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ROLAPITANT, ロラピタント

December 3, 2018 9:31 am / 1 Comment on ROLAPITANT, ロラピタント

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

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

ChemSpider 2D Image | rolapitant | C25H26F6N2O2

Rolapitant

Molecular FormulaC₂₅H₂₆F₆N₂O₂
Average mass500.477 Da

(5S,8S)-8-({(1R)-1-[3,5-Bis(trifluorométhyl)phényl]éthoxy}méthyl)-8-phényl-1,7-diazaspiro[4.5]décan-2-one

1,7-Diazaspiro[4.5]decan-2-one, 8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-, (5S,8S)-

552292-08-7 [RN]

8882

NLE429IZUC

SCH 619734

SCH-619734

Varubi®

UNII-NLE429IZUC

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

Rolapitant Hydrochloride Hydrate was approved by the U.S. Food and Drug Administration (FDA) on Sep 1, 2015. It was developed by Tesaro, then marketed as Varubi^® by Tesaro in US.

Rolapitant Hydrochloride Hydrate is a selective and competitive antagonist of human substance P/NK1 receptors used to treat chemotherapy-induced nausea and vomiting.
Varubi^® is available as tablet for oral use, containing 90 mg of free Rolapitant. The recommended dose is 180 mg approximately 1 to 2 hours prior to the start of chemotherapy.

In contrast to other NK-1 inhibitors that play an essential role in delayed CINV therapy, rolapitant shows no inhibition of CYP3A4, eliminating the need for concern when coadministering with CYP34A substrates. Additionally, rolapitant is an orally active agent with a relatively long half-life (180 h), providing potential opportunities for single- and prechemotherapy-based treatments.

In three large clinical trials involving patients receiving moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC), subjects using rolapitant as a cotherapy with granisetron and dexamethasone showed a significant improvement in complete response compared to those receiving treatments of granisetron and dexamethasone.

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.

Rolapitant (INN,^[2] trade name Varubi /vəˈruːbi/ və-ROO-bee in the US and Varuby in Europe) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK₁ receptor antagonist (antagonist for the NK₁ receptor).^[3] It has been approved as a medication for the treatment of chemotherapy-induced nausea and vomiting (CINV) after clinical trials showed it to have similar or improved efficacy and some improvement in safety over existing drugs for this application.^[4]^[5]^[6]^[7

Medical uses

Rolapitant is used in combination with other antiemetic (anti-vomiting) agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.^[1] The approved antiemetic combination consists of rolapitant plus dexamethasone and a 5-HT₃ antagonist.^[8]

Contraindications

Under the US approval, rolapitant is contraindicated in combination with thioridazine, whose inactivation could be inhibited by rolapitant.^[9] Under the European approval, it is contraindicated in combination with St. John’s Wort, which is expected to accelerate inactivation of rolapitant.^[8]

Side effects

In studies comparing chemotherapy plus rolapitant, dexamethasone and a 5-HT₃ antagonist to chemotherapy plus placebo, dexamethasone and a 5-HT₃ antagonist, most side effects had comparable frequencies in both groups, and differed more between chemotherapy regimens than between rolapitant and placebo groups. Common side effects included decreased appetite (9% under rolapitant vs. 7% under placebo), neutropenia (9% vs. 8% or 7% vs. 6%, depending on the kind of chemotherapy), dizziness (6% vs. 4%), indigestion and stomatitis (both 4% vs. 2%).^[9]

Overdose

Up to eightfold therapeutic doses have been given in studies without problems.^[8]

Interactions

Rolapitant moderately inhibits the liver enzyme CYP2D6. Blood plasma concentrations of the CYP2D6 substrate dextromethorphanhave increased threefold when combined with rolapitant; and increased concentrations of other substrates are expected. The drug also inhibits the transporter proteins ABCG2 (breast cancer resistance protein, BCRP) and P-glycoprotein (P-gp), which has been shown to increase plasma concentrations of the ABCG2 substrate sulfasalazine twofold and the P-gp substrate digoxin by 70%.^[8]

Strong inducers of the liver enzyme CYP3A4 decrease the area under the curve of rolapitant and its active metabolite (called M19); for rifampicin, this effect was almost 90% in a study. Inhibitors of CYP3A4 have no relevant effect on rolapitant concentrations.^[8]

Pharmacology

Pharmacodynamics

Both rolapitant and its active metabolite M19 block the NK₁ receptor with high affinity and selectivity: to block the closely related receptor NK₂ or any other of 115 tested receptors and enzymes, more than 1000-fold therapeutic concentrations are necessary.^[10]

Pharmacokinetics

The major active metabolite, M19 (C4-pyrrolidine-hydroxylated rolapitant).^[8] The stereochemistry of the hydroxyl group is unknown.

Rolapitant is practically completely absorbed from the gut, independently of food intake. It undergoes no measurable first-pass effect in the liver. Highest blood plasma concentrations are reached after about four hours. When in the bloodstream, 99.8% of the substance are bound to plasma proteins.^[8]

It is metabolized by the liver enzyme CYP3A4, resulting in the major active metabolite M19 (C4-pyrrolidine-hydroxylated rolapitant) and a number of inactive metabolites. Rolapitant is mainly excreted via the feces (52–89%) in unchanged form, and to a lesser extent via the urine (9–20%) in form of its inactive metabolites. Elimination half-life is about seven days (169 to 183 hours) over a wide dosing range.^[8]

Chemistry

The drug is used in form of rolapitant hydrochloride monohydrate, a white to off-white, slightly hygroscopic crystalline powder. Its maximum solubility in aqueous solutions is at pH 2–4.^[10]

Patents

WO 2003051840

PATENT

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 NK₁receptor 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.

PATENT

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 NaHCO₃solution. 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 NaHCO₃solution. 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.

PATENT

US8552191

Figure US08552191-20131008-C00028

Figure US08552191-20131008-C00029

Figure US08552191-20131008-C00030

Figure US08552191-20131008-C00031

Figure US08552191-20131008-C00032

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

…………………

Figure US08552191-20131008-C00016

Figure US08552191-20131008-C00017

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

……………

update added

By RTT News, May 12, 2014,

(RTTNews.com) – TESARO Inc. ( TSRO ) announced positive top-line results from the third and final Phase 3 trial of rolapitant, an investigational neurokinin-1 or NK-1 receptor antagonist in development for the prevention of chemotherapy-induced nausea and vomiting (CINV).

The rolapitant arm in this trial, which enrolled patients receiving cisplatin-based, highly emetogenic chemotherapy or HEC, successfully achieved statistical significance over the standard therapy arm for the primary and all secondary endpoints. The adverse event profile for rolapitant remains consistent with that seen in previous clinical studies.

The third Phase 3 study of rolapitant was an international, multicenter, randomized, double-blind, active-controlled study that enrolled 532 cancer patients receiving cisplatin-based chemotherapy regimens at a dose equal to or greater than 60 mg/m2. Patients were randomized to receive either control, which consisted of a 5-HT3 receptor antagonist plus dexamethasone, or 200 milligrams of oral rolapitant plus control. The rolapitant arm in this study successfully achieved statistical significance over the control arm for the primary endpoint of complete response (CR) in the delayed phase of CINV.

In addition, the rolapitant arm also successfully achieved statistical significance over the control arm for the key secondary endpoints of CR in the acute (0 to 24 hour) and overall (0 to 120 hour) phases of CINV, for the secondary endpoint of no significant nausea, and for all other secondary endpoints.

Safety and tolerability data for patients who received rolapitant were similar to the results for those who received control, and were consistent with earlier clinical studies. The most frequently observed adverse events were balanced across treatment arms and included fatigue, constipation and loss of appetite.

The company noted that preparations continue in support of a submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in mid-2014.

The oral rolapitant NDA will include data from one Phase 3 study in patients receiving moderately emetogenic chemotherapy (MEC), in addition to one Phase 2 and two Phase 3 trials in patients receiving cisplatin-based, highly emetogenic chemotherapy (HEC), including the trial announced today.

The top-line results of the Phase 3 trial in MEC and the prior Phase 3 trial in HEC were previously announced by TESARO in December 2013.

Rolapitant is an investigational agent and, as such, has not been approved by the U.S. FDA or any regulatory agencies.

CLIP

Rolapitant Hydrochloride Hydrate (Varubi)

Rolapitant hydrochloride hydrate, originally discovered by Schering-Plough and later developed by TESARO, Inc., was approved by the FDA in September 2015 for the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in combination with other antiemetic agents.(67) Rolapitant is a highly selective NK-1 receptor antagonist, exhibiting >1000-fold selectivity for NK-1 over human NK-2 and NK-3 receptors in vitro.(68) In contrast to other NK-1 inhibitors that play an essential role in delayed CINV therapy,(69) rolapitant shows no inhibition of CYP3A4,(68)eliminating the need for concern when coadministering with CYP34A substrates. Additionally, rolapitant is an orally active agent with a relatively long half-life (180 h),(68, 70) providing potential opportunities for single- and prechemotherapy-based treatments.(71)

Rolapitant features a fascinating molecular architecture consisting of two tetrasubstituted stereogenic carbon centers situated at the 2- and 5-carbons within a central piperidine ring and a spirocyclic array residing at the 5-position and a phenyl ring and ethereal linkage branching from the 2-position (Scheme 17). The overall synthetic strategy to secure rolapitant hydrochloride hydrate relies upon the union of two advanced chiral building blocks that contain functional groups capable of securing the central piperidine ring. These two key intermediates, pyroglutamate derivative 93 and allylic amine 94, each bear one of the essential stereocenters embedded within the structure of the active pharmaceutical ingredient.(73) The first of these advanced intermediates, amidoaldehyde 93, is generated directly by base-mediated decomposition of pyroglutamic aminal 92, which was prepared according to the route shown in Scheme 18. Subjection of 92 to triethylamine in EtOH/H₂O at ambient temperatures led to generation of chiral allyl aldehyde 93, which was not isolated but condensed immediately with amine 94 (Scheme 19) in the presence of refluxing toluene to provide divinyl imine 95, which underwent immediate reduction using NaBH(OAc)₃ in AcOH/toluene to furnish the free amine.

The free amine was converted to the corresponding tosylate monohydrate salt and triturated, providing 96 as a white crystalline powder after subjection to TsOH·H₂O in i-PrOH/H₂O. Divinyl amine 96 could then be reacted with a solution of TsOH in toluene, distilled, and directly combined with a toluene solution of Hoveyda–Grubbs second-generation catalyst (HG-II) under heating conditions, leading to the desired ring-closing metathesis product 97 as the HCl salt (85% yield over two steps) after filtration, distillation, and workup with 12N HCl. Washing of a toluene solution of 97 with aqueous NaOH and subsequent treatment of the resulting organic solution with H₂, wet Pd/C, and additional granular activated carbon (Nuchar Aquaguard) led to the fully reduced piperidine product in high yield (95%). Rolapitant hydrochloride hydrate XIII was accessed thereafter by precipitation from a solution of EtOH/i-PrOH/H₂O/HCl, providing the product as a white solid (91% yield).(73)

Scheme 17. Synthesis of Rolapitant Hydrochloride Hydrate (XIII)

Scheme 18. Synthesis of Fragment 92 of Rolapitant Hydrochloride Hydrate (XIII)

Scheme 19. Synthesis of Fragment 94 of Rolapitant Hydrochloride Hydrate (XIII)

Aldehyde precursor 92 was accessed in a four-step sequence starting from commercially available l-pyroglutamic acid 98 (Scheme 18).(73, 74) Condensation of 98 with trimethylacetaldehyde at elevated temperatures in the presence of methanesulfonic acid and NMP prior to careful addition of TFAA led to formation of pyrrolo-oxazolidone 99 in 72% yield. Deprotonation (LHMDS) and stereoselective alkylation of 99 with methyl formate, assisted by addition of copper chloride as a Lewis acid, provided access to carbaldehyde 100 in moderate yield (61%) as a single diastereomer(74) after aqueous workup and crystallization from MTBE.

Wittig olefination of aldehyde 100 (Ph₃PCH₃Br/LHMDS) followed by aqueous workup and precipitation of triphenylphosphine oxide via addition of MgCl₂ constructed an allyl lactone intermediate in 63% yield as an off-white solid, which then immediately underwent partial reduction with LiAlH(Ot-Bu)₃to smoothly deliver the key aldehyde precursor 92 in 83% yield as an inconsequential mixture of diastereomers (the stereocenter of consequence arose from the naturally occurring l-pyroglutamic acid 98), which could be employed directly in Scheme 17.(73)

Generation of 94 began with commercially available N-Cbz-(S)-phenylglycine 101 based on reports by O’Donnell and co-workers (Scheme 19).(75) Reaction of 101 with benzaldehyde dimethylacetal under Lewis acid conditions (BF₃·Et₂O) in diethyl ether led to high yield, diastereoselectivity, and enantioselectivity of trans-disubstituted oxazolidinone 102. In this case, selection of diethyl ether as a solvent was essential, as the use of DCM under similar reaction conditions favored formation of the undesired cis-product. Removal of the most acidic proton within 102 by means of KHMDS in toluene/THF, followed by alkylation with commercially available bromomethyl ether (103) in THF, led to 68% yield of 104 as a single diastereomer.(73, 76)

Reduction of 104 to the corresponding lactol (LiAlH₄/Et₂O) and subsequent ring opening with KHCO₃/H₂O in NMP yielded the intermediate aldehyde, which was readily converted to 105 via addition of the crude aldehyde solution to a mixture of Ph₃PCH₃Br and NaHMDS in toluene.

As described in Scheme 15, triphenylphosphine oxide scavenge by way of MgCl₂ enabled generation of crude product in good purity after a simple filtration. TMSI-mediated Cbz removal converted 105to the resulting free amine. Formation of the maleic acid salt enabled the product to be isolated as a crystalline solid in high purity without chromatography. Treatment of the maleate salt with NaOH in toluene provided the free base 94, which was incorporated as previously described in Scheme 17 without the need for additional purification.(73)

67 . Syed, Y. Y. Rolapitant: First Global Approval Drugs 2015, 75, 1941– 1945 DOI: 10.1007/s40265-015-0485-8
68.Duffy, R. A.; Morgan, C.; Naylor, R.; Higgins, G. A.; Varty, G. B.; Lachowicz, J. E.; Parker, E. M. Rolapitant (SCH 619734): A Potent, Selective and Orally Active Neurokinin NK1 Receptor Antagonist with Centrally-mediated Antiemetic Effects in Ferrets Pharmacol., Biochem. Behav. 2012, 102, 95– 100 DOI: 10.1016/j.pbb.2012.03.021
69.Janelsins, M. C.; Tejani, M. A.; Kamen, C.; Peoples, A. R.; Mustian, K. M.; Morrow, G. R. Current Pharmacotherapy for Chemotherapy-induced Nausea and Vomiting in Cancer Patients Expert Opin. Pharmacother. 2013, 14, 757– 766 DOI: 10.1517/14656566.2013.776541
70.Navari, R. M. Rolapitant for the Treatment of Chemotherapy-induced Nausea and Vomiting Expert Rev. Anticancer Ther. 2015, 15, 1127– 1133 DOI: 10.1586/14737140.2015.1088787
71.Romero, D. Chemotherapy Rolapitant – a New and Safer Antiemetic Agent Nat. Rev. Clin. Oncol. 2015, 12,562 DOI: 10.1038/nrclinonc.2015.144
72.(a) Schwartzberg, L. S.; Modiano, M. R.; Rapoport, B. L.; Chasen, M. R.; Gridelli, C.; Urban, L.; Poma, A.;Arora, S.; Navari, R. M.; Schnadig, I. D. Safety and Efficacy of Rolapitant for Prevention of Chemotherapy-induced Nausea and Vomiting after Administration of Moderately Emetogenic Chemotherapy or Anthracycline and Cyclophosphamide Regimens in Patients with Cancer: a Randomised, Active-controlled, Double-blind, Phase 3 Trial Lancet Oncol. 2015, 16, 1071– 1078 DOI: 10.1016/S1470-2045(15)00034-0

(b) Rapoport, B.; Schwartzberg, L.; Chasen, M.; Powers, D.; Arora, S.;Navari, R.; Schnadig, I. Efficacy and Safety of Rolapitant for Prevention of Chemotherapy-induced Nausea and Vomiting Over Multiple Cycles of Moderately or Highly Emetogenic Chemotherapy Eur. J. Cancer 2016,57, 23– 30 DOI: 10.1016/j.ejca.2015.12.023
73.Wu, G. G.; Werne, G.; Fu, X.; Orr, R. K.; Chen, F. X.; Cui, J.; Sprague, V. M.; Zhang, F.; Xie, J.; Zeng, L.;Castellanos, L. P.; Chen, Y.; Poirier, M.; Mergelsberg, I. Process and Intermediates for the Synthesis of 8-[[1-[3,5-bis-(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one Compounds. WO 2010028232A1, 2010.
74.Dikshit, D. K.; Maheshwari, A.; Panday, S. K. Self Reproduction of Chirality in Pyroglutamates: Reactions at α-Position with Electrophiles Tetrahedron Lett. 1995, 36, 6131– 6134 DOI: 10.1016/0040-4039(95)01160-J
75.O’Donnell, M. J.; Fang, Z.; Ma, X.; Huffman, J. C. New Methodology for the Synthesis of α,α-Dialkylamino Acids Using the ″Self-regeneration of Stereocenters″ Method: α-Ethyl-α-phenylglycine Heterocycles 1997,46, 617– 630 DOI: 10.3987/COM-97-S83
76.Paliwal, S.; Reichard, G. A.; Wang, C.; Xiao, D.; Tsui, H.-C.; Shih, N.-Y.; Arredondo, J. D.; Wrobleski, M. L.;Palani, A. Preparation of Pyrrolidine and Piperidine Derivatives for Therapeutic Use as Neurokinin 1 (NK1) Receptor Antagonists. WO 2003051840A1, 2003.

REF

HETEROCYCLES 1997 46 PG 617 630

Paper | Special issue | Vol 46, No. 1, 1997, pp.617-630
Published online, 1st January, 1970

DOI: 10.3987/COM-97-S83

■ New Methodology for the Synthesis of α,α-Dialkylamino Acids Using the “Self-Regeneration of Stereocenters” Method: α-Ethyl-α-phenylglycine

Martin J. O’Donnell,* Zhiqiang Fang, Xiaojun Ma, and John C. Huffman

*Department of Chemistry, Indiana University-Purdue University at Indianapolis, Indianapolis, IN 46202, U.S.A.

Abstract

The stereoselective room temperature ethylations of protected oxazolidinones from phenylglycine by phase-transfer catalysis or with KOtBu as base are used to prepare optically active α-ethyl-α-phenylglycine.

PATENT

https://patents.google.com/patent/CN106866669A/en

⑴ Route A:

[0005] ⑵ Route B:

[0007] (3) Route C:

[0009] Scheme C, wherein the method further comprises synthesizing Via, namely:

Won] now, with respect to the other two routes, from the reaction step, time costs, material costs, product yield and product purity of view, comparing the current line C is respected, it is more suitable for production. But even so, there are still a number of route C the following questions:

[0012] [1], the synthesis of compound V, there is a slow reaction, and the reaction was not complete and so on;

[0013] [2], when Via a salt, the desired product is low chiral purity and yield to be improved;

[0014] [3], when VIII recrystallized grain size to be improved.

CLIP

Image result for rolapitant synthesis

References

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

References

^ Jump up to:^a ^b “Varubi (rolapitant) Tablets, for Oral Use. Full Prescribing Information” (PDF). TESARO, Inc. 1000 Winter St., #3300, Waltham, MA 02451.
^ “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 59” (PDF). World Health Organization. p. 64. Retrieved 5 October 2016.
^ Duffy, R. A; Morgan, C; Naylor, R; Higgins, G. A; Varty, G. B; Lachowicz, J. E; Parker, E. M (2012). “Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets”. Pharmacol Biochem Behav. 102 (1): 95–100. doi:10.1016/j.pbb.2012.03.021. PMID 22497992.
^ Jordan, K; Jahn, F; Aapro, M (2015). “Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): a comprehensive review”. Ann Oncol. 26 (6): 1081–90. doi:10.1093/annonc/mdv138. PMID 25755107.
^ Nasir, S. S; Schwartzberg, L. S (2016). “Recent Advances in Preventing Chemotherapy-Induced Nausea and Vomiting”. Oncology. 30 (8): 750–62. PMID 27539626.
^ Rapoport, B; Schwartzberg, L; Chasen, M; Powers, D; Arora, S; Navari, R; Schnadig, I (2016). “Efficacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting over multiple cycles of moderately or highly emetogenic chemotherapy”. Eur J Cancer. 57: 23–30. doi:10.1016/j.ejca.2015.12.023. PMID 26851398.
^ Chasen, M. R; Rapoport, B. L (2016). “Rolapitant for the treatment of chemotherapy-induced nausea and vomiting: a review of the clinical evidence”. Future Oncol. 12 (6): 763–78. doi:10.2217/fon.16.11. PMID 26842387.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “Varuby: EPAR – Product Information” (PDF). European Medicines Agency. 2017-05-31.
^ Jump up to:^a ^b FDA Professional Drug Information on Varubi. Accessed 2017-10-11.
^ Jump up to:^a ^b “Varuby: EPAR – Public assessment report” (PDF). European Medicines Agency. 2017-05-31.

Rolapitant
Clinical data

Pronunciation	/roʊˈlæpɪtænt/ roh-LAP-i-tant
Trade names	Varubi (US), Varuby (EU)
Synonyms	SCH 619734
AHFS/Drugs.com	varubi
License data	EU EMA: by INN
Routes of administration	By mouth (tablets)
ATC code	A04AD14 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	nearly 100%
Protein binding	99.8%
Metabolism	CYP3A4
Metabolites	C4-pyrrolidine-hydroxylated rolapitant (major)
Elimination half-life	169–183 hours
Excretion	Feces (52–89%), urine (9–20%)^[1]
Identifiers
IUPAC name [show]
CAS Number	552292-08-7
PubChem CID	10311306
IUPHAR/BPS	5749
DrugBank	DB09291
ChemSpider	8486772
UNII	NLE429IZUC
KEGG	D10742
ChEBI	CHEBI:90908
Chemical and physical data
Formula	C₂₅H₂₆F₆N₂O₂
Molar mass	500.476 g/mol
3D model (JSmol)	Interactive image
SMILES [hide] FC(F)(F)c(c4)cc(C(F)(F)F)cc4C(C)OCC3(c2ccccc2)NCC1(CC3)NC(=O)CC1

/////////////ROLAPITANT, ロラピタント, FDA 2015, Schering-Plough, TESARO,

Selexipag, セレキシパグ ,селексипаг , سيليكسيباق ,

November 30, 2018 9:16 am / Leave a comment

ChemSpider 2D Image | Selexipag | C26H32N4O4S

Selexipag

Molecular FormulaC₂₆H₃₂N₄O₄S
Average mass496.622 Da

Selexipag, Uptravi

475086-01-2 CAS

(C₂₆H₃₂N₄O₄S, M_r = 496.6 g/mol)

A prostacyclin receptor (PGI2) agonist used to treat pulmonary arterial hypertension (PAH).

NIPPON SHINYAKU….INNOVATOR

セレキシパグ

UNII-5EXC0E384L

селексипаг [Russian] [INN]

سيليكسيباق [Amharic] [INN]

2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methylsulfonyl)acetamide

475086-01-2 [RN]

5EXC0E384L

9231

Acetamide, 2-[4-[(5,6-diphenyl-2-pyrazinyl)(1-methylethyl)amino]butoxy]-N-(methylsulfonyl)-

Selexipag (brand name Uptravi) is a drug developed by Actelion for the treatment of pulmonary arterial hypertension (PAH). Selexipag and its active metabolite, ACT-333679 (MRE-269) (the free carboxylic acid), are agonists of the prostacyclin receptor, which leads to vasodilation in the pulmonary circulation.^[1]

FDA approves new orphan drug to treat pulmonary arterial hypertension

12/22/2015

On December 21, the U.S. Food and Drug Administration approved Uptravi (selexipag) tablets to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive, and debilitating rare lung disease that can lead to death or the need for transplantation.

December 22, 2015

“Uptravi offers an additional treatment option for patients with pulmonary arterial hypertension,” said Ellis Unger, M.D., director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research. “The FDA supports continued efforts to provide new treatment options for rare diseases.”

PAH is high blood pressure that occurs in the arteries that connect the heart to the lungs. It causes the right side of the heart to work harder than normal, which can lead to limitations on exercise ability and shortness of breath, among other more serious complications.

Uptravi belongs to a class of drugs called oral IP prostacyclin receptor agonists. The drug acts by relaxing muscles in the walls of blood vessels to dilate (open) blood vessels and decrease the elevated pressure in the vessels supplying blood to the lungs.

Uptravi’s safety and efficacy were established in a long-term clinical trial of 1,156 participants with PAH. Uptravi was shown to be effective in reducing hospitalization for PAH and reducing the risks of disease progression compared to placebo. Participants were exposed to Uptravi in this trial for a median duration of 1.4 years.

Common side effects observed in those treated with Uptravi in the trial include headache, diarrhea, jaw pain, nausea, muscle pain (myalgia), vomiting, pain in an extremity, and flushing.

Uptravi was granted orphan drug designation. Orphan drug designation provides incentives such as tax credits, user fee waivers, and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

Uptravi is marketed by San Francisco-based Actelion Pharmaceuticals US, Inc.

The US FDA granted it Orphan Drug status^[2] (for PAH). It was approved by the U.S. FDA on 22 December 2015.^[2]

In 2016, the EMA granted marketing authorization in the E.U. for this indication and launch took place shortly after in Germany and the United Kingdom. In Japan, Nippon Shinyaku received approval for the treatment of PAH in 2016.

Selexipag was approved by the U.S. Food and Drug Administration (FDA) on Dec 21, 2015, approved by European Medicine Agency (EMA) on May 12, 2016. It was originally developed by Nippon Shinyaku and then it was licensed to Actelion for co-development. It is marketed as Uptravi^® by Actelion in US and EU.

Selexipag is a prostacyclin receptor (PGI2) agonist, which leads to vasodilation in the pulmonary circulation. It is indicated for the treatment of pulmonary arterial hypertension (PAH).

Uptravi^® is available as tablets for oral use, containing 200, 400, 600, 800, 1000, 1200, 1400, or 1600 mcg of selexipag. The initial dose is 200 mcg twice daily, and increase the dose by 200 mcg twice daily at weekly intervals to the highest tolerated dose up to 1600 mcg twice daily.

ACT-333679 or MRE-269, the active metabolite of selexipag

SYNTHESIS DEPICT

PATENT

US2012/101276

http://www.google.st/patents/US20120101276?hl=pt-PT&cl=en

The present invention relates to a crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as “compound A”).

BACKGROUND OF THE INVENTION

Compound A has an excellent PGI2 agonistic effect and shows a platelet aggregation inhibitory effect, a vasodilative effect, a bronchodilative effect, a lipid deposition inhibitory effect, a leukocyte activation inhibitory effect, etc. (see, for example, in WO 2002/088084 (“WO ‘084”)).

Specifically, compound A is useful as preventive or therapeutic agents for transient ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud’s disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute-phase cerebral thrombosis, pulmonary embolism), hypertension, pulmonary hypertension, ischemic disorder (e.g., cerebral infarction, myocardial infarction), angina (e.g., stable angina, unstable angina), glomerulonephritis, diabetic nephropathy, chronic renal failure, allergy, bronchial asthma, ulcer, pressure ulcer (bedsore), restenosis after coronary intervention such as atherectomy and stent implantation, thrombocytopenia by dialysis, the diseases in which fibrosis of organs or tissues is involved [e.g., Renal diseases (e.g., tuburointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease), digestive diseases (e.g., hepatocirrhosis, viral hepatitis, chronic pancreatitis and scirrhous stomachic cancer), cardiovascular diseases (e.g, myocardial fibrosis), bone and articular diseases (e.g, bone marrow fibrosis and rheumatoid arthritis), skin diseases (e.g, cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix), obstetric diseases (e.g., hysteromyoma), urinary diseases (e.g., prostatic hypertrophy), other diseases (e.g., Alzheimer’s disease, sclerosing peritonitis; type I diabetes and organ adhesion after operation)], erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic operation for removing prostata, and vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease, intestinal tuberculosis, ischemic colitis and intestinal ulcer associated with Behcet disease), gastritis, gastric ulcer, ischemic ophthalmopathy (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular necrosis of bone, intestinal damage caused by administration of a non-steroidal anti-inflammatory agent (e.g., diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib) (there is no particular limitation for the intestinal damage so far as it is damage appearing in duodenum, small intestine and large intestine and examples thereof include mucosal damage such as erosion and ulcer generated in duodenum, small intestine and large intestine), and symptoms associated with lumbar spinal canal stenosis (e.g., paralysis, dullness in sensory perception, pain, numbness, lowering in walking ability, etc. associated with cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, diffuse spinal canal stenosis or sacral stenosis) etc. (see, for example, in WO ‘084, WO 2009/157396, WO 2009/107736, WO 2009/154246, WO 2009/157397, and WO 2009/157398).

In addition, compound A is useful as an accelerating agent for angiogenic therapy such as gene therapy or autologous bone marrow transplantation, an accelerating agent for angiogenesis in restoration of peripheral artery or angiogenic therapy, etc. (see, for example, in WO ‘084).

Production of Compound A

Compound A can be produced, for example, according to the method described in WO ‘084, and, it can also be produced according to the production method mentioned below.

Step 1:

6-Iodo-2,3-diphenylpyrazine can be produced from 6-chloro-2,3-diphenylpyrazine by reacting it with sodium iodide. The reaction is carried out in the presence of an acid in an organic solvent (e.g., ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, or their mixed solvent). The acid to be used is, for example, acetic acid, sulfuric acid, or their mixed acid. The amount of sodium iodide to be used is generally within a range of from 1 to 10 molar ratio relative to 6-chloro-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the acid to be used, but may be generally within a range of from 60° C. to 90° C. The reaction time varies depending on the kinds of the solvent and the acid to be used and on the reaction temperature, but may be generally within a range of from 9 hours to 15 hours.

Step 2:

5,6-Diphenyl-2-[(4-hydroxybutyl(isopropyl)amino]pyrazine can be produced from 6-iodo-2,3-diphenylpyrazine by reacting it with 4-hydroxybutyl(isopropyl)amine. The reaction is carried out in the presence of a base in an organic solvent (e.g., sulfolane, N-methylpyrrolidone, N,N-dimethylimidazolidinone, dimethyl sulfoxide or their mixed solvent). The base to be used is, for example, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate or their mixed base. The amount of 4-hydroxybutyl(isopropyl)amine to be used may be generally within a range of from 1.5 to 5.0 molar ratio relative to 6-iodo-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from 170° C. to 200° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 5 hours to 9 hours.

Step 3:

Compound A can be produced from 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine by reacting it with N-(2-chloroacetyl)methanesulfonamide. The reaction is carried out in the presence of a base in a solvent (N-methylpyrrolidone, 2-methyl-2-propanol or their mixed solvent). The base to be used is, for example, potassium t-butoxide, sodium t-butoxide or their mixed base. The amount of N-(2-chloroacetyl)methanesulfonamide to be used may be generally within a range of from 2 to 4 molar ratio relative to 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from −20° C. to 20° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 0.5 hours to 2 hours.

The compounds to be used as the starting materials in the above-mentioned production method for compound A are known compounds, or can be produced by known methods.

PATENT

WO 2002088084

and

http://www.google.fm/patents/WO2009157398A1?cl=en

PAPER

Bioorganic and Medicinal Chemistry, 2007 , vol. 15, 21 p. 6692 – 6704

compd 31

PAPER

Bioorganic and Medicinal Chemistry, 2007 , vol. 15, 24 p. 7720 – 7725

Full-size image (5 K) 2a is the drug

N-Acylsulfonamide and N-acylsulfonylurea derivatives of the carboxylic acid prostacyclin receptor agonist 1 were synthesized and their potential as prodrug forms of the carboxylic acid was evaluated in vitro and in vivo. These compounds were converted to the active compound 1 by hepatic microsomes from rats, dogs, monkeys, and humans, and some of the compounds were shown to yield sustained plasma concentrations of 1 when they were orally administered to monkeys. These types of analogues, including NS-304 (2a), are potentially useful prodrugs of 1.

http://www.sciencedirect.com/science/article/pii/S0968089607007614

PATENT

WO 2011024874

A. Preparation of
Compound A Compound A can be produced , for example, by the method described in Patent Document 1, but can also be produced by the production method described below.
[

Step 2]
6-iodo-2,3-diphenylpyrazine can be produced by reacting 6-chloro-2,3-diphenylpyrazine with sodium iodide. This reaction is carried out in an organic solvent (for example, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, or a mixed solvent thereof) in the presence of an acid. As the acid to be used, for example, acetic acid, sulfuric acid, or a mixed acid thereof can be mentioned. The amount of sodium iodide used is, for example, suitably in the range of 1 mole to 10 moles, preferably in the range of 2 time moles to 3 times the amount of 1 mole of 6-chloro-2,3-diphenylpyrazine . The reaction temperature varies depending on the raw materials used and the type of acid, but is usually carried out within the range of 60 ° C. to 90 ° C. The reaction time varies depending on the starting materials used, the type of acid and the reaction temperature, but it is usually within the range of 9 hours to 15 hours.Step 2
5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] pyrazine can be prepared by reacting 6-iodo-2,3-diphenylpyrazine with 4-hydroxybutyl (isopropyl) amine. This reaction is carried out in an organic solvent (for example, sulfolane, N-methylpyrrolidone, N, N-dimethylimidazolidinone, dimethylsulfoxide or a mixed solvent thereof) in the presence of a base. Examples of the base used include sodium hydrogencarbonate, potassium hydrogen carbonate, potassium carbonate, sodium carbonate, and mixed bases thereof. The amount of 4-hydroxybutyl (isopropyl) amine to be used is, for example, suitably in the range of 1.5 mol to 5.0 mol per 1 mol of 6-iodo-2,3-diphenylpyrazine, It is within the range of 2 mol to 3 mol. The reaction temperature varies depending on the type of raw material and base used, but is usually carried out within the range of 170 ° C. to 200 ° C. The reaction time varies depending on the type of raw materials and base used and the reaction temperature, but it is usually within the range of 5 hours to 9 hours.Step 3
Compound A can be prepared by reacting 5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] pyrazine with N- (2-chloroacetyl) -methanesulfonamide. This reaction is carried out in an organic solvent (N-methylpyrrolidone, 2-methyl-2-propanol or a mixed solvent thereof) in the presence of a base. Examples of the base to be used include potassium t-butoxide, sodium t-butoxide or mixed bases thereof. The amount of N- (2-chloroacetyl) -methanesulfonamide used is, for example, 2 to 4 mol per 1 mol of 5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] It is suitable within the range, and preferably within the range of 2 mol to 3 mol. The reaction temperature varies depending on the type of raw material and base used, but is usually carried out within the range of -20 ° C. to 20 ° C. The reaction time varies depending on the kinds of raw materials and bases used and the reaction temperature, but it is usually within the range of 0.5 hour to 2 hours.Each compound used as a raw material in the above-mentioned production method of compound A is a known compound or can be produced according to a known method.

[0016]

B. Preparation of salt of the present invention The salt of the
present invention can be obtained, for example, by the following method.
The salt of the present invention can be prepared by dissolving the compound A in an appropriate solvent (for example, an ether solvent (for example, dimethoxyethane, tetrahydrofuran), an ester solvent (for example, isopropyl acetate), an aromatic hydrocarbon (for example, toluene), acetonitrile After dissolving and adding a desired base, if necessary, the mixed solution is left to stand at room temperature or under cooling in the state of concentrating or stirring or leaving it stationary. The precipitate formed is collected by filtration , Followed by washing with an appropriate solvent to obtain the desired salt of the present invention. When cooling, not only cooling but also gradual cooling or rapid cooling may be effective in obtaining good crystals. It is also effective to obtain good crystals by adding an ether solvent (for example, t-butyl methyl ether), an ester solvent (for example, ethyl acetate), and an aromatic hydrocarbon (for example, toluene) There are cases.The amount of the solvent used for dissolving the compound A is suitably in the range of 10 ml to 300 ml with respect to the compound A 1 g, for example.
The amount of the base to be used for preparing the salt of the present invention is suitably in the range of 0.5 mol to 1.2 mol with respect to the mol of the compound A 1.
Further, the salt of the present invention, which is a crystal, can be obtained by, for example, the method described in Examples described later.

Example　1 t- butylamine Form I crystal of the salt
Compound A (40 mg) with 0.5mL dimethoxyethane (hereinafter, referred to as. “DME”) was dissolved in, and t- butylamine (1.1 eq) were added, 25 1 ° C. at 8 it was stirred for hours. Thereafter, the reaction solution was added t- butyl methyl ether (1mL), at -20 ° C. 3 and held hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried, I-form crystals of t- butylamine salt ( 3 to afford 9.9mg). B Powder X-ray diffraction spectrum of type I crystal obtained t- butylamine salt using the apparatus shown in Figure 1.
Melting point: 152.5 ℃
elemental analysis (C 3 0 H 4 3 N 5 O 4 S + 0.0 3 H 2 as O)
calculated value (%) C:　6 3 .1 8 H: 7 . 6 1 N: 12 .2 8　measured value (%) C: 6 2. 8 5 H: 7 . 6 4 N: 12.52 1 H-NMR (DMSO-D 6 ): delta 8 .15 (s, 1H), 7 .55 – 7 . 8 0 (M, 2H), 7 .10- 7 . .45 (M, 10H), 4 7 . 0-4 8 5 (M, 1H), 3 . 6 6 (s, 2H), 3 .4 7 (t, 2H), 3 .45 (t, 2H), 2. 7 3 (s, 3 H), 1.50-1. 7 5 (M, 4H), 1.2 3 (s, 9H), 1.22 (D, 6 H)
Example 2　I-form crystal of the potassium salt
Compound A tetrahydrofuran with (40mg) 12mL (hereinafter, referred to as. “THF”) was dissolved in, 0.1M aqueous potassium hydroxide solution (1.1 eq) was added, 40 ℃ It was heated and stirred in for 15 minutes. After that, it was evaporated under reduced pressure, the solvent. The residue it was added ethyl acetate (200μL). While shaking the mixture heated to 50 ° C. 8 was allowed to cool to 25 ℃ over hours. After repeated two more times this step, at -20 ° C. 3 and held hours. The resulting precipitated crystals were collected by filtration under reduced pressure, and dried to obtain Form I crystal of the potassium salt. B Powder X-ray diffraction spectrum of type I crystal of the obtained potassium salt using the apparatus shown in Fig. 1 H-NMR (DMSO-D 6 ): delta 8 .14 (s, 1H), 7 .1 8 – 7 . 3 8 . (M, 10H), 4 7 . 2-4 8 4 (M, 1H) , 3 . 6 5 (s, 2H), 3 .4 7 (t, 2H), 3 .45 (t, 2H), 2. 7 2 (s, 3 H), 1.55-1. 7 0 ( M, 4H), 1.2 3 (D, 6 H)
Example 3　 II-form crystals of the potassium salt
Compound A with (40mg) was dissolved in THF and 12mL, 0.1M aqueous potassium hydroxide solution (1.1 eq) was added and heated with stirring for 15 min at 40 ℃. After that, it was evaporated under reduced pressure, the solvent. The residue it was added ethyl acetate (200μL). While shaking the mixture heated to 50 ° C. 8 was allowed to cool to 25 ℃ over hours. This operation was repeated two more times, at -20 ° C. 3 and held hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, after drying, 40 ℃, relative humidity 7 while 5% of thermo-hygrostat 7 left for days to give crystalline Form II of the potassium salt. B Powder X-ray diffraction spectrum of crystalline Form II of the resulting potassium salt using the apparatus Fig 3 is shown in.

Example 4　III type crystal of the potassium salt
Compound A , in addition to (100mg) acetonitrile (1mL), and stirred with heating, Compound A was dissolved, followed by cooling to 20 ℃. To a solution 3 .5M potassium hydroxide / ethanol solution (1.1 eq) was added and stirred for 200 minutes at 20 ℃. While stirring the mixture 7 after a heated stirring for 1 hour to 0 ° C., and then cooled to 10 ℃ over 10 hours. Further heated while the mixture 6 is heated to 0 ℃, t- butyl methyl ether (0. 3 after adding mL), cooled to 20 ℃ over 10 hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried, III type crystal of the potassium salt ( 7 to afford 5mg). The powder X-ray diffraction spectrum of the type III crystal of the obtained potassium salt using R unit is shown in FIG. Furthermore, in differential scanning calorimetry, of about 7 endothermic peak was observed at around 4 ° C..
Elemental analysis (C 2 6 H 3 1 N 4 O 4 . SK + 0 7 8 H 2 as O)
calculated value (%) C: 5 6 .91　H: 5.9 8 N: 10.21
measured value (%) C: 5 6 . 6 1 H: 5.55 N:. 10 3 6

EXAMPLE 5　IV-type crystal of the potassium salt
Compound A , in addition to (50mg) and ethyl acetate (1mL), and stirred with heating, Compound A was dissolved, followed by cooling to 20 ℃. To a solution 3 .5M potassium hydroxide / ethanol solution (2.2 eq) was added and 2 at 20 ° C. 3 and stirred for hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried to obtain Form IV crystal of the potassium salt (41mg). The powder X-ray diffraction spectrum of crystalline Form IV of the resulting potassium salt using R unit is shown in FIG. Furthermore, in differential scanning calorimetry, an endothermic peak was observed at around approximately 91 ℃.

Paper

J Med Chem 2015, 58(18): 7128

PATENT

WO 2018008042

https://patents.google.com/patent/WO2018008042A1/en

The present invention relates to an improved and novel processes for the preparation of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N-(methylsulfonyl) acetamide compound of formula- 1 , which is represented by the following structural formula- l .

Formula-

The present invention also relates to novel crystalline forms of the compound of formula- 1 and process for the preparation thereof.

Background of the Invention:

2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide is known as Selexipag. It is developed by Nippon Shinyaku under the brand name of Uptravi®, for the treatment of pulmonary arterial hypertension.

2- {4-[(5,6-diphenylpyTazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide was firstly described in US7205302B2 herein after referred as US ‘302. The said patent also describes its process for the preparation. According to this process the final product was obtained with low yield and purity.

US8791 122 (herein after referred as US’ 122) patent describes crystalline form-I, II and III of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N-(methylsulfonyl) acetamide. Because of drug compounds having, for example, improved stability, solubility, shelf life and in vivo pharmacology, are consistently sought, there is an ongoing need for new or pure salts, hydrates, solvates and polymorphic forms of existing drug molecules. The novel crystalline forms of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N- (methylsulfonyl) acetamide described herein help meet this requirement.

US ‘ 122 patent describes amorphous form of the compound of formula- 1 . This patent does not disclose any detailed process for amorphous form and PXRD pattern of amorphous compound of formula- 1 .

Figure imgf000019_0001

Examples:

Example-1 Preparation of 4-((5₎6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol compound of formula-8

A mixture of 5-chloro-2,3-diphenylpyrazine (25 gm) compound of formula-7a and 4- (isopropyl amino)butan- 1 -ol (108 gm) was heated to 190-195°C and stirred the reaction i mixture for 10- 12 hours at same temperature. Cooled the reaction mixture to 25-35°C. To this reaction mixture n-heptane followed by water were added slowly at 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. Filter the precipitated solid, washed with water and dried to get the title compound.

Yield: 30 gm.

Example-2: Preparation of tert-butyl 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino) butoxy)acetate

Potassium hydroxide solution (96.6 gm of potassium hydroxide dissolved in 175 ml of water) was added to the mixture of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan- l -ol (25 gm) and toluene ( 175 ml) at 25-30°C and stirred the reaction mixture for 30 minutes at the same temperature. Cooled the reaction mixture to 0-5°C. Tert-butyl bromoacetate (94 gm) was slowly added to the reaction mixture at 0-5°C and stirred the reaction for 60 minutes at same temperature. Raised the temperature of the reaction mixture to 25-30°C and maintained for 60 minutes. Both the aqueous and organic layers were separated. The aqueous layer was extracted with toluene and combined the organic layers. Organic layer was washed with hydrochloric acid solution followed by with aqueous sodium bicarbonate solution. Organic layer was dried with sodium sulphate and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.

Yield: 29 gm.

Example-3: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy) acetic acid compound of formula-6

Aqueous sodium hydroxide solution (7.5 gm of sodium hydroxide was dissolved in 80 ml of water) was added to the solution of tert-butyl 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl) amino)butoxy)acetate (30 gm) in methanol (290 ml) at 30-35°C. Heated the reaction mixture to reflux temperature and stirred for 3 hours at the same temperature. Distilled off solvent completely from the reaction mixture under reduced pressure and cooled the reaction mixture to 25-30°C. Water was added to the obtained compound and acidified the reaction mixture using diluted hydrochloric acid at the same temperature. Extracted the reaction mixture with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and dried with sodium sulphate. Distilled off the solvent from the organic layer under reduced pressure. Diisopropyl ether (60 ml) was added to the obtained compound at 25-30°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid, washed with diisopropyl ether and dried to get the title compound.

Yield: 19 gm.

Example-4: Preparation of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropy.)amino]butoxy}- N-(methylsulfonyl) acetamide compound of formula-1

Triethylamine (9.6 gm) was added to the mixture of 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid (10 gm), dichloro methane (100 ml), N,N- dicyclohexylcarbodiimide (4.9 gm), hydroxybenzotriazole (3.5 gm) and methane sulfonamide (3.39 gm) at 25-30°C and stirred the reaction mixture for 12 hours at the same temperature. Filtered the unwanted compounds from the reaction mixture and washed with dichloromethane. The organic layer was washed with water, followed by with aqueous citric acid solution and then washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure. To this residue ethyl acetate (20 ml) and carbon (1 gm) were added at 25-30°C and stirred the reaction mixture for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. The obtained filtrate was slowly added to the mixture of n-heptane and water at 25-30°C and stirred for 10 hours. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 4.5 gm.

Example-5: Preparation of 2-{4-f(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}- N-(methylsulfonyl) acetamide compound of formula-1

Sodium t-butoxide (96.6 gm) was added to the mixture of n-methy pyrrolidinone (125 ml) and 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (25 gm) compound of formula-8 at 0-5°C and stirred the reaction for 20 minutes at the same temperature. 2-chloro- N-(methylsulfonyl)acetamide (23.7 gm) was slowly added to the reaction mixture at 0-5°C and raise the temperature of the reaction mixture to 25-30°C. Stirred the reaction mixture for 10-12 hours at 25-30°C and water was added to it at the same temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and distilled off the solvent from the organic layer under reduced pressure. To this residue ethyl acetate (50 ml) and carbon (2.5 gm) were added at 25-30°C and stirred the reaction mixture for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. The obtained filtrate was slowly added to the mixture of n-heptane and water at 25-30°C and stirred for 10 hours. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 14 gm.

Example-6: Preparation of 2-chIot^*o- -(methylsulfonyl)acetamide

A mixture of methane sulfonamide (100 gm) and chloroacetyl chloride (356.4 gm) was heated to reflux temperature and stirred it for 10 hours at the same temperature. Cooled the reaction mixture to – 10 to -5°C and stirred it for 2 hours at the same temperature. Filtered the precipitated, solid, washed with toluene followed by n-heptane and dried to get the title compound.

Yield: 175 gm.

ExampIe-7: Purification of the compound of formula-1

Methanol (20 ml) was added to the compound of formula-1 (2 gm) at 25-30°C and heated to reflux temperature. Dichloromethane (3 ml) was added to the reaction mixture at reflux temperature and stirred for 15 minutes at the same temperature. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure to get the title compound. Yield: 2 gm

Example-8: Preparation of N-isopropyI-5,6-diphenylpyrazin-2-amine (Formula-4) Isopropyl bromide (5.5 gm) was added to the mixture of 2-amino -5,6-diphenylpyrazine ( 10 gm), potassium tert-butoxide (9 gm) and dimethylformamide (50 ml) at 25-30°C, slowly heated to 80-85°C and stirred the reaction mixture for 6 hours at same temperature. The reaction mixture was cooled to 10- 15°C, diluted the reaction mixture with water and stirred it for 2 hours at the same temperature. Filtered the obtained solid and dried to get the title compound.

Yield: 9.5 gm

ExampIe-9: Preparation of N-isopropyl-5,6-diphenylpyrazin-2-amine (Formula-4)

A mixture of 5-chloro-2,3-diphenylpyrazine ( 10 gm), isopropyl amine (7.5 gm) and potassium carbonate (10.5 gm) and dioxane (50 ml) were heated to 40-45°C and stirred the reaction mixture for 12 hrs at the same temperature. The reaction mixture was cooled to 10- 15°C, diluted with water and extracted with dichloromethane. Combined the organic layers was washed with aqueous sodium hydrochloride solution and dried over anhydrous sodium sulphate. Distilled off the solvent completely from the organic layer under reduced pressure to provide the title compound.

Yield: 9 gm

Example-10: Preparation of 2-(4-chlorobutoxy)aceticacid (Formula-5a)

2-bromoaceticacid (10 gm) was slowly added to a mixture of l-chlorobutan-4-ol (7.2 gm), potassium carbonate (26.5 gm) and acetonitrile (50 ml) at 25-30°C. The reaction mixture was heated to 75-80°C and stirred the reaction mixture for 6 hours at same temperature. The reaction mixture was cooled to 25-30°C and diluted with , water. Acidified the reaction mixture using diluted hydrochloric acid at 25-30°C. The reaction mixture extracted with dichloromethane. Combined the organic layers was dried over anhydrous sodium sulphate and distilled off the solvent under reduced pressure to provide the title compound.

Yield: 10.5 gm.

Example-11: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino) butoxy)acetic acid (formula-6)

A mixture of N-isopropyl-5,6-diphenylpyrazin-2-amine (8 gm), potassium carbonate (7.5 gm) and acetonitrile (40 ml) was stirred for 1 hr at 25-30°C. A solution of 2-(4-chlorobutoxy) aceticacid (5.4 gm) in acetonitrile (15 ml) was slowly added to the reaction mixture at 25- 30°C. Heated the reaction mixture to reflux and stirred for 12 hours at the same temperature. The reaction mixture was cooled to 10-15°C and diluted with wateT. Acidified the reaction mixture using diluted hydrochloric acid and extracted the reaction mixture using ethyl acetate. Combined the organic layers and dried over sodium sulphate. Distilled off the solvent completely from the organic layer to get the title compound.

Yield: 8.5 gm

Example-12: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyt)amino)butoxy)- N-(methylsulfonyl)acetamide (formula-1)

A mixture of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (5 gm), HATU (5.4 gm), triethylamine (1.5 gm) and dimethylformamide (20 ml) was stirred for 1 hr at 5-10°C under nitrogen atmosphere. Methane sulfonamide (5.2 gm) was slowly added to the reaction mixture at 5-10°C and stirred for 12 hrs at the same temperature. The reaction mixture was diluted with water and stirred for 2 hrs. The precipitated solid was filtered and dried to get the title compound.

Yield: 4.5 gm

Example-13: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetonitrile (Formula-12)

To the mixture of 4-((5,6-diphenylpyrazin-2-yI)(isopropyl)amino)butan-l-ol ( 10 gm), tetrabutyl ammoniumbromide (0.2 gm), potassium carbonate (7.6 gm) and acetone (50 mL), chloroacetonitrile (3.2 gm) was added at 25-30°C. Heated the reaction mixture to reflux temperature and stirred the reaction mixture for 6 hrs at the same temperature. The reaction mixture was cooled to 10- 15°C and filtered the reaction mixture. Distilled off the solvent completely from the filtrate to get the tile compound.

Yield: 9 gm

Example-14: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy) acetic acid (formula-6)

Sodium hydroxide (3.5 gm) was added to a solution of 2-(4-((5,6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetonitrile (8 gm) in methanol (60 ml) and water (30 ml). The reaction mixture was heated to 65-70°C and maintained for 6 hrs. The reaction mixture was cooled to 10°C, acidified with diluted hydrochloric acid and stirred at same temperature for 2 hr. The obtained solid was filtered and dried to provide the title compound.

Yield: 7.5 gm

Example-15: Preparation of 2-chloro-N-(methylsulfonyl)acetamide (Formula-16)

The mixture of methane sulfonamide (50 gm) and chloroacetyl chloride (92 gm) was heated to 1 10-1 15°C and stirred the reaction mixture for 7 hours at the same temperature. The reaction mixture was cooled to 25-30°C and dichloromethane was added to the reaction mixture at the same temperature. Cooled the reaction mixture to 15-20°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid and washed with dichloromethane. The obtained solid was recrystallized using dichloromethane to get pure title compound. Yield: 80 gm. M.R.: U0- 1 15°C. Purity by HPLC: 98.85%.

Example-16: Preparation of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (Formula-8)

The mixture of 5-chloro-2,3-diphenylpyrazine ( 100 gm) and 4-(isopropylamino)butan-l -ol (245.5 gm) was heated to 190-195°G and stirred the reaction mixture for 12 hours at the same temperature. The reaction was cooled to 25-30°C and n-heptane was added to the reaction mixture. The reaction mixture was further cooled to 10-15°C, water was slowly added to the reaction mixture and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with water. Dichloromethane (300 ml) was added to the obtained solid and stirred for 5 minutes. Both the organic and aqueous layers were separated. The organic layer was dried with sodium sulphate, distilled off the solvent from the organic layer completely under reduced pressure and co-distilled with n-heptane. 400 ml of n-heptane was added to the obtained compound at 25-30°C, heated the reaction mixture to 45-50°C and stirred for 30 minutes at the same temperature. The reaction mixture was cooled to 15-20°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with n-heptane and dried to get the title compound.

Yield: 82 gm. M.R.: 100-105°C. Purity by HPLC: 95.4%.

Example-17: Purification of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (Formula-8)

n-Heptane (750 ml) was slowly added to pre-cooled solution of 4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butan- l -ol (100 gm) in acetone (250 ml) was cooled to 0-5°C. Stirred the reaction mixture for 4 hours at the same tempereature. Filtered the precipitated solid, washed with n-heptane and dried to get the pure title compound.

Yield: 54 gm. Purity by HPLC: 99.92%.

Example-18: Preparation of crystalline form-L of compound of formula-1

Melting the compound of formula-1 (10 gm) at 140-145°C under reduced pressure for 15 minutes. The above obtained oily residue was added to 100 ml of pre-cooled n-heptane at 0- 5°C. Stirred the reaction mixture for 6 hr at 0-5°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 9 gm; PXRD of the obtained compound is depicted in figure- 10 and DSC thermogram is depicted in figure- 1 1. Example-19: Preparation of crystalline form-P of compound of formula-1

Yield: 9 gm; PXRD of the obtained compound is depicted in figure-7, its IR is depicted in figure-8 and its DSC is depicted in figure-9.

Example-20: Preparation of crystalline form-P of compound of formula-1

Melting the compound of formula-1 (10 gm) at 140-145°C under reduced pressure for 15 minutes. The above obtained oily residue was added to 100 ml of n-heptane at 30-40°C.

Stirred the reaction mixture for 36 hours at 30-40°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 9 gm; PXRD of the obtained compound is similar to the figure-7.

Example-21 : Preparation of amorphous form of compound of formula-1

Melting the compound of formula-1 ( 10 gm) at 140- 145°C under reduced pressure for 15 minutes and the above obtained oily residue was cooled to 0-5°C. Unload the obtained compound and dried to get the title compound. Yield: 9 gm; Purity by HPLC: 99.74%. PXRD of the obtained compound is depicted in figure-5 and IR is depicted in figure-6.

Exaniple-22: Preparation of crystalline form-I of compound of formula-1

Melting the compound of formula-1 (5 gm) at 140-145°C under reduced pressure for 15 minutes. 50 ml of n-heptane was added to the above obtained oily residue at 115-120°C.

Stirred the reaction mixture for 20 minutes at 1 15- 120°C. Cooled the reaction mixture to 25-

30°C and stirred for 60 minutes at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred the reaction mixture for 60 minutes at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 4 gm; Purity by HPLC: 99.68%.

PATENT

CN 108675964

PATENT

CN 106316967

PATENT

WO 2017029594

PATENT

US8791122

Form-I II III

https://patents.google.com/patent/US8791122B2/en

Figure US08791122-20140729-C00002

PATENT

https://patents.google.com/patent/WO2018022704A1/en

Selexipag has the chemical name 2-{4-[(5,6-diphenylpyrazin-2- yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide. Selexipag has the following chemical structure:

[0004] Selexipag is being developed by Actelion and Nippon Shinyaku for the treatment of arteriosclerosis obliterans, pulmonary hypertension and Raynaud’s disease secondary to systemic sclerosis.

[0005] Selexipag is disclosed in US 7,205,302. US 8,791,122, US 9,284,280 and US 2014- 0155414 disclose polymorphs of Selexipag, denominated forms I, II and III. WO

2017/040872 discloses form IV and V of Selexipag.

xample 1: Preparation of Selexipag

[00126] A. Route 1

[00127] Crude Selexipag can be obtained by any method known in the art, for example by the method described in US 7,205,302 or according to the following.

[00128] B. Route 2

[00129] Step a: Preparation of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl)amino)butan-l-ol

[00130] To 50 g (0.161 mol) of 5-bromo-2,3-diphenylpyrazine, 116 g (0.884 mol, 5.5 eq/mol) of 4-(isopropylamino)-butan-l-ol and 13.33 g of KI (0.080 mol, 0.5 Eq/mol) were added. The reaction mixture was stirred, warmed and then heated up to 140°C for about 18- 20 hrs. The reaction was monitored by TLC up to completion (starting material about 1% by TLC). The reaction mixture was cooled down to room temperature. After the reaction was completed, the following work up step was performed:

[00131] Option 1 : Ethyl acetate was added (500 mL, 10 vol) and the organic phase was washed with water (150 mL, 3 vol). The organic phase was separated and aqueous phase was extracted with ethyl acetate (150 mL, 3 vol). The organic phases were joined and washed with water (200 mL, 2 vol) three times.

[00132] The solvent was distilled off under vacuum at not more than (“NMT”) 40°C until 1 vol (oil appearance).

[00133] Option 2: The material (mixture) was dissolved in acetone (250 mL, 5 vol), the solution obtained was cooled down to 0°C to 5°C and anti-solvent / water was added (1000 mL, 20 vol) for 40 minutes, then the suspension was stirred for about 30 minutes at about 0°C-5°C. The solid material was filtered and washed with water (200 mL, 4 vol). Crude wet product was obtained as yellow solid yielding 101.8 % WY (87 % MY), HPLC purity 90.8% on area at this stage.

[00134] The crude material, obtained in either of the above described options, was purified through crystallization from acetone :«-heptane as follows: to a solution of 4-((5,6-diphenyl- pyrazin-2-yl)(isopropyl)amino)butan-l-ol crude in acetone (175 mL, 3.5 vol) at 0°C – 5°C, hexane (600 mL, 12 vol) dropwise in about 120 min was added, then the precipitated mixture was cooled down to about -10°C and stirred for about 60 min. The product was filtered off and washed with hexane (250 mL, 5 vol) and dried under vacuum at 25°C. Pure product was obtained as yellowish solid yielding overall 77.2%, (66.5% MY), HPLC purity 98.2% on area.

[00135] Step b: Preparation (2-bromo-N-(methylsulfonyl)-acetamide)

[00136] To a suspension of 50 g (0.526 mol) of methanesulfonamide in toluene (625 mL, 12.5 vol) and isopropyl acetate (625 mL, 12.5 vol), 159.1 g (0.789 mol) of bromo-acetyl- bromide (“BAB”) was added under nitrogen atmosphere. The reaction mixture was heated up to about 90°C for about 8 hours under a nitrogen stream. The reaction was monitored by TLC up to completion (starting material about 1% by TLC). The reaction mixture was cooled down to about 40°C and concentrated under vacuum until 10 volumes. Subsequently, toluene was added (250 mL, 5 vol) and distilling off solvents is carried out at NMT 30°C until 10 volumes. Then was added dichloromethane (100 mL, 2 vol) and the mixture was cooled down at 0°C and is stirred for 90 min. The solid was filtered and washed with

dichloromethane (100 mL, 2 vol). Crude product was obtained as beige solid material yielding 187% WY (83% MY), HPLC purity 99.2% at this stage. [00137] The crude material (83 g) was purified through re-slurring with dichloromethane (166 mL, 2 vol; preferably 332 mL, 4 vol) by stirring at about 32°C for about 60 min. The crystallization mixture was cooled down to about 0°C-5°C and stirring for 30 min, filtered off and washed with dichloromethane (100 mL, 2 vol). Subsequently, the material was dried at 35°C for 24 hours. Pure and dried material was obtained as white off solid yielding overall 173%, (77% MY), HPLC purity 99.6 % on area.

[00138] Step c: Preparation of (2-[4-[(5,6-diphenyl-2-pyrazinyl)(l- methylethyl)amino]butoxy]-N-(methylsulfonyl)-acetamide) – Selexipag

[00139] To 10 g (0.028 mol) of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl)amino) butan-l-ol was added a strong base (6.0 eq/mol), previously suspended in an appropriate solvent, within a range of from -10°C to 40°C under a nitrogen atmosphere and stirred for 60 min. Then, a solution of 17.9 g (3.0 eq/mol) of 2-bromo-N-(methylsulfonyl)-acetamide, previously dissolved in the same solvent, is added dropwise within a range of from 120 tol 80 min, controlling the exothermic temperature. The reaction was monitored by TLC up to completion. Subsequently, the mixture reaction was cooled down around 5°C and water is added by controlling the exotherm (NMT 15°C). Finally, an acetic acid solution was added and the suspension was stirred for about 60 min at 0°C -5°C. The product (crude) was filtered off and washed with water. An amorphous solid was obtained. The crude product was purified by crystallization from ethanol:THF.

[00140] Step d: Purification of Selexipag

[00141] Crude Selexipag can be purified by crystallization in an organic solvent for example alcohols such as ethanol, iso-amyl alcohol, iso-propyl alcohol, butanol; ethers such as tetrahydrofuran, hydrocarbons such as heptane and mixed solvents thereof.

[00142] C. Route 3

[00143] 33.3 g (0.297 mol, 6.0 eq/mol) of potassium tert-butoxide were dissolved in DMF (2.8 vol) in a flask (500 mL) under nitrogen atmosphere and stirred for 15 min. Then, a solution of 17.9 g (0.049 mol, 1.0 eq/mol) of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl) amino) butan-l-ol (SLX-4) dissolved in DMF (1.2 vol) was added in one portion. The reaction mixture was stirred for 60 min within a temperature range from 20°C to 25°C at 150 rpm Then, a solution of 32.1 g (0.15 mol, 3.0 Eq/mol) of 2-bromo-N-(methylsulfonyl)- acetamide (SLX-9), previously dissolved in DMF (1.3 vol), was added dropwise for 120 minutes by controlling the temperature (exothermic process).

[00144] The reaction mixture was quenched with cool water (0.33 vol), transferred into a flask of more capacity (1000 mL) and placed in an ice bath. Cool water (38.32 vol) was added to the reaction mixture and the pH was adjusted to 5.0 with AcOH (0.33 vol). The mixture was stirred at 300 rpm for 40 min. Then, the flask with the reaction mixture was stored in the refrigerator at 8°C. After 8h, the solid was filtered and washed with cool water (5 vol, 2 times). The crude product (yellow solid) was drained (i.e. dried) for 30 min and was stored at 8°C.

Example 2: Preparation of crystalline Selexipag Form IV

[00145] A. Route 1

[00146] 3.0 g of Selexipag was dissolved in dimethylformamide (“DMF”) (12 mL, 4 vol). The obtained solution was added dropwise to a pre-cooled acetic acid solution (0.06 M, 120 mL, from 2°C to 8°C) to obtain a suspension. The suspension was stirred within a range of from 2°C to 8°C for 30 min; then the material was filtered, washed with water (10 mL, 3.3 vol) and drained (i.e. dried) for 10 minutes. The solid material (amorphous) was suspended in heptane (25 mL, 7.5 vol) and the obtained suspension was stirred for 30 minutes at room temperature. The material was filtered, washed with heptane (20 mL, 6.6 vol) and drained (i.e. dried) under vacuum for at least 30 minutes at room temperature to obtain the Form IV Crystal.

[00147] B. Route 2

[00148] Crude Selexipag (1.0 g, amorphous solid, obtained from the synthesis) was dissolved in ethyl acetate (5 vol, 5 mL), then water was added (10 vol, 10 mL) into the solution, the mixture was stirred for about 10 minutes and the pH was adjusted to a range of from 8.0 to 9.0 by titration with K2CO₃ solution. The phases were separated; the pH of the aqueous phase was adjusted to a range of from 3.5 to 5.0 by titration with acetic acid. Then, ethyl acetate (10 vol, 10 mL) was added into the aqueous phase, the obtained mixture was stirred and the phases were separated. The organic phase was distilled off under reduced pressure (from 2 to 3 volumes), and a solution was obtained. The obtained concentrated solution was quickly added to a mixture (suspension) of Form IV in ^-heptane (17 mL, 17 vol), over a period of less than 5 minutes, (the suspension temperature was of from 15°C to 25°C), and a suspension was obtained. The obtained suspension was stirred (155rpm) for 90 minutes at a temperature of from 0°C to 5°C. The suspension was filtered, washed with heptane, squeezed for 15 minutes and dried at 25°C, under vacuum, for about 14 hours. The product was analyzed by PXRD – Form IV was obtained.

[00149] The above procedure can be performed by dissolving the crude amorphous starting material in any suitable organic solvent, for example ester solvent. Example 3: Preparation of (2-[4-[(5,6-diphenyl-2-pyrazinyl)(l- methylethyl)amino] butoxy] -N-(methylsulfonyl)-acetamide) – Selexipag

SLX-4 SLX-9 SLX-6

[00150] 9.2 grams (0.082 mol, 5.9 eq/mol) of potassium tert-butoxide were combined with DMF (2.7 vol, 13.5 mL) in a flask (50 mL) under nitrogen atmosphere and a suspension was formed and was stirred for 20 min. Then, 5.0 g (0.014 mol, 1.0 eq/mol) of 4-((5,6-diphenyl- pyrazin-2-yl)(isopropyl)amino)butan-l-ol (SLX-4) as solid powder was added under nitrogen atmosphere. The reaction mixture was stirred for 60 min within a temperature range from 20°C to 25°C and at 170 rpm. Then, a solution of 8.9 g (0.041 mol, 3.0 eq/mol) of 2-bromo- N-(methylsulfonyl)-acetamide (SLX-9), previously dissolved in DMF (1.3 vol, 6.5 mL), was added dropwise for 120 minutes by controlling the temperature (exothermic process). After the end of addition, the reaction was completed, and the reaction mixture was quenched with cold water (0.5 vol, 2.5 mL), subsequently transferred into a flask of more capacity (500 mL) and placed into an ice bath. Cold water (40 vol, 200 mL) was added into the suspension and the pH was adjusted within the range from 4.0 to 5.0 with acetic acid. The obtained mixture was stirred for 120 min. The crude amorphous product was collected by filtration and washed twice with cold water (5 vol, 25 mL). The product was drained (i.e. dried) for 30 min and isolated as a yellow-brown solid which was stored within the range from 2°C to 8°C for approximately 17 hours. Then, the crude amorphous material was dissolved in ethyl acetate (15 vol, 75 mL) and water was added into the solution (30 vol, 150 mL). The pH was adjusted from 8.0 to 9.0 by addition of potassium carbonate solution, the phases were separated and the aqueous phase was washed twice with ethyl acetate (7.5 vol, 37.5 mL). The pH of the final aqueous phase was adjusted to a range from 4.0 to 5.0 with acetic acid. Then, ethyl acetate was added (30 vol, 150 mL) and the phases were separated. The organic phase was washed twice with water (7.5 vol, 37.5 mL). The organic phase was distilled off under reduced pressure (from 6 to 7 volumes, or from 6 to 15 volumes) and a solution was obtained.

[00151] In a different flask (capacity of 250 mL with a PTFE stirrer blade), a suspension of 0.05 g of Selexipag Form IV in ^-heptane (30 volumes, 150 mL) was stirred for 60 minutes within the range 0°C to 5°C and this suspension was added into the above ethyl acetate concentrated solution at room temperature over a period of less than 5 minutes. The final suspension was cooled down to 0°C to 5°C and stirred (220 rpm) for 120 minutes. The solid product was filtered off and washed twice with cold heptane (5 vol, 25 mL). The product was drained (i.e. dried) overnight. The product was analyzed by PXRD – Form VI was obtained, PXRD pattern is depicted in Figure 1.

PATENT

CN105949135

https://patents.google.com/patent/CN105949135A/en

Figure CN105949135AD00052

Example 1

[0027] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0028] 4 – [(tert-butoxycarbonyl) (isopropyl) amino] butanol -1_ (20 (^, 0.09111 〇1) and tert-butyl bromoacetate (21 · lg, 0 llmol) solution. The reaction was stirred for 2 hours to burn dichloromethane (90mL), was added tetrabutylammonium chloride (0.72g, 2.6mmol), potassium hydroxide (7.3g, 0.13mol) and water (12.0g), the reaction mixture was 25 ° C The reaction solution was concentrated under reduced pressure and rotary evaporated to dryness and extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxycarbonyl) (isopropyl yl) aminobutoxy] acetate, as a pale yellow oil (26.6 g of), a yield of 89.0%, the reaction formula of this step is as follows:

[0029]

[0030] B) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0031] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (26. (^, 0.075! 11〇1) was dissolved in methanol (50 mL), was added sodium hydroxide solution (NaOH = 3 · 3g, 0 · 08mol; water 9 · 0g), was heated to 80 ° C for 6 hours, cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] acetic acid (20.7 g of), a yield of 95.0%, the reaction formula of this step is as follows:

[0033] C) Preparation of 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0034] [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (20 (^, 0.07 11〇1) and a hoot “-.! P sitting carbonyldiimidazole (14.0g, 0.09mo 1 ) was dissolved in tetrahydro-thiopyran Misaki (70 mL), with stirring, was added methyl sulfonamide (7.9g, 0.08mol), the reaction mixture was 90 ° C the reaction stirred for 18 hours, the reaction solution was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide as an off-white solid (21.2 g), yield 83.7%, the reaction formula of this step is as follows:

[0036] D) Preparation of SIPA Seiler: 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (20 (^, 0.055111〇1. ) and dissolved in methanol (1101 ^), trifluoroacetic acid (6.88,0.06111〇1), 65 ° (: the reaction stirred for 6 hours to complete the reaction, the reaction was added dropwise to a stirred solution of water (200 mL), cooled to 0 ° C crystallization for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), and then dissolved in methanol (40 mL), was added 5 – chloro-2,3-diphenyl-pyrazine (16 · 0g, 0 · 06mol), N, N- diisopropylethylamine (15 · 5g, 0 · 12mol), the reaction mixture was stirred reactor 8 100 ° C hours, the reaction was cooled to room temperature, water (40 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (25.0 g of), a yield of 92.3%, the reaction step formula as follows:

[0037]

[0038] Example 2

[0039] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0040] 4 – [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol (23 (^, 0.10111 〇1) and tert-butyl bromoacetate (25 · 2g, 0 · 13mol) was dissolved. burning in 1,2-dichloroethane (110mL), was added tetrabutylammonium bromide (1 · lg, 3 · 5mmol), sodium hydroxide (6.4g, 0.16mol) and water (14.0g), the reaction mixture was 30 ° C The reaction was stirred for 3 hours, the reaction solution was concentrated by rotary evaporation to dryness under reduced pressure and extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxy butoxycarbonyl) (isopropyl) aminobutoxy] acetate, as a pale yellow oil (30.3 g of), a yield of 88.2%, the reaction of the present step is the same formula as in Example 1;

[0041] B) Preparation of [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0042] [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (30. (^, 0.09! 11〇1) was dissolved in ethanol (85 mL), was added potassium hydroxide solution ( 1 (! = 5.78,0.10111〇1 01; 128 water), heated to 75 ° (: 7 hours, cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] acetic acid, an off-white solid (23.5 g of), a yield of 93.7%, the reaction of the present step is the same formula as in Example 1;

[0043] C) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0044] [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (23 (^, 0.08 11〇1) and Chi ^ -! Dicyclohexyl carbodiimide (22. lg, 0. llmol) was dissolved in chloroform (120 mL), with stirring, was added methyl sulfonamide (9.8g, 0. lOmol), the reaction mixture was 80 ° C the reaction stirred for 19 hours, the reaction solution was concentrated by rotary evaporation to dryness, ethyl acetate was added and extracted dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide, off-white the solid (24.8 g of), a yield of 85.0%, the reaction of the present step is the same formula as in Example 1;

[0045] D) Preparation of SIPA Seiler: 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (24 (^, 0.065111〇1. ) and dissolved in ethanol (1601 ^), trifluoroacetic acid (9 (^, 0.08111〇1.), 70 ° (: the reaction was stirred for 7 hours to complete the reaction, the reaction was added dropwise to a stirred solution of water (260 mL of), cooled crystallization to 0 ° C for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), and then dissolved in ethanol (90 mL) , 5-chloro-2,3-diphenyl-pyrazine (! 11〇1 21.8 8,0.08), triethylamine (14.98,0.15111〇1), the reaction mixture was 100 ° (: The reaction was stirred for 18 hours, the reaction solution cooled to room temperature, water (40 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (29.6 g of), a yield of 91.0%, the reaction of the present step is the same formula as in Example 1 .

[0046] Example 3

[0047] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0048] 4 – [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol (12g, 0.05mol) and t-butyl bromoacetate (12.1g, 0.06mol) was dissolved in chloroform (70mL), was added tetrabutylammonium iodide (0 · 5g, 1 · 3mmol), lithium hydroxide (1 · 7g, 0 · 07mol) and water (6.5 g of), the reaction mixture was stirred 20 ° C for 4 hours, the reaction solution under reduced pressure concentrated by rotary evaporation to dryness, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxycarbonyl) (isopropyl) aminobutyrate oxygen yl] acetate, as a pale yellow oil (15.6 g of), a yield of 86.8%, the reaction of the present step is the same formula as in Example 1;

[0049] B) Preparation of [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0050] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (15.0g, 0.04mol) was dissolved in isopropanol (40mL), was added a solution of lithium hydroxide (LiOH = 1 · 3g, 0 · 05mol; water 6 · 0g), was heated to 70 ° C for 8 hours, cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl) aminobutyrate oxy] acetic acid as an off-white solid (11.7 g), 93.0% yield, this step is the same reaction scheme of Example 1;

[0051] C) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0052] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (11 (^, 0.04! 11〇1) and 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide (8.38,0.05111〇1) was dissolved in acetonitrile (4〇1111 ^), with stirring, was added methyl sulfonamide (5.] ^, 0.05mol), the reaction mixture was 95 ° C the reaction stirred for 22 hours, The reaction solution was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide as an off-white solid (11.7 g), yield 84.2%, the reaction of the present step is the same formula as in Example 1;

[0053] D) Preparation of SIPA Seiler: 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (11 (^, 0.03111〇1. ) and dissolved in dichloromethane (601 ^), trifluoroacetic acid (4.48,0.04111〇1), 50 ° (: the reaction was stirred for 10 hours to water (120 mL completion of the reaction, the reaction liquid was added to a stirred), cooled to crystallization 0 ° C for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), and then dissolved in tert-butanol (40 mL ), 5-chloro-2,3-diphenyl-pyrazine (9.68,0.036 11〇1), 4-dimethylaminopyridine (8.18,0.07111〇1), the reaction mixture was 110 ° (:! reaction was stirred for 14 hours the reaction was cooled to room temperature, water (15 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (13.5 g of), a yield of 90.5%, the reaction in this step is the same formula Example 1.

[0054] Example 4

[0055] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0056] 4 – [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol (15 (^, 0.065111〇1) and t-butyl bromoacetate (17.78,0.09111〇1) was dissolved in toluene (701] 11 ^), was added tetrabutylammonium hydrogen sulfate (0.888,2.61] 11] 1〇1), potassium carbonate (15.2 area, 0.1 lmol) and water (9.5 g of), the reaction mixture was stirred 40 ° C for 1.5 hours, the reaction solution was concentrated under reduced pressure and rotary evaporated to dryness and extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxycarbonyl) (isopropyl propyl) aminobutoxy] acetate, as a pale yellow oil (19.6 g of), in the same reaction formula in this step a yield of 87.5% in Example 1;

[0057] B) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0058] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (19 (^, 0.055! 11〇1) was dissolved in tert-butanol (60 mL), hydroxide solution of cesium (CsOH = 11. lg, 0.07mol; water, 8.0 g), the reaction was heated to 75 ° C for 6.5 hours cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] acetic acid, an off-white solid (15.0 g of), a yield of 94.2%, the reaction of the present step is the same formula as in Example 1;

[0059] C) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0060] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (15.0g, 0.05mol) and diazabicyclo 1,8_

[5.4.0] – | -7- dilute (9.5 region, 0.06111〇1) was dissolved in toluene (8〇1111 ^), with stirring, was added methyl sulfonamide (5.7 region, 0.06mo 1), the reaction mixture was 105 ° C for 16 hours, the reaction solution was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] -N- (methylsulfonyl) acetamide as an off-white solid (16.6 g of), 87.3% yield, this step is the same reaction scheme of Example 1;

[0061] D) Preparation of SIPA Seiler: 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (16 (^, 0.04111〇. 1) and dissolved in ethyl acetate (^ 1,301,111), trifluoroacetic acid (5.78,0.051] 1〇1), 80 <€ the reaction was stirred for 5 hours to complete the reaction, the reaction was added dropwise to a stirred solution of water (150 mL), was cooled to 0 ° C crystallization for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), then dissolved in isopropanol (50 mL), was added 5-chloro-2,3-diphenyl-pyrazine (13.58,0.05 11〇1!), a hoot dimethylaniline (12.28,0.10111〇1), the reaction mixture was 95 ° (: The reaction was stirred 12 hours, the reaction was cooled to room temperature, water (40 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (19.7 g of), a yield of 91.0%, the reaction step formula in Example 1.

//////////////

Selexipag (C₂₆H₃₂N₄O₄S, M_r = 496.6 g/mol) ist ein Diphenylpyrazin-Derivat. Es wird in der Leber zum aktiven Metaboliten ACT-333679 (MRE-269) biotransformiert. Selexipag unterscheidet sich strukturell von Prostazyklin und anderen Prostazylin-Rezeptor-Agonisten.

References

1 Sitbon, O.; Morrell, N. (2012). “Pathways in pulmonary arterial hypertension: The future is here”. European Respiratory Review 21 (126): 321–327. doi:10.1183/09059180.00004812. PMID 23204120.
2 New Drug Approved for Rare Lung Disorder. PPN. 23 Dec 2015 Has link to GRIPHON study results

Kuwano et al. NS-304, an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 2007;322:1181-1188.
Kuwano et al. A long-acting and highly selective prostacyclin receptor agonist prodrug, NS-304, ameliorates rat pulmonary hypertension with unique relaxant responses of its active form MRE-269 on rat pulmonary artery. J Pharmacol Exp Ther 2008;326:691-699.
Simonneau G, Lang I, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N. Selexipag, an oral, selective IP receptor agonist for the treatment of pulmonary arterial hypertension Eur Respir J 2012; 40: 874-880
Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010;104:9-21.
Sitbon, O.; Morrell, N. (2012). “Pathways in pulmonary arterial hypertension: The future is here”. European Respiratory Review 21 (126): 321–327. doi:10.1183/09059180.00004812. PMID 23204120.
Publication numberPriority datePublication dateAssigneeTitle

WO2016193994A12015-05-292016-12-08Megafine Pharma (P) Ltd.Amorphous selexipag and process for preparation thereof

WO2017040872A12015-09-032017-03-09Teva Pharmaceuticals International GmbhSolid state forms of selexipag

WO2017042731A12015-09-102017-03-16Lupin LimitedAmorphous form of selexipag and solid dispersion thereof

WO2017109772A1 *2015-12-202017-06-29Mapi Pharma Ltd.Amorphous form of selexipag

WO2018008042A1 *2016-07-052018-01-11Maithri Drugs Private LimitedNovel process for the preparation of 2-{4-[(5,6-diphenyl pyrazin-2-yl)(isopropyl)amino]butoxy}-n-(methylsulfonyl)acetamide and novel polymorphs thereof

WO2018015974A12016-07-202018-01-25Mylan Laboratories LimitedPolymorphic forms and amorphous solid dispersion of selexipag

WO2018022704A12016-07-262018-02-01Teva Pharmaceuticals International GmbhCrystalline form vi of selexipag

WO2018078383A12016-10-272018-05-03Cipla LimitedPharmaceutical composition comprising amorphous selexipag

Family To Family Citations

WO2009107736A1 *2008-02-282009-09-03日本新薬株式会社Fibrosis inhibitor

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WO2017029594A1 *2015-08-172017-02-23Dr. Reddy’s Laboratories LimitedProcesses for preparation of selexipag and its amorphous form

WO2017042828A3 *2015-09-102017-04-27Megafine Pharma (P) Ltd.Process for the preparation of selexipag

EP3192502A12016-01-152017-07-19Sandoz AgPharmaceutical composition of selexipag

WO2017168401A1 *2016-04-012017-10-05Honour (R&D)Process for the preparation of diphenylpyrazine derivatives

CN105949135A *2016-05-102016-09-21湖南欧亚生物有限公司Synthetic method of selexipag

EP3335699A12016-12-152018-06-20H e x a l AktiengesellschaftSelexipag formulation in liquisolid system

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COMPOUNDS CAPABLE OF MODULATING/PRESERVING ENDOTHELIAL INTEGRITY FOR USE IN PREVENTION OR TREATMENT OF ACUTE TRAUMATIC COAGULOPATHY AND RESUSCITATED CARDIAC ARREST [US2015057325]	2013-03-26	2015-02-26
INHIBITION OF NEOVASCULARIZATION BY SIMULTANEOUS INHIBITION OF PROSTANOID IP AND EP4 RECEPTORS [US2014275200]	2014-03-05	2014-09-18
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METHODS OF IDENTIFYING CRITICALLY ILL PATIENTS AT INCREASED RISK OF DEVELOPMENT OF ORGAN FAILURE AND COMPOUNDS FOR THE TREATMENT HEREOF [US2014322207]	2014-07-11	2014-10-30
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Selexipag
Names

IUPAC name 2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide
Other names ACT-293987, NS-304
Identifiers
CAS Number	475086-01-2
ChEMBL	ChEMBL238804
ChemSpider	8089417
IUPHAR/BPS	7552
Jmol interactive 3D	Image
KEGG	D09994
PubChem	9913767
UNII	P7T269PR6S
InChI [show]
SMILES [show]
Properties
Chemical formula	C₂₆H₃₂N₄O₄S
Molar mass	496.6 g·mol⁻¹

//////////ACT-333679, MRE-269, Selexipag, セレキシパグ , UNII-5EXC0E384L, селексипаг , سيليكسيباق , Orphan Drug, fda 2015, NS 304, ACT 293987, Uptravi, EU 2016,

CC(C)N(CCCCOCC(=O)NS(=O)(=O)C)C1=CN=C(C(=N1)C2=CC=CC=C2)C3=CC=CC=C3

Selexipag (Uptravi)

Selexipag and its active metabolite, the corresponding carboxylic acid, are nonprostanoid prostaglandin I2 (PGI-2) receptor agonists (Scheme 8).(24) The N-methylsulfonamide within selexipag is hydrolyzed to the corresponding carboxylic acid in vivo by hepatic microsomes at a rate which provides a slow-release pharmacological effect.(24) The compound was originally discovered by Nippon Shinyaki and later licensed to Actelion for development. The drug was approved in 2015 and first launched for the oral treatment of pulmonary arterial hypertension (PAH) in the U.S. in 2016 to delay disease progression and reduce the risk of hospitalization.(25)

The synthesis of selexipag began with condensation of commercially available benzil (51) and glycinamide hydrochloride in the presence of concentrated sodium hydroxide in refluxing MeOH to yield hydroxypyrazine 52. This compound was subsequently converted to 5-chloro-2,3-diphenylpyrazine (53) upon treatment with refluxing POCl₃ in the presence of a catalytic amount of H₂SO₄.(26) Chloride 53 was then subjected to neat 4-(isopropylamino)-1-butanol (54, prepared by the reductive alkylation of 4-amino-1-butanol and acetone with hydrogen over PtO₂ in EtOH) at 190 °C to give aminopyrazinyl alcohol 55 in 56% yield as colorless crystals. Alcohol 55 was alkylated with tert-butyl bromoacetate using Bu₄NHSO₄ as a phase-transfer catalyst and 40% aqueous KOH in benzene to give ester 56. Although it is particularly unusual to employ benzene on a production scale, these are the only reported conditions for this transformation. The crude ester 56 was then saponified using methanolic sodium hydroxide to yield the corresponding carboxylic acid 57 in 62% as pale-yellow crystals in two steps from compound 55. Finally, the carboxylic acid 57 was coupled with methanesulfonamide in the presence of CDI and DBU in THF to give selexipag (VI) in 77% yield.(27

24.Asaki, T.; Kuwano, K.; Morrison, K.; Gatfield, J.; Hamamoto, T.; Clozel, M. Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension J. Med. Chem. 2015,58, 7128– 7137 DOI: 10.1021/acs.jmedchem.5b00698
25.Skoro-Sajer, N.; Lang, I. M. Selexipag for the Treatment of Pulmonary Arterial Hypertension Expert Opin. Pharmacother. 2014, 15, 429– 436 DOI: 10.1517/14656566.2014.876007
26.Karmas, G.; Spoerri, P. E. The Preparation of Hydroxypyrazines and Derived Chloropyrazines J. Am. Chem. Soc. 1952, 74, 1580– 1584 DOI: 10.1021/ja01126a070
27.Asaki, T.; Hamamoto, T.; Sugiyama, Y.; Kuwano, K.; Kuwabara, K. Structure-activity Studies on Diphenylpyrazine Derivatives: a Novel Class of Prostacyclin Receptor Agonists Bioorg. Med. Chem. 2007,15, 6692– 6704 DOI: 10.1016/j.bmc.2007.08.010

FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

November 30, 2018 12:58 am / Leave a comment

FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM627093.htm?utm_campaign=11282018_PR_FDA%20approves%20treatment%20for%20LEMS&utm_medium=email&utm_source=Eloqua

November 28, 2018

Release

“There has been a long-standing need for a treatment for this rare disorder,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “Patients with LEMS have significant weakness and fatigue that can often cause great difficulties with daily activities.”

In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with other autoimmune diseases, but more commonly occurs in patients with cancer such as small cell lung cancer, where its onset precedes or coincides with the diagnosis of cancer. The prevalence of LEMS is estimated to be three per million individuals worldwide.

The efficacy of Firdapse was studied in two clinical trials that together included 64 adult patients who received Firdapse or placebo. The studies measured the Quantitative Myasthenia Gravis score (a 13-item physician-rated categorical scale assessing muscle weakness) and the Subject Global Impression (a seven-point scale on which patients rated their overall impression of the effects of the study treatment on their physical well-being). For both measures, the patients receiving Firdapse experienced a greater benefit than those on placebo.

The most common side effects experienced by patients in the clinical trials were burning or prickling sensation (paresthesia), upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension and muscle spasms. Seizures have been observed in patients without a history of seizures. Patients should inform their health care provider immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Firdapse also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Firdapse to Catalyst Pharmaceuticals, Inc.

///////////Priority Review, Breakthrough Therapy, Firdapse, Orphan Drug designation, fda 2018, amifampridine

VIXOTRIGINE, раксатригин , راكساتريجين , 维索曲静 ,

November 29, 2018 1:47 pm / Leave a comment

VIXOTRIGINE

Molecular FormulaC₁₈H₁₉FN₂O₂
Average mass314.354 Da
раксатригин , راكساتريجين , 维索曲静 ,

(5R)-5-{4-[(2-Fluorobenzyl)oxy]phényl}-L-prolinamide

10287

2-Pyrrolidinecarboxamide, 5-[4-[(2-fluorophenyl)methoxy]phenyl]-, (2S,5R)-

934240-30-9 [RN]

QQS4J85K6Y

Raxatrigine

UNII:QQS4J85K6Y

Vixotrigine (INN, USAN), formerly known as raxatrigine (INN, USAN), is an analgesic which is under development by Convergence Pharmaceuticals for the treatment of lumbosacral radiculopathy (sciatica) and trigeminal neuralgia (TGN).^[1]^[2]^[3] Vixotrigine was originally claimed to be a selective central Na_v1.3 blocker, but was subsequently redefined as a selective peripheral Na_v1.7 blocker.^[4]Following this, vixotrigine was redefined once again, as a non-selective voltage-gated sodium channel blocker.^[4] As of January 2018, it is in phase III clinical trials for trigeminal neuralgia and is in phase II clinical studies for erythromelalgia and neuropathic pain.^[5] It was previously under investigation for the treatment of bipolar disorder, but development for this indication was discontinued.^[5]

WO2018085521 , claiming novel dosage regimen, assigned to Biogen Inc and Biogen Ma Inc , naming a different team. Biogen, following the acquisition of Convergence Pharmaceuticals , that previously acquired clinical assets from GlaxoSmithKline , is developing vixotrigine ( phase 2 , in November 2018), a voltage-gated sodium channel 1.7 inhibitor, for treating neuropathic pain associated with trigeminal neuralgia, and small fibre neuropathy

PATENT

WO 2011/029762.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011029762

Preparation 1 : Methyl 4-(2-fluorobenzyloxy)benzoate (P1)

Methylparaben (8.85 g, 58.19 mmol) and K₂CO₃ (16.1 g, 1 16.38 mmol) were stirred in acetonitrile (100 mL) for 5 minutes and then 2-fluorobenzyl bromide (10 g, 52.9 mmol) was added. The suspension was heated to 50-55 °C and held for 2 hours. The mixture was then cooled to 20-25 °C, filtered, and the filtrate solution concentrated to a thick residue. The residue was then dissolved in CH₂CI₂, washed with a 1 M Na₂CO₃ solution, dried over Na₂SO₄, and concentrated to a solid. The solid was then stirred vigorously for 1 hour in just enough hexanes to allow for agitation (~40 mL) and then cooled to 0-5 °C. After 15 minutes, the product was isolated by filtration and washed with -25 mL of hexanes. After drying under vacuum, 1 was isolated as a white solid (13.1 g, 87% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.96-7.90 (2H, m), 7.57 (2H, apparent td, J = 7.7, 1.8 Hz),

7.48-7.39 (1 H, m), 7.30-7.21 (2H, m), 7.17-7.12 (2H, m), 5.22 (2H, s), 3.81 (3H, s).

¹³C NMR (100 MHz, DMSO-d₆) δ 166.2, 162.4, 160.8 (d, J = 247 Hz), 131.6, 131.1 (d, J = 3.8

Hz), 131.0 (d, J = 8.3 Hz), 124.9 (d, J = 3.4 Hz), 123.5 (d, J = 14.1 Hz), 122.6, 1 15.8 (d, J =

21.0 Hz), 115.0, 64.2 (d, J = 3.4 Hz), 52.2.

LRMS (m/e) : 261.3 [MH]⁺.

Preparation 2: 4-(2-fluorobenzyloxy)benzoic acid (P2).

Methyl 4-(2-fluorobenzyloxy)benzoate (P1 , 10.0 g, 26.9 mmol) was dissolved in methanol (60 mL) and THF (90 mL). A 45 wt% potassium hydroxide solution (20 mL) was then added and

the resulting exotherm was controlled by a water bath. After 1.5 days at 20-25 °C the solution became a thick suspension. Using a water bath to control the exotherm, 20 mL of concentrated HCl was added. The mixture was then concentrated to remove the THF and methanol and 150 mL water was added. The solid was isolated by filtration and washed with 50 mL water. After drying under vacuum, the title compound was isolated as a white crystalline solid (9.4 g, 99% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.95-7.89 (2H, m), 7.58 (2H, apparent td, J = 7.5, 1.7 Hz), 7.48-7.41 (1 H, m), 7.30-7.22 (2H, m), 7.16-7.10 (2H, m), 5.22 (2H, s).

¹³C NMR (100 MHz, DMSO-d₆) δ 167.3, 162.1 , 160.8 (d, J = 246 Hz), 131.7, 131.2 (d, J = 3.8 Hz), 131.0 (d, J = 8.3 Hz), 124.9 (d, J = 3.4 Hz), 123.8, 123.6, 115.8 (d, J = 21.0 Hz), 114.9, 64.2 (d, J = 3.4 Hz).

LRMS (m/e) 247.2 [MH]⁺.

Preparation 3: 4-(2-fluorobenzyloxy)-N-methyl-N-methoxybenzamide (P3).

4-(2-fluorobenzyloxy)benzoic acid (P2, 5.5 g, 22.3 mmol) was suspended in thionyl chloride (16.5 mL) and heated to 65 °C and held for 3 hours during which time the reactor was kept under a slow sweep of nitrogen. The mixture was then concentrated to a thick oil under hi vac to remove all traces of residual thionyl chloride. The residue was then diluted in CH₂CI₂ (20 mL) and cooled to 0 °C. In a separate flask, a solution of diaza(1 ,3)bicycle[5.4.0]undecane (DBU, 8.0 mL, 8.15 g, 53.52 mmol) and N-methoxy-N-methyl amine hydrochloride (2.61 g, 26.76 mmol) in CH₂CI₂ (20 mL) was made and slowly added to the solution at 0 °C. After warming to 20-25 °C, the mixture was washed with 1 M HCl and then with a saturated NaHCO₃ solution. After drying over Na₂SO₄, the solution was concentrated to a thick residue. The mixture was then purified by flash column chromatography eluting with 0→ 100% EtOAc/hexanes (gradient). Concentration of the fractions containing the title compound gave an oil that crystallized upon standing (6.0 g, 93% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.66-7.62 (2H, m), 7.58 (2H, apparent td, J = 7.5, 1.7 Hz), 7.48-7.41 (1 H, m), 7.30-7.23 (2H, m), 7.12-7.07 (2H, m), 5.20 (2H, s), 3.55 (3H, s), 3.25 (3H, s).

¹³C NMR (100 MHz, DMSO-d₆) δ 168.9, 168.0 (d, J = 246 Hz), 163.0, 131.2 (d, J = 3.8 Hz), 130.9 (d, J = 8.2 Hz), 130.4, 126.9, 124.9 (d, J = 3.4 Hz), 123.8 (d, J = 14.8 Hz), 115.8 (d, J = 21.0 Hz), 114.4, 64.0 (d, J = 3.8 Hz), 60.9, 33.8.

LRMS (m/e) 290.3 [MH]⁺.

Preparation 4: 1-(4-[2-fluorobenzyloxy]phenyl)-2-propen-1-one (P4).

4-(2-fluorobenzyloxy)-N-methyl-N-methoxybenzamide (P3, 6.0 g, 20.7 mmol) was dissolved in THF (100 mL) and cooled to -78 °C. A 1.0 M solution of vinyl magnesium bromide in THF (31 mL, 31 mmol) was added and the cold bath was removed. Upon warming to 20-25 °C, the mixture was poured into a vigorously stirred solution of 1 M HCl. The resulting mixture was extracted twice with CH₂CI₂. The combined organic layers were then washed with 1 M HCl, then with a saturated NaHCO₃ solution, dried over Na₂SO₄, and concentrated to a thick residue. The product was purified by flash column chromatography eluting with 0→ 40% acetone hexanes (gradient). Concentration of the fractions containing 4 gave an oil that crystallized upon standing (4.83 g, 91% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 8.06-8.01 (2H, m), 7.59 (1 H, apparent td, J = 7.5, 1.7 Hz), 7.48-7.38 (2H, m), 7.30-7.22 (2H, m), 7.21-7.16 (2H, m), 6.32 (1 H, dd, J = 17.0, 2.0 Hz), 5.92 (1 H, dd, J = 10.5, 2.0 Hz), 5.26 (2H, s).

¹³C NMR (100 MHz, DMSO-d₆) δ 188.3, 162.6, 160.8 (d, J = 246 Hz), 132.5, 131.3, 131.2 (d, J = 3.8 Hz), 131.0 (d, J = 8.2 Hz), 130.3, 129.7, 124.9 (d, J = 3.1 Hz), 123.6 (d, J = 14.4 Hz), 115.8 (d, J = 21.0 Hz), 115.2, 64.3 (d, J = 3.4 Hz).

LRMS (m/e) 257.3 [MH]⁺.

Preparation 6: Ethyl-5-(4-[2-fluorobenzyloxy]phenyl)-3,4-dihydro-2H-pyrrole-2- carboxylate (P5)

(S)-4-lsopropyl-2-[(S)-2-(diphenylphosphino) ferrocen-1-yl]oxazoline (18.8 mg, 0.039 mmol) and Cu(MeCN)₄PF₆ (14.5 mg, 0.039 mmol) were added to a dried, nitrogen swept reaction vessel. Anhydrous, degassed, BHT inhibited THF (5.0 mL) was then added and the mixture was stirred for 30 minutes at 20-25 °C. The resulting solution was then cooled to -78 °C and a solution of 1-(4-[2-fluorobenzyloxy]phenyl)-2-propen-1-one (P4, 2.0 g, 7.80 mmol) and ethyl N-(diphenylmethylidene)glycinate (2.29 g, 8.58 mmol) in THF (15 mL total volume) was added over 1-2 minutes. After 3-5 minutes, a solution of DBU (5.9 mg, 0.039 mmol) in THF (0.5 mL total volume) was added. The solution was then stirred for 8-12 hours at -78 °C. The reaction mixture was then warmed to 0-5 °C and 1 M H₂SO₄ (aq., 25 mL) was then added. The reaction mixture was then warmed to 20-25 °C and mixed vigorously for 2 hours. The mixture was then poured into a rapidly stirring solution of NaHCO₃ (saturated, enough to bring the pH to≥ 7.0). After 5minut.es of stirring, the mixture was extracted twice with TBME and the organic extracts were pooled, dried over Na₂SO₄, and concentrated to near dryness. The resulting residue was purified by flash column chromatography eluting with 0→ 40% acetone/hexanes (gradient). Concentration of the fractions containing the title compound gave a crystalline solid (2.23 g, 84% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.85-7.80 (2H, m), 7.58 (1H, apparent td, J = 7.5, 1.7 Hz), 7.47-7.41 (1 H, m), 7.30-7.22 (2H, m), 7.13-7.09 (2H, m), 5.21 (2H, s), 4.82-4.76 (1 H, m), 4.14 (2H, q, J = 7.1 Hz), 3.13-3.02 (1 H, m), 2.98-2.87 (1 H, m), 2.32-2.21 (1 H, m), 2.09-1.98 (1 H, m), 1.22 (3H, t, J = 7.02 Hz).

¹³C NMR (100 MHz, DMSO-d₆) δ 174.8, 173.1 , 160.8 (d, J = 246 Hz), 160.6, 131.1 (d, J = 3.8 Hz), 130.9 (d, J = 8.3 Hz), 130.0, 127.1 , 124.9 (d, J = 3.1 Hz), 123.9 (d, J = 14.4 Hz), 1 15.8 (d, J = 21.0 Hz), 115.0, 74.2, 64.0 (d, J = 3.8 Hz), 60.7, 35.3, 26.6, 14.4.

LRMS (m/e) 342.4 [MH]⁺.

Preparation 6: 1-{4-[(phenylmethyl)oxy]phenyl}-2-propen-1-one (P6).

1-{4-[(phenylmethyl)oxy]phenyl}-2-propen-1-one may be prepared from N-methyl-N-(methyloxy)-4-[(phenylmethyl)oxy]benzamide using analogous procedures as those described above for the preparation of P4. N-methyl-N-(methyloxy)-4-[(phenylmethyl)oxy]benzamide may be prepared according to procedures known from the literature (Cowart, M. et. al. J. Med. Chem. 2005, 48, 38).

¹H NMR (400 MHz, DMSO-d₆) δ 8.05-8.00 (2H, m), 7.50-7.32 (6H, m), 7.18-7.14 (2H, m),

6.32 (1 H, dd, J = 16.9, 2.1 Hz), 5.92 (1 H, dd, J = 10.5, 2.1 Hz), 5.23 (2H, s).

¹³C NMR (100 MHz, DMSO-d₆) d 188.3, 162.8, 136.8, 132.5, 131.3, 130.1 , 129.6, 128.9,

128.4, 128.2, 115.3, 69.9.

LRMS (m/e) 239.3 [MH]⁺.

Praparation 7a and 7b Ethyl (2R)-2-[(diphenylmethylidene)amino]-5-(4-[2-fluorobenzyloxy]phenyl)-5-oxopentanoate (P7a) and Ethyl (2S)-2-[(diphenylmethylidene)amino]-5-(4-[2-fluorobenzyloxy]phenyl)-5-oxopentanoate (P7b).

The Ligand (according to Table 1 below reported, 0.0084 mmol) and Cu(MeCN)₄PF₆ (3.13 mg, 0.0084 mmol) were added to a dried, nitrogen swept reaction vessel. Anhydrous, degassed, BHT inhibited THF (0.4 mL) was then added and the mixture was stirred for 30 minutes at 20-25 °C. The resulting solution was then cooled to -20 to -21 °C and a solution of 1-{4-[(phenylmethyl)oxy]phenyl}-2-propen-1-one (P6, 100mg, 0.42 mmol) and ethyl N-(diphenylmethylidene)glycinate (123.5 mg, 0.462 mmol) in THF (0.5 mL total volume) was added over 1-2 minutes. After 1-5 minutes, a solution of DBU (1.27 mg, 0.0084 mmol) in THF (0.1 mL total volume) was added. The solution was then stirred for 8-12 hours at -20 to -25 °C. After this time the reactions were complete and an aliquot of each reaction mixture was diluted in 10% iPrOH / hexanes and analyzed by chiral HPLC. An analytically pure sample was obtained by subjecting the concentrated reaction mixture to flash column chromatography eluting with 0→ 40% acetone hexanes (gradient). Concentration of the fractions containing 7a and 7b (94:6) gave a thick syrup (187 mg, 88% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.91-7.86 (2H, m), 7.54-7.32 (13H, m), 7.13-7.07 (4H, m), 5.20 (2H, s), 4.11-4.05 (2H, m), 4.02 (1 H, dd, J = 8.0, 4.8 Hz), 3.01-2.91 (2H, m), 2.27-2.21 (1 H, m), 2.14-2.08 (1 H, m), 1.16 (3H, t, J = 7.2 Hz).

¹³C NMR (100 MHz, DMSO-d₆) δ 197.3, 171.2, 170.0, 162.1 , 138.8, 136.5, 135.6, 130.5, 130.1 , 129.6, 128.7, 128.6, 128.5, 128.2, 128.1 , 128.0, 127.7, 127.3, 114.6, 69.4, 63.8, 60.5, 33.6, 27.7, 14.0.

Example 1: (5R)-5-(4-[2-fluorobenzyioxy]phenyl)-L-prolinamide (E1)

A mixture of 5% Pt/C (Johnson Mathey B102022-5, 100 mg) was added to a solution of Ethyl -5-(4-[2-fluorobenzyloxy]phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (P5, obtained as above reported, 1.0 g, 2.93 mmol) in ethanol (12 mL). Acetic acid (1.2 ml.) was then added and the reaction vessel was purged with N₂ and then H₂. The mixture was hydrogenated at 50 psi of H₂ at 15-20 °C for at least 2h. Upon completion of the reaction (monitored by H₂ uptake), the mixture was filtered through celite, then through a 0.2 μm PTFE filter and concentrated to approximately 1.5 mL. The mixture was diluted with 1 :1 iPrOAc/TBME and washed with a saturated solution of NaHCO₃. After concentrating the organics to a thick residual oil (986mg, 98% crude yield; LCMS retention time 2.04 minutes, calculated 344.4 [MH]⁺, found 344.3 [MH]⁺), a solution of ammonia in methanol (ca 7 M) was added in two portions (4 mL initially and then 1 mL after ~10 hrs). After the additions were complete, the reaction stirred for at least 24 hrs at 15-20 °C. Upon completion of the reaction, the mixture was concentrated to dryness. The solid was suspended in a mixture of toluene/TBME 1 :1 (~4 mL) at 18-23 °C with vigorous mixing. After 2hrs at 18-23 °C, the mixture was cooled to 0-5 °C and held for 1 hr. The solid was isolated by filtration and washed with TBME (~4 mL). Drying the solid in a vacuum oven at approximately 40 °C gave the title compound as an off white-solid (720 mg, 78% yield from P5).

Analysis of the sample obtained, performed on CHIRALCEL OJ analytical HPLC column (10% iPrOH/hexanes, 1 mL/min, rt), revealed the presence in minor amounts of (5S)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-D-prolinamide (enantiomer of the title compound); retention times: (5S)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-D-prolinamide 36.3 min (1.2%), E1 41.8 min (98.8%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.55 (1 H, apparent td, J = 7.6, 1.6 Hz), 7.45-7.32 (4H, m), 7.29-7.21 (2H, m), 7.14 (1 H, br. s), 7.00-6.95 (2H, m), 5.12 (2H, s), 4.10 (1 H, dd, J = 9.4, 5.8 Hz), 3.56 (1 H, dd, J = 9.4, 4.4 Hz), 2.14-1.96 (2H, m), 1.92-1.82 (1 H, m), 1.47-1.36 (1 H, m). ¹³C NMR (100 MHz, DMSO-d₆) δ 177.1 , 160.3 (d, J = 246 Hz), 157.0, 137.1 , 130.6 (d, J = 3.8 Hz), 130.3 (d, J = 8.3 Hz), 127.6, 124.5 (d, J = 3.4 Hz), 124.0 (d, J = 14.4 Hz), 115.3 (d, J = 21.0 Hz), 114.4, 63.5 (d, J = 3.8 Hz), 61.7, 59.9, 34.1 , 30.4.

Example 2: (5R)-5-(4-[2-fluorobenzyloxy]phenyl)-L-prolinamide hydrochloride (E2)

To a solution of E1 ( 72 mg, 0.23 mmol) in a mixture of ethyl acetate (1.0 ml) and methanol (1.0 ml) was added 4M HCl in 1 ,4-dioxane (57.5 uL, 0.23 mmol) at 0°C. The mixture was stirred for 1.5h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to afford the title compound as a white solid (75 mg, 93% yield).

¹H NMR (300 MHz, DMSO-d₆) δ 10.89 (1 H, br. s), 8.12 (1 H, s), 8.1 1 (1 H, br. s), 7.73 (1 H, s), 7.60-7.39 (4H, m), 7.30-7.21 (2H, m), 7.13-7.06 (2H, m), 5.18 (2H, s), 4.66-4.56 (1 H, m), 4.36-4.28 (1 H, m), 2.42-1.94 (4H, m).

PATENT

WO-2018213686

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018213686&tab=PCTDESCRIPTION&maxRec=1000

Novel crystalline forms of vixotrigine and their anhydrous form or solvates (designated as Forms A-C), processes for their preparation and composition comprising them are claimed.

The hydrochloride salt of (2S, 5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide, herein referred to as the compound of formula (I):

(I)

is described in WO 2007/042239 as having utility in the treatment of diseases and conditions mediated by modulation of use-dependent voltage-gated sodium channels. The synthetic preparation of (2S, 5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide hydrochloride is described in both WO 2007/042239 and WO 2011/029762.

However, there is a need for the development of crystalline forms of such a-carboxamide pyrrolidine derivatives, which have desirable pharmaceutical properties

Example 1 : (5/?)-5-(4-{[(2-Fluorophenyl)methyl]oxy}phenyl)-L-prolinamide hydrochloride (E1 )

. HCI

The compound of Example 1 may be prepared as described in Example 2,

Procedures 1 to 5 of WO 2007/042239.

Example 2: (5 ?)-5-(4-{[(2-Fluorophenyl)methyl]oxy}phenyl)-L-prolinamide hydrochloride Form 1 (Anhydrous A) (E2)

25.0 mg of Example 1 was added to a 3 mL scintillation vial. THF (2.00 mL) was added and the resulting suspension stirred for 10 minutes. The suspension was filtered through a 0.45 μηι PTFE filter and the filtrate vial placed inside a 20 mL scintillation vial. Hexanes (2 mL) were placed in the outer vial, the entire system sealed and stored at room temperature for 3 days, after which time a crop of colorless crystals was evident in the 3 mL vial. One of these crystals was selected for a single crystal X-ray diffraction experiment. Full characterisation is shown in Figures 1 and 2 and Tables 1 and 2 below

References

Jump up^ Convergence Pharmaceuticals. “CNV1014802 – Convergence Pharmaceuticals”.
Jump up^ Stephen McMahon; Martin Koltzenburg; Irene Tracey; Dennis C. Turk (1 March 2013). Wall & Melzack’s Textbook of Pain: Expert Consult – Online. Elsevier Health Sciences. p. 508. ISBN 0-7020-5374-0.
Jump up^ Bagal, Sharan K.; Chapman, Mark L.; Marron, Brian E.; Prime, Rebecca; Ian Storer, R.; Swain, Nigel A. (2014). “Recent progress in sodium channel modulators for pain”. Bioorganic & Medicinal Chemistry Letters. 24 (16): 3690–9. doi:10.1016/j.bmcl.2014.06.038. ISSN 0960-894X. PMID 25060923.
^ Jump up to:^a ^b Keppel Hesselink, Jan M. (2017). “Moving targets in sodium channel blocker development: the case of raxatrigine: from a central NaV1.3 blocker via a peripheral NaV1.7 blocker to a less selective sodium channel blocker”. Journal of Medicine and Therapeutics. 1 (1). doi:10.15761/JMT.1000104. ISSN 2399-9799.
^ Jump up to:^a ^b https://adisinsight.springer.com/drugs/800027679

External links

Vixotrigine – AdisInsight

Vixotrigine
Clinical data

Synonyms	Raxatrigine; CNV1014802; GSK-1014802; BIIB 074
Routes of administration	By mouth
ATC code	None
Identifiers
IUPAC name [show]
CAS Number	934240-30-9 934240-35-4 (mesylate)
PubChem CID	16046068
ChemSpider	13174481
KEGG	D11179
Chemical and physical data
Formula	C₁₈H₁₉FN₂O₂
Molar mass	314.354 g/mol
3D model (JSmol)	Interactive image
SMILES [hide] C1CC(NC1C2=CC=C(C=C2)OCC3=CC=CC=C3F)C(=O)N

Patent ID	Title	Submitted Date	Granted Date
US2017304265	Paroxysmal Extreme Pain Disorder Treatment	2015-10-02
US2017096708	DIAGNOSTIC METHOD	2015-06-03

Patent ID	Title	Submitted Date	Granted Date
US2017369437	Process for Preparing Alpha-Carboxamide Pyrrolidine Derivatives	2015-12-23
US9006271	5-[5-[2-(3, 5-BIS(TRIFLUOROMETHYL)PHENYL)-2-METHYLPROPANOMETHYLPROPANOYLMETHYLAMINO]-4-(4-FLUORO-2-METHYLPHENYL)]-2-PYRIDINYL-2-ALKYL-PROLINAMIDE AS NK1 RECEPTOR ANTAGONISTS	2014-05-16	2014-09-04
US8759542	Process for preparing alpha-carboxamide derivatives	2010-09-01	2014-06-24
US2017304264	Novel Erythromelalgia Treatment	2015-10-02
US2017290802	Novel Small Fibre Neuropathy Treatment	2015-10-02

Patent ID	Title	Submitted Date	Granted Date
US8093268	PHARMACEUTICAL COMPOSITIONS COMPRISING 2-METHOXY-5-(5-TRIFLUOROMETHYL-TETRAZOL-1-YL-BENZYL)-(2S-PHENYLPIPERIDIN-3S-YL-)	2010-05-06	2012-01-10
US2010105688	PHARMACEUTICAL COMPOSITIONS COMPRISING 3, 5-DIAMINO-6-(2, 3-DICHLOPHENYL)-1, 2, 4-TRIAZINE OR R(-)-2, 4-DIAMINO-5-(2, 3-DICHLOROPHENYL)-6-FLUOROMETHYL PYRIMIDINE AND AN NK1	2010-04-29
US8153681	Method of treating epilepsy by administering 5-(4{[(2-fluorophenyl)methyl]oxy}phenyl)prolinamide	2010-04-29	2012-04-10
US2009318530	PHARMACEUTICAL COMPOSITIONS COMPRISING NK1 RECEPTOR ANTAGONISTS AND SODIUM CHANNEL BLOCKERS	2009-12-24
US7655693	Compounds	2008-11-13	2010-02-02

Patent ID	Title	Submitted Date	Granted Date
US7855218	Compounds	2008-12-11	2010-12-21
US2017340646	Methods and Compositions for Decreasing Gastric Emptying	2017-08-18
US9763955	Methods and Compositions for Decreasing Gastric Emptying	2016-02-19	2016-08-25
US8822504	5-[5-[2-(3, 5-bis(trifluoromethyl)phenyl)-2-methylpropanomethylpropanoylmethylamino]-4-(4-fluoro-2-methylphenyl)]-2-pyridinyl-2-alkyl-prolinamide as NK1 receptor antagonists	2012-11-20	2014-09-02
US8143306	Methods of treating bipolar disorders	2011-04-28	2012-03-27

Patent ID	Title	Submitted Date	Granted Date
US8633214	Spiro (piperidine-4, 2â€²-pyrrolidine)-1-(3, 5-trifluoromethylphenyl) methylcarboxamides as NK1 tachikynin receptor antagonists	2012-11-21	2014-01-21
US8344005	5-[5-[2-(3, 5-BIS(Trifluoromethyl)Phenyl)-2-MethylpropanoMethylpropanoylmethylamino]-4-(4-Fluoro-2-Methylphenyl)]-2-Pyridinyl-2-Alkyl-Prolinamide As NK1 Receptor Antagonists	2011-03-10
US8367692	Spiro (Piperidine-4, 2′-Pyrrolidine)-1-(3, 5-Trifluoromethyl Phenyl) Methylcarboxamides As NK1 Tachikynin Receptor Antagonists	2011-03-03
US8153623	Compounds	2010-12-23	2012-04-10
US2009286836	Novel Compounds	2009-11-19

////////////VIXOTRIGINE, раксатригин , راكساتريجين , 维索曲静 , QQS4J85K6Y, Raxatrigine, UNII:QQS4J85K6Y

Anthony Crasto conferred ABPnews award for “Outstanding contribution to Education Sector”

November 28, 2018 1:39 pm / Leave a comment

Conferred prestigious award at event ABP News Presents Healthcare Leadership Awards 26th November, 2018 at Taj Lands End, Mumbai India
Dedicated to Shobha Crasto Aishal crasto Lionel crasto
Service to education is service to humanity
Society recognises efforts done towards it

/////////////award, event ABP News, Healthcare, Leadership, 26th, November, 2018, Taj Lands End, Mumbai, India, education, anthony crasto

Omidenepag isopropyl, オミデネパグイソプロピル

November 28, 2018 10:07 am / Leave a comment

Image result for Omidenepag isopropyl

Omidenepag isopropyl

DE-117

Glycine, N-(6-((((4-(1H-pyrazol-1-yl)phenyl)methyl)(3-pyridinylsulfonyl)amino)methyl)-2-pyridinyl)-, 1-methylethyl ester

[[6-[[[4-(Pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)amino]methyl]pyridin-2-yl]amino]acetic acid isopropyl ester

C26H28N6O4S, 520.6033, CAS: 1187451-19-9

APPROVED 2018/9/21 PMDA, JAPAN 2018, Eybelis

Antiglaucoma, Prostaglandin E2 receptor agonist, Treatment of Open-Angle Glaucoma and Ocular Hypertension

Originator Ube Industries
Developer Santen Pharmaceutical
Class Eye disorder therapies; Pyrazoles; Pyridines; Small molecules; Sulfonamides
Mechanism of Action Prostaglandin E EP2 receptor agonists

Registered Glaucoma; Ocular hypertension

27 Sep 2018 Santen initiates enrolment in the phase III Spectrum 5 trial for Glaucoma and Ocular hypertension in USA (Ophthalmic) (NCT03697811)
21 Sep 2018 Santen Pharmaceutical and Ube Industries plan phase III trials for omidenepag isopropyl in USA in the second half of 2018
21 Sep 2018 Registered for Ocular hypertension and Glaucoma in Japan (Ophthalmic) – First global approval

SYNTHESIS

PATENT

WO 2009113600

WO 2010113957

JP 2011057633

PATENT

WO 2015190507

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015190507&tab=FULLTEXT&maxRec=1000

[Example 1]
[Formula

10] 2 – {[6 – ({N-[4-(1H-pyrazol-1-yl) benzyl] pyridin-3-sulfonamido} methyl) pyridin-2-yl] amino} Synthesis of isopropyl acetate

　To a glass vessel having an inner volume of about 50 ml equipped with a stirring device, a thermometer and an upper cooling device, 3.21 g (10.00 mmol) of N- [4- (1H-pyrazol-1-yl) benzyl] , 2.43 g (10.0 mmol) of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate obtained in Example 6, 6.65 g (20.4 mmol) of cesium carbonate and 17.6 g of acetonitrile was added, and the mixture was heated and stirred at 80 ° C. In the high performance liquid chromatography analysis, the reaction was carried out for 2 hours until the area percentage of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate became 0.03% or less, I went for hours. The reaction conversion ratios of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate after heating and stirring 1 hour and 2 hours were 99.88% and 99.97% . After completion of the reaction, the reaction solution was cooled to room temperature, filtered using Celite (trade name), and the filtrate was washed with acetonitrile. Quantitative analysis of the obtained filtrate by high performance liquid chromatography revealed that 5.08 g of the objective substance was contained (reaction yield: 97.5%). Next, the reaction solution was concentrated under reduced pressure until the weight of the liquid reached 7.85 g, 42.8 g of toluene was added, and the mixture was washed three times with water. 31.5 ml (31.5 mmol) of 1 mol / L hydrochloric acid was added to the obtained organic layer, and the mixture was stirred at room temperature for 20 minutes and then separated. Note that 0.17 g (corresponding to 3.2% yield) of target product was contained in the organic layer after liquid separation. 42.8 g of toluene and 34.6 ml (34.6 mmol) of 1 mol / L sodium hydroxide aqueous solution were added to the obtained aqueous layer, and the mixture was heated to 40 ° C. and stirred for 20 minutes. After filtration at 40 ° C. in the hot state, liquid separation was carried out. The obtained organic layer was washed twice with water. The organic layer was concentrated under reduced pressure until the weight of the liquid reached 8.97 g, and 7.40 g of 2-propanol was added. After warming to 60 ° C., it was slowly cooled and stirred at 33 ° C. for 30 minutes, then slowly cooled to 5 ° C. or less, and further stirred at the same temperature for 1 hour. Precipitated The solid was filtered, washed with chilled 2-propanol and then vacuum dried at 50 ° C. to give 2 – {[6 – ({N- [4- (1 H-pyrazol- 1 – yl) benzyl] pyridine- 3 – sulfonamido} methyl) pyridin-2-yl] amino} acetic acid was obtained as a slightly brown solid (2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate Isolated yield of standard 75.1%). The quantitative purity by HPLC high performance chromatography method was 99.5%, and 0.04% of N- [4- (1H-pyrazol-1-yl) benzyl] pyridine-3-sulfonamide as a raw material was contained It was. Also, in the measurement (wavelength 260 nm) by the HPLC high performance liquid chromatography method, there was no impurity showing an area% of 0.1% or more.

　Physical property values of the obtained 2 – {[6 – ({N- [4- (1 H-pyrazol-1 -yl) benzyl] pyridine-3-sulfonamido} methyl) pyridin-2- yl] amino} , It was as follows.
EI-MS (m /
z):. 520 [M] CI-MS (m /
^[Mz):. ⁺ 1] 1 H-NMR (CDCl _3, [delta] (ppm)): 1.24 (6H, d, J = 6.3 Hz), 5.07 (1 H, se, J = 5.5 Hz), 3.82 (2 H, d, J = 5.5 Hz), 4.31 (2 H, s), 4.64 (2 H, s), 4.94 J = 6.3 Hz), 6.26 (1 H, d, J = 8.3 Hz), 6.41 (1 H, dd, J = 7.2, 0.5 Hz), 6.46 (1 H, dd, J = 2.5, 1.8 Hz), 7.25 (2H, m), 7.71 (1H, dd, J = 8.3, 7.2 Hz), 7.32 (1H, ddd, J = 8.0, 4.9, 0.8 Hz), 7.37-7.42 J = 1.8, 0.6 Hz), 7.93 (1 H, dd, J = 2.6, 0.6 Hz), 7.94 (1 H, ddd, J = 8.0, 2.4, 1.7 Hz), 8.69 (1 H, dd, J = 4.8, 1.6 Hz ), 8.98 (IH, dd, J = 2.4, 0.8
^Hz). 13 C-NMR (CDCl ₃, δ (ppm)): 21.8, 43.7, 51.0, 51.1, 68.9, 107.4, 107.7, 112.6, 119.2, 123.3, 126.7, 129.9, 133.8, 134.6, 137.3, 137.6, 139.8, 141.1, 148.0, 152.6, 153.2, 157.3 , 1737 (C = O), (2981, 2933) (CH), 3437 (NH) , 170.5.
IR (KBr cm ^-1 ): 764 (CH), 1161 (S = O), 1525 .
elemental analysis; Calcd: C, 59.80%; H, 5.31%; N, 16.07%
Found: C, 59.98%; H, 5.42%; N, 16.14%.

[Example 2]
[Formula

11] 2 – ({6 – [(N-benzyl-3-sulfonamido) methyl] pyridin-2-yl} amino) -acetic acid isopropyl

　0.253 g (1.02 mmol) of N-benzylpyridine-3-sulfonamide, 0.253 g (1.02 mmol) of 2- { 0.243 g (1.00 mmol) of isopropyl acetate, 0.665 g (2.04 mmol) of cesium carbonate and 1.76 g of acetonitrile were added, and the mixture was heated and stirred at 80 ° C. did. In the high performance liquid chromatography analysis, the reaction was carried out for 2 hours until the area percentage of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate became 0.03% or less, I went for hours. The reaction conversion rates of 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetic acid isopropyl acetate after 1 hour and 2 hours from the start of heating and stirring were 99.81% and 99.99% It was. After completion of the reaction, the reaction solution was cooled to room temperature, filtered using Celite (trade name), and the filtrate was washed with acetonitrile. Quantitative analysis of the obtained filtrate by high-performance liquid chromatography revealed that 0.430 g of the target product was contained (reaction yield: 94.5%). Next, the reaction solution was concentrated under reduced pressure until the weight of the liquid reached 0.785 g, 4.3 g of toluene was added, and the mixture was washed three times with water. At this time, an emulsion containing the desired product was produced, but it was discarded together with the aqueous layer. 3.15 ml (3.15 mmol) of 1 mol / L hydrochloric acid was added to the obtained organic layer, and the mixture was stirred at room temperature for 20 minutes and then separated. To the obtained aqueous layer, 4.27 g of toluene and 3.46 ml (3.46 mmol) of 1 mol / L sodium hydroxide aqueous solution were added, the mixture was heated to 40 ° C. and stirred for 20 minutes. After separation, the obtained organic layer was washed twice with water. The organic layer was concentrated under reduced pressure to a liquid weight of 0.239 g to obtain isopropyl 2 – ({6 – [(N-benzylpyridine-3-sulfonamido) methyl] pyridin-2-yl} amino) acetate as a light brown solid (Obtained as a raw material based on isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate Rate 53.8%). The quantitative purity by HPLC high performance liquid chromatography method was 98.0%. Also, in the measurement (wavelength 260 nm) by the HPLC high performance liquid chromatography method, there was no impurity showing an area% of 0.1% or more.

　Physical property values of the obtained 2 – ({6 – [(N-benzylpyridine-3-sulfonamido) methyl] pyridin-2-yl} amino) acetate isopropylate were as follows.
EI-MS (m /
z):. 454 [M] CI-MS (m /
^[Mz):. ⁺ 1] 1 H-NMR (CDCl ₃ , [delta] (ppm)): 1.27 (6H, d, J = 5.3 Hz), 5.09 (1 H, sep, J = 6.3 Hz), 3.82 (2H, d, J = 5.4 Hz), 4.31 (2H, s), 4.62 7.26 – 7.33 (7 H, m), 7.90 – 7.93 (1 H, m), 8.69 (1 H, m), 6.26 (1 H, d, J = 8.3 Hz)
¹³ C-NMR (CDCl ₃ , δ (ppm)): 21.8, 43.8, 51.1, 51.6, 69.0, 1 H, dd, J = 4.8, 1.6 Hz), 8.95 (1 H, dd, J = 107.2, 112.6, 123.2, 127.9, 128.6, 128.8, 134.7, 135.6, 137.6, 137.7, 148.2, 152.5, 153.6, 157.3, 170.5
IR (KBr cm ^-1
Calcd: C, 60.77%; H, 5.77%; N, 12.33%
Found (C = : C, 61.03%; H, 5.85%; N, 12.15%.

Example 3 Synthesis
of

2 – {[6 – ({N- [4- (1 H-pyrazol-1 -yl) benzyl] pyridine-3-sulfonamido} methyl) pyridin- Synthesis of isopropyl acetate

　641 mg (2.04 mmol) of N- [4- (1H-pyrazol-1-yl) benzyl] pyridine-3-sulfonamide was added to a glass container having an inner volume of about 30 ml equipped with a stirrer, a thermometer and an upper cooling device, , 485 mg (2.00 mmol) of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate obtained in Example 6, 1.33 g (4.08 mmol) of cesium carbonate and 3.53 g And the mixture was stirred at 30 ° C. The reaction was carried out for 26 hours until the area percentage of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate was 0.3% or less in the high performance liquid chromatography analysis, I went for hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was washed with acetonitrile. Quantitative analysis of the obtained filtrate by high performance liquid chromatography showed that 991 mg of the desired product was contained (reaction yield 95.2%).

Example 4
Synthesis of Isopropyl Acetate of 2 – {[6 – ({N- [4- (1 H-pyrazol-1 -yl) benzyl] pyridine-3-sulfonamido) methyl)

　To a glass container having an inner volume of about 50 ml equipped with a stirring device, a thermometer and an upper cooling device, 3.21 g (10.00 mmol) of N- [4- (1H-pyrazol-1-yl) benzyl] 2.43 g (10.0 mmol) of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate obtained in Example 6, 2.82 g (20.4 mmol) potassium carbonate obtained in Example 6 and 17.6 g of acetonitrile was added, and the mixture was heated and stirred at 80 ° C. The reaction was carried out for 10 hours in the high performance liquid chromatography analysis until the area percentage of isopropyl 2 – {[6- (chloromethyl) pyridin-2-ylamino] acetate as raw material was 0.03% or less. The reaction conversion rate of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate was 43.9% after 1 hour from the start of heating and stirring. After completion of the reaction, the reaction solution was cooled to room temperature, filtered using Celite (trade name), and the filtrate was washed with acetonitrile. Quantitative analysis of the obtained filtrate by high performance liquid chromatography revealed that 5.00 g of the target product was contained (reaction yield 96.0%). Next, the reaction solution was concentrated under reduced pressure until the weight of the liquid reached 7.85 g, 42.77 g of toluene was added, and then washed three times with water. 31.5 ml (31.5 mmol) of 1 mol / L hydrochloric acid was added to the obtained organic layer, and the mixture was stirred at room temperature for 20 minutes and then separated. Incidentally, 0.62 g (corresponding to a yield of 11.8%) of the target product was contained in the organic layer after liquid separation. 42.77 g of toluene and 34.6 ml (34.6 mmol) of a 1 mol / L sodium hydroxide aqueous solution were added to the obtained aqueous layer, and the mixture was heated to 40 ° C. and stirred for 20 minutes. After filtration at 40 ° C. in the hot state, liquid separation was carried out. The obtained organic layer was washed twice with water. The organic layer was concentrated under reduced pressure until the weight of the liquid reached 8.97 g, and 7.40 g of 2-propanol was added. After heating to 60 ° C., it was slowly cooled and stirred at a temperature at which crystal began to precipitate for 30 minutes, then slowly cooled to 5 ° C. or less, and stirred at the same temperature for 1 hour. The obtained slurry was filtered, and the obtained filtrate was washed with water After washing with cooled 2-propanol and vacuum drying at 50 ° C., 2 – {[6 – ({N- [4- (1 H-pyrazol-1 -yl) benzyl] pyridine- Methyl) pyridin-2-yl] amino} acetic acid 3.90 g as a slightly brown solid (isolation based on isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate Rate 74.9%). The quantitative purity by HPLC high performance chromatography method was 99.0%, and 0.11% of N- [4- (1H-pyrazol-1-yl) benzyl] pyridine-3-sulfonamide as a raw material was contained It was.

Comparative Example 1
Synthesis of Isopropyl Acetate of 2 – {[6 – ({N- [4- (1 H-pyrazol-1 -yl) benzyl] pyridine-3-sulfonamido} methyl)

　To a glass vessel having an inner volume of about 50 ml equipped with a stirring device, a thermometer and an upper cooling device, 3.21 g (10.00 mmol) of N- [4- (1H-pyrazol-1-yl) benzyl] , 2.43 g (10.0 mmol) of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate obtained in Example 6, 2.16 g (20.4 mmol) of sodium carbonate and 17.6 g of acetonitrile was added, and the mixture was heated and stirred at 80 ° C. In the high performance liquid chromatography analysis, the reaction was carried out for 110 hours until the area percentage of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate became 0.05% or less. The reaction conversion rate of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate 1 hour after the start of heating and stirring was 0.92%. After completion of the reaction, the reaction solution was cooled to room temperature, filtered using Celite (trade name), and the filtrate was washed with acetonitrile. Quantitative analysis of the obtained filtrate by high performance liquid chromatography revealed that 0.72 g of the target product was contained (reaction yield: 13.8%). Next, the solution was concentrated under reduced pressure until the weight of the solution reached 7.85 g, 42.6 g of toluene was added, and the mixture was washed three times with water. Since the tar component was separated at the time of washing with water, it was discarded together with the aqueous layer. 31.5 ml (31.5 mmol) of 1 mol / L hydrochloric acid was added to the obtained organic layer, and the mixture was stirred at room temperature for 20 minutes and then separated. 42.6 g of toluene and 34.6 ml (34.6 mmol) of 1 mol / L sodium hydroxide aqueous solution were added to the obtained aqueous layer, and the mixture was heated to 40 ° C. and stirred for 20 minutes. After filtration at 40 ° C. in the hot state, liquid separation was carried out, and the obtained organic layer was washed twice with water. The organic layer was concentrated under reduced pressure to give isopropyl acetate (2 – {[6 – ({N- [4- (1 H-pyrazol- 1 – yl) benzyl] pyridine- To obtain a dark brown viscous liquid containing 0.764. The quantitative purity by HPLC high performance chromatography method was 60.2%, the pure content was 0.

Example 5
Synthesis of 2 – {[6- (hydroxymethyl) pyridin-2-yl] amino} acetate isopropylate

　948 g of 2-propanol and 76.7 g of concentrated sulfuric acid were added to a glass container having an inner volume of about 2 L and equipped with a stirring device, a thermometer and an upper cooling device, and the mixture was heated to 75 ° C. To this was added 2 – {[(t-butoxycarbonyl) (6-hydroxymethylpyridin-2-yl)] amino} acetic acid tert- butyl ester synthesized by the method described in Reference Example 3- (b) A mixed solution of 135 g of butyl, 45 g of toluene and 311 g of 2-propanol was added dropwise over 40 minutes, followed by heating and stirring at 78 ° C. for 6 hours. After cooling, 677 g of toluene and 406 g of water were added under an internal pressure of 20 hPa and an external temperature of 40 ° C. until the amount of liquid reached 309 g, and the mixture was stirred at room temperature and then separated. The obtained aqueous layer was added dropwise to a mixed solution of 129 g of separately prepared sodium hydrogencarbonate, 812 g of water, and 677 g of toluene over 20 minutes, stirred at room temperature for 1 hour, separated, and the aqueous layer was washed with 338 g . The obtained organic layer was mixed and washed with 426 g of a 5 wt% sodium chloride aqueous solution to obtain 1370 g of an organic layer. Approximately 1356 g of this was taken out, concentrated to a liquid volume of 113 g, and then toluene was added until the liquid amount reached 300 g. 190 g of n-heptane was added to the solution, and the solution was warmed to 45 ° C. to dissolve the crystals, followed by cooling to 35 ° C. A small amount of separately synthesized seed crystals was added in the same way and stirred at 35 ° C. for 1 hour, the crystals gradually increased. 365 g of n-heptane was added dropwise over 30 minutes, cooled for 40 minutes until the internal temperature reached 5 ° C., and stirred at the same temperature for 30 minutes. The precipitated crystals were separated by filtration, washed with n-heptane and then dried under reduced pressure at 50 ° C. to obtain 70.4 g of isopropyl 2 – {[6- (hydroxymethyl) pyridin-2-yl] amino} . The quantitative purity by HPLC high performance chromatography was 94.3%, and the pure content was 66.4 g (raw material 2 – {[(t-butoxycarbonyl) (6-hydroxymethylpyridin-2-yl )] Amino} acetate as t-butyl acetate in an isolated yield of 74.7%).

　Physical properties of the obtained 2 – {[6- (hydroxymethyl) pyridin-2-yl] amino} acetate isopropyl were as follows.
EI-MS (m /
z):. 224 [M] CI-MS (m /
^[Mz):. ⁺ 1] 1 H-NMR (CDCl _3, [delta] (ppm)): 1.27 (6H, d, J = 6.3 Hz), 3.76 (IH, s), 4.10 (2H, d, J = 5.5 Hz), 4.59 (2H, s), 5.00 (IH, s), 5.10 (IH, m), 6.36
¹³ C-NMR (CDCl _3, δ (ppm) ), 6.51 (1 H, dd, J = 7.3, 0.7 Hz), 7.41 (1 H, ddd, J = 5.74, 3.88 Hz ) ): 21.8, 44.1, 63.5, 69.0, 106.6, 109.5, 138.0, 156.8, 156.9, 170.7
IR (KBr cm ^-1): 416, 469, 531, 559, 731, 785, 826, 862, 903, 916, 941, 980, 1014, 1052, 1082, 1106, 1131, 1147, 1182, 1217, 1256, 1276, 1347, 1378,
Calcd: C, 58.91% Calcd: C, 58.91% (C = O) ; H, 7.19%; N, 12.49%
Found: C, 58.99%; H, 7.17%; N, 12.48%.

Example 6
Synthesis of 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate isopropylate

　To a solution of 35.7 g of isopropyl 2 – {[6- (hydroxymethyl) pyridin-2-yl] amino} acetate obtained in Example 5 in 396 g of methylene chloride was added 19.6 g of thionyl chloride at room temperature Was added dropwise over 20 minutes, and the mixture was stirred at room temperature for 1 hour. The obtained reaction solution was added dropwise to a mixed liquid slurry of 37.8 g of sodium hydrogencarbonate and 149 g of water, and the mixture was stirred at room temperature for 20 minutes. After liquid separation, 6.73 g of magnesium sulfate was added to the organic layer, dehydrated and the filtrate was concentrated to dryness at 50 ° C. to obtain 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate 37 .8 g as a light brown solid.

　Physical properties of the obtained 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate isopropyl were as follows.
EI-MS (m /
z):. 242 [M] CI-MS (m /
^[Mz):. ⁺ 1] 1 H-NMR (CDCl _3, [delta] (ppm)): 1.24 (6H, m) J = 8.3 Hz), 4.7 (2H, d, J = 5.4 Hz), 4.48 (2H, s), 5.03 (IH, s), 5.10 (IH, m), 6.39
¹³ C-NMR (CDCl _3, δ (ppm)): 21.8, 44.0, 44.7, 68.9, 107.7, 112.2, 138.1, 1 H NMR (CDCl _3, δ (ppm)): 7.43 (1H, dd, J = 7.8, 7.8 Hz)154.6, 157.3, 170.7
IR (KBr cm ^-1): 415, 446, 530, 560, 627, 735, 804, 827, 874, 903, 939, 952, 982, 1042, 1088, 1108, 1128, 1144, 1167, 1180, 1219, 1269, 1281, 1350,
Elemental analysis: 1378, 1400, 1420, 1434, 1470, 1525 (C = N), 1580, 1613, 1690, 1728 (C = O), 2878, 2934 (CH), 2981 (CH), 3379Calcd: C, 54.44%; H, 6.23%; N, 11.54%
Found: C, 54.46%; H, 6.23%; N, 11.56%.

PAPER

Journal of Medicinal Chemistry (2018), 61(15), 6869-6891.

Identification of a Selective, Non-Prostanoid EP2 Receptor Agonist for the Treatment of Glaucoma: Omidenepag and its Prodrug Omidenepag Isopropyl

Ryo Iwamura *^†

, Masayuki Tanaka^†, Eiji Okanari^†, Tomoko Kirihara^‡, Noriko Odani-Kawabata^‡, Naveed Shams^‡^§, and Kenji Yoneda^†

^† Pharmaceuticals Research Laboratory, UBE Industries, Ltd., 1978-5 Kogushi, Ube, Yamaguchi 755-8633, Japan

^‡ R&D Division, Santen Pharmaceutical Co., Ltd., Grand Front Osaka Tower A 4-20, Ofukacho, Kita-ku, Osaka 530-8552, Japan

^§ R&D Division, Santen Inc., 6401 Hollis Street, Suite 125, Emeryville, California 94608, United States

J. Med. Chem., 2018, 61 (15), pp 6869–6891

DOI: 10.1021/acs.jmedchem.8b00808

*Phone: (+81)836-31-6432. Fax: (+81)836-31-4383. E-mail: 30487u@ube-ind.co.jp.

EP2 receptor agonists are expected to be effective ocular hypotensive agents; however, it has been suggested that agonism to other EP receptor subtypes may lead to undesirable effects. Through medicinal chemistry efforts, we identified a scaffold bearing a (pyridin-2-ylamino)acetic acid moiety as a promising EP2-selective receptor agonist. (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetic acid 13ax (omidenepag, OMD) exerted potent and selective activity toward the human EP2 receptor (h-EP2). Low doses of omidenepag isopropyl (OMDI), a prodrug of 13ax, lowered intraocular pressure (IOP) in ocular normotensive monkeys. OMDI was selected as a clinical candidate for the treatment of glaucoma.

Isopropyl (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2- ylamino)acetate (OMDI)

white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.87 (dd, J = 2.4, 0.7 Hz, 1H), 8.75 (dd, J = 4.8, 1.6 Hz, 1H), 8.48 (dd, J = 2.4, 0.5 Hz, 1H), 8.08 (ddd, J = 8.1, 2.4, 1.6 Hz, 1H), 7.80–7.77 (m, 2H), 7.74 (dd, J = 1.8, 0.5 Hz, 1H), 7.51 (ddd, J = 8.1, 4.8, 0.7 Hz, 1H), 7.36–7.33 (m, 2H), 7.26 (dd, J = 8.3, 7.1 Hz, 1H), 6.89 (t, J = 6.1, 1H), 6.54 (dd, J = 2.4, 1.8 Hz, 1H), 6.38 (d, J = 8.3 Hz, 1H), 6.34 (d, J = 7.1 Hz, 1H), 4.87 (sept, J = 6.3 Hz, 1H), 4.62 (s, 2H), 4.21(s, 2H), 3.76 (d, J = 6.1 Hz, 2H), 1.10 (d, J = 6.3 Hz, 6H). ¹³C NMR (proton-decoupled spectrum, 500 MHz, DMSO-d₆) δ 171.2 (s), 158.1 (s), 153.4 (s), 153.2 (s), 147.6 (s), 141.4 (s), 139.6 (s), 137.5 (s), 137.0 (s), 135.1 (s), 134.4 (s), 129.9 (s), 128.2 (s), 124.4 (s), 118.8 (s), 111.4 (s), 108.3 (assigned for two nonequivalent carbons with identical chemical shift), 68.0 (s), 51.9 (s), 51.2 (s), 43.1 (s), 22.0 (s). MS (CI+) m/z521 (M + H)⁺. IR wavelength [cm^–1] 3437 (N–H), 1736 (C═O), 1608, 1525, and 1511 (C═C and C═N), 1321 (SO₂), 1161 (SO₂). Elemental analysis [%] (average of three experiments) calculated for C₂₆H₂₈N₆O₄S: C 59.98, H 5.42, N 16.14. Found: C 59.76, H 5.28, N 16.01. TLC R_f value 0.39 (ethyl acetate).

//////////////Omidenepag isopropyl, JAPAN 2018, オミデネパグイソプロピル , DE-117, UBE, SANTEN

CC(C)OC(=O)CNc1cccc(CN(Cc2ccc(cc2)n3cccn3)S(=O)(=O)c4cccnc4)n1

FDA approves new treatment for patients with acute myeloid leukemia

November 24, 2018 2:15 am / Leave a comment

FDA approves new treatment Daurismo (glasdegib) for patients with acute myeloid leukemia

The U.S. Food and Drug Administration today approved Daurismo (glasdegib) tablets to be used in combination with low-dose cytarabine (LDAC), a type of chemotherapy, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are 75 years of age or older or who have other chronic health conditions or diseases (comorbidities) that may preclude the use of intensive chemotherapy.

November 21, 2018

Release

“Intensive chemotherapy is usually used to control AML, but many adults with AML are unable to have intensive chemotherapy because of its toxicities. Today’s approval gives health care providers another tool to use in the treatment of AML patients with various, unique needs. Clinical trials showed that overall survival was improved using Daurismo in combination with LDAC compared to LDAC alone for patients who would not tolerate intensive chemotherapy,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. The National Cancer Institute at the National Institutes of Health estimates that in 2018, approximately 19,520 people will be diagnosed with AML and approximately 10,670 patients with AML will die of the disease. Almost half of the adults diagnosed with AML are not treated with intensive chemotherapy because of comorbidities and chemotherapy related toxicities.

The efficacy of Daurismo was studied in a randomized clinical trial in which 111 adult patients with newly diagnosed AML were treated with either Daurismo in combination with LDAC or LDAC alone. The trial measured overall survival (OS) from the date of randomization to death from any cause. Results demonstrated a significant improvement in OS in patients treated with Daurismo. The median OS was 8.3 months for patients treated with Daurismo plus LDAC compared with 4.3 months for patients treated with LDAC only.

Common side effects reported by patients receiving Daurismo in clinical trials include low red blood cell count (anemia), tiredness (fatigue), bleeding (hemorrhage), fever with low white blood cell count (febrile neutropenia), muscle pain, nausea, swelling of the arms or legs (edema), low platelet counts (thrombocytopenia), shortness of breath (dyspnea), decreased appetite, distorted taste (dysgeusia), pain or sores in the mouth or throat (mucositis), constipation and rash.

The prescribing information for Daurismo includes a Boxed Warning to advise health care professionals and patients about the risk of embryo-fetal death or severe birth defects. Daurismo should not be used during pregnancy or while breastfeeding. Pregnancy testing should be conducted in females of reproductive age prior to initiation of Daurismo treatment and effective contraception should be used during treatment and for at least 30 days after the last dose. The Boxed Warning also advises male patients of the potential risk of drug exposure through semen and to use condoms with a pregnant partner or a female partner that could become pregnant both during treatment and for at least 30 days after the last dose. Daurismo must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. Patients should also be advised not to donate blood or blood products during treatment. Health care providers should also monitor patients for changes in the electrical activity of the heart, called QT prolongation.

The FDA granted this application Priority Review designation. Daurismo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Daurismo to Pfizer.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm626443.htm?utm_campaign=112118_PR_FDA%20approves%20new%20treatment%20for%20patients%20with%20acute%20myeloid%20leukemia&utm_medium=email&utm_source=Eloqua

//////////////Daurismo, glasdegib, fda 2018, Priority Review, Orphan Drug

FDA approves first treatment Gamifant (emapalumab) specifically for patients with rare and life-threatening type of immune disease

November 23, 2018 11:18 am / Leave a comment

FDA approves first treatment Gamifant (emapalumab) specifically for patients with rare and life-threatening type of immune disease

The U.S. Food and Drug Administration today approved Gamifant (emapalumab) for the treatment of pediatric (newborn and above) and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. This FDA approval is the first for a drug specifically for HLH.

“Primary HLH is a rare and life-threatening condition typically affecting children and this approval fills an unmet medical need for these patients,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “We are committed to continuing to expedite the development and review of therapies that offer meaningful treatment options for …

November 20, 2018

Release

The U.S. Food and Drug Administration today approved Gamifant (emapalumab-lzsg) for the treatment of pediatric (newborn and above) and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. This FDA approval is the first for a drug specifically for HLH.

HLH is a condition in which the body’s immune cells do not work properly. The cells become overactive releasing molecules, which leads to inflammation. The immune cells start to damage the body’s own organs, including the liver, brain and bone marrow. It can be inherited, which is known as primary or “familial” HLH. It can also have non-inherited causes. People with primary HLH usually develop symptoms within the first months or years of life. Symptoms may include fever, enlarged liver or spleen and decreased number of blood cells.

The efficacy of Gamifant was studied in a clinical trial of 27 pediatric patients with suspected or confirmed primary HLH with either refractory, recurrent or progressive disease during conventional HLH therapy or who were intolerant of conventional HLH therapy. The median age of the patients in the trial was 1 year old. The study showed that 63 percent of patients experienced a response and 70 percent were able to proceed to stem cell transplant.

Common side effects reported by patients receiving Gamifant in clinical trials included infections, hypertension, infusion-related reactions, low potassium and fever. Patients receiving Gamifant should not receive any live vaccines and should be tested for latent tuberculosis. Patients should be closely monitored and treated promptly for infections while receiving Gamifant.

The FDA granted this application Priority Review and Breakthrough Therapydesignation. Gamifant also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Gamifant to Novimmune SA.

LINK https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM626263.htm?utm_campaign=112018_PR_FDA%20approves%20treatment%20for%20patients%20with%20HLH%20l&utm_medium=email&utm_source=Eloqua

////////////Gamifant, emapalumab, FDA 2018

Lumateperone

November 20, 2018 10:44 am / Leave a comment

ChemSpider 2D Image | Lumateperone | C24H28FN3O

Lumateperone

Molecular FormulaC₂₄H₂₈FN₃O
Average mass393.497 Da

4-((6bR,10aS)-3-Methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one

1-Butanone, 1-(4-fluorophenyl)-4-(2,3,6b,9,10,10a-hexahydro-3-methyl-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-

1-(4-fluorophenyl)-4-{4-methyl-1,4,12-triazatetracyclo[7.6.1.0⁵,¹⁶.0¹⁰,¹⁵]hexadeca-5,7,9(16)-trien-12-yl}butan-1-one

313368-91-1 [RN]

70BSQ12069, Lumateperone, PHASE 3, ITI-007

4- methylbenzenesulfonate. SALT

Molecular Formula:	C₃₁H₃₆FN₃O₄S
Molecular Weight:	565.704 g/mol

(6bR,10aS)-8-[4-(4-Fluorophenyl)-4-oxobutyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-ium 4-methylbenzenesulfonate

1187020-80-9 [RN]

1-Butanone, 1-(4-fluorophenyl)-4-[(6bR,10aS)-2,3,6b,9,10,10a-hexahydro-3-methyl-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl]-, 4-methylbenzenesulfonate (1:1)

ITI-007 tosylate

JIE88N006O

Lumateperone tosylate [USAN]

UNII:JIE88N006O

ITI 007

Originator Bristol-Myers Squibb
Develope rIntra-Cellular Therapies
Class Antidepressants; Antipsychotics; Pyrroles; Quinoxalines; Sleep disorder therapies
Mechanism of Action Dopamine receptor modulators; NR2B N-Methyl D-Aspartate receptor modulators; Serotonin 2A receptor antagonists; Serotonin plasma membrane transport protein inhibitors; Serotonin uptake inhibitors
07 Nov 2018 Intra-Cellular Therapeutics completes enrolment in the phase III Study 401 trial for Bipolar depression (Monotherapy) in USA
16 Oct 2018 Intra-Cellular Therapies plans to launch lumateperone for Schizophrenia in USA
02 Aug 2018 Intra-Cellular plans a clinical trial for Depressive disorders in 2H of 2018

Highest Development Phases

Preregistration Schizophrenia
Phase III Behavioural disorders; Bipolar depression
Phase II Sleep maintenance insomnia
Preclinical Mental disorders
No development reported Mood disorders

Lumateperone (INN; developmental code names ITI-007, ITI-722) is an investigational atypical antipsychotic which is currently under development by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb, for the treatment of schizophrenia.^[1]^[2] It is also being developed by Intra-Cellular Therapies for the treatment of bipolar disorder, depression, and sleep and behavioral disturbance in dementia, autism, and other neuropsychiatric disorders.^[3] As of September 2015, lumateperone has passed the first of two phase III clinical trials for schizophrenia.^[4] In November 2017 the US FDA awarded Intra-Cellular Therapies Fast Track designation for lumateperone.^[5]

Pharmacology

Pharmacodynamics

Relative to presently-available antipsychotics, lumateperone possesses a unique and novel mechanism of action.^[6]^[7] It acts as a 5-HT_2A receptor antagonist (K_i = 0.54 nM), a partial agonist of presynaptic D₂ receptors and an antagonist of postsynaptic D₂ receptors (K_i = 32 nM), and a serotonin transporter blocker (K_i = 61 nM).^[6]^[8] It also possesses affinity for the D₁ receptor (K_i = 52 nM) and lower affinity for the α_1A– and α_1B-adrenergic receptors (K_i = 73 nM at α₁), 5-HT_2C receptor (K_i = 173 nM), and D₄ receptor.^[6] Lumateperone does not significantly bind to the 5-HT_2B, H₁ (K_i > 1,000 nM), muscarinic acetylcholine receptors, or many other sites (K_i > 100 nM).^[6]

Lumateperone shows a 60-fold difference in its affinities for the 5-HT_2A and D₂ receptors, which is far greater than that of most or all existing atypical antipsychotics, such as risperidone (12-fold), olanzapine (12.4-fold), and aripiprazole (0.18-fold).^[6]^[9] It is thought that this property may improve the effectiveness and reduce the side effect profile of lumateperone relative to currently-available antipsychotics, a hypothesis which is supported by the observation of minimal catalepsy in mice treated with the drug.^[6]^[9] Moreover, it has been expressed that this property could result in full occupancy and blockade of the 5-HT_2A at low doses, with dose-dependent adjustable modulation of the D₂ receptor, as well as the SERT, possible with increasing doses, which would uniquely allow for clinical optimization of efficacy and side effect incidence.^[6]^[9]

Unlike most current antipsychotics, such as haloperidol, risperidone, and olanzapine, lumateperone does not disrupt striatal dopamine signaling, a property which is likely due to its partial agonism of presynaptic D₂ receptors.^[6] In accordance, similarly to aripiprazole, which is also a partial agonist of presynaptic D₂ receptors, lumateperone showed no striatum-based motor side effects (i.e., catalepsy) in animals.^[6]

Clinical studies

In phase II clinical trials, lumateperone showed statistically-significant efficacy in improvement of psychosis at a dose of 60 mg daily.^[2] In addition, it distinguished itself from its comparator risperidone in reducing negative symptoms, including improvement in social function, as well as in alleviating depressive symptoms in schizophrenia patients with comorbid depression, whereas risperidone had no effect.^[2]^[10] Lumateperone also distinguished itself from risperidone in that it produced little or no weight gain, did not negatively affect metabolic parameters (i.e., insulin, glucose, triglyceride, and cholesterol levels), did not increase prolactin levels, and did not show a rate of the side effect of akathisia that differed from placebo.^[2]^[10] In addition, lumateperone did not produce any changes in cardiovascular function, such as QTc prolongation, and unlike risperidone, it did not produce a measurable increase heart rate.^[7] Due to its favorable influence on metabolic parameters, it was concluded that lumateperone, unlike many other available antipsychotics such as risperidone, may not cause an increase in the risk of diabetes or cardiovascular disease, and hence may prove to be a significant improvement relative to many existing antipsychotic drugs in terms of long-term safety and tolerability.^[2]

Lumateperone, at a dose of 60 mg per day, was not found to be associated with any statistically significant treatment-emergent side effects relative to placebo.^[10] At a dose of 120 mg daily, the most frequent adverse effect observed was sedation/somnolence, reported by 32.5% of patients.^[10] There was no evidence of extrapyramidal symptoms or increase in suicidal ideation or behavior.^[10]

SYNTHESIS

MEDCHEM

PAPER

https://pubs.acs.org/doi/abs/10.1021/jm401958n

dx.doi.org/10.1021/jm401958n | J. Med. Chem. 2014, 57, 2670−2682

5 (367 mg, 53%yield) as a gray solid.

1H NMR (DMSO-d6, 500 MHz) δ 9.10 (br, 1H),8.10−8.01 (m, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.42−7.33 (m, 2H), 7.11 (d, J = 7.8 Hz, 2H), 6.65−6.57 (m, 1H), 6.51 (d, J = 7.3 Hz, 1H), 6.42 (d, J = 7.9 Hz, 1H), 3.59 (dd, J = 12.2, 6.5 Hz, 1H), 3.52−3.37 (m, 3H), 3.37−3.28 (m, 2H), 3.25−3.20 (m, 1H), 3.18−2.99 (m, 5H), 2.81 (s, 3H), 2.71 (td, J = 10.2, 3.0 Hz, 1H), 2.63−2.52 (m, 1H), 2.28 (s, 3H), 2.27−2.22 (m, 1H), 2.15−1.93 (m, 3H).

13C NMR (DMSOd6, 126 MHz) δ 197.2, 165.1 (d, JCF = 252 Hz), 145.6, 137.6, 137.3, 135.2, 133.1, 130.9 (d, JCF = 10 Hz), 128.1, 126.7, 125.5, 120.6, 115.7 (d, JCF = 22 Hz), 112.5, 109.3, 62.2, 55.5, 52.5, 49.8, 47.8, 43.7, 38.6, 37.0, 34.9, 21.7, 20.8, 18.0.

MS (ESI) m/z 394.2 [M + H]+.

HRMS (ESI) m/z calcd for C24H29FN3O [M + H]+, 394.2295; found, 394.2292. UPLC purity, 97.7%; retention time, 2.06 min (method A).

PATENT

WO 2000077002

WO 2000077010

US 20040220178

WO 2008112280

WO 2009114181

WO 2011133224

PATENT

WO 2017172811

0003] l-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH,7H- pyrido[3′,4′:4,5]pyrrolo[l,2,3-de]quinoxalin-8-yl)-butan-l-one (sometimes referred to as 4- ((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH-pyrido[3′,4′:4,5]pyrrolo[l,2,3- de]quinoxalin-8(7H)-yl)-l-(4-fluorophenyl)-l-butanone, or as ITI-007), has the following structure:

[0004] ITI-007 is a potent 5-HT2A receptor ligand (Ki=0.5 nM) with strong affinity for dopamine (DA) D2 receptors (Ki=32 nM) and the serotonin transporter (SERT) (Ki=62 nM) but negligible binding to receptors (e.g., HI histaminergic, 5-HT2C, and muscarinic) associated with cognitive and metabolic side effects of antipsychotic drugs. ΠΊ-007 is currently in clinical trials, i.a., for treatment of schizophrenia. While ITI-007 is a promising drug, its production and formulation present challenges. In free base form, ITI-007 is an oily, sticky solid, with poor solubility, not only in water but also in many organic solvents. Making salts of the compound has proven to be unusually difficult. A hydrochloride salt form of ITI-007 was disclosed in US 7183282, but this salt is hygroscopic and shows poor stability. A toluenesulfonic acid addition salt (tosylate) of ITI- 007 was finally identified and described in WO 2009/114181.

[0005] There is a need for alternative stable, pharmaceutically acceptable solid forms of ITI-007, which can be readily incorporated into galenic formulations.

XAMPLES

[0027] The following equipment and methods are used to isolate and characterize the exemplified co-crystal forms:

[0028] X-ray powder diffraction (XRPD): The X-ray powder diffraction studies are performed using a Bruker AXS D2 PHASER in Bragg-Brentano configuration, equipment #1549 / #2353. The equipment uses a Cu anode at 30kV, 10 mA; sample stage standard rotating; monochromatization by a Κβ-filter (0.5% Ni). Slits: fixed divergence slits 1.0mm (=0.61°), primary axial Soller slit 2.5°, secondary axial Soller slit 2.5°. Detector: Linear detector LYNXEYE with receiving slit 5° detector opening. The standard sample holder (0.1 mm cavity in (510) silicon wafer) has a minimal contribution to the background signal. Measurement conditions: scan range 5 – 45° 2Θ, sample rotation 5 rpm, 0.5s/step, 0.010°/step, 3.0mm detector slit; and all measuring conditions are logged in the instrument control file. As system suitability, corundum sample A26- B26-S (NIST standard) is measured daily. The software used for data collection is Diffrac. Commander v2.0.26. Data analysis is done using Diffrac.Eva vl.4. No background correction or smoothing is applied to the patterns.

[0029] Simultaneous thermogravimetry (TGA) and differential scanning calorimetry (DSC) or TGA/DSC analysis: The TGA/DSC studies are performed using a Mettler Toledo TGA/DSC 1 Stare System, equipment #1547, auto-sampler equipped, using pin-holed Al- crucibles of 40 μΐ. Measurement conditions: 5 min 30.0 °C, 30.0 – 350.0 °C with 10 °C/min., N2 flow of 40 ml/min. The software used for instrument control and data analysis is STARe vl2.10.

[0030] Differential scanning calorimetry (DSC): The DSC studies are performed using a Mettler Toledo DSC1 STARe System, equipment #1564. The samples are made using Al crucibles (40 μΐ; pierced). Typically 1 – 8 mg of sample is loaded onto a pre- weighed Al crucible and is kept at 30°C for 5 minutes, after which it is heated at 10°C/min from 30°C to 350 °C and kept at 350°C for 1 minute. A nitrogen purge of 40 ml/min is maintained over the sample. As system suitability check Indium and Zinc are used as references. The software used for data collection and evaluation is STARe Software vl2.10 build 5937. No corrections are applied to the thermogram.

[0031] Polarized light microscopy (PLM): The microscopy studies are performed using an Axio Vert 35M, equipped with an AxioCamERc 5s, equipment #1612. The microscope is equipped with four lenses: Zeiss A-Plan 5x/0.12, Zeiss A-Plan lOx/0.25, LD A-Plan 20x/0.30 and Achros TIGMAT 32x/0.40. Data collection and evaluation is performed using Carl Zeiss Zen Axio Vision Blue Edition Lite 2011 vl.0.0.0 software. A small amount of sample is loaded on an object glass and carefully spread until a thin layer is obtained.

[0032] Dynamic Vapour Sorption (DVS): The Dynamic Vapour Sorption studies are performed using a Surface Measurement Systems Ltd. DVS-1 No Video, equipment #2126. The sample is loaded into a balance pan, typically 20-30 mg, and equilibrated at 0% RH. After the material was dried, the RH is increased with 10% per step for 1 hour per increment, ending at 95% RH. After completion of the sorption cycle, the sample was dried using the same method. The software used for data collection is DVSWin v3.01 No Video. Data analysis is performed using DVS Standard Analysis Suite v6.3.0 (Standard).

[0033] Particle size distribution (PSD): The particle size distribution studies are performed using a Malvern Instruments Mastersizer, equipment #1712. The Mastersizer uses a 300RF lens range of 0.05 μηι – 900 mm. Polydisperse is used as analysis model. Measurement conditions: before each sample measurement a background measurement is performed, the background scan time is 12 seconds (12000 snaps). Each sample is dispersed in Multipar G, refractive index of 1.42. The obscuration range on sample dispersion is between 10%-30%. Each sample is measured 6 times at t=0 and t=30 minutes and the measurement scan time is 10 seconds (10000 snaps). The targeted stirring speed of the sample dispersion unit is 2000+10 rpm. Data collection and evaluation is performed using Mastersizer S Version 2.19 software. [0034] Capillary Melting Point: The capillary melting point is determined on a Biichi Melting Point B-545, equipment #000011, conform USP guidelines.

[0035] X-ray fluorescence (XRF): The X-ray fluorescence studies are performed using a Bruker AXS S2 RANGER, equipment #2006. Using an end-window X-ray tube with Palladium anode and an ultra-thin Beryllium window (75 μιη) for superior light element analysis. As detector the Xflash V5 detector with Cr, Ti, Al, Ta collimator (energy resolution < 129 eV FWHM at 100 000 cps Mnka) is used. The S2 Ranger is equipped with an autosampler with integrated 28 position X- Y automatic sample changer with exchangeable tray, which allows maximum sample diameter of 40 mm. Samples are mounted in steel rings of 51.5 mm diameter for automatic operation. Measurement conditions: disposable liquid cups (35 mm inner diameter, 40 mm outer diameter) with polypropylene foil 5 μιη. As system suitability check a copper disk is measured daily and a glass disk, containing several elements, is measured weekly. The software used for data collection is S2 Ranger Control Software V4.1.0. Data analysis is performed using SPECTRA EDX V2.4.3 evaluation software. No background correction or smoothing is applied to the patterns.

[0036] Fourier transform infrared spectroscopy (FT-IR): The FT-IR studies are performed using a Thermo Scientific Nicolet iS50, equipment # 2357. An attenuated total reflectance (ATR) technique was used with a beam splitter of KBr. Experiment setup of the collected sample is used number of scans 16 with a resolution of 4from 400 cm^“1 to 4000 cm^“1. The software OMNIC version 9.2 is used for data collection and evaluation.

[0037] Thermogravimetric analysis (TGA) with infrared spectroscopy (TGA-IR):

In TGA-IR, the off-gassing materials are directed through a transfer line to a gas cell, where the infrared light interacts with the gases. The temperature ramp and first derivative weight loss information from the TGA is shown as a Gram-Schmidt (GS) profile; the GS profile essentially shows the total change in the IR signal relative to the initial state. In most cases, the GS and the derivative weight loss will be similar in shape, although the intensity of the two can differ. For this experiment are two devices coupled to each other. The TGA studies are performed using a Mettler Toledo TGA/DSCl STARe System with a 34-position auto sampler, equipment #1547. The samples are made using Al crucibles (100 μΐ; pierced). Typically 20-50 mg of sample is loaded into a pre- weighed Al crucible and is kept at 30°C for 5 minutes after which it is heated at 10°C/min from 30°C to 350°C. A nitrogen purge of 40 ml/min is maintained over the sample. The TGA-IR module of the Nicolet iS50 is coupled to the TGA/DSCl. The IR studies were performed using a Thermo Scientific Nicolet iS50, equipment # 2357. Experiment setup of the collected series, the profile Gram-Schmidt is used number of scans 10 with a resolution of 4. The software OMNIC version 9.2 is used for data collection and evaluation.

[0038] High performance liquid chromatography (HPLC): The high performance liquid chromatography analyses are performed on LC-31, equipped with an Agilent 1100 series G1322A degasser equipment #1894, an Agilent 1100 series G1311A quaternary pump equipment #1895, an Agilent 1100 series G1313A ALS equipment #1896, an Agilent 1100 series G1318A column equipment #1897 and an Agilent 1100 series G1314A VWD equipment #1898 / LC-34, equipped with an Agilent 1200 series G1379B degasser equipment #2254, an Agilent 1100 series G1311A quaternary pump equipment #2255, Agilent 1100 series G1367A WPALS equipment #1656, an Agilent 1100 series G1316A column equipment #2257 and an Agilent 1100 series G1315B DAD equipment #2258. Data is collected and evaluated using Agilent ChemStation for LC systems Rev. B.04.02[96]. Solutions are prepared as follows: Mobile phase A: Add 800 ml of MilliQ water to a 1L volumetric flask. Add 1 ml of TFA and homogenize. Fill up to the mark with MilliQ; Mobile phase B: Add 800 ml of Acetonitrile to a 1L volumetric flask. Add 1 ml of TFA and homogenize. Fill up to the mark with Acetonitrile; Diluent: 50/50 MeOH/ACN.

Example 1: Co-crystal screen

[0039] Solubility of free base in various solvents is evaluated, and based on the results of the solubility range, suitable solvents are selected for the co-crystal screen. Co-crystal formation is based on hydrogen bonding and stacking of the molecules, meaning the co-former selection is based on active groups. Grinding is a method to form co-crystals, however the free base itself is an oil/ sticky solid and therefore not suitable for this method. The free base and counter ion are added to a solution in a certain ratio to give the chance to form a co-crystal, similar to salt formation. We found the best method is to add a saturated solution of the co-former to that of the free base to find an optimal ratio for co-crystal formation.

[0040] Three different experiments are performed with each of 26 candidate co-formers, which include sugar alcohols, amino acids, and other compounds identified as having potential to for co- crystals; adding solutions stepwise, slurry experiments and cooling crystallization experiments. The free base and co-former are dissolved prior to adding to each other. Co-formers are added in a 1 : 1 , 2: 1 and 1 :2 ratio to the free base. All experiments are performed using four different solvents, methanol, acetonitrile, ethyl acetate and toluene. All solids are characterized by XRPD. Two different ITI-007 free base co-crystals formed, with nicotinamide and with isonicotinamide. Both co-crystals were obtained by slurry experiments in methanol.

Example 2: Isonicotinamide co-crystal

[0041] Isonicotinamide forms a possible co-crystal with ITI-007 free base by slurrying the mixture in methanol and ethyl acetate, appearing as a red/brown and yellow solid respectively. TGA-DSC analysis of the experiment using isonicotinamide in methanol results in two endothermic events,

Both endothermic events do not correspond to the free base or the co-former, which means ITI-007 free base-isonicotinamide co-crystal is formed. HPLC and Ή-ΝΜΡ analyses confirm both of the free base and the co-former to be present. Using isonicotinamide in ethyl acetate, however, does not result in a co-crystal and, no endothermic event is present in the TGA/DSC analysis.

[0042] The slurry experiment in methanol is repeated at a gram scale. First, ITI-007 free base and isonicotinamide are each dissolved in methanol. Subsequently, the obtained solutions are mixed in a 1: 1 ratio and the resulting mixture is stirred at room temperature for 2 hours. The mixture remains a clear solution, which is evaporated under vacuum to give a brown sticky solid. XRPD analysis shows the brown sticky solid to be crystalline, as shown in Figure 1, ITI-007 free base-isonicotinamide co-crystal has formed. The corresponding peak list is showing in Table 1. The XRPD shows clustered peaks which is likely due to preferred orientation.

PATENT

WO 2018189646

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=B7967631262D0B0FD9D0AE25DA9CE085.wapp1nC?docId=WO2018189646&tab=PCTDESCRIPTION&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=&recNum=1824&maxRec=71295115

The present application relates to solid state forms of Lumateperone p-Tosylate and processes for preparation thereof.

The drug compound is having the adopted name “Lumateperone” and it has chemical name: l-(4-fluorophenyl)-4-[(6bR,10aS)-2,3,6b,9,10,10a-hexahydro-3-methyl-lH-pyrido[3′,4′:4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl] 1-Butanone; and a structure depicted by Formula I.

Formula I

International Patent Application Publication Nos. WO2000077002A1, WO2009145900 A 1 and WO2013155504A1 which are incorporated herein in their entirety reported Lumateperone and its related compounds. These compounds have been found to be useful as 5-HT2 receptor agonists and antagonists used in treating disorders of the central nervous system including a disorder associated with 5HT2C or 5HT2A receptor modulation selected from obesity, anorexia, bulemia, depression, a anxiety, psychosis, schizophrenia, migraine, obsessive -compulsive disorder, sexual disorders, depression, schizophrenia, migraine, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, sleep disorders, conditions associated with cephalic pain, social phobias, gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility. International Patent Application Publication No. WO2008112280A1 disclose process(es) for preparing Lumateperone and its salts.

International Patent Application Publication No. WO2009114181A2 disclose crystalline forms of the p-Tosylate salt of compound of Formula (I), WO 2017172784 Al disclose oxalate, aminosalicylate, cyclamate salts of Lumateperone, WO 2017172811 Al

disclose co-crystal of Lumateperone with iso-nicotinamide, nicotinatinamide, WO 2018031535 Al disclose crystalline Form Fl of Lumateperone ditosylate.

Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form. For some therapeutic indications, one bioavailability pattern may be favored over another. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation.

In view of the above, it is therefore, desirable to stable amorphous form of Lumateperone j?-tosylate. The amorphous form provided herein is at least stable under ordinary stability conditions with respect to purity, storage and is free flowing powder.

Amorphous solid dispersions of drugs are generally known to improve the stability and solubility of drug products. However, some of such amorphous solid dispersions are found to be unstable over time. Amorphous solid dispersions of drugs tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the solubility of crystalline drug material compared to amorphous drug material. The present invention, however provides stable amorphous solid dispersions of Lumateperone j?-tosylate with improved solubility. Moreover, the present invention provides solid dispersions of Lumateperone j?-tosylate which may be reproduced easily and is amenable for processing into a dosage form

EXAMPLE 1 : PREPARATION OF AMORPHOUS LUMATEPERONE p-TOSYLATE

Lumateperone j?-tosylate (500 mg) was dissolved in methanol (25 mL) at room temperature for clear solution and filtered to remove undissolved particles. The resultant filtrate was subjected to fast solvent evaporation using rotavapor at about 55^°C to afford the solid compound. The said solid was dried under vacuum at about 45^°C to afford the amorphous Lumateperone p-tosylate according to Figure 1.

References

Jump up^ Sylvain Celanire; Sonia Poli (13 October 2014). Small Molecule Therapeutics for Schizophrenia. Springer. pp. 31–. ISBN 978-3-319-11502-3.
^ Jump up to:^a ^b ^c ^d ^e Intra-Cellular Therapies, Inc. (2015). “Intra-Cellular Therapies Announces Further Analyses of the Phase 2 Clinical Trial of ITI-007 in Schizophrenia at the 168th Annual Meeting of the American Psychiatric Association”. GlobeNewswire, Inc.
Jump up^ Intra-Cellular Therapies. “Product Pipeline – Intra-Cellular Therapies”. Archived from the original on 2015-05-11. Retrieved 2015-05-19.
Jump up^ Intra-Cellular Therapies. “Intra-Cellular Therapies Announces Positive Top-Line Results From the First Phase 3 Trial of ITI-007 in Patients With Schizophrenia and Confirms the Unique Pharmacology of ITI-007 in a Separate Positron Emission Tomography Study”. intracellulartherapies. Archived from the original on 2016-03-21.
Jump up^ “Intra-Cellular Therapies Receives FDA Fast Track Designation for Lumateperone for the Treatment of Schizophrenia | Intra-Cellular Therapies Inc”. Intra-Cellular Therapies Inc. Retrieved 2017-11-25.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ Snyder GL, Vanover KE, Zhu H, Miller DB, O’Callaghan JP, Tomesch J, Li P, Zhang Q, Krishnan V, Hendrick JP, Nestler EJ, Davis RE, Wennogle LP, Mates S (2015). “Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission”. Psychopharmacology. 232 (3): 605–21. doi:10.1007/s00213-014-3704-1. PMC 4302236. PMID 25120104.
^ Jump up to:^a ^b Nancy A. Melville (2015). “Novel Drug Promising for Schizophrenia”. Medscape Medical News.
Jump up^ Li P, Zhang Q, Robichaud AJ, Lee T, Tomesch J, Yao W, Beard JD, Snyder GL, Zhu H, Peng Y, Hendrick JP, Vanover KE, Davis RE, Mates S, Wennogle LP (2014). “Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders”. J. Med. Chem. 57 (6): 2670–82. doi:10.1021/jm401958n. PMID 24559051.
^ Jump up to:^a ^b ^c Davis RE, Vanover KE, Zhou Y, Brašić JR, Guevara M, Bisuna B, Ye W, Raymont V, Willis W, Kumar A, Gapasin L, Goldwater DR, Mates S, Wong DF (2015). “ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D 2 receptors and serotonin transporters using positron emission tomography in healthy volunteers”. Psychopharmacology. 232 (15): 2863–72. doi:10.1007/s00213-015-3922-1. hdl:10044/1/24121. PMID 25843749.
^ Jump up to:^a ^b ^c ^d ^e Intra-Cellular Therapies, Inc. (2013). “Intra-Cellular Therapies Announces Positive Topline Phase II Clinical Results of ITI-007 for the Treatment of Schizophrenia”. PRNewswire.

External links

Lumateperone
Clinical data

Synonyms	ITI-007; ITI-722
Routes of administration	By mouth
Identifiers
IUPAC name [show]
CAS Number	313368-91-1
PubChem CID	9821941
ChemSpider	7997690
UNII	70BSQ12069
KEGG	D11169
Chemical and physical data
Formula	C₂₄H₂₈FN₃O
Molar mass	393.496
3D model (JSmol)	Interactive image
SMILES [hide] c3cc(F)ccc3C(=O)CCCN5CC2C(CC5)N1CCN(C)c4c1c2ccc4

Patent ID	Title	Submitted Date	Granted Date
US8648077	SUBSTITUTED HETEROCYCLE FUSED GAMMA-CARBOLINES SOLID	2011-05-12
US9371324	ORGANIC COMPOUNDS	2015-02-20	2015-06-18
US8993572	ORGANIC COMPOUNDS	2011-04-22	2013-08-08
US9586960	SUBSTITUTED HETEROCYCLE FUSED GAMMA-CARBOLINES SOLID	2015-11-30	2016-07-07
US9199995	SUBSTITUTED HETEROCYCLE FUSED GAMMA-CARBOLINES SOLID	2014-02-11	2014-10-30

////// Lumateperone, PHASE 3, ITI-007, ITI-722

FDA approves new drug Aemcolo (rifamycin), to treat travelers’ diarrhea

November 17, 2018 3:29 am / Leave a comment

FDA approves new drug to treat travelers’ diarrhea

The U.S. Food and Drug Administration today approved Aemcolo (rifamycin), an antibacterial drug indicated for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli (E. coli), not complicated by fever or blood in the stool.

“Travelers’ diarrhea affects millions of people each year and having treatment options for this condition can help reduce symptoms of the condition,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Travelers’ diarrhea is the most common travel-related illness, affecting an estimated 10 to 40 percent of travelers worldwide each year. Travelers’ diarrhea is defined by …

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm626121.htm?utm_campaign=111618_PR_FDA%20approves%20new%20drug%20to%20treat%20travelers%E2%80%99%20diarrhea&utm_medium=email&utm_source=Eloqua

November 16, 2018

Release

The U.S. Food and Drug Administration today approved Aemcolo (rifamycin), an antibacterial drug indicated for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli (E. coli), not complicated by fever or blood in the stool.

Travelers’ diarrhea is the most common travel-related illness, affecting an estimated 10 to 40 percent of travelers worldwide each year. Travelers’ diarrhea is defined by having three or more unformed stools in 24 hours, in a person who is traveling. It is caused by a variety of pathogens, but most commonly bacteria found in food and water. The highest-risk destinations are in most of Asia as well as the Middle East, Africa, Mexico, and Central and South America.

The efficacy of Aemcolo was demonstrated in a randomized, placebo-controlled clinical trial in 264 adults with travelers’ diarrhea in Guatemala and Mexico. It showed that Aemcolo significantly reduced symptoms of travelers’ diarrhea compared to the placebo.

The safety of Aemcolo, taken orally over three or four days, was evaluated in 619 adults with travelers’ diarrhea in two controlled clinical trials. The most common adverse reactions with Aemcolo were headache and constipation.

Aemcolo was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool or diarrhea due to pathogens other than noninvasive strains of E. coli and is not recommended for use in such patients. Aemcolo should not be used in patients with a known hypersensitivity to rifamycin, any of the other rifamycin class antimicrobial agents (e.g. rifaximin), or any of the components in Aemcolo.

The FDA granted Aemcolo a Qualified Infectious Disease Product (QIDP)designation. QIDP designation is given to antibacterial and antifungal drug products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, the Aemcolo marketing application was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame.

The FDA granted approval of Aemcolo to Cosmo Technologies, Ltd.

///////////////// Aemcolo, rifamycin, fda 2018, qidp, priority review

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