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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS 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 year tenure till date Dec 2017, 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, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 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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FDA approves first drug Epidiolex (cannabidiol) comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy


The U.S. Food and Drug Administration today approved Epidiolex (cannabidiol) [CBD] oral solution for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients two years of age and older. This is the first FDA-approved drug that contains a purified drug substance derived from marijuana. It is also the first FDA approval of a drug for the treatment of patients with Dravet syndrome.

June 25, 2018

Release

The U.S. Food and Drug Administration today approved Epidiolex (cannabidiol) [CBD] oral solution for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients two years of age and older. This is the first FDA-approved drug that contains a purified drug substance derived from marijuana. It is also the first FDA approval of a drug for the treatment of patients with Dravet syndrome.

CBD is a chemical component of the Cannabis sativa plant, more commonly known as marijuana. However, CBD does not cause intoxication or euphoria (the “high”) that comes from tetrahydrocannabinol (THC).

It is THC (and not CBD) that is the primary psychoactive component of marijuana.

“This approval serves as a reminder that advancing sound development programs that properly evaluate active ingredients contained in marijuana can lead to important medical therapies. And, the FDA is committed to this kind of careful scientific research and drug development,” said FDA Commissioner Scott Gottlieb, M.D. “Controlled clinical trials testing the safety and efficacy of a drug, along with careful review through the FDA’s drug approval process, is the most appropriate way to bring marijuana-derived treatments to patients. Because of the adequate and well-controlled clinical studies that supported this approval, prescribers can have confidence in the drug’s uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes. We’ll continue to support rigorous scientific research on the potential medical uses of marijuana-derived products and work with product developers who are interested in bringing patients safe and effective, high quality products. But, at the same time, we are prepared to take action when we see the illegal marketing of CBD-containing products with serious, unproven medical claims. Marketing unapproved products, with uncertain dosages and formulations can keep patients from accessing appropriate, recognized therapies to treat serious and even fatal diseases.”

Dravet syndrome is a rare genetic condition that appears during the first year of life with frequent fever-related seizures (febrile seizures). Later, other types of seizures typically arise, including myoclonic seizures (involuntary muscle spasms). Additionally, status epilepticus, a potentially life-threatening state of continuous seizure activity requiring emergency medical care, may occur. Children with Dravet syndrome typically experience poor development of language and motor skills, hyperactivity and difficulty relating to others.

Lennox-Gastaut syndrome begins in childhood. It is characterized by multiple types of seizures. People with Lennox-Gastaut syndrome begin having frequent seizures in early childhood, usually between ages 3 and 5. More than three-quarters of affected individuals have tonic seizures, which cause the muscles to contract uncontrollably. Almost all children with Lennox-Gastaut syndrome develop learning problems and intellectual disability. Many also have delayed development of motor skills such as sitting and crawling. Most people with Lennox-Gastaut syndrome require help with usual activities of daily living.

“The difficult-to-control seizures that patients with Dravet syndrome and Lennox-Gastaut syndrome experience have a profound impact on these patients’ quality of life,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “In addition to another important treatment option for Lennox-Gastaut patients, this first-ever approval of a drug specifically for Dravet patients will provide a significant and needed improvement in the therapeutic approach to caring for people with this condition.”

Epidiolex’s effectiveness was studied in three randomized, double-blind, placebo-controlled clinical trials involving 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome. Epidiolex, taken along with other medications, was shown to be effective in reducing the frequency of seizures when compared with placebo.

The most common side effects that occurred in Epidiolex-treated patients in the clinical trials were: sleepiness, sedation and lethargy; elevated liver enzymes; decreased appetite; diarrhea; rash; fatigue, malaise and weakness; insomnia, sleep disorder and poor quality sleep; and infections.

Epidiolex must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. As is true for all drugs that treat epilepsy, the most serious risks include thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression and panic attacks. Epidiolex also caused liver injury, generally mild, but raising the possibility of rare, but more severe injury. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine.

Under the Controlled Substances Act (CSA), CBD is currently a Schedule I substance because it is a chemical component of the cannabis plant. In support of this application, the company conducted nonclinical and clinical studies to assess the abuse potential of CBD.

The FDA prepares and transmits, through the U.S. Department of Health and Human Services, a medical and scientific analysis of substances subject to scheduling, like CBD, and provides recommendations to the Drug Enforcement Administration (DEA) regarding controls under the CSA. DEA is required to make a scheduling determination.

The FDA granted Priority Review designation for this application. Fast-Track designation was granted for Dravet syndrome. Orphan Drug designation was granted for both the Dravet syndrome and Lennox-Gastaut syndrome indications.

The FDA granted approval of Epidiolex to GW Research Ltd.

Image result for Epidiolex (cannabidiol)
/////////// Epidiolex, cannabidiol, fda 2018, Dravet syndrome, epilepsy, Priority Review , Fast-Track designation, Orphan Drug designation

Selurampanel, BGG 492


Selurampanel.svg

Selurampanel, BGG492, 

cas 912574-69-7

Chemical Formula: C16H19N5O4S
Exact Mass: 377.1158

UNII-7WG1MR7DAR;

N-(7-isopropyl-6-(1-methyl-1H-pyrazol-5-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)methanesulfonamide

N-[7-Isopropyl-6-(1-methyl-1H-pyrazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]methanesulfonamide

PHASE 2 , FOR EPILEPSY, TITINUS

NOVARTIS INNOVATOR

Selurampanel (INN, code name BGG492) is a drug closely related to the quinoxalinedione series which acts as a competitive antagonist of the AMPA and kainate receptors and, as of 2015, is being investigated in clinical trials by Novartis for the treatment ofepilepsy.[1][2][3] It has also been studied in the acute treatment of migraine, and was found to produce some pain relief, but with a relatively high rate of side effects.[4]

UNII-7WG1MR7DAR.png

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006108591&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 44: N-[7-IsopropyI-6-(l-methyl-lH-pyrazol-4-yl)-2,4-dioxo-l,4-dihydro-2H-quinazoIin-3-yl]-methanesulfonamide
2-Amino-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester

The 2-amino-5-iodo-4-isopropyl-benzoic acid methyl ester required for the coupling reaction described below was prepared according to the procedures described in WO 2004/033435 Al.

The l-methyl-5-tributylstannanyl-lH-pyrazole required for the coupling reaction was prepared according to the procedure described above.

2-Amino-5-iodo-4-isopropyl-benzoic acid methyl ester (300 mg, 0.94 mmol) and l-methyl-5-tributylstannanyl-lH-pyrazole (523 mg, 1.5 equiv) were weighed in air and added in a flame-dried flask. [Bistriphenylphosphine]dichloropalladium (67.3 mg, 0.1 equiv) was added and the flask was closed by a septum. Dioxane (1 mL) was added and the mixture was stirred for 18 h (TLC control) at 100 0C. The mixture was dissolved with EtOAc, filtered and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc / hexanes (4:6)) to yield 2-amino-4-isopropyl-5-(2-methyl-2H- pyrazol-3-yl)-benzoic acid methyl ester (169 mg, 66%) as a yellow solid. (ESI-MS: m/z 21 A [M+H]+, rt 5.20 min).

2-(4-Chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester

4-Chlorophenyl-chloroformate (88 μL, 1.1 equiv) was added to a solution of 2-amino-4-isopropyl-5-(2~ methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (156 mg, 0.57 mmol) in dioxane (1.5 mL). The mixture was stirred for 2 h (TLC control) at 80 0C. The mixture was evaporated to dryness. The obtained yellow solid was used in the next step without further purification, (rt 6.77 min)

N-[7-Isopropyl-6-(2-methyl-2H-pyrazol-3 -yl)-2,4-dioxo- 1 ,4-dihydro-2H-quinazolin-3 -yl] -methanesulfonamide

CH3SO2NHNH2 (79.5 mg, 1.1 equiv) and J-Pr2NEt (225 μL, 2 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (281 mg, 0.65 mmol) in dioxane (8 mL). The mixture was stirred for 16 h (TLC control) at 80 0C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (MeOH / DCM (1:9)) to provide N-[7-isopropyl-6-(2-methyl-2H-pyrazol-3 ~yl)-2,4-dioxo- 1 ,4-dihydro-2H-quinazolin-3 -yl]-methanesulfonamide as a white solid (120 mg, 48%) (ESI-MS: m/z 378 [M+H]+, rt 4.20 min).

 

Patent Submitted Granted
Substituted 1H-quinazoline-2,4-diones useful as AMPA receptor ligands [US7655666] 2008-06-26 2010-02-02
N-(2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-(trifluoromethyl)-1,4-dihydro-2H-quinazolin-3-yl)methanesulfonamide [US8012988] 2010-06-10 2011-09-06
2,4-DIOXO-1,4-DIHYDRO-2H-QUINAZOLIN-3-YL-SULFONAMIDE DERIVATIVES [US2013053381] 2011-05-18 2013-02-28
Use of 1H-quinazoline-2,4-diones [US2013090346] 2012-09-05 2013-04-11
Use of 1H-quinazoline-2,4-diones [US2013096145] 2011-06-24 2013-04-18
Use of 1H-quinazoline-2,4-diones [US2014163050] 2014-02-12 2014-06-12
FOMULATION COMPRISING 1 H-QUINAZOLINE-2, 4-DIONE AMPA RECEPTOR ANTAGONISTS, IN THE FORM OF IMMEDIATE RELEASE TABLETS AND PREPARATION THEREOF [US2012263791] 2010-12-21 2012-10-18
Use of 1H-Quinazoline-2,4-Diones [US2014018376] 2010-10-20 2014-01-16
1-H-QUINAZOLINE-2, 4-DIONES FOR USE IN THE TREATMENT OF NEURONAL CEROID LIPOFUSCINOSIS [US2012122903] 2010-07-23 2012-05-17

References

  1. Faught, Edward (2014). “BGG492 (selurampanel), an AMPA/kainate receptor antagonist drug for epilepsy”. Expert Opinion on Investigational Drugs 23 (1): 107–113.doi:10.1517/13543784.2014.848854. ISSN 1354-3784.
  2.  Belcastro, Vincenzo; Verrotti, Alberto (2015). “Novel Molecular Targets for Drug-Treatment of Epilepsy”: 183–199.doi:10.1007/978-3-319-12283-0_10.
  3.  Hanada, Takahisa (2014). “The AMPA receptor as a therapeutic target in epilepsy: preclinical and clinical evidence”. Journal of Receptor, Ligand and Channel Research: 39.doi:10.2147/JRLCR.S51475. ISSN 1178-699X.
  4.  Gomez-Mancilla B, Brand R, Jürgens TP, et al. (February 2014). “Randomized, multicenter trial to assess the efficacy, safety and tolerability of a single dose of a novel AMPA receptor antagonist BGG492 for the treatment of acute migraine attacks”. Cephalalgia 34 (2): 103–13.doi:10.1177/0333102413499648. PMID 23963355.
Selurampanel
Selurampanel.svg
Systematic (IUPAC) name
N-[7-Isopropyl-6-(2-methylpyrazol-3-yl)-2,4-dioxo-1H-quinazolin-3-yl]methanesulfonamide
Identifiers
CAS Number 912574-69-7
ATC code None
PubChem CID 45381907
ChemSpider 32698379
Chemical data
Formula C16H19N5O4S
Molar mass 377.418 g/mol

see……..http://apisynthesisint.blogspot.in/2016/02/selurampanel-bgg-492.html

////Selurampanel, BGG492, 912574-69-7

CC(C)c1cc2c(cc1c3ccnn3C)c(=O)n(c(=O)[nH]2)NS(=O)(=O)C

CS(=O)(NN1C(NC2=C(C=C(C3=CC=NN3C)C(C(C)C)=C2)C1=O)=O)=O

FDA Approves Implanted Brain Stimulator for Epilepsy


 

epilepsy

THURSDAY Nov. 14, 2013 — The U.S. Food and Drug Administration on Thursday gave its approval to a new implanted device that lowers the rate of seizures among people with epilepsy

http://www.drugs.com/news/fda-approves-implanted-brain-stimulator-epilepsy-48978.html

Actavis to Launch Generic Epilepsy/Bipolar Drug


LAMOTRIGINE

 

PARSIPPANY, N.J., July 15, 2013 (AP) — Drugmaker Actavis Inc. said Monday it’s received U.S. approval to sell a generic version of Lamictal, a tablet for treating epilepsy and bipolar disorder.

Actavis, based in Parsippany, N.J., said the Food and Drug Administration has granted approval for it to sell lamotrigine tablets in doses of 25, 50, 100 and 200 milligrams.http://www.pharmalive.com/actavis-to-launch-generic-epilepsybipolar-drug

Lamotrigine, marketed in the US and most of Europe as Lamictal /ləˈmɪktəl/ byGlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used off-label as an adjunct in treating depression. For epilepsy, it is used to treat focal seizures, primary and secondary tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. Like many other anticonvulsant medications, Lamotrigine also seems to act as an effective mood stabilizer, and has been the first U.S.Food and Drug Administration (FDA)-approved drug for this purpose since lithium, a drug approved almost 30 years earlier. It is approved for the maintenance treatment of bipolar type I. Chemically unrelated to other anticonvulsants (due to lamotrigine’s being aphenyltriazine), lamotrigine has many possible side-effects. Lamotrigine is generally accepted to be a member of the sodium channel blocking class of antiepileptic drugs,but it could have additional actions since it has a broader spectrum of action than other sodium channel antiepileptic drugs such as phenytoin and carbamazepine and is effective in the treatment of the depressed phase of bipolar disorder, whereas other sodium channel blocking antiepileptic drugs are not. In addition, lamotrigine shares few side-effects with other, unrelated anticonvulsants known to inhibit sodium channels, which further emphasizes its unique properties. Lamotrigine is inactivated by hepatic glucuronidation.

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