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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Avacopan


Avacopan.png
EFD
ChemSpider 2D Image | Avacopan | C33H35F4N3O2
Figure imgf000059_0001

Avacopan

アバコパン

авакопан [Russian] [INN]

أفاكوبان [Arabic] [INN]

阿伐可泮 [Chinese] [INN]

FormulaC33H35F4N3O2
CAS1346623-17-3
Mol weight581.6435

(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

(2R,3S)-2-(4-Cyclopentylaminophenyl)-l-(2-fluoro-6-methylbenzoyl)piperidine-3- carboxylic acid (4-methyl-3-trifluoromethylphenyl)amide

3-​Piperidinecarboxamid​e, 2-​[4-​(cyclopentylamino)​phenyl]​-​1-​(2-​fluoro-​6-​methylbenzoyl)​-​N-​[4-​methyl-​3-​(trifluoromethyl)​phenyl]​-​, (2R,​3S)​-

  • (2R,3S)-2-[4-(Cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]-3-piperidinecarboxamide
  • (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

APPROVED PMDA JAPAN 2021/9/27, Tavneos

File:Animated-Flag-Japan.gif - Simple English Wikipedia, the free  encyclopedia

Anti-inflammatory, Complement C5a receptor antagonist

Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis

Avacopan

(2R,3S)-2-[4-(Cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

C33H35F4N3O2 : 581.64
[1346623-17-3]

CCX 168

Avacopan wasunder investigation in clinical trial NCT02994927 (A Phase 3 Clinical Trial of CCX168 (Avacopan) in Patients With ANCA-Associated Vasculitis).

VFMCRP announces approval for TAVNEOS® (avacopan) for the treatment of ANCA-associated vasculitis in Japan

  • First orally administered therapy for the treatment of two types of ANCA-associated vasculitis approved in Japan
  • Partner Kissei to market TAVNEOS® in Japan, with launch expected as soon as possible following National Health Insurance (NHI) price listing

September 27, 2021 02:02 AM Eastern Daylight Time

ST. GALLEN, Switzerland–(BUSINESS WIRE)–Vifor Fresenius Medical Care Renal Pharma (VFMCRP) today announced that Japan’s Ministry of Health and Labor Welfare (MHLW) has granted its partner, Kissei Pharmaceutical Co., Ltd., marketing authorization approval for TAVNEOS® for the treatment of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the two main types of ANCA-associated vasculitis, a rare and severe autoimmune renal disease with high unmet medical need.

“We are delighted that TAVNEOS® has been approved in Japan, the first market worldwide, and congratulate our partner Kissei for this significant milestone”

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“We are delighted that TAVNEOS® has been approved in Japan, the first market worldwide, and congratulate our partner Kissei for this significant milestone,” said Abbas Hussain, CEO of Vifor Pharma Group. “ANCA-associated vasculitis is officially designated an intractable disease in Japan, indicating a rare disease without any effective treatment but for which long-term treatment is required. There is significant unmet medical need of over 10,000 patients in Japan, and we believe in the potential of TAVNEOS® for treating it. We are confident that Kissei will fully focus on bringing this breakthrough treatment to this patient population, helping them lead better, healthier lives.”

The approval is based on the marketing authorization application filing by Kissei which was supported by positive clinical data from the pivotal phase-III trial ADVOCATE in a total of 331 patients with MPA and GPA in 18 countries and regions, including Japan. TAVNEOS® demonstrated superiority over standard of care at week 52 based on Birmingham Vasculitis Activity Score (BVAS).

VFMCRP holds the rights to commercialize TAVNEOS® outside the U.S.. In June 2017, VFMCRP granted Kissei the exclusive right to develop and commercialize TAVNEOS® in Japan. Kissei expects to begin to market TAVNEOS® as soon as possible following NHI price listing. Outside Japan, TAVNEOS is currently in regulatory review with various agencies, including the U.S. Food and Drug Administration and the European Medicines Agency.

About Vifor Pharma Group

Vifor Pharma Group is a global pharmaceuticals company. It aims to become the global leader in iron deficiency, nephrology and cardio-renal therapies. The company is a partner of choice for pharmaceuticals and innovative patient-focused solutions. Vifor Pharma Group strives to help patients around the world with severe and chronic diseases lead better, healthier lives. The company develops, manufactures and markets pharmaceutical products for precision patient care. Vifor Pharma Group holds a leading position in all its core business activities and consists of the following companies: Vifor Pharma and Vifor Fresenius Medical Care Renal Pharma (a joint company with Fresenius Medical Care). Vifor Pharma Group is headquartered in Switzerland, and listed on the Swiss Stock Exchange (SIX Swiss Exchange, VIFN, ISIN: CH0364749348).

For more information, please visit viforpharma.com.

About Kissei Pharmaceutical Co., Ltd.

Kissei Pharmaceutical Co., Ltd. is a Japanese pharmaceutical company with approximately 70 years of history. Based on its management philosophy, “contributing to society through high-quality, innovative pharmaceutical products” and “serving society through our employees”, Kissei is concentrating on providing innovative pharmaceuticals to patients worldwide as a strongly R&D-oriented corporation. Kissei is engaged in R&D and licensing activities in the field of nephrology/dialysis, urology, and unmet medical needs in other disease areas. Kissei has an established collaboration with VFMCRP for sucroferric oxyhydroxide which Kissei fully developed in Japan as P-TOL® (known as Velphoro® in Europe/US) for the treatment of hyperphosphatemia. Since the launch in 2015, the market share of P-TOL® has been steadily expanding in Japan. For more information about Kissei Pharmaceutical, please visit www.kissei.co.jp.

About ChemoCentryx Inc.

ChemoCentryx is a biopharmaceutical company developing new medications for inflammatory and autoimmune diseases and cancer. ChemoCentryx targets the chemokine and chemoattractant systems to discover, develop and commercialize orally-administered therapies. Besides ChemoCentryx’s lead drug candidate, avacopan, ChemoCentryx also has early stage drug candidates that target chemoattractant receptors in other inflammatory and autoimmunediseases and in cancer.

About ANCA-associated vasculitis

ANCA-associated vasculitis is a systemic disease in which over-activation of the complement pathway further activates neutrophils, leading to inflammation and destruction of small blood vessels. This results in organ damage and failure, with the kidney as the major target, and is fatal if not treated. Currently, treatment for ANCA-associated vasculitis consists of courses of non-specific immuno-suppressants (cyclophosphamide or rituximab), combined with the administration of daily glucocorticoids (steroids) for prolonged periods of time, which can be associated with significant clinical risk including death from infection.

About TAVNEOS® (avacopan)

Avacopan is an orally-administered small molecule that is a selective inhibitor of the complement C5a receptor C5aR1. By precisely blocking the receptor (the C5aR) for the pro-inflammatory complement system fragment, C5a on destructive inflammatory cells such as blood neutrophils, avacopan arrests the ability of those cells to do damage in response to C5a activation, which is known to be the driver of inflammation. Moreover, avacopan’s selective inhibition of only the C5aR1 leaves the beneficial C5a l pathway through the C5L2 receptor functioning normally.

ChemoCentryx is also developing avacopan for the treatment of patients with C3 Glomerulopathy (C3G) and hidradenitis suppurativa (HS). The U.S. Food and Drug Administration has granted avacopan orphan-drug designation for ANCA-associated vasculitis, C3G and atypical hemolytic uremic syndrome. The European Commission has granted orphan medicinal product designation for avacopan for the treatment of two forms of ANCA vasculitis: microscopic polyangiitis and granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), as well as for C3G. In October 2020, European Medicines Agency (EMA) accepted to review the Marketing Authorization Application (MAA) for avacopan for the treatment of patients with ANCA-associated vasculitis (granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)).

On May 6, 2021 the U.S. Food & Drug Administration’s (FDA’s) Arthritis Advisory Committee narrowly voted in support of avacopan, a C5a receptor inhibitor, for the treatment of adult patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis. Although the panelists were excited about the possibility of a steroid-sparing therapy, some raised questions about whether results from the single phase 3 trial could adequately inform the risk/benefit assessment.1 The FDA will weigh the panel’s recommendation as it considers possible approval.

Treatment Needs for ANCA-Associated Vasculitis

ANCA-associated vasculitis is a rare, severe and sometimes fatal form of vasculitis characterized by inflammation of small vessels, often including those in the kidney. One factor that distinguishes it from other forms of vasculitis is the dom­inant role of neutrophils in its pathogenesis. From work in both animal and mouse models, we know activation of the alternative complement pathway plays a role in the disease pathogenesis, triggering attraction and activation of neutrophils in a complex feedback loop.1-3

Morbidity and mortality from ANCA-associated vasculitis has improved in recent decades, partly due to the introduction of new treatment regimens. The FDA approved rituximab for ANCA-associated vasculitis in 2011, and, in 2018, its label was extended to include maintenance therapy. Most patients with newly diagnosed ANCA-associated vasculitis are now started on a tapering dose of glucocorticoids, paired either with cyclo­phosphamide or rituximab, with a later follow-up maintenance dose of rituximab at around six months.

High doses of glucocorticoids are often used for remission induction, and they may also be employed as part of maintenance therapy, flare management and relapsing disease. This is a concern for practitioners, who hope to reduce the toxicity that results from glucocorticoid use, especially when given at high doses for prolonged periods.

Avacopan is the first drug to be specifically developed for a vasculitis indication. Other vasculitis therapies—such as tocilizumab for giant cell arteritis or rituximab for ANCA-associated vasculitis—were first approved for other diseases. Avacopan is an oral C5a receptor antagonist that selectively blocks the effects of C5a, thus dampening neutrophil attraction and activation. It does not have FDA approval for other indications, but has orphan drug status for ANCA-associated vasculitis (specifically for microscopic polyangiitis and granulomatosis with polyangiitis) and for C3 glomerulopathy, a rare kidney disease.

Arthritis Advisory Panel Meeting

The FDA generally requires evidence from at least two adequate and well-controlled phase 3 trials to establish effectiveness of a drug. However, it exercises regulatory flexibility in certain circumstances, such as for some rare diseases. In this case, it may consider the results of a well-designed single study if the evidence is statistically persuasive and clinically meaningful.4

Study design is a challenge for any manufacturer attempting to develop a product to potentially decrease steroid use because the FDA does not accept steroid sparing as an assessable outcome for clinical trials. For example, in the GiACTA trial, the phase 3 trial used as evidence for approval of tocilizumab for patients with giant cell arteritis, the biotechnology company Genentech wanted to give tocilizumab and demonstrate patients could then be safely taken off glucocorticoids. But the FDA required a more complicated multi-arm design.5

Other issues come up because of the way gluco­corticoids have been used historically. Although they have been used for vasculitis since before drug licensing was introduced, glucocorticoids are not themselves licensed for ANCA-associated vasculitis, which brings up certain regulatory barriers in study design. Additionally, the efficacy of glucocorticoids in vasculitis to control disease activity or prevent relapse has never been officially quantified in a placebo-controlled trial.

ADVOCATE Design

For avacopan, ChemoCentryx based its application on a single phase 3 trial and two phase 2 trials.1-3 In pre-meeting documents and during the meeting itself, the company drew comparisons to the RAVE trial, used to establish the non-inferiority of rituximab to standard cyclophosphamide therapy in patients with ANCA-associated vasculitis.6 In this case, a single phase 3 trial (with supporting phase 2 data) was used as evidence for approval of rituximab.

The phase 3 trial of avacopan, ADVOCATE, used a similar, double-blind, double-dummy design.1 ADVOCATE included 331 patients with either new or relapsing ANCA-associated vasculitis. Half the participants received 30 mg of avacopan twice a day orally, as well as a prednisone placebo, out to the study’s end at 12 months. The other half received oral prednisone (tapered to 0 mg at five months) plus an avacopan placebo.

Additionally, patients received immunosuppressive treatment, either cyclo­phosphamide (35%) or rituximab (65%), at the discretion of the prescribing physician. Patients who had received cyclophosphamide also received follow-up azathio­prine at week 15. But after initial treatment, no patients received maintenance rituximab, as would now be common practice.

Prior to enrollment, many participants were already receiving glucocorticoids as part of their treatment, to help get their disease under control. Thus, open-label prednisone treatment continued to be tapered for the early part of the trial in both groups up to the end of week 4. This had to be tapered to 20 mg or less of prednisone daily before beginning the trial, in both treatment groups.

As reported by the investigators, at week 26, the avacopan group was non-inferior to the prednisone group in terms of sustained remission. At the study’s conclusion at week 52, 66% of patients in the avacopan group were in sustained remission, as were 55% of those in the prednisone group. Thus, in terms of remission, avacopan was superior to gluco­corticoids at week 52 (P=0.007).

The researchers also provided encouraging secondary endpoints related to a number of other parameters, including reduced glucocorticoid-related toxicities, fewer relapses, better quality of life measures and improvements in kidney functioning (e.g., glomerular filtration rate changes).

David R.W. Jayne, MD, a professor of clinical auto­immunity at the University of Cambridge and director of the Vasculitis and Lupus Service at Addenbrooke’s Hospital, Cambridge, England, was one of the ADVOCATE investigators and says that in the context of previous vasculitis trials, which have only rarely displayed positive effects from interventions, the ADVOCATE results are impressive.

“We’ve never seen quality-of-life benefits or [glomerular filtration rate] recovery benefits in other vasculitis trials, but we saw them consistently in this one,” says Dr. Jayne.

………………………………………………………………………………………………………………………….

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……………………………………………………………………………………………………………………………

PATENT

Example 1: Preparation of Free Base Crystalline Form of Compound 1

      Crude Compound 1 was prepared essentially as described in WO 2016/053890.
      A free base crystalline form of Compound 1 was prepared by dissolving 18 g of crude Compound 1 in 50 mL acetone with heating at 40° C. (a concentration of about ˜0.36 g/mL). The warm solution was passed through a 10 μm polyethylene filter. The solution was then loaded into rotary evaporator at 30° C. bath temperature and 180 rpm rotational speed. The solid collected was dried further in a 45° C. oven for 1 hour. The XRPD data of the crystalline form is shown in Error! Reference source not found., and the table of peaks measured are listed in Table 1, below.

Example 2: Preparing an Amorphous Form of Compound 1

      Method 1
      Crude Compound 1 was prepared essentially as described in WO 2016/053890.
      Crude Compound 1 (15 grams) was dissolved into 40 mL of acetone at 40° C. temperature. The solution was spray dried using a Buchi B290 Spray Dryer, equipped with a peristaltic pump. The spray drying process was completed by using target inlet temperature of 80° C., target spray rate of 5 mL/min, and process gas flow rate of 20.60 CFM. The spray dried powder collected in the sample collection chamber was the amorphous form of Compound 1 as assessed by XRFD, shown in Error! Reference source not found.
      Method 2 An amorphous form of Compound 1 was prepared by dissolving 1 g of the free base crystalline form of Compound 1 in 9 mL of acetone without any heating (a concentration of about ˜0.11 g/mL). The solution was passed through a 10 μm polyethylene filter by gravity. The solution was then loaded into rotary evaporator at 45° C. bath temperature and 220 rpm rotational speed. The solid collected was dried further in a 45° C. oven for 30 hour. The XRPD data of the starting material (in crystalline form) and the amorphous form produced from Method 2 are shown in Error! Reference source not found.A & FIG. 3B. The DSC data of the starting material (in crystalline form) and the amorphous form produced from Method 2 are shown in Error! Reference source not found. Experimental details related to DSC data collection are described in Example 3.

PATENT

WO 2021163329 

https://patents.google.com/patent/WO2021163329A1/en

PATENT

https://patents.google.com/patent/US20170283446A1/en

PATENT

Example 1: A Besylate Salt of Compound 1 (Form I)

      
 (MOL) (CDX)
      A 3-L round bottom flask equipped with a magnetic stirrer was charged with (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (Compound 1, 250 g, 430 mmol) and MeCN (1.84 L, 8 vol). The resulting mixture was stirred and heated to 75° C. (internal temperature) for 30 min to form a clear solution, and filtered through polyethylene frit filter and rinsed with MeCN (230 mL). To this solution at 60° C. was slowly added a pre-filtered solution of benzenesulfonic acid hydrate (77.9 g, 442 mmol (based on monohydrate), 1.03 eq) in MeCN (276 mL, 3 vol) over 10 min and rinsed with MeCN (92 mL) (internal temperature dropped to 55° C.). The resulting solution was cooled to 50° C., seeded with besylate crystals of Compound 1 (˜100 mg) and slowly cooled to 45° C. over 1 h. The resulting mixture was slowly cooled to RT and stirred for 42 h. The solid was collected by filtration, washed with MeCN (230 mL×2), air-dried and then dried in an oven under vacuum at 50° C. overnight (48 h) to afford N-cyclopentyl-4-((2R,3S)-1-(2-fluoro-6-methylbenzoyl)-3-((4-methyl-3-(trifluoromethyl)phenyl)-carbamoyl)piperidin-2-yl)benzenaminium benzenesulfonate as off-white crystals, with a recovery yield of 266.5 g (84%). 1H NMR (400 MHz, DMSO-d 6) (RT) δ 10.44 (s, 1H), 7.90-7.83 (m, 1H), 7.65-6.95 (m, 14H), 6.42-6.34 (m, 1H), 6.05-5.00 (br, 1H), 3.85-3.70 (m, 1H), 3.22-3.00 (m, 3H), 2.38-2.28 (m, 4H), 2.20-1.40 (m, 15H); (65° C.) δ 10.22 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.68-6.70 (m, 15H), 6.44-6.35 (m, 1H), 3.72-3.65 (m, 1H), 3.25-2.98 (m, 3H), 2.40-2.28 (m, 4H), 2.22-1.40 (m, 15H). MS: (ES) m/z calculated for C 333643[M+H] 582.3, found 582.2. A plot of the XRPD is shown in FIG. 1, and Table 1, below, summarizes significant peaks observed in the XRPD plot. HPLC (both achiral analytical and chiral): >99%. Elemental Analysis consistent with formula of C 3941435S, KF: 0.66%.

PATENT

 WO 2011163640

https://patents.google.com/patent/WO2011163640A1

Figure imgf000028_0002

Example 11[0147] The following are representative compounds prepared and evaluated using methods similar to the examples herein. Characterization data is provided for the compounds below. Biological evaluation is shown in Figure 1 for these compounds and others prepared as described herein.(2R,3S)-2-(4-Cyclopentylaminophenyl)-l-(2-fluoro-6-methylbenzoyl)piperidine-3- carboxylic acid (4-methyl-3-trifluoromethylphenyl)amide

Figure imgf000059_0001

[0148] 1H NMR (400 MHz, TFA-d) δ 7.91 (d, J= 8.6 Hz, 1 H), 7.84 (d, J= 8.6 Hz, 1 H), 7.58-6.82 (m, 8 H), 6.75 (t, J= 8.6 Hz, 1 H), 4.10-4.00 (m, 1H), 3.60-3.47 (m, 1H), 3.45-3.41 (m, 1H), 3.33-3.25 (m, 1H), 2.44-2.22 (m, 7H), 2.04-1.92 (m, 4H), 1.82-.169 (m, 7H)

PATENTUS 20110275639https://patents.google.com/patent/US20110275639PATENT
https://patents.google.com/patent/US20160090357A1/en

  • [0097]This example illustrates the preparation of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide by the method provided more generally in FIG. 1 (Scheme 1) using the reagents provided below:
  • [0098]Step 1:
  • [0099]An oven-dried 12 L, 3-necked flask equipped with a mechanical stirrer, condenser, and thermometer was charged with acrolein diethyl acetal (1127 g, 8.666 mole, 1.05 equiv.) and warmed up to 40° C. A mixture of solid ethyl 3-(4-nitrophenyl)-3-oxo-propanoate (1956 g, 8.253 mole) and (R)-(−)-2-phenylglycinol (>99.5% e.e., 1187 g, 8.666 mole, 1.05 equiv.) was added in portions over 40 min. to maintain a stirrable mixture at an internal temperature of approximately 40° C. After all solids were added, the mixture was stirred at 40° C. for 10 minutes. 4M HCl in dioxane (206.2 mL, 0.825 mole, 10 mol. %) was subsequently added through the condenser within 2 minutes and the internal temperature was increased to 70 OC. The reaction was stirred for 22 h whereupon LC-MS showed consumption of starting materials and enamine intermediate. The heating was turned off and ethanol (6.6 L) was added. The solution was then seeded with 4 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate and stirred at room temperature for 18 h. The solid was subsequently filtered off and 0.1 L of ethanol was used to rinse the flask and equipment onto the filter. The isolated solid was then washed three times on the filter with ethanol (250 mL each) and dried under vacuum to generate 1253 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate as a bright yellow solid (38% yield, 98.5% HPLC wt/wt purity, 0.15 wt % of EtOH).
  • [0100]Step 2:
  • [0101]260 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate (0.659 mol), 0.66 L of ethanol, and 56 g of palladium catalyst (10% Pd/C, Degussa type E101 NE/W, 50% wet, 21.5 wt. % of powder, 4.0 mol % Pd) were placed in a 2.2 L Parr bottle and purged with nitrogen. The bottle was mounted on a Parr shaker apparatus and hydrogen was added at a rate to keep the external temperature of the bottle below 30° C. After 4 hours, the consumption of hydrogen slowed down. The bottle was then shaken under 50 psi of hydrogen for 2 hours. 94 mL of glacial acetic acid (1.65 mol, 2.5 equiv.) was subsequently added to the bottle and the bottle was purged three times with hydrogen at 50 psi. The bottle was then shaken under 35-55 psi of hydrogen for 48 hours, keeping the temperature below 30° C. The bottle was removed from the apparatus and 55 mL of 12M HCl aq. was added (0.659 mol, 1 equiv.) followed by 87 mL of cyclopentanone (0.989 mol, 1.5 equiv.). The bottle was purged three times with hydrogen at 50 psi and then shaken under 50 psi of hydrogen for 16-20 hours. The mixture was removed from the apparatus and filtered through a fritted funnel containing celite (80 g) and then washed three times with 0.125 L of ethanol. 54.1 g of anhydrous sodium acetate (0.659 mol, 1 equiv.) was added and the mixture was concentrated in vacuo at 40-55° C. to remove 0.9 L of the volatile components. 2.0 L of acetonitrile was added and 2.0 L of volatile components were removed in vacuo. The crude material was diluted with 1.0 L of acetonitrile and mechanically stirred at r.t. for 30 minutes. The mixture was filtered through Celite (40 g) and the cake was washed with 0.28 L of acetonitrile. The combined filtrates gave a solution of the crude amine acetate (Solution A, e.e. =78%). Solutions A of two independent runs were combined for further processing.
  • [0102]In a 12-L 3-neck flask equipped with a mechanical stirrer, internal thermometer, and reflux condenser (−)-O,O′-di-p-toluoyl-L-tartaric acid (1.019 kg, 2.64 mol, 2 equiv.) was dissolved in 5.8 L of acetonitrile. The mixture was heated to 60° C. with stirring, followed by a quick addition of 1 L of Solution A. The resultant solution was seeded with 4 g of the crystalline ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate (−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) and stirred at 60° C. for 15 minutes. After 15 minutes at 60 OC the seed bed has formed. The remaining amount of Solution A was added over a period of 2.5 hours, maintaining an internal temperature at 60° C. When the addition was complete, the heat source was turned off and the mixture was stirred for 17 hours, reaching a final temperature of 22.5° C. The suspension was filtered and the solids were washed with 0.50 L of acetonitrile to rinse the equipment and transfer all solids onto the filter. The resultant wet solids were washed on the funnel with 3.0 L of acetonitrile and dried in a vacuum oven at 45° C. for 48 hours to provide 1.005 kg of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate (−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) as an off-white solid (70% yield, contains 1 wt. % of acetonitrile). The enantiomeric ratio of the product was 99.4:0.6.
  • [0103]Step 3:
  • [0104]In a 5 L 3-necked flask equipped with a mechanical stirrer and an addition funnel, solid anhydrous potassium carbonate (K2CO3, 226 g, 1.64 mol, 4.1 equiv.) was dissolved in H2O (0.82 L) and cooled to ambient temperature. MTBE (0.82 L) was added, followed by solid ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate (−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) (436 g, 0.400 mol). The mixture was vigorously stirred at r.t. for 1 hour, then 2-fluoro-6-methylbenzoyl chloride (72.5 g, 0.420 mmol, 1.05 equiv.) in MTBE (0.14 L) was added dropwise over 1 hour. The product started precipitating from the reaction before addition of the acid chloride was completed. The reaction was vigorously stirred at r.t. for 30 minutes and monitored by LC-MS for the disappearance of starting material. The mixture was subsequently transferred to a 5 L evaporation flask using 0.3 L of MTBE to rinse the equipment and remove all solids. The mixture was concentrated in vacuo to remove the MTBE, then 0.3 L of heptane was added and the mixture was evaporated again to leave only the product suspended in aqueous solution. The flask was removed from the rotavap and water (0.82 L) and heptane (0.82 L) were added. The suspension was vigorously stirred for 16 hours using a mechanical stirrer. The contents were then filtered and the solid was washed with water (2×0.42 L) and heptane (0.42 L). The solid was dried in a vacuum oven at 45° C. to provide 172 g of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate as an off-white powder (95% yield).
  • [0105]Step 4:
  • [0106]A 0.5 L 3-necked round-bottom flask was dried overnight in an oven at 200° C. and then cooled under a stream of nitrogen. The flask was equipped with a magnetic stir bar, nitrogen inlet, and a thermometer. The flask was charged with 30.2 g of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate (66.7 mmol), 11.5 mL of 4-methyl-5-trifluoromethylaniline (80 mmol, 1.2 equiv.) and 141 mL of dry toluene under an atmosphere of nitrogen. Nitrogen was bubbled through the resultant solution for 10 minutes and then the solution was warmed to 30° C. The oil bath was removed and 100 mL of a 2 M solution of AlMein toluene (Aldrich, 200 mmol, 3 equiv.) was cannulated into the reaction mixture at a rate maintaining the reaction temperature between 35-40° C., a process that took approximately 45 minutes. The temperature of the reaction mixture was then increased to 55° C. over a period of 1 hour and the reaction mixture was stirred at 55° C. for 8 hours, whereupon all of the starting ester was consumed (monitored by LC-MS). The reaction was subsequently cooled overnight to ambient temperature and the solution was then cannulated into a mechanically stirred 1 L flask containing a solution of 67.8 g of sodium potassium tartrate tetrahydrate (240 mmol, 3.6 equiv.) in 237 mL of water, pre-cooled to 10 OC in an ice bath. The addition process took approximately 30 minutes, during which the reaction mixture self-heated to 57° C. The empty reaction flask was subsequently rinsed with 20 mL of dry toluene and the solution was combined with the quench mixture. The mixture was then cooled to r.t. with stirring, 91 mL of ethyl acetate was added, and the mixture was stirred an additional 15 minutes. The mixture was subsequently filtered through a pad of Celite and the filtrate was allowed to separate into two layers. The organic layer was then separated and washed with a solution of 5.7 g of sodium potassium tartrate tetrahydrate (20 mmol) in 120 mL of water and then with two 120 mL portions of water. The wet organic solution was concentrated in vacuo to a weight of ˜150 g and a solvent exchange with ethanol was performed maintaining a total volume of 0.2-0.3 L, until <1 mol. % toluene with respect to ethanol was observed by 1H NMR. The solution was then evaporated at elevated temperature to a weight of 223 g and heated to reflux. Mechanical stirring was initiated and 41 mL of water was added. The resulting solution was seeded with (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide crystals at 60 OC and then slowly cooled to r.t. over 2 hours. The slurry was subsequently stirred for 18 hours and the solids were filtered off. The solids were then washed with two 30 mL portions of 7:3 ethanol/water and dried in a vacuum oven for 24 hours at 50 OC to afford 31.0 g of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide as off-white crystals (80% yield). Analytical data: HPLC purity: 99.59%; >99.8% d.e. and e.e. by HPLC; ICP-OES Pd: <1 ppm; Al: δ ppm; residual toluene by headspace GC-MS: 15 ppm; microash<0.1%; K—F 0.1%. 1H NMR (400 MHz, TFA-d) δ 7.91 (d, J=8.6 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.58-6.82 (m, 8H), 6.75 (t, J=8.6 Hz, 1H), 4.10-4.00 (m, 1H), 3.60-3.47 (m, 1H), 3.45-3.41 (m, 1H), 3.33-3.25 (m, 1H), 2.44-2.22 (m, 7H), 2.04-1.92 (m, 4H), 1.82-1.69 (m, 7H), MS: (ES) m/z 582 (M+H+).

PATENT

WO2019236820

The present disclosure is directed to, inter alia, methods of treating ANCA-associated vasculitis (AAV) in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of avacopan, having the structure shown below:

References

  1. Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the treatment of ANCA-associated vasculitisN Engl J Med. 2021 Feb 18;384(7):599–609.
  2. Merkel PA, Niles J, Jimenez R, et al. Adjunctive treatment with avacopan, an oral C5a receptor inhibitor, in patients with antineutrophil cytoplasmic antibody-associated vasculitisACR Open Rheumatol. 2020;2(11):662–671.
  3. Jayne DRW, Bruchfeld AN, Harper L, et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitisJ Am Soc Nephrol. 2017 Sep;28(9):2756–2767.
  4. U.S. Department of Health and Human Services. Food and Drug Administration. Demonstrative substantial evidence of effectiveness for human drug and biological products: Guidance for industry. 2019.
  5. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritisN Engl J Med. 2017 Jul 27;377(4):317–328.
  6. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitisN Engl J Med. 2010 Jul 15;363(3):221–232.
  7. Warrington KJ. Avacopan—time to replace glucocorticoids? N Engl J Med. 2021 Feb 18;384(7):664–665.

////////////Avacopan, アバコパン , JAPAN 2021, APPROVALS 2021, CCX 168, авакопан , أفاكوبان , 阿伐可泮 , 

CC1=C(C(=CC=C1)F)C(=O)N2CCCC(C2C3=CC=C(C=C3)NC4CCCC4)C(=O)NC5=CC(=C(C=C5)C)C(F)(F)F

wdt-21

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Upacicalcet sodium hydrate


Upacicalcet sodium hydrate (JAN).png

Upacicalcet sodium hydrate, ウパシカルセトナトリウム水和物

CAS 2052969-18-1

1333218-50-0 free

PMDA JAPAN APPROVED 2021/6/23, Upasita

Calcium sensing receptor agonist

(2S)-2-amino-3-[(3-chloro-2-methyl-5-sulfophenyl)carbamoylamino]propanoic acid

FormulaC11H13ClN3O6S. Na. xH2O
  • OriginatorAjinomoto Pharma
  • DeveloperSanwa Kagaku Kenkyusho
  • ClassAmines; Chlorobenzenes; Propionic acids; Small molecules; Sulfonic acids; Toluenes
  • Mechanism of ActionCalcium-sensing receptor agonists
  • RegisteredSecondary hyperparathyroidism
  • 25 Jun 2021Chemical structure information added
  • 23 Jun 2021Sanwa Kagaku Kenkyusho and Kissei Pharmaceutical agree to co-promote upacicalcet in Japan for Secondary hyperparathyroidism
  • 23 Jun 2021Registered for Secondary hyperparathyroidism in Japan (IV) – First global approval
Upacicalcet Sodium HydrateMonosodium 3-({[(2S)-2-amino-2-carboxyethyl]carbamoyl}amino)-5-chloro-4-methylbenzenesulfonate hydrateC11H13ClN3NaO6S▪xH2O
[2052969-18-1 , anhydride]

Announcement of Marketing Authorization Approval in Japan and Co-promotion Agreement of UPASITA® IV Injection Syringe for the Treatment of Secondary Hyperparathyroidism in Dialysis Patients

SANWA KAGAKU KENKYUSHO Co., Ltd. (Head Office: Nagoya, President and CEO : Shusaku Isono, Suzuken Group, ; “SANWA KAGAKU”) has received Marketing Authorization approval today for UPASITA® IV Injection Syringes (generic name: Upacicalcet Sodium Hydrate; “UPASITA®”) for the treatment of secondary hyperparathyroidism in patients on hemodialysis.

UPASITA® was created by Ajinomoto Pharmaceuticals Co., Ltd. (currently EA Phama Co., Ltd.) and developed by SANWA KAGAKU for the treatment of secondary hyperparathyroidism under a licensing agreement with EA Pharma. UPASITA® acts on calcium sensing receptor in the parathyroid and suppresses excessive secretions of parathyroid hormones (PTH). UPASITA® is administered by intravenous injection to dialysis patients through dialysis circuit by physicians or medical staffs upon completion of dialysis and such administration is expected to reduce the burden of patients with many oral medications whose drinking water volume is severely restricted.

Regarding provision of medical and drug information, SANWA KAGAKU entered into a co-promotion agreement in Japan with Kissei Pharmaceutical Co., Ltd. (Head Office: Matsumoto, Nagano; Chairman and CEO: Mutsuo Kanzawa ; “Kissei”). SANWA KAGAKU will handle the production, marketing, and distribution of the Product while SANWA KAGAKU and Kissei collaboratively promote it to medical institutions in the field in accordance with the agreement. Through the co-promotion activity in the field, SANWA KAGAKU and Kissei will contribute to the treatment of dialysis patients suffering from secondary hyperparathyroidism.

《Reference》

About secondary hyperparathyroidism (SHPT)
SHTP is one of complications that occur as chronic kidney disease (chronic kidney failure) progresses and is a pathological condition where excessive PTH is secreted by the parathyroid gland. It has been reported that excessive secretion of parathyroid hormone promotes efflux of phosphorus and calcium from the bone into the blood, thereby increasing the risk of developing bone fractures and arteriosclerosis due to calcification of the cardiovascular system and affecting the vital prognosis.

Product Summary of UPASITA® IV Injection Syringe for Dialysis
Brand name:
UPASITA® IV Injection Syringe for Dialysis 25μg
UPASITA® IV Injection Syringe for Dialysis 50μg
UPASITA® IV Injection Syringe for Dialysis 100μg
UPASITA® IV Injection Syringe for Dialysis 150μg
UPASITA® IV Injection Syringe for Dialysis 200μg
UPASITA® IV Injection Syringe for Dialysis 250μg
UPASITA® IV Injection Syringe for Dialysis 300μg

Generic Name (JAN):
Upacicalcet Sodium Hydrate

Date of Marketing Approval:
June 23, 2021

Indications:
Secondary hyperparathyroidism in patients on hemodialysis

Dosage and Administration:
In adults, UPASITA® is usually administered into venous line of the dialysis circuit at the end of dialysis session during rinse back at a dose of 25 μg sodium upacicalcet 3 times a week as a starting dose.
The starting dose can be 50 μg depending on the concentration of serum calcium. Thereafter, the dose may be adjusted in a range from 25 to 300 μg while parathyroid hormone (PTH) and serum calcium level should be carefully monitored in patients.

SYN

WO 2020204117

PATENT

WO 2011108724

WO 2011108690

JP 2013063971

WO 2016194881

JP 6510136 

PATENT

WO 2016194881

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016194881&tab=FULLTEXT(Example 1)  Synthesis of
(2S) -2-amino-3-{[(5-chloro-2-hydroxy-3-sulfophenyl) carbamoyl] amino} propanoic acid (Compound 1 )
[Chemical formula 14]
CDI 150. 2 g (926.6Mmol, 1.1 eq. vs Boc-DAP-O t Bu) to and stirred at 5 ° C. acetone was added 750mL (3.0L / kg). 250 g (842.6 mmol) of Boc-DAP-OtBu was added in two portions, and the mixture was washed with 125 mL (0.5 L / kg) of acetone. After stirring for 30 minutes, completion of the IC (imidazolylcarbonylation) reaction was confirmed by HPLC. 282.6 g (1263.8 mmol, 1.5 eq.) Of ACHB was added in 3 portions, and the mixture was washed with 125 mL (0.5 L / kg) of acetone. After raising the temperature to 30 ° C. and stirring for 18 hours, the completion of the urea conversion reaction was confirmed by HPLC. After cooling to 5 ° C., 124.5 mL (1432.4 mmol, 1.7 eq.) Of concentrated hydrochloric acid was added, and the mixture was stirred for 1 hour. The precipitated unwanted material was filtered and washed with 1000 mL (4.0 L / kg) of acetone. The filtrate was concentrated to 1018 g (4.1 kg / kg), the temperature was raised to 50 ° C., and 625.0 mL (7187 mmol, 8.5 eq.) Of concentrated hydrochloric acid was added dropwise. After stirring for 30 minutes and confirming the completion of deprotection by HPLC, 750 mL of water was added (3.0 L / kg). This liquid was concentrated under reduced pressure to 1730 g (6.9 kg / kg) to precipitate a solid. After stirring at 20 ° C. for 14 hours, vacuum filtration was performed. The filtered solid was washed with 500 mL (2.0 L / kg) of acetone and then dried under reduced pressure at 60 ° C. for 6 hours to obtain 201.4 g of the target product (64.5%).
1H-NMR (400MHz, DMSO-d6): δ 8.3 (s, 1H), 8.2 (bs, 3H), 8.1 (d, 1H, J = 2.6Hz), 7.3 (t, 1H, J = 6.0Hz), 7.0 (d, 1H, J = 2.6Hz), 4.0-4.1 (m, 1H), 3.6-3.7 (m, 1H), 3.4-3.5 (m, 1H)[0026](Example 2) Synthesis of
(2S) -2-amino-3-{[(3-sulfophenyl) carbamoyl] amino} propanoic acid (Compound 2 )
[Chemical
formula 15] CDI 120.2 g (741.2 mmol, 1. 600 mL (3.0 L / kg) of acetone was added to 1 eq. Vs Boc-DAP-OtBu), and the mixture was stirred at 5 ° C. 200 g (673.9 mmol) of Boc-DAP-OtBu was added in two portions, and the mixture was washed with 100 mL (0.5 L / kg) of acetone. After stirring for 30 minutes, the completion of the IC reaction was confirmed by HPLC. 175.0 g (1010.8 mmol, 1.5 eq.) Of ABS was added in 3 portions and washed with 100 mL (0.5 L / kg) of acetone. After raising the temperature to 30 ° C. and stirring for 18 hours, the completion of the urea conversion reaction was confirmed by HPLC. After cooling to 5 ° C., 99.6 mL (1145.4 mmol, 1.7 eq.) Of concentrated hydrochloric acid was added, and the mixture was stirred for 1 hour. The precipitated unwanted material was filtered and washed with 1400 mL (7.0 L / kg) of acetone. The filtrate was concentrated to 800.1 g (4.0 kg / kg), heated to 50 ° C., and then 500.0 mL (5750.0 mmol, 8.5 eq.) Of concentrated hydrochloric acid was added dropwise. After stirring for 30 minutes and confirming the completion of deprotection by HPLC, 600 mL of water was added (3.0 L / kg). This liquid was concentrated under reduced pressure to 1653.7 g to precipitate a solid. After aging at 20 ° C. for 15 hours, vacuum filtration was performed. The filtered solid was washed with 400 mL (2.0 L / kg) of acetone and then dried under reduced pressure at room temperature for 6 hours to obtain 140.3 g of the desired product (net 132.2 g, 64.7%).
1H-NMR (400MHz, DMSO-d6): δ 8.8 (s, 1H), 8.2 (bs, 3H), 7.7 (s, 1H), 7.3-7.4 (m, 1H), 7.1-7.2 (m, 2H) , 6.3-6.4 (bs, 1H), 4.0-4.1 (bs, 1H), 3.6-3.7 (bs, 1H), 3.5-3.6 (bs, 1H)[0027](Example 3) Synthesis of
(2S) -2-amino-3-{[(3-chloro-2-methyl-5-sulfophenyl) carbamoyl] amino} propanoic acid (Compound 3 )
[Chemical formula 16]
CDI 14. To 4 g (88.8 mmol, 1.05 eq. Vs Boc-DAP-OtBu), 75 mL (3.0 L / kg vs DAP-OtBu) of acetone was added and stirred at 5 ° C. After adding 25 g (84.3 mmol) of Boc-DAP-OtBu in two portions and stirring for 30 minutes, the completion of the IC reaction was confirmed by HPLC. 26.1 g (118.0 mmol, 1.4 eq.) Of ACTS was added in 3 portions and washed with 25 mL (1.0 L / kg) of acetone. After the temperature was raised to 30 ° C., the mixture was stirred overnight, and the completion of the urea conversion reaction was confirmed by HPLC. After concentrating under reduced pressure at 10 kPa and 40 ° C. until the solvent was completely removed, 37.5 mL (1.5 L / kg) of water and 22.8 mL (257.6 mmol) of concentrated hydrochloric acid were added to perform deprotection for 2 hours. After confirming the completion of the reaction by HPLC, the mixture was cooled to 5 ° C., 60 mL (2.4 L / kg) of MeCN was added, and the mixture was stirred overnight. Further, when 120 mL (4.8 L / kg) of MeCN was added, stratification occurred, so 10 mL (0.4 L / kg) of water and 2.5 mL (0.1 L / kg) of MeCN were added. The precipitated solid was filtered under reduced pressure, washed with 60 mL of MeCN / water (1/2), and then dried under reduced pressure at 60 ° C. for 14 hours to obtain 20.1 g of the desired product as a white solid (net18.3 g, yield 61). 0.8%).
1H-NMR (400MHz, DMSO-d6): δ 14.70-13.30 (bs, 1H), 8.27 (bs, 3H), 8.15 (s, 1H), 7.98 (d, 1H, J = 1.6Hz), 7.27 (d , 1H, J = 1.6Hz), 6.82 (t, 1H, J = 6.0Hz), 4.04 (bs, 1H), 3.70-3.60 (m, 1H), 3.60-3.50 (m, 1H), 2.22 (s, 3H)[0028](Example 4) Synthesis of
compound 3 using phenylchloroformate as a carbonyl group-introducing reagent
(Step 1)
[Chemical
formula 17] MeCN 375 mL (7.5 L / kg vs ACTS), Py for 50 g (225.6 mmol) of ACTS. 38.1 mL (473.7 mmol, 2.1 eq.) Was added and stirred at 25 ° C. 29.9 mL (236.8 mmol, 1.05 eq.) Of ClCO 2 Ph (phenyl chloroformate) was added dropwise, and after stirring for 30 minutes, completion of the CM (carbamate) reaction was confirmed by HPLC. 68.9 g (232.4 mmol) of Boc-DAP-OtBu was added, 97.5 mL (699.3 mmol, 3.1 eq.) Of TEA was added dropwise, and the mixture was stirred at 25 ° C. for 3 hours. The completion of the urea conversion reaction was confirmed by HPLC. Here, 103.5 g of the total amount of 517.43 g was used to move to the next step (down to ACTS 10 g scale).
30 mL of water was added and concentrated to 77.0 g at 40 ° C. and 5 kPa. After 100 mL (10 L / kg) of AcOEt was added and the liquid separation operation was performed, 30 mL of water was added to the organic layer and the liquid separation operation was performed again. The organic layer was concentrated to 47.6 g at 40 ° C. and 10 kPa, and then 15 mL (1.5 L / kg) of AcOEt and 100 mL (10 L / kg) of THF were added. Again, it was concentrated to 50.7 g and THF was added up to 146 g. When it was concentrated again to 35.5 g and added to AcOEt 30 mL (3 L / kg) and THF 100 mL (10 L / kg), a solid was precipitated. It was cooled to 5 ° C. and aged overnight. The precipitated solid was filtered under reduced pressure, washed with 20 mL (2.0 L / kg) of THF, and then dried under reduced pressure at 40 ° C. for 3 hours overnight at 30 ° C. to obtain 24.9 g of the desired product as a white solid (net). 23.0 g, 83.6%).
1 H-NMR (400MHz, DMSO-d6): δ 8.86 (bs, 1H), 8.09 (s, 1H), 7.88 (s, 1H), 7.25 (d, 1H, J = 1.6Hz), 7.14 (d, 1H, J = 7.6Hz), 6.60 (t, 1H, J = 5.6Hz), 4.00-3.90 (m, 1H), 3.60-3.50 (m, 1H), 3.30-3.20 (m, 1H), 3.15-3.05 (m, 6H), 2.19 (s, 3H), 1.50-1.30 (m, 18H), 1.20-1.10 (m, 9H)

(Step 2)
[Chemical

formula 18] Compound 4 21.64 g (net. 20.0 g, 68 mL of water (3.4 L / kg vs. compound 4) vs. 32.8 mmol) ) Was added, the mixture was stirred at 50 ° C., and 12 mL (135.6 mmol, 4.1 eq.) Of concentrated hydrochloric acid was added dropwise. After stirring for 1 hour, the temperature was raised to 70 ° C. to dissolve the precipitated solid. After confirming the completion of the reaction by HPLC, the mixture was cooled to 50 ° C. and aged for 1 hour, and then cooled to 5 ° C. over 4 hours. The precipitated solid was filtered under reduced pressure, washed with 40 mL (2.0 L / kg) of MeCN / water (2/1), and then dried under reduced pressure at 60 ° C. for 3 hours to obtain 11.2 g of the desired product as a white solid (11.2 g). net 10.5 g, 91.1%).[0029](Example 5)
[Chemical
formula 19] MeCN 10.0 mL (10.0 L / kg vs ACSS), Py 0.75 mL (9.25 mmol, 2.05 eq.) For 1.00 g (4.51 mmol) of ACTS. , And stirred at 8 ° C. After dropping 0.59 mL (4.74 mmol, 1.05 eq.) Of ClCO 2 Ph, raising the temperature to room temperature and stirring for 1 hour, completion of the CM conversion reaction was confirmed by HPLC. 1.33 g (4.51 mmol, 1.0 eq.) Of Boc-DAP-OtBu was added, 1.92 mL (13.76 mmol, 3.05 eq.) Of TEA was added dropwise, and the mixture was stirred at 40 ° C. for 1 hour. After confirming the completion of the urea conversion reaction by HPLC, the mixture was concentrated until the solvent was completely removed. 1.0 mL of water and 2.0 mL of concentrated hydrochloric acid (22.6 mmol, 5.0 eq.) Were added, and the mixture was stirred at 50 ° C. for 4 hours. After confirming the completion of deprotection by HPLC, MeCN 7.5 mL (7.5 L / kg), 1 M HCl aq. After adding 4.5 mL, the mixture was stirred at 5 ° C. overnight. The precipitated solid was filtered under reduced pressure, washed with 3.0 mL (3.0 L / kg) of MeCN, and then dried at 60 ° C. overnight to obtain 1.28 g of the desired product as a white solid (net 1.18 g, 77). .0%).[0030](Example 6)
(Step 1)
3-({[(2S) -2-amino-3-methoxy-3-oxopropyl] carbamoyl} amino) -5-chloro-4-methylbenzene-1-sulfonic acid ( Synthesis of Compound 5 )
[Chemical formula 20] To
5 g (22.56 mmol) of ACTS, 37.5 mL (7.5 L / kg vs ACTS) of MeCN and 3.81 mL (47.38 mmol, 2.1 eq.) Of Py were added. The mixture was stirred at 25 ° C. 2.99 mL (23.68 mmol, 1.05 eq.) Of ClCO 2 Ph was added dropwise, and after stirring for 30 minutes, the completion of the CM reaction was confirmed by HPLC. 5.92 g (23.23 mmol, 1.03 eq.) Of Boc-DAP-OMe was added, 9.75 mL (69.93 mmol, 3.1 eq.) Of TEA was added dropwise, and the mixture was stirred at 25 ° C. for 3 hours. 0.4 g (1.58 mmol, 0.07 eq.) Of Boc-DAP-OMe and 0.22 mL (1.58 mmol, 0.07 eq.) Of TEA were added, and the completion of the ureaization reaction was confirmed by HPLC. 7.32 mL (112.8 mmol, 5.0 eq.) Of MsOH was added, the temperature was raised to 50 ° C., and the mixture was stirred for 4 hours. After confirming the completion of deprotection by HPLC, the mixture was cooled to 25 ° C. and 37.5 mL (7.5 L / kg) of MeCN and 7.5 mL (1.5 L / kg) of water were added to precipitate a solid. It was cooled to 5 ° C. and aged for 16 hours. The precipitated solid was filtered under reduced pressure, washed with 20 mL (4.0 L / kg) of water / MeCN (1/2), and then dried under reduced pressure at 40 ° C. for 5 hours to obtain 7.72 g of the target product as a white solid (772 g of the target product). net 7.20 g, 87.3%).
1H-NMR (400MHz, DMSO-d6): δ 8.39 (bs, 3H), 8.16 (d, 1H, J = 1.2Hz), 7.90 (d, 1H, J = 1.6Hz), 7.28 (d, 1H, J = 1.6Hz), 6.78 (t, 1H, J = 5.6Hz), 4.20-4.10 (m, 1H), 3.77 (s, 3H), 3.70-3.60 (m, 1H), 3.55-3.45 (m, 1H) , 2.21 (s, 3H)
HRMS (FAB  ): calcd for m / z 364.0369 (MH), found The m / z 364.0395 (MH)

(step 2)
[Formula 21]

compound 5 10.64 g (net Non 10.0 g, To 27.34 mmol), 18 mL of water (1.8 L / kg vs. compound 5 ) was added and stirred at 8 ° C. 3.42 mL (57.41 mmol, 2.1 eq.) Of a 48% aqueous sodium hydroxide solution was added dropwise, and the mixture was washed with 1.0 mL (1.0 L / kg) of water and then stirred at 8 ° C. for 15 minutes. After confirming the completion of hydrolysis by HPLC, the temperature was raised to 25 ° C. and 48% HBr aq. The pH was adjusted to 5.8 by adding about 3.55 mL. After confirming the precipitation of the target product by dropping 65 mL (6.5 L / kg) of IPA, the mixture was aged for 1 hour. 81 mL (8.1 L / kg) of IPA was added dropwise and aged at 8 ° C. overnight. The precipitated solid was filtered under reduced pressure, washed with 20 mL (2.0 L / kg) of IPA, and then dried under reduced pressure at 40 ° C. for 4 hours to obtain 10.7 g of the desired product as a white solid (net 9.46 g, 92. 6%).
1 H-NMR (400MHz, DMSO-d6): δ8.76 (s, 1H), 7.91 (d, 1H, J = 1.6Hz), 8.00-7.50 (bs, 2H), 7.24 (d, 1H, J = 1.6Hz), 7.20 (t, 1H, J = 5.6Hz), 3.58-3.54 (m, 1H), 3.47-3.43 (m, 1H), 3.42-3.37 (m, 1H), 2.23 (s, 3H)[0031](Example 7)
(Step 1)
[Chemical
formula 22] For 10.0 g (45.1 mmol) of ACTS, 50 mL (5.0 L / kg vs ACTS) of MeCN, 7.46 mL (92.5 mmol, 2.05 eq. ) Was added, and the mixture was stirred at 8 ° C. 5.98 mL (47.4 mmol, 1.05 eq.) Of ClCO 2 Ph was added dropwise, the temperature was raised to 25 ° C., and the mixture was stirred for 1 hour, and then the completion of the CM reaction was confirmed by HPLC. 100 ml of acetone (10.0 L / kg vs ACTS) was added, the mixture was cooled to 8 ° C., and aged for 1 hour. The precipitated solid was filtered under reduced pressure, washed with 30 mL of acetone (3.0 L / kg vs ACTS), and then dried under reduced pressure at 60 ° C. for 2 hours to obtain 17.8 g of the target product (net 14.4 g as a free form). Quant).
1 H-NMR (400MHz, DMSO-d6): δ 9.76 (bs, 1H), 8.93-8.90 (m, 2H), 8.60-8.50 (m, 1H), 8.10-8.00 (m, 2H), 7.60 (s , 1H), 7.50-7.40 (m, 3H), 7.30-7.20 (m, 3H), 2.30 (s, 3H)

(Step 2)
[Chemical 23]

Compound 6 To 5.0 g (11.9 mmol), 50 ml of acetonitrile and 3.53 g (11.9 mmol) of Boc-DAP-OtBu were added, and the mixture was stirred at 8 ° C. 3.5 ml (25 mmol) of triethylamine was added dropwise, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and 25 ml of ethyl acetate and 5 ml of water were added for extraction. The organic layer was washed with 5 ml of water, the solvent was distilled off, 50 ml of tetrahydrofuran was added, the mixture was cooled to 8 ° C., and aged for 1 hour. The precipitated solid was filtered under reduced pressure, washed with 10 ml of tetrahydrofuran, and dried under reduced pressure at 60 ° C. overnight to obtain 6.3 g of the desired product as a white solid.[0032](Example 8)
[Chemical
formula 24] For 1.08 g (4.89 mmol) of ACTS, 8.1 mL (7.5 L / kg vs ACTS) of MeCN and 827 μL (10.27 mmol, 2.1 eq.) Of Py were added. In addition, it was stirred at room temperature. ClCO 2 Ph 649 μL (5.14 mmol, 1.05 eq.) Was added dropwise, and the mixture was stirred for 30 minutes, and then the completion of the CM conversion reaction was confirmed by HPLC. 1.48 g (5.04 mmol, 1.03 eq.) Of Cbz-DAP-OMe HCl was added, 2.1 mL (15.17 mmol, 3.1 eq.) Of TEA was added dropwise, and the mixture was stirred at room temperature for about 5 hours. After confirming the completion of the urea conversion reaction by HPLC, the mixture was concentrated until the solvent was completely removed. 15.0 mL of 30% HBr / AcOH was added, and the mixture was stirred at room temperature for 70 minutes, and the completion of deprotection was confirmed by HPLC. After concentration to dryness, 10 mL of water and 4 mL of AcOEt were added to carry out an extraction operation, and then the aqueous layer was stirred at room temperature overnight. The precipitated solid was filtered under reduced pressure, washed with 15 mL of water and 10 mL of AcOEt, and then dried at 40 ° C. for 3 hours to obtain 1.45 g of the desired product as a white solid (58.8%).[0033](Example 9) Synthesis of compound 7 ( methyl ester of compound 1 )
using phenyl chloroformate as a carbonyl group introduction reagent [Chemical  formula 25] MeCN 73 mL (14.6 L) with respect to 5.00 g (22.4 mmol) of ACHB. / Kg vs ACHB), Py 3.8 mL (47 mmol, 2.1 eq.), Was added and stirred at 40 ° C. After adding 3.0 mL (24 mmol, 1.05 eq.) Of ClCO 2 Ph and stirring for 30 minutes, the completion of the CM conversion reaction was confirmed by HPLC. 5.87 g (23 mmol, 1.0 eq.) Of Boc-DAP-OMe was added, washed with a small amount of MeCN, 9.7 mL (70 mmol, 3.1 eq.) Of TEA was added dropwise, and the mixture was stirred at 40 ° C. for 3 hours. After confirming the completion of the urea conversion reaction by HPLC, the mixture was cooled to room temperature. 7.3 mL (112 mmol, 5.0 eq.) Of MsOH was added, the temperature was raised to 50 ° C., and the mixture was stirred for 7 hours. Further, 1.5 mL (23 mmol, 1.0 eq.) Of MsOH was added, and the reaction was carried out at 50 ° C. overnight. After confirming the completion of deprotection by HPLC, 90 mL of acetone was added to the reaction solution, and the mixture was cooled to room temperature. The precipitated solid was obtained and dried under reduced pressure at 60 ° C. to obtain the desired product. 1 H-NMR (400MHz, DMSO-d6): δ 7.22 (m, 1H), 7.14 (m, 1H), 4.36 (m, 1H), 3.80 (s, 3H), 3.20-3.40 (m, 2H).[0034](Example 10) Synthesis of
compound 5 using 4-chlorophenylchloroformate as a carbonyl group-introducing reagent
[Chemical formula 26] For
5.00 g (22.6 mmol) of ACTS, 73 mL (14.6 L / kg vs ACTS) of MeCN, 3.8 mL (47 mmol, 2.1 eq.) Of Py was added and stirred at 40 ° C. After adding 3.25 mL (23.7 mmol, 1.05 eq.) Of 4-chloroformic acid 4-chlorophenylate and stirring at 40 ° C. for 1.5 hours, completion of the CM conversion reaction was confirmed by HPLC. Add 5.92 g (23.2 mol, 1.0 eq.) Of Boc-DAP-OMe, wash with a small amount of MeCN, add 9.7 mL (70 mmol, 3.1 eq.) Of TEA, and stir at 40 ° C. for 2 hours. did. After confirming the completion of the urea conversion reaction by HPLC, the mixture was cooled to room temperature. 7.3 mL (113 mmol, 5.0 eq.) Of MsOH was added, the temperature was raised to 50 ° C., and the mixture was stirred for 3.5 hours. After confirming the completion of deprotection by HPLC, the reaction solution was cooled to room temperature, 7.5 mL of water was added, the mixture was cooled to 8 ° C., and the mixture was stirred overnight. The precipitated solid was filtered, washed with a small amount of MeCN water, and dried at 60 ° C. overnight to obtain 6.94 g of the desired product as a white solid (84.1%).[0035](Example 11) Synthesis of
compound 5 using 4-nitrophenyl chloroformate as a carbonyl group-introducing reagent
[Chemical formula 27]
73 mL (14.6 L / kg vs. ACTS) of MeCN with respect to 5.00 g (22.6 mmol) of ACTS. , Py 3.8 mL (47 mmol, 2.1 eq.), And stirred at 40 ° C. 4.77 mL (23.7 mmol, 1.05 eq.) Of 4-nitrophenyl chloroformate was added dropwise, and the mixture was stirred at 40 ° C. for 3.5 hours, and then the completion of the CM reaction was confirmed by HPLC. Add 5.92 g (23.2 mmol, 1.0 eq.) Of Boc-DAP-OMe, wash with a small amount of MeCN, add 9.7 mL (70 mmol, 3.1 eq.) Of TEA, and stir at 40 ° C. for 2 hours. did. After confirming the completion of the urea conversion reaction by HPLC, the mixture was cooled to room temperature. 7.3 mL (113 mmol, 5.0 eq.) Of MsOH was added, the temperature was raised to 50 ° C., and the mixture was stirred for 3.5 hours. After confirming the completion of deprotection by HPLC, the reaction solution was cooled to room temperature, 7.5 mL of water was added, the mixture was cooled to 8 ° C., and the mixture was stirred overnight. The precipitated solid was filtered, washed with a small amount of MeCN water, and dried at 60 ° C. overnight to obtain 5.96 g of the desired product as a white solid (72.2%).[0036](Example 12) Synthesis of
compound 3 using Boc-DAP-OH
[Chemical 28]
MeCN 73 mL (14.6 L / kg vs ACTS), Py 3.8 mL, relative to 5.00 g (22.6 mmol) of ACTS. (47 mmol, 2.1 eq.) Was added and stirred at 40 ° C. After adding 3.00 mL (23.8 mmol, 1.05 eq.) Of phenylchloroformate and stirring at 40 ° C. for 0.5 hours, the completion of the CM conversion reaction was confirmed by HPLC (CM conversion reaction product: 4.37 minutes). , ACTS: N.D.). Add 4.75 g (23.2 mmol, 1.0 eq.) Of Boc-DAP-OH, wash with a small amount of MeCN, add 9.7 mL (70 mmol, 3.1 eq.) Of TEA, and stir at 40 ° C. for 2 hours. did. After confirming the completion of the urea-forming reaction by HPLC (urea-forming reaction product: 3.81 minutes, CM-forming reaction product: 0.02 area% vs. urea-forming reaction product), the mixture was cooled to room temperature. By adding 7.3 mL (113 mmol, 5.0 eq.) Of MsOH, raising the temperature to 50 ° C., stirring for 4.5 hours, and further adding 1.5 mL (23 mmol, 1.0 eq.) Of MsOH, stirring for 1 hour. , The formation of the target product was confirmed by HPLC (Compound 3: 2.49 minutes, urea conversion reaction product: 0.50 area vs. compound 3, area of compound 3 with respect to the total area excluding pyridine: 71.0 area).

PATENT

JP 6510136

PATENT

WO 2020204117

Reference Example 1
Synthesis of 3-{[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonate sodium (Compound A1) 
(Step 1)
Synthesis of
3 -({[(2S) -2-amino-3-methoxy-3-oxopropyl] carbamoyl} amino) -5-chloro-4-methylbenzene-1-sulfonic acid 3-amino- 37.5 mL (7.5 L / kg vs ACTS) of acetonitrile and 3.81 mL (47.38 mmol, 2.1 eq.) Of pyridine against 5 g (22.56 mmol) of 5-chloro-4-methylbenzenesulfonic acid (ACTS). Was added and stirred at 25 ° C. 2.99 mL (23.68 mmol, 1.05 eq.) Of ClCO 2 Ph was added dropwise, and after stirring for 30 minutes, the completion of the carbamate reaction was confirmed by HPLC. Add 5.92 g (23.23 mmol, 1.03 eq.) Of 3-amino-N- (tert-butoxycarbonyl) -L-alanine methyl ester hydrochloride and 9.75 mL (69.93 mmol, 3.1 eq.) Triethylamine. Was added dropwise, and the mixture was stirred at 25 ° C. for 3 hours. Add 0.4 g (1.58 mmol, 0.07 eq.) Of 3-amino-N- (tert-butoxycarbonyl) -L-alanine methyl ester hydrochloride and 0.22 mL (1.58 mmol, 0.07 eq.) Of triethylamine. Then, the completion of the urea conversion reaction was confirmed by HPLC. 7.32 mL (112.8 mmol, 5.0 eq.) Of methanesulfonic acid was added, the temperature was raised to 50 ° C., and the mixture was stirred for 4 hours. After confirming the completion of deprotection by HPLC, the mixture was cooled to 25 ° C. and 37.5 mL (7.5 L / kg) of acetonitrile and 7.5 mL (1.5 L / kg) of water were added to precipitate a solid. It was cooled to 5 ° C. and aged for 16 hours. The precipitated solid was filtered under reduced pressure, washed with 20 mL (4.0 L / kg) of water / acetonitrile (1/2), and then dried under reduced pressure at 40 ° C. for 5 hours to obtain 7.72 g of the desired product as a white solid (. net 7.20 g, 87.3%).

1 H-NMR (400MHz, DMSO-d6): δ 8.39 (bs, 3H), 8.16 (d, 1H, J = 1.2Hz), 7.90 (d, 1H, J = 1.6Hz), 7.28 (d, 1H, J = 1.6Hz), 6.78 (t, 1H, J = 5.6Hz), 4.20-4.10 (m, 1H), 3.77 (s, 3H), 3.70-3.60 (m, 1H), 3.55-3.45 (m, 1H) ), 2.21 (S, 3H)HRMS (FAB  ): Calcd For M / Z 364.0369 (MH & lt;), Found M / Z 364.0395 (MH & lt;) 
(Step 2)
(2)
Compound obtained in step 1 of synthesis of 3-{[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonate . To 64 g (net 10.0 g, 27.34 mmol), 18 mL of water (1.8 L / kg vs. the compound of Step 1) was added, and the mixture was stirred at 8 ° C. 3.42 mL (57.41 mmol, 2.1 eq.) Of a 48% aqueous sodium hydroxide solution was added dropwise, and the mixture was washed with 1.0 mL (1.0 L / kg) of water and then stirred at 8 ° C. for 15 minutes. After confirming the completion of hydrolysis by HPLC, the temperature was raised to 25 ° C. and 48% HBr aq. About 3.55 mL was added to adjust the pH to 5.8. After confirming the precipitation of the desired product by dropping 65 mL (6.5 L / kg) of isopropyl alcohol, the mixture was aged for 1 hour. 81 mL (8.1 L / kg) of isopropyl alcohol was added dropwise and the mixture was aged at 8 ° C. overnight. The precipitated solid was filtered under reduced pressure, washed with 20 mL (2.0 L / kg) of isopropyl alcohol, and then dried under reduced pressure at 40 ° C. for 4 hours to obtain 10.7 g of the desired product as a white solid (net 9.46 g, 92). .6%).
1 H-NMR (400MHz, DMSO-d6): δ8.76 (s, 1H), 7.91 (d, 1H, J = 1.6Hz), 8.00-7.50 (bs, 2H), 7.24 (d, 1H, J = 1.6Hz), 7.20 (t, 1H, J = 5.6Hz), 3.58-3.54 (m, 1H), 3.47-3.43 (m, 1H), 3.42-3.37 (m, 1H), 2.23 (s, 3H)

キッセイ薬品工業株式会社

///////////Upacicalcet sodium hydrate, Upasita, ウパシカルセトナトリウム水和物 , APPROVALS 2021, JAPAN 2021, Upacicalcet

wdt

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Meglimin hydrochloride


Imeglimin hydrochloride (JAN).png
Imeglimin.svg

Meglimin hydrochloride

Imeglimin
hydrochloride

Twymeeg

FormulaC6H13N5. HCl
CAS775351-61-6 (HCl). , C6H14ClN5 191.66CAS 775351-65-0, FREEFORM 155.20
Mol weight191.6619

AntidiabeticAPPROVED PMDA JAPAN2021/6/23, イメグリミン塩酸塩

(4R)-6-N,6-N,4-trimethyl-1,4-dihydro-1,3,5-triazine-2,6-diamine

DB12509

NCGC00378621-02

HY-14771

Q6003719

UNII-UU226QGU97

UU226QGU97

1,3,5-Triazine-2,4-diamine,1,6-dihydro-N,N,6-trimethyl-,(+)-(9CI)

(4R)-6-N,6-N,4-trimethyl-1,4-dihydro-1,3,5-triazine-2,6-diamine

Imeglimin [INN]

Emd 387008 (R-imeglimin) HCl

EMD-387008

JAPAN

Twymeeg Tablets 500 mg
(Sumitomo Dainippon Pharma Co., Ltd.)

japan flag waving animated gif | Japan flag, Japanese flag, Flag

Imeglimin is an experimental drug being developed as an oral anti-diabetic.[1][2] It is an oxidative phosphoryl

Imeglimin (brand name Twymeeg) is an oral anti-diabetic medication.[1][2] It was approved for use in Japan in June 2021.[3]

It is an oxidative phosphorylation blocker that acts to inhibit hepatic gluconeogenesis, increase muscle glucose uptake, and restore normal insulin secretion. It is the first approved drug of this class of anti-diabetic medication.

A review of phenformin, metformin, and imeglimin - Yendapally - 2020 - Drug Development Research - Wiley Online Library
A review of phenformin, metformin, and imeglimin - Yendapally - 2020 - Drug Development Research - Wiley Online Library

PATENT

https://patents.google.com/patent/WO2012072663A1/enEXAMPLESExample 1 : Synthesis and isolation of (+)-2-amino-3,6-dihydro-4-dimethylamino-6- methyl-l,3,5-triazine hydrochloride by the process according to the invention

Preliminary step: Synthesis of racemic 2-amino-3,6-dihydro-4-dimethylamino- 6-methyl-l,3,5-triazine hydrochloride:

Figure imgf000013_0001

Metformin hydrochloride is suspended in 4 volumes of isobutanol. Acetaldehyde diethylacetal (1.2 eq.) and para-toluenesulfonic acid (PTSA) (0.05 eq) are added and the resulting suspension is heated to reflux until a clear solution is obtained. Then 2 volumes of the solvent are removed via distillation and the resulting suspension is cooled to 20°C. The formed crystals are isolated on a filter dryer and washed with isobutanol (0.55 volumes). Drying is not necessary and the wet product can be directly used for the next step.Acetaldehyde diethylacetal can be replaced with 2,4,6-trimethyl-l,3,5-trioxane (paraldehyde).- Steps 1 and 2: formation of the diastereoisomeric salt and isolation of the desired diastereoisomer

Figure imgf000013_0002

Racemic 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine hydrochloride wet with isobutanol (obtained as crude product from preliminary step without drying) and L-(+)-Tartaric acid (1 eq.) are dissolved in 2.2 volumes of methanol at 20-40°C. The obtained clear solution is filtered and then 1 equivalent of triethylamine (TEA) is added while keeping the temperature below 30°C. The suspension is heated to reflux, stirred at that temperature for 10 minutes and then cooled down to 55°C. The temperature is maintained at 55°C for 2 hours and the suspension is then cooled to 5- 10°C. After additional stirring for 2 hours at 5-10°C the white crystals are isolated on a filter dryer, washed with methanol (2 x 0.5 Vol) and dried under vacuum at 50°C. The yield after drying is typically in the range of 40-45%

– Steps 3 and 4: transformation of the isolated diastereoisomer of the tartrate salt into the hydrochloride salt and recovery of the salt

Figure imgf000014_0001

γ ethanol HN^NH(+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt is suspended in 2 volumes of ethanol and 1.02 equivalents of HCl-gas are added under vacuum (-500 mbar). The suspension is heated to reflux under atmospheric pressure (N2) and 5% of the solvent is removed via distillation. Subsequent filtration of the clear colourless solution into a second reactor is followed by a cooling crystallization, the temperature is lowered to 2°C. The obtained suspension is stirred at 2°C for 3 hours and afterwards the white crystals are isolated with a horizontal centrifuge. The crystal cake is washed with ethanol and dried under vacuum at 40°C. The typical yield is 50-55% and the mother liquors can be used for the recovery of about 25-30%) of (+)-2-amino- 3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate.Example 2: Modification of the solvent of steps 3 and 4

– Steps 3 and 4: transformation of the isolated diastereoisomer of the tartrate salt into the hydrochloride salt and recovery of the salt

Figure imgf000014_0002

HN^NH acetone HN^NH(+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt synthesized according to steps 1 and 2 of example 1 is suspended in 1 volume (based on total amount of (+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt) of acetone at 20°C. To this suspension 1.01 equivalents of 37% Hydrochloric acid are added. The suspension is heated to reflux under atmospheric pressure (N2) and water is added until a clear solution is obtained. 1.5 vol of acetone are added at reflux temperature. The compound starts crystallising and the obtained suspension is kept at reflux for 2 hours followed by a cooling crystallization to 0°C. The obtained suspension is stirred at 0°C for 2 hours and the white crystals are isolated by centrifugation. The crystal cake is washed with isopropanol and dried under vacuum at 40°C in a continuous drying oven.

References

  1. ^ Vuylsteke V, Chastain LM, Maggu GA, Brown C (September 2015). “Imeglimin: A Potential New Multi-Target Drug for Type 2 Diabetes”Drugs in R&D15 (3): 227–32. doi:10.1007/s40268-015-0099-3PMC 4561051PMID 26254210.
  2. ^ Dubourg J, Fouqueray P, Thang C, Grouin JM, Ueki K (April 2021). “Efficacy and Safety of Imeglimin Monotherapy Versus Placebo in Japanese Patients With Type 2 Diabetes (TIMES 1): A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 3 Trial”Diabetes Care44 (4): 952–959. doi:10.2337/dc20-0763PMID 33574125.
  3. ^ Poxel SA (June 23, 2021). “Poxel and Sumitomo Dainippon Pharma Announce the Approval of TWYMEEG® (Imeglimin hydrochloride) for the Treatment of Type 2 Diabetes in Japan” (Press release).

Clinical data
Trade namesTwymeeg
Legal status
Legal statusRx-only in Japan
Identifiers
showIUPAC name
CAS Number775351-65-0
PubChem CID24812808
ChemSpider26232690
UNIIUU226QGU97
CompTox Dashboard (EPA)DTXSID50228237 
Chemical and physical data
FormulaC6H13N5
Molar mass155.205 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

/////////Imeglimin hydrochloride, Twymeeg, JAPAN 2021, APPROVALS 2021, Antidiabetic, イメグリミン塩酸塩, ATI DIABETES, DIABETES, Imeglimin

CC1N=C(NC(=N1)N(C)C)N.Cl

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Diclofenac etalhyaluronate sodium


Display Structure of DICLOFENAC ETALHYALURONATE SODIUM
2D chemical structure of 1398396-25-2

Diclofenac etalhyaluronate sodium

RN: 1398396-25-2
UNII: LG1II3835L

Molecular Formula, [(C30-H35-Cl2-N3-O12)a-(C14-H20-N-Na-O11)b]n-H2-O

Molecular Weight, 1101.8195

HYALURONIC ACID PARTLY AMIDIFIED WITH 2-(2-(2-((2,6-DICHLOROPHENYL)AMINO)PHENYL)ACETYLOXY)ETHANAMINE, SODIUM SALT

HYALURONAMIDE, N-(2-((2-(2-((2,6-DICHLOROPHENYL)AMINO)PHENYL)ACETYL)OXY)ETHYL), SODIUM SALT

SI 613

APPROVED PMDA JAPAN 2021/3/23, Joycle

Anti-inflammatory, Joint function improving agent

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Treatment of Signs and Symptoms of Osteoarthritis of the Knee

Chemical structure of N-[2-[[2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetyl]oxy]ethyl]hyaluronamide (diclofenac etalhyaluronate, SI-613)

Diclofenac Etalhyaluronate Sodium

Sodium hyaluronate partially amidated with 2- (2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetyloxy) ethaneamine

Hyaluronic acid sodium salt partly amidified with 2- (2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetyloxy) ethanamine

[(C 30 H 35 Cl 2 N 3 O 12 ) a (C 14 H 20 NNaO 11 ) b ] n
[ 1398396-25-2 ]

Hyaluronic acid/non-steroidal anti-inflammatory drug; Hyaluronic acid/NSAID; JOYCLU; ONO 5704; ONO-5704/SI-613; SI-613

  • OriginatorSeikagaku Corporation
  • DeveloperOno Pharmaceutical; Seikagaku Corporation
  • ClassAmides; Analgesics; Antirheumatics; Drug conjugates; Glycosaminoglycans; Nonsteroidal anti-inflammatories
  • Mechanism of ActionCyclooxygenase inhibitors
  • RegisteredOsteoarthritis
  • Phase IITendinitis
  • 23 Mar 2021Registered for Osteoarthritis in Japan (Intra-articular)
  • 25 Sep 2020Phase II for Osteoarthritis is still ongoing in USA (Seikagaku Corporation pipeline, September 2020)
  • 25 Sep 2020Phase II for Tendinitis is still ongoing in Japan (Seikagaku Corporation pipeline, September 2020)

In today’s aging society, osteoarthritis (hereinafter also referred to as “OA” in the present specification), which is a dysfunction caused by joint pain and joint degeneration, is the most common joint disease in the world. It is one of the major causes of physical disorders that interfere with daily life in the elderly. Further, as a disease accompanied by swelling and pain in joints, rheumatoid arthropathy (hereinafter, also referred to as “RA” in the present specification), which is polyarthritis, is known. In RA as well, when the condition progresses over a long period of time, cartilage and bones are destroyed and degeneration or deformation occurs, resulting in physical disorders that interfere with daily life, such as narrowing the range in which joints can be moved.

Currently, preparations using hyaluronic acid and its derivatives are used as medicines for arthropathy such as osteoarthritis and rheumatoid arthropathy. Hyaluronic acid preparations are usually formulated as injections, and for the purpose of improving dysfunction due to arthropathy and suppressing pain through the lubricating action, shock absorption action, cartilage metabolism improving action, etc. of hyaluronic acid, the affected knee, It is administered directly to joints such as the shoulders. Commercialized hyaluronic acid preparations include, for example, those containing purified sodium hyaluronate as an active ingredient (for example, Alz (registered trademark) and Svenir (registered trademark)). The preparation requires continuous administration of 3 to 5 times at a frequency of once a week.
In addition, preparations containing crosslinked hyaluronan as an active ingredient require three consecutive doses once a week (for example, Synvisc®), or treatment is completed with a single dose. For single dose administration (eg, Synvisc-One®, Gel-One®, MONOVISC®) are known.On the other hand, steroids and non-steroidal anti-inflammatory compounds are known as quick-acting drugs, and are also used for treatments aimed at relieving joint pain caused by OA and RA. For example, the steroid triamcinolone acetonide has been used as a therapeutic target for joint diseases such as rheumatoid arthritis. Triamcinolone acetonide is commercially available as a drug that is injected intra-articularly and requires administration every 1 to 2 weeks for treatment. Further, as non-steroidal anti-inflammatory compounds, for example, ointments containing diclofenac sodium as an active ingredient and oral administration agents are known.It is also known that a mixture or a conjugate of hyaluronic acid or a derivative thereof and a steroid or a non-steroidal anti-inflammatory compound is used as an active ingredient. For example, a mixture of crosslinked hyaluronic acid and triamcinolone hexaacetonide (CINGAL®) has been commercialized as a single-dose drug. Further, a compound in which hyaluronic acid or a derivative thereof is linked to a steroid or a non-steroidal anti-inflammatory compound is also known. For example, Patent Documents 1 and 2 describe derivatives in which an anti-inflammatory compound is introduced into hyaluronic acid via a spacer. These aim to achieve both fast-acting pain relief and long-term pain relief through improvement of dysfunction. However, it has not yet reached the stage where it can be said that sufficient treatment methods for OA and RA have been established and provided.

PATENT

 WO 2018168920

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018168920

<Synthesis Example>
 Aminoethanol-diclofenac-introduced sodium hyaluronate (test substance) was synthesized according to the method described in Examples of International Publication No. 2005/066241 (hyaluronic acid weight average molecular weight: 800,000, introduction rate). : 18 mol%).
 More specifically, it was synthesized by the following method.
 2.155 g (10.5 mmol) of 2-bromoethylamine hydrobromide is dissolved in 20 mL of dichloromethane, 1.436 mL (10.5 mmol) of triethylamine is added under ice-cooling, and di-tert-butyl-dicarbonate (Boc) is added. 2 O) 2.299 g (10.5 mmol) of a dichloromethane solution of 5 mL was added and stirred. After stirring at room temperature for 90 minutes, ethyl acetate was added, and the mixture was washed successively with 5 wt% citric acid aqueous solution, water and saturated brine. After dehydration with sodium sulfate, the solvent was distilled off under reduced pressure to obtain Boc-aminoethyl bromide.
 5 mL of a dimethylformamide (DMF) solution of 2.287 g (10.2 mmol) of Boc-aminoethyl bromide obtained above is ice-cooled, 6 mL of a DMF solution of 3.255 g (10.2 mmol) of diclofenac sodium is added, and the mixture is added at room temperature. Stirred overnight. The mixture was stirred at 60 ° C. for 11 hours and at room temperature overnight. Ethyl acetate was added, and the mixture was sequentially separated and washed with a 5 wt% aqueous sodium hydrogen carbonate solution, water, and saturated brine. After dehydration with sodium sulfate, ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (toluene: ethyl acetate = 20: 1 (v / v), 0.5% by volume triethylamine) to obtain Boc-aminoethanol-diclofenac.
 2.108 g (4.80 mmol) of Boc-aminoethanol-diclofenac obtained above was dissolved in 5 mL of dichloromethane, 20 mL of 4M hydrochloric acid / ethyl acetate was added under ice-cooling, and the mixture was stirred for 2.5 hours. Diethyl ether and hexane were added and precipitated, and the precipitate was dried under reduced pressure. As a result, aminoethanol-diclofenac hydrochloride was obtained. Structure 1 was identified by-NMR
  H: 1 H-NMR (500 MHz, CDCl 3 ) [delta] (ppm) = 3.18 (2H, t, NH 2 CH 2 CH 2 O-), 3.94 (2H, s, Ph-CH 2 -CO), 4.37 (2H, t, NH 2 CH 2 CH 2 O-), 6.47-7.31 (8H, m, Aromatic H, NH).
 After dissolving 500 mg (1.25 mmol / disaccharide unit) of hyaluronic acid having a weight average molecular weight of 800,000 in 56.3 mL of water / 56.3 mL of dioxane, imide hydroxysuccinate (1 mmol) / 0.5 mL of water, water-soluble carbodiimide Hydrochloride (WSCI / HCl) (0.5 mmol) / water 0.5 mL, aminoethanol-diclofenac hydrochloride (0.5 mmol) / (water: dioxane = 1: 1 (v / v), 5 mL obtained above ) Was added in sequence, and the mixture was stirred all day and night. 7.5 mL of a 5 wt% sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the mixture was stirred for about 4 hours. 215 μL of a 50% (v / v) acetic acid aqueous solution was added to the reaction solution for neutralization, and then 2.5 g of sodium chloride was added and the mixture was stirred. 400 ml of ethanol was added to precipitate, and the precipitate was washed twice with an 85% (v / v) aqueous ethanol solution, twice with ethanol, and twice with diethyl ether, dried under reduced pressure overnight at room temperature, and aminoethanol-diclophenac. Introduction Sodium hyaluronate (test substance) was obtained. The introduction rate of diclofenac measured by a spectrophotometer was 18 mol%.

PATENT

 WO 2018168921

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018168921

//////////Diclofenac etalhyaluronate sodium, JOYCLU, ONO 5704, ONO-5704/SI-613, SI 613, JAPAN 2021, Joycle, APPROVALS 2021

#Diclofenac etalhyaluronate sodium, #JOYCLU, #ONO 5704, #ONO-5704/SI-613, #SI 613, #JAPAN 2021, #Joycle, #APPROVALS 2021

Anamorelin hydrochloride


Anamorelin.svg

Anamorelin249921-19-5[RN]
3-{(2R)-3-{(3R)-3-Benzyl-3-[(trimethylhydrazino)carbonyl]-1-piperidinyl}-2-[(2-methylalanyl)amino]-3-oxopropyl}-1H-indole
3-Piperidinecarboxylic acid, 1-[(2R)-2-[(2-amino-2-methyl-1-oxopropyl)amino]-3-(1H-indol-3-yl)-1-oxopropyl]-3-(phenylmethyl)-, 1,2,2-trimethylhydrazide, (3R)-8846анаморелинأناموريلين阿那瑞林 

FormulaC31H42N6O3
Molar mass546.716 g·mol−1

Anamorelin.svg.HCL

Anamorelin hydrochloride

3-Piperidinecarboxylic acid, 1-[(2R)-2-[(2-amino-2-methyl-1-oxopropyl)amino]-3-(1H-indol-3-yl)-1-oxopropyl]-3-(phenylmethyl)-, 1,2,2- trimethylhydrazide, hydrochloride (1:1), (3R)-

FormulaC31H42N6O3. HCl
CAS861998-00-7
Mol weight583.1645

APPROVED JAPAN PMDA Adlumiz, 22/1/2021

アナモレリン塩酸塩

ONO-7643RC-1291ST-1291

Antineoplastic, Growth hormone secretagogue receptor (GHSR) agonist

Anamorelin is a non-peptidic ghrelin mimetic
Treatment of cancer anorexia and cancer cachexia

Anamorelin hydrochloride has been submitted New Drug Application (NDA) for the treatment of cachexia in non-small cell lung cancer (NSCLC) patients.

It was originally developed by Novo Nordisk, then it was licensed to Ono and Helsinn Therapeutics for the treatment of cachexia and anorexia in cancer patients.

Anamorelin hydrochloride has been submitted New Drug Application (NDA) for the treatment of cachexia in non-small cell lung cancer (NSCLC) patients.

It was originally developed by Novo Nordisk, then it was licensed to Ono and Helsinn Therapeutics for the treatment of cachexia and anorexia in cancer patients.

Company:Novo Nordisk (Originator) , Helsinn,Ono

Anamorelin (INN) (developmental code names ONO-7643RC-1291ST-1291), also known as anamorelin hydrochloride (USANJAN), is a non-peptideorally-activecentrally-penetrant, selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) with appetite-enhancing and anabolic effects which is under development by Helsinn Healthcare SA for the treatment of cancer cachexia and anorexia.[2][3][4]

Anamorelin significantly increases plasma levels of growth hormone (GH), insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein 3 (IGFBP-3) in humans, without affecting plasma levels of prolactincortisolinsulinglucoseadrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), or thyroid-stimulating hormone (TSH).[3][5] In addition, anamorelin significantly increases appetite, overall body weightlean body mass, and muscle strength,[4][5] with increases in body weight correlating directly with increases in plasma IGF-1 levels.[3]

As of February 2016, anamorelin has completed phase III clinical trials for the treatment of cancer cachexia and anorexia associated with non-small-cell lung carcinoma.[6][7]

On 18 May 2017, the European Medicines Agency recommended the refusal of the marketing authorisation for the medicinal product, intended for the treatment of anorexia, cachexia or unintended weight loss in patients with non-small cell lung cancer. Helsinn requested a re-examination of the initial opinion. After considering the grounds for this request, the European Medicines Agency re-examined the opinion, and confirmed the refusal of the marketing authorisation on 14 September 2017.[8] The European Medicines Agency concluded that the studies show a marginal effect of anamorelin on lean body mass and no proven effect on hand grip strength or patients’ quality of life. In addition, following an inspection at clinical study sites, the agency considered that the safety data on the medicine had not been recorded adequately. Therefore, the agency was of the opinion that the benefits of anamorelin did not outweigh its risks.[9]

EMA

The chemical name of anamorelin hydrochloride is 2-Amino-N-((R)-1-((R)-3-benzyl-3-(1,2,2-trimethylhydrazine-1-carbonyl)piperidin-1-yl)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)-2-methylpropanamide hydrochloride corresponding to the molecular formula C31H42N6O3•HCl and has a relative molecular mass 583.16 g/mol and has the following structure:

str1

The structure of the active substance was elucidated by a combination of 1 H-NMR, 13C-NMR, elemental analysis, FT-IR, UV and and mass spectrometry. Anamorelin HCl appears as a white to off-white hygroscopic solid, freely soluble in water, methanol and ethanol, sparingly soluble in acetonitrile and practically insoluble in ethyl acetate, isopropyl acetate and n-heptane. Its pka was found to be 7.79 and the partition coefficient 2.98. It has two chiral centres with the R,R absolute configuration, which is controlled in the active substance specification by chiral HPLC. Based on the presented data, neither anamorelin hydrochloride, nor any of its salts have been previously authorised in medicinal products in the European Union. Anamorelin is therefore considered as a new active substance.

SYN

OPRD

PATENT

WO 9958501

PATENT

WO 2001034593

https://patents.google.com/patent/WO2001034593A1/enExample 1A procedure for the preparation of the compound which is either 2-Amino-N-[(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1- (1 H-indol-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide

Figure imgf000017_0001

or2-Amino-N-[(1R)-2-[(3S)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1- (1 H-indol-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide

Figure imgf000017_0002

Step aPiperidine-1 ,3-dicarboxylic acid 1-tetf-butyl ester 3-ethyl ester

Figure imgf000017_0003

A one-necked round-bottom flask (1 I) equipped with a magnetic stirrer and addition funnel was charged with NaOH-pellets (15,6 g), tetrahydrofuran (400 ml) and ethylnipecotate (50 ml, 324 mmol). To the stirred mixture at room temperature was added dropwise a solution of Boc2O (84,9 g, 389 mmol) dissolved in tetrahydrofuran (150 ml) (1 hour, precipitation of white solid, NaOH-pellets dissolved, exoterm). The mixture was stirred overnight at room temperature. The mixture was added to EtOAc (500 ml) and H2O (2000 ml), and the aqueous layer was re-extracted with EtOAc (2 X 500 ml) and the combined organic layers were washed with brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo to afford piperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (82,5 g) as a thin yellow oil.1H-NMR (300 MHz, CDCI3): δ 1,25 (t, 3H, CH3); 1 ,45 (s, 9H, 3 X CH3); 2,05 (m, 1H); 2,45 (m, 1H); 2,85 (m, 1 H); 3,95 (d (broad), 1 H); 4,15 (q, 2H, CH2)Step b3-Benzylpiperidine-1 ,3-dicarboxylic acid 1-tetf-butyl ester 3-ethyl ester (racemic mixture)

Figure imgf000018_0001

A three-necked round-bottom flask (2 I) equipped with a magnetic stirrer, thermometer, nitrogen bubbler and addition funnel was evacuated, flushed with nitrogen, charged with anhydrous tetrahydrofuran (500 ml) and cooled to -70 °C. Then lithium diisopropylamine (164 ml of a 2,0 M solution in tetrahydrofuran, 327 mmol) was added. To the stirred solution at -70 °C was added dropwise over 45 min. a solution of piperidine-1 ,3-dicarboxylic acid 1- tert-butyl ester 3-ethyl ester (80 g, 311 mmol) in anhydrous tetrahydrofuran (50 ml) (temperature between -70 °C and -60 °C, clear red solution). The mixture was stirred for 20 min. and followed by dropwise addition over 40 min. of a solution of benzylbromide (37 ml, 311 mmol) in anhydrous tetrahydrofuran (250 ml) (temperature between -70 °C and -60 °C). The mixture was stirred for 1 hour at -70 °C, and then left overnight at room temperature (pale orange).The reaction mixture was concentrated in vacuo to approx. 300 ml, transferred to a separating funnel, diluted with CH2CI2 (900 ml) and washed with H2O (900 ml). Due to poor separation the aqueous layer was re-extracted with CH2CI2 (200 ml), the combined organic layers were washed with aqueous NaHSO4 (200 ml, 10%), aqueous NaHCO3 (200 ml, saturated), H2O (200 ml), brine (100 ml), dried over MgSO4> filtered and concentrated in vacuo to afford an oil, which was dissolved in EtOAc(1):heptane(10) and aged overnight. The solids formed was removed by filtration, washed with heptane and dried in vacuo to give a racemic mixture of 3-benzylpiperidine-1 ,3-dicarboxylic acid 1-ter–butyl ester 3-ethyl ester (81 ,4 g). ■ HPLC (h8): Rt = 15,79 min.LC-MS: Rt = 7,67 min. (m+1) = 348,0Step c 3-Benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester (racemic mixture)

Figure imgf000019_0001

3-Benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (81 g, 233 mmol) was dissolved in EtOH (400 ml) and NaOH (400 ml, 16% aqueous solution) in a one neck round- bottom flask (1 L) equipped with a condenser and a magnetic stirrer. The mixture was refluxed for 10 h under nitrogen, and cooled to room temperature, concentrated in vacuo to approx. 600 ml (precipitation of a solid), diluted with H2O (400 ml), cooled in an icebath, and under vigorous stirring acidified with 4 M H2SO4 until pH = 3 (final temperature: 28 °C). The mixture was extracted with EtOAc (2 X 700 ml), and the combined organic layers were washed with brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo to afford an oil, which was dissolved in EtOAc(1):heptane(10) and aged overnight. The crystals formed were removed by filtration, washed with heptane and dried in vacuo to give a racemic mixture of 3-benzylpiperidine-1 ,3-dicarboxylic acid 1-tetf-butyl ester (66,0 g)HPLC (h8): Rt = 12,85 min.LC-MS: Rt = 5,97 min. (m+1) = 320,0Chirale HPLC (Chiracel OJ, heptane(92):iPrOH(8):TFA(0,1)): Rt = 8,29 min. 46,5 % Rt = 13,69 min. 53,5 %Step d(3R)-3-Benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester or (3S)-3-Benzylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester

(Resolution of 3-Benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester)

Figure imgf000020_0001

3-Benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester (76 g, 238 mmol) was dissolved in EtOAc (3,0 L) in a one neck flask (5L) equipped with magnetic stirring. Then H2O (30 ml), R(+)-1-phenethylamine (18,2 ml, 143 mmol) and Et3N (13,2 ml, 95 mmol) were added and the mixture was stirred overnight at room temperature resulting in precipitation of white crystals (41 ,9 g), which were removed by filtration, washed with EtOAc and dried in vacuo. The precipitate was dissolved in a mixture of aqueous NaHSO4 (300 ml, 10%) and EtOAc (600 ml), layers were separated and the aqueous layer re-extracted with EtOAc (100 ml). The combined organic layers were washed with brine (100 ml), dried over MgSO4 and filtered. The solvent was removed in vacuo to afford a colourless oil, which was dissolved in EtOAc(1):heptane(10) and aged overnight. The crystals that had been formed were removed by filtration, washed with heptane and dried in vacuo to give one compound which is either (3R)-3-benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester or (3S)-3-benzylpiperidine- 1,3-dicarboxylic acid 1-tert-butyl ester (27,8 g).Chirale HPLC (Chiracel OJ, heptane(92):iPrOH(8):TFA(0,1)):Rt = 7,96 min. 95,8 % eeStep e(3R)-3-Benzyl-3-(N,N’1N’-trimethylhvdrazinocarbonyl)piperidine-1-carboxylic acid tert-butyl ester or (3S)-3-Benzyl-3-(N,N’,N’-trimethylhvdrazinocarbonyl)piperidine-1-carboxylic acid tert-butyl ester

Figure imgf000020_0002

Trimethylhydrazine dihydrochloride (15,3 g, 104 mmol) was suspended in tetrahydrofuran (250 ml) in a one-neck round-bottom flask (1 I) equipped with a large magnetic stirrer, and an addition funnel/nitrogen bubbler. The flask was then placed in a water-bath (temp: 10- 20°C), bromo-rrts-pyrrolydino-phosphonium-hexafluorophosphate (40,4 g, 86,7 mmol) was added, and under vigorous stirring dropwise addition of diisopropylethylamine (59 ml, 347 mmol). The mixture (with heavy precipitation) was stirred for 5 min., and a solution of the product from step d which is either (3R)-3-benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester or (3S)-3-benzylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester (27,7 g, 86,7 mmol) in tetrahydrofuran (250 ml) was added slowly over 1 ,5 hour. The mixture was stirred overnight at room temperature. The reaction was diluted with EtOAc (1000 ml), washed with H2O (500 ml), aqueous NaHSO4, (200 ml, 10%), aqueous NaHCO3 (200 ml, saturated), brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo to afford a thin orange oil. The mixture was dissolved in EtOAc (300 ml), added to SiO2 (150 g) and concentrated in vacuo to a dry powder which was applied onto a filter packed with SiO2 (150 g), washed with heptan (1 I) and the desired compound was liberated with EtOAc (2,5 I). After concentration in vacuo, the product which is either (3R)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)-piperidine-1- carboxylic acid tert-butyl ester or (3S)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)- piperidine-1-carboxylic acid tert-butyl ester (49 g) as an orange oil was obtained.HPLC (h8): Rt = 14,33 min.Ste f(3R)-3-Benzyl-piperidine-3-carboxylic acid trimethylhydrazide or (3S)-3-Benzyl-piperidine-3- carboxylic acid trimethylhydrazide

Figure imgf000021_0001

The product from step e which is either (3R)-3-Benzyl-3-(N,N’,N’- trimethylhydrazinocarbonyl)-piperidine-1 -carboxylic acid tert-butyl ester or (3S)-3-Benzyl-3- (N,N’,N’-trimethylhydrazinocarbonyl)-piperidine-1 -carboxylic acid tert-butyl ester (56,7 g, 100,9 mmol) was dissolved in EtOAc (500 ml) (clear colourless solution) in a one-neck roundbottom flask (2L) equipped with magnetic stirring. The flask was then placed in a waterbath (temp: 10-20 °C), and HCI-gas was passed through the solution for 5 min. (dust- like precipitation). After stirring for 1 hour (precipitation of large amount of white crystals), the solution was flushed with N2 to remove excess of HCI. The precipitate was removed by gentle filtration, washed with EtOAc (2 X 100 ml), and dried under vacuum at 40 °C overnight to give the product which is either (3R)-3-benzyl-piperidine-3-carboxylic acid trimethylhydrazide or (3S)-3-benzyl-piperidine-3-carboxylic acid trimethylhydrazide (37,0 g).HPLC (h8): Rt = 7,84 min.Step q r(1 R)-2-r(3R)-3-Benzyl-3-(N,N’,N’-trimethylhvdrazinocarbonyl)piperidin-1-vn-1-((1 H-indol-3- yl)methyl)-2-oxoethvncarbamic acid tert-butyl ester or .(1 R)-2-..3S)-3-Benzyl-3-(N,N’,N’- trimethylhvdrazinocarbonyl)piperidin-1-vn-1-((1 H-indol-3-yl)methyl)-2-oxoethyllcarbamic acid tert-butyl ester

Figure imgf000022_0001

Boc-D-Trp-OH (32,3 g, 106 mmol) was dissolved in dimethylacetamide (250 ml) in a one- neck roundbottom flask (500 ml) equipped with a magnetic stirrer and a nitrogen bubbler. The solution was cooled to 0-5 °C and 1-hydroxy-7-azabenzotriazole (14,4 g, 106 mmol), 1- ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride (20,3 g, 106 mmol), N- methylmorpholine (11 ,6 ml, 106 mmol) were added. After stirring for 20 min. at 0-5 °C the product from step f which is either (3R)-3-benzyl-piperidine-3-carboxylic acid trimethylhydrazide or (3S)-3-benzyl-piperidine-3-carboxylic acid trimethylhydrazide (37,0 g, 106 mmol) and N-methylmorpholine (24,4 ml, 223 mmol) were added. The reaction was stirred overnight at room temperature. The mixture was then added to EtOAc (750 ml) and washed with aqueous NaHSO4 (300 ml, 10 %). The layers were allowed to separate, and the aqueous layer was re-extracted with EtOAc (500 ml). The combined organic layers were washed with H2O (100 ml), aqueous NaHCO3 (300 ml, saturated), H2O (100 ml), brine (300 ml), dried over MgSO4, filtered and concentrated in vacuo to afford the product which is either [(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-((1H- indol-3-yl)methyl)-2-oxoethyl]carbamic acid tert-butyl ester or [(1 R)-2-[(3S)-3-benzyl-3- (N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-((1 H-indol-3-yl)methyl)-2- oxoethyljcarbamic acid tert-butyl ester (56,7g) as an orange oil.HPLC (h8): Rt = 14,61 min.LC-MS: Rt = 7,35 min. (m+1 ) = 562,6Step h1 -f(2R)-2-Amino-3-(1 H-indol-3-yl)propionylH3R)-3-benzylpiperidine-3-carboxylic acid trimethylhydrazide or 1-f(2R)-2-Amino-3-(1 H-indol-3-yl)propionvn-(3S)-3-benzylpiperidine-3- carboxylic acid trimethylhydrazide

Figure imgf000023_0001

The product from step g which is either [(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’- trimethylhydrazinocarbonyl)piperidin-1 -yl]-1 -((1 H-indol-3-yl)methyl)-2-oxoethyl]carbamic acid tert-butyl ester or [(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1- yl]-1-((1 H-indol-3-yl)methyl)-2-oxoethyl]carbamic acid tert-butyl ester (56,7 g, 100,9 mmol) was dissolved in EtOAc (500 ml) (clear colourless solution) in a one-neck round-bottom flask (2L) equipped with magnetic stirring. The flask was then placed in a water-bath (temp: 10-20 °C), and HCI-gas was passed through the solution for 10 min. (heavy precipitation of oil). The mixture was flushed with N2 to remove excess of HCI and then separated into an oil and an EtOAc-layer. The EtOAc-layer was discarded. The oil was dissolved in H2O (500 ml), CH2CI2 (1000 ml), and solid Na2CO3 was added until pH > 7. The layers were separated, and the organic layer was washed with H2O (100 ml), brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo to afford the product which is either 1-[(2R)-2-amino-3-(1 H-indol- 3-yl)propionyl]-(3R)-3-benzylpiperidine-3-carboxylic acid trimethylhydrazide or 1-[(2R)-2- amino-3-(1H-indol-3-yl)propionyl]-(3S)-3-benzylpiperidine-3-carboxylic acid trimethylhydrazide (27 g) as an orange foam.HPLC (h8): Rt = 10,03 min.Step i(1-r(1 R)-2-r(3R)-3-Benzyl-3-(N,N’,N’-trimethylhvdrazinocarbonyl)piperidin-1-vn-1-(1H-indol-3- ylmethyl)-2-oxo-ethylcarbamovπ-1 -methylethyl fcarbamic acid tert-butyl ester or1-r(1 R)-2-r(3S)-3-Benzyl-3-(N,N’.N’-trimethylhvdrazinocarbonyl)piperidin-1-vn-1-(1 H-indol-3- ylmethyl)-2-oxo-ethylcarbamovπ-1-methylethyl)carbamic acid tert-butyl ester

Figure imgf000024_0001

Boc-Aib-OH (11 ,9 g, 58,4 mmol) was dissolved in dimethylacetamide (125 ml) in a one-neck roundbottom flask (500 ml) equipped with a magnetic stirrer and nitrogen bubbler. To the stirred solution at room temperature were added 1-hydroxy-7-azabenzotriazole (7,95 g, 58,4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride (11 ,2 g, 58,4 mmol), and diisopropylethylamine (13,0 ml, 75,8 mmol). After 20 min. (yellow with precipitation) a solution of the product from step h which is either 1-[(2R)-2-amino-3-(1 H-indol-3- yl)propionyl]-(3R)-3-benzylpiperidine-3:carboxylic acid trimethylhydrazide or 1-[(2R)-2- amino-3-(1 H-indol-3-yl)propionyl]-(3S)-3-benzylpiperidine-3-carboxylic acid trimethylhydrazide (27,0 g, 58,4 mmol) in dimethylacetamide (125 ml) was added. The reaction was stirred at room temperature for 3 h. The mixture was added to EtOAc (750 ml) and washed with aqueous NaHSO4 (300 ml, 10 %). The layers were allowed to separate, and the aqueous layer was re-extracted with EtOAc (500 ml). The combined organic layers were washed with H2O (100 ml), aqueous NaHCO3 (300 ml, saturated), H2O (100 ml), brine (300 ml), dried over MgSO4, filtered and concentrated in vacuo to approx. 500 ml. Then SiO2 (150 g) was added and the remaining EtOAc removed in vacuo to give a dry powder which was applied onto a filter packed with SiO2 (150 g), washed with heptan (1 L), and the desired compound was liberated with EtOAc (2,5 L). After concentration in vacuo, the product which is either {1-[(1 R)-2-[(3R)-3-benzyl-3-(N, N’, N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1- (1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methylethyl}carbamic acid tert-butyl ester or {1-[(1R)-2-[(3S)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1 H-indol-3- ylmethyl)-2-oxo-ethylcarbamoyl]-1-methylethyl}carbamic acid tert-butyl ester 33,9 g as an orange foam was obtained.HPLC (h8): Rt = 14,05 min.Step j2-Amino-N-r(1 R)-2-f(3R)-3-benzyl-3-(N,N’,N’-trimethylhvdrazinocarbonyl)piperidin-1-vπ-1- (1 H-indol-3-ylmethyl)-2-oxoethyll-2-methylpropionamide, fumarate or2-Amino-N-r(1 R)-2-r(3S)-3-benzyl-3-(N1N’1N’-trimethylhvdrazinocarbonyl)piperidin-1-yll-1- (1H-indol-3-ylmethyl)-2-oxoethvπ-2-methylpropionamide, fumarate

Figure imgf000025_0001

The product from step i which is either {1-[(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’- trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1- methylethyl}carbamic acid tert-butyl ester or {1-[(1 R)-2-[(3S)-3-benzyl-3-(N,N’,N’- trimethylhydrazinocarbonyl)piperidin-1 -yl]-1 -(1 H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1 – methylethyljcarbamic acid tert-butyl ester (23,8 g, 36,8 mmol) was dissolved in of EtOAc (800 ml) (clear yellow solution) in a one neck round-bottom flask (1L) equipped with magnetic stirring. The flask was then placed in a water-bath (temp: 10-20 °C), and HCI-gas was passed through the solution for 5 min. (dust-like precipitation). After stirring for 1 hour (precipitation of large amount of yellow powder), the solution was flushed with N2 to remove excess of HCI. The precipitate was removed by gentle filtration and dried under vacuum at 40 °C overnight.The non-crystallinic precipitate was dissolved in H2O (500 ml) and washed with EtOAc (100 ml). Then CH2CI2 (1000 ml) and solid Na2CO3 was added until pH > 7. The 2 layers were separated, and the aqueous layer was e-extracted with CH2CI2 (200 ml). The combined organic layers were washed with brine (100 ml), dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and redissolved in EtOAc (500 ml) in a one neck round-bottom flask (1 L) equipped with magnetic stirring. A suspension of fumaric acid (3,67 g) in isopropanol (20 ml) and EtOAc (50 ml) was slowly added (5 min.), which resulted in precipitation of a white crystallinic salt. After 1 hour the precipitation was isolated by filtration and dried overnight in vacuum at 40 °C to give the fumarate salt of the compound which is either 2-amino-N-[(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1- yl]-1-(1 H-indol-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide or 2-amino-N-[(1 R)-2-[(3S)-3- benzyl-3-(N,N,,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1 H-indol-3-ylmethyl)-2- oxoethyl]-2-methylpropionamide (13,9 g) as a white powder.HPLC (A1): Rt = 33,61 min.HPLC (B1): Rt = 34,62 min. LC-MS: Rt = 5,09 min. (m+1) = 547,4 
ClaimsHide Dependent 
1. The compound obtainable by the procedure as described in example 1 , or a pharmaceutically acceptable salt thereof.2. The compound obtainable by the procedure as described in example 1 , and which compound is2-Amino-N-[(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1- (1 H-indol-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide

Figure imgf000027_0001

or a pharmaceutically acceptable salt thereof.3. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.4. A pharmaceutical composition according to claim 3 for stimulating the release of growth hormone from the pituitary.5. A pharmaceutical composition according to claim 3 or claim 4 for administration to animals to increase their rate and extent of growth, to increase their milk and wool production, or for the treatment of ailments.6. A method of stimulating the release of growth hormone from the pituitary of a mammal, the method comprising administering to said mammal an effective amount of a compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof, or of a composition according to any one of claims 3 – 5.7. A method of increasing the rate and extent of growth, the milk and wool production, or for the treatment of ailments, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, or of a composition according to any one of claims 3-5.8. Use of a compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof for the preparation of a medicament.9. Use according to claim 8 wherein the medicament is for stimulating the release of growth hormone from the pituitary of a mammal.

PATENT

CN 108239141

PATENT

US 20130281701

Growth hormone is a major participant in the control of several complex physiologic processes, including growth and metabolism. Growth hormone is known to have a number of effects on metabolic processes, e.g., stimulation of protein synthesis and free fatty acid mobilization and to cause a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiency in growth hormone can result in a number of severe medical disorders, e.g., dwarfism.
      The release of growth hormone from the pituitary is controlled, directly or indirectly, by number of hormones and neurotransmitters. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary. Other compounds which stimulate the release of growth hormone from the pituitary have also been described. For example, arginine, L-3,4-dihydroxyphenylalanine (1-Dopa), glucagon, vasopressin, PACAP (pituitary adenylyl cyclase activating peptide), muscarinic receptor agonists and a synthetic hexapeptide, GHRP (growth hormone releasing peptide) release endogenous growth hormone either by a direct effect on the pituitary or by affecting the release of GHRH and/or somatostatin from the hypothalamus.
      The use of certain compounds for increasing the levels of growth hormone in mammals has previously been proposed. For example, U.S. Pat. Nos. 6,303,620 and 6,576,648 (the entire contents of which are incorporated herein by reference), disclose a compound: (3R)-1-(2-methylalanyl-D-tryptophyl)-3-(phenylmethyl)-3-piperidinecarboxylic acid 1,2,2-trimethylhydrazide, having the following chemical structure:

 (MOL) (CDX) which acts directly on the pituitary cells under normal experimental conditions in vitro to release growth hormone therefrom. This compound is also known under the generic name “anamorelin.” This growth hormone releasing compound can be utilized in vitro as a unique research tool for understanding, inter alia, how growth hormone secretion is regulated at the pituitary level. Moreover, this growth hormone releasing compound can also be administered in vivo to a mammal to increase endogenous growth hormone release.

Example 1

Crystallization of (3R)-1-(2-methylalanyl-D-tryptophyl)-3-(phenylmethyl)-3-piperidinecarboxylic acid 1,2,2-trimethylhydrazide form A

      0.0103 g of (3R)-1-(2-methylalanyl-D-tryptophyl)-3-(phenylmethyl)-3-piperidinecarboxylic acid 1,2,2-trimethylhydrazide was dissolved in methanol (0.1 mL) in a glass vial. The glass vial was then covered with PARAFILM® (thermoplastic film) which was perforated with a single hole. The solvent was then allowed to evaporate under ambient conditions. An X-ray diffraction pattern showed the compound was crystalline ( FIG. 1).

PATENT

WO 2017067438

https://patents.google.com/patent/WO2017067438A1/enAnamorelin, whose chemical name is: (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2- Trimethylformylhydrazide is a compound that increases mammalian growth hormone levels and has a compound structure as shown in Formula I:

Figure PCTCN2016102385-appb-000001

Cancer cachexia is a state of consumption in which patients lose a lot of weight and muscle mass. It is necessary for the treatment of cachexia because it weakens the patient, affects the quality of life and interferes with the patient’s treatment plan. The drug alamorelin produces the same effect as the so-called “starved hormone” ghrelin, which stimulates hunger. Alamolin is a mimetic of ghrelin, which is secreted by the stomach and is a ligand for growth hormone receptors. . Alamolin binds to this receptor, causing the release of growth hormone, causing a metabolic cascade that affects a variety of different factors, including fat-removing body weight, as well as blood sugar metabolism. Therefore, alamorelin can also enhance the appetite of patients and help patients stay healthy. The 2014 European Society of Medical Oncology (ESMO) in Madrid, Spain, announced that Alamolin is expected to be the first drug in history to effectively improve cancer cachexia.Alamolin is a drug developed by Helsinn Therapeutics (Switzerland) from Novo Nordisk for the development of a cachexia and anorexia for patients with cancer, including non-small cell lung cancer. It can also be used to treat hip fractures and preventive diseases. The strength of the elderly and the elderly has continued to decline. In two key, 12-week Phase III clinical trials (ROMANA 1, ROMANA 2), alamorelin can significantly increase the body fat loss, and is generally tolerated; the incidence of serious adverse drug reactions is less than 3%, mainly related to hyperglycemia and diabetes. Compared with the placebo group, alamorelin continued to increase body weight and improve cancer anorexia-cachexia-related symptoms and concerns; however, there was no significant difference in the improvement of grip strength between the alamolin group and the placebo group. Therefore, this product has excellent clinical value and market value.The polymorphic form of the drug free base and its preparation are reported as follows:Synthesis of (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylmethyl is disclosed in the patent ZL99806010.0 A method for synthesizing hydrazide, and using [(1R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylmethylcarbonyl)piperidin-1-yl tert-Butyl ester of 1-((1H-indol-3-yl)methyl)-2-oxoethyl]carbamate is dissolved in dichloromethane, then trifluoroacetic acid is added to remove tert-butyl formate After the base, the mixture was concentrated to remove the solvent, and then the product was extracted with dichloromethane, and the obtained extract was concentrated to dryness to give (3R)-1-(2-methylalanyl-D-color ammonia as an amorphous powder. Acyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazide.Patent ZL00815145.8 discloses the synthesis of alamorelin and its compounds as pharmaceutically acceptable salts, relating to novel diastereomeric compounds, pharmaceutically acceptable salts thereof, compositions containing them and their use in therapy Lack of use of medical conditions caused by growth hormone. Synthesis of (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformyl is disclosed in this patent. The synthesis method of hydrazine, and using [(1R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylmethylcarbonylcarbonyl)piperidin-1-yl] 1-((1H-Indol-3-yl)methyl)-2-oxoethyl]carbamic acid tert-butyl ester was dissolved in ethyl acetate, and then hydrogen chloride gas was passed to remove the tert-butyl formate protection group. , the solid is dissolved in water, and then the pH is adjusted to about 7 with sodium carbonate, and the product is extracted with dichloromethane; the extract phase is concentrated to obtain (3R)-1-(2-methylalanyl-D-tryptophan). -3-Benzyl-3-piperidine 1,2,2-trimethylformylhydrazide.Patent WO2006016995 discloses (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylmethyl as a medicament Crystalline polymorphs of hydrazides, methods of producing and separating these polymorphs, and pharmaceutical compositions and drug therapies containing these polymorphs, the crystalline polymorphs for direct application to the pituitary Gland cells release the growth hormone. This patent discloses (4R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazone 4 Crystal form: Form A, Form B, Form C and Form D. The patent also provides the preparation of 3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazone. The method of crystal form, especially the preparation method of Form C, in which the method of removing the tert-butyl formate protecting group of methanesulfonic acid in methanol is utilized without exception. As a well-known cause in the art, clinical studies have found that mesylate is genotoxic, and its DNA alkylation leads to mutagenic effects, in which methyl methanesulfonate and ethyl methanesulfonate have been reported. (eg document EMEA/44714/2008). The invention adopts hydrochloric acid or hydrogen chloride gas to remove the tert-butyl formate protecting group, avoids the method of removing methanesulfonic acid, thereby avoiding the risk of the genotoxic impurities in the process, and increasing the risk. The safety of the drug.(3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-three prepared by the patent ZL99806010.0 and the patent ZL00815145.8 Methyl formyl hydrazide, no data on the purity of its compounds, we found that (3R)-1-(2-methylalanyl-D-tryptophan)-3 was prepared by this method. -Benzyl-3-piperidine 1,2,2-trimethylformylhydrazide does not help to remove the impurities produced, and the purity of the obtained product is not high, and it is difficult to meet the medicinal requirements. And (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethyl obtained by the preparation method of the present invention. The crystal form of the formyl hydrazide has a purity of 99.8% and a single impurity of less than 0.1%, which fully meets the requirements for medicinal purity. Moreover, the crystal form is stable to conditions such as pressure, temperature, humidity and illumination, and the preparation method is simple in operation and suitable for industrial production.Example 1:300 g of [(1R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylcarbamidocarbonyl)piperidin-1-yl]-1-(( 1H-Indol-3-yl)methyl)-2-oxoethyl]carbamic acid tert-butyl ester was added to the reaction flask, and then 4 L of dichloromethane was added to the reaction flask, and the raw material was completely dissolved by stirring.Then, the reaction system is cooled to 10 ° C or lower in an ice bath, hydrogen chloride gas is continuously supplied to the reaction liquid, and solids are gradually precipitated, and the reaction is further maintained at about 10 ° C for 3 to 5 hours, and the sample is detected. After the reaction of the raw materials is completed, the reaction system is completed. 1.5 L of water was added thereto, the solid was completely dissolved, and then the pH was adjusted to about 8 with a 20% aqueous sodium hydroxide solution, and the layers were separated; the aqueous phase was extracted once more with dichloromethane, and the organic phases were combined.The organic phase was dried over anhydrous sodium sulfate for 3 hrs, filtered, and then evaporated to ethylamine 3-Benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude 246 g, yield 97.2%. HPLC content (area normalization method) was 96.1%.Example 2:300 g of [(1R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylcarbamidocarbonyl)piperidin-1-yl]-1-(( 1H-Indol-3-yl)methyl)-2-oxoethyl]carbamic acid tert-butyl ester was added to the reaction flask, 36% concentrated hydrochloric acid was added to the reaction flask, and the reaction system was heated to 40 with stirring. The reaction was carried out at ° C to 50 for 3 hours.Then, the sample is detected. After the reaction of the raw material is completed, the reaction system is cooled to 10 or less, and 2.0 L of dichloromethane is added to the reaction system, and then the pH is adjusted to about 8 with a 20% aqueous sodium hydroxide solution, and the aqueous phase is further separated. It was extracted once with dichloromethane and the organic phases were combined.The organic phase was dried over anhydrous sodium sulfate for 3 hrs, filtered, and then evaporated to ethylamine 3-Benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude 248 g, yield 98%. HPLC content (area normalization method) was 96.2%.Preparation of (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazone E crystal formExample 3Taking the above amorphous (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude product 10g was added to the reaction flask and 30 ml of N- was added.Methylpyrrolidone, stirred and dissolved completely. Then, 60 ml of water was added dropwise to the reaction flask at room temperature, and the reaction liquid was heated to 60 ° C. The solution became cloudy, and a white solid was gradually precipitated, and stirring was continued for 2 hours.Slowly cooled to below 20 ° C, filtered, and the filter cake was washed with a mixture of N-methylpyrrolidone / H 2 O; the cake was vacuum dried at about 55 ° C to obtain (3R)-1-(2-methylalanyl) -D-tryptophan)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazide (white solid, 9.5 g), HPLC content (area normalization) 99.72%. The XRD pattern is shown in Fig. 1, the DSC chart is shown in Fig. 2, and the TGA pattern is shown in Fig. 3, where the crystal form is defined as the E crystal form. The DSC of the crystal form has an endotherm at 120.05, the TGA is heated at 60A, and the crystal loss of 5 is about 3.1%. Combined with the Karl Fischer method, the moisture content of the product is determined. 3.1% and 3.2% indicate that the sample is present as a monohydrate.Example 4:Taking the above amorphous (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude product 10 g was added to the reaction flask, 30 ml of N,N-dimethylformamide was added, stirred, and dissolved completely. Then, 30 ml of water was added dropwise to the reaction flask at room temperature, and the reaction solution was heated to 50 ° C. The solution became cloudy, and a white solid was gradually precipitated, and stirring was continued for 2 h.Slowly cool to below 10 ° C, filter, filter cake washed with N, N-dimethylformamide / H 2 O mixture; vacuum cake dried at around 55 ° C to obtain (3R)-1-(2-A Alanyl-D-tryptophanyl-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazide (white solid, 8.5 g), HPLC content (area normalization) ) 99.87%. Upon comparison, it was confirmed that the solid was in the E crystal form.Example 5:Taking the above amorphous (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude product 10 g was added to the reaction flask, 30 ml of dimethyl sulfoxide was added, stirred, and dissolved completely. Then, 40 ml of water was added dropwise to the reaction flask at room temperature, and the reaction liquid was heated to 60 ° C, the solution became cloudy, and a white solid was gradually precipitated, and stirring was continued for 2 hours.Slowly cooled to below 10 ° C, filtered, and the filter cake was washed with a mixture of dimethyl sulfoxide / H 2 O; the cake was vacuum dried at about 50 ° C to obtain (3R)-1-(2-methylalanyl) -D-tryptophanyl-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazide (white solid, 9.1 g), HPLC content (area normalization) 99.61%. Upon comparison, it was confirmed that the solid was in the E crystal form.Example 6Taking the above amorphous (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude product 10 g was added to the reaction flask, 40 ml of 1,4-dioxane was added, stirred, and dissolved completely. Then, 50 ml of water was added dropwise to the reaction flask at room temperature, and the reaction solution was heated to 70 ° C. The solution became cloudy, and a white solid was gradually precipitated, and stirring was continued for 2 hours.Slowly cooled to below 10 ° C, filtered, and the filter cake was washed with a mixture of 1,4-dioxane/H 2 O; the cake was vacuum dried at about 50 ° C to obtain (3R)-1-(2-methyl alanyl-D-tryptophan-3-Benzyl-3-piperidine 1,2,2-trimethylformylhydrazide (white solid, 8.7 g), HPLC content (area normalization) 99.11%. Upon comparison, it was confirmed that the solid was in the E crystal form.Example 7Taking the above amorphous (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude product 10 g was added to the reaction flask, 40 ml of N,N-dimethylacetamide was added, stirred, and dissolved completely. Then, 40 ml of water was added dropwise to the reaction flask at room temperature, and the reaction solution was heated to 70 ° C. The solution became cloudy, and was slowly cooled to about 50 ° C. Seed crystals were added thereto, and cooling was continued to gradually precipitate a solid.The reaction system was cooled to about 10 ° C, filtered, and the filter cake was washed with a mixture of N,N-dimethylacetamide/H 2 O; the cake was vacuum dried at about 50 ° C to obtain (3R)-1-(2- Methylalanyl-D-tryptophanyl-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazide (white solid, 8.1 g), HPLC content (area normalized) Law) 99.78%. Upon comparison, it was confirmed that the solid was in the E crystal form.Example 7Taking the above amorphous (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude product 10 g was added to the reaction flask, 50 ml of acetone was added, stirred, and dissolved completely. Then, 70 ml of water was added dropwise to the reaction flask at room temperature, and the reaction liquid was heated to 45 ° C. The solution became cloudy, and a white solid was gradually precipitated, and stirring was continued for 2 hours.Slowly cool to below 10 ° C, filter, filter cake washed with acetone / H 2 O mixture; filter cake vacuum dried at around 50 ° C to obtain (3R)-1-(2-methylalanyl-D-color Aminoacyl-3-phenylmethyl-3-piperidine 1,2,2-trimethylformylhydrazide (white solid, 9.3 g), HPLC content (area normalization) 98.9%. Upon comparison, it was confirmed that the solid was in the E crystal form.

SYN

Reference:

1. Org. Process Res. Dev. 200610, 339–345.

Abstract

Abstract Image

The rapid process development of a scaleable synthesis of the pseudotripeptide RC-1291 for preclinical and clinical evaluation is described. By employing a nontraditional N-to-C coupling strategy, the peptide chain of RC-1291 was assembled in high yield, with minimal racemization and in an economical manner by introducing the most expensive component last. A one-pot deprotection/crystallization procedure was developed for the isolation of RC-1291 free base, which afforded the target compound in excellent yield and with a purity of >99.5% without chromatographic purification.

(R,R)-2-Amino-N-[2-[3-benzyl-3-(N,N′,N′-trimethyl-hydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)- 2-oxo-ethyl]-2-methyl-propionamide (1). Crude 7 (911 g; 1.28 mol theoretical)10 was dissolved in methanol (4.12 L) in a 22-L round-bottom flask equipped with a mechanical stirrer, a temperature probe, a reflux condenser, a gas (N2) inlet, and an addition funnel. The solution was heated to 55 °C; then methanesulfonic acid (269.5 g, 2.805 mol) was added over a period of 15 min. (Caution: gas evolution!) The solution was then heated to 60 °C for a period of 1 h, after which HPLC analysis showed that no 7 remained. The temperature of the reaction mixture was increased to reflux (68-72 °C) over a period of 35 min, while simultaneously adding a solution of KOH (85%, 210.4 g, 3.187 mol) in water (4.12 L). The clear, slightly yellow solution was then allowed to cool to 20 °C at a rate of 5 °C/h. The free base of RC1291 (1) crystallized as a pale-yellow solid, which was isolated by filtration. The filter cake was washed with two portions of 50% aqueous methanol (500 mL each) and then dried under high vacuum at 20 ( 5 °C to afford 1 as an off-white, crystalline solid (595 g, 85% yield for two steps, >99.5% AUC by HPLC).

HRMS (ESI) calcd for C31H43N6O3 [M + H]+ 547.3397, found 547.3432.

1H NMR (DMSO-d6; 413 K) δ 10.30 (s, 1H), 7.85 (bs, 1H), 7.50 (d, J ) 7.8 Hz, 1H), 7.27 (d, J ) 8.1 Hz, 1H), 7.1-7.2 (m, 3H), 6.95-7.0 (m, 5H), 5.07 (t, J ) 6.3 Hz, 1H), 3.54 (d, J ) 12.3 Hz, 1H), 3.36 (bs, 1H), 3.15-3.30 (m, 1H), 3.06 (dd, J ) 7.2, 14.4 Hz, 1H), 2.96 (dd, J ) 6.0, 14.3 Hz, 2H), 2.7-2.8 (m, 6H), 2.43 (m, 6H), 2.09 (bs, 1H), 1.73 (bs, 1H), 1.45-1.55 (m, 2H), 1.3-1.40 (m, 1H), 1.18 (s, 3H), 1.15 (s, 3H).

13C NMR (DMSO-d6; 413 K) δ 175.8, 173.4, 170.3, 137.0, 135.7, 129.0, 127.2, 127.1, 125.3, 122.9, 120.1, 117.6, 110.7, 109.4, 53.6, 49.0, 47.0, 42.7, 38.5, 30.7, 28.2, 28.0, 23.2, 21.1.

PAPER

https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.8b00322

Cachexia and muscle wasting are very common among patients suffering from cancer, chronic obstructive pulmonary disease, and other chronic diseases. Ghrelin stimulates growth hormone secretion via the ghrelin receptor, which subsequently leads to increase of IGF-1 plasma levels. The activation of the GH/IGF-1 axis leads to an increase of muscle mass and functional capacity. Ghrelin further acts on inflammation, appetite, and adipogenesis and for this reason was considered an important target to address catabolic conditions. We report the synthesis and properties of an indane based series of ghrelin receptor full agonists; they have been shown to generate a sustained increase of IGF-1 levels in dog and have been thoroughly investigated with respect to their functional activity.

Abstract Image

Patent

https://patents.google.com/patent/EP2838892A1/enGrowth hormone is a major participant in the control of several complex physiologic processes including growth and metabolism. Growth hormone is known to have a number of effects on metabolic processes such as stimulating protein synthesis and mobilizing free fatty acids, and causing a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiencies in growth hormone can result in dwarfism and other severe medical disorders.The release of growth hormone from the pituitary gland is controlled directly and indirectly by a number of hormones and neurotransmitters. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin.The use of certain compounds to increase levels of growth hormone in mammals has previously been proposed. Anamorelin is one such compound. Anamorelin is a synthetic orally active compound originally synthesized in the 1990s as a growth hormone secretogogue for the treatment of cancer related cachexia. The free base of anamorelin is chemically defined as:® (3R) 1 -(2-methylaIanyl~D ryptophyl)~3-(phenylraethyl)~3~piperidineearboxylie acid 1 ,2,2trimethyihydrazide,* 3-{(2R)-3-{(3R)-3-benzyi-3-| (trimethylhydrazino)carbonyi]piperidin-l»yl}-2-[(2»met hylaianyl)amino]-3-ox.opropyi}-IH-indole, or• 2-Amino-N-[(lR)-2-[(3R)-3~benzyWcarbony piperidin- 1 -yl] – 1-( 1 H-indol-3 -yl^^and has the below chemical structure; 
U.S. Patent No. 6,576,648 to Artkerson reports a process of preparing anamorelin as the fumarate salt, with the hydrochloride salt produced as an intermediate in Step (j) of Example 1 . U.S. Patent No. 7,825, 138 to Lorimer describes a process for preparing crystal forms of the free base of anamorelin.There is a need to develop anamorelin monohydrochloride as an active pharmaceutical ingredient with reduced impurities and improved stability over prior art forms of anamorelin hydrochloride, such as those described in U.S. Patent No, 6,576,648, having good solubility, bioavailability and processabi!ity. There is also a need to develop methods of producing pharmaceutically acceptable forms of anamorelin monohydrochloride thai have improved yield over prior art processes, reduced residual solvents, and controlled distribution of chloride content,it has unexpectedly been discovered that the process of making the hydrochloride salt of anamorelin described in Step (j) of U.S. Patent No. 6.576,648 can result in excessive levels of chloride in the final product, and that this excess chloride leads to the long-term instability of the final product due at least, partially to an increase in the amount of the less stable dihydrochloride salt of anamorelin. Conversely, because anamorelin free base is less soluble in water than the hydrochloride salt, deficient chloride content in the final product can lead to decreased solubility of the molecule. The process described in U.S. Patent No, 6,576,648 also yields a final product that contains more than 5000 ppm (0.5%) of residual solvents, which renders the product less desirable from a pharmaceutical standpoint, as described in CH Harmonized Tripartite Guideline. See Impurities; Guideline for residual solvents Q3C(R3). in order to overcome these problems, methods have been developed which, for the first time, allow for the efficient and precise control of the reaction between anarnorehn tree base and hydrochloric acid in situ, thereby increasing the yield of anarnorehn monohydrochioride from the reaction and reducing the incidence of unwanted anamorelin dihydroeh ride. According to the method, the free base of anamorelin is dissolved in an organic solvent and combined with water and hydrochloric acid, with the molar ratio of anarnorehn and chloride tightly controlled to prevent an excess of chloride in the final product. The water and hydrochloric acid can be added either sequentially or at the same time as long as two separate phases are formed. Without wishing to be bound by any theory, it is believed thai as the anamorelin free base in the organic phase is protonated by the hydrochloric acid it migrates into the aqueous phase. The controlled ratio of anamorelin free base and hydrochloric acid and homogenous distribution in the aqueous phase allows for the controlled formation of the monohydrochioride salt over the dihydrochloride, and the controlled distribution of the resulting chloride levels within individual batches and among multiple batches of anamorelin monohydrochioride.Thus, in a fust embodiment the invention provides methods for preparing anamorelin monohydrochioride or a composition comprising anamorelin monohydrochioride comprising: (a) dissolving anamorelin free base in an organic solvent to form a solution; (b) mixing said solution with water and hydrochloric acid for a time sufficient to: (i) react said anamorelin free base with said hydrochloric acid, and (ii) form an organic phase and an aqueous phase; (c) separating the aqueous phase from the organic phase; and (d) isolating anamorelin monohydrochioride from the aqueous phase.In a particularly preferred embodiment, the molar ratio of anamorelin to hydrochloric acid used in the process is less than or equal to 1 : 1 , so as to reduce the production of anamorelin dihydrochloride and other unwanted chemical species. Thus, for example, hydrochloric acid can be added at a molar ratio of from 0,90 to 1 ,0 relative to said anamorelin, from 0.90 to 0.99, or from 0.93 to 0.97.n another particularly preferred embodiment, the anamorelin monohydrochioride or a composition comprising anamorelin monohydrochioride is isolated from the aqueous phase via spray drying, preferably preceded by distillation. This technique has proven especially useful in the manufacture of anamorelin monohydrochioride or a composition comprising anamorelin monohydrochioride because of the excellent reduction in solvent levels observed, and the production of a stable amorphous form of anamorelin monohydrochioride or a composition comprising anamorelin monohydrochioride. In other embodiments, the invention relates to the various forms of anamorelin monohvdrochloride and compositions comprising anamorelin monohvdrochloride produced by the methods of the present invention. In a first embodiment, which derives from the controlled chloride content among batches accomplished by the present methods, the invention provides anamorelin monohvdrochloride or a composition comprising anamorelin monohydrochloride having an inter-batch chloride content of from 5.8 to 6.2%, preferably from 5.8 to less than 6.2%. Alternatively, the invention provides anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride having a molar ratio of chloride to anamorelin less than or equal to 1 : 1 , such as from 0.9 to 1.0 or 0.99, in yet another embodiment the invention provides an amorphous form of anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride. Further descriptions of the anamorelin monohydrochloride and compositions comprising the anamorelin monohydrochloride are given in the detailed description which follows.EXAMPLE 1 . PREPARATION OF ANAMOREUN HYDROCHLORIDEVarious methods have been developed to prepare the hydrochloric acid salt of anarnorelin, with differing results.In a first method, which is the preferred method of the present invention, anarnorelin free base was carefully measured and dissolved in isopropyl acetate. Anarnorelin free base was prepared according to known method (e.g., U.S. Patent No, 6,576,648). A fixed volume of HCl in water containing various molar ratios (0.80, 0,95, 1.00 or 1.05) of HCl relative to the anarnorelin free base was then combined with the anamorelin/isopropyl acetate solution, to form a mixture having an organic and an aqueous phase, The aqueous phase of the mixture was separated from the organic phase and the resulting aqueous phase was concentrated by spray drying to obtain the batches of anarnorelin monohydrochloride (or a composition comprising anarnorelin monohydrochloride ) shown in Table 1 A.Approximately 150mg of the resulting spray dried sample of anarnorelin monohydrochloride (or composition comprising anarnorelin monohydrochloride) was accurately weighed out and dissolved in methanol (50mL). Acetic acid (5mL) and distilled water (5mL) were added to the mixture. The resulting mixture was potentiometricaJ ly titrated using 0,0 IN silver nitrate and the e dpoint was determined. A blank determination was also performed and correction was made, if necessary. The chloride content in the sample was calculated by the following formula. This measurement method of chloride content was performed without any cations other than proton (! !  ).Chloride content (%) = VxNx35.453x l 00x l 00/{Wx[1 00-(water content (%))-(residual solvent (%))]}V: volume at the endpoint (ml.)N; actual normality of 0.01 mol/L silver nitrate35.453 : atomic weight of ChlorineW: weight of sample (mg)TABLE 1 AHCl Chloride ContentThis data showed that anamorelin monohydrochlonde produced by a fixed volume of HCl in water containing 0.80 or 1 .05 molar equivalents of HC1 relative to anamorelin free base had levels of chloride thai were undesirable, and associated with product instability as shown in Example 3.Alternatively, a fixed volume of HCl in water containing 0.95 moles of HCl relative to anamorelin free base was used to prepare anamorelin monohydrochlonde (or composition comprising anamorelin monohydrochloride) as follows. Anamorelin free base (18.8g, 34.4mmoi) and isopropyl acetate (341.8g) were mixed in a 1000 mL flask. The mixture was heated at 40±5°C to confirm dissolution of the crystals and then cooled at 25±5°C. Distilled water (22.3g) and 3.6% diluted hydrochloric acid (33. Ig, 32.7mmoL 0.95 equivalents) were added into the flask and washed with distilled water. After 30 minutes stirring, the reaction was static for more than 15 minutes and the lower layer (aqueous layer) was transferred into a separate 250mL flask. Distilled water was added to the flask and concentrated under pressure at 50i5cC. The resulting aqueous solution was then filtered and product isolated by spray drying to afford anamorelin monohydrochlonde A (the present invention).The physical properties of anamorelin monohydrochloride A were compared to anamorelin monohydrochloride produced by a traditional comparative method (“anamorelin monohydrochloride B”) (comparative example). Anamorelin mono hydrochloride B in the comparative example was produced by bubbling HCl gas into isopropyl acetate to produce a 2M solution of HCl, and reacting 0.95 molar equivalents of the 2M HCl in isopropyl acetate with anamorelin free base. The physical properties of anamorelin monohydrochloride B are reported in Table IB. This data shows that when 0.95 equivalents of HCl is added to anamorelin free base, the chloride content (or amount of anamorelin dihydrochloride) is increased, even when a stoichiometric ratio of hydrochloride to anamorelin of less than 1 ,0 is used, possibly due to uncontrolled precipitation. In addition, this data shows that the concentration of residual solvents in anamorelin monohydrochloride B was greater than the concentration in anamorelin monohydrochloride A, TABLE I B 
A similar decrease in residual solvent concentration was observed when 2-methyltetrahydrofuran was used as the dissolving solvent for anamorelin free base instead of isopropvi acetate in the process for preparing spray dried anamorelin monohydrochloride A (data not reported).The residual solvent (organic volatile impurities) concentration (specifically isopropyl acetate) of anamorelin monohydrochloride in TABLE IB was measured using gas chromatography (GC-2010, Shimadzu Corporation) according to the conditions shown in TABLE 1 C,

References

  1. ^ Leese PT, Trang JM, Blum RA, de Groot E (March 2015). “An open-label clinical trial of the effects of age and gender on the pharmacodynamics, pharmacokinetics and safety of the ghrelin receptor agonist anamorelin”Clinical Pharmacology in Drug Development4 (2): 112–120. doi:10.1002/cpdd.175PMC 4657463PMID 26640742.
  2. ^ Currow DC, Abernethy AP (April 2014). “Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome”. Future Oncology10 (5): 789–802. doi:10.2217/fon.14.14PMID 24472001.
  3. Jump up to:a b c Garcia JM, Polvino WJ (June 2009). “Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers”. Growth Hormone & IGF Research19 (3): 267–73. doi:10.1016/j.ghir.2008.12.003PMID 19196529.
  4. Jump up to:a b Garcia JM, Boccia RV, Graham CD, Yan Y, Duus EM, Allen S, Friend J (January 2015). “Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials”. The Lancet. Oncology16 (1): 108–16. doi:10.1016/S1470-2045(14)71154-4PMID 25524795.
  5. Jump up to:a b Garcia JM, Friend J, Allen S (January 2013). “Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study”. Supportive Care in Cancer21 (1): 129–37. doi:10.1007/s00520-012-1500-1PMID 22699302S2CID 22853697.
  6. ^ Zhang H, Garcia JM (June 2015). “Anamorelin hydrochloride for the treatment of cancer-anorexia-cachexia in NSCLC”Expert Opinion on Pharmacotherapy16 (8): 1245–53. doi:10.1517/14656566.2015.1041500PMC 4677053PMID 25945893.
  7. ^ Temel JS, Abernethy AP, Currow DC, Friend J, Duus EM, Yan Y, Fearon KC (April 2016). “Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials”. The Lancet. Oncology17 (4): 519–531. doi:10.1016/S1470-2045(15)00558-6PMID 26906526.
  8. ^ “Adlumiz”. European Medicines Agency.
  9. ^ “Refusal of the marketing authorisation for Adlumiz (anamorelin hydrochloride): Outcome of re-examination” (PDF). European Medicines Agency. 15 September 2017.

External links

Clinical data
Routes of
administration
Oral
ATC codeNone
Pharmacokinetic data
Elimination half-life6–7 hours[1]
Identifiers
showIUPAC name
CAS Number249921-19-5
PubChem CID9828911
ChemSpider8004650
UNIIDD5RBA1NKF
CompTox Dashboard (EPA)DTXSID20179702 
Chemical and physical data
FormulaC31H42N6O3
Molar mass546.716 g·mol−1
3D model (JSmol)Interactive image
hideSMILESCC(C)(C(=O)NC(CC1=CNC2=CC=CC=C21)C(=O)N3CCCC(C3)(CC4=CC=CC=C4)C(=O)N(C)N(C)C)N
hideInChIInChI=1S/C31H42N6O3/c1-30(2,32)28(39)34-26(18-23-20-33-25-15-10-9-14-24(23)25)27(38)37-17-11-16-31(21-37,29(40)36(5)35(3)4)19-22-12-7-6-8-13-22/h6-10,12-15,20,26,33H,11,16-19,21,32H2,1-5H3,(H,34,39)/t26-,31-/m1/s1Key:VQPFSIRUEPQQPP-MXBOTTGLSA-N

///////Anamorelin hydrochloride, Anamorelin, APPROVALS 2021,  JAPAN 2021,  PMDA,  Adlumiz, 22/1/2021, アナモレリン塩酸塩, анаморелин , أناموريلين ,阿那瑞林 , ONO 7643RC 1291ST 1291, 

#Anamorelin hydrochloride, #Anamorelin, #APPROVALS 2021,  #JAPAN 2021,  #PMDA,  #Adlumiz, 22/1/2021, #アナモレリン塩酸塩, #анаморелин , #أناموريلين ,阿那瑞林 , #ONO 7643, #RC 1291, #ST 1291, 

Tozinameran, Pfizer–BioNTech COVID‑19 vaccine


Covid19 vaccine biontech pfizer 3.jpg

SEQUENCE1

gagaauaaac uaguauucuu cuggucccca cagacucaga gagaacccgc51caccauguuc guguuccugg ugcugcugcc ucuggugucc agccagugug101ugaaccugac caccagaaca cagcugccuc cagccuacac caacagcuuu151accagaggcg uguacuaccc cgacaaggug uucagaucca gcgugcugca201cucuacccag gaccuguucc ugccuuucuu cagcaacgug accugguucc251acgccaucca cguguccggc accaauggca ccaagagauu cgacaacccc301gugcugcccu ucaacgacgg gguguacuuu gccagcaccg agaaguccaa351caucaucaga ggcuggaucu ucggcaccac acuggacagc aagacccaga401gccugcugau cgugaacaac gccaccaacg uggucaucaa agugugcgag451uuccaguucu gcaacgaccc cuuccugggc gucuacuacc acaagaacaa501caagagcugg auggaaagcg aguuccgggu guacagcagc gccaacaacu551gcaccuucga guacgugucc cagccuuucc ugauggaccu ggaaggcaag601cagggcaacu ucaagaaccu gcgcgaguuc guguuuaaga acaucgacgg651cuacuucaag aucuacagca agcacacccc uaucaaccuc gugcgggauc701ugccucaggg cuucucugcu cuggaacccc ugguggaucu gcccaucggc751aucaacauca cccgguuuca gacacugcug gcccugcaca gaagcuaccu801gacaccuggc gauagcagca gcggauggac agcuggugcc gccgcuuacu851augugggcua ccugcagccu agaaccuucc ugcugaagua caacgagaac901ggcaccauca ccgacgccgu ggauugugcu cuggauccuc ugagcgagac951aaagugcacc cugaaguccu ucaccgugga aaagggcauc uaccagacca1001gcaacuuccg ggugcagccc accgaaucca ucgugcgguu ccccaauauc1051accaaucugu gccccuucgg cgagguguuc aaugccacca gauucgccuc1101uguguacgcc uggaaccgga agcggaucag caauugcgug gccgacuacu1151ccgugcugua caacuccgcc agcuucagca ccuucaagug cuacggcgug1201uccccuacca agcugaacga ccugugcuuc acaaacgugu acgccgacag1251cuucgugauc cggggagaug aagugcggca gauugccccu ggacagacag1301gcaagaucgc cgacuacaac uacaagcugc ccgacgacuu caccggcugu1351gugauugccu ggaacagcaa caaccuggac uccaaagucg gcggcaacua1401caauuaccug uaccggcugu uccggaaguc caaucugaag cccuucgagc1451gggacaucuc caccgagauc uaucaggccg gcagcacccc uuguaacggc1501guggaaggcu ucaacugcua cuucccacug caguccuacg gcuuucagcc1551cacaaauggc gugggcuauc agcccuacag agugguggug cugagcuucg1601aacugcugca ugccccugcc acagugugcg gcccuaagaa aagcaccaau1651cucgugaaga acaaaugcgu gaacuucaac uucaacggcc ugaccggcac1701cggcgugcug acagagagca acaagaaguu ccugccauuc cagcaguuug1751gccgggauau cgccgauacc acagacgccg uuagagaucc ccagacacug1801gaaauccugg acaucacccc uugcagcuuc ggcggagugu cugugaucac1851cccuggcacc aacaccagca aucagguggc agugcuguac caggacguga1901acuguaccga agugcccgug gccauucacg ccgaucagcu gacaccuaca1951uggcgggugu acuccaccgg cagcaaugug uuucagacca gagccggcug2001ucugaucgga gccgagcacg ugaacaauag cuacgagugc gacaucccca2051ucggcgcugg aaucugcgcc agcuaccaga cacagacaaa cagcccucgg2101agagccagaa gcguggccag ccagagcauc auugccuaca caaugucucu2151gggcgccgag aacagcgugg ccuacuccaa caacucuauc gcuaucccca2201ccaacuucac caucagcgug accacagaga uccugccugu guccaugacc2251aagaccagcg uggacugcac cauguacauc ugcggcgauu ccaccgagug2301cuccaaccug cugcugcagu acggcagcuu cugcacccag cugaauagag2351cccugacagg gaucgccgug gaacaggaca agaacaccca agagguguuc2401gcccaaguga agcagaucua caagaccccu ccuaucaagg acuucggcgg2451cuucaauuuc agccagauuc ugcccgaucc uagcaagccc agcaagcgga2501gcuucaucga ggaccugcug uucaacaaag ugacacuggc cgacgccggc2551uucaucaagc aguauggcga uugucugggc gacauugccg ccagggaucu2601gauuugcgcc cagaaguuua acggacugac agugcugccu ccucugcuga2651ccgaugagau gaucgcccag uacacaucug cccugcuggc cggcacaauc2701acaagcggcu ggacauuugg agcaggcgcc gcucugcaga uccccuuugc2751uaugcagaug gccuaccggu ucaacggcau cggagugacc cagaaugugc2801uguacgagaa ccagaagcug aucgccaacc aguucaacag cgccaucggc2851aagauccagg acagccugag cagcacagca agcgcccugg gaaagcugca2901ggacgugguc aaccagaaug cccaggcacu gaacacccug gucaagcagc2951uguccuccaa cuucggcgcc aucagcucug ugcugaacga uauccugagc3001agacuggacc cuccugaggc cgaggugcag aucgacagac ugaucacagg3051cagacugcag agccuccaga cauacgugac ccagcagcug aucagagccg3101ccgagauuag agccucugcc aaucuggccg ccaccaagau gucugagugu3151gugcugggcc agagcaagag aguggacuuu ugcggcaagg gcuaccaccu3201gaugagcuuc ccucagucug ccccucacgg cgugguguuu cugcacguga3251cauaugugcc cgcucaagag aagaauuuca ccaccgcucc agccaucugc3301cacgacggca aagcccacuu uccuagagaa ggcguguucg uguccaacgg3351cacccauugg uucgugacac agcggaacuu cuacgagccc cagaucauca3401ccaccgacaa caccuucgug ucuggcaacu gcgacgucgu gaucggcauu3451gugaacaaua ccguguacga cccucugcag cccgagcugg acagcuucaa3501agaggaacug gacaaguacu uuaagaacca cacaagcccc gacguggacc3551ugggcgauau cagcggaauc aaugccagcg ucgugaacau ccagaaagag3601aucgaccggc ugaacgaggu ggccaagaau cugaacgaga gccugaucga3651ccugcaagaa cuggggaagu acgagcagua caucaagugg cccugguaca3701ucuggcuggg cuuuaucgcc ggacugauug ccaucgugau ggucacaauc3751augcuguguu gcaugaccag cugcuguagc ugccugaagg gcuguuguag3801cuguggcagc ugcugcaagu ucgacgagga cgauucugag cccgugcuga3851agggcgugaa acugcacuac acaugaugac ucgagcuggu acugcaugca3901cgcaaugcua gcugccccuu ucccguccug gguaccccga gucucccccg3951accucggguc ccagguaugc ucccaccucc accugcccca cucaccaccu4001cugcuaguuc cagacaccuc ccaagcacgc agcaaugcag cucaaaacgc4051uuagccuagc cacaccccca cgggaaacag cagugauuaa ccuuuagcaa4101uaaacgaaag uuuaacuaag cuauacuaac cccaggguug gucaauuucg4151ugccagccac acccuggagc uagcaaaaaa aaaaaaaaaa aaaaaaaaaa4201aaaagcauau gacuaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa4251aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa

Sequence Modifications

TypeLocationDescription
modified baseg-1m7g
modified baseg-13′-me
modified basea-2am
uncommon linkg-1 – a-25′->5′ triphosphate

Tozinameran

Pfizer–BioNTech COVID-19 vaccine

トジナメラン (JAN);
コロナウイルス修飾ウリジンRNAワクチン;

RNA (recombinant 5′-​[1,​2-​[(3′-​O-​methyl)​m7G-​(5’→5′)​-​ppp-​Am]​]​-​capped all uridine→N1-​methylpseudouridine-​substituted severe acute respiratory syndrome coronavirus 2 secretory signal peptide contg. spike glycoprotein S1S2-​specifying plus 5′- and 3′-​untranslated flanking region-​contg. poly(A)​-​tailed messenger BNT162b2)​, inner salt

Nucleic Acid Sequence

Sequence Length: 42841106 a 1315 c 1062 g 801 umodified

APPROVED JAPAN Comirnaty, 2021/2/14

CAS 2417899-77-3

5085ZFP6SJ

UNII-5085ZFP6SJ

Bnt-162b2

Bnt162b2

Active immunization (SARS-CoV-2)

Tozinameran is mRNA encoding full length of spike protein analog of SARS-CoV-2

Target Severe acute respiratory syndrome coronavirus 2 spike glycoprotein

Coronavirus disease – COVID-19

FORMROUTESTRENGTH
Injection, suspensionIntramuscular0.23 mg/1.8mL
SuspensionIntramuscular30 mcg
NAMEINGREDIENTSDOSAGEROUTELABELLERMARKETING STARTMARKETING END  
Pfizer-BioNTech Covid-19 VaccinePfizer-BioNTech Covid-19 Vaccine (0.23 mg/1.8mL)Injection, suspensionIntramuscularPfizer Manufacturing Belgium NV2020-12-12Not applicableUS flag 
NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
Comirnaty 30 mcgIntramuscularBio N Tech Manufacturing Gmb H2021-01-06Not applicableEU flag 
Pfizer-BioNTech Covid-19 VaccineSuspension30 mcgIntramuscularBiontech Manufacturing Gmbh2020-12-14Not applicableCanada flag 
Pfizer-BioNTech Covid-19 VaccineInjection, suspension0.23 mg/1.8mLIntramuscularPfizer Manufacturing Belgium NV2020-12-12Not applicableUS flag 

The Pfizer–BioNTech COVID‑19 vaccine (pINNtozinameran), sold under the brand name Comirnaty,[13] is a COVID-19 vaccine developed by the German company BioNTech in cooperation with Pfizer. It is both the first COVID-19 vaccine to be authorized by a stringent regulatory authority for emergency use[14][15] and the first cleared for regular use.[16]

It is given by intramuscular injection. It is an RNA vaccine composed of nucleoside-modified mRNA (modRNA) encoding a mutated form of the spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles.[17] The vaccination requires two doses given three weeks apart.[18][19][20] Its ability to prevent severe infection in children, pregnant women, or immunocompromised people is unknown, as is the duration of the immune effect it confers.[20][21][22] As of February 2021, it is one of two RNA vaccines being deployed against COVID‑19, the other being the Moderna COVID‑19 vaccine. A third mRNA-based COVID-19 vaccine, CVnCoV, is in late-stage testing.[23]

Trials began in April 2020; by November, the vaccine had been tested on more than 40,000 people.[24] An interim analysis of study data showed a potential efficacy of over 90% in preventing infection within seven days of a second dose.[19][20] The most common side effects include mild to moderate pain at the injection site, fatigue, and headache.[25][26] As of December 2020, reports of serious side effects, such as allergic reactions, have been very rare,[a] and no long-term complications have been reported.[28] Phase III clinical trials are ongoing: monitoring of the primary outcomes will continue until August 2021, while monitoring of the secondary outcomes will continue until January 2023.[18]

In December 2020, the United Kingdom was the first country to authorize the vaccine on an emergency basis,[28] soon followed by the United States, the European Union and several other countries globally.[29][30][6][31][32]

BioNTech is the initial developer of the vaccine, and partnered with Pfizer for development, clinical research, overseeing the clinical trials, logistics, finances and for manufacturing worldwide with the exception of China.[33] The license to distribute and manufacture in China was purchased by Fosun, alongside its investment in BioNTech.[34][35] Distribution in Germany and Turkey is by BioNTech itself.[36] Pfizer indicated in November 2020, that 50 million doses could be available globally by the end of 2020, with about 1.3 billion doses in 2021.[20]

Pfizer has advanced purchase agreements of about US$3 billion for providing a licensed vaccine in the United States, the European Union, the United Kingdom, Japan, Canada, Peru, Singapore, and Mexico.[37][38] Distribution and storage of the vaccine is a logistics challenge because it needs to be stored at temperatures between −80 and −60 °C (−112 and −76 °F),[39] until five days before vaccination[38][39] when it can be stored at 2 to 8 °C (36 to 46 °F), and up to two hours at temperatures up to 25 °C (77 °F)[40][11] or 30 °C (86 °F).[41][42] In February 2021, Pfizer and BioNTech asked the U.S. Food and Drug Administration (FDA) to update the emergency use authorization (EUA) to permit the vaccine to be stored at between −25 and −15 °C (−13 and 5 °F) for up to two weeks before use.[43]

Development and funding

Before COVID-19 vaccines, a vaccine for an infectious disease had never before been produced in less than several years, and no vaccine existed for preventing a coronavirus infection in humans.[44] After the COVID-19 virus was detected in December 2019,[45] the development of BNT162b2 was initiated on 10 January 2020, when the SARS-CoV-2 genetic sequences were released by the Chinese Center for Disease Control and Prevention via GISAID,[46][47][48] triggering an urgent international response to prepare for an outbreak and hasten development of preventive vaccines.[49][50]

In January 2020, German biotech-company BioNTech started its program ‘Project Lightspeed’ to develop a vaccine against the new COVID‑19 virus based on its already established mRNA-technology.[24] Several variants of the vaccine were created in their laboratories in Mainz, and 20 of those were presented to experts of the Paul-Ehrlich-Institute in Langen.[51] Phase I / II Trials were started in Germany on 23 April 2020, and in the U.S. on 4 May 2020, with four vaccine candidates entering clinical testing. The Initial Pivotal Phase II / III Trial with the lead vaccine candidate ‘BNT162b2’ began in July. The Phase III results indicating a 95% effectiveness of the developed vaccine were published on 18 November 2020.[24]

BioNTech received a US$135 million investment from Fosun in March 2020, in exchange for 1.58 million shares in BioNTech and the future development and marketing rights of BNT162b2 in China,[35] Hong Kong, Macau and Taiwan.[52]

In June 2020, BioNTech received €100 million (US$119 million) in financing from the European Commission and European Investment Bank.[53] In September 2020, the German government granted BioNTech €375 million (US$445 million) for its COVID‑19 vaccine development program.[54]

Pfizer CEO Albert Bourla stated that he decided against taking funding from the US government’s Operation Warp Speed for the development of the vaccine “because I wanted to liberate our scientists [from] any bureaucracy that comes with having to give reports and agree how we are going to spend the money in parallel or together, etc.” Pfizer did enter into an agreement with the US for the eventual distribution of the vaccine, as with other countries.[55]

Clinical trials

See also: COVID-19 vaccine § Clinical trials started in 2020

Preliminary results from Phase I–II clinical trials on BNT162b2, published in October 2020, indicated potential for its efficacy and safety.[17][56] During the same month, the European Medicines Agency (EMA) began a periodic review of BNT162b2.[57]

The study of BNT162b2 is a continuous-phase trial in Phase III as of November 2020.[18] It is a “randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection, and efficacy study in healthy individuals”.[18] The early-stage research determined the safety and dose level for two vaccine candidates, with the trial expanding during mid-2020 to assess efficacy and safety of BNT162b2 in greater numbers of participants, reaching tens of thousands of people receiving test vaccinations in multiple countries in collaboration with Pfizer and Fosun.[20][35]

The Phase III trial assesses the safety, efficacy, tolerability, and immunogenicity of BNT162b2 at a mid-dose level (two injections separated by 21 days) in three age groups: 12–15 years, 16–55 years or above 55 years.[18] For approval in the EU, an overall vaccine efficacy of 95% was confirmed by the EMA.[58] The EMA clarified that the second dose should be administered three weeks after the first dose.[59]

Efficacy endpointVaccine efficacy (95% confidence interval) [%]
After dose 1 to before dose 252.4 (29.5, 68.4)
≥10 days after dose 1 to before dose 286.7 (68.6, 95.4)
Dose 2 to 7 days after dose 290.5 (61.0, 98.9)
≥7 days after dose 2 (subjects without evidence of infection prior to 7 days after dose 2)
Overall95.0 (90.0, 97.9)
16–55 years95.6 (89.4, 98.6)
≥55 years93.7 (80.6, 98.8)
≥65 years94.7 (66.7, 99.9)

The ongoing Phase III trial, which is scheduled to run from 2020 to 2022, is designed to assess the ability of BNT162b2 to prevent severe infection, as well as the duration of immune effect.[20][21][22]

Pfizer and BioNTech started a Phase II/III randomized control trial in healthy pregnant women 18 years of age and older (NCT04754594).[60] The study will evaluate 30 µg of BNT162b2 or placebo administered via intramuscular injection in 2 doses, 21 days apart. The Phase II portion of the study will include approximately 350 pregnant women randomized 1:1 to receive BNT162b2 or placebo at 27 to 34 weeks’ gestation. The Phase III portion of this study will assess the safety, tolerability, and immunogenicity of BNT162b2 or placebo among pregnant women enrolled at 24 to 34 weeks’ gestation. Pfizer and BioNTech announced on 18 February 2021 that the first participants received their first dose in this trial.[61]

Vaccine technology

See also: RNA vaccine and COVID-19 vaccine § Technology platforms

The BioNTech technology for the BNT162b2 vaccine is based on use of nucleoside-modified mRNA (modRNA) which encodes part of the spike protein found on the surface of the SARS-CoV-2 coronavirus (COVID‑19), triggering an immune response against infection by the virus protein.[62]

The vaccine candidate BNT162b2 was chosen as the most promising among three others with similar technology developed by BioNTech.[18][62][56] Prior to choosing BNT162b2, BioNTech and Pfizer had conducted Phase I trials on BNT162b1 in Germany and the United States, while Fosun performed a Phase I trial in China.[17][63] In these Phase I studies, BNT162b2 was shown to have a better safety profile than the other three BioNTech candidates.[63]

Sequence

The modRNA sequence of the vaccine is 4,284 nucleotides long.[64] It consists of a five-prime cap; a five prime untranslated region derived from the sequence of human alpha globin; a signal peptide (bases 55–102) and two proline substitutions (K986P and V987P, designated “2P”) that cause the spike to adopt a prefusion-stabilized conformation reducing the membrane fusion ability, increasing expression and stimulating neutralizing antibodies;[17][65] a codon-optimized gene of the full-length spike protein of SARS-CoV-2 (bases 103–3879); followed by a three prime untranslated region (bases 3880–4174) combined from AES and mtRNR1 selected for increased protein expression and mRNA stability[66] and a poly(A) tail comprising 30 adenosine residues, a 10-nucleotide linker sequence, and 70 other adenosine residues (bases 4175–4284).[64] The sequence contains no uridine residues; they are replaced by 1-methyl-3′-pseudouridylyl.[64]

Composition

In addition to the mRNA molecule, the vaccine contains the following inactive ingredients (excipients):[67][68][8]

The first four of these are lipids. The lipids and modRNA together form nanoparticles. ALC-0159 is a polyethylene glycol conjugate (that is, a PEGylated lipid).[69]

The vaccine is supplied in a multidose vial as “a white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection“.[11][12] It must be thawed to room temperature and diluted with normal saline before administration.[12]

Authorizations

Expedited

The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) gave the vaccine “rapid temporary regulatory approval to address significant public health issues such as a pandemic” on 2 December 2020, which it is permitted to do under the Medicines Act 1968.[70] It was the first COVID‑19 vaccine to be approved for national use after undergoing large scale trials,[71] and the first mRNA vaccine to be authorized for use in humans.[14][72] The United Kingdom thus became the first Western country to approve a COVID‑19 vaccine for national use,[73] although the decision to fast-track the vaccine was criticised by some experts.[74]

On 8 December 2020, Margaret “Maggie” Keenan, 90, from Fermanagh, became the first person to receive the vaccine.[75] In a notable example of museums documenting the pandemic, the vial and syringe used for that first dose were saved acquired by The Science Museum in London for its permanent collection.[76] By 20 December, 521,594 UK residents had received the vaccine as part of the national vaccination programme. 70% had been to people aged 80 or over.[77]

After the United Kingdom, the following countries expedited processes to approve the Pfizer–BioNTech COVID‑19 vaccine for use: Argentina,[78] Australia,[79] Bahrain,[80] Canada,[7][81] Chile,[82] Costa Rica,[83] Ecuador,[82] Hong Kong,[84] Iraq,[85] Israel,[86] Jordan,[87] Kuwait,[88] Mexico,[89] Oman,[90] Panama,[91] the Philippines,[92] Qatar,[93] Saudi Arabia,[32][94] Singapore,[95][96] the United Arab Emirates,[97] and the United States.[10]

The World Health Organization (WHO) authorized it for emergency use.[98]

In the United States, an emergency use authorization (EUA) is “a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the current COVID‑19 pandemic”, according to the FDA.[99] Following an EUA issuance, BioNTech and Pfizer are expected to continue the Phase III clinical trial to finalize safety and efficacy data, leading to application for licensure (approval) of the vaccine in the United States.[99][100][101] The United States Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) approved recommendations for vaccination of those aged 16 years or older.[102][103]

Standard

On 19 December 2020, the Swiss Agency for Therapeutic Products (Swissmedic) approved the Pfizer–BioNTech COVID‑19 vaccine for regular use, two months after receiving the application, stating that the vaccine fully complied with the requirements of safety, efficacy and quality. This is the first authorization under a standard procedure.[1][104] On 23 December, a Lucerne resident, a 90-year-old woman, became the first person to receive the vaccine in Switzerland.[105] This marked the beginning of mass vaccination in continental Europe.[106]

On 21 December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting conditional marketing authorization for the Pfizer–BioNTech COVID‑19 vaccine under the brand name Comirnaty.[2][107][108] The recommendation was accepted by the European Commission the same day.[107][109]

On February 23, 2021, the Brazilian Health Regulatory Agency approved the Pfizer–BioNTech COVID-19 vaccine under its standard marketing authorization procedure. It became the first COVID-19 vaccine to receive definitive registration rather than emergency use authorization in the country.[110]

Adverse effects

The adverse effect profile of the Pfizer–BioNTech COVID‑19 vaccine is similar to that of other adult vaccines.[20] During clinical trials, the side effects deemed very common[a] are (in order of frequency): pain and swelling at the injection site, tiredness, headache, muscle aches, chills, joint pain, and fever.[68] Fever is more common after the second dose.[68] These effects are predictable and to be expected, and it is particularly important that people be aware of this to prevent vaccine hesitancy.[111]

Severe allergic reaction has been observed in approximately 11 cases per million doses of vaccine administered.[112][113] According to a report by the US Centers for Disease Control and Prevention 71% of those allergic reactions happened within 15 minutes of vaccination and mostly (81%) among people with a documented history of allergies or allergic reactions.[112] The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) advised on 9 December 2020, that people who have a history of “significant” allergic reaction should not receive the Pfizer–BioNTech COVID‑19 vaccine.[114][115][116] On 12 December, the Canadian regulator followed suit, noting that: “Both individuals in the U.K. had a history of severe allergic reactions and carried adrenaline auto injectors. They both were treated and have recovered.”[67]

On 28 January 2021, the European Union published a COVID-19 vaccine safety update which found that “the benefits of Comirnaty in preventing COVID‑19 continue to outweigh any risks, and there are no recommended changes regarding the use the vaccine.”[113][117] No new side effects were identified.[113]

Manufacturing

A doctor holding the Pfizer vaccine

Pfizer and BioNTech are manufacturing the vaccine in their own facilities in the United States and in Europe in a three-stage process. The first stage involves the molecular cloning of DNA plasmids that code for the spike protein by infusing them into Escherichia coli bacteria. In the United States, this stage is conducted at a small pilot plant in Chesterfield, Missouri[118] (near St. Louis). After four days of growth, the bacteria are killed and broken open, and the contents of their cells are purified over a week and a half to recover the desired DNA product. The DNA is stored in tiny bottles and frozen for shipment. Safely and quickly transporting the DNA at this stage is so important that Pfizer has used its company jet and helicopter to assist.[119]

The second stage is being conducted at plants in Andover, Massachusetts[120] in the United States, and in Germany. The DNA is used as a template to build the desired mRNA strands. Once the mRNA has been created and purified, it is frozen in plastic bags about the size of a large shopping bag, of which each can hold up to 5 to 10 million doses. The bags are placed on special racks on trucks which take them to the next plant.[119]

The third stage is being conducted at plants in Portage, Michigan[121] (near Kalamazoo) in the United States, and Puurs in Belgium. This stage involves combining the mRNA with lipid nanoparticles, then filling vials, boxing vials, and freezing them.[119] Croda International subsidiary Avanti Polar Lipids is providing the requisite lipids.[122] As of November 2020, the major bottleneck in the manufacturing process was combining mRNA with lipid nanoparticles.[119]

In February 2021, Pfizer revealed this entire sequence initially took about 110 days on average from start to finish, and that the company was making progress on reducing that number to 60 days.[123] Vaccine manufacturers normally take several years to optimize the process of making a particular vaccine for speed and cost-effectiveness before attempting large-scale production.[123] Due to the urgency presented by the COVID-19 pandemic, Pfizer began production immediately with the process by which the vaccine had been originally formulated in the laboratory, then started to identify ways to safely speed up and scale up that process.[123]

BioNTech announced in September 2020 that it had signed an agreement to acquire from Novartis a manufacturing facility in Marburg, Germany, to expand their vaccine production capacity.[124] Once fully operational, the facility would produce up to 750 million doses per year, or over 60 million doses per month. The site will be the third BioNTech facility in Europe which currently produces the vaccine, while Pfizer operates at least four production sites in the United States and Europe.

Advance orders and logistics

Pfizer indicated in its 9 November press release that 50 million doses could be available by the end of 2020, with about 1.3 billion doses provided globally by 2021.[20] In February 2021, BioNTech announced it would increase production by more than 50% to manufacture two billion doses in 2021.[125]

In July 2020, the vaccine development program Operation Warp Speed placed an advance order of US$1.95 billion with Pfizer to manufacture 100 million doses of a COVID‑19 vaccine for use in the United States if the vaccine was shown to be safe and effective.[34][126][127][128] By mid-December 2020, Pfizer had agreements to supply 300 million doses to the European Union,[129] 120 million doses to Japan,[130] 40 million doses (10 million before 2021) to the United Kingdom,[22] 20 million doses to Canada,[131] an unspecified number of doses to Singapore,[132] and 34.4 million doses to Mexico.[133] Fosun also has agreements to supply 10 million doses to Hong Kong and Macau.[134] The Hong Kong government said it would receive its first batch of one million doses by the first quarter of 2021.[135]

BioNTech and Fosun agreed to supply Mainland China with a batch of 100 million doses in 2021, subject to regulatory approval. The initial supply will be delivered from BioNTech’s production facilities in Germany.[136]

The vaccine is being delivered in vials that, once diluted, contain 2.25 ml of vaccine (0.45 ml frozen plus 1.8ml diluent).[101] According to the vial labels, each vial contains five 0.3 ml doses, however excess vaccine may be used for one, or possibly two, additional doses.[101][137] The use of low dead space syringes to obtain the additional doses is preferable, and partial doses within a vial should be discarded.[101][138] The Italian Medicines Agency officially authorized the use of excess doses remaining within single vials.[139] As of 8 January 2021, each vial contains six doses.[68][140][141][138] In the United States, vials will be counted as five doses when accompanied by regular syringes and as six doses when accompanied by low dead space syringes.[142]

Temperature the Pfizer vaccine must be kept at to ensure effectiveness, roughly between −80 and −60 °C (−112 and −76 °F)

Logistics in developing countries which have preorder agreements with Pfizer—such as Ecuador and Peru—remain unclear.[38] Even high-income countries have limited cold chain capacity for ultracold transport and storage of a vaccine that degrades within five days when thawed, and requires two shots three weeks apart.[38] The vaccine needs to be stored and transported at ultracold temperatures between −80 and −60 °C (−112 and −76 °F),[39][22][38][143][144] much lower than for the similar Moderna vaccine. The head of Indonesia‘s Bio Farma Honesti Basyir stated that purchasing the vaccine is out of the question for the world’s fourth-most populous country, given that it did not have the necessary cold chain capability. Similarly, India’s existing cold chain network can only handle temperatures between 2 and 8 °C (36 and 46 °F), far above the requirements of the vaccine.[145][146]

In January 2021, Pfizer and BioNTech offered to supply 50 million doses of COVID‑19 vaccine for health workers across Africa between March and the end of 2021, at a discounted price of US$10 per dose.[147]

Name

BNT162b2 was the code name during development and testing,[17][148] tozinameran is the proposed international nonproprietary name (pINN),[149] and Comirnaty is the brand name.[1][2] According to BioNTech, the name Comirnaty “represents a combination of the terms COVID‑19, mRNA, community, and immunity.”[150][151]

The vaccine also has the common name “COVID‑19 mRNA vaccine (nucleoside-modified)”[2] and may be distributed in packaging with the name Pfizer–BioNTech COVID‑19 Vaccine.”[152]

How the Pfizer-BioNTech Vaccine Works

By Jonathan Corum and Carl ZimmerUpdated Jan. 21, 2021Leer en español

The German company BioNTech partnered with Pfizer to develop and test a coronavirus vaccine known as BNT162b2, the generic name tozinameran or the brand name Comirnaty. A clinical trial demonstrated that the vaccine has an efficacy rate of 95 percent in preventing Covid-19.

A Piece of the Coronavirus

The SARS-CoV-2 virus is studded with proteins that it uses to enter human cells. These so-called spike proteins make a tempting target for potential vaccines and treatments.

Spikes

Spike

protein

gene

CORONAVIRUS

Like the Moderna vaccine, the Pfizer-BioNTech vaccine is based on the virus’s genetic instructions for building the spike protein.

mRNA Inside an Oily Shell

The vaccine uses messenger RNA, genetic material that our cells read to make proteins. The molecule — called mRNA for short — is fragile and would be chopped to pieces by our natural enzymes if it were injected directly into the body. To protect their vaccine, Pfizer and BioNTech wrap the mRNA in oily bubbles made of lipid nanoparticles.

Lipid nanoparticles

surrounding mRNA

Because of their fragility, the mRNA molecules will quickly fall apart at room temperature. Pfizer is building special containers with dry ice, thermal sensors and GPS trackers to ensure the vaccines can be transported at –94°F (–70°C) to stay viable.

Entering a Cell

After injection, the vaccine particles bump into cells and fuse to them, releasing mRNA. The cell’s molecules read its sequence and build spike proteins. The mRNA from the vaccine is eventually destroyed by the cell, leaving no permanent trace.

VACCINE

PARTICLES

VACCINATED

CELL

Spike

protein

mRNA

Translating mRNA

Three spike

proteins combine

Spike

Cell

nucleus

Spikes

and protein

fragments

Displaying

spike protein

fragments

Protruding

spikes

Some of the spike proteins form spikes that migrate to the surface of the cell and stick out their tips. The vaccinated cells also break up some of the proteins into fragments, which they present on their surface. These protruding spikes and spike protein fragments can then be recognized by the immune system.

Spotting the Intruder

When a vaccinated cell dies, the debris will contain many spike proteins and protein fragments, which can then be taken up by a type of immune cell called an antigen-presenting cell.

Debris from

a dead cell

Engulfing

a spike

ANTIGEN-

PRESENTING

CELL

Digesting

the proteins

Presenting a

spike protein

fragment

HELPER

T CELL

The cell presents fragments of the spike protein on its surface. When other cells called helper T cells detect these fragments, the helper T cells can raise the alarm and help marshal other immune cells to fight the infection.

Making Antibodies

Other immune cells, called B cells, may bump into the coronavirus spikes on the surface of vaccinated cells, or free-floating spike protein fragments. A few of the B cells may be able to lock onto the spike proteins. If these B cells are then activated by helper T cells, they will start to proliferate and pour out antibodies that target the spike protein.

HELPER

T CELL

Activating

the B cell

Matching

surface proteins

VACCINATED

CELL

B CELL

SECRETED

ANTIBODIES

Stopping the Virus

The antibodies can latch onto coronavirus spikes, mark the virus for destruction and prevent infection by blocking the spikes from attaching to other cells.

ANTIBODIES

VIRUS

Killing Infected Cells

The antigen-presenting cells can also activate another type of immune cell called a killer T cell to seek out and destroy any coronavirus-infected cells that display the spike protein fragments on their surfaces.

ANTIGEN-PRESENTING CELL Presenting a spike protein fragment ACTIVATED KILLER T CELL INFECTED CELL Beginning to kill the infected cell

Remembering the Virus

The Pfizer-BioNTech vaccine requires two injections, given 21 days apart, to prime the immune system well enough to fight off the coronavirus. But because the vaccine is so new, researchers don’t know how long its protection might last.

First dose, 0.3ml

Second dose, 21 days later

A preliminary study found that the vaccine seems to offer strong protection about 10 days after the first dose, compared with people taking a placebo:

Cumulative incidence of Covid-19 among clinical trial participants 2.5% 2.0 People taking a placebo

1.5 1.0 Second dose First dose People taking the

Pfizer-BioNTech vaccine

0.5

0

1

2

3

4

8

12

16

Weeks after the first dose

It’s possible that in the months after vaccination, the number of antibodies and killer T cells will drop. But the immune system also contains special cells called memory B cells and memory T cells that might retain information about the coronavirus for years or even decades.

For more about the vaccine, see Pfizer’s Covid Vaccine: 11 Things You Need to Know.

Preparation and Injection

Each vial of the vaccine contains 5 doses of 0.3 milliliters. The vaccine must be thawed before injection and diluted with saline. After dilution the vial must be used within six hours.

A diluted vial of the vaccine at Royal Free Hospital in London.Jack Hill/Agence France-Presse

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External links

“Tozinameran”Drug Information Portal. U.S. National Library of Medicine.

A vial of the Pfizer–BioNTech COVID‑19 vaccine
Vaccine description
Target diseaseCOVID‑19
TypemRNA
Clinical data
Trade namesComirnaty[1][2]
Other namesBNT162b2, COVID-19 mRNA vaccine (nucleoside-modified)
License dataEU EMAby INNUS DailyMedPfizer-BioNTech_COVID-19_Vaccine
Pregnancy
category
AU: B1[3]
Routes of
administration
Intramuscular
ATC codeNone
Legal status
Legal statusAU: S4 (Prescription only) [4][5]CA: Authorized by interim order [6][7]UK: Conditional and temporary authorization to supply [8][9]US: Unapproved (Emergency Use Authorization)[10][11][12]EU: Conditional marketing authorization granted [2]CH: Rx-only[further explanation needed][1]
Identifiers
CAS Number2417899-77-3
PubChem SID434370509
DrugBankDB15696
UNII5085ZFP6SJ
KEGGD11971
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 COVID-19 Portal

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#Tozinameran, #APPROVALS 2021,   #JAPAN 2021,  Comirnaty, #Coronavirus disease, #COVID-19, #BNT162b2 , #BNT162b2, #SARS-CoV-2 Vaccine, #RNA ingredient BNT-162B2, #corona

The Pfizer-BioNTech COVID-19 vaccine (Tozinameran, INN), also known as BNT162b2, is one of four advanced mRNA-based vaccines developed through “Project Lightspeed,” a joint program between Pfizer and BioNTech.2,3 Tozinameran is a nucleoside modified mRNA (modRNA) vaccine encoding an optimized full-length version of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein. It is designed to induce immunity against SARS-CoV-2, the virus responsible for causing COVID-19.2 The modRNA is formulated in lipid nanoparticles for administration via intramuscular injection in two doses, three weeks apart.1,3

Tozinameran is undergoing evaluation in clinical trials in both the USA (NCT04368728) and Germany (NCT04380701).4,5 Tozinameran received fast track designation by the U.S. FDA on July 13, 2020.6 On December 11, 2020, the FDA issued an Emergency Use Authorization (EUA) based on 95% efficacy in clinical trials and a similar safety profile to other viral vaccines over a span of approximately 2 months.1 Tozinameran was granted an EUA in the UK on December 2, 2020,8 and in Canada on December 9, 20207 for active immunization against SARS-CoV-2.12

Currently, sufficient data are not available to determine the longevity of protection against COVID-19, nor direct evidence that the vaccine prevents the transmission of the SARS-CoV-2 virus from one individual to another.9 Fact sheets for caregivers, recipients, and healthcare providers are now available.10,11

Tozinameran has not yet been fully approved by any country. In both the UK and Canada, Tozinameran is indicated under an interim authorization for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals aged 16 years and older.7,8

On December 11, 2020, the U.S. Food and Drug Administration granted emergency use authorization (EUA) for Tozinameran to prevent COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients aged 16 years and above.9 Safety and immune response information for adolescents 12-15 years of age will follow, and studies to further explore the administration of Tozinameran in pregnant women, children under 12 years of age, and those in special risk groups will be evaluated in the future.1

This vaccine should only be administered where appropriate medical treatment for immediate allergic reactions are immediately available in the case of an acute anaphylactic reaction after vaccine administration.12 Tozinameran administration should be postponed in any individual suffering from an acute febrile illness. Its use should be carefully considered in immunocompromised individuals and individuals with a bleeding disorder or on anticoagulant therapy. Appropriate medical treatment should be readily available in case of an anaphylactic reaction following vaccine administration.7,8

Tozinameran contains nucleoside modified mRNA (modRNA) encapsulated in lipid nanoparticles that deliver the modRNA into host cells. The lipid nanoparticle formulation facilitates the delivery of the RNA into human cells.12 Once inside these cells, the modRNA is translated by host machinery to produce the SARS-CoV-2 spike (S) protein antigen, which is subsequently recognized by the host immune system. Tozinameran has been shown to elicit both neutralizing antibody and cellular immune responses to the S protein, which helps protect against subsequent SARS-CoV-2 infection.7,8

Tozinameran is a nucleoside modified mRNA (modRNA) vaccine encoding an optimized full-length version of the SARS-CoV-2 spike (S) protein, translated and expressed in cells in vaccinated individuals to produce the S protein antigen against which an immune response is mounted. As with all vaccines, protection cannot be guaranteed in all recipients, and full protection may not occur until at least seven days following the second dose.7,8

In U.S. clinical trials, the vaccine was 95% effective in preventing COVID-19; eight COVID-19 cases occurred in the vaccine group and 162 cases occurred in the placebo group. Of the total 170 COVID-19 cases, one case in the vaccine group and three cases in the placebo group were considered to be severe infections.1,9

  1. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, Perez JL, Perez Marc G, Moreira ED, Zerbini C, Bailey R, Swanson KA, Roychoudhury S, Koury K, Li P, Kalina WV, Cooper D, Frenck RW Jr, Hammitt LL, Tureci O, Nell H, Schaefer A, Unal S, Tresnan DB, Mather S, Dormitzer PR, Sahin U, Jansen KU, Gruber WC: Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec 10. doi: 10.1056/NEJMoa2034577. [PubMed:33301246]
  2. Gen Eng News: BNT162 vaccine candidates [Link]
  3. BioNTech BNT162 Update [Link]
  4. Clinical Trial NCT04368728 [Link]
  5. Clinical Trial NCT04380701 [Link]
  6. FDA fast track designation: BNT162b1 and BNT162b2 [Link]
  7. Health Canada Interim Product Monograph: BNT162b2 SARS-CoV-2 Vaccine [Link]
  8. MHRA Interim Product Monograph: BNT162b2 SARS-CoV-2 Vaccine [Link]
  9. FDA News Release: FDA Takes Key Action in Fight Against COVID-19 By Issuing Emergency Use Authorization for First COVID-19 Vaccine [Link]
  10. Pfizer: Fact Sheet for Healthcare Providers Administering Vaccine, Pfizer-BioNtech COVID-19 vaccine [Link]
  11. Pfizer: Fact Sheet for Recipients and Caregivers, Pfizer BioNTech COVID-19 vaccine [Link]
  12. FDA Emergency Use Authorization: Full EUA Prescribing information, Pfizer-BioNTech COVID-19 vaccine [Link]
  13.  
    PHASESTATUSPURPOSECONDITIONSCOUNT2Active Not RecruitingPreventionCoronavirus Disease 2019 (COVID‑19)12, 3Active Not RecruitingPreventionCoronavirus Disease 2019 (COVID‑19)11, 2Active Not RecruitingPreventionCoronavirus Disease 2019 (COVID‑19)11, 2RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19) / Protection Against COVID-19 and Infections With SARS CoV 2 / Respiratory Tract Infections (RTI) / RNA Virus Infections / Vaccine Adverse Reaction / Viral Infections / Virus Diseases1 

PF 04965842, Abrocitinib


PF-04965842, >=98% (HPLC).png

img

2D chemical structure of 1622902-68-4

PF-04965842

PF 04965842, Abrocitinib

UNII: 73SM5SF3OR

CAS Number 1622902-68-4, Empirical Formula  C14H21N5O2S, Molecular Weight 323.41

N-[cis-3-(Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclobutyl]-1-propanesulfonamide,

N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide

1-Propanesulfonamide, N-(cis-3-(methyl-7H-pyrrolo(2,3-d)pyrimidin-4-ylamino)cyclobutyl)-

N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide

PHASE 3, for the potential oral treatment of moderate-to-severe atopic dermatitis (AD)

Jak1 tyrosine kinase inhibitor

UPDATE…… JAPAN APPROVED, 2021, 2021/9/27, CIBINQO

THE US

In February 2018, the FDA granted Breakthrough Therapy designation for the treatment of patients with moderate-to-severe AD

PHASEIII

In December 2017, a randomized, double-blind, placebo-controlled, parallel-group, phase III trial (NCT03349060; JADE Mono-1; JADE; B7451012; 2017-003651-29) of PF-04965842 began in patients aged 12 years and older (expected n = 375) with moderate-to-severe AD

PRODUCT PATENT

Pub. No.:   WO/2014/128591   International Application No.:   PCT/IB2014/058889
Publication Date: 28.08.2014 International Filing Date: 11.02.2014

EXPIRY  Roughly 2034

form powder
color white to beige
solubility DMSO: 10 mg/mL, clear
storage temp. room temp
    Biochem/physiol Actions
    • PF-04965842 is a Janus Kinase (JAK) inhibitor selective for JAK1 with an IC50value of 29 nM for JAK1 compared to 803 nM for JAK2, >10000 nM for JAK3 and 1250 nM for Tyk2. JAKs mediate cytokine signaling, and are involved in cell proliferation and differentiation. PF-04965842 has been investigated as a possible treatment for psoriasis.
  • Originator Pfizer
  • Class Skin disorder therapies; Small molecules
  • Mechanism of Action Janus kinase 1 inhibitors

Highest Development Phases

  • Phase IIIAtopic dermatitis
  • DiscontinuedLupus vulgaris; Plaque psoriasis

Most Recent Events

  • 08 Mar 2018Phase-III clinical trials in Atopic dermatitis (In children, In adults, In adolescents) in USA (PO) (NCT03422822)
  • 14 Feb 2018PF 4965842 receives Breakthrough Therapy status for Atopic dermatitis in USA
  • 06 Feb 2018Pfizer plans the phase III JADE EXTEND trial for Atopic Dermatitis (In children, In adults, In adolescents) in March 2018 (PO) (NCT03422822)

This compound was developed by Pfizer for Kinase Phosphatase Biology research. To learn more about Sigma′s partnership with Pfizer and view other authentic, high-quality Pfizer compounds,

Image result for PF-04965842

PF-04965842 is an oral Janus Kinase 1 inhibitor being investigated for treatment of plaque psoriasis.

Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been i mplicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune d iseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer’s disease. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation , survival, apoptosis, mitogenesis, cell cycle control, and cel l mobility implicated in the aforementioned and related diseases.

Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play a central role in cytoki ne signaling (Kisseleva et al., Gene, 2002, 285 , 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression. Numerous cytokines are known to activate the JAK family. These cytokines include, the IFN family (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma, IL- 10, IL- 19, IL-20, IL-22), the gp 130 family (IL-6, IL- 11, OSM, LIF, CNTF, NNT- 1//SF-3, G-CSF, CT- 1, Leptin, IL- 12 , I L-23), gamma C family (IL-2 , I L-7, TSLP, IL-9, IL- 15 , IL-21, IL-4, I L- 13), IL-3 family (IL-3 , IL-5 , GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF- 1, HGF), and G-protein coupled receptors (ATI).

There remains a need for new compounds that effectively and selectively inhibit specific JAK enzymes, and JAK1 in particular, vs. JAK2. JAK1 is a member of the Janus family of protein kinases composed of JAK1, JAK2, JAK3 and TYK2. JAK1 is expressed to various levels in all tissues. Many cytokine receptors signal through pairs of JAK kinases in the following combinations: JAK1/JAK2, JAK1/JAK3, JAK1/TYK2 , JAK2/TYK2 or JAK2/JAK2. JAK1 is the most broadly

paired JAK kinase in this context and is required for signaling by γ-common (IL-2Rγ) cytokine receptors, IL—6 receptor family, Type I, II and III receptor families and IL- 10 receptor family. Animal studies have shown that JAK1 is required for the development, function and homeostasis of the immune system. Modulation of immune activity through inhibition of JAK1 kinase activity can prove useful in the treatment of various immune disorders (Murray, P.J.

J. Immunol., 178, 2623-2629 (2007); Kisseleva, T., et al., Gene, 285 , 1-24 (2002); O’Shea, J . J., et al., Ceil , 109, (suppl .) S121-S131 (2002)) while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer H., et al., Cell, 93(3), 397-409 (1998);

Parganas E., et al., Cell, 93(3), 385-95 (1998)).

Figure

Tofacitinib (1), baricitinib (2), and ruxolitinib (3)

SYNTHESIS 5+1 =6 steps

Main synthesis

Journal of Medicinal Chemistry, 61(3), 1130-1152; 2018

INTERMEDIATE

CN 105732637

ONE STEP

CAS 479633-63-1,  7H-Pyrrolo[2,3-d]pyrimidine, 4-chloro-7-[(4- methylphenyl)sulfonyl]-

Image result for PF-04965842

Pfizer Receives Breakthrough Therapy Designation from FDA for PF-04965842, an oral JAK1 Inhibitor, for the Treatment of Patients with Moderate-to-Severe Atopic Dermatitis

Wednesday, February 14, 2018 8:30 am EST
 

Dateline:

NEW YORK

Public Company Information:

NYSE:
PFE
US7170811035
 
“We look forward to working closely with the FDA throughout our ongoing Phase 3 development program with the hope of ultimately bringing this important new treatment option to these patients.”
 

NEW YORK–(BUSINESS WIRE)–Pfizer Inc. (NYSE:PFE) today announced its once-daily oral Janus kinase 1 (JAK1) inhibitor PF-04965842 received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe atopic dermatitis (AD). The Phase 3 program for PF-04965842 initiated in December and is the first trial in the J AK1 A topic D ermatitis E fficacy and Safety (JADE) global development program.

“Achieving Breakthrough Therapy Designation is an important milestone not only for Pfizer but also for patients living with the often devastating impact of moderate-to-severe atopic dermatitis, their providers and caregivers,” said Michael Corbo, Chief Development Officer, Inflammation & Immunology, Pfizer Global Product Development. “We look forward to working closely with the FDA throughout our ongoing Phase 3 development program with the hope of ultimately bringing this important new treatment option to these patients.”

Breakthrough Therapy Designation was initiated as part of the Food and Drug Administration Safety and Innovation Act (FDASIA) signed in 2012. As defined by the FDA, a breakthrough therapy is a drug intended to be used alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. If a drug is designated as a breakthrough therapy, the FDA will expedite the development and review of such drug.1

About PF-04965842 and Pfizer’s Kinase Inhibitor Leadership

PF-04965842 is an oral small molecule that selectively inhibits Janus kinase (JAK) 1. Inhibition of JAK1 is thought to modulate multiple cytokines involved in pathophysiology of AD including interleukin (IL)-4, IL-13, IL-31 and interferon gamma.

Pfizer has established a leading kinase research capability with multiple unique kinase inhibitor therapies in development. As a pioneer in JAK science, the Company is advancing several investigational programs with novel selectivity profiles, which, if successful, could potentially deliver transformative therapies for patients. Pfizer has three additional kinase inhibitors in Phase 2 development across multiple indications:

  • PF-06651600: A JAK3 inhibitor under investigation for the treatment of rheumatoid arthritis, ulcerative colitis and alopecia areata
  • PF-06700841: A tyrosine kinase 2 (TYK2)/JAK1 inhibitor under investigation for the treatment of psoriasis, ulcerative colitis and alopecia areata
  • PF-06650833: An interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor under investigation for the treatment of rheumatoid arthritis

Working together for a healthier world®

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world’s best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com. In addition, to learn more, please visit us on www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_NewsLinkedInYouTube and like us on Facebook at Facebook.com/Pfizer.

DISCLOSURE NOTICE: The information contained in this release is as of February 14, 2018. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.

This release contains forward-looking information about PF-04965842 and Pfizer’s ongoing investigational programs in kinase inhibitor therapies, including their potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical trial commencement and completion dates and regulatory submission dates, as well as the possibility of unfavorable clinical trial results, including unfavorable new clinical data and additional analyses of existing data; risks associated with preliminary data; the risk that clinical trial data are subject to differing interpretations, and, even when we view data as sufficient to support the safety and/or effectiveness of a product candidate, regulatory authorities may not share our views and may require additional data or may deny approval altogether; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when drug applications may be filed in any jurisdictions for any potential indication for PF-04965842 or any other investigational kinase inhibitor therapies; whether and when any such applications may be approved by regulatory authorities, which will depend on the assessment by such regulatory authorities of the benefit-risk profile suggested by the totality of the efficacy and safety information submitted, and, if approved, whether PF-04965842 or any such other investigational kinase inhibitor therapies will be commercially successful; decisions by regulatory authorities regarding labeling, safety and other matters that could affect the availability or commercial potential of PF-04965842 or any other investigational kinase inhibitor therapies; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2016 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.sec.gov  and www.pfizer.com .

Image result for PF-04965842

# # # # #

1 Food and Drug Administration Fact Sheet Breakthrough Therapies at https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htmaccessed on January 25, 2018

PATENT

CA 2899888

PATENT

WO 2014128591

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=6767BBB5964A985E88C9251B6DF3182B.wapp2nB?docId=WO2014128591&recNum=233&maxRec=8235&office=&prevFilter=&sortOption=&queryString=EN_ALL%3Anmr+AND+PA%3Apfizer&tab=PCTDescription

PFIZER INC. [US/US]; 235 East 42nd Street New York, New York 10017 (US)

BROWN, Matthew Frank; (US).
FENWICK, Ashley Edward; (US).
FLANAGAN, Mark Edward; (US).
GONZALES, Andrea; (US).
JOHNSON, Timothy Allan; (US).
KAILA, Neelu; (US).
MITTON-FRY, Mark J.; (US).
STROHBACH, Joseph Walter; (US).
TENBRINK, Ruth E.; (US).
TRZUPEK, John David; (US).
UNWALLA, Rayomand Jal; (US).
VAZQUEZ, Michael L.; (US).
PARIKH, Mihir, D.; (US)

COMPD 2

str1

Example 2 : N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane- l -sulƒonamide

This compound was prepared using 1-propanesulfonyl chloride. The crude compound was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (93 : 7) to afford the title compound as a tan sol id (78% yield). 1NMR (400 MHz, DMSO-d6): δ 11.60 (br s, 1 H), 8.08 (s, 1 H), 7.46 (d, 1 H), 7.12 (d, 1 H), 6.61 (d, 1 H), 4.81-4.94 (m, 1 H), 3.47-3.62 (m, 1 H), 3.23 (s, 3 H), 2.87-2.96 (m, 2 H), 2.52-2.63 (m, 2 H), 2.14-2.27 (m, 2 H) 1.60- 1.73 (m, 2 H) 0.96 (t, 3 H). LC/MS (exact mass) calculated for C14H21N5O2S;

323.142, found (M + H+); 324.1.

PAPER

 Journal of Medicinal Chemistry (2018), 61(3), 1130-1152.

Abstract Image

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b01598

N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (25)

Compound 48a·2HBr …………..was collected by filtration, washed with 2:1 EtOH/H2O (100 mL), and again dried overnight in a vacuum oven at 40 °C.
 
1H NMR (400 MHz, DMSO-d6): 11.64 (br s, 1H), 8.12 (s, 1 H), 7.50 (d, J = 9.4 Hz, 1H), 7.10–7.22 (m, 1H), 6.65 (dd, J= 1.8, 3.3 Hz, 1H), 4.87–4.96 (m, 1H), 3.53–3.64 (m, 1H), 3.27 (s, 3H), 2.93–2.97 (m, 2H), 2.57–2.64 (m, 2H), 2.20–2.28 (m, 2H), 1.65–1.74 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).
 
LC/MS m/z (M + H+) calcd for C14H22N5O2S: 324. Found: 324. Anal. Calcd for C14H21N5O2S: C, 51.99; H, 6.54; N, 21.65; O, 9.89; S, 9.91. Found: C, 52.06; H, 6.60; N, 21.48; O, 10.08; S, 9.97.
 

SchmiederG.DraelosZ.PariserD.BanfieldC.CoxL.HodgeM.KierasE.Parsons-RichD.MenonS.SalganikM.PageK.PeevaE. Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled study Br. J. Dermatol. 2017DOI: 10.1111/bjd.16004

Compound 25N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide is available through MilliporeSigma (cat. no. PZ0304).

REFERENCES

1: Schmieder GJ, Draelos ZD, Pariser DM, Banfield C, Cox L, Hodge M, Kieras E, Parsons-Rich D, Menon S, Salganik M, Page K, Peeva E. Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled study. Br J Dermatol. 2017 Sep 26. doi: 10.1111/bjd.16004. [Epub ahead of print] PubMed PMID: 28949012

 2 Journal of Medicinal Chemistry (2018), 61(3), 1130-1152.

  • Originator Pfizer
  • Class Anti-inflammatories; Antipsoriatics; Pyrimidines; Pyrroles; Skin disorder therapies; Small molecules; Sulfonamides
  • Mechanism of Action Janus kinase 1 inhibitors
  • Phase III Atopic dermatitis
  • Discontinued Lupus vulgaris; Plaque psoriasis
  • 21 May 2019Pfizer initiates enrolment in a phase I trial in Healthy volunteers in USA (PO) (NCT03937258)
  • 09 May 2019 Pfizer plans a phase I pharmacokinetic and drug-drug interaction trial in healthy volunteers in May 2019 (NCT03937258)
  • 30 Apr 2019 Pfizer completes a phase I trial (In volunteers) in USA (PO) (NCT03626415)

/////////PF 04965842, Abrocitinib, Phase III,  Atopic dermatitis, pfizer

CCCS(=O)(N[C@H]1C[C@@H](N(C)C2=C3C(NC=C3)=NC=N2)C1)=O

CCCS(=O)(=O)N[C@@H]1C[C@@H](C1)N(C)c2ncnc3[nH]ccc23

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Iobenguane I 131


Iobenguane I-131.png

Iobenguane I 131

FDA approves first treatment for rare adrenal tumors

The U.S. Food and Drug Administration today approved Azedra (iobenguane I 131) injection for intravenous use for the treatment of adults and adolescents age 12 and older with rare tumors of the adrenal gland (pheochromocytoma or paraganglioma) that cannot be surgically removed (unresectable), have spread beyond the original tumor site and require systemic anticancer therapy. This is the first FDA-approved drug for this use.
 
 
update………APPROVED  JAPAN 2021, 2021/9/27, Raiatt MIBG-I 131

July 30, 2018

Release

The U.S. Food and Drug Administration today approved Azedra (iobenguane I 131) injection for intravenous use for the treatment of adults and adolescents age 12 and older with rare tumors of the adrenal gland (pheochromocytoma or paraganglioma) that cannot be surgically removed (unresectable), have spread beyond the original tumor site and require systemic anticancer therapy. This is the first FDA-approved drug for this use.

“Many patients with these ultra-rare cancers can be treated with surgery or local therapies, but there are no effective systemic treatments for patients who experience tumor-related symptoms such as high blood pressure,” 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. “Patients will now have an approved therapy that has been shown to decrease the need for blood pressure medication and reduce tumor size in some patients.”

Pheochromocytomas are rare tumors of the adrenal glands. These glands are located right above the kidneys and make hormones including stress hormones called epinephrines and norepinephrines. Pheochromocytomas increase the production of these hormones, leading to hypertension (high blood pressure) and symptoms such as headaches, irritability, sweating, rapid heart rate, nausea, vomiting, weight loss, weakness, chest pain or anxiety. When this type of tumor occurs outside the adrenal gland, it is called a paraganglioma.

The efficacy of Azedra was shown in a single-arm, open-label, clinical trial in 68 patients that measured the number of patients who experienced a 50 percent or greater reduction of all antihypertensive medications lasting for at least six months. This endpoint was supported by the secondary endpoint, overall tumor response measured by traditional imaging criteria. The study met the primary endpoint, with 17 (25 percent) of the 68 evaluable patients experiencing a 50 percent or greater reduction of all antihypertensive medication for at least six months. Overall tumor response was achieved in 15 (22 percent) of the patients studied.

The most common severe side effects reported by patients receiving Azedra in clinical trials included low levels of white blood cells (lymphopenia), abnormally low count of a type of white blood cells (neutropenia), low blood platelet count (thrombocytopenia), fatigue, anemia, increased international normalized ratio (a laboratory test which measures blood clotting), nausea, dizziness, hypertension and vomiting.

As it is a radioactive therapeutic agent, Azedra includes a warning about radiation exposure to patients and family members, which should be minimized while the patient is receiving Azedra. The risk of radiation exposure is greater in pediatric patients. Other warnings and precautions include a risk of lower levels of blood cells (myelosuppression), underactive thyroid, elevations in blood pressure, renal failure or kidney injury and inflammation of lung tissue (pneumonitis). Myelodysplastic syndrome and acute leukemias, which are cancers of the blood and bone marrow, were observed in patients who received Azedra, and the magnitude of this risk will continue to be studied. Azedra can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception after receiving Azedra. Radiation exposure associated with Azedra may cause infertility in males and females.

The FDA granted this application Fast TrackBreakthrough Therapy and Priority Review designations. Azedra 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 Azedra to Progenics Pharmaceuticals, Inc.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm615155.htm?utm_campaign=07302018_PR_treatment%20for%20rare%20adrenal%20tumors&utm_medium=email&utm_source=Eloqua

Iobenguane I-131.png

Iobenguane (131I); Iobenguane I 131; Iobeguane I 131; 3-Iodobenzylguanidine; 131I-MIBG; Azedra

77679-27-7 CAS NUMBER

PATENT US 4584187

Guanidine, [[3-(iodo-131I)phenyl]methyl]-

  • [[3-(Iodo-131I)phenyl]methyl]guanidine
  • 131I-MIBG
  • Azedra
  • Iobenguane (131I)
  • Iobenguane I 131
  • Ultratrace Iobenguane 131I
  • [131I]-m-Iodobenzylguanidine
  • [131I]-m-Iodobenzylguanidine
  • m-Iodobenzylguanidine-131I
  • m-[131I]Iodobenzylguanidine
Molecular Formula: C8H10IN3
Molecular Weight: 279.095 g/mol
 
Image result for Iobenguane I 131Image result for Iobenguane I 131
(I 131-meta-iodobenzylguanidine sulfate)
Iobenguane sulfate; M-Iodobenzylguanidine hemisulfate; MIBG; 87862-25-7; 3-Iodobenzylguanidine hemisulfate; 3-Iodobenzyl-guanidine hemisulfate
Molecular Formula: C16H22I2N6O4S
Molecular Weight: 648.259 g/mol

AdreView
(iobenguane I 123) Injection for Intravenous Use

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SYN

CN 106187824

DESCRIPTION

AdreView (iobenguane I 123 Injection) is a sterile, pyrogen-free radiopharmaceutical for intravenous injection. Each mL contains 0.08 mg iobenguane sulfate, 74 MBq (2 mCi) of I 123 (as iobenguane sulfate I 123) at calibration date and time on the label, 23 mg sodium dihydrogen phosphate dihydrate, 2.8 mg disodium hydrogen phosphate dihydrate and 10.3 mg (1% v/v) benzyl alcohol with a pH of 5.0 – 6.5. Iobenguane sulfate I 123 is also known as I 123 meta-iodobenzlyguanidine sulfate and has the following structural formula:

AdreView (iobenguane I 123) Structural Formula Illustration

Physical Characteristics

Iodine 123 is a cyclotron-produced radionuclide that decays to Te 123 by electron capture and has a physical half-life of 13.2 hours.

 

Iobenguane I-131 is a guanidine analog with specific affinity for tissues of the sympathetic nervous system and related tumors. The radiolabeled forms are used as antineoplastic agents and radioactive imaging agents. (Merck Index, 12th ed) MIBG serves as a neuron-blocking agent which has a strong affinity for, and retention in, the adrenal medulla and also inhibits ADP-ribosyltransferase.

Iobenguane i-131 is a Radioactive Diagnostic Agent. The mechanism of action of iobenguane i-131 is as a Radiopharmaceutical Activity.

Iobenguane I-131 is an I 131 radioiodinated synthetic analogue of the neurotransmitter norepinephrineIobenguane localizes to adrenergic tissue and, in radioiodinated forms, may be used to image or eradicate tumor cells that take up and metabolize norepinephrine.

Iobenguane, also known as metaiodobenzylguanidine or mIBG, or MIBG (tradename Adreview) is a radiopharmaceutical,[1] used in a scintigraphy method called MIBG scan. Iobenguane is a radiolabeled molecule similar to noradrenaline.

The radioisotope of iodine used for the label can be iodine-123 (for imaging purposes only) or iodine-131 (which must be used when tissue destruction is desired, but is sometimes used for imaging also).

 

Pheochromocytoma seen as dark sphere in center of the body (it is in the left adrenal gland). Image is by MIBG scintigraphy, with radiation from radioiodine in the MIBG. Two images are seen of the same patient from front and back. Note dark image of the thyroid due to unwanted uptake of iodide radioiodine from breakdown of the pharmaceutical, by the thyroid gland in the neck. Uptake at the side of the head are from the salivary glands. Radioactivity is also seen in the bladder, from normal renal excretion of iodide.

It localizes to adrenergic tissue and thus can be used to identify the location of tumors[2] such as pheochromocytomas and neuroblastomas. With I-131 it can also be used to eradicate tumor cells that take up and metabolize norepinephrine.

Thyroid precautions

Thyroid blockade with (nonradioactive) potassium iodide is indicated for nuclear medicine scintigraphy with iobenguane/mIBG. This competitively inhibits radioiodine uptake, preventing excessive radioiodine levels in the thyroid and minimizing the risk of thyroid ablation ( in the case of I-131). The minimal risk of thyroid carcinogenesis is also reduced as a result.

The FDA-approved dosing of potassium iodide for this purpose are as follows: infants less than 1 month old, 16 mg; children 1 month to 3 years, 32 mg; children 3 years to 18 years, 65 mg; adults 130 mg.[3] However, some sources recommend alternative dosing regimens.[4]

Not all sources are in agreement on the necessary duration of thyroid blockade, although agreement appears to have been reached about the necessity of blockade for both scintigraphic and therapeutic applications of iobenguane. Commercially available iobenguane is labeled with iodine-123, and product labeling recommends administration of potassium iodide 1 hour prior to administration of the radiopharmaceutical for all age groups,[5] while the European Associated of Nuclear Medicine recommends (for iobenguane labeled with either I-131 or I-123,) that potassium iodide administration begin one day prior to radiopharmaceutical administration, and continue until the day following the injection, with the exception of newborns, who do not require potassium iodide doses following radiopharmaceutical injection.[4]

Product labeling for diagnostic iodine-131 iobenguane recommends potassium iodide administration one day before injection and continuing 5 to 7 days following.[6] Iodine-131 iobenguane used for therapeutic purposes requires a different pre-medication duration, beginning 24–48 hours prior to iobenguane injection and continuing 10–15 days following injection.[7]

Alternative imaging modality for pheochromocytoma

The FDOPA PET/CT scan has proven to be nearly 100% sensitive for detection of pheochromocytomas, vs. 90% for MIBG scans.[8][9][10] Centers which offer FDOPA PET/CT, however, are rare.

Clinical trials

Iobenguane I 131 for cancers

Iobenguane I 131 (as Azedra) has had a clinical trial as a treatment for malignant, recurrent or unresectable pheochromocytoma and paraganglioma, and the US FDA has granted it a Priority Review.[11]

 
PATENTS
Patent ID

 

Title

 

Submitted Date

 

Granted Date

 

US7658910 PREPARATION OF RADIOLABELLED HALOAROMATICS VIA POLYMER-BOUND INTERMEDIATES
2008-04-10
2010-02-09
US2008241063 Combination set of Meta-Iodobenzyl guanidine freezing crystal and making method thereof and method for making a radioactive iodine marker
2007-03-29
2008-10-02
US7273601 Preparation of radiolabelled haloaromatics via polymer-bound intermediates
2003-01-16
2007-09-25
US6461585 Preparation of radiolabelled haloaromatics via polymer-bound intermediates
2002-10-08
US2010274052 PREPARATION OF RADIOLABELLED HALOAROMATICS VIA POLYMER-BOUND INTERMEDIATES
2010-10-28
/////////////// Azedra, iobenguane I 131, fda 2018, Progenics Pharmaceuticals, Fast TrackBreakthrough Therapy,  Priority Review, orphan drug, Iobenguane (131I), Iobenguane I 131, Iobeguane I 131, 3-Iodobenzylguanidine, 131I-MIBG, Azedra
C1=CC(=CC(=C1)I)CN=C(N)N
wdt-4

NEW DRUG APPROVALS

ONE TIME

$10.00

Abaloparatide, абалопаратид , أبالوباراتيد , 巴罗旁肽 ,


Chemical structure for Abaloparatide

Abaloparatide

BA058
BIM-44058
UNII-AVK0I6HY2U

BA058; BIM-44058; CAS  247062-33-5

MW 3960.5896, MF C174 H300 N56 O49

абалопаратид [Russian] [INN]
أبالوباراتيد [Arabic] [INN]
巴罗旁肽 [Chinese] [INN]
str1

NAME………C2.29-methyl(22-L-glutamic acid(F>E),23-L-leucine(F>L),25-L-glutamic acid(H>E),26-L-lysine(H>K),28-L-leucine(I>L),30-L-lysine(E>K),31-L-leucine(I>L))human parathyroid hormone-related protein-(1-34)-proteinamide
L-Alaninamide, L-alanyl-L-valyl-L-seryl-L-alpha-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-alpha-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-alpha-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-alpha-glutamyl-L-leucyl-L-leucyl-L-alpha-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-

L-Alaninamide, L-alanyl-L-valyl-L-seryl-L-α-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-α-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-α-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-α-glutamyl-L-leucyl-L-leucyl-L-α-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-

  1. C2.29-methyl(22-L-glutamic acid(F>E),23-L-leucine(F>L),25-L-glutamic acid(H>E),26-L-lysine(H>K),28-L-leucine(I>L),30-L-lysine(E>K),31-L-leucine(I>L))human parathyroid hormone-related protein-(1-34)-proteinamide

Biologic Depiction

Abaloparatide biologic depiction
IUPAC Condensed

H-Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

Sequence

AVSEHQLLHDKGKSIQDLRRRELLEKLLXKLHTA

HELM

PEPTIDE1{A.V.S.E.H.Q.L.L.H.D.K.G.K.S.I.Q.D.L.R.R.R.E.L.L.E.K.L.L.[Aib].K.L.H.T.A.[am]}$$$$

IUPAC

(N-(L-alanyl-L-valyl-L-seryl-L-alpha-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-alpha-aspartyl-L-lysyl-glycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-alpha-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-alpha-glutamyl-L-leucyl-L-leucyl-L-alpha-glutamyl-L-lysyl-L-leucyl-L-leucyl)-2-aminoisobutyryl)-L-lysyl-L-leucyl-L-histidyl-L-threonyl-L-alaninamide

Tymlos

FDA 4/28/2017

To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies
Drug Trials Snapshot

2D chemical structure of 247062-33-5

Image result for AbaloparatideImage result for Abaloparatide

CLINICAL……….https://clinicaltrials.gov/search/intervention=Abaloparatide%20OR%20BA058%20OR%20BIM-44058

BIM-44058 is a 34 amino acid analog of native human PTHrP currently in phase III clinical trials at Radius Health for the treatment of postmenopausal osteoporosis. Radius is also developing a microneedle transdermal patch using a 3M drug delivery system in phase II clinical trials. The drug candidate was originally developed at Biomeasure (a subsidiary of Ipsen), and was subsequently licensed to Radius and Teijin Pharma.

Abaloparatide (brand name Tymlos; formerly BA058) is a parathyroid hormone-related protein (PTHrP) analog drug used to treat osteoporosis. Like the related drug teriparatide, and unlike bisphosphonates, it is an anabolic (i.e., bone growing) agent.[1] A subcutaneous injection formulation of the drug has completed a Phase III trial for osteoporosis.[2] This single study found a decrease in fractures.[3] In 28 April 2017, it was approved by Food and drug administration (FDA) to treat postmenopausal osteoporosis.

Image result for Abaloparatide

Therapeutics

Medical use

Abaloparatide is indicated to treat postmenopausal women with osteoporosis who are more susceptible to bone fractures.[2]

Dosage

The dose recommended is 80mcg subcutaneous injection once a day, administered in the periumbilical area using a prefilled pen device containing 30 doses.[4]

Warnings and Precautions

Preclinical studies revealed that abaloparatide systemic daily administration leads to a dose- and time-dependent increase in the incidence of osteosarcoma in rodents.[5] However, whether abaloparatide-SC will cause osteosarcoma in humans is unknown. Thus, the use of abaloparatide is not recommended for individuals at increased risk of osteosarcoma. Additionally, its use is not advised for more than 2 years during a patient’s lifetime.[4][6]

Image result for Abaloparatide

Side Effects

The most common side effects reported by more than 2% of clinical trials subjects are hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain and vertigo.[4]

Pharmacology

Abaloparatide is 34 amino acid synthetic analog of PTHrP. It has 41% homology to parathyroid hormone (PTH) (1-34) and 76% homology to parathyroid hormone-related protein (PTHrP) (1-34).[7] It works as an anabolic agent for the bone, through selective activation of the parathyroid hormone 1 receptor (PTH1R), a G protein-coupled receptor (GPCR) expressed in the osteoblasts and osteocytes. Abaloparatide preferentially binds the RG conformational state of the PTH1R, which in turn elicits a transient downstream cyclic AMP signaling response towards to a more anabolic signaling pathway.[8][9]

History

Preclinical studies

Abaloropatide was previously known as BA058 and BIM-44058 while under development. The anabolic effects of abaloparatide on bone were demonstrated in two preclinical studies conducted in ovarectomized rats. Both studies showed increased cortical and trabecular bone volume and density, and trabecular microarchitecture improvement in vertebral and nonvertebral bones after short-term[10] and long-term[11] daily subcutaneous injection of abaloparatide compared to controls. Recent studies indicated a dose-dependent increased in bone mass and strength in long-term abalorapatide treatment.[12] However, it was also indicated that prolonged abalorapatide-SC treatment leads to increased incidence of osteosarcoma.[5] To date, there is no yet evidence for increased risk of bone tumors due to prolonged abalorapatide systemic administration in humans. Based on this preclinical data, the FDA does not advised the use of abaloparatide-SC for more than 2 years, or in patients with history of Paget disease and/or other conditions that exacerbates the risk of developing osteosarcoma.[4]

Clinical Trials

Phase II trials were initiated in 2008. A 24-week randomized trial was conducted in postmenopausal women with osteoporosis (n=222) assessing bone mass density (BMD) changes as the primary endpoint.[13] Significant BMD increase at doses of 40 and 80 mcg were found in the lumbar spine, femur and hips of abaloparatide-treated participants compared to placebo. Additionally, abaloparatide showed superior anabolic effects on the hips compared to teriparatide.[14]

In the phase III (2011-2014) Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial, a 18-months randomized, multicenter, double-blinded, placebo-controlled study evaluated the long-term efficacy of abaloparatide compared to placebo and teriparatide in 2,463 postmenopausal women (± 69 years old).[2] Women who received daily injections of abaloparatide experienced substantial reduction in the incidence of fractures compared to placebo. Additionally, greater BMD increase at 6, 12 and 18 months in spinal, hips and femoral bones was observed in abaloparatide compared to placebo and teriparatide-treated subjects.[3]

Participants who completed 18 months of abaloparatide or placebo in the ACTIVE study were invited to participate in an extended open-labeled study – ACTIVExtend study (2012-2016).[15] Subjects (n=1139) received additional 2 years of 70 mg of alendronate, Vitamin D (400 to 800 IU), and calcium (500–1000 mg) supplementation daily. Combined abaloparatide and alendronate therapy reduced significantly the incidence of vertebral and nonvertebral fractures.[16]

A clinical trial assessing the effectiveness of abaloparatide in altering spinal bone mineral density (BMD) in male subjects is expected to start in the first quarter of 2018. If successful, Radius Health aims to submit a sNDA to expand the use of abaloparatide-SC to treat men with osteoporosis.[17]

In addition to the injectable form of abaloparatide, a transdermal patch is also in development.[1]

Commercialization

As previously noted, abaloparatide-SC is manufactured by Radius Health, Inc. (Nasdaq: RDUS), a biomedical company based in Waltham, Massachusetts. This company is focused on the development of new therapeutics for osteoporosis, cancer and endocrine diseases. Abaloparatide is the only drug currently marketed by Radius Health. RDUS reported that sales for abaloparatide were $3.5million for the third quarter of 2017.[17] The company announced a net loss of $57.8 million, or $1.31 per share for the third quarter of 2017, compared to $19.2 million for the same quarter of 2016.[18] The net loss most likely reflects the substantial expenses associated with the preparation and launching of abaloparatide into the US market in May 2017.

In July 2017, Radius Health licensed rights to Teijin Limited for abaloparatide-SC manufacture and commercialization in Japan. Teijin is developing abaloparatide-SC under agreement with Ipsen Pharma S.A.S., and is conducting a phase III clinical trial in Japanese patients with osteoporosis.[19]

Regulatory Information

Radius Health filed a Marketing Authorization Application (MAA) in November 2015,[20] which was validated in December, 2015, and still under regulatory assessment by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). As in July 2017, the CHMP issued a second Day-180 List of Outstanding Issues, which Radius is addressing with the CHMP.[17]

In February 2016 a NDA was filed to the FDA, Radius NDA for abaloparatide-SC was accepted in May, 2016.[21] A Prescription Drug User Fee Act (PDUFA) date was initially granted in March 30, 2016, but then extended to June 30, 2017.[22] As previously stated, abaloparatide injection was approved for use in postmenopausal osteoporosis on April 28, 2017.[6]

Intellectual Property

Radius Health currently holds three patents on abaloparatide-SC, with expiration dates from 2027-2028.[23] The patents relate to the drug composition (US 8148333), and the drug delivery methods (US 7803770 B2 and US 8748382-B2).

As previously mentioned, Teijin Limited was granted use of Radius Health intellectual property in July 2017, for the development, manufacture and commercialization of abaloparatide-sc in Japan.

PATENT

http://www.google.com/patents/EP2206725A1?cl=en

  1. A peptide of the formula:

    [Glu22, 25, Leu23, 2831, Lys26, Aib29, Nle30]hPTHrP(1-34)NH2;
    [Glu22, 25, Leu23, 28, 3031, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, 25,29, Leu23, 28, 30, 31, Lys26]hpTHrP(1-34)NH2; [Glu22, 25, 29, Leu23, 28, 31, Lys26, Nle30]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11, 23, 28, 31, His14, Cha15, Glu22, 25, Lys26, 30, Aib29]hPTHrP (1-34)NH2; [Cha22, Leu23, 28, 31, Glu25, 29, Lys26, Nle30]hPTHrP(1-34)NH2; [Cha7, 1115]hPTHrP(1-34)NH2; [Cha7, 8, 15]hPTHrP(1-34)NH2; [Glu22, Leu23, 28, Aib25, 29, Lys26]hpTHrP(1-34)NH2; [Aib29]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Lys26, Aib29, 30]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Aib26, 29, Lys30] hPTHrP(1-34)NH2; or [Leu27, Aib29]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.

PATENT

SEE……http://www.google.com.ar/patents/US8148333?cl=en

PATENT

SEE…………http://www.google.im/patents/US20090227498?cl=pt

EP5026436A Title not available
US3773919 Oct 8, 1970 Nov 20, 1973 Du Pont Polylactide-drug mixtures
US4767628 Jun 29, 1987 Aug 30, 1988 Imperial Chemical Industries Plc Polylactone and acid stable polypeptide
WO1994001460A1* Jul 13, 1993 Jan 20, 1994 Syntex Inc Analogs of pth and pthrp, their synthesis and use for the treatment of osteoporosis
WO1994015587A2 Jan 5, 1994 Jul 21, 1994 Steven A Jackson Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides
WO1997002834A1* Jul 3, 1996 Jan 30, 1997 Biomeasure Inc Analogs of parathyroid hormone
WO1997002834A1* 3 Jul 1996 30 Jan 1997 Biomeasure Inc Analogs of parathyroid hormone
WO2008063279A2* 3 Oct 2007 29 May 2008 Radius Health Inc A stable composition comprising a bone anabolic protein, namely a pthrp analogue, and uses thereof
US5695955 * 23 May 1995 9 Dec 1997 Syntex (U.S.A.) Inc. Gene expressing a nucleotide sequence encoding a polypeptide for treating bone disorder
US20030166836 * 6 Nov 2002 4 Sep 2003 Societe De Conseils De Recherches Et D’application Scientefiques, S.A.S., A France Corporation Analogs of parathyroid hormone
US20050282749 * 14 Jan 2005 22 Dec 2005 Henriksen Dennis B Glucagon-like peptide-1 (GLP-1); immunotherapy; for treatment of obesity
Tymlos abaloparatide 4/28/2017 To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies
Drug Trials Snapshot
Abaloparatide
Clinical data
Trade names Tymlos
Synonyms BA058, BIM-44058
Routes of
administration
Subcutaneous injection
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C174H299N56O49
Molar mass 3,959.65 g·mol−1
3D model (JSmol)

/////////FDA 2017, Abaloparatide, TYMLOS, RADIUS HEALTH, PEPTIDE, BA058, BIM 44058; 247062-33-5, абалопаратид أبالوباراتيد 巴罗旁肽 , JAPAN 2021, APPROVALS 2021

update

Abaloparatide acetate

JAPAN 2021 APPROVED C174H300N56O49. (C2H4O2)x

2021/3/23

CCC(C)C(C(=O)NC(CCC(=O)N)C(=O)NC(CC(=O)O)C(=O)NC(CC(C)C)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCC(=O)O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)O)C(=O)NC(CCCCN)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C)(C)C(=O)NC(CCCCN)C(=O)NC(CC(C)C)C(=O)NC(CC1=CN=CN1)C(=O)NC(C(C)O)C(=O)NC(C)C(=O)N)NC(=O)C(CO)NC(=O)C(CCCCN)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CC(=O)O)NC(=O)C(CC2=CN=CN2)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCC(=O)N)NC(=O)C(CC3=CN=CN3)NC(=O)C(CCC(=O)O)NC(=O)C(CO)NC(=O)C(C(C)C)NC(=O)C(C)N

FDA approves new diagnostic imaging agent FLUCICLOVINE F-18 to detect recurrent prostate cancer


FLUCICLOVINE F-18

Cyclobutanecarboxylic acid, 1-amino-3-(fluoro-18F)-, trans- [

  • Molecular FormulaC5H818FNO2
  • Average mass132.124 Da
Axumin (fluciclovine F 18)
fluciclovinum (18F)
GE-148
NMK36
trans-1-Amino-3-(18F)fluorcyclobutancarbonsäure [German] [ACD/IUPAC Name]
trans-1-Amino-3-(18F)fluorocyclobutanecarboxylic acid [ACD/IUPAC Name]
UNII-38R1Q0L1ZE
anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid
cas 222727-39-1
PMDA JAPAN 2021, 2021/3/23, Axumin
05/27/2016 11:27 AM EDT
The U.S. Food and Drug Administration today approved Axumin, a radioactive diagnostic agent for injection. Axumin is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels following prior treatment.

May 27, 2016

Release

The U.S. Food and Drug Administration today approved Axumin, a radioactive diagnostic agent for injection. Axumin is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels following prior treatment.

Prostate cancer is the second leading cause of death from cancer in U.S. men. In patients with suspected cancer recurrence after primary treatment, accurate staging is an important objective in improving management and outcomes.

“Imaging tests are not able to determine the location of the recurrent prostate cancer when the PSA is at very low levels,” said Libero Marzella, M.D., Ph.D., director of the Division of Medical Imaging Products in the FDA’s Center for Drug Evaluation and Research. “Axumin is shown to provide another accurate imaging approach for these patients.”

Two studies evaluated the safety and efficacy of Axumin for imaging prostate cancer in patients with recurrent disease. The first compared 105 Axumin scans in men with suspected recurrence of prostate cancer to the histopathology (the study of tissue changes caused by disease) obtained by prostate biopsy and by biopsies of suspicious imaged lesions. Radiologists onsite read the scans initially; subsequently, three independent radiologists read the same scans in a blinded study.

The second study evaluated the agreement between 96 Axumin and C11 choline (an approved PET scan imaging test) scans in patients with median PSA values of 1.44 ng/mL. Radiologists on-site read the scans, and the same three independent radiologists who read the scans in the first study read the Axumin scans in this second blinded study. The results of the independent scan readings were generally consistent with one another, and confirmed the results of the onsite scan readings. Both studies supported the safety and efficacy of Axumin for imaging prostate cancer in men with elevated PSA levels following prior treatment.

Axumin is a radioactive drug and should be handled with appropriate safety measures to minimize radiation exposure to patients and healthcare providers during administration. Image interpretation errors can occur with Axumin PET imaging. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended.

The most commonly reported adverse reactions in patients are injection site pain, redness, and a metallic taste in the mouth.

Axumin is marketed by Blue Earth Diagnostics, Ltd., Oxford, United Kingdom

Patent

http://www.google.com/patents/WO2014023775A1?cl=en

The non-natural amino acid [ F]-l-amino-3-fluorocyclobutane-l-carboxylic acid

([18F]-FACBC, also known as [18F]-Fluciclovine) is taken up specifically by amino acid transporters and has shown promise for tumour imaging with positron emission tomography (PET).

A known synthesis of [18F]-FACBC begins with the provision of the protected precursor compound 1 -(N-(t-butoxycarbonyl)amino)-3 –

[((trifluoromethyl)sulfonyl)oxy]-cyclobutane-l-carboxylic acid ethyl ester. This precursor compound is first labelled with [18F]-fluoride:

II before removal of the two protecting groups:

IT III

EP2017258 (Al) teaches removal of the ethyl protecting group by trapping the [18F]- labelled precursor compound (II) onto a solid phase extraction (SPE) cartridge and incubating with 0.8 mL of a 4 mol/L solution of sodium hydroxide (NaOH). After 3 minutes incubation the NaOH solution was collected in a vial and a further 0.8 mL 4 mol/L NaOH added to the SPE cartridge to repeat the procedure. Thereafter the SPE cartridge was washed with 3 mL water and the wash solution combined with the collected NaOH solution. Then 2.2 mL of 6 mol/L HCl was then added with heating to 60°C for 5 minutes to remove the Boc protecting group. The resulting solution was purified by passing through (i) an ion retardation column to remove Na+ from excess NaOH and Cl~ from extra HCl needed to neutralise excess of NaOH to get a highly acidic solution before the acidic hydrolysis step, (ii) an alumina column, and (iii) a reverse-phase column. There is scope for the deprotection step(s) and/or the

purification step in the production of [18F]-FACBC to be simplified.

Example 1: Synthesis of f FIFACBC

No-carrier- added [18F]fluoride was produced via the 180(p,n)18F nuclear reaction on a GE PETtrace 6 cyclotron (Norwegian Cyclotron Centre, Oslo). Irradiations were performed using a dual-beam, 30μΑ current on two equal Ag targets with HAVAR foils using 16.5 MeV protons. Each target contained 1.6 ml of > 96% [180]water (Marshall Isotopes). Subsequent to irradiation and delivery to a hotcell, each target was washed with 1.6 ml of [160]water (Merck, water for GR analysis), giving approximately 2-5 Gbq in 3.2 ml of [160]water. All radiochemistry was performed on a commercially available GE FASTlab™ with single-use cassettes. Each cassette is built around a one-piece-moulded manifold with 25 three-way stopcocks, all made of polypropylene. Briefly, the cassette includes a 5 ml reactor (cyclic olefin copolymer), one 1 ml syringe and two 5 ml syringes, spikes for connection with five prefilled vials, one water bag (100 ml) as well as various SPE cartridges and filters. Fluid paths are controlled with nitrogen purging, vacuum and the three syringes. The fully automated system is designed for single-step fluorinations with cyclotron-produced [18F]fluoride. The FASTlab was programmed by the software package in a step-by-step time-dependent sequence of events such as moving the syringes, nitrogen purging, vacuum, and temperature regulation. Synthesis of

[18F]FACBC followed the three general steps: (a) [18F]fluorination, (b) hydrolysis of protection groups and (c) SPE purification.

Vial A contained K222 (58.8 mg, 156 μπιοΐ), K2C03 (8.1 mg, 60.8 μπιοΐ) in 79.5% (v/v)

MeCN(aq) (1105 μΐ). Vial B contained 4M HC1 (2.0 ml). Vial C contained MeCN

(4.1ml). Vial D contained the precursor (48.4 mg, 123.5 μιηοΐ) in its dry form (stored at -20 °C until cassette assembly). Vial E contained 2 M NaOH (4.1 ml). The 30 ml product collection glass vial was filled with 200 mM trisodium citrate (10 ml). Aqueous

[18F]fluoride (1-1.5 ml, 100-200 Mbq) was passed through the QMA and into the 180-

H20 recovery vial. The QMA was then flushed with MeCN and sent to waste. The trapped [18F]fluoride was eluted into the reactor using eluent from vial A (730 μΐ) and then concentrated to dryness by azeotropic distillation with acetonitrile (80 μΐ, vial C). Approximately 1.7 ml of MeCN was mixed with precursor in vial D from which 1.0 ml of the dissolved precursor (corresponds to 28.5 mg, 72.7 mmol precursor) was added to the reactor and heated for 3 min at 85°C. The reaction mixture was diluted with water and sent through the tC18 cartridge. Reactor was washed with water and sent through the tC18 cartridge. The labelled intermediate, fixed on the tC18 cartridge was washed with water, and then incubated with 2M NaOH (2.0 ml) for 5 min after which the 2M NaOH was sent to waste. The labelled intermediate (without the ester group) was then eluted off the tC18 cartridge into the reactor using water. The BOC group was hydrolysed by adding 4M HC1 (1.4 ml) and heating the reactor for 5 min at 60 °C. The reactor content with the crude [18F]FACBC was sent through the HLB and Alumina cartridges and into the 30 ml product vial. The HLB and Alumina cartridges were washed with water (9.1 ml total) and collected in the product vial. Finally, 2M NaOH (0.9 ml) and water (2.1 ml) was added to the product vial, giving a purified formulation of [18F]FACBC with a total volume of 26 ml. Radiochemical purity was measured by radio-TLC using a mixture of MeCN:MeOH:H20:CH3COOH (20:5:5: 1) as the mobile phase. The radiochemical yield (RCY) was expressed as the amount of radioactivity in the [18F]FACBC fraction divided by the total used [18F]fluoride activity (decay corrected). Total synthesis time was 43 min.

The RCY of [18F]FACBC was 62.5% ± 1.93 (SD), n=4.

/////FDA,  diagnostic imaging agent,  recurrent prostate cancer, fda 2016, Axumin, marketed, Blue Earth Diagnostics, Ltd., Oxford, United Kingdom, fluciclovine F 18

C1[C@@](C[C@H]1[18F])(N)C(=O)O

UPDATE

FLUCICLOVINE

Image result for FLUCICLOVINE

LINK https://newdrugapprovals.org/2016/05/28/fda-approves-new-diagnostic-imaging-agent-fluciclovine-f-18-to-detect-recurrent-prostate-cancer/

SEE EMA

Axumin : EPAR – Summary for the public EN = English 06/07/2017

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004197/human_med_002100.jsp&mid=WC0b01ac058001d124

Marketing-authorisation holder Blue Earth Diagnostics Ltd
Revision 0
Date of issue of marketing authorisation valid throughout the European Union 22/05/2017

Contact address:

Blue Earth Diagnostics Ltd
215 Euston Road
London NW1 2BE
United Kingdom

Manufacture, characterisation and process controls

The active substance fluciclovine (18F) is prepared from the precursor AH113487 by nucleophilic substitution
of a triflate group by 18F-fluoride, followed by two deprotection steps. Due to the short half-life of the 18Ffluorine
radioisotope, each batch is prepared on the day of clinical use.
The active substance is prepared in a proprietary automated synthesiser unit. The synthesiser module is
computer-controlled. A fluid path for synthesis is provided in the form of a single use cassette (FASTlab). The
cassette contains 3 reagent vials and 3 solid phase cartridges. Two other reagent vials are supplied
separately as they have a recommended storage temperature of 2-8°C. These 2 vials are inserted into the
cassette on the day of production.
Assessment report
EMA/237809/2017 Page 13/90
Fluciclovine (18F) is produced in a continuous operation from the precursor AH113487. Due to the radioactive
nature of the process, and the short half-life of [18F] fluorine, intermediates are not isolated and there is no
opportunity for operator intervention or in-process testing. Control of the synthesis of fluciclovine (18F) from
the precursor is achieved through the automated synthesis platform, which is pre-programmed with
synthesis parameters optimised for the process. On-board detectors record transfers of radioactivity through
the fluid path at critical points and monitor temperature and pressure as appropriate so that the operator
may track the progress of the synthesis.
The active substance fluciclovine (18F) progressses immediately to purification, formulation and dispensing as
the finished product within a single, continuous operation. Validation of the manufacturing process for
fluciclovine (18F) is therefore described as part of finished product validation.
The characterisation of the active substance is in accordance with the EU guideline on chemistry of new
active substances.
As mentioned, the manufacture of the active substance and finished product takes place in a single,
continuous process. The active substance is not isolated at any point. Therefore, relevant information about
impurities is given only for the finished product.
For the same reason, information for the container closure system is provided only for the finished product.http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004197/WC500230836.pdf

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