE
US6080877	6-28-2000	Taxanes
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WO0001699	1-14-2000	NOVEL INDOLOCARBAZOLE DERIVATIVES USEFUL FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES AND CANCER
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WO9966944	12-30-1999	METHODS FOR IDENTIFYING NOVEL MULTIMERIC AGENTS THAT MODULATE RECEPTORS METHODS FOR IDENTIFYING NOVEL MULTIMERIC AGENTS THAT MODULATE RECEPTORS

……….. ChemSpider 2D Image | Azasetron | C17H20ClN3O3 AZASETRON

AZASETRON

NMR OF HCL SALT

http://file.selleckchem.com/downloads/nmr/S210601-Azasetron-hydrochloride-NMR-Selleck.pdf

…………….

SYNTHESIS

US4892872

EXAMPLE 15

To a solution of 3.0 g of 3-aminoquinuclidine and 3.0 g of N-methylmorpholine in 60 ml of chloroform is added 6.2 g of 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid chloride under cooling and stirring followed by stirring for 2 hours. The resultant solution is washed with water, aqueous sodium hydrogen carbonate and then water, and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanol-isopropyl ether and treated with ethanolic hydrochloric acid to give 6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 281

………..

SYNTHESIS AND + AND – ISOMERS

US4892872

EXAMPLE 36

A solution of 6 g of 6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide and 2.7 g of D-(-)-tartaric acid in 100 ml of methanol and 200 ml of ethanol is allowed to stand. The precipitated crystals are collected by filtration and recrystallized from methanol repeatedly to give the R-(+) isomer, [α].sub.D.sup.25 =+36.72 (c=1, chloroform), melting at 177 with ethanolic hydrochloric acid, and then the precipitated crystals are collected by filtration and dried to give the R-(+) isomer hydrochloride, [α].sub.D.sup.25 =+1.4 (c=1, water), melting at 309

By using L-(+)-tartaric acid in a similar manner, the R-(-) optical isomer, [α].sub.D.sup.25.5 =-36.76 (c=1, chloroform), melting at 176 [α].sub.D.sup.25.5 =-1.2 (c=1, water), melts at 310

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

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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Aeterna Zentaris Submits New Drug Application to FDA for Macimorelin Acetate (AEZS-130) for Evaluation of AGHD

January 7, 2014 6:14 am / 2 Comments on Aeterna Zentaris Submits New Drug Application to FDA for Macimorelin Acetate (AEZS-130) for Evaluation of AGHD

New Drug Approvals

Macimorelin

CAS 381231-18-1

Chemical Formula: C26H30N6O3

Exact Mass: 474.23794

Molecular Weight: 474.55480

Elemental Analysis: C, 65.80; H, 6.37; N, 17.71; O, 10.11

zoom the structure

945212-59-9 (Macimorelin acetate)

AEZS-130
ARD-07
D-87875
EP-01572
EP-1572
JMV-1843

USAN (ab-26)
MACIMORELIN ACETATE

THERAPEUTIC CLAIM
Diagnostic agent for adult growth hormone deficiency (AGHD)
CHEMICAL NAMES
1. D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-, acetate (1:1)
2. N2-(2-amino-2-methylpropanoyl-N1-[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]- D-tryptophanamide acetate

MOLECULAR FORMULA
C26H30N6O3.C2H4O2
MOLECULAR WEIGHT
534.6

SPONSOR
Aeterna Zentaris GmbH
CODE DESIGNATIONS
D-87575, EP 1572, ARD 07
CAS REGISTRY NUMBER
945212-59-9

Macimorelin (also known as AEZS-130, EP-1572) is a novel synthetic small molecule, acting as a ghrelin agonist, that is orally active and stimulates the secretion of growth hormone (GH). Based on results of Phase 1 studies, AEZS-130 has potential applications for the treatment of cachexia, a condition frequently associated with severe chronic diseases such as cancer, chronic obstructive pulmonary disease and AIDS. In addition to the therapeutic application, a Phase 3 trial with AEZS-130 as a…

View original post 2,777 more words

Amla, The World’s Most Powerful Anti-Oxidant Food!

January 7, 2014 1:01 am / Leave a comment

World Drug Tracker: Japanese Knotweed (Polygonum cuspidatum) used in Chinese Medicine, known as Hu Zhang (Tiger Cane).

January 6, 2014 12:20 pm / Leave a comment

World Drug Tracker: Japanese Knotweed (Polygonum cuspidatum) used in Chinese Medicine, known as Hu Zhang (Tiger Cane).

World Drug Tracker: VESTIPITANT (Phase II GSK)

January 6, 2014 11:40 am / Leave a comment

World Drug Tracker: VESTIPITANT (Phase II GSK)

World Drug Tracker: SOVAPREVIR in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1

January 6, 2014 11:39 am / Leave a comment

World Drug Tracker: SOVAPREVIR in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1

WANT TO KNOW ABOUT VIR SERIES CLICK

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OVAPREVIR

SOVAPREVIR

(2S, 4R) -1 – [(2S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl) butanoyl]-N-{(1R, 2S) -1 – [(cyclopropanesulfonyl) carbamoyl]-2-ethenylcyclopropyl} -4 – [(7-methoxy-2-phenylquinolin-4-yl) oxy] pyrrolidine-2-carboxamide

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

PATENT

US 2009048297 ENTRY 60

WO 2008008502

CN 103420991

THERAPEUTIC CLAIM ….Treatment of hepatitis C

CHEMICAL NAMES

1. 2-Pyrrolidinecarboxamide, N-[(1R,2S)-1-[[(cyclopropylsulfonyl)amino]carbonyl]-2-
ethenylcyclopropyl]-1-[(2S)-3,3-dimethyl-1-oxo-2-[2-oxo-2-(1-piperidinyl)ethyl]butyl]-4-
[(7-methoxy-2-phenyl-4-quinolinyl)oxy]-, (2S,4R)-

2. (2S,4R)-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-1-{(2S)-
3,3-dimethyl-2-[2-oxo-2-(piperidin-1-yl)ethyl]butanoyl}-4-[(7-methoxy-2-phenylquinolin-
4-yl)oxy]pyrrolidine-2-carboxamide

MOLECULAR FORMULA C43H53N5O8S

MOLECULAR WEIGHT 800.0

SPONSOR Achillion Pharmaceuticals, Inc.

CODE DESIGNATION ACH-0141625

CAS REGISTRY NUMBER 1001667-23-7

ACH-0141625
Sovaprevir
UNII-2ND9V3MN6O

Sovaprevir (formerly ACH-0141625), an HCV NS3 protease inhibitor, is in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1.

In 2012, fast track designation was assigned by the FDA for the treatment of hepatitis C (HCV). In 2013, a clinical hold was placed for the treatment of hepatitis C (HCV) in combination with atazanavir after elevations in liver enzymes associated with the combination of both compounds.

Sovaprevir, previously referred to as ACH-1625, is an investigational, next-generation NS3/4A protease inhibitor discovered by Achillion that is currently on clinical hold. In 2012, Fast Track status was granted by the U.S. Food and Drug Administration (FDA) to sovaprevir for the treatment of chronic hepatitis C viral infection (HCV).

Achillion has initiated a Phase 2 clinical trial (007 Study) to evaluate the all-oral, interferon-free combination of sovaprevir and its second-generation NS5A inhibitor, ACH-3102, with ribavirin (RBV), for a 12 week treatment duration, in treatment naïve, genotype 1 (GT1) HCV patients. In July 2013, sovaprevir was placed on clinical hold after elevated liver enzymes were observed in a Phase 1 healthy subject drug-drug interaction study evaluating the effects of concomitant administration of sovaprevir with ritonavir-boosted atazanavir.

In accordance with the clinical hold, the FDA provided that no new clinical trials that included dosing with sovaprevir could be initiated, however, the FDA allowed continued enrollment and treatment of patients in the Phase 2 -007 clinical trial evaluating 12-weeks of sovaprevir in combination with ACH-3102 and RBV for patients with treatment-naive genotype 1 HCV. In September 2013, after reviewing Achillion’s response, the FDA stated that although all issues identified in the June 2013 letter had been addressed, it had concluded that the removal of the clinical hold was not warranted at this time.

The FDA requested, among other things, additional analysis to more fully characterize sovaprevir pharmacokinetics and the intrinsic and extrinsic factors that may lead to higher than anticipated exposures of sovaprevir or other potential toxicities in addition to the observed liver enzyme elevations.

The FDA also requested Achillion’s proposed plan for future clinical trials in combination with other directly-acting antivirals. At the request of the FDA, Achillion plans to submit a proposed plan for analyzing the additional clinical, non-clinical and pharmacokinetic data requested before the end of 2013, and if that analysis plan is approved by the FDA, submit a complete response during the first half of 2014. Achillion retains worldwide commercial rights to sovaprevir.

Sovaprevir has demonstrated activity against all HCV genotypes (GT), including equipotent activity against both GT 1a and 1b (IC₅₀ ~ 1nM) in vitro.

With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios, sovaprevir has been clinically demonstrated to allow for once-daily, non-boosted dosing.

THE CURRENT SAFETY DATABASE FOR SOVAPREVIR INCLUDES MORE THAN 560 SUBJECTS DOSED TO DATE AND DEMONSTRATES THAT SOVAPREVIR IS WELL TOLERATED IN THESE SUBJECTS.

Sovaprevir has demonstrated high rates of clinical cures in combination with pegylated-interferon and RBV in a challenging, real world, patient population of genotype 1 treatment-naive patients.

100% of GT1b subjects achieved a rapid virologic response (RVR) in the 007 Study evaluating the interferon-free combination of sovaprevir + ACH-3102 + RBV for 12 weeks. The Phase 2 study is ongoing.

Sovaprevir in vitro retains activity against mutations that confer resistance to 1st-generation protease inhibitors.

In clinical studies to date, sovaprevir has demonstrated a high pharmacologic barrier to resistance with no on-treatment viral breakthrough reported to date in GT1b patients.

Sovaprevir is believed to be synergistic when combined with other classes of DAAs, including the second-generation NS5A inhibitor, ACH-3102.

For more information about the next-generation NS3/4A protease inhibitor, sovaprevir, please see the Related Links on this page or visit Resources.

Sovaprevir is an investigational compound. Its safety and efficacy have not been established. (Updated December 2013)

SOVAPREVIR

An estimated 3% of the world’s population is infected with the hepatitis C virus. Of those exposed to HCV, 80% become chronically infected, at least 30% develop cirrhosis of the liver and 1-4% develop hepatocellular carcinoma. Hepatitis C Virus (HCV) is one of the most prevalent causes of chronic liver disease in the United States, reportedly accounting for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. Chronic HCV infection is the most common cause of liver transplantation in the U.S., Australia, and most of Europe. Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in the United States. While the acute phase of HCV infection is usually associated with mild symptoms, some evidence suggests that only about 15% to 20% of infected people will clear HCV.

HCV is an enveloped, single-stranded RNA virus that contains a positive-stranded genome of about 9.6 kb. HCV is classified as a member of the Hepacivirus genus of the family Flaviviridae. At least 4 strains of HCV, GT-1-GT-4, have been characterized.

The HCV lifecycle includes entry into host cells; translation of the HCV genome, polyprotein processing, and replicase complex assembly; RNA replication, and virion assembly and release. Translation of the HCV RNA genome yields a more than 3000 amino acid long polyprotein that is processed by at least two cellular and two viral proteases. The HCV polyprotein is:

NH2-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH.

The cellular signal peptidase and signal peptide peptidase have been reported to be responsible for cleavage of the N-terminal third of the polyprotein (C-E1-E2-p7) from the nonstructural proteins (NS2-NS3-NS4A-NS4B-NS5A-NS5B). The NS2-NS3 protease mediates a first cis cleavage at the NS2-NS3 site. The NS3-NS4A protease then mediates a second cis-cleavage at the NS3-NS4A junction. The NS3-NS4A complex then cleaves at three downstream sites to separate the remaining nonstructural proteins. Accurate processing of the polyprotein is asserted to be essential for forming an active HCV replicase complex.

Once the polyprotein has been cleaved, the replicase complex comprising at least the NS3-NS5B nonstructural proteins assembles. The replicase complex is cytoplasmic and membrane-associated. Major enzymatic activities in the replicase complex include serine protease activity and NTPase helicase activity in NS3, and RNA-dependent RNA polymerase activity of NS5B. In the RNA replication process, a complementary negative strand copy of the genomic RNA is produced. The negative strand copy is used as a template to synthesize additional positive strand genomic RNAs that may participate in translation, replication, packaging, or any combination thereof to produce progeny virus. Assembly of a functional replicase complex has been described as a component of the HCV replication mechanism. Provisional application 60/669,872 “Pharmaceutical Compositions and Methods of Inhibiting HCV Replication” filed Apr. 11, 2005, is hereby incorporated by reference in its entirety for its disclosure related to assembly of the replicase complex.

Current treatment of hepatitis C infection typically includes administration of an interferon, such as pegylated interferon (IFN), in combination with ribavirin. The success of current therapies as measured by sustained virologic response (SVR) depends on the strain of HCV with which the patient is infected and the patient’s adherence to the treatment regimen. Only 50% of patients infected with HCV strain GT-1 exhibit a sustained virological response. Direct acting antiviral agents such as ACH-806, VX-950 and NM 283 (prodrug of NM 107) are in clinical development for treatment of chronic HCV. Due to lack of effective therapies for treatment for certain HCV strains and the high mutation rate of HCV, new therapies are needed.

…………………………………………

https://www.google.co.in/patents/US20090048297

(2S,4R)-1-((S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-N-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide

SOVAPREVIR IS DESCRIBED AS 60 IN CLAIM

SYNTHESIS OF INTERMEDIATE 13 BELOW AND ALSO COMPD 8 IE SOVAPREVIR IN STEP 4

Example 1

SYNTHESIS OF 1-((2S,4R)-1-((S)-2-TERT-BUTYL-4-OXO-4-(PIPERIDIN-1-YL)BUTANOYL)-4-(7-METHOXY-2-PHENYLQUINOLIN-4-YLOXY)PYRROLIDINE-2-CARBOXAMIDO)-2-VINYLCYCLOPROPANECARBOXYLIC ACID

Step 1. Preparation of N-(cyclopropylsulfonyl)-1-(BOC-amino)-2-vinylcyclopropanecarboxamide

CDI (2.98 g, 18.4 mm, 1.1 eq) is dissolved in ethyl acetate. N-Boc-cyclopropylvinyl acid (3.8 g, 16.7 mm, 1.0 eq), prepared via the procedure given by Beaulieu, P. L. et al. (J. Org. Chem. 70: 5869-79 (2005)) is added to the CDI/ethyl acetate mixture and stirred at RT until the starting material is consumed. Cyclopropyl sulfonamine (2.2 g, 18.4 mm, 1.1 eq) is added to this mixture followed by DBU (2.1 ml, 20.5 mm, 1.23 eq) and the mixture is stirred at RT for 2 h. Workup and purification by silica gel chromatography provides 2g of compound 2.

Step 2. Preparation of (2S,4R)-tert-butyl 2-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carboxylate and (2S,4R)—N-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide

Compound 1 (4.3 g, 9.3 mmol, 1.1 eq), prepared according to the method given ins WO 02/060926, in DMF is stirred with O-(Benzotriazol-lyl)-N,N,N′,N′-Tetramethyluronium hexafluorophosphate (4.1 g, 10.5 mmol, 1.3 eq) for 30 minutes, followed by addition of cyclopropylamine 2 (1.92 g, 8.3 mmol, 1.0 eq) and N-methylmorpholine (2.52 g, 25.0 mmol, 3.0 eq). The mixture is stirred over night and the solvent removed under reduced pressure. The resulting residue is diluted with ethyl acetate and washed with saturated aqueous NaHCO₃. The organic solvent is dried over MgSO₄and concentrated under reduced pressure to afford crude 3, which is used for next step without further purification.

Compound 3 in 10 ml dry CH₂Cl₂is treated with 5 mL TFA and stirred over night. The solvent is removed and the residue recrystallized from ethyl acetate to afford 4.12 g Compound 4 (61% yield two steps).

Step 3. Preparation of (3S)-3-((2S,4R)-2-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid

The Acid 5 (58 mg, 0.25 mmol, 1.2 eq), prepared via the procedure given by Evans, D. A., et al. (J. Org. Chem. 64: 6411-6417 (1999)) in 1.2 mL DMF is stirred with 4 (138 mg, 0.21 mmol), HATU (160 mg, 0.42 mmol, 2.0 eq), and DIEA (0.63 mmol, 3.0 eq) overnight. The mixture is subjected to HPLC purification to afford 121 mg 6 (77% yield), which is further treated with 0.5 mL TFA in 1.0 mL DCM overnight. The solvent was removed to provide Compound 7 in 100% yield.

Step 4. Preparation of (2S,4R)-1-((S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-N-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide

PLEASE NOTE 8 IS SOVAPREVIR

The Acid 7 (0.15 mmol) in 1.0 mL DMF is stirred with pepridine (excess, 0.6 mmol, 4 eq), HATU (115 mg, 0.3 mmol, 2.0 eq), and DIEA (0.45 mmol, 3.0 eq) for 4 hrs. The mixture is subjected to HPLC purification to afford 77.1 mg 8.

Step 5. Preparation of (3S)-3-((2S,4R)-2-(1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid

Step 5. Preparation of (3S)-3-((2S,4R)-2-(1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid

The Acid 5 (105 mg, 0.46 mmol, 1.2 eq) in 1.2 mL DMF is stirred with 9 (202 mg, 0.38 mmol), HATU (290 mg, 0.76 mmol, 2.0 eq), and DIEA (1.2 mmol, 3.0 eq) overnight. The mixture is subjected to HPLC purification to afford 204.3 mg 10 (75% yield), which is further treated with 0.5 mL TFA in 1.0 mL DCM overnight. The solvent is removed to provide 11 in 100% yield.

Step 6. Preparation of Final Product

The Acid 11 (30 mg, 0.045 mmol) in 1.0 mL DMF is stirred with pepridine (0.27 mmol, 6 eq), HATU (34 mg, 0.09 mmol, 2.0 eq), and DIEA (0.14 mmol, 3.0 eq) for 2 hrs. The mixture is subjected to HPLC purification to afford 21.2 mg 12 (65% yield), which is hydrolyzed in methanol with 2N NaOH for 6 hrs. The mixture is acidified with 6N HCl and subjected to HPLC purification to afford 7.6 mg 13.

………………………………

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NETUPITANT

January 6, 2014 4:52 am / 2 Comments on NETUPITANT

NETUPITANT

Ro 67-3189/000
UNII-7732P08TIR
Ro-67-3189

Netupitant, an NK-1 antagonist is under development for the treatment of overactive bladder. HELSINN GROUP

CAS: 290297-26-6

290296-54-7 (di HCl)

U.S. Pat. Nos. 6,303,790, 6,531,597, 6,297,375 and 6,479,483, 6,719,996 and 6,593,472 to Hoffmann La Roche(originator).

IUPAC/Chemical name:

2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)propanamide

Chemical Formula: C30H32F6N4O
Exact Mass: 578.24803
Molecular Weight: 578.59
Elemental Analysis: C, 62.28; H, 5.57; F, 19.70; N, 9.68; O, 2.77

Netupitant is another selective NKi receptor antagonist under development by Helsinn Healthcare, having the formula 2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2- methylphenyl)-6-(4-methylpiperazin- l-yl)pyridin-3-yl]propanamide, or Benzeneacetamide, N,a,a-trimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-l-piperazinyl)-3-pyridinyl]-3,5- bis(trifluoromethyl)-, and the below chemical structure:

Netupitant is a tachykinin NK-1 antagonist which had been in phase III clinical trials at Helsinn for the prophylaxis of chemotherapy-induced nausea and vomiting and in phase II clinical studies for the treatment of overactive bladder. However, no recent development has been reported for this research.

NK-1 receptor antagonists work by blocking the action of neurokinin-1 (Substance P), a naturally-occurring neurotransmitter in the brain that causes emesis. Netupitant was originally developed at Roche. In June 2005, Helsinn and Roche signed a licensing agreement granting Helsinn worldwide rights to the drug candidate.

Methods of synthesizing and formulating netupitant and its prodrugs are described in U.S. Patent Nos. 6,297,375, 6,719,996 and 6,593,472 to Hoffmann La Roche.

Netupitant is a highly selective NK1 receptor antagonist, which is thought to work by blocking the action of substance P, an endogenous neurotransmitter contained in high concentrations in the vomiting center of the brainstem that can stimulate the vomiting reflex. Netupitant is currently under phase III trials.

Chemotherapy is one of the treatment options utilized by oncologists in treating different types of cancers. Nausea and vomiting are the most common side-effects experienced by cancer patients when administered with chemotherapy. Netupitant-palonosetron, which is currently in Phase III trials helps in preventing CINV. The blockage of P/NK1 receptors by Netupitant in the central nervous system inhibits the binding of endogenous tachykinin neuropeptide substance and this result in preventing the chemotherapy-induced nausea and vomiting. Moreover, Palonosetron helps in the blockage of serotonin at 5-hydroxytryptamine type 3 (5-HT3) receptors and it also helps in the chemotherapy-induced nausea and vomiting.

Netupitant-Palonosetron FDC is estimated to answer significant unmet needs of the CINV market post its launch that is expected to be commercialized in 2014, as it would overcome the problems associated with current treatment with 5-HT3 receptor antagonists. Similar to Emend, Netupitant-Palonosetron FDC would gain considerable patient pool after its estimated launch in 2014, and subsequently match the patient share of Aloxi by 2018. Netupitant-Palonosetron FDC sales are expected to reach an estimated USD 515.0 million USD by 2018. FDC combination of 5-HT3 receptor antagonist and neurokinin-1 (NK1) receptor antagonist have shown better efficacy results in Phase II clinical trials for CINV patients and would thus lead to high uptake due to shifting physician and patient preference pattern towards better treatment for CINV.

Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).

The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting. The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-l-receptor antagonist. US5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.

With the development of the 5-HT₃ antagonist in the early 1990s, there emerged new strategies in the medical community to better control nausea and vomiting caused by various medical procedures, including chemotherapy (CINV), surgery (PONV), and radiation therapy (RINV). When added to steroids such as dexamethasone, several 5-HT₃ antagonists have been demonstrated to significantly improve the standard of life for patients undergoing emetogenic medical procedures. Examples of 5-HT₃ antagonists include ondansetron, marketed by

GlaxoSmithKline, and palonosetron, developed by Helsinn Healthcare.

Methods of synthesizing and formulating netupitant and its prodrugs are described in U.S. Patent Nos. 6,297,375, 6,719,996 and 6,593,472 to Hoffmann La Roche.

Other representative NKi antagonists include ZD4974 (developed by AstraZeneca), CGP49823 (developed by Ciba-Geigy), Lanepitant and LY686017 (developed by Eli Lilly), FK888 (developed by Fujisawa), Vofopitant, Vestipitant and Orvepitant (developed by

GlaxoSmithKline), Befetupitant (developed by Hoffmann-La Roche), Rl 16031 (developed by Janssen), L-733060 and L-736281 (developed by Merck), TKA731, NKP608 and DNK333 (developed by Novartis), CP-96345, CP-99994, CP- 122721, CJ-17493, CJ-11974 and CJ-11972 (developed by Pfizer), RP67580 and Dapitant (developed by Rhone-Poulenc Rorer),

Nolpitantium and SSR240600 (developed by Sanofi-Aventis), SCH388714 and Rolapitant (developed by Schering-Plough), TAK637 (developed by Takeda), HSP117 (developed by Hisamitsu), KRP103 (developed by Kyorin Pharm) and SLV317 (developed by Solvay).

Chemical structures of the above-mentioned NKi antagonists are shown below and discussion of those compounds as well as other NKi antagonists is present in Expert Opin. Ther. Patents (2010) 20(8), pp 1019- 1045 by Huang et al.

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WO 2013057554

WO 2011061622

WO 2010119347

WO 2003006016

WO 2006002860///

WO 2002085458

US 2002091265…….

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J. Org. Chem., 2006, 71 (5), pp 2000–2008

DOI: 10.1021/jo0523666

http://pubs.acs.org/doi/full/10.1021/jo0523666

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https://www.google.co.in/patents/US6297375

(2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide) which has the formula Ib

and to pharmaceutically acceptable acid addition salts thereof.

The compound of formula Ib and its salts is also characterized by valuable therapeutic properties as a highly selective antagonist of the Neurokinin 1 (NK-1, substance P) The present compound of formula lb and its pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises

a) reacting the compound of formula

with the compound of formula

to the compound of formula

EXAMPLE 14

2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide hydrochloride (1:2)

a) 1-Methyl-4-(5-nitro-pyridin-2-yl)-piperazine

To a solution of 20 g (126 mmol) of 2-chloro-5-nitropyridine in 200 ml tetrahydrofuran were added dropwise 35 ml (315 mmol) 1-methylpiperazine within 10 min. The reaction mixture was refluxed for additional 1.5 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was re-dissolved in 200 ml ethyl acetate. The organic phase was washed with 200 ml 1 N sodium bicarbonate solution, dried (magnesium sulfate) and evaporated to give 27.9 g (quantitative) of the title compound as a yellow solid.

MS m/e (%):223 (M+H⁺, 100).

b)2,2-Dimethyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-propionamide

To a solution of 27.9 g (125.5 mmol) of 1-methyl-4-(5-nitro-pyridin-2-yl)-piperazine in 400 ml methanol were added 2.6 g of 10% of palladium on activated charcoal. The reaction mixture was hydrogenated (room temperature to ca. 45° C., 1 bar) until the theoretical amount of hydrogen was taken up (about 2 h). The catalyst was filtered off and was washed twice with 100 ml portions of methanol. The filtrate was evaporated in vacuo to give 28 g of a purple oil which consisted to ca. 90% of the desired aniline derivative according to analysis by thin layer chromatography.

This crude product was dissolved in a mixture of 400 ml tetrahydrofuran and 100 ml diethyl ether. After cooling to 0° C., 30 ml (215 mmol) of triethylamine were added in one portion. Stirring was continued while 26 g (215 mmol) of pivaloyl chloride were added dropwise within a period of 10 min. The ice bath was removed and the reaction mixture was stirred for 1 h at room temperature. Then, the solvent was removed in vacuo and the residue was suspended in 200 ml 1 N sodium bicarbonate solution. The product was extracted three times with 200 ml portions of dichloromethane, dried (sodium sulfate) and purified by flash chromatography to give 30 g (86%) of the title compound as pink crystals.

MS m/e (%):277 (M+H⁺, 100).

c) N-[4-Iodo-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-2,2-dimethyl-propionamide

A solution of 30 g (108 mmol) 2,2-dimethyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-propionamide and 58 ml (380 mmol) N,N,N′,N′-tetramethylethylenediamine under argon in 650 ml tetrahydrofuran was cooled in a dry ice bath to −78° C. Within lh, 239 ml (380 mmol) of a 1.6 N n-butyllithium solution in hexane were added dropwise. The reaction mixture was allowed to warm up to −30° C. overnight. After cooling again to −78° C., 43.6 g (170 mmol) iodine dissolved in 60 ml tetrahydrofuran were added dropwise during 15 min. The dry ice bath was replaced by an ice bath and a solution of 90 g (363 mmol) sodium thiosulfate pentahydrate in 250 ml water were added within 10 min when the temperature of the reaction mixture had reached 0° C. Then, 1000 ml diethyl ether were added and the organic layer was separated. The aqueous layer was extracted twice with 500 ml dichloromethane and the combined organic layers were dried (magnesium sulfate) and evaporated. Flash chromatography gave 18.5 g (42%) of the title compound as a light brown oil which crystallized upon standing at room temperature.

MS m/e (%): 403 (M+H⁺, 100).

d) 2,2-Dimethyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-propionamide

A mixture of 54 g (134 mmol) N-[4-iodo-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-2,2-dimethyl-propionamide, 420 ml toluene, 150 ml 2 N sodium carbonate solution, 4.63 g (3.9 mmol) tetrakis(triphenylphosphine)palladium(0) and 20.16 g (147 mmol) o-tolylboronic acid was heated under argon at 80° C. for 12 h. After cooling to room temperature, the aqueous phase was separated and washed twice with toluene. The combined organic layers were washed with 50 ml brine, dried (sodium sulfate), evaporated and dried in vacuo to yield 49 g (quantitative) of the title compound as a brown oil.

MS m/e (%): 367 (M+H⁺, 100).

e) 6-(4-Methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-ylamine

A suspension of 56 g (152 mmol) 2,2-dimethyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-propionamide in 1300 ml 3 N hydrochloric acid solution was heated to 90-95° C. overnight. The reaction mixture was cooled to room temperature, washed with three 500 ml portions diethyl ether and filtered over celite. The filtrate was diluted with 500 ml water and was adjusted to pH 7-8 by addition of 28% sodium hydroxide solution under ice cooling. The product was extracted with four 1000 ml portions of dichloromethane. The combined organic layers were washed with 500 ml brine, dried (magnesium sulfate) and evaporated to give 35 g (82%) of the title compound as a light brown oil.

MS m/e (%):283 (M+H⁺, 100).

f) Methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine

A solution of 35 g (124 mmol) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-ylamine in 270 ml trimethyl orthoformate and 8 drops trifluoroacetic acid was heated for 3 h at 130° C. The reaction mixture was evaporated and dried in vacuo for 30 min. The residual oil was dissolved in 100 ml tetrahydrofuran and was added dropwise under ice cooling to 9.4 g (248 mmol) lithium aluminum hydride in 300 ml tetrahydrofuran. The reaction mixture was stirred for lh at room temperature, cooled to 0° C. again and acidified (pH 1-2) by addition of 28% hydrochloric acid solution. After stirring for 5 min, 28% sodium hydroxide solution was added to reach pH 10. The solution was filtered over celite, evaporated and purified by flash chromatography to give 23.6 g (64%) of the title compound as a light brown oil.

MS m/e (%):297 (M+H⁺, 100).

g) 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide

A solution of 20 g (67.5 mmol) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine and 17.5 ml (101 mmol) N-ethyldiisopropylamine in 200 ml dichloromethane was cooled in an ice bath and a solution of 24 g (75 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 50 ml dichloromethane was added dropwise. The reaction mixture was warmed to 35-40° C. for 3 h, cooled to room temperature again and was stirred with 250 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 31.6 g (81%) of the title compound as white crystals. M.p. 155-157° C.

MS m/e (%): 579 (M+H⁺, 100).

h)2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide hydrochloride (1:2)

To a solution of 31.6 g (54.6 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide in 250 ml diethyl ether were added under ice cooling 60 ml 3 N hydrochloric acid solution in diethyl ether. After stirring for 15 min at 0° C., the suspension was evaporated to dryness, re-suspended in 100 ml diethyl ether, filtered and dried in vacuo to give 34.8 g (98%) of the title compound as white crystals. M.p. 235-238° C.

MS m/e (%): 579 (M+H⁺, 100).

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US20130231315

2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)propanamide (Netupitant)

Other general procedures of preparing similar compounds to intermediate 1 of Scheme 1 are also disclosed in U.S. Pat. Nos. 6,303,790, 6,531,597, 6,297,375 and 6,479,483, the entirety of which are incorporated herein by reference.

Synthesis of methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine

Step 1:

13.0 g (82.5 mMol) 6-Chloro-nicotinic acid in 65 ml THF were cooled to 0° C. and 206.3 ml (206.3 mMol) o-tolylmagnesium chloride solution (1M in THF) were added over 45 minutes. The solution obtained was further stirred 3 hours at 0° C. and overnight at room temperature. It was cooled to −60° C. and 103.8 ml (1.8 Mol) acetic acid were added, followed by 35 ml THF and 44.24 g (165 mMol) manganese(III) acetate dihydrate. After 30 minutes at −60° C. and one hour at room temperature, the reaction mixture was filtered and THF removed under reduced pressure. The residue was partitioned between water and dichloromethane and extracted. The crude product was filtered on silica gel (eluent: ethyl acetate/toluene/formic acid 20:75:5) then partitioned between 200 ml aqueous half-saturated sodium carbonate solution and 100 ml dichloromethane. The organic phase was washed with 50 ml aqueous half-saturated sodium carbonate solution, The combined aqueous phases were acidified with 25 ml aqueous HCl 25% and extracted with dichloromethane. The organic extracts were dried (Na₂SO₄) and concentrated under reduced pressure to yield 10.4 g (51%) of 6-chloro-4-o-tolyl-nicotinic acid as a yellow foam. MS (ISN): 246 (M−H, 100), 202 (M-CO₂H, 85), 166 (36).

Step 2:

To a solution of 8.0 g (32.3 mMol) 6-chloro-4-o-tolyl-nicotinic acid in 48.0 ml THF were added 3.1 ml (42.0 mMol) thionylchloride and 143 .mu.l (1.8 mMol) DMF. After 2 hours at 50° C., the reaction mixture was cooled to room temperature and added to a solution of 72.5 ml aqueous ammonium hydroxide 25% and 96 ml water cooled to 0″C. After 30 minutes at 0° C., THF was removed under reduced pressure and the aqueous layer was extracted with ethyl acetate. Removal of the solvent yielded 7.8 g (98%) 6-chloro-4-o-tolyl-nicotinamide as a beige crystalline foam. MS (ISP): 247 (M+H³⁰, 100).

Step 3:

1.0 g (4.05 mMol) 6-Chloro-4-o-tolyl-nicotinamidein 9.0 ml 1-methyl-piperazine was heated to 100° C. for 2 hours. The excess N-methyl-piperazine was removed under high vacuum and the residue was filtered on silica gel (eluent: dichloromethane) to yield 1.2 g (95%) 6-(4-methyl-piperazin-1yl)-4-o-tolyl-nicotinamide as a light yellow crystalline foam. MS (ISP): 311 (M+H⁺, 100), 254 (62).

Step 4:

A solution of 0.2 g (0.6 mMol) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide in 1.0 ml methanol was added to a solution of 103 mg (2.6 mMol) sodium hydroxide in 1.47 ml (3.2 mMol) NaOCl (13%) and heated for 2 hours at 70° C. After removal of methanol, the aqueous layer was extracted with ethyl acetate. The combined. organic extracts were dried (Na₂SO₄), concentrated under reduced pressure and the residue filtered on silica gel (eluent: dichloromethane/methanol 4:1) to yield 100 mg (70%) 6-(4-methyl-piperazine-1-yl)-4o-tolyl-pyridin-3-ylamine as a brown resin. MS (ISP): 283 (M+H⁺, 100), 226 (42).

Step 5:

2.15 ml (11.6 mMol) Sodium methoxide in methanol were added over 30 minutes to a suspension of 0.85 g (4.6 mMol) N-bromosuccinimide in 5.0 ml dichloromethane cooled to −5° C. The reaction mixture was stirred 16 hours at −5° C. Still at this temperature, a solution of 1.0 g (3.1 mMol) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide in 5.0 ml methanol was added over 20 minutes and stirred for 5 hours. 7.1 ml (7.1 mMol) Aqueous HCl 1N and 20 ml dichloromethane were added. The phases were separated and the organic phase was washed with deionized water. The aqueous phases were extracted with dichloromethane, brought to pH=8 with aqueous NaOH 1N and further extracted with dichloromethane. The latter organic, extracts were combined, dried (Na₂SO₄) and concentrated to yield 1.08 g (quant.) [6-(4-methyl-piperazin-1yl)-4-o-tolyl-pyridin-3-yl]-carbamic acid methyl ester as a grey foam. MS (ISP): 341 (M+H⁺, 100), 284 (35).

Step 6:

A solution of 0.5 g (1.4 mMol) [6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-carbamic acid methyl ester in 3.0 ml dichloromethane was added over 10 minutes to a solution of 1.98 ml (6.9 mMol) Red-Al.RTM. (70% in toluene) and 2.5 ml toluene (exothermic, cool with a water bath to avoid temperature to go >50° C.). The reaction mixture was stirred 2 hours at 50° C. in CH₂Cl₂, extracted with ethyl acetate and cooled to 0° C. 4 ml Aqueous NaOH 1N were carefully (exothermic) added over 15 minutes, followed by 20 ml ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with deionized water and brine, dried (Na₂SO₄) and concentrated under reduced pressure to yield 0.37 g (89%) methyl-[6-4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine as an orange resin. MS (ISP): 297 (M+H⁺, 100).

Synthesis of 2-(3,5-bis-Trifluoromethyl-phenyl)-2-methyl-propionyl Chloride

15.0 g (50 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionic acid were dissolved in 127.5 ml dichloromethane in the presence of 0.75 ml DMF. 8.76 ml (2 eq.) Oxalyl chloride were added and after 4.5 hours, the solution was rotary evaporated to dryness. 9 ml Toluene were added and the resulting solution was again rotary evaporated, then dried under high vacuum yielding 16.25 g (quant.) of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride as a yellow oil of 86% purity according to HPLC analysis. NMR (250 MHz, CDCl₃): 7.86 (br s, 1H); 7.77, (br s, 2H, 3 H_arom); 1.77 (s, 6H, 2 CH₃).

Synthesis of 2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)propanamide (Netupitant)

A solution of 20 g (67.5 mmol) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine and 17.5 ml (101 mmol) N-ethyldiisopropylamine in 200 ml dichloromethane was cooled in an ice bath and a solution of 24 g (75 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 50 ml dichloromethane was added dropwise. The reaction mixture was warmed to 35-40° C. for 3 h, cooled to room temperature again and was stirred with 250 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane, The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 31.6 g (81%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1yl)-4-(o-tolyl)pyridin-3yl)propanamide as white crystals. M.P. 155-157° C.; MS m/e (%): 579 (M+H⁺, 100).

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http://www.google.com/patents/US20130231315

N OXIDE SYNTHESIS

Synthesis of 5-(2-(3,5-bis(trifluoromethyl)phenyl-N,2-dimethylpropanamido)2-(4-methylpiperazin-1yl)-4-(o-tolyl)pyridine 1-oxide

Step 1:

The solution of 6-chloropyridin-3-amine (115 g, 0.898 mol) and (Boc)₂O (215.4 g, 0.988 mol) in 900 mL of dioxane was refluxed overnight. The resulting solution was poured into 1500 mL of water. The resulting solid was collected, washed with water and re-crystallized from EtOAc to afford 160 g tert-butyl (6-chloropyridin-3yl)carbamate as a white solid (Yield: 78.2%).

Step 2:

To the solution of tert-butyl (6-chloropyridin-3-yl)carbamate (160 g, 0.7 mol) in 1 L of anhydrous THF was added n-BuLi (600 mL, L5 ml) at −78° C. under N₂atmosphere. After the addition was finished, the solution was stirred at −78° C. for 30 min, and the solution of I₂(177.68 g, 0.7 mol) in 800 mL of anhydrous THF was added. Then the solution was stirred at −78° C. for 4 hrs, TLC indicated the reaction was over. Water was added for quench, and EtOAc was added to extract twice. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered and purified by flash chromatography to afford 80 g of tert-butyl (6-chloro-4-iodopyridin-3-yl)carbamate as a yellow solid (32.3%).

Step 3:

To the solution of tert-butyl (6-chloro-4-iodopyridin-3-yl)carbamate (61 g, 0.172 mol) in 300 of anhydrous THF was added 60% NaH (7.6 g, 0.189 mol) at 0° C. under N₂atmosphere. After the addition was finished, the solution was stirred for 30 min, and then the solution of MeI (26.92 g, 0.189 mol) in 100 mL of dry THF was added. Then the solution was stirred at 0° C. for 3 hrs. TLC indicated the reaction was over. Water was added for quench, and EtOAc was added to extract twice. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered and concentrated to afford 63 g of crude tert-butyl (6-chloro-4-iodopyridin-3-yl)methyl)carbamate used into the following de-protection without the further purification.

Step 4:

To the solution of tert-butyl (6-chloro-4-iodopyridin-3-yl)(methyl)carbamate (62.5 g, 0.172 mol) in 500 mL of anhydrous DCM was added 180 mL of TFA. Then the solution was stirred at room temperature for 4 hrs. Concentrated to remove the solvent, and purified by flash chromatography to afford 45.1 g 6-chloro-4-iodo-N-methylpyridin-3-amine as a yellow solid (Yield: 97.3%).

Step 5:

To the solution of 6-chloro-4-iodo-N-methylpyridin-3-amine (40.3 g, 0.15 mol) and 2-methylbenzene boric acid (24.5 g, 0.18 mol) in 600 mL of anhydrous toluene was added 400 mL of 2 N aq. Na₂CO₃solution, Pd(OAc)₂(3.36 g, 15 mmol) and PPh₃(7.87 g, 0.03 mmol), The solution was stirred at 100° C. for 2 hrs. Cooled to room temperature, and diluted with water. EtOAc was added to extract twice. The combined organic phases were washed with water and brine consecutively, dried over Na₂SO₄, concentrated and purified by flash chromatography to afford 19 g 6-chloro-N-methyl-4-(o-tolyl)pyridin-3-amine as a white solid (Yield: 54.6%).

Step 6:

To the solution of 6-chloro-N-methyl-4-(o-tolyl)pyridin-3-amine (18.87 g, 81.3 mmol) and DMAP (29.8 g, 243.9 mmol) in 200 mL of anhydrous toluene was added the solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (28.5 g, 89.4 mmol) in toluene under N₂atmosphere. The solution was heated at 120° C. for 23 hrs. Cooled to room temperature, poured into 1 L of 5% aq. NaHCO₃solution, and extracted with EtOAc twice. The combined organic phases were washed by water and brine consecutively, dried. over Na₂SO₄, filtered and purified by flash chromatography to afford 35 g 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-tolyl)pyridin-3-yl)-N,2-dimethylpropanamide as a white solid (Yield: 83.9%).

Step 7:

To the solution of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(o-tolyl)pyridin-3-yl)-N,2-dimethylpropanamide (5.14 g, 10 mmol) in 60 mL of DCM was added m-CPBA (6.92 g, 40 mmol) at 0° C. under N₂atmosphere. Then the solution was stirred overnight at room temperature. 1 N aq. NaOH solution was added to wash twice for removing the excess m-CPBA. and a side product. The organic phase was washed by brine, dried over Na₂SO₄, filtered and concentrated to afford 5.11 g of crude 5-(2-(3,5-bis(trifluoromethyl)phenyl-N,2-dimethylpropanamido)-2-chloro-4(o-tolyl)pyridine 1-oxide as a white solid (Yield: 96.4%).

Step 8:

To the solution of crude 5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-2-chloro-4-(o-tolyl)pyridine 1-oxide (5.1 g, 9.62 mmol) in 80 mL of n-BuOH was added N-methylpiperazine (7.41 g, 74.1 mmol) under N₂atmosphere. Then the solution was stirred at 80° C. overnight. Concentrated and purified by flash chromatography to afford 4.98 g 5-(2-(3,5-bis(trifluoromethyl)phenyl-N,2-dimethylpropanamido)-2-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridine 1-oxide as a white solid (Yield: 87.2%), ¹HNMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.93 (s, 1H), 7.78 (s, 2H), 7.38 (m, 2H), 7.28 (m, 1H), 7.17 (m, 1H), 7.07 (s, 1H), 5.50 (s, 3H), 2.72 (d, J=4.4 Hz, 4H), 2.57 (m, 3H), 2.40 (s, 3H), 2.23 (s, 3H), 1.45-1.20 (m, 6H).

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https://www.google.co.in/patents/US6479483

EXAMPLE 14 2-(3,5-bis-Trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperan-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide Hydrochloride (1:2)

a) 1-Methyl-4-(5-nitro-pyridin-2-yl)-piperazine

MS m/e (%): 223 (M+H⁺, 100).

b) 2,2-Dimethyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl-propionamide

MS m/e (%): 277 (M+H⁺, 100).

c) N-[4-Iodo-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-2,2-dimethyl-propionamide

A solution of 30 g (108 mmol) 2,2-dimethyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-propionamide and 58 ml (380 mmol) N,N,N′,N′-tetramethylethylenediamine under argon in 650 ml tetrahydrofuran was cooled in a dry ice bath to −78° C. Within 1 h, 239 ml (380 mmol) of a 1.6 N n-butyllithium solution in hexane were added dropwise. The reaction mixture was allowed to warm up to −30° C. overnight. After cooling again to −78° C., 43.6 g (170 mmol) iodine dissolved in 60 ml tetrahydrofuran were added dropwise during 15 min. The dry ice bath was replaced by an ice bath and a solution of 90 g (363 mmol) sodium thiosulfate pentahydrate in 250 ml water were added within 10 min when the temperature of the reaction mixture had reached 0° C. Then, 1000 ml diethyl ether were added and the organic layer was separated. The aqueous layer was extracted twice with 500 ml dichloromethane and the combined organic layers were dried (magnesium sulfate) and evaporated. Flash chromatography gave 18.5 g (42%) of the tide compound as a light brown oil which crystallized upon standing at room temperature.

MS m/e (%): 403 (M+H⁺, 100).

d) 2,2-Dimethyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-propionamide

MS m/e (%): 367 (M+H⁺, 100).

e) 6-(4-Methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-ylamine

MS m/e (%):283 (M+H⁺, 100).

f) Methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine

A solution of 35 g (124 mmol) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-ylamine in 270 ml trimethyl orthoformate and 8 drops trifluoroacetic acid was heated for 3 h at 130° C. The reaction mixture was evaporated and dried in vacuo for 30 min. The residual oil was dissolved in 100 ml tetrahydrofuran and was added dropwise under ice cooling to 9.4 g (248 mmol) lithium aluminum hydride in 300 ml tetrahydrofuran. The reaction mixture was stirred for 1 h at room temperature, cooled to 0° C. again and acidified (pH 1-2) by addition of 28% hydrochloric acid solution. After stirring for 5 min, 28% sodium hydroxide solution was added to reach pH 10. The solution was filtered over celite, evaporated and purified by flash chromatography to give 23.6 g (64%) of the title compound as a light brown oil.

MS m/e (%): 297 (M+H⁺, 100).

g) 2-(3,5-bis-Trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide

A solution of 20 g (67.5 mmol) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]amine and 17.5 ml (101 mmol) N-ethyldiisopropylamine in 200 ml dichloromethane was cooled in an ice bath and a solution of 24 g (75 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 50 ml dichloromethane was added dropwise. The reaction mixture was warmed to 35-40° C. for 3 h, cooled to room temperature again and was stirred with 250 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 31.6 g (81%) of the title compound as white crystals. M.p. 155-157° C.

MS m/e (%): 579 (M+H⁺, 100).

h) 2-(3,5-bis-Trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide Hydrochloride (1:2)

To a solution of 31.6 g (54.6 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide in 250 ml diethyl ether were added under ice cooling 60 ml 3 N hydrochloric acid solution in diethyl ether. After stirring for 15 min at 0° C., the suspension was evaporated to dryness, re-suspended in 100 ml diethyl ether, filtered and dried in vacuo to give 34.8 g (98%) of the title compound as white crystals. M.p. 235-238° C.

MS m/e (%): 579 (M+H⁺, 100).

…………………………….

Research and development of an efficient process for the construction of the 2,4,5-substituted pyridines of NK-1 receptor antagonists
Org Process Res Dev 2006, 10(6): 1157

Management of chemotherapy-induced nausea and vomiting : focus on newer agents and new uses for older agents.

Navari RM.

Drugs. 2013 Mar;73(3):249-62. doi: 10.1007/s40265-013-0019-1. Review.

Efficient synthesis of novel NK1 receptor antagonists: selective 1,4-addition of grignard reagents to 6-chloronicotinic acid derivatives. Hoffmann-Emery F, Hilpert H, Scalone M, Waldmeier P. J Org Chem. 2006 Mar 3;71(5):2000-8. Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists. Hoffmann T, Bös M, Stadler H, Schnider P, Hunkeler W, Godel T, Galley G, Ballard TM, Higgins GA, Poli SM, Sleight AJ. Bioorg Med Chem Lett. 2006 Mar 1;16(5):1362-5. Epub 2005 Dec 5. http://www.sciencedirect.com/science/article/pii/S0960894X05014824 ……………………………………. http://www.helsinn.com/public/download/HELSINN%20GROUP%20POWER%20POINT%20PRESENTATION.pdf ……………………………………………………….

US6897226 *	9 Jul 2003	24 May 2005	Hoffmann-La Roche Inc.	NK-1 receptor active amine oxide prodrugs
US7211579 *	15 Mar 2006	1 May 2007	Hoffmann-La Roche Inc.	NK-1 receptor antagonists
US8426450	23 May 2012	23 Apr 2013	Helsinn Healthcare Sa	Substituted 4-phenyl pyridines having anti-emetic effect
WO2011061622A1	18 Nov 2010	26 May 2011	Helsinn Healthcare S.A.	Compositions for treating centrally mediated nausea and vomiting
WO2013057554A2	10 Oct 2012	25 Apr 2013	Helsinn Healthcare Sa	Therapeutic combinations of netupitant and palonosetron

US8426450	23 May 2012	23 Apr 2013	Helsinn Healthcare Sa	Substituted 4-phenyl pyridines having anti-emetic effect
WO2011061622A1	18 Nov 2010	26 May 2011	Helsinn Healthcare S.A.	Compositions for treating centrally mediated nausea and vomiting
WO2013057554A2	10 Oct 2012	25 Apr 2013	Helsinn Healthcare Sa	Therapeutic combinations of netupitant and palonosetron

……………………………………………………………………………………….

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

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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