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ORGANIC SPECTROSCOPY

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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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Azeliragon


Azeliragon.png

Azeliragon

C32H38ClN3O2, 532.1 g/mol

CAS 603148-36-3

TTP488

UNII-LPU25F15UQ

LPU25F15UQ

TTP-488; PF-04494700

3-[4-[2-butyl-1-[4-(4-chlorophenoxy)phenyl]imidazol-4-yl]phenoxy]-N,N-diethylpropan-1-amine

MOA:RAGE inhibitor

Indication:Alzheimer’s disease (AD)

Status:Phase III (Active), Dementia, Alzheimer’s type
Company:vTv Therapeutics (Originator)

Azeliragon

Azeliragon is in phase III clinical for the treatment of Alzheimer’s type dementia.

Azeliragon was originally by TransTech Pharma (now vTv Therapeutics), then licensed to Pfizer in 2006.

Pfizer discontinued the research in 2011, now vTv Therapeutics continues the further reaserch.

vTv Therapeutics  (previously TransTech Pharma) is developing azeliragon, an orally active antagonist of the receptor for advanced glycation end products (RAGE), for the treatment of Alzheimer’s disease (AD) in patients with diabetes.  In June 2019, this was still the case .

Azeliragon was originally developed at TransTech Pharma. In September 2006, Pfizer entered into a license agreement with the company for the development and commercialization of small- and large-molecule compounds under development at TransTech. Pursuant to the collaboration, Pfizer gained exclusive worldwide rights to develop and commercialize TransTech’s portfolio of RAGE modulators, including azeliragon.

Reference:

1. WO03075921A2.

2. US2008249316A1.

US 20080249316

VTV Therapeutics

Azeliragon (TTP488) is an orally bioavailable small molecule that inhibits the receptor for advanced glycation endproducts (RAGE). A Phase 2 clinical trial to evaluate azeliragon as a potential treatment of mild-AD in patients with type 2 diabetes is ongoing.  The randomized, double-blind, placebo-controlled multicenter trial is designed as sequential phase 2 and phase 3 studies operationally conducted under one protocol. For additional information on the study, refer to NCT03980730 at Clinicaltrials.gov.

RAGE is an immunoglobulin-like cell surface receptor that is overexpressed in brain tissues of patients with AD. The multiligand nature of RAGE is highlighted by its ability to bind diverse ligands such as advanced glycation end-products (AGEs), linked to diabetic complications and β-amyloid fibrils, a hallmark of AD. The association between type 2 diabetes and AD is well documented. A linear correlation between circulating hemoglobin A1c (HbA1c) levels and cognitive decline has been demonstrated in the English Longitudinal Study of Ageing.

PATENT

WO-2019190823

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019190823&tab=PCTDESCRIPTION&_cid=P12-K1K59I-21476-1

Novel crystalline forms of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine and its salt ( azeliragon ) (deignated as forms III and IV) as RAGE inhibitors useful for treating  psoriasis, rheumatoid arthritis and Alzheimer’s disease.

The Receptor for Advanced Glycation Endproducts (RAGE) is a member of the immunoglobulin super family of cell surface molecules. Activation of RAGE in different tissues and organs leads to a number of pathophysiological consequences. RAGE has been implicated in a variety of conditions including: acute and chronic inflammation (Hofmann et al., Cell 97:889-901 (1999)), the development of diabetic late complications such as increased vascular permeability (Wautier et al., J. Clin. Invest. 97:238-243 (1995)), nephropathy (Teillet et al., J. Am. Soc. Nephrol. 11 : 1488- 1497 (2000)), atherosclerosis (Vlassara et. al., The Finnish Medical Society DUODECIM, Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et al., Diabetologia 42:603-607 (1999)). RAGE has also been implicated in Alzheimer’s disease (Yan et al., Nature 382: 685-691 , (1996)), erectile dysfunction, and in tumor invasion and metastasis (Taguchi et al., Nature 405: 354-357, (2000)).

Binding of ligands such as advanced glycation endproducts (AGEs), S100/calgranulin/EN-RAGE, b-amyloid, CML (Ne-Carboxymethyl lysine), and amphoterin to RAGE has been shown to modify expression of a variety of genes. For example, in many cell types interaction between RAGE and its ligands generates oxidative stress, which thereby results in activation of the free radical sensitive transcription factor NF-kB, and the activation of NF-kB regulated genes, such as the cytokines IL- 1 b, TNF- a, and the like. In addition, several other regulatory pathways, such as those involving p21 ras.

MAP kinases, ERK1 and ERK2, have been shown to be activated by binding of AGEs and other ligands to RAGE. In fact, transcription of RAGE itself is regulated at least in part by NF-kB. Thus, an ascending, and often detrimental, spiral is fueled by a positive feedback loop initiated by ligand binding. Antagonizing binding of physiological ligands to RAGE, therefore, is our target, for down-regulation of the pathophysiological changes brought about by excessive concentrations of AGEs and other ligands for RAGE.

Pharmaceutically acceptable salts of a given compound may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, melting point, crystal shape, compaction behavior, flow properties, and/or solid state stability. These differences affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Although U.S. Patent No. 7,884,219 discloses Form I and Form II of COMPOUND I as a free base, there is a need for additional drug forms that are useful for inhibiting RAGE activity in vitro and in vivo, and have properties suitable for large-scale manufacturing and formulation. Provided herein

PATENT

WO03075921

PATENT

WO2019190822

PATENT

WO2008123914

Publications

Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics

Presentations and Posters

Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics

///////////Azeliragon, psoriasis, rheumatoid arthritis, Alzheimer’s disease, TTP-488,  PF-04494700, RAGE inhibitors, TransTech Pharma, PHASE 3, Dementia, Alzheimer’s type,

CCCCC1=NC(=CN1C2=CC=C(C=C2)OC3=CC=C(C=C3)Cl)C4=CC=C(C=C4)OCCCN(CC)CC

JNJ-54861911, Atabecestat , атабецестат , أتابيسيستات ,


2D chemical structure of 1200493-78-2imgChemSpider 2D Image | atabecestat | C18H14FN5OS

Atabecestat, JNJ-54861911

Cas 1200493-78-2

367.40, C18 H14 F N5 O S

2-Pyridinecarboxamide, N-[3-[(4S)-2-amino-4-methyl-4H-1,3-thiazin-4-yl]-4-fluorophenyl]-5-cyano-
  • N-[3-[(4S)-2-Amino-4-methyl-4H-1,3-thiazin-4-yl]-4-fluorophenyl]-5-cyano-2-pyridinecarboxamide
  • Atabecestat
  • атабецестат [Russian] [INN]
    أتابيسيستات [Arabic] [INN]

Atabecestat is a beta-secretase inhibitor drug candidate.

(S)-N-(3-(2-amino-4-methyl-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide

JNJ-54861911
N-{3-[(4S)-2-Amino-4-methyl-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-5-cyano-2-pyridinecarboxamide
2-Pyridinecarboxamide, N-[3-[(4S)-2-amino-4-methyl-4H-1,3-thiazin-4-yl]-4-fluorophenyl]-5-cyano-

WO 2017111042, 1H-NMR (CDCl3) δ: 1.71 (3H, s), 4.06 (3H, s), 6.29 (2H, d, J = 2.4 Hz), 7.07 (1H, dd, J = 11.3, 8.8 Hz), 7.65 (2H, dd, J = 6.8, 2.8 Hz), 7.86 (1H, ddd, J = 8.8, 4.1, 2.8 Hz), 8.19 (1H, dd, J = 8.1, 2.0 Hz), 8.43 (1H, d, J = 8.1 Hz), 8.89 (1H, d, J = 2.0 Hz), 9.81 (1H, s).
[α]D -11.8±1.0° (DMSO, 23°C, c=0.518)

Image result

Structure of JNJ54861911.
Credit: Tien Nguyen/C&EN

Presented by: Yuji Koriyama, associate director at Shionogi & Co.

Target: β-site amyloid presursor protein cleaving enzyme 1 (BACE1), an enzyme whose buildup is implicated in Alzheimer’s disease

Disease: Alzheimer’s disease

Reporter’s notes: Presented by Koriyama, who told the audience he was attending the ACS National Meeting for the first time, JNJ-5486911 joins dozens of clinical candidates from many companies in Phase II and III trials to treat Alzheimer’s disease. Researchers started with a hit that inhibited BACE1 with approximately 2,600 nM affinity and advanced the program until finally reaching a compound with roughly 1 nM affinity. The compound is being jointly developed by Shionogi & Co. and Janssen Pharmaceuticals.

  • Originator Shionogi
  • Developer Janssen Research & Development
  • Class Antidementias; Small molecules
  • Mechanism of Action Amyloid precursor protein secretase inhibitors

Highest Development Phases

  • Phase II/III Alzheimer’s disease

Most Recent Events

  • 16 Jul 2017 Pharmacodynamics data from preclinical trials in Alzheimer’s disease presented at the Alzheimer’s Association International Conference (AAIC-2017)
  • 15 Dec 2016 Biomarkers information updated
  • 01 Jun 2016 Janssen Research & Development completes a phase I pharmacokinetic interaction trial in Healthy volunteers in Germany (PO) (NCT02611518)
  • Image result for Janssen Research & Development

SYNTHESIS

PATENTS

WO 2009151098

Applicants: SHIONOGI & CO., LTD. [JP/JP]; 1-8, Doshomachi 3-chome, Chuo-ku, Osaka-shi, Osaka 5410045 (JP) (For All Designated States Except US).
HORI, Akihiro [JP/JP]; (JP) (For US Only).
YONEZAWA, Shuji [JP/JP]; (JP) (For US Only).
FUJIKOSHI, Chiaki [JP/JP]; (JP) (For US Only).
MATSUMOTO, Sae [JP/JP]; (JP) (For US Only).
KOORIYAMA, Yuuji [JP/JP]; (JP) (For US Only).
UENO, Tatsuhiko [JP/JP]; (JP) (For US Only).
KATO, Terukazu [JP/JP]; (JP) (For US Only)
Inventors: HORI, Akihiro; (JP).
YONEZAWA, Shuji; (JP).
FUJIKOSHI, Chiaki; (JP).
MATSUMOTO, Sae; (JP).
KOORIYAMA, Yuuji; (JP).
UENO, Tatsuhiko; (JP).
KATO, Terukazu; (JP)

PATENT

WO 2011071057

PATENT

WO 2017175855

PATENT

WO 2017111042

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017111042&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Scheme 1-D
[Chem. 27]

Example 1-4
Preparation of Compound 15
[Chem. 31]

Compound 12 (3.0 g, 20.3 mmol) was dissolved in N-methylpyrrolidone (18 mL), and the solution was cooled to 5°C. Thionyl chloride (3.1 g, 26.1 mmol) was added to obtain a solution of Compound 13.
To a suspension of Compound 11 (5.0 g, 16.8 mmol) in ethyl acetate (50 mL) were added sodium bicarbonate (3.5 g, 42.0 mmol) and water (50 mL), and the mixture was stirred for 5 min at 20°C.
The layers were separated, and the organic layer was concentrated to 10 g under reduced pressure. N-Methylpyrrolidone (5 mL) and 35% hydrochloric acid (0.9 g) were added, and the mixture was cooled to 3°C. The solution of Compound 13 and N-methylpyrrolidone (1.5 mL) were added to obtain a solution of Compound 15.
The solution of Compound 15 was added to a mixture of water (15 mL) and ethyl acetate (10 mL). After stirring the mixture for 1 hour, triethylamine (14.8 g, 14.6 mmol), N-methylpyrrolidone (1.5 mL) and water (5 mL) were added and further stirred for 1 hour. Water (45 mL) was added, and the mixture was stirred for 1 hour, filtered and dried to obtain crystals of Compound 15 (Crystalline Form I, 5.71 g, 92.4%).

Compound 15
1H-NMR (CDCl3) δ: 1.71 (3H, s), 4.06 (3H, s), 6.29 (2H, d, J = 2.4 Hz), 7.07 (1H, dd, J = 11.3, 8.8 Hz), 7.65 (2H, dd, J = 6.8, 2.8 Hz), 7.86 (1H, ddd, J = 8.8, 4.1, 2.8 Hz), 8.19 (1H, dd, J = 8.1, 2.0 Hz), 8.43 (1H, d, J = 8.1 Hz), 8.89 (1H, d, J = 2.0 Hz), 9.81 (1H, s).
[α]D -11.8±1.0° (DMSO, 23°C, c=0.518)

Example 1-5
To a suspension of Compound 11 (1831 g, 6.2 mol) in ethyl acetate (18L) were added sodium bicarbonate (1293 g, 15.4 mol) and water (18L), and the mixture was stirred for 5 min at 20°C. The layers were separated, and the organic layer was concentrated to 3.8 kg under reduced pressure to obtain a concentrated solution of Compound 14.
Compound 12 (912 g, 6.2 mol) was dissolved in N-methylpyrrolidone (64L), and the solution was cooled to 4°C. Thionyl chloride (951 g, 8.0 mol) was added, and the mixture was stirred for 30 min. The concentrated solution of Compound 14 was added to obtain a solution of Compound 15.
The solution of Compound 15 and N-methylpyrrolidone (1.6 L) were added to water (18 L), and the mixture was stirred for 40 min at 25°C. 24% sodium hydroxide in water (5 kg), sodium bicarbonate (259 g, 3.1 mmol) and water (2.7 L) were added to the mixture. The mixture was stirred for 1 hour, filtered and dried to obtain crystals (metastable Form II) of Compound 15 (1.93 kg, 85.4%).

Example 1-3
Preparation of Compound 11
[Chem. 30]

A suspension of Compound 9 (20.0 g, 29.0 mmol) in N,N-dimethylacetamide (30 mL) was cooled to 5°C. 1,8-diazabicyclo(5,4,0)-7-undecene (39.7 g, 260.8 mmol) was added, and the mixture was stirred for 22 hours. Water (70 mL) was added to afford a solution of Compound 10.

To a mixture of ethyl acetate (200 mL), water (40 mL) and 62% sulfuric acid (12.7 g) was added the solution of Compound 10, and the mixture was cooled to 10°C. 15% sulfuric acid (3.7 g) was added, and the mixture was warmed to 20°C. The layers were separated, and the organic layer was washed with 5% sodium chloride in water (95 g). The layers were separated, and the organic layer was concentrated in vacuo to 42 mL. Ethyl acetate (20 mL) and 50% potassium carbonate in water (20 g) were added, and the mixture was warmed to 40°C. 4-chlorobenzenethiol (6.29 g, 43.5 mmol) and ethyl acetate (11 mL) were added, and the mixture was stirred for 1 hour. After cooling to 20°C, ethyl acetate (100 mL), water (68 mL) and 15% hydrochloric acid (42.6 g) were added. The layers were separated, and ethyl acetate (149 mL) and 20% potassium carbonate in water (40.5 g) were added to the aqueous layer. The layers were separated, and the organic layer was washed with water (100 mL). The layers were separated, and the organic layer was concentrated to 20 mL. Acetic acid (1.7 g, 29.0 mmol) was added, and the mixture was cooled to 5°C and stirred for 90 min, filtered and dried to afford 7.19 g of crystals of Compound 11 (yield: 83.4%, optical purity of (S)-isomer: 100%).

Compound 11
1H-NMR (DMSO-d6) δ: 6.74 (1H, dd, J=11.86, 8.56 Hz), 6.62 (1H, dd, J=6.97, 2.93 Hz), 6.35-6.40 (2H, m), 6.11 (1H, dd, J=9.60, 4.71 Hz), 1.90 (3H, s), 1.49 (3H, s).

The optical purity was determined as follows.
(Sample Preparation)
25 mg of Compound 11 was weighed and dissolved in a solvent to prepare a 50 mL sample solution.

(Method)
Using liquid chromatography, the peak area was determined by automatic integration method for each of (R)- and (S)-isomers of Compound 11.

(Conditions)
Detector: ultraviolet absorptiometer (wave length: 230 nm)
Column: CHIRALCEL OD-RH, φ4.6×150 mm, 5 μm, (Daicel Corporation)
Column Temp.: constant at around 40°C
Mobile Phase: water/acetonitrile (LC grade)/methanol (LC grade)/triethylamine (1320:340:340:1)
Flow Rate: 1.0 mL/min (retention time of Compound 11: about 8 min for (R)-isomer, about 9 min for (S)-isomer)
Time span of measurement: over 15 min from the sample injection
Injection Volume: 10 μL
Sample Cooler Temp.: constant at around 25°C
Autoinjector Rinse Solution: water/acetonitrile (1:1)

http://www.shionogi.co.jp/en/

Image result for HORI, Akihiro SHIONOGI

//////////////JNJ-54861911, Atabecestat , атабецестат , أتابيسيستات ,Phase III , Alzheimer’s disease, DEMENTIA, Shionogi, Developer,  Janssen Research & Development

C[C@]1(C=CSC(N)=N1)c3cc(NC(=O)c2ccc(C#N)cn2)ccc3F

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