New Drug Approvals

ROLAPITANT HYDROCHLORIDE

• Rolapitant HCl
• Rolapitant hydrochloride
• Sch 619734
• SCH619734
• UNII-57O5S1QSAQ

(5S ,8S)-8-[[(1R)-1-[3 ,5-
Bis(trifluoromethyl)phenyl] ethoxy] methyl]-8-phenyl-1,7-
diazaspiro[4.5]decan-2-one hydrochloride monohydrate.   

CAS 914462-92-3

Empirical Formula: C25H26F6N2O2 · HCl · H2O 

Molecular Weight:  555 

USAN Name: Rolapitant hydrochloride 

INN Name:  rolapitantum or rolapitant 

phase 3

CAS Number: 552292-08-7 (rolapitant free base); 914462-92-3 (rolapitant HCl monohydrdate).

It is in late-stage trials of its drug rolapitant, which showed promising mid-stage results in reducing nausea and vomiting in patients undergoing chemotherapy

Rolapitant hydrochloride is a tachykinin neurokinin 1 (NK1) antagonist in phase III clinical trials at Tesaro for the prevention of chemotherapy-induced nausea and vomiting (CINV). Phase II clinical trials are also under way at OPKO for this indication. At Merck & Co., phase II clinical studies were also under way for the treatment of chronic idiopathic cough and for the prevention of chemotherapy-induced nausea; however, no recent developments have been reported for these indications.

NK1 is a G-protein coupled receptor found in the central and peripheral nervous systems. Substance P is the endogenous ligand for this receptor, whose activation leads to the production of inositol triphosphate. NK1 is believed to be involved in the emetic response.

The drug candidate was originally developed by Schering-Plough (now Merck & Co.), and in 2009 it was licensed to OPKO for the prevention of nausea and vomiting related to cancer chemotherapy and surgery. In 2010, rolapitant was licensed by OPKO to Tesaro on a worldwide basis for the prevention of chemotherapy-induced nausea and vomiting.

Rolapitant is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of >1000-fold. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM.  (source: Pharmacol Biochem Behav.2012 Mar 31.

Rolapitant is a potent, selective NK1 receptor antagonist that is rapidly absorbed, has a remarkably long half-life (up to180 hours), and appears to have a low potential for drug-drug interactions.  A randomized, multicenter, double-blind, dose-ranging study of rolapitant was conducted with placebo and active control groups. Six hundred nineteen adult women undergoing open abdominal surgery were randomly assigned in equal ratios to 1 of 6 study arms: oral rolapitant in 5-mg, 20-mg, 70-mg, or 200-mg doses; IV ondansetron 4 mg; or placebo, stratified by history of PONV or motion sickness. The primary study endpoint was absence of emetic episodes, regardless of use of rescue medication, at 24 hours after extubation.RESULTS: Groups assigned to rolapitant 20-mg, 70-mg, and 200-mg had a higher incidence of no emesis in comparison with placebo at 24 hours after surgery. A linear relationship between rolapitant dose and primary outcome was seen. The probability of an emetic episode was significantly lower in the rolapitant 70-mg and 200-mg groups in comparison with placebo (P ≤ 0.001 based on the log-rank test). No significant differences were noted between rolapitant and the active control (ondansetron) at 24 hours after surgery, but there was a higher incidence of no emesis (regardless of rescue medication use) in the rolapitant 200- and 70-mg groups at 72 and 120 hours, respectively. CONCLUSION: Rolapitant is superior to placebo in reducing emetic episodes after surgery and reduces the incidence of vomiting in a dose-dependent manner. No differences in side effect profile were observed between rolapitant and placebo.

1: Gan TJ, Gu J, Singla N, Chung F, Pearman MH, Bergese SD, Habib AS, Candiotti KA, Mo Y, Huyck S, Creed MR, Cantillon M; Rolapitant Investigation Group. Rolapitant for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial. Anesth Analg.
2011 Apr;112(4):804-12. Epub 2011 Mar 8. PubMed PMID: 21385988.

2.  Reddy GK, Gralla RJ, Hesketh PJ. Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis. Support Cancer Ther. 2006 Apr 1;3(3):140-2. PubMed PMID: 18632487.

3. Drug Data Rep 2003, 25(8): 703

4. A multicenter, randomized, double blind, active-controlled study of the safety and efficacy of rolapitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving moderately emetogenic chemotherapy (NCT01500226)
ClinicalTrials.gov Web Site 2012, February 06

5. Efficacy and safety of rolapitant, a novel NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting in subjects receiving highly emetogenic chemotherapy
48th Annu Meet Am Soc Clin Oncol (ASCO) (June 1-5, Chicago) 2012, Abst 9077

6. Proposed international nonproprietary names (Prop. INN): List 97
WHO Drug Inf 2007, 21(2): 160

………………………………

patents

WO 2003051840

WO 2008118328

………………………….

The preparation of diazaspirodecan-2-ones for example, 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one, for example, (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) has been described in U.S. Pat. No. 7,049,320 (the ‘320 patent), issued May 23, 2006, the disclosure of which is incorporated herein in its entirety by reference.

The compounds described in the ‘320 patent are classified as tachykinin compounds, and are antagonists of neuropeptide neurokinin-1 receptors (herein, “NK-1” receptor antagonists). Other NK₁ receptor antagonists and their synthesis have been described, for example, those described in Wu et al, Tetrahedron 56, 3043-3051 (2000); Rombouts et al, Tetrahedron Letters 42, 7397-7399 (2001); and Rogiers et al, Tetrahedron 57, 8971-8981 (2001) and in published international application no. WO05/100358, each of which are incorporated herein in their entirety by reference.

“NK-1” receptor antagonists have been shown to be useful therapeutic agents, for example, in the treatment of pain, inflammation, migraine, emesis (vomiting), and nociception. Among many compounds disclosed in the above-mentioned ‘320 patent are several novel diazaspirodecan-2-ones, including the compound of Formula I, which are useful in the treatment of nausea and emesis associated with chemotherapy treatments (Chemotherapy-induced nausea and emesis, CINE).

The synthesis method for preparing the compound of Formula I described in the ‘320 patent generally follows Scheme I in the provision of 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxyl}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds.

The process for the preparation of the compound of Formula I described in the ‘320 patent is carried out in 18 individual steps from commercially available starting materials (see the ‘320 patent at col. 43, line 55 to col. 45, line 20; col. 75. line 55 to col. 80, line 21; col. 90 lines 35 to 63; and col. 98, line 1 to col. 99. line 24). In many steps of the process described in the ‘320 patent, intermediate compounds must be isolated or isolated and purified before use in a subsequent step, often utilizing column chromatography for this purpose.

……………………………

US7049320

Examples 72a and 72b

Step 1:

To a solution of crude Compound 53 (19 g) in CH₂Cl₂ (300 ml) at RT, DIEA (15 ml, 0.087 mol) was added, followed by triphosgene (4.34 g, 0.015 mol). The mixture was stirred at RT for 18 h and was filtered through a pad of silica. Solvents were removed in vacuum to give crude Compound 60 as yellow oil which was used in the next reaction without further purifications.

Step 2:

To the crude Compound 60 in THF (200 ml) at 0° C., LiBH₄ (1.26 g, 0.058 mol) was added in small portions. The mixture was stirred at RT for 18 h before quenching with saturated NH₄Cl solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (100×2). The combined organic layers were dried (MgSO₄) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4:1 (v/v)] gave Compound 61 (12.9 g, 62% overall) as white foam.

Step 3:

Oxalyl chloride (4.2 ml, 0.048 mol) was added to a solution of DMSO (6.8 m[, 0.096) in CH₂Cl₂ (300 ml) at −78° C. under N₂. The mixture was stirred at −78° C. for 15 min before a solution of Compound 61 (8.5 g, 0.012 mol) in CH₂Cl₂ (100 ml) was added. The mixture was stirred at −78° C. for a further 1 h and Et₃N (23.5 ml) was added. The cooling bath was removed and the mixture was warmed to RT before it was quenched with saturated NaHCO₃ solution. Layers were separated and the aqueous was extracted with CH₂Cl₂ (150 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum gave an aldehyde as yellow oil. To a mixture of NaH (1.44 g, 0.036 mol) in THF at 0° C., methyl diethylphosphonoacetate (6.6 ml, 0.036 mol) was added. The mixture was stirred at 0° C. for 15 min and a solution of aldehyde in THF (100 ml) was added. The cooling bath was removed and the mixture was stirred at RT for 1 h. The reaction was quenched with saturated NH₄Cl solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4:1 (v/v)] gave an ester as white foam. The ester was dissolved in EtOH (100 ml) and a catalytic amount of palladium (1.28 g, 10% on carbon) was added. The mixture was shaken under H₂ (50 psi) for 2 days. Catalytic amount of Pd(OH)₂ (20% on carbon) was then added to the mixture and the mixture was again shaken under H₂ (50 psi) for 5 h. The mixture was filtered through a pad of Celite and solvents were removed in vacuum to give a white foam. The foam was then dissolved in CH₂Cl₂ (200 ml) and TFA (8.9 ml, 0.12 mol) was added. The mixture was stirred at RT for 18 h and was cooled at 0° C. before it was neutralized with saturated NaHCO₃ solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Solvents were removed in vacuum to give a yellow oil. The oil was dissolved in CH₃OH (50 ml) and a catalytic amount of K₂CO₃ (166 mg, 0.0012 mol) was added. The mixture was heated at 60° C. for 2 h. After being cooled to RT, the mixture was filtered through a pad of silica and solvents were removed in vacuum. Purification by column chromatography (EtOAc) gave the mixture of two isomers Example 72a and 72b (2.3 g, 38% overall) as white foam. Separation by HPLC using Chiralcel OD [hexane-isopropanol, 95:5 (v/v)] gave the less polar major isomer Example 72a as white foam. Electrospray MS [M+1]⁺=501.1. Continuous elution with the same solvent system gave the more polar minor isomer Example 72b as colorless oil.

Electrospray MS [M+1]⁺=501.1.

………………………..

US8552191

Example 6 Preparation of Formula I Compound Salt: (5S,8S)-8-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one hydrochloride monohydrate

…………………

https://www.google.it/patents/US8552191?hl=it&dq=WO+2008118328&ei=alDCUs-_KYiIrQeg3oCwDw&cl=en

……………

update added

……………

Aprepitant (MK-0869L-754,030), lUPAC name 5-([(2R,3S)-2-((R)-1 -[3,5- bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluorophenyl)morpholino]methyl)-1 /-/-1 ,2,4- triazol-3(2H)-one,

as described and claimed in the following US patents: US5,719,147, US 5,538,982, US 6,048,859, US 6,096,742 and US 6,235,735, the contents of which are incorporated herein by reference in their entirety. Also described in: Hale JJ et al, J Med Chem 1998; 41 (23) 4607-14; as well as pro-drugs thereof, such as:

Fosaprepitant (L-758,298, Emend) lUPAC name [3-{[(2R,3S)-2-[(1 R)-1 -[3,5- bis(trifluoromethyl)phenyl] ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl}-5-oxo- 2H- 1 ,2,4-triazol-1 -yl]phosphonic acid

e.g. in the form of a salt such as the dimeglumine salt as described and claimed at least in US 5,691 ,336, the contents of which are incorporated herein by reference in its entirety; b. ZD4974 as described in WO02026724 and WO01077089, the contents of which are incorporated herein by reference in its entirety:

The following compound, described in WO01077069 and WO00059873, the contents of which are incorporated herein by reference in entirety:

d. The following compound described in DE19519245, the contents of which are incorporated herein by reference in its entirety:

e. The following compound described in WO9732865, the contents of which are incorporated herein by reference in its entirety:

f. The following compound described in EP1295599, the contents of which are incorporated herein by reference in its entirety:

g. CGP49823 described in WO9626183 and WO9610562, the contents of which are incorporated herein by reference in their entirety:

h. The following compound as described in WO9514017, the contents of which are incorporated herein by reference in its entirety:

LY303870, Lanepitant, described in WO9907681 , the contents of which incorporated herein by reference in its entirety:

j. LI 686017, described in WO03091226, the contents of which are incorporated

herein by reference in its entirety:

k. FK888, as described in Hagiwara D et al, J Med Chem 1994; 37: 2090-9 and

WO9222569, WO93141 13, WO9321215, EP655442 and WO9637488, the contents of which are incorporated herein by reference in their entirety:

I. The following compound, described in WO9222569, WO93141 13, WO9321215, EP655442 and WO9637488, the contents of which are incorporated herein by reference in their entirety:

m. The following compound, described in WO9222569, WO93141 13, WO9321215, EP655442 and WO9637488, the contents of which are incorporated herein by reference in their entirety:

n. The following compound, described in WO00053572, the contents of which are incorporated herein by reference in its entirety:

o. Netupitant, described in WO020008232, the contents of which are incorporated herein by reference in its entirety:

p. Befetupitant, described in WO020008232, the contents of which are incorporated herein by reference in its entirety:

q. The following compound, described in WO202062784 and WO020008232, the

contents of which are incorporated herein by reference in their entirety:

r. R1 16031 , described in WO9724356 and WO0716440, the contents of which are incorporated herein by reference in their entirety:

s. The following compound, described in EP522808, the contents of which are incorporated herein by reference in its entirety:

t. The following compound:

KA731 , described in WO9831704, the contents of which are incorporated herein by reference in its entirety:

x. NKP608, described in WO04024714, the contents of which are incorporated herein by reference in its entirety:

y. CP96,345 described in Lowe JA et al. 1992; 35:2591 -600, and in WO92021677, the contents of which are incorporated herein by reference in their entirety;

z. The following compound, described in Lowe JA et al. J Med Chem 1994; 37:2831 – 40, and in WO92021677, the contents of which are incorporated herein by reference in their entirety;

aa.CP99,994, described in Desai MC et al. J Med Chem 1992; 35:491 1 -3, the contents of which are incorporated herein by reference in its entirety;

bb.CP-122,721 described in Rosen TJ et al. Bioorg Med Chem Lett 1998; 8:281 -4, the contents of which are incorporated herein by reference in its entirety:

cc. CJ-17,493, described in WO9925714, the contents of which are incorporated herein by reference in its entirety:

dd.Ezlopitant, CJ-1 1 ,974 described in WO1992021677 the contents of which are

incorporated herein by reference in its entirety:

ee.Maropitant, CJ-1 1 ,972, described in WO1992021677, US 6,222,038 and US

6,255,230, the contents of which are incorporated herein by reference in their entirety:

ff. RP77580 described in EP429366, the contents of which are incorporated herein reference in its entirety:

gg.Dapitant, RPR100893, described in WO9321 154, the contents of which are incorporated herein by reference in its entirety:

hh.The following compound, described in EP512901 , the contents of which are incorporated herein by reference in its entirety:

ii. Nolpitantium, SR140333 described in EP512901 , the contents of which are incorporated herein by reference in its entirety:

jj. The following compound, described in WO9526338, the contents of which are incorporated herein by reference in its entirety:

kk. SSR240600, described in WO00068292, the contents of which are incorporated herein by reference in its entirety:

II. SCH388714 described in WO06065654, the contents of which are incorporated herein by reference in its entirety:

mm. The following compound described in Paliwal S et al, Bioorg Med Chem Lett 2008; 18:4168-71 , the contents of which are incorporated herein by reference in its entirety:

nn.Rolapitant, described in WO03051840, the contents of which are incorporated

herein by reference in its entirety:

oo. The following compound, dexcribed in EP566069, the contents of which are

incorporated herein by reference in its entirety:

pp.TAK-637, described in JP10259184, the contents of which are incorporated herein by reference in its entirety:

qq.The following compound described in JP2004002334, the contents of which are incorporated herein by reference in its entirety:

rr. The following compound described in JP2007277231 and JP2008239618, the contents of which are incorporated herein by reference in their entirety:

. The following compound described in JP2007277231 and JP2008239618, the contents of which are incorporated herein by reference in their entirety:

tt. The following compound described in WO9317032 and WO951 1686, the contents of which are incorporated herein by reference in their entirety:

The following compound described in WO9630367 and WO01025233, the contents of which are incorporated herein by reference in their entirety:

vv. HSP1 17 described in WO9630367 and WO01025233, the contents of which are incorporated herein by reference in their entirety:

ww. The following compound, described in Set S, et al. Bioorg Med Chem ILKett 2005; 15:1479-84 and WO03062245, the contents of which are incorporated herein by reference in their entirety:

xx. The following compound, described in Seto S, et al. Bioorg Med Chem Lett 2005;

15:1479-84 and WO03062245, the contents of which are incorporated herein by reference in their entirety:

yy. The following compound, KRP-103, described in WO03062245 and WO05019225, the contents of which are incorporated herein by reference in their entirety:

zz. The following compound described in WO06106727, the contents of which are incorporated herein by reference in its entirety:

aaa. The following compound, described in WO07074491 , the contents of which are incorporated herein by reference in its entirety:

bbb. SLV317, described in US20020065276, the contents of which are

incorporated herein by reference in its entirety: