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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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


Selexipag.svg

ChemSpider 2D Image | Selexipag | C26H32N4O4S

Selexipag

  • Molecular FormulaC26H32N4O4S
  • Average mass496.622 Da

SelexipagUptravi

475086-01-2 CAS

(C26H32N4O4S, Mr = 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 metaboliteACT-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

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.

“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”).

Figure US20120101276A1-20120426-C00001

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.

Figure US20120101276A1-20120426-C00002

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 .

Figure imgf000003_0001

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

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 36 hours 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-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:

Figure imgf000002_0001

[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

Figure imgf000024_0001

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]

Figure CN105949135AD00071

[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:

Figure CN105949135AD00081

[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:

Figure CN105949135AD00082

[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]

Figure CN105949135AD00083

[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, Mr = 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. Kuwano et al. NS-304, an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 2007;322:1181-1188.
  2. 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.
  3. 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
  4. Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010;104:9-21.
  5. Sitbon, O.; Morrell, N. (2012). “Pathways in pulmonary arterial hypertension: The future is here”. European Respiratory Review 21 (126): 321–327. doi:10.1183/09059180.00004812PMID 23204120.
  6. Publication numberPriority datePublication dateAssigneeTitle
    WO2016193994A12015-05-292016-12-08Megafine Pharma (P) Ltd.Amorphous selexipag and process for preparation thereof
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    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
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    WO2009107736A1 *2008-02-282009-09-03日本新薬株式会社Fibrosis inhibitor
    CN106279047A2015-05-132017-01-04上海适济生物科技有限公司Preparation method of prostacyclin receptor agonist
    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
Patent Submitted Granted
Methods of identifying critically ill patients at increased risk of development of organ failure and compounds for the treatment hereof [US8877710] 2009-12-30 2014-11-04
Form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and method for producing the same [US8791122] 2010-06-25 2014-07-29
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
INHIBITION OF NEOVASCULARIZATION BY INHIBITION OF PROSTANOID IP RECEPTORS [US2014275238] 2014-03-05 2014-09-18
Fibrosis inhibitor [US8889693] 2014-04-10 20
Patent Submitted Granted
Heterocyclic compound derivatives and medicines [US7205302] 2004-05-27 2007-04-17
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
THERAPEUTIC COMPOSITIONS CONTAINING MACITENTAN [US2014329824] 2014-07-18 2014-11-06
Sustained Release Composition of Prostacyclin [US2014303245] 2012-08-10 2014-10-09
COMPOUNDS CAPABLE OF MODULATING/PRESERVING ENDOTHELIAL INTEGRITY FOR USE IN PREVENTION OR TREATMENT OF ACUTE TRAUMATIC COAGULOPATHY AND RESUSCITATED CARDIAC ARREST [US2013261177] 2011-09-30 2013-10-03
METHODS OF TREATMENT OF PATIENTS AT INCREASED RISK OF DEVELOPMENT OF ISCHEMIC EVENTS AND COMPOUNDS HEREOF [US2013040898] 2011-04-29 2013-02-14
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Selexipag
Selexipag.svg
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
475086-01-2 Yes
ChEMBL ChEMBL238804 
ChemSpider 8089417 Yes
7552
Jmol interactive 3D Image
KEGG D09994 Yes
PubChem 9913767
UNII P7T269PR6S Yes
Properties
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)
Figure
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
  1. 24.AsakiT.KuwanoK.MorrisonK.GatfieldJ.HamamotoT.ClozelM. Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension J. Med. Chem. 2015,587128– 7137 DOI: 10.1021/acs.jmedchem.5b00698

  2. 25.Skoro-SajerN.LangI. M. Selexipag for the Treatment of Pulmonary Arterial Hypertension Expert Opin. Pharmacother. 201415429– 436 DOI: 10.1517/14656566.2014.876007

  3. 26.KarmasG.SpoerriP. E. The Preparation of Hydroxypyrazines and Derived Chloropyrazines J. Am. Chem. Soc. 1952741580– 1584 DOI: 10.1021/ja01126a070

  4. 27.AsakiT.HamamotoT.SugiyamaY.KuwanoK.KuwabaraK. Structure-activity Studies on Diphenylpyrazine Derivatives: a Novel Class of Prostacyclin Receptor Agonists Bioorg. Med. Chem. 2007,156692– 6704 DOI: 10.1016/j.bmc.2007.08.010

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


 

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

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.

“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 ,


Raxatrigine.svg

Vixotrigine.png

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 (INNUSAN), formerly known as raxatrigine (INNUSAN), 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 Nav1.3 blocker, but was subsequently redefined as a selective peripheral Nav1.7 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

  1. Jump up^ Convergence Pharmaceuticals. “CNV1014802 – Convergence Pharmaceuticals”.
  2. 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.
  3. 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 Letters24 (16): 3690–9. doi:10.1016/j.bmcl.2014.06.038ISSN 0960-894XPMID 25060923.
  4. 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 Therapeutics1 (1). doi:10.15761/JMT.1000104ISSN 2399-9799.
  5. Jump up to:a b https://adisinsight.springer.com/drugs/800027679

External links

Vixotrigine – AdisInsight

Vixotrigine
Raxatrigine.svg
Clinical data
Synonyms Raxatrigine; CNV1014802; GSK-1014802; BIIB 074
Routes of
administration
By mouth
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
Chemical and physical data
Formula C18H19FN2O2
Molar mass 314.354 g/mol
3D model (JSmol)
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, 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”


DSC00403 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

47008795_2403920969650620_7189873006959656960_n 47115866_2405353396174044_6443851833482936320_nDSC00394

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


1187451-19-9.pngImage 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.
 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%.
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.
 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 .
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

 Pharmaceuticals Research LaboratoryUBE Industries, Ltd.1978-5 Kogushi, Ube, Yamaguchi 755-8633, Japan
 R&D DivisionSanten Pharmaceutical Co., Ltd.Grand Front Osaka Tower A 4-20, Ofukacho, Kita-ku, Osaka 530-8552, Japan
§ R&D DivisionSanten Inc.6401 Hollis Street, Suite 125, Emeryville, California 94608, United States
J. Med. Chem.201861 (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.
Abstract Image

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 Rf 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


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.
“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  ..

November 21, 2018

Release

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.

“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


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.

“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 patients with rare conditions.”

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


ChemSpider 2D Image | Lumateperone | C24H28FN3O

ITI-007.svg

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
Image result for Lumateperone
Image result for Lumateperone

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-007ITI-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 disorderdepression, and sleep and behavioral disturbance in dementiaautism, and other neuropsychiatric disorders.[3] As of September 2015, lumateperone has passed the first of two phase IIIclinical 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-HT2A receptor antagonist (Ki = 0.54 nM), a partial agonist of presynaptic D2 receptors and an antagonist of postsynaptic D2 receptors (Ki = 32 nM), and a serotonin transporter blocker (Ki = 61 nM).[6][8] It also possesses affinity for the D1 receptor (Ki = 52 nM) and lower affinity for the α1A and α1B-adrenergic receptors (Ki = 73 nM at α1), 5-HT2C receptor (Ki = 173 nM), and D4 receptor.[6] Lumateperone does not significantly bind to the 5-HT2BH1 (Ki > 1,000 nM), muscarinic acetylcholine receptors, or many other sites (Ki > 100 nM).[6]

Lumateperone shows a 60-fold difference in its affinities for the 5-HT2A 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-HT2A 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., insulinglucosetriglyceride, 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).

str1

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:

Figure imgf000002_0001

[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,

Figure imgf000013_0001

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

  1. Jump up^ Sylvain Celanire; Sonia Poli (13 October 2014). Small Molecule Therapeutics for Schizophrenia. Springer. pp. 31–. ISBN 978-3-319-11502-3.
  2. 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.
  3. Jump up^ Intra-Cellular Therapies. “Product Pipeline – Intra-Cellular Therapies”. Archived from the original on 2015-05-11. Retrieved 2015-05-19.
  4. 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.
  5. 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.
  6. 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”Psychopharmacology232 (3): 605–21. doi:10.1007/s00213-014-3704-1PMC 4302236PMID 25120104.
  7. Jump up to:a b Nancy A. Melville (2015). “Novel Drug Promising for Schizophrenia”. Medscape Medical News.
  8. 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. Chem57 (6): 2670–82. doi:10.1021/jm401958nPMID 24559051.
  9. 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”. Psychopharmacology232 (15): 2863–72. doi:10.1007/s00213-015-3922-1hdl:10044/1/24121PMID 25843749.
  10. 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
ITI-007.svg
Clinical data
Synonyms ITI-007; ITI-722
Routes of
administration
By mouth
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C24H28FN3O
Molar mass 393.496
3D model (JSmol)
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


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 …

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 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 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

Nemorexant


Nemorexant.svg

Nemorexant.png

ChemSpider 2D Image | LMQ24G57E9 | C23H23ClN6O2

Nemorexant

ACT-541468, UNII LMQ24G57E9

[(2S)-2-(5-Chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-1-pyrrolidinyl][5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone
1505484-82-1 [RN]
LMQ24G57E9
Methanone, [(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-1-pyrrolidinyl][5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]-
  • Originator Actelion Pharmaceuticals
  • Developer Idorsia Pharmaceuticals
  • Class Sleep disorder therapies
  • Mechanism of Action Orexin receptor type 1 antagonists; Orexin receptor type 2 antagonists
  • Phase III Insomnia
  • 19 Oct 2018 Idorsia Pharmaceuticals plans a phase I trial for Liver disorders (Hepatic impairment) in November 2018 (PO) (NCT03713242)
  • 09 Oct 2018 Idorsia Pharmaceuticals completes a phase I trial in Insomnia (In volunteers) in Netherlands (PO) (NCT03609775)
  • 27 Sep 2018 Idorsia Pharmaceuticals plans a phase I trial for Hepatic impairment in November 2018 , (NCT03686995)

Nemorexant (developmental code name ACT-541468) is a dual orexin receptor antagonist (DORA) which was originated by Actelion Pharmaceuticals and is under development by Idorsia Pharmaceuticals for the treatment of insomnia.[1][2] It acts as a selective dual antagonist of the orexin receptors OX1 and OX2.[1][2] As of June 2018, nemorexant is in phase III clinical trials for the treatment of insomnia.[1]

Idorsia is developing nemorexant, a dual orexin receptor antagonist (DORA), for the oral treatment of insomnia and investigating the program for the treatment of COPD. In May 2018, a phase III study was initiated in subjects with insomnia disorder and in September 2018, a phase I trial was initiated in COPD.

PATENT

WO2013182972 ,

PATENT

WO2015083094 ,

Patent

WO 2015083070

Synthesis of nemorexant, using 2-methyl-L-proline hydrochloride as the starting material

N-Protection of 2-methyl-L-proline hydrochloride with Boc2O gives N-Boc-2-methyl-L-proline,

Which upon condensation with 4-chloro-3-methylbenzene-1,2-diamine using HATU and DIEA in CH2Cl2 affords the corresponding amide.

Cyclization of diamine in the presence of AcOH at 100 °C provides imidazole derivative,

Whose Boc moiety is removed by means of HCl in dioxane to yield 5-chloro-4-methyl-2-[2(S)-methylpyrrolidin-2-yl]benzimidazole hydrochloride.

N-Acylation of pyrrolidine derivative with 5-methoxy-2-(1,2,3-triazol-2-yl)benzoic acid  using HATU and DIEA in CH2Cl2 produces Nemorexant

5-methoxy-2-(1,2,3-triazol-2-yl)benzoic acid (prepared by the coupling of 2-iodo-5-methoxybenzoic acid with 1,2,3-triazole using CuI and Cs2CO3 in DMF)

PATENT

WO 2016020403

PATENT

WO 2015083071

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E3DE4EDE68FD728AEE93D43C4BCBF8DA.wapp2nC?docId=WO2015083071&tab=PCTDESCRIPTION&maxRec=1000

Reference Example 1

1) Synthesis of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid

2-lodo-5-methoxy benzoic acid (15.0 g; 53.9 mmol) is dissolved in anhydrous DMF (45 ml) followed by the addition of 1 H-1 ,2,3-triazole (7.452 g; 108 mmol) and cesium carbonate (35.155 g; 108 mmol). By the addition of cesium carbonate the temperature of the reaction mixture increases to 40°C and gas evolved from the reaction mixture. Copper(l)iodide (514 mg; 2.7 mmol) is added. This triggers a strongly exothermic reaction and the temperature of the reaction mixture reaches 70°C within a few seconds. Stirring is continued for 30 minutes. Then the DMF is evaporated under reduced pressure followed by the addition of water (170 ml) and EtOAc (90 ml). The mixture is vigorously stirred and by the addition of citric acid monohydrate the pH is adjusted to 3-4. The precipitate is filtered off and washed with water and EtOAc and discarded. The filtrate is poured into a separation funnel and the phases are separated. The water phase is extracted again with EtOAc. The combined organic layers are dried over MgS04, filtered and the solvent is evaporated to give 7.1 g of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid as a white powder of 94% purity (6 % impurity is the regioisomerically N1-linked triazolo-derivative); tR [min] = 0.60; [M+H]+ = 220.21

2) Synthesis of (S)-1 -(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid

2-Methyl-L-proline hydrochloride (99.7 g; 602 mmol) is dissolved in a 1/1-mixture of MeCN and water (800 ml) and triethylamine (254 ml; 1810 mmol) is added. The temperature of the reaction mixture slightly rises. The reaction mixture is cooled to 10°C to 15°C followed by careful addition of a solution of Boc20 (145 g; 662 mmol) in MeCN (200 ml) over 10 minutes.

Stirring at RT is continued for 2 hours. The MeCN is evaporated under reduced pressure and aq. NaOH solution (2M; 250 ml) is added to the residual aq. part of the reaction mixture. The water layer is washed with Et20 (2x 300 ml) then cooled to 0°C followed by slow and careful addition of aq. HCI (25%) to adjust the pH to 2. During this procedure a suspension forms.

The precipitate is filtered off and dried at HV to give 1 10.9 g of the title compound as a beige powder; tR [min] = 0.68; [M+H]+ = 230.14

3) Synthesis of (S)-tert-butyl 2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-2-

(S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (60 g; 262 mmol) and HATU (100 g; 264 mmol) is suspended in DCM (600 ml) followed by the addition of DIPEA (84.6 g; 654 mmol) and 6-chloro-2,3-diaminotoluene (41 g; 262 mmol). The reaction mixture is stirred at rt for 14 hours then concentrated under reduced pressure and to the residue is added water followed by the extraction of the product with EtOAc (3x). The combined organic layers are washed with brine, dried over MgS04, filtered and the solvent is evaporated under

reduced pressure to give 185 g of the title compound as a dark brownish oil, which is used in the next step without further purification; tR [min] = 0.89; [M+H]+ = 368.01

4) Synthesis of (S)-tert-butyl 2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylpyrrolidine-1 -carboxylate

(S)-tert-butyl 2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-2-methylpyrrolidine-1-carboxylate (185 g; 427 mmol) are dissolved in AcOH (100%; 611 ml), heated to 100°C and stirring continued for 90 minutes. The AcOH is evaporated under reduced pressure and the residue is dissolved in DCM followed by careful addition of saturated sodium bicarbonate solution. The phases are separated, the aq. phase is extracted once more with DCM, the combined aq. phases are dried over MgS04, filtered and the solvent is evaporated under reduced pressure to give 142.92 g of the title compound as a dark brown oil which is used in the next step without further purification; tR [min] = 0.69; [M+H]+ = 350.04

5) Synthesis of (S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1 H-benzo[d]imidazole hydrochloride

(S)-tert-butyl 2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (355.53 g; 1.02 mol) are dissolved in dioxane (750 ml) followed by careful addition of HCI solution in dioxane (4M; 750 ml; 3.05 mol). The reaction mixture is stirred for 3 hours followed by the addition of Et20 (800 ml) which triggered precipitation of the product. The solid is filtered off and dried at high vacuum to give 298.84 g of the title compound as a redish powder; tR [min] = 0.59; [M+H]+ = 250.23

6) Synthesis of [(S)-2-(5-chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-pyrrolidin-1- -(5-methoxy-2-[1,2,3]triazol-2-yl-phenyl)-methanone

(S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1 H-benzo[d]imidazole hydrochloride (62.8 g; 121 mmol) is dissolved in DCM (750 ml) followed by the addition of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (62.8 g; 121 mmol) and DIPEA (103 ml; 603 mmol). Stirring is continued for 10 minutes followed by the addition of HATU (47 g; 124 mmol). The reaction mixture is stirred for 16 hours at RT. The solvents are evaporated under reduced pressure and the residue is dissolved in EtOAc (1000 ml) and washed with water (3x 750 ml). The organic phase is dried over MgS04, filtered and the solvent is evaporated under reduced pressure. The residue is purified by CC with EtOAc / hexane = 2 / 1to give 36.68 g of the title compound as an amorphous white powder. tR [min] = 0.73; [M+H]+ = 450.96

Table 1 : Characterisation data for COMPOUND as free base in amorphous form

II. Preparation of crystalline forms of COMPOUND

Example 1 :

Preparation of seeding material of COMPOUND hydrochloride in crystalline Form 1

10 mg COMPOUND is mixed with 0.2 mL 0.1 M aq. HCI and 0.8 mL EtOH. The solvent is fully evaporated and 0.05 mL isopropanol is added. Alternatively 0.05 mL methyl-isobutylketone can be added. The sample is stored closed at room temperature for 4 days and crystalline material of COMPOUND hydrochloride in crystalline Form 1 is obtained. This material can be used as seeding material for further crystallization of COMPOUND hydrochloride in crystalline Form 1.

Example 2: Preparation and characterization of COMPOUND hydrochloride in crystalline form 1

5g COMPOUND is mixed with 0.9 mL 1 M aq. HCI and 20 mL EtOH. The solvent is evaporated and 25 mL isopropanol is added. Seeds of COMPOUND hydrochloride are added and the sample is allowed to stand at room temperature. After about 2 days the suspension is filtered and the solid residue is dried at reduced pressure (2 mbar for 1 hour) and allowed to equilibrate open for 2 hours at 24°C/46% relative humidity. The obtained solid is COMPOUND hydrochloride in crystalline Form 1

Table 2: Characterisation data for COMPOUND hydrochloride in crystalline form 1

PATENT

WO-2018202689

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018202689&tab=PCTDESCRIPTION&maxRec=1000

Process for the preparation of a crystalline potassium salt of a 2-(2H-[1,2,3]triazol-2-yl)-benzoic acid derivatives is claimed. Compound is disclosed to be useful for the preparation of pharmaceuticals, especially certain orexin receptor antagonists such as nemorexant .

References

  1. Jump up to:a b c https://adisinsight.springer.com/drugs/800044843
  2. Jump up to:a b Equihua-Benítez AC, Guzmán-Vásquez K, Drucker-Colín R (July 2017). “Understanding sleep-wake mechanisms and drug discovery”. Expert Opin Drug Discov12 (7): 643–657. doi:10.1080/17460441.2017.1329818PMID 28511597.
  3. Muehlan, C.; Heuberger, J.; Juif, P.E.; Croft, M.; van Gerven, J.; Dingemanse, J.
    Accelerated development of the dual orexin receptor antagonist ACT-541468: Integration of a microtracer in a first-in-human study
    Clin Pharmacol Ther 2018, 104(5): 1022
  4. A Study to Evaluate the Pharmacokinetics of ACT-541468 in Subjects With Mild, Moderate and Severe Hepatic Impairment (NCT03713242)
    ClinicalTrials.gov Web Site 2018, October 24
  5. Boof, M.-.L.; Ufer, M.; Halabi, A.; Dingemanse, J.
    Impact of the dual orexin receptor antagonist ACT-541468 on the pharmacokinetics of the CYP3A4 probe drug midazolam and assessment of the effect of food on ACT-541468
    119th Annu Meet Am Soc Clin Pharmacol Ther (ASCPT) (March 21-24, Orlando) 2018, Abst PI-043 
  6. Muehlan, C.; Brooks, S.; Zuiker, R.; van Gerven, J.; Dingemanse, J.
    Night-time administration of ACT-541468, a novel dual orexin receptor antagonist: Characterization of its pharmacokinetics, next-day residual effects, safety, and tolerability
    32nd Annu Meet Assoc Sleep Soc (SLEEP) (June 2-6, Baltimore) 2018, Abst 0008 
  7. Proposed international nonproprietary names (Prop. INN): List 118
    WHO Drug Inf 2017, 31(4): 635

External links

Patent ID

Title

Submitted Date

Granted Date

US9790208 CRYSTALLINE SALT FORM OF (S)-(2-(6-CHLORO-7-METHYL-1H-BENZO[D]IMIDAZOL-2-YL)-2-METHYLPYRROLIDIN-1-YL)(5-METHOXY-2-(2H-1, 2, 3-TRIAZOL-2-YL)PHENYL)METHANONE AS OREXIN RECEPTOR ANTAGONIST
2014-12-02
US2016368901 CRYSTALLINE FORM OF (S)-(2-(6-CHLORO-7-METHYL-1H-BENZO[D]IMIDAZOL-2-YL)-2-METHYLPYRROLIDIN-1 -YL)(5-METHOXY-2-(2H-1, 2, 3-TRIAZOL-2-YL)PHENYL)METHANONE AND ITS USE AS OREXIN RECEPTOR ANTAGONISTS
2014-12-02
Nemorexant
Nemorexant.svg
Clinical data
Synonyms ACT-541468
Routes of
administration
By mouth
Drug class Orexin antagonist
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C23H23ClN6O2
Molar mass 450.927 g/mol
3D model (JSmol)

///////////////Nemorexant, ACT-541468, Phase III,  Insomnia

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