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Loxiglumide

December 10, 2013 3:37 am / 1 Comment on Loxiglumide

Loxiglumide

Loxiglumide, CR-1505
molecular formula :C21H30Cl2N2O5
molecular weight 461.3793
CAS NO:107097-80-3

WO 1987003869

Rottapharm (Originator)

4-[(3,4-Dichlorobenzoyl)amino]-5-[(3-methoxypropyl)pentylamino]-5-oxopentanoic acid, (±)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N-pentylglutaramic acid

Cholecystokinin (CCK) belongs to the group of substances known as brain-gut peptides and function as a neuropeptide and as a gut hormone. (Noble et al., Pharmacol. Rev. 1999, 51(4):745-781; Crawley et al., Peptides 1994, 15(4):731-755). It is now evident that at least two different receptors, namely CCK1 (formerly CCKA or alimentary) and CCK2 (formerly CCKB or brain) receptors, mediate CCK biological actions. (Noble et al., Pharmacol. Rev., 1999, 51(4):745-781; Woodruff and Hughes, Ann. Rev. Pharmacol. 1991, 31:469-501). CCK1 receptors are found in peripheral tissues, including the GI tract.

CCK is secreted primarily in response to meals and plays a well-recognized role in regulating gallbladder contraction and pancreatic enzyme secretion. Over the last decade, considerable evidence has emerged to support the concept that CCK plays an equally important role in the regulation of motor and sensory functions at various levels of the human upper GI tract. Specifically, the native peptide delays gastric emptying, modulates gastric sensory function (especially in response to fat), increases the rate of meal-induced, transient lower esophageal sphincter relaxations (TLESRs) and affects small bowel and colonic transit.

The CCK1 antagonists loxiglumide and dexloxiglumide have demonstrated the ability to reverse the physiologic effects of CCK on gastric emptying and to decrease dyspeptic symptoms induced by air distension and fat infusion. By example,loxiglumide reduced both exogenous and endogenous CCK-induced delay in gastric emptying of liquids and solids in healthy subjects (Borovicka et al., Am J Physiol. 1996, 271:448-453; Schwizer et al., Gut. 1997, 41(4):500-504). Dexloxiglumide reversed the diminished tolerance to water volume that occurred from CCK release in response to duodenal lipid infusion; the effect was due to reduction of intragastric volume, primarily due to accelerated gastric emptying (Lal et al., Am J Physiol Gastrointest Liver Physiol. 2004, 287(1):72-79). When proximal gastric relaxation was produced in healthy subjects by duodenal infusion of lipid, a potent stimulus of CCK release, the relaxation was reversed by loxiglumide (Feinle et al., Gastroenterology 1996, 110(5):1379-1385). Also, loxiglumide modulated antro-pyloroduodenal dysmotility, which is postulated to play a role in generation of dyspeptic symptoms, after it was experimentally induced in healthy subjects by intraduodenal infusion of a mixed liquid meal (Katschinski et al., Eur J Clin Invest. 1996, 26(7):574-583). Loxiglumide was also able to reverse the lowering of intragastric pressure of healthy subjects after duodenal infusion of lipids induced sensations such as fullness and nausea (See Feinle et al., 1996).

In patients with nonulcer dyspepsia and delayed gastric emptying, loxiglumide was shown to accelerate gastric emptying by comparison to placebo (Chua AS, Bekkering M, et al., 1994). Loxiglumide significantly improved dyspeptic symptoms in patients with non-ulcer dyspepsia in an 8-week study (Chua et al., Ann N Y Acad. Sci. 1994, 713:298-299). In another study in patients with functional dyspepsia, aggravation of nausea, fullness, discomfort, bloating and pain was produced by duodenal infusion of lipid with or without balloon distension; dexloxiglumide significantly improved dyspepsia symptom scores compared to placebo (Feinle et al., Gut. 2001, 48(3): 347-355).

Pharmaceutical compositions comprising CCKB antagonists and a proton pump inhibitor to control gastric acid secretion in gastrointestinal disorders have been described in the literature. (See WO 04/098610, WO 04/101533, WO 04/098609, WO 03/041714, WO 01/90078, WO 01/85724, WO 01/85723, WO 01/85704, WO 01/85167, and WO 93/12817) CCK-B receptors mediate CCK biological actions in the brain and are one of several regulators of gastric acid secretion. It is the CCK1 receptors, however, that mediate the CCK biological actions in peripheral tissues including gastric emptying and esophageal sphincter effects.

In addition, combination therapy of a PPI and a second agent, e.g., loxiglumide, to improve impaired esophageal motility has been disclosed as a possible treatment to gastroesophageal reflux disease. (Tonini et al., Drugs 2004, 64(4): 347-361). International Application Nos. PCT/EP2004/050936 and PCT/EP2005/050336 also disclose pharmaceutical combinations of a proton pump inhibitor and a compound that modifies gastrointestinal motility. Both international applications disclose that dexloxiglumide may be useful for therapy of irritable bowel syndrome (IBS) or GERD and may be used to modify gastrointestinal motility.

D,l-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylamino)-5-oxopentanoic acid (CR 1505; loxiglumide) is a newly developed analog of proglumide.

N-(3,4-dichlorobenzoyl)-glutamic acid anhydride (I) is condensed with N-(3-methoxypropyl)-N-pentylamine (II) in water at 5 °C to produce Loxiglumide.

loxiglumide

Percent Composition: C 54.67%, H 6.55%, Cl 15.37%, N 6.07%, O 17.34%

Literature References: Cholecystokinin type-1 (CCK-1) antagonist. Prepn: F. Makovec et al., WO 8703869; eidem, US 4769389(1987, 1988 both to Rotta).

Pharmacology and receptor binding: I. Setnikar et al., Arzneim.-Forsch. 37, 703 (1987). Pharmacokinetics: idem et al., ibid. 38, 716 (1988). Effect on bilio-pancreatic secretion: W. E. Schmidt et al., Digestion 46, Suppl. 2, 232 (1990). Clinical evaluation in irritable bowel syndrome: P. A. Cann et al., Ann. N.Y. Acad. Sci. 713, 449 (1994); in nonulcer dyspepsia: A. S. B. Chua et al. ibid. 451; in pancreatitis: K. Shiratori et al., Pancreas 25, e1 (2002).

Properties: Crystals from acetone, mp 113-115°. pKa ~5. Soly in water: 0.01%.

Melting point: mp 113-115°

pKa: pKa ~5

………………………………………………………………….

Derivative Type: (R)-Form

CAS Registry Number: 119817-90-2

Additional Names: Dexloxiglumide

Manufacturers’ Codes: CR-2017

Literature References: HPLC determn in plasma: R. Brodie et al., J. Chromatogr. B 784, 91 (2003). In vitro biopharmaceutical properties: S. Tolle-Sander et al., J. Pharm. Sci. 92, 1968 (2003). Clinical pharmacokinetics: C. Webber et al., Xenobiotica 33, 625 (2003). Clinical evaluation in irritable bowel syndrome: F. Cremonini et al., Am. J. Gastroenterol. 100, 652 (2005).

Properties: Soly (mg/ml): 33 (pH 3.4), 533 (pH 7.5). pKa 4.48.

pKa: pKa 4.48

Therap-Cat: Gastroprokinetic.

Keywords: CCK Antagonist; Gastroprokinetic.

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FDA Advisory Committee Recommends Approval of Takeda’s Investigational Biologic Vedolizumab

December 10, 2013 3:27 am / Leave a comment

Deerfield, Ill., December 9, 2013 and Osaka, Japan, December 10, 2013 — Takeda Pharmaceutical Company Limited (“Takeda”) and its wholly-owned subsidiary, Takeda Pharmaceuticals U.S.A., Inc., today announced that a joint panel of members from the Gastrointestinal Drugs and Drug Safety and Risk Management Advisory Committees of the United States (U.S.) Food and Drug Administration (FDA) voted to recommend approval of Takeda’s vedolizumab for the treatment of adults with moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD). All 21 committee members voted that based on currently available efficacy and safety data, the benefits outweigh the potential risks of vedolizumab to support approval for UC. Specifically, 13 committee members supported approval for UC patients who have failed steroids or immunosuppressants or TNF-α antagonists, while eight committee members supported approval for UC patients who have failed immunosuppressants or TNF-α antagonists (the indicated population would not include patients that failed steroids only). Twenty of the 21 committee members voted to support approval for CD. Specifically, 14 committee members supported approval for CD patients who have failed steroids or immunosuppressants or TNF-α antagonists while six supported approval for CD patients who have failed immunosuppressants or TNF-α antagonists (the indicated population would not include patients that failed steroids only).

read at

http://www.drugs.com/nda/vedolizumab_131209.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+December+9%2C+2013

About Crohn’s disease and ulcerative colitis
Crohn’s disease (CD) and ulcerative colitis (UC) are the two most common forms of inflammatory bowel disease (IBD), which is marked by inflammation in the lining of the GI tract. CD can impact any part of the digestive tract, and common symptoms may include abdominal pain, diarrhea, rectal bleeding, weight loss, and/or fever. UC impacts the large intestine only, which includes the colon and the rectum. The most common symptoms of UC include abdominal discomfort and blood or pus in diarrhea. There is no known cause for CD or UC, although many researchers believe that the interaction of an outside agent, such as a virus or bacteria, with the body’s immune system may trigger them. No cure exists for CD or UC; the aim of IBD treatments is to induce and maintain remission, or achieve extended periods of time when patients do not experience symptoms.

About vedolizumab
Vedolizumab was developed for the treatment of CD and UC, as a gut-selective, humanized monoclonal antibody that specifically antagonizes the alpha4beta7 (α4β7) integrin, which is expressed on a subset of circulating white blood cells. These cells have been shown to play a role in mediating the inflammatory process in CD and UC. α4β7 binds with a specific adhesion molecule primarily expressed in the intestinal tract. Therefore, vedolizumab, by preventing this interaction, has a gut selective effect.

About Takeda Pharmaceutical Company Limited
Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for patients worldwide through leading innovation in medicine. Additional information about Takeda is available through its corporate website, http://www.takeda.com.

Vedolizumab is a monoclonal antibody being developed by Millennium Pharmaceuticals, Inc. for the treatment of ulcerative colitis and Crohn’s disease.It binds to integrin α₄β₇(LPAM-1, lymphocyte Peyer’s patch adhesion molecule 1).^[1]^[2]

The molecule was first identified by Dr. Andrew Lazarovits [1][2] as the murine MLN0002 homologue. His discovery of the mouse equivalent of this antibody—originally applied to anti-rejection strategies in kidney transplantation—was published in the journal Nature in 1996. The drug was then licensed to Millennium Pharmaceuticals of Boston for further development.

As of October 2009, vedolizumab is undergoing Phase III trials.^[3] Clinical trials indicate that Vedolizumab was found safe and highly effective for inducing and maintaining clinical remission in patients with moderate to severe ulcerative colitis [3]. Dr. Brian Faegan, head researcher, reported an absence of any instances of progressive multifocal leukoencephalopathy (PML), which is a particularly important finding [4]. It looks like it will be an effective abiologic agent without some of the toxicity issues previously seen with anti-TNF drugs .

It is widely believed now that “vedolizumab can be used either as a first-line treatment or in case of anti-TNF failure”

Statement On A Nonproprietary Name Adopted By The USAN Council – Vedolizumab, American Medical Association.
Soler, D; Chapman, T; Yang, LL; Wyant, T; Egan, R; Fedyk, ER (2009). “The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases”. The Journal of Pharmacology and Experimental Therapeutics 330 (3): 864–75. doi:10.1124/jpet.109.153973. PMID 19509315.
ClinicalTrials.gov NCT00790933 Study of Vedolizumab (MLN0002) in Patients With Moderate to Severe Crohn’s Disease (GEMINI II)

RIVASTIGMINE

December 9, 2013 8:02 am / 1 Comment on RIVASTIGMINE

RIVASTIGMINE

123441-03-2 cas no

129101-54-8 CAS NO

Rivastigmine, (sold under the trade name Exelon) is a parasympathomimetic orcholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s typeand dementia due to Parkinson’s disease. The drug can be administered orally or via atransdermal patch; the latter form reduces the prevalence of side effects, which typically include nausea and vomiting.The drug is eliminated through the urine, and appears to have relatively few drug-drug interactions.

Rivastigmine was developed by Marta Weinstock-Rosin of the Department of Pharmacology, at the Hebrew University of Jerusalem and sold to Novartis by Yissum for commercial development.(It is a semi-synthetic derivative of physostigmine) It has been available in capsule and liquid formulations since 1997. In 2006, it became the first product approved globally for the treatment of mild to moderate dementia associated withParkinson’s disease; and in 2007 the rivastigmine transdermal patch became the first patch treatment for dementia

PATENT

US 4,948,807

Patent 5,602,176
Issued: February 11, 1997
Inventor(s): Enz; Albert
Assignee(s): Sandoz Ltd.Patent expiration dates:

February 11, 2014

R. Amstutz, A. Enz, M. Marzi, M. Boelsterli, M. Walsinshaw

Amstutz, R.; Enz, A.; Marzi, M.; Boelsterli, J.; Walkinshaw, M. (1990). “Cyclische Phenyl-carbamate des Miotin-Typs und ihre Wirkung auf die Acetylcholinesterase”. Helvetica Chimica Acta(in German) 73 (3): 739. doi:10.1002/hlca.19900730323.

Rivastigmine hydrogen tartrate is chemically known as (S)-N-Ethyl-N-methyl-3- [1-(dimethylamino) ethyl]-phenyl carbamate hydrogen- (2R, 3R)-tartrate (hereinafter referred to as “rivastigmine tartrate”) and has structural Formula I.
Rivastigmine hydrogen tartrate is administered for the inhibition of reversible cholinesterase and is marketed under the brand name EXELON^™ as capsules containing 0.5, 3, 4.5 and 6 mg rivastigmine base equivalent.
U.S. Patent No. 4,948,807 describes the compound N-ethyl, N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate and its pharmacologically acceptable salts along with a pharmaceutical composition useful for treating anticholinesterase activity in humans.
U.S. Patent No. 5,602,176 describes (S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-phenyl carbamate in free base or acid addition salt form as useful for its anticholinesterase activity.
International Application Publication No. WO 2004/037771 A1 and European Patent 193926 describe a process for the preparation of (S)-3-[1-(dimethylamino)-ethyl]-phenyl-N-ethyl-N-methyl carbamate by the reaction of optically active m-hydroxyphenylethyl dimethylamine with a carbamoylhalide
International application No. WO 2005/058804A1 describes a process for the preparation of rivastigmine by streoselective reduction.

The synthesis of rivastigmine was reported in U.S. Pat. No. 5,602,176, GB2409453, and Yonwen, Jiang et. al. [Journal of East China Normal University (Natural Science), 2001, 1, 61-65], in which the method is disclosed as: preparing racemic rivastigmine by a series of reactions, then salifying the result with D-(+)-O, o′-bis-p-tolyl formacyl tartaric acid monohydrate (D-DTTA) to separate the racemic mixture, and recrystallizing at least three time to obtain (S)-rivastigmine with an optical purity of above 99%. The final yield is only 5.14%.

A method for resolution of a intermediate of rivastigmine is disclosed in WO200403771, in which S-(+)-camphor sulfonic acid is used to separate racemic intermediates of 3-(1-(S)—(N,N-dimethylamino) ethyl)phenol, and optically pure 3-(1-(S)—(N,N-dimethylamino) ethyl)phenol is obtained after three times recrystallization and then condensates with N-methyl-N-ethyl-amino formacyl chloride to obtain (S)-rivastigmine. The specific synthesis route is shown below:

A method for resolution of a intermediate of rivastigmine is also disclosed in WO2007014973, in which S-(+)-camphor sulfonic acid is used to separate racemic intermediates of 3-(1-(methylamino) ethyl)phenol, and the result condensates with N-methyl-N-ethyl-amino formacyl chloride to obtain N-methylethylcarbamino-3-[(S)-1-(methylamino)-ethyl]phenyl ester, and a methylation is then performed on the nitrogen atom followed by salifying with L-(+)-tartaric acid so that rivastigmine is obtained. The methylation needs a reduction system of sodium cyanoborohydride/formaldehyde, in which sodium cyanoborohydride is highly toxic, so that the method is not suitable for industrial production. The specific synthesis route is shown below:

The resolution methods mentioned above are time consuming with low yields, so that final yields are reduced and costs are increased, which are not beneficial for industrial production and the optical purity of rivastigmine cannot be guaranteed.

K. Han, C. Kim, J. Park*, M.-J. Kim*
Pohang University of Science and Technology, Korea
Chemoenzymatic Synthesis of Rivastigmine via Dynamic Kinetic Resolution as a Key Step
J. Org. Chem. 2010, 75: 3105-3108

Rivastigmine (Exelon®) is an acetylcholinesterase inhibitor that is prescribed for the treatment of mild to moderate dementia in patients with Alzheimer’s disease and Parkinson’s disease. The key step in the synthesis depicted is a dynamic kinetic resolution of the benzylic secondary alcohol B involving a lipase (Novozyme 435) coupled with a polymer-bound racemization catalyst (C).

The polymer-bound racemization catalyst C was prepared by heating a polymer-bound benzoyl chloride with [Ph4(η4-C4CO]Ru(CO)3 in toluene for one day. The catalyst can be recycled several times. The enzymatic resolution was performed on a 1 mmol scale. For an alternative chemoenzymatic synthesis of rivastigmine, see: J. Mangas-Sánchez et al. J. Org. Chem. 2009, 74, 5304.

………………………….

http://www.google.com/patents/EP1980552A2

EXAMPLES

EXAMPLE 1:

To a solution of 200 g of 3-hydroxyacetophenone of Formula IX in 400 ml of acetone, 244 g of potassium carbonate were charged and stirred for about 10 minutes. To the above reaction mixture 204 g of dimethyl sulphate was added for about 60 minutes followed by heating to about 45 °C and stirred for about 1 hour. After completion of the reaction, the reaction mixture was quenched by charging of 800 ml of water. Organic and aqueous layers were separated and 370 g of ammonium formate was added to the organic layer. The contents were then heated to about 180 °C and stirred for about 2 hours. The reaction mixture was then cooled to about 30° C and 600 ml of water was charged. The mixture was extracted with ethyl acetate (1×400 ml, 2×150 ml). The organic layers were combined and charged 600 ml of hydrogen chloride in isopropanol (18% w/w) followed by heating to about 75 °C and stirred for about 3 hours. The mixtures was distilled completely at about 65 °C under vacuum and again charge 100 ml ethyl acetate and distilled completely at about 65°C to afford residue.
600 ml of ethyl acetate was charged to the residue and stirred for 30 minutes. Filtered the solid and was washed with 200 ml of ethyl acetate. The wet solid was then charged into 600 ml of water and pH was adjusted to about 11 by addition of 68.8 ml of 40% aqueous sodium hydroxide. The reaction mixture was extracted with ethyl acetate (1×200 ml, 2×100 ml). Organic and aqueous layers were separated and the organic layer was distilled off completely at about 65 °C under vacuum to afford 128 g of the title compound.
HPLC purity: 99.1%

EXAMPLE 2:

To a solution of 40 g of 1- (3-methoxyphenyl) ethyl amine of Formula VI in 1400 ml of isopropyl alcohol, 41.2 g of L-(+)-mandelic acid was added and stirred for about 15 minutes. The mixture was heated to about 75°C and stirred for about 45 minutes followed by cooling to about 37°C and stirred for about 10 minutes. The separated solid was filtered and the solid was washed 80 ml of isopropyl alcohol. The solid obtained was suck dried for 3 hours to obtain the wet compound of the diasteromeric salt of Formula V.
The obtained diasteromeric salt of Formula V was charged into a clean and dry round bottom flask containing 480 ml of isopropyl alcohol followed by heating to reflux. The resultant solution was stirred at reflux for about 45 minutes followed by cooling to about 37° C and stirred for about 10 minutes. Solid was separated by filtration and the solid was washed with 20 ml of isopropyl alcohol. The solid obtained was dried at about 55 °C for about 2 hours to yield 29 g of the title compound.
Purity by chiral HPLC: 99.9%.

EXAMPLE 3:

To a solution of 200 g of S-(-)-1-(3-methoxyphenyl)ethyl amine L (+)-Mandalate (diasteromeric salt) of Formula V in 800 ml of water, charged 148 g of formaldehyde (40%), 182.1 g of formic acid (98%) and the contents were heated to about 100 °C. The resultant mixture was stirred at about 100 °C for about 5 hours. After the completion of the reaction, the mixture was cooled to about 30° C and washed with toluene (3x1000ml). Aqueous layer pH was adjusted to 10.5 using 160 ml of 40% aqueous sodium hydroxide solution and extracted with ethyl acetate (2×500 ml). The organic layers were combined and washed with water (2×400 ml). The organic layer was distilled completely at about 60 °C under vacuum to yield 108 g of the title compound.
Purity by HPLC: 98.15%.

EXAMPLE 4:

50 g of S-(-)-[1-(3-methoxyphenyl) ethyl] dimethyl amine of Formula IV and 283 g of 48% aqueous HBr solution were charged into a clean and round bottom flask followed by heating to about 110° C and stirred for about 6 hours. After completion of the reaction, the mixture was cooled to about 30°C and charged 250 ml of water and pH was adjusted to about 10.5 using 162 ml caustic lye and the reaction mixture was extracted with ethyl acetate ((1×150 ml, 2×50 ml)). The organic layer thus obtained was washed with water (2×50 ml) and treated with activated charcoal. The organic layer is filtered through celite and washed with 100 ml of ethyl acetate. The filtrate was distilled completely at below 60° C under vacuum. To the residue charged 200 ml of n-heptane at about 50°C and stirred for about 90 minutes at about 25°C. The separated solid was filtered and washed the solid with n-heptane 50 ml and suck dried. The solid obtained was dried at about 50°C for about 5 hours to yield 41.5 g of the title compound.
Purity by HPLC: 99.07%.

EXAMPLE 5:

6 kg of S-(-)-[1-(3-hydroxyphenyl) ethyl] dimethyl amine of Formula III and 12 L of Methyl Isobutyl Ketone(MIBK) were charged and stirred for about 10 minutes. To this reaction solution 3.44 kg of pyridine, 1.18 kg of tetrabutylammonium bromide were charged and stirred for about 15 minutes to form clear solution. 3.97 kg of N-ethyl, N-methyl carbomyl chloride was added to the reaction mixture for about 30 minutes. Heated the contents to about 30°C and stirred for about 15 hours. After completion of the reaction 48 lit of water was charged and pH was adjusted to about 1.5 using 3.72 lit of 36% aqueous hydrochloric acid. Stirred the contents for about 30 minutes at about 25°C and aqueous layer was separated. The aqueous layers were then washed with MIBK (2×12 lit) and separate the aqueous layer. Aqueous layer pH was adjusted to 12.5 using 6 lit of 40% aqueous sodium hydroxide solution and stirred for about 15 minutes. The aqueous layer was then extracted with MIBK (2×12 lit) and separated the organic layer. Washed the organic layer with water (2×12 lit) and separated the organic layer. The obtained organic layer was distilled off completely at about 60°C to afford residue.
To the obtained residue 48 lit of ethyl acetate was added and pH of the reaction solution was adjusted to about 2 by adding about 6 lit of f 18% hydrochloride in isopropyl alcohol at about 5°C and stirred for about 90 minutes for solid separation. The separated solid was filtered and washed with 6 lit of ethyl acetate. The obtained wet solid was again charged into a reaction containing 30 lit of water and adjusted the pH to about 12.5 using 1.8 lit of 40% aqueous sodium hydroxide solution(caustic lye). The reaction mass was extracted with MIBK (2×12 lit) and the combined organic layer was washed with water (2×12 lit). The organic layer was distilled completely at about 60°C to afford residue.
To the obtained residue 48 lit of ethyl acetate was added and pH of the reaction solution was adjusted to about 2 by adding about 6 lit of f 18% hydrochloride in isopropyl alcohol at about 5°C and stirred for about 90 minutes for solid separation. The separated solid was filtered and washed with 6 lit of ethyl acetate. The obtained wet solid was again charged into a reaction containing 30 lit of water and adjusted the pH to about 12.5 using 1.8 lit of 40% aqueous sodium hydroxide solution. The reaction mass was extracted with MIBK (2×12 lit) and the combined organic layer was washed with water (2x121it). The organic layer was distilled completely at about 60°C to afford the title compound
Purity by HPLC. 99.33%

EXAMPLE 6

3 kg of rivastigmine freebase of Formula II in 105 lit of acetone, 1.8 kg of L-(+)-Tartaric acid was charged and heated to about 60° C followed by stirring for about 30 minutes for complete dissolution. The resulting reaction solutions was passed through celite and wash the bed with 13.5 lit acetone to made particle free. The obtained clear solution was distilled off up to 50% of the initial volume and cooled to 30°C. 12 g of rivastigmine hydrogen tartrate was added and stirred for about 60 minutes. The reaction mixture was heated to reflux and stirred for about 60 minutes and cooled to about 30°C and stirred for about 60 minutes for solid separation. The separated solid was filtered and washed the solid with 3 lit of acetone. Solid obtained was dried at about 60° C for about 9 hours to afford 4.10 kg of the title compound.
Purity by HPLC: 97.37%.

………………………

Achiral bis-imine in combination with CoCl₂: A remarkable effect on enantioselectivity of lipase-mediated acetylation of racemic secondary alcohol

K. Arunkumar^1,2, M. Appi Reddy¹, T. Sravan Kumar¹, B. Vijaya Kumar¹, K. B. Chandrasekhar²,P. Rajender Kumar¹ and Manojit Pal³

¹Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road Miyapur, Hyderabad 500 049, India
²Department of Chemistry, Jawaharlal Nehru Technological University of Anantapur, Anantapur 515002, Andhra Pradesh, India,
³Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra Pradesh, India

Corresponding author email

Associate Editor: S. Flitsch

Beilstein J. Org. Chem. 2010, 6, 1174–1179.

SPECTRAL DATA FOR FREE BASE DEPICTED AS (S)-8

1H NMR (CDCl3, 300 MHz) δ 1.17-1.27 (m, 3H), 1.37 (d, 3H, J = 6.4 Hz, CH3), 2.21 (s, 6H), 3.04 (s, 3H, CH3), 3.25 (q, J1 = 7.2 Hz, J2 = 6.4 Hz), 3.43 (q, 1H, J1 = 7.2 Hz, J2 = 6.8 Hz), 3.48 (q, 1H, J1 = 6.8 Hz, J2 = 7.2 Hz), 7.01 (d, 1H, J = 8.0 Hz), 7 . 1 8 ( d , 1 H , J = 8 . 0 H z ) ,7.26 (s, 1H,), 7.33 (t, 1H, J = 8.0 Hz);

13C NMR (CDCl3, 100 MHz) δ 154.4 (1C, C=O), 151.4 (CH), 129.3
(CH), 124.7 (CH), 121.2 (CH), 120.8 (2C, CH), 77.1 (1C), 66.0 (1C, CH2), 43.9 (2C, N-Me),34.6 (1C, Mecarbamoyl), 20.3 (1C, CH3), 12.4 (1C, Mecarbamoyl); M/z 251.20 (M+ H) +;

IR (cm -1, KBr) 2975, 1723 (C=O); HRMS (ESI): calcd for C14H22N2O2 (M+ H)+251.1760, found 251.1767;

[α]20D = -33.90 (C=1, CHCl3).

……………………………

http://www.google.com/patents/US8324429

US8324429

SPECTRAL DATA FOR TARTRATE

Figure US08324429-20121204-C00001

Optical rotation [α]²⁰ _D=+6.0°, C=5, ethanol; mp 122.3-124.1

¹H NMR (CDCl₃) δ ppm: 1.24, 1.16 (2×t, 3H), 1.67 (d, 3H), 2.65 (s, 6H), 2.96, 3.05 (2×s, 3H), 3.37, 3.45 (2×q, 2H), 4.34 (q, 1H), 4.47 (s, 2H), 7.14 (t, 1H), 7.20 (s, 1H), 7.28 (d, 1H), 7.39 (t, 1H); MS (ESI) m/z: 251.2.

…………………………….

US8324429

FREE BASE

Optical rotation [α]²⁰ _D=−32.1°, C=5, ethanol.

¹H NMR (CDCl₃) δ ppm: 1.22 (m, 3H), 1.35 (q, 3H), 2.20 (s, 6H), 3.02 (d, 3H), 3.25 (m, 1H), 3.44 (s, 2H), 7.05 (m, 3H), 7.27 (m, 1H); MS (ESI) m/z: 251.2 (M⁺+1).

Figure US08324429-20121204-C00011

DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

Farletuzumab

December 9, 2013 7:23 am / Leave a comment

Farletuzumab

Farletuzumab (MORAb-003) is a monoclonal antibody^[1] which is being investigated for the treatment of ovarian cancer.^[2]^[3]

This drug was developed by Morphotek, Inc.

It is targeted at FR-alpha which is overexpressed in some cancers such as ovarian cancer.

USAN FARLETUZUMAB
PRONUNCIATION far” le tooz’ oo mab
THERAPEUTIC CLAIM Treatment of cancer
CHEMICAL NAMES
1. Immunoglobulin G1, anti-(human receptor FR-α (folate receptor α)) (human-mouse monoclonal MORAb-003 heavy chain), disulfide with human-mouse monoclonal MORAb-003 κ-chain, dimer
2. Immunoglobulin G1, anti-(human folate receptor alpha (ovarian tumor-associated antigen Mov18)); humanized mouse monoclonal MORAb-003 γ1 heavy chain (222-217′)-disulfide with humanized mouse monoclonal MORAb-003 κ light chain (228-228”:231-231”)-bisdisulfide dimer
MOLECULAR FORMULA C6466H9928N1716O2020S42
MOLECULAR WEIGHT 145.4 kDa

MANUFACTURER Morphotek, Inc.
CODE DESIGNATION MORAb-003
CAS REGISTRY NUMBER 896723-44-7

Farletuzumab, a humanized monoclonal antibody that targets the folate receptor alpha (FRα), could potentially be used in the treatment of patients with relapsed ovarian cancer, according to the results of a recent open-label phase II trial.Armstrong and colleagues investigated the efficacy of farletuzumab as a single agent or in combination with standard chemotherapy in patients with relapsed ovarian cancer following first-line therapy.

Farletuzumab is a humanized IgG1 monoclonal antibody that targets
the human folate receptor FRα, which is overexpressed in most ovarian
epithelial cancers. It is being developed by Morphotek (now part of
Eisai) for the treatment of ovarian cancer, with regulatory submissions
in 2012.

The pivotal Phase III study in ovarian cancer began
in March 2009; Phase II studies in other indications have since begun.
The 900-patient Phase III study is evaluating two doses of
farletuzumab as an add-on to the standard treatment regimen of
carboplatin and a taxane; this study is completed in
September 2012. A 165-patient study in lung adenocarcinoma began in
December 2010. The initial Phase I study in 25 patients with epithelial
ovarian cancers showed farletuzumab to be well tolerated, with evidence
of efficacy in 36% of the patients (Konner et al. 2010).22

Phase II data from a 54-patient study were presented at the 2008 ASCO meeting, with at least some evidence of efficacy seen in 90% of the treated patients.
Farletuzumab represents one of a number of new treatment options
being developed for the treatment of ovarian cancer, with several other
modalities such as kinase inhibition or PARP inhibition also showing
promise. However, the available evidence suggests that farletuzumab
is likely to represent a significant enhancement in the subset of ovarian
cancer patients at which it has been targeted. If it becomes widely
accepted as a component of the platinum-based treatment regimen, then
it can be expected to be a significant commercial success.

Statement On A Nonproprietary Name Adopted By The Usan Council – Farletuzumab, American Medical Association.
ClinicalTrials.gov: Phase II Efficacy and Safety Study of MORAb-003 in Platinum-Resistant or Refractory Relapsed Ovarian Cancer
ClinicalTrials.gov: Phase III Efficacy and Safety of MORAb-003 in Subjects With Platinum-sensitive Ovarian Cancer in First Relapse

…………………

Monoclonal antibodies for tumors

Tumor (“-t(u[m])-“)

Human (“-tumu-“)	Adecatumumab Cixutumumab Conatumumab Daratumumab Drozitumab Duligotumab Dusigitumab Figitumumab Ganitumab Glembatumumab vedotin Intetumumab Iratumumab Lexatumumab Lucatumumab Mapatumumab Narnatumab Necitumumab Ofatumumab Olaratumab Panitumumab Patritumab Pritumumab Radretumab Rilotumumab Robatumumab Teprotumumab Tovetumab Vantictumab Votumumab Zalutumumab “-melu-” (melanoma): Flanvotumab

Mouse (“-tumo-“)	Altumomab pentetate Anatumomab mafenatox Arcitumomab Bectumomab Blinatumomab CC49 Detumomab Ibritumomab tiuxetan Minretumomab Mitumomab Moxetumomab pasudotox Naptumomab estafenatox Nofetumomab merpentan Pemtumomab^† Pintumomab Racotumomab Satumomab pendetide Solitomab Taplitumomab paptox Tenatumomab Tositumomab 3F8 “-govo-” (ovarian tumor): Abagovomab · Igovomab · Oregovomab “-pro-” (prostate tumor): Capromab pendetide “-colo-” (colonic tumor): Edrecolomab · Nacolomab tafenatox

Chimeric (“-tuxi-“)	Amatuximab Bavituximab Brentuximab vedotin Cetuximab Ensituximab Futuximab Girentuximab Indatuximab ravtansine Margetuximab Rituximab Siltuximab Ublituximab “-mexi-” (melanoma): Ecromeximab

Humanized (“-tuzu-“)	Obinutuzumab Alemtuzumab Bevacizumab Bivatuzumab mertansine Cantuzumab mertansine Cantuzumab ravtansine Citatuzumab bogatox Clivatuzumab tetraxetan Dacetuzumab Dalotuzumab Elotuzumab^† Etaracizumab Farletuzumab Ficlatuzumab Gemtuzumab ozogamicin Imgatuzumab Inotuzumab ozogamicin Labetuzumab Lintuzumab Lorvotuzumab mertansine Matuzumab^§ Milatuzumab Nimotuzumab Ocaratuzumab Onartuzumab Oportuzumab monatox Parsatuzumab Pertuzumab Sibrotuzumab Simtuzumab Tacatuzumab tetraxetan Tigatuzumab Trastuzumab Tucotuzumab celmoleukin Veltuzumab Vorsetuzumab mafodotin

Rat/mouse hybrid (“-tumaxo-“)	Catumaxomab Ertumaxomab

Chimeric + humanized (“-tuxizu-“)	Ontuxizumab

Traxoprodil mesylate

December 9, 2013 1:04 am / Leave a comment

Traxoprodil mesylate

Traxoprodil mesylate
MF:C23-H35-N-O2.C-H4-O3-S
MW:453.6401
CAS:189894-57-3 mesylate

134234-12-1 (free base)

Traxoprodil mesylate, CP-101606-27,

(S, S) -1 – (4-Hydroxyphenyl) -2 – [4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol methanesulfonate trihydrate

Pfizer (Originator)

Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, NMDA Antagonists

J Med Chem 1995, 38, 16, 3138, EP 1151995,EP 1149831,

US 5272160,WO 1997007098 , US 6645986

this exhibits activity as NMDA (N-methyl-D-aspartic acid) receptor antagonists and are useful in the treatment of epilepsy, anxiety, cerebral ischemia, muscular spasms, multiinfarct dementia, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, urinary incontinence and degenerative CNS (central nervous system) disorders such as stroke, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

The free base, the anhydrous mesylate and methods of preparing them are referred to, generically, in United States Patent 5,185,343, which issued on February 9, 1993. They and their use in treating certain of the above disorders are referred to, specifically, in United States Patent 5,272,160, which issued on December 21 , 1993. Their use in treating the above disorders is referred to in lntemational Patent Application PCT/IB 95/00380, which designates the United States and was filed on May 18, 1995. Their use in combination with a compound capable of enhancing and thus restoring the balance of excitatory feedback from the ventral lateral nucleus of the thalamus into the cortex to treat Parkinson’s disease is referred to in International Patent Application PCT/IB 95/00398, which designates the United States and was filed on May 26, 1995. The foregoing U.S. patents and patent applications are incoφorated herein by reference in their entireties.

NMDA is an excitatory amino acid. The excitatory amino acids are an important group of neurotransmitters that mediate excitatory neurotransmission in the central nervous system. Glutamic acid and aspartic acid are two endogenous ligands that activate excitatory amino acid (EAA) receptors. There are two types of EAA receptors, ionotropic and metabotropic, which differ in their mode of signal transduction. There are at least three distinct ionotropic EAA receptors characterized by the selective agonist that activates each type: the NMDA, the AMPA (2-amino-3-(5-methyl-3- hdyroxyisoxazol-4-yl)propanoic acid) and the kainic acid receptors. The ionotropic EAA receptors are linked to ion channels that are permeable to sodium and, in the case of NMDA receptors, calcium. Metabotropic receptors, linked to phosphoinositide hydrolysis by a membrane associated G-protein, are activated by quisqualic acid, ibotenic acid, and (1S, 3R)-1-aminocyclopentane 1 ,3-dicarboxyiic acid.

The NMDA receptor is a macromolecular complex consisting of a number of distinct binding sites that gate on ion channels permeable to sodium and calcium ions. Hansen and Krogsgaard-Larson, Med. Res. Rev.. .10, 55-94 (1990). There are binding sites for glutamic acid, glycine, and polyamines, and a site inside the ion channel where compounds such as phencyclidine (PCP) exert their antagonist effects.

Competitive NMDA antagonists are compounds that block the NMDA receptor by interacting with the glutamate binding site. The ability of a particular compound to competitively bind to the NMDA glutamate receptor may be determined using a radioligand binding assay, as described by Murphy e l., British J. Pharmacol.. 95, 932- 938 (1988). The antagonists may be distinguished from the agonists using a rat cortical wedge assay, as described by Harrison and Simmonds, British J. Pharmacol.. 84, 381- 391 (1984). Examples of competitive NMDA antagonists include D-2 amino 5- phosphonopentanoic acid (D-AP5), and D-2-amino-7-phosphonoheptanoic acid, Schoepp et a]. , J. Neur. Transm.. 85, 131-143 (1991).

4-Hydroxypropiophenone (I) was protected as the triisopropylsilyl ether (II) and subsequently brominated with elemental bromine in CCl4. The resultant bromo ketone (III) was subsequently coupled with 4-hydroxy-4-phenylpiperidine (IV) to afford the racemic amino ketone (V). This was stereoselectively reduced with NaBH4 in EtOH yielding the threo-amino alcohol (VI). Then, desilylation of (VI) with tetrabutylammonium fluoride furnished the racemic phenol compound. Resolution into the enantiomers has been reported by formation of the . corresponding D-tartaric acid salts Finally, the title product was obtained by dissolving D-(-)-tartaric salt (VII) in water in the presence of methanesulfonic acid

EXAMPLE 1 Enantiomeric (1S,2S)- and (1R,2R)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanols

(+)-Tartaric acid (300 mg, 2 mmol) was dissolved in 30 mL warm methanol. Racemic 1S*,2S*-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (655 mg, 2 mmol) was added all at once. With stirring and gentle warming a colorless homogeneous solution was obtained. Upon standing at ambient temperature 24 hours, 319 mg (66%) of a fluffy white precipitate was obtained. This product was recrystallized from methanol to give 263 mg of the (+)-tartrate salt of levorotatory title product as a white solid; mp 206.5-207.5.degree. C.; [alpha].sub.D =-36.2.degree.. This salt (115 mg) was added to 50 mL of saturated NaHCO.sub.3. Ethyl acetate (5 mL) was added and the mixture was vigorously stirred 30 minutes. The aqueous phase was repeatedly extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over calcium sulfate, and concentrated. The tan residue was recrystallized from ethyl acetate-hexane to give 32 mg (39%) of white, levorotatory title product; mp 203-204 C.sub.20 H.sub.25 NO.sub.3 : C, 73.37; H, 7.70; N. 4.28. Found: C, 72.61; H, 7.45; N. 4.21.

The filtrate from the (+)-tartrate salt preparation above was treated with 100 mL saturated aqueous NaHCO.sub.3 and extracted well with ethyl acetate. The combined organic extracts were washed with brine, dried over calcium sulfate and concentrated to give 380 mg of recovered starting material (partially resolved). This material was treated with (-)-tartaric acid (174 mg) in 30 mL of methanol as above. After standing for 24 hours, filtration gave 320 mg (66%) of product which was further recrystallized from methanol to produce 239 mg of the (-)-tartrate salt of dextrorotatory title product; mp 206.5-207.5.degree. C. [alpha].sub.D =+33.9.degree.. The latter was converted to dextrorotatory title product in the manner above in 49% yield; mp 204-205 Found: C, 72.94; H. 7.64; N, 4.24.

EXAMPLE 2 (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-yl)-1-propanol Methanesulfonate Trihydrate

STEP 1

A 50 gallon glass lined reactor was charged with 17.1 gallons of acetone, 8.65 kilograms (kg) (57.7 mol) of 4′-hydroxypropiophenone, 9.95 kg (72.0 mol) of potassium carbonate and 6.8 liters (l) (57.7 mol) of benzylbromide. The mixture was heated to reflux (56 hours. Analysis of thin layer chromatography (TLC) revealed that the reaction was essentially complete. The suspension was atmospherically concentrated to a volume of 10 gallons and 17.1 gallons of water were charged. The suspension was granulated at 25 product was filtered on a 30″ Lapp and washed with 4.6 gallons of water followed by a mixture of 6.9 gallons of hexane and 2.3 gallons of isopropanol. After vacuum drying at 45 (96.4%) of the above-depicted product.

A second run was carried out with 9.8 kg (65.25 mol) of 4′-hydroxypropiophenone using the procedure described above. After drying 15.1 kg (96.3%) of the above-depicted product was obtained.

STEP 2

Under a nitrogen atmosphere, a 100 gallon glass lined reactor was charged with 75 gallons of methylene chloride and 28.2 kg (117.5 mol) of the product from step 1. The solution was stirred five minutes and then 18.8 kg of bromine was charged. The reaction was stirred for 0.5 hours at 22 complete. To the solution was charged 37 gallons of water and the mixture was stirred for 15 minutes. The methylene chloride was separated and washed with 18.5 gallons of saturated aqueous sodium bicarbonate. The methylene chloride was separated, atmospherically concentrated to a volume of 40 gallons and 60 gallons of isopropanol was charged. The concentration was continued until a pot temperature of 80 40 gallons were obtained. The suspension was cooled to 20 granulated for 18 hours. The product was filtered on a 30″ Lapp and washed with 10 gallons of isopropanol. After vacuum drying at 45 yielded 29.1 kg (77.6%) of the above-depicted product.

STEP 3

Under a nitrogen atmosphere, a 20 gallon glass lined reactor was charged with 4.90 kg (15.3 mol) of the product from step 2, 7.0 gallons of ethyl acetate, 2.70 kg (15.3 mol) of 4-hydroxy-4-phenylpiperidine and 1.54 kg of triethylamine (15.3 mol). The solution was heated to reflux (77 C.) for 18 hours. The resulting suspension was cooled to 20 Analysis by TLC revealed that the reaction was essentially complete. The byproduct (triethylamine hydrobromide salt) was filtered on a 30″ Lapp and washed with 4 gallons of ethyl acetate. The filtrate was concentrated under vacuum to a volume of 17 liters. The concentrate was charged to 48 liters of hexane and the resulting suspension granulated for 2 hours at 20 gallons of hexane. After vacuum drying at 50 kg (77%) of the above-depicted product.

A second run was carried out with 3.6 kg (11.3 mol) of the product from step 2 using the procedure described above. After drying 4.1 kg (87%) of the above-depicted product was obtained.

STEP 4

Under a nitrogen atmosphere, a 100 gallon glass lined reactor was charged with 87.0 gallons of 2B ethanol and 1.7 kg (45.2 mol) of sodium borohydride. The resulting solution was stirred at 25 kg (22.6 mol) of the product from step 3 was charged. The suspension was stirred for 18 hours at 25-30 reaction was essentially complete to the desired threo diastereoisomer. To the suspension was charged 7.8 liters of water. The suspension was concentrated under vacuum to a volume of 40 gallons. After granulating for 1 hour, the product was filtered on a 30″ Lapp and washed with 2 gallons of 2B ethanol. The wet product, 9.4 gallons of 2B-ethanol and 8.7 gallons of water were charged to a 100 gallon glass lined reactor. The suspension was stirred at reflux (78 cooled to 25 water followed by 4 gallons of 2B ethanol. After air drying at 50 C., this yielded 8.2 kg (86.5%) of the above-depicted product. This material was recrystallized in the following manner.

A 100 gallon glass lined reactor was charged with 7.9 kg (18.9 mol) of the product from step 3, 20 gallons of 2B ethanol and 4 gallons of acetone. The suspension was heated to 70 solution was concentrated atmospherically to a volume of 15 gallons. The suspension was cooled to 25 product was filtered on a 30″ Lapp. The wet product and 11.7 gallons of 2B ethanol was charged to a 100 gallon glass lined reactor. The suspension was heated to reflux (78 cooled to 25 of 2B ethanol. After air drying at 50 (70.6%) of the above-depicted product.

STEP 5

Under a nitrogen atmosphere, a 50 gallon glass lined reactor was charged with 825 g of 10% palladium on carbon (50% water wet), 5.5 kg (13.2 mol) of the product from step 4 and 15.5 gallons of tetrahydrofuran (THF). The mixture was hydrogenated between 40-50 time, analysis by TLC revealed that the reduction was essentially complete. The reaction was filtered through a 14″ sparkler precoated with Celite and washed with 8 gallons of THF. The filtrate was transferred to a clean 100 gallon glass lined reactor, vacuum concentrated to a volume of 7 gallons and 21 gallons of ethyl acetate were charged. The suspension was atmospherically concentrated to a volume of 10 gallons and a pot temperature of 72 filtered on a 30″ Lapp and washed with 2 gallons of ethyl acetate. After air drying at 55 above-depicted product (i.e., the free base).

STEP 6

A 100 gallon glass lined reactor was charged with 20 gallons of methanol and 3.7 kg (11.4 mol) of the product from step 5 (i.e., the free base). The suspension was heated to 60 D-(-)-tartaric acid were charged. The resulting solution was heated to reflux (65 suspension was cooled to 35 with 1 gallon of methanol. The wet solids were charged to a 100 gallon glass lined reactor with 10 gallons of methanol. The suspension was stirred for 18 hours at 25 Lapp and washed with 2 gallons of methanol. After air drying at 50 C. this yielded 2.7 kg (101%) of the above-depicted product (i.e., the tartaric acid salt of the free base (R-(+)-enantiomer)). This material was purified in the following manner:

A 100 gallon glass lined reactor was charged with 10.6 gallons of methanol and 2.67 kg (5.6 mol) of the above tartaric acid salt. The suspension was heated to reflux (80 to 30 methanol. After air drying at 50 of the above-depicted product (i.e., the tartaric acid salt of the free base).

STEP 7

•Tar tar i c Rc i d

A 55 liter nalgene tub was charged with 30 liters of water and 1056 g (12.6 mol) of sodium bicarbonate at 20 charged 2.0 kg (4.2 mol) of the product from step 6 (i.e., the tartaric acid salt of the free base). The suspension was stirred for 4 hours during which a great deal foaming occurred. After the foaming ceased, the suspension was filtered on a 32 cm funnel and washed with 1 gallon of water. After air drying at 50 the above-depicted product (i.e., the free base).

STEP 8

A 22 liter flask was charged with 1277 g (3.9 mol) of product from step 7 and 14 liters of water. The suspension was warmed to 30 g (3.9 mol) of methane sulfonic acid were charged. The resulting solution was warmed to 60 washed with 2 liters of water. The speck-free filtrate was concentrated under vacuum to a volume of 6 liters. The suspension was cooled to 0-5 18″ filter funnel and washed with 635 ml of speck-free water. After air drying at 25 above-depicted product (i.e., the mesylate salt trihydrate).

Proton and Carbon Nuclear Magnetic Resonance (NMR) Spectra of the Mesylate Salt Trihydrate

The proton and carbon NMR spectra of the mesylate salt trihydrate are described below. Chemical shift assignments in CD₃OD (relative to tetramethylsilane (TMS) were made on the basis of ‘HJH Correlated Spectroscopy (COSY), ‘H-‘O Distortionless Enhancement by Polarization Transfer (DEPT), and ‘HJ’C Heteronuclear Chemical Shift Correlation (HETCOR) two-dimensional NMR experiments. The tentative proton and carbon peak assignments are given below and are consistent with the structure of the mesylate salt trihydrate. III

assignment, 13 C (δ, ppm),   Protons,  1 H (δ, ppm)
4'          159.2            0         --        
1"'         148.2            0         -- 
1'          132.6            0         -- 
2'          129.8            2         7.30 (m) 
3"'         129.5  m         2         7.38 (t) 
4"'         128.4            1         7.30 (m) 
2"'         125.6            2         7.56 (d) 
3'          116.5            2         6.84 (d) 
1           73.5             1         4.66 (d) 
4"          69.8             0         -- 
2           68.3             1         3.58 (m) 
6"(1)       48.8             2         3.32 (d),3.72(t) 
2"(1)       43.2             2         3.58 (m) 
4           39.5             3         2.70 (s) 
5"(2)       36.6             2         2.64 (t),1.98(d) 
3"(2)       36.5             2         2.42 (t),1.98(d) 
3           9.7              3         1.12(d)

(1) The 6″ and 2″ positions are not chemically equivalent; the assignments may be interchangeable. (2) The 5″ and 3″ positions are not chemically equivalent the assignments may be interchangeable. The proton splitting pattem at 1.96-2.06 ppm appears as two doublets when acquired on a high-field instrument (500 MHz), but only as a triplet when acquired with a lower field (300 MHz) instrument. This is believed to be due to a salt effect arising from the mesylate.

FDA Breakthrough Therapy Designation: Third Drug Receives FDA Approval

December 9, 2013 1:02 am / Leave a comment

Orphan Druganaut Blog

The FDA approves on December 6, the third drug to have the coveted Breakthrough Therapy Designation (BTD). The approval is for Gilead Sciences’ non-orphan drug Sovaldi (Sofosbuvir) for the treatment of patients with chronic Hepatitis C (HCV). What is a “breakthrough” about this approval is the fact that Sovaldi is the first drug that safely and with efficacy, treats particular types of HCV without the need for co-administration of Interferon.

Per Gilead Sciences’ Press Release, approximately 4 million Americans are infected with HCV in the United States. The current standard of care for HCV is up to 48 weeks with a pegylated interferon (peg-IFN)/ribavirin (RBV)-containing regimen, depending on the patient’s particular HCV genotype. Sovaldi is a once-daily oral nucleotide analog polymerase inhibitor receiving approval for chronic HCV as a part of a combination antiviral treatment regimen. The drug blocks a protein used by HCV to replicate.

According to a Reuters online article, most patients will be…

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World Drug Tracker: Novartis’ panobinostat impresses in myeloma trial

December 8, 2013 2:56 am / Leave a comment

World Drug Tracker: Novartis’ panobinostat impresses in myeloma trial

World Drug Tracker

December 8, 2013 2:55 am / Leave a comment

World Drug Tracker

Iloperidone (Fanapt)

December 7, 2013 7:27 am / Leave a comment

Iloperidone (Fanapt), ILO-522, HP-873, Zomaril, 133454-47-4, antipsychotic

1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone; 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine; 4′-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3′-methoxyacetophenone

Aventis Pharma (Originator), Novartis (Licensee), Titan (Licensee)Vanda Pharmaceuticals (Licensee)

Iloperidone(Fanapt) is a monoamine directed towards acting upon and antagonizing specific neurotransmitters, particularly multiple dopamine and serotonin receptor subtypes.

Schizophrenia is a chronic, severe, and debilitating mental disorder that affects approximately 2.4 million Americans, around 1.1% of the population. The net cost of this disorder is staggering as estimates from 2002 reveal this disorder to cost $62.7 billion. A major issue with the treatment of schizophrenia is that patients show varying levels of response and tolerance to available therapies. Although the symptoms of the disease are very severe, estimates show that approximately 3 out of 4 patients discontinue medication prior to completing 18 months of treatment, many times due to the severe side effects of the approved medications.

Synthesis

J.T. Strupczewski, K.J. Bordeau, Y. Chiang, E.J. Glamkowski, P.G.
Conway, R. Corbett, H.B. Hartman, M.R. Szewczak, C.A. Wilmot andG.C. Helsley, J. Med. Chem., 38, 1119 (1995).

US 4355037
V. Miklos, WO Patent 031497 (2010).
J.T. Strupczewski, EP Patent 0402644 (1990)

The product is protected by the U.S. Pat. No. 5,364,866, U.S. Pat. No. RE 39198 E and EP 402644 B1.U.S. Pat. No. 5,364,866 and U.S. Pat. No. 5,663,449.EP 542136, EP 612318, EP 730452, JP 95501055, JP 97511215, US 5364866, US 5776963, WO 9309102, WO 9511680.US 4355037,EP 0542136; EP 0612318; EP 0730452; EP 0957102; EP 0959075; EP 0959076; EP 0963984; JP 1995501055; JP 1997511215; US 5364866; US 5776963; WO 9309102; WO 9511680

The first reported synthetic method for Iloperidone is described in patent EP 402644 A1.

In U.S. Patent US5776963 and patent family EP4 (^ 644, there is disclosed a method for preparing iloperidone,

The synthetic method reported(4, 5) for 1 involves two chemical steps: O-alkylation of acetovanillone (2) with 1-bromo-3-chloropropane (3) to obtain chloro derivative 4 followed byN-alkylation of piperidine intermediate 5 with 4. The reported process for 4 comprises O-alkylation of 2 with 3 in acetone in the presence of potassium carbonate for 20 h to provide 4as an oil after usual work up, which was then vacuum (0.1 mmHg) distilled to collect desired product 4 at 141–143 °C with around 85% yield (Scheme 1, Path A). Some of the drawbacks of this process are as follows: longer reaction time (around 20 h), formation of 6–7% of dimer impurity (10, Scheme 2), high-vacuum distillation to achieve the quality, which is always a cumbersome process at industrial scale, requiring special apparatus and skill set, and degradation and charring of some portion of product during high-vacuum distillation. Further, the next step comprises N-alkylation of 4 with 5 in N,N-dimethylformamide (DMF) in the presence of potassium carbonate to provide iloperidone (1) as a crude solid, which was purified by crystallization using ethanol to yield pure 1 with 58% yield (Scheme 1, Path A). Some of the lacunae observed with the above process includes the following: (a) low yields, (b) formation of carbamate impurity 13 (Scheme 2) in the range 15–20% due to the use of potassium carbonate, (c) ineffective purification by crystallization using ethanol to eliminate carbamate impurity below 0.15%, and (d) iloperidone obtained by the above synthetic process was beige in color.

Scheme 1. Reported (Path A) and Improved (Path B) Process for Preparation of 1

Scheme 2. Flow Chart Representing the Formation of Impurities

A few other improved processes reported…(Improved and Efficient Process for the Production of Highly Pure Iloperidone: A Psychotropic Agent)subsequently for 1 follow the same reaction sequence (Scheme 1, Path A) using compounds 4 and 5 as key starting materials with different bases and solvents.(6-13) However, the reported processes do not address a control mechanism for impurities 8, 9, 11, and 13 (Scheme 2) formed during the synthesis of 1. In order to eliminate these impurities, the reported processes involve employment of multiple purifications using a single solvent or mixture of solvents or purification by means of formation of the acid addition salt of 1 followed by converting back to pure 1.(6-13)

The synthetic route is as follows:

The reaction of piperidine-4-carboxylic acid (I) with formic acid and acetic anhydride gives 1-formylpiperidine-4-carboxylic acid (II), which is treated with SOCl2 and acetic anhydride to yield the corresponding acyl chloride (III). The Friedel-Crafts condensation of (III) with refluxing 1,3-difluorobenzene (IV) by means of AlCl3 affords 4-(2,4-difluorobenzoyl)-1-formylpiperidine (V), which is treated with hydroxylamine in refluxing ethanol to give the corresponding oxime (VI). The cyclization of (VI) by means of NaH in hot THF/DMF yields 6-fluoro-3-(1-formylpiperidin-4-yl)-1,2-benzisoxazole (VII), which is treated with HCl in refluxing ethanol to afford 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole (VIII). Finally, this compound is condensed with 4-(3-chloropropoxy)-3-methoxyacetophenone (IX) by means of K2CO3 in hot DMF. The intermediate 4-(3-chloropropoxy)-3-methoxyacetophenone (IX) can be obtained by condensation of 4-hydroxy-3-methoxyacetophenone (IX) with 3-chcloropropyl bromide (X) by means of NaH or K2CO3 in DMF.

Iloperidone, also known as Fanapt, Fanapta, and previously known as Zomaril, is an atypical antipsychotic for the treatment ofschizophrenia.

Accordingly, 6-fluoro-3-(4-piperidyl)-1,2-benzoxazole 1 and 1-[4-(3-chloropropoxy)-3-methoxy-phenyl]ethanone 2 were heated in presence of potassium carbonate using dimethylformamide solvent to afford 1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)-1-piperidyl]propoxy]-3-methoxy-phenyl]ethanone also called Iloperidone

It was approved by the U.S. Food and Drug Administration (FDA) for use in the United States on May 6, 2009.

It’s not yet approved in India.

Hoechst Marion Roussel Inc. made initial inquiries into the drug; however, in May 1996, they discontinued research, and in June 1997 gave research rights to Titan Pharmaceuticals. Titan then handed over worldwide development, manufacturing and marketing rights to Novartis in August 1998. On June 9, 2004, Titan Pharmaceuticals announced that the Phase III development rights have been acquired by Vanda Pharmaceuticals. The original launch date was scheduled for 2002. On November 27, 2007, Vanda Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) had accepted their New Drug Application for iloperidone, confirming the application is ready for FDA review and approval. On July 28, 2008, the FDA issued a “Not Approvable” letter to Vanda Pharmaceuticals concerning the drug, stating that further trials are required before a decision can be made concerning marketed usage of iloperidone.

Chemically designated as 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, is a second generation atypical antipsychotic agent. Iloperidone, also known as Fanapt, Fanapta, and Zomaril, was approved by the U.S. Food and Drug Administration (FDA) for use in the United States on May 6, 2009 and is indicated for the acute treatment of schizophrenia in adults. Iloperidone has been shown to act as an antagonist at all tested receptors. It was found to block the sites of noradrenalin (α2C), dopamine (D2A and D3), and serotonin (5-HT1A and 5-HT6) receptors.(2) In addition, pharmacogenomic studies identified single nucleotide polymorphisms associated with an enhanced response to iloperidone during acute treatment of schizophrenia. It is considered an “atypical” antipsychotic because it displays serotonin receptor antagonism, similar to other atypical antipsychotics. The older typical antipsychotics are primarily dopamine antagonists.(3)

Iloperidone won FDA approval for use treating schizophrenia in the United States on May 6, 2009

Iloperidone (1-[4-[3-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone) is an atypical new-generation antipsychotic medicament belonging to the class of piperidinyl-benzisoxazole derivatives, which is used to treat schizophrenia, bipolar disorder and other psychiatric conditions. Iloperidone acts as a serotonin/dopamine receptor antagonist (5-HT_2A/D₂).

Iloperidone, also known as Fanapt, Fanapta, and previously known as Zomaril, is an atypical antipsychotic drug used for the treatment of schizophrenia. The chemical name of iloperidone is l-[4-[3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l- piperidinyl]propoxy] -3-methoxyphenyl]ethanone.

EP 0402644 patent discloses first synthetic route of synthesis of iloperidone as shown in Scheme I, which consists of alkylation reaction between l-(4-(3-chloropropoxy-3- methoxyphenyl)ethanone of the formula (II) and 6-fluoro-3-piperidin-4-yl-l ,2 benzisoxazole hydrochloride of the formula (III) in presence of potassium carbonate in N,N dimethyl formamide. The reaction has been subsequently worked up and the compound of formula (I) is extracted from water using ethyl acetate. The compound of formula (I) is purified by crystallization using ethanol. The overall yield of compound of formula (I) is 58%.

Formula (I)

SCHEME 1 Further, we have analyzed the reported synthetic route for synthesis of iloperidone; following limitations have been observed and identified in the reported synthetic route:

a) The yield obtained using said synthetic route as reported in US RE39198 is 58%. Hence, this route of synthesis is not cost efficient at commercial scale due to low yield;

b) Use of potassium carbonate as a base in reaction leads to formation of carbon dioxide as one of the side products during the reaction, which further hinders in the manufacturing process by actively participating in manufacturing process and thereby leads to the formation o

Formula (IV)

which is in the range of 15-20%, and thereby resulting in low yield of iloperidone;

c) Purification by crystallization using ethanol as a solvent is not effective in eliminating or controlling carbamate impurity below 0.15% as per the ICH guide lines for the known impurities; and

d) Iloperidone obtained by the above synthetic process is beige in colour.

CN101768154 discloses the synthesis of iloperidone by N-alkylation reaction between l-(4-(3- chloropropoxy-3-methoxyphenyl)ethanone of the formula (II) and 6-fluoro-3-piperidin-4-yl-l,2 benzisoxazole hydrochloride of the formula (III) in inorganic alkaline solution, particularly; alkali metal carbonate solution. We have analyzed the reported synthetic route for synthesis of iloperidone and have observed and identified that the use of alkaline carbonate solution leads to the formation of carbamate impurity in the range of 1 to 1.5%.

Several patents were published after, describing essentially the same synthetic way such as US5364866 and US5663449.

The synthesis of iloperidone is described in USRE39198 (corresponding to EP 0 402 644 example 3) according to the following synthesis scheme:

In agreement with said patent, the intermediate isolated, 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, is reacted with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride in N,N-dimethyl formamide at 90° C. for 16 hours. When the reaction is complete, the mixture is poured into water and extracted with ethyl acetate. The crude product thus obtained is crystallised twice from ethanol to give crystallised iloperidone with a total yield of 58%.

The yield of this process is very low; moreover, the process begins with two isolated intermediates, and requires an aqueous extractive work-up step with an increase in volumes and consequent reduction in the productivity and efficiency of the process. Said process also requires a double crystallisation step to obtain a beige product. The quality levels obtained are not described in the text of the example, but a beige color does not suggest a high-quality product, as iloperidone is a white substance.

The synthesis of intermediate 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone is disclosed in U.S. Pat. No. 4,366,162. Example 1 describes the preparation of said intermediate by reacting acetovanillone with 1-bromo-3-chloropropane in acetone with potassium carbonate. At the end of the reaction the resulting product is purified by distillation and obtained as an oily intermediate which is left to stand in order to obtain the solid intermediate.

The synthesis of intermediate 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone is also disclosed in U.S. Pat. No. 4,810,713. Preparation 12 describes the synthesis of said intermediate from acetovanillone and 1-bromo-3-chloropropane in sodium hydroxide alkalinized water. At the end of the reaction the product obtained is extracted in toluene, the organic phases are washed with basic aqueous solutions and finally, the intermediate 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone is crystallised with the aid of diisopropyl ether. The intermediate isolated is then recrystallised twice from cyclohexane and twice from petroleum ether.

An alternative process for the synthesis of iloperidone is reported in CN 102070626.

Scheme 2 shows the synthesis procedure:

The decision to alkylate acetovanillone with 1-chloro-3-propanol requires an extra synthesis step (to convert the OH group to an OR leaving group) compared with the procedure reported by the combination of patents USRE39198 (EP402644) and U.S. Pat. No. 4,366,162/U.S. Pat. No. 4,810,713, making said process less efficient from the economic standpoint.

WO2011061750 discloses an alternative iloperidone synthesis process as reported in Scheme 3:

Said process uses reagents such as methyl magnesium chloride to effect the Grignard reaction to convert the aldehyde group to a secondary alcohol group, which are much more complicated to manage on an industrial scale than the synthesis methods previously described. Moreover, the oxidation reaction of the next step uses reagents such as chromic acid or potassium permanganate, which have a very high environmental impact and very low industrial applicability.

WO2011055188 discloses a process for the synthesis of iloperidone comparable to the one reported in USRE39198 from two isolated intermediates 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride. The same patent application also gives preparation examples of the intermediate 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone isolated as crystalline solid by procedures similar to those known in the literature.

CN 101824030 reports an iloperidone synthesis method similar to that of CN 102070626 which involves the same problems of inefficiency due to the additional step of inserting the leaving group required for alkylation with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride.

CN 101781243 discloses an alternative iloperidone synthesis process as reported in Scheme 4.

Said process is not advantageous compared with the preceding processes as the intermediate with the oxime group, due to the nature of this functional group, is particularly liable to degradation due to the action of numerous factors such as the presence of metals, acid pHs and basic pHs.

CN101768154 discloses a process for the synthesis of iloperidone comparable to the one reported in USRE39198 from two isolated intermediates, 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride.

CN 101735208 describes a process for the synthesis of iloperidone comparable to the one reported in CN 101781243, namely through the intermediate with the functional oxime group.

IN 2007MU01980 discloses a process for the synthesis of iloperidone comparable to the one reported in USRE39198 from two isolated intermediates, 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride.

WO 2010031497 describes an alternative iloperidone synthesis process as reported in Scheme 5.

The considerable economic disadvantage of the process reported in WO2010031497 is based on the fact that by reversing the order of alkylation and performing that of intermediate 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride first, a greater loss of yield is generated on this intermediate which, according to the literature, is more difficult to synthesise and consequently more expensive than the intermediate 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, with a globally greater economic inefficiency of the iloperidone preparation process.

CN 102212063 discloses a process for the synthesis of iloperidone with the same arrangement of the synthesis steps as patent application WO 2010031497.

WO2011154860 describes a process for the synthesis of iloperidone wherein a phase transfer catalyst is used to prepare the intermediate 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone which, as in all the other preparation examples previously described, is crystallised, isolated and dried before use in the next step with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride. Scheme 6 shows the synthesis scheme of the process of WO2011154860.

………………………………

US20100076196

……………………………………

WO2012123963A2

EXAMPLE 1:

Tetrabutyl ammonium bromide (2.40 gm) was added to a stirred solution of Potassium hydroxide (0.724 kg) in mixture of Heptane (2.0L). and water (10.0L), followed by addition of 1- [4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2, 1.0kg) and 6-fluoro-3-piperidin-4-yl-l,2- benzisoxazole hydrochloride^, 1.1 1kg) at 30°C. This reaction mass was stirred for 15 to 20 min. The temperature of the reaction mass was raised to 70°C and was maintained for 8 to 10 hours. After completion of reaction (by TLC, Mobile Phase: Toluene/ Acetone/Ethyl acetate = 6:2:2 mL), the mixture was cooled to 30°C, diluted with dichloromethane (2.5 L) and stirred for 30 minutes. The dichloromethane layer was separated. The aqueous layer was re-extracted with dichloromethane (1.0L). The combined dichloromethane layer was washed with water (1.5L) and decolorized with activated charcoal (0.05 kg). The solvent was distilled off completely to obtain the residue. The residue obtained was dissolved in isopropyl alcohol (5.0L) at reflux temperature to obtain the clear solution. The clear solution obtained was cooled to 30°C followed by 0°C and stirred for 60 min to precipitate out crystals. The colorless crystals of compound (I) obtained were filtered. The crystalline solid was dried under vacuum (650-700 mm/Hg) to obtain pure compound (I) as a crystalline solid. HPLC analysis was performed for the crystalline solid obtained. The purity of Iloperidone, impurity profile and yield are shown in table 1 below.

Table 1 : Analysis data of iloperidone i.e. purity, yield and impurity profile.

EXAMPLE 2:

Tetrabutyl ammonium bromide (2.40 gm) was added to a stirred solution of Potassium hydroxide (0.724 kg) in mixture of Heptane (2.0L) and water (10.0L), followed by addition of 1- [4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2, 1.0kg) and 6-fluoro-3-piperidin-4-yl-l,2- benzisoxazole hydrochloride^, 1.1 1kg) at 30°C. This reaction mass was stirred for 15 to 20 min. The temperature of the reaction mass was raised to 70°C and maintained for 8 to 10 hours. After completion of reaction (by TLC, Mobile Phase: Toluene/ Acetone/Ethyl acetate = 6:2:2 mL), the mixture was cooled to 30°C, the reaction mixture was filtered to obtain wet crude iloperidone. Further, the obtained wet crude was dried at 60-65 °C under vacuum to furnish crude iloperidone (1.72 kg). The dried crude iloperidone was dissolved in isopropyl alcohol (5.0 L) at reflux temperature and decolorized with activated charcoal (0.05 kg). Obtained filtrate was cooled to 30°C followed by 0°C and stirred for 60 min to precipitate out crystals. The colorless crystals of compound (I) obtained were filtered. The crystalline solid was dried under vacuum (650-700 mm/Hg) to obtain pure compound (I) as a crystalline solid. HPLC analysis was performed for the crystalline solid obtained. The purity of Iloperidone, impurity profile and yield are shown in table 2 below.

Table 2: Analysis data of iloperidone i.e. purity, yield and impurity profile.

EXAMPLE-3:

……………………..

US20130261308

UPLC-MS [M+H+]=427

1H-NMR (in DMSO) (chemical shifts expressed in ppm with respect to the TMS signal): 2.06-1.78 (6H, m); 2.13 (2H, m); 2.49 (2H, t); 2.52 (2H, m); 2.97 (2H, m); 3.11 (1H, tt); 3.83 (3H, s); 4.12 (2H, t); 7.06 (1H, d); 7.22 (1H, m); 7.46 (1H, d); 7.61-7.58 (2H, m); 7.94 (1H, dd).

………………………………

.Improved and Efficient Process for the Production of Highly Pure Iloperidone: A Psychotropic Agent

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/op400335p

http://pubs.acs.org/doi/full/10.1021/op400335p?prevSearch=iloperidone&searchHistoryKey=

The present work describes an improved and highly efficient process for the synthesis ofiloperidone (1), an antipsychotic agent, which is free from potential impurities. The synthesis comprises N-alkylation of 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone (4) with 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride (5) in a mixture of water and heptane as solvent and sodium hydroxide as a base in the presence of tetrabutylammonium bromide as a phase transfer catalyst to yield iloperidone (1) with a yield of around 95% and a purity of 99.80% by HPLC. The present work also describes the optimization details performed to achieve the process attributes responsible for high yield and purity.

FT-IR (KBr, λmax, cm–1): 3031, 2949, 2779, 2746, 2822, 1669, 1614, 1585, 1510, 1462, 1448, 1415, 1380, 1313, 1262, 1221, 1177, 1150, 1123, 1077, 1034, 997, 985, 955, 884, 876, 853, 812, 781, 643, 610, 569, 475.

1H NMR (CDCl3): δ 2.03–2.10 (m, 6H), 2.12–2.18 (m, 2H), 2.55–2.56 (s, 3H), 2.58–2.60 (t, 2H), 3.02–3.09 (m, 3H), 3.91 (s, 3H), 4.10–4.19 (t, 2H), 6.91–6.93 (d, 1H), 7.01–7.06 (dd, 1H), 7.21–7.24 (dd, 1H), 7.51–7.52 (d, 1H), 7.53–7.56 (dd, 1H), 7.69–7.65 (dd, 1H).

13C NMR (CDCl3): 26.02, 26.40, 30.36, 34.34, 53.36, 54.90, 55.80, 67.16, 97.04, 97.31, 110.20, 111.02, 111.98, 112.23, 117.12, 122.36, 122.46, 123.06, 130.11, 149.00, 152.66, 160.91, 162.60, 163.53, 163.66, 165.09, 198.59.

MS (ESI, m/z): 427.2 [M + H].+

Anal. Calcd (%) for C24H27FN2O4(426.48): C, 67.54; H, 6.33; found (%): C, 67.24; H, 6.18.

HPLC

HPLC analysis developed at Megafine India using a Hypersil BDS C18 column (250 mm × 4.6 mm, particle size 5 μm); mobile phase A comprising a mixture of 5.0 mM ammonium dihydrogen orthophosphate buffer and 0.1% triethylamine; mobile phase B comprising a mixture of acetonitrile/methanol in the ratio 80:20 v/v; gradient elution: time (min)/A (v/v): B (v/v); T0.01/65:35, T8.0/65:35, T25.0/35:65, T35.0/35:65, T37.0/65:35, T45.0/65:35; flow rate 1.0 mL/min; column temperature 30 °C; wavelength 225 nm. The observed retention time of iloperidone under these chromatographic conditions is about 17.0 min.

…….

http://www.asianjournalofchemistry.co.in/User/ViewFreeArticle.aspx?ArticleID=25_10_2

N oxide impurity

m.p. 155-157 ºC;

FT-IR (KBr, νmax, cm-1):
3083, 2958, 2878, 1655, 1606, 1584, 1509, 1467, 1419, 1348,1273, 1223, 1182, 1143, 1121, 1032, 971, 957, 881, 857, 813,
802;

1H NMR (300 MHz, CDCl3)

δ 1.89-1.93 (m, 2H), 2.31-2.40 (m, 2H), 2.55 (s, 3H), 2.60-2.72 (m, 2H), 3.29-3.52 (m,
2H), 3.29-3.52 (m, 2H), 3.29-3.52 (m, 2H), 3.29-3.52 (m, 1H),3.85 (s, 3H), 4.23(t, 2H, J = 6.0 Hz), 7.11 (d, 1H, J = 8.4 Hz),7.30-7.36 (m, 1H), 7.62-7.65 (m, 1H), 7.71-7.74 (dd, J = 9.3and 2.0 Hz, 1H), 8.02-8.07 (dd, J = 8.7 and 5.4 Hz, 1H);

13CNMR (75 MHz, CDCl3)

δ 22.13, 24.70, 26.35, 31.49, 55.54,63.21, 67.07, 67.82, 97.51, 110.35, 111.86, 112.67, 123.11,
123.67, 129.95, 148.63, 152.22, 160.79, 163.10, 163.69,196.40;

MS (ESI, m/z): 443 [M + H]+.

Anal. calcd. (%) forC24H27N2O5F (442.19): C, 65.15; H, 6.15; N, 6.33; found (%):C, 65.11; H, 6.09; N, 6.29.

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INTERMEDIATES

Acetovanillon (4-hydroxy-3-methoxyacetophenone) 6 is also a first-generation fine chemical obtained as a reaction product from the oxidation−hydrolysis of lignosulfonate LS. The compound serves as substrate in synthetic processes leading to several second-generation fine chemicals, such as acetoveratron, veratric acid, and veratric acid chloride. Moreover, recently, a new compound iloperidone REF 20,21 34 [1-(3-(4-acetyl-2-methoxyphenoxy)propyl)-4-(6-fluorobenzisoxazol-3-yl)piperidine] that includes an acetovanillon 6 moiety was reported to be under development for use as an antipsychotic dopamine D2 antagonist and a 5-HT2Aantagonist.

The synthesis of iloperidone 34 is performed by means of an eight-step synthetic process. The acetovanillon 6, which constitutes an integral part of this substance, is condensed with 3-chloropropylbromide 43 in DMF in the presence of potassium carbonate or sodium hydride as base to obtain the key intermediate 44. In the last step of the process 44 is reacted with 42 to afford iloperidone 34. The intermediate 42 is synthesised by reacting piperidine-4-carboxylic acid 35 with formic acid and acetic acid anhydride to obtain 1-formylpiperidine-4-carboxylic acid 36 that upon treatment with thionyl chloride in acetic acid anhydide gives the corresponding acyl chloride 37 (1-formylpiperidine-4-carbonyl chloride). Under Friedel−Craft conditions, the acyl chloride 37 is condensed with 1,3-difluorobenzene 38 to afford 4-(2,4-difluorobenzoyl)piperidine-1-carbaldehyde 39. Treatment of this intermediate with hydroxylamine in refluxing ethanol yields the oxime 40 (4-[(2,4-difluorophenyl)hydroxyiminomethyl]piperidine-1-carbaldehyde). When the oxime 40 is exposed to basic conditions by means of sodium hydride in hot DMF and THF in the following step, a cyclisation proceeds to afford benzo[d]isoxazol 41 (4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine-1-carbaldehyde), which upon treatment with HCl in refluxing ethanol affords the key intermediate 42.

FANAPT is a psychotropic agent belonging to the chemical class of piperidinyl-benzisoxazole derivatives. Its chemical name is 4′-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3′-methoxyacetophenone. Its molecular formula is C₂₄H₂₇FN₂O₄ and its molecular weight is 426.48. The structural formula is:

FANAPT® (iloperidone) Structural Formula Illustration

Iloperidone is a white to off-white finely crystalline powder. It is practically insoluble in water, very slightly soluble in 0.1 N HCl and freely soluble in chloroform, ethanol, methanol, and acetonitrile.

Title: Iloperidone

CAS Registry Number: 133454-47-4

CAS Name: 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone

Manufacturers’ Codes: HP-873; ILO-522

Trademarks: Zomaril (Novartis)

Molecular Formula: C24H27FN2O4

Molecular Weight: 426.48

Percent Composition: C 67.59%, H 6.38%, F 4.45%, N 6.57%, O 15.01%

Literature References: Combined dopamine (D2) and serotonin (5HT2) receptor antagonist. Prepn: J. T. Strupczewski et al., EP402644; eidem, US 5364866 (1990, 1994 both to Hoechst-Roussel); eidem, J. Med. Chem. 38, 1119 (1995).

Pharmacology: M. R. Szewczak et al., J. Pharmacol. Exp. Ther. 274, 1404 (1995).

Clinical pharmacokinetics: S. M. Sainati et al., J. Clin. Pharmacol.35, 713 (1995).

HPLC determn in plasma: A. E. Mutlib, J. T. Strupczewski, J. Chromatogr. B 669, 237 (1995). Receptor binding study: S. Kongsamut et al., Eur. J. Pharmacol. 317, 417 (1996).

Review of pharmacology and therapeutic potential in schizophrenia: J. M. K. Hesselink, Curr. Opin. Cent. Peripher. Nerv. Syst. Invest. Drugs 2, 71-78 (2000); K. K. Jain, Expert Opin. Invest. Drugs 9, 2935-2943 (2000).

Properties: Crystals from ethanol, mp 118-120°.

Melting point: mp 118-120°

Therap-Cat: Antipsychotic.

Keywords: Antipsychotic; Benzisoxazoles; Serotonin-Dopamine Antagonist.

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DRUG SPOTLIGHT …TRANDOLAPRIL » All About Drugs

December 7, 2013 2:58 am / Leave a comment

DRUG SPOTLIGHT …TRANDOLAPRIL » All About Drugs

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Enrupatinib
Enrupatinib CAS 2222689-47-4 MF C27H26N6O3 MW 482.5 g/mol 6-[3-methoxy-4-[(6-methyl-3-pyridinyl)methoxy]anilino]-3-morpholin-4-ylquinoxaline-5-carbonitrile colony-stimulating factor 1 receptor (CSF1R) inhibitor, antineoplastic, EI 1071, EI-1071, 9L35RVQ9J6 ENRUPATINIB is a small molecule drug…
Emestedastat
Emestedastat CAS 1346013-80-6 MF C19H19N5O2S MW381.5 g/mol [(1R,3r,5S)-3-hydroxy-3-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-8-yl][5-(1H-pyrazol-4-yl)thiophen-3-yl]methanone11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor, UE-2343, UE 2343, 106ELK29GH Emestedastat (proposed brand name Xanamem; developmental code name UE-2343) is a steroidogenesis inhibitor which…
Direclidine
Direclidine CAS 1803346-98-6 MF C19H30N4O2 MW346.5 g/mol ethyl 2-[4-(2-methylpyrazol-3-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate 6-Azaspiro[3.4]octane-6-carboxylic acid, 2-[4-(1-methyl-1H-pyrazol-5-yl)-1-piperidinyl]-, ethyl ester, cis- ethyl (2r,4s)-2-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylatemuscarinic M4 receptor positive allosteric modulator, TXB4V44U24, NBI-1117568, NBI 1117568…
Dezecapavir
Dezecapavir CAS 2570323-59-8 MF C37H29ClF9N9O5S MW918.19 1H-Cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-acetamide, N-[(1S)-1-[(3S)-3-[4-chloro-1-methyl-3-[(methylsulfonyl)amino]-1H-indazol-7-yl]-3,4-dihydro-4-oxo-7-(3,3,3-trifluoropropoxy)pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-, (3bS,4aR)- N-[(1S)-1-[(3P)-3-[4-chloro-3-(methanesulfonamido)-1-methyl-1H-indazol-7-yl]-4-oxo-7-(3,3,3-trifluoropropoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1Hcyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl]acetamideinhibitor of viral replication, antiviral, SEK9LN2LSM, VH 4011499, VH4011499, VH-4011499, VH 499, GSK2838232, GSK 2838232 Dezecapavir…
Deulorlatinib
Deulorlatinib CAS 2131126-33-3 MFC21H162H3FN6O2, MW 409.4 g/mol (10R)-7-amino-12-fluoro-2-(2H3)methyl-10,16-dimethyl15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitriletyrosine kinase inhibitor, antineoplastic, 7PW3UT8C9B, TGRX 326, TGRX-326 Deulorlatinib is an orally bioavailable inhibitor of the receptor tyrosine kinases anaplastic lymphoma…
Cenacitinib
Cenacitinib CAS 2641636-52-2 MF C19H19F2N7O3 MW431.4 Urea, N-[(1R,2S)-2-fluorocyclopropyl]-N′-[5-[(7-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl)amino]-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl]- N-{5-[(7-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl)amino]-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl}-N′-[(1R,2S)-2-fluorocyclopropyl]urea Janus kinase inhibitor, anti-inflammatory, VTX958, VTX 958, SB88R8KGL3 VTX958 for the Treatment of Moderately to Severely…
Casdatifan
Casdatifan CAS 2709069-30-5 MF C21H17F4NO3S, 439.4 g/mol (5R,6S,8R)-3,5,6-trifluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (5R,6S,8R)-3,5,6-trifluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (5R,6S,8R)-3,5,6-trifluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (5R,6S,8R)-3,5,6-trifluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-methanesulfonyl-2, 3-dihydro-1H-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrilehypoxia-inducible factor (HIF) inhibitor, antineoplastic, AB 521, DP73UWL6LE Casdatifan is an orally bioavailable allosteric inhibitor…
Cambritaxestat
Cambritaxestat CAS 1979939-16-6 MFC25H22ClF3N4O2 MW502.9 g/mol N-[(1S)-1-(4-chlorophenyl)ethyl]-3-[3-[[4-(trifluoromethoxy)phenyl]methyl]imidazo[4,5-b]pyridin-2-yl]propanamide N-[(1S)-1-(4-chlorophenyl)ethyl]-3-(3-{[4-(trifluoromethoxy)phenyl]methyl}-3H-imidazo[4,5-b]pyridin-2-yl)propanamideautotaxin inhibitor, antineoplastic, Orphan Drug, IOA 289, IOA-289, IOA289, LYY3P2KA27, CRT 0273750 Cambritaxestat is an autotaxin inhibitor. Cambritaxestat is…
Brexanolone caprilcerbate
Brexanolone caprilcerbate CAS 2681264-65-1 MFC48H78O12 MW 847.1 g/mol 1-O-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxymethyl] 5-O-[1,3-di(octanoyloxy)propan-2-yl] 3-methylpentanedioate 1-[1,3-bis(octanoyloxy)propan-2-yl] 5-[({[(20-oxo-5α-pregnan3α-yl)oxy]carbonyl}oxy)methyl] 3-methylpentanedioateGABAA receptor positive allosteric modulator, K3KLQ9T6WM, PHASE 2, Brexanolone caprilcerbate (INNTooltip International Nonproprietary Name;…
Branosotine
Branosotine CAS 2412849-26-2 MF C26H26FN7O MW471.5 g/mol 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]-7-methoxy-3H-benzimidazole-5-carbonitrile 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-7-methoxy-1H-1,3-benzimidazole-5-carbonitrilesomatostatin receptor agonist (veterinary use), 4L2VN6D3D8Branosotine is a small molecule drug. The usage of the INN stem ‘-sotine’…

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