CASOPITANT

CASOPITANT
Tachykinin NK1 Antagonists
(2S,4S)-4-(4-Acetyl-1-piperazinyl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide
4-(S)-(4-Acetyl-piperazin-1-yl)-2- (R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl- phenyl)-ethyl]-methylamide
414910-30-8  MESYLATE
414910-27-3 (free base)
679769
GW-679769
GW-679769B

MF C30H35F7N4O2.CH4O3S MESYLATE
Molecular Weight	712.719

Casopitant (trade names Rezonic (US), Zunrisa (EU)) is an neurokinin 1 (NK₁) receptor antagonist undergoing research for the treatment of chemotherapy-induced nausea and vomiting (CINV).^[1] It is currently under development by GlaxoSmithKline (GSK).
In July 2008, the company filed a marketing authorisation application with the European Medicines Agency. The application was withdrawn in September 2009 because GSK decided that further safety assessment was necessary.^[2]    Casopitant mesylate, a tachykinin NK1 receptor antagonist, had been filed for approval in the U.S. and the E.U. by GlaxoSmithKline for the prophylaxis of chemotherapy-induced nausea/vomiting.
In 2009 the company discontinued the development of the drug candidate for this indication. An MAA had also been filed for the treatment of postoperative nausea and vomiting, and in 2009 the application was withdrawn by the company.
Additional phase II clinical trials were ongoing at GlaxoSmithKline for the treatment of depression, anxiety, sleep disorders, fibromyalgia and overactive bladder, however, no recent developments have been reported for these indications.

1.  Lohr L (2008). "Chemotherapy-induced nausea and vomiting". Cancer J 14 (2): 85–93.doi:10.1097/PPO.0b013e31816a0f07. PMID 18391612.
2.  "GlaxoSmithKline withdraws its marketing authorisation application for Zunrisa". London: EMEA. 13 October 2009. Retrieved 21 December 2009
3. Casopitant mesilate
   Drugs Fut 2008, 33(9): 737
4. WO 2002032867
5. WO 2008046882
6. Development of a control strategy for a defluorinated analogue in the manufacturing process of casopitant mesylate
   Org Process Res Dev 2010, 14(4): 832 NMR FREE BASE, MESYLATE
7. WO 2006061233
8. WO 2004091616
9. US20040014770 ENTRY 1B MP MESYLATE 243
10. Tetrahedron, 2010 ,  vol. 66,  26  p. 4769 - 4774 NMR FREE BASE
11. Journal of Medicinal Chemistry, 2011 ,  vol. 54,   4  p. 1071 - 1079 NMR MESYLATE

WO2006061233A1 *

Dec 7, 2005

Jun 15, 2006

Glaxo Group Ltd

The use of medicament 4-(s)-(4-acetyl-piperazin-1-yl)-2-(r)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(r)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide

WO2001044200A2 *	Dec 14, 2000	Jun 21, 2001	David J Blythin	Selective neurokinin antagonists
WO2002010141A1 *	Jul 25, 2001	Feb 7, 2002	Michael Kirk Ahlijanian	Imidazole derivatives
WO2002032867A1 *	Oct 12, 2001	Apr 25, 2002	Giuseppe Alvaro	Chemical compounds
US20020123491 *	Dec 14, 2000	Sep 5, 2002	Neng-Yang Shih	Selective neurokinin antagonists
US20030064980 *	Jun 6, 2002	Apr 3, 2003	Neng-Yang Shih	Selective neurokinin antagonists
US20030144270 *	Nov 12, 2002	Jul 31, 2003	Schering Corporation	NK1 antagonists

Casopitant (Rezonic, Zunrisa, casopitant mesylate, GW-679769, 679769, CAS #414910-27-3), 4-(4-Acetyl-piperazin-1-yl)-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide, is a NK-1 receptor antagonist.
Casopitant is under investigation for the treatment of emesis, nausea, drug-induced nausea, chemotherapy-induced nausea and vomiting, post-operative nausea and vomiting, sleep disorders, anxiety disorders, depressive disorders, overactive bladder, and myalgia (Drug Report for Casopitant, Thomson Investigational Drug Database (Sep. 15, 2008); Reddy et al., Supportive Cancer Therapy 2006, 3(3), 140-142; and WO 2006/061233).
Casopitant has also shown promise in treating disorders of the central nervous system, tinitis, and sexual dysfunction (WO 2006/061233).
compound may be of value in the treatment of Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder and Sexual Aversion Disorder sexual arousal disorders such as Female Sexual Arousal Disorder and Male Erectile Disorder orgasmic disorders such as Female Orgasmic Disorder, Male Orgasmic Disorder and Premature Ejaculation sexual pain disorder such as Dyspareunia and Vaginismus, Sexual Dysfunction Not Otherwise Specified; paraphilias such as Exhibitionism, Fetishism, Frotteurism, Pedophilia, Sexual Masochism, Sexual Sadism Transvestic Fetishism, Voyeurism and Paraphilia Not Otherwise Specified gender identity disorders such as Gender Identity Disorder in Children and Gender Identity Disorder in Adolescents or Adults and Sexual Disorder Not Otherwise Specified.

Casopitant is subject to CYP3A4-mediated oxidative metabolism at the 3-carbon of the piperazine ring to form a hydroxylated metabolite which may be further oxidized to the corresponding 3-oxo metabolite (Minthorn et al, Drug Metab. Disp., 2008, 36(9), 1846-1852). Adverse effects associated with casopitantadministration include: neutropenia, nausea, hiccups, headache, constipation, dizziness, pruritis, alopecia, and fatigue.
Overactive bladder is a term for a syndrome that encompasses urinary frequency, with or without urge incontinence, generally but not necessarily combined with pollacisuria and nocturia. Overactive bladder is also characterised by involuntary detrusor contractions which are either triggered by provocation or occur spontaneously. If the detrusor hyperactivity observed is based on neurological causes (e. g. Parkinson's disease, apoplexy, some forms of multiple sclerosis, spinal cord injury or the cross section of the bone marrow) it is known as neurogenic detrusor hyperactivity. If no clear cause can be detected this is known as idiopathic detrusor hyperactivity. In addition, detrusor hyperactivity may be associated with anatomical changes in the lower urinary tract, for example, in patients with bladder outlet obstruction (an enlargement of the prostate gland in males)
International patent application WO 02/32867 describes novel piperidine derivatives. A 0 particular preferred compound described therein is 4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)- (4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid

...........................................................................
CASOPITANT MESYLATE

US20040014770
EXAMPLE 4
[0330] 4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-Carboxylic Acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide Methanesulphonate
[0331] A solution of intermediate 4a (7.7 g) in acetonitrile (177 mL) was added to a solution of 1-acetyl-piperazine (3.9 g) in acetonitrile (17.7 mL) followed by sodium triacetoxyborohydride (6.4 g) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours and then quenched with a saturated sodium hydrogen carbonate (23.1 mL) and water (61.6 mL). The resulting solution was concentrated in vacuo, then AcOEt (208 mL) was added; the layers were separated and the aqueous layer was back-extracted with further AcOEt (2×77 mL). The collected organic phases were washed with brine (2×118 mL), dried and concentrated in vacuo to give the crude mixture of syn and anti diastereomers (nearly 1:1) as a white foam (9.5 g).
[0332] A solution of this intermediate in THF (85.4 mL) was added to a solution of methansulfonic acid (0.890 mL) in THF (6.1 mL) at r.t. After seeding, the desired syn diastereomer started to precipitate. The resulting suspension was stirred for 3 hours at 0° C. and then filtered under a nitrogen atmosphere. The resulting cake was washed with cold THF (15.4 mL) and dried in vacuo at +20° C. for 48 hours to give the title compound as a white solid (4.44 g).
[0333] NMR (d₆-DMSO): δ (ppm) 9.52 (bs, 1H); 7.99 (bs, 1H); 7.68 (bs, 2H); 7.23 (m, 1H); 6.95 (dd, 1H); 6.82 (m, 1H); 5.31 (q, 1H); 4.45 (bd, 1H); 4.20 (dd, 1H); 3.99 (bd, 1H); 3.65-3.25 (bm, 5H); 3.17 (m, 1H); 2.96 (m, 1H); 2.88-2.79 (m+m, 2H); 2.73 (s, 3H); 2.36 (s, 3H); 2.30 (s, 3H); 2.13-2.09 (bd+bd, 2H); 2.01 (s, 3H); 1.89-1.73 (m+m, 2H); 1.46 (d, 3H).
[0334] m.p 243.0° C.
[0335] The compound is isolated in a crystalline form.

intermediate 4a is needed  for above syn, ignore 4b
[0168] Intermediate 4
[0169] 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-Carboxylic Acid, [1-(R)-3,5-bis-trifluoromethyl-phenyl)ethyl]-Methylamide (4a) and 2-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-Carboxylic Acid, [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-Methylamide (4b) Method A
[0170] A solution of triphosgene (147 mg) dissolved in dry DCM (5 mL) was added drop-wise to a solution of intermediate 2 (250 mg) and DIPEA (860 μL) in dry DCM (15 mL) previously cooled to 0° C. under a nitrogen atmosphere. After 2 hours, [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride (503 mg) and DIPEA (320 μL) in dry acetonitrile (20 mL) were added and the mixture was heated to 70° C. for 16 hours. Further [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride (170 mg) and DIPEA (100 μL) were added and the mixture was stirred at 70° C. for further 4 hours. Next, the mixture was allowed to cool to r.t., taken up with AcOEt (30 mL), washed with a 1N hydrochloric acid cold solution (3×15 mL) and brine (2×10 mL). The organic layer was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH/AcOEt 8:2) to give:
[0171] 1. intermediate 4a (230 mg) as a white foam,
[0172] 2. intermediate 4b (231 mg) as a white foam. ................ignore
[0173] Intermediate 4a
[0174] NMR (d₆-DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55 (m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).
[0175] Intermediate 4b
[0176] NMR (d₆-DMSO): δ (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98 (dd, 1H); 6.93 (dt, 1H); 5.29 (q, 1H); 5.24 (t, 1H); 3.56 (m, 1H); 3.48 (m, 1H); 2.70 (s, 3H); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H). ........ ignore
[0177] Intermediate 4a
[0178] Method B
[0179] A saturated sodium hydrogen carbonate solution (324 mL) was added to a solution of intermediate 9 (21.6 g) in AcOEt (324 mL) and the resulting mixture was vigorously stirred for 15 minutes. The aqueous layer was back-extracted with further AcOEt (216 mL) and the combined organic extracts were dried and concentrated in vacuo to give intermediate 8 as a yellow oil, which was treated with TEA (19 mL) and AcOEt (114 mL). The solution obtained was added drop-wise over 40 minutes to a solution of triphosgene (8 g) in AcOEt (64 mL) previously cooled to 0° C. under a nitrogen atmosphere, maintaining the temperature between 0° C. and 8° C.
[0180] After stirring for 1 hours at 0° C. and for 3 hours at 20° C., [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride (29.7 g), AcOEt (190 mL) and TEA (38 mL) were added to the reaction mixture which was then heated to reflux for 16 hours.
[0181] The solution was washed with 10% sodium hydroxide solution (180 mL), 1% hydrochloric acid solution (4×150 mL), water (3×180 mL) and brine (180 mL). The organic layer was dried and concentrated in vacuo to a residue, which was purified through a silica pad (CH/AcOEt 9:1) to give the title compound (21.5 g) as a brown thick oil.
[0182] NMR (d₆-DMSO): 6 (ppm) 7.97-7.77 (bs+bs, 3H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m, 2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).
intermediate 2
[0152] Intermediate 2
[0153] 2-(4-Fluoro-2-methyl-phenyl)-piperidine-4-one
[0154] Method A
[0155] 2-Methyl-4-fluoro-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) and the solution was stirred at r.t. under a nitrogen atmosphere. After 1 hour the mixture was heated at reflux for 16 hours and then allowed to cool to r.t. This solution was slowly added to a refluxing solution of p-toluensulphonic acid (10.6 g) in dry benzene (50 mL) previously refluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated potassium carbonate solution and taken up with AcOEt (50 mL). The aqueous phase was extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layer was dried and concentrated in vacuo to a yellow thick oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6N hydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours. The solution was basified with solid potassium carbonate and extracted with DCM (5×50 mL). The combined organic phases were washed with brine (50 mL), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil.
[0156] Method B
[0157] L-selectride (1M solution in dry THF, 210 mL) was added drop-wise, over 80 minutes, to a solution of intermediate 1 (50 g) in dry THF (1065 mL) previously cooled to −72° C. under a nitrogen atmosphere. After 45 minutes, 2% sodium hydrogen carbonate solution (994 mL) was added drop-wise and the solution was extracted with AcOEt (3×994 mL). The combined organic phases were washed with water (284 mL) and brine (568 mL). The organic phase was dried and concentrated in vacuo to get 1-benzyloxycarbonyl-2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as a pale yellow thick oil (94 g) which was used as a crude.
[0158] This material (94 g) was dissolved in AcOEt (710 mL), then 10% Pd/C (30.5 g) was added under a nitrogen atmosphere. The slurry was hydrogenated at 1 atmosphere for 30 minutes. The mixture was filtered through Celite and the organic phase was concentrated in vacuo to give the crude 2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as a yellow oil. This material was dissolved in AcOEt (518 mL) at r.t. and racemic camphorsulphonic acid (48.3 g) was added. The mixture was stirred at r.t for 18 hours, then the solid was filtered off, washed with AcOEt (2×50 mL) and dried in vacuo for 18 hours to give 2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one, 10-camphorsulfonic acid salt as a pale yellow solid (68.5 g). (M.p.: 167-169° C.-NMR (d₆-DMSO): 6 (ppm) 9.43 (bs, 1H); 9.23 (bs, 1H); 7.66 (dd, 1H); 7.19 (m, 2H); 4.97 (bd, 1H); 3.6 (m, 2H); 2.87 (m, 3H); 2.66 (m, 1H); 2.53 (m, 2H); 2.37 (s+d, 4H); 2.22 (m, 1H); 1.93 (t, 1H); 1.8 (m, 2H); 1.26 (m, 2H); 1.03 (s, 3H); 0.73 (s, 3H).
[0159] This material (68.5 g) was suspended in AcOEt (480 mL) and stirred with a saturated sodium hydrogen carbonate (274 mL). The organic layer was separated and washed with further water (274 mL). The organic phase was dried and concentrated in vacuo to give the title compound (31 g) as a yellow-orange oil.
[0160] NMR (d₆-DMSO): 6 (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2.82 (dt, 1H); 2.72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H).
[0161] MS (ES/+): m/z=208 [MH]⁺.

intermediate 9
[0220] Intermediate 9
[0221] 2-(R)-(4-Fluoro-2-methyl-phenyl)-piperidin-4-one Mandelic Acid.
[0222] A solution of L-(+)-mandelic acid (22.6 g) in AcOEt (308 mL) was added to a solution of intermediate 2 (31 g) in AcOEt (308 mL). Then isopropanol (616 mL) was added and the solution was concentrated in vacuo to 274 mL. The solution was then cooled to 0° C. and further cold isopropanol (96 mL) was added. The thick precipitate was stirred under nitrogen for 5 hours at 0° C., then filtered and washed with cold Et2O (250 mL) to give the title compound as a pale yellow solid (20.3 g).
[0223] M.p.: 82-85° C.
[0224] NMR (d₆-DMSO): δ (ppm) 7.51 (dd, 1H); 7.40 (m, 2H); 7.32 (m, 2H); 7.26 (m, 1H); 7.0 (m, 2H); 4.95 (s, 1H); 4.04 (dd, 1H); 3.31 (m, 1H); 2.88 (m, 1H); 2.49-2.2 (m, 4H); 2.29 (s, 3H).
[0225] Chiral HPLC: HP 1100 HPLC system; column Chiralcel OD-H, 25 cm×4.6 mm; mobile phase: n-hexane/isopropanol 95:5+1% diethylamine; flow: 1.3 ml/min; detection: 240/215 nm; retention time 12.07 minutes.


......................
NMR
mesylate

Org. Process Res. Dev., 2010, 14 (6), pp 1337–1346

DOI: 10.1021/op100150b

http://pubs.acs.org/doi/abs/10.1021/op100150b

¹H NMR (600 MHz, DMSO-d₆): 9.57 (br s, 1H), 7.99 (br s, 1H), 7.68 (br s, 2H), 7.23 (m, 1H), 6.95 (dd, 1H), 6.82 (m, 1H), 5.31 (q, 1H), 4.45 (m, 1H), 4.20 (dd, 1H), 3.99 (m, 1H), 3.56 (m, 1H), 3.47 (m, 3H), 3.37 (m, 1H), 3.15 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.80 (t, 1H), 2.74 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (m, 1H), 2.08 (m, 1H), 2.10 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.46 (d, 3H), MS: m/z 617 [MH]⁺, as free base.


...............
http://pubs.acs.org/doi/full/10.1021/op100209c

Org. Process Res. Dev., 2010, 14 (6), pp 1407–1419

DOI: 10.1021/op100209c

---

(2R,4S)-4-(4-Acetyl-1-piperazinyl)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide Methanesulfonate Salt (Casopitant Mesylate 1)

A solution of casopitant 2 (0.86 wt) was diluted with EtOAc (overall solution of 2 in EtOAc was 4 L) and acetone (4.5 L) and was heated to the required temperature (from 39 °C). Thereafter, neat methanesulfonic acid (0.12 L, 1.64 mol) was charged, followed by a slurry of 2 (0.005 kg) in EtOAc (0.05 L) as seed. The obtained suspension was stirred for 1 h followed by the addition of 3 L of isooctane in the required time (1 h). The slurry was cooled to 20 °C in 2 h and aged 3 h. The suspension was filtered and the solid washed with EtOAc (3 × 4 L). The white solid was dried overnight under vacuum at 40 °C to give the desired casopitant mesylate 1 (0.94 kg).

¹H NMR (600 MHz, DMSO-d₆) δ 9.57 (br s, 1H), 7.99 (br s, 1H), 7.68 (br s, 2H), 7.23 (m, 1H), 6.95 (dd, 1H), 6.82 (m, 1H), 5.31 (q, 1H), 4.45 (m, 1H), 4.20 (dd, 1H), 3.99 (m, 1H), 3.56 (m, 1H), 3.47 (m, 3H), 3.37 (m, 1H), 3.15 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.80 (t, 1H), 2.74 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (m, 1H), 2.08 (m, 1H), 2.10 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.46 (d, 3H). MS: m/z 617 [MH]⁺, as free base.

.............

Org. Process Res. Dev., 2010, 14 (4), pp 805–814

DOI: 10.1021/op1000622

http://pubs.acs.org/doi/abs/10.1021/op1000622

NMR CASOPITANT FREE BASE

(2R,4S)-4-(4-Acetyl-1-piperazinyl)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide (Casopitant 2)

HCOOH (0.49 L, 13 mol) was added to a cooled suspension of NaBH(OAc)₃ (0.82 kg, 3.87 mol) in CH₃CN (4 L), keeping the internal temperature between 10−15 °C; then the lines were washed with more CH₃CN (1 L), and the mixture was stirred for 40 min.

1-Acetylpiperazine (0.7 kg, 5.46 mol) was added neat over the solution of piperidone-urea 3, and the mixture was diluted with CH₃CN (3 L). The resulting mixture was added over the previous suspension; fresh CH₃CN (4 L) was used to wash the line. The reaction mixture was stirred at 15 °C for 12 h. The solvent was evaporated under reduced pressure to 4 L.

The resulting suspension was diluted with fresh EtOAc (4 L), and then washed with ammonia [21% w/w solution (4 L, 11.25 M in NH₃)], Na₂CO₃ [15% w/w solution (4 L)]. More EtOAc (4 L) was added, and the organic layer was washed with water (4 L). The organic phase was then concentrated to 2.5 L; again fresh EtOAc (4 L) was added, and the solution was concentrated to 2.5 L to give a solution of casopitant 2.

¹H NMR (600 MHz, DMSO-d₆): δ 7.99 (s, 1H), 7.68 (s, 2H), 7.18 (dd, 1H), 6.90 (dd, 1H), 6.76 (td, 1H), 5.33 (q, 1H), 4.14 (dd, 1H), 3.38 (m, 5H), 2.71 (s, 3H), 2.72 (m, 1H), 2.54 (m, 1H), 2.47 (m, 2H), 2.41 (m, 2H), 2.34 (s, 3H), 1.95 (s, 3H), 1.85 (m, 1H), 1.77 (m, 1H), 1.62 (dq, 1H), 1.47 (d, 3H), 1.40 (q, 1H).

.....................................

J. Med. Chem., 2011, 54 (4), pp 1071–1079

DOI: 10.1021/jm1013264

http://pubs.acs.org/doi/full/10.1021/jm1013264?prevSearch=casopitant&searchHistoryKey=
(2R,4S)-1′-acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4′-bipiperidine-1-carboxamide methanesulfonate salt 16a (casopitant)
nmr mesylate
¹H NMR (600 MHz, DMSO-d₆): 9.57 (bs, 1H), 7.99 (bs, 1H), 7.68 (bs, 2H), 7.23 (m, 1H), 6.95 (dd, 1H), 6.82 (m, 1H), 5.31 (q, 1H), 4.45 (m, 1H), 4.20 (dd, 1H), 3.99 (m, 1H), 3.56 (m, 1H), 3.47 (m, 3H), 3.37 (m, 1H), 3.15 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.80 (t, 1H), 2.74 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (m, 1H), 2.08 (m, 1H), 2.10 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.46 (d, 3H). MS: m/z 617 [MH]⁺, as free base.
syn of intermediates

^a(a) (i) 2-Bromo-5-fluorotoluene, Mg, THF, 60−70 °C; (ii) 4-methoxypyridine, benzyl chloroformate, THF, −20 °C, then Grignard’s reagent, −20 °C, 1 h; (b) (i) tris(triphenylphosphine)rhodium(I) chloride, 2-propanol, H₂ (p = 5 atm), 60 °C, 5 h; (ii) Pd/C 5%, H₂ (p = 4 atm), 20 °C, 5 h; (iii) (R,S)-10-camphorsulfonic acid, toluene; (c) CH₂Cl₂, H₂O, 8% NaHCO₃ (aq); l-(+)-mandelic acid, 2-propanol, heptanes; (d) MeNH₂, EtOH, NaBH₄, 25 °C, 1.5 h; (e) (i) ethyl acetate, NaHCO₃ (aq. sat. soln), 5; (ii) triphosgene, triethylamine, ethyl acetate, then 5, 20 °C, 2 h; (f) R′RNH, CH₃CN, NaBH(OAc)₃, room temp, 24 h.

THANKS AND REGARD'S
DR ANTHONY MELVIN CRASTO Ph.D
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
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I was  paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

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

Japanese Knotweed (Polygonum cuspidatum) is widely used in Chinese Medicine, where it is known as Hu Zhang (Tiger Cane). The root is the part used and in my opinion, it is a plant medicine that American herbalists should use more frequently.

Many of you are probably quite familiar with this herb as it is an aggressive, difficult to eradicate, weedy plant. I have actually seen it paved over with macadam and grow right through the asphalt. 

The dried root is used in TCM to dispel damp heat and wind damp conditions with blood stasis and pain. From a western perspective this means it acts as an anti-inflammatory, antibacterial and analgesic.

 It is used to treat osteo- and rheumatoid arthritis, trauma injuries (orally and topically) and I find it to be quite effective for treating Lyme-induced arthritis and post-Lyme arthralgias. 

Having said that, there are many websites that claim this herb can "cure" Lyme disease. I can say with a fair amount of certainty that it does not. 

The root is also used for damp heat (inflammation and/or infection) in the genitourinary, gastrointestinal and respiratory tracts and has been successfully used as part of a protocol to treat jaundice, dysentery, hepatitis, nephritis, bronchitis and pneumonia. 

Japanese Knotweed is the richest known source of the antioxidant stilbene known as Res

veratrol and the young tops can be cooked and eaten, with a taste similar to Rhubarb.

NETUPITANT « New Drug Approvals

NETUPITANT « New Drug Approvals:

'via Blog this'

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

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.

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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 MgSO₄ and concentrated under reduced pressure to afford crude 3, which is used for next step without further purification.

Compound 3 in 10 ml dry CH₂Cl₂ is 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.

....................................

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

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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