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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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LORNOXICAM


Lornoxicam skeletal.svg
ChemSpider 2D Image | Lornoxicam | C13H10ClN3O4S2
Lornoxicam

LORNOXICAM

chlortenoxicam

  • Molecular FormulaC13H10ClN3O4S2
  • Average mass371.819 Da

70374-39-9[RN]Chlortenoxicam, CTX, ER09126G7A
2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide, 6-chloro-4-hydroxy-2-methyl-N-2-pyridinyl-, 1,1-dioxide
6233
6-Chlor-4-hydroxy-2-methyl-N-(pyridin-2-yl)-2H-thieno[2,3-e][1,2]thiazin-3-carboxamid-1,1-dioxid
6-Chloro-4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-thieno[2,3-e][1,2]thiazine-3-carboxamide 1,1-dioxide

  • Chlortenoxicam, Ro-13-9297
  • ATC:M01AC05
  • CCRIS 8589
  • Ro 13-9297

Lorcam (Taisho Pharmaceutical Co.) / Xafon (Nycomed)LornoxicamCAS Registry Number: 70374-39-9 
CAS Name: 6-Chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide 
Additional Names: 6-chloro-4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl)-2H-thieno[2,3-e]-1,2-thiazine-1,1-dioxide; chlortenoxicam 
Manufacturers’ Codes: Ro-13-9297; TS-110 
Trademarks: Xefo (Nycomed) 
Molecular Formula: C13H10ClN3O4S2 
Molecular Weight: 371.82 
Percent Composition: C 41.99%, H 2.71%, Cl 9.53%, N 11.30%, O 17.21%, S 17.25% 
Literature References: Cyclooxygenase inhibitor; structurally similar to tenoxicam, q.v.
Prepn: R. Pfister et al.,DE2838851eidem,US4180662 (both 1979 to Hoffmann-La Roche).Clinical pharmacokinetics: S. I. Ankier et al.,Postgrad. Med. J.64, 752 (1988). Symposium on pharmacology and clinical experience: ibid.66, Suppl. 4, S1-S50 (1990). Overview of pharmacology and safety assessment: T. P. Pruss et al.,ibid. S18. 
Properties: Orange to yellow crystals, mp 225-230° (dec). pKa2 4.7. uv max: 371 nm. Partition coefficient (n-octanol/pH 7.4 buffer): 1.8. LD50 orally in mice, rats, rabbits, dogs, monkeys: >10 mg/kg (Pruss). 
Melting point: mp 225-230° (dec) 
pKa: pKa2 4.7 
Log P: Partition coefficient (n-octanol/pH 7.4 buffer): 1.8 
Absorption maximum: uv max: 371 nm 
Toxicity data: LD50 orally in mice, rats, rabbits, dogs, monkeys: >10 mg/kg (Pruss) 
Therap-Cat: Anti-inflammatory; analgesic. 
Keywords: Analgesic (Non-Narcotic); Anti-inflammatory (Nonsteroidal); Thiazinecarboxamides.

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/////////////////////////////////////////////////////////////////////////////////////////////////////
SYN

CAS-RNFormulaChemical NameCAS Index Name
504-29-0C5H6N22-aminopyridine2-Pyridinamine
7790-94-5ClHO3Schlorosulfonic acidChlorosulfuric acid
56946-84-0C5H5Cl2NO2S22,5-dichloro-N-methyl-3-thiophenesulfonamide3-Thiophenesulfonamide, 2,5-dichloro-N-methyl-
3172-52-9C4H2Cl2S2,5-dichlorothiopheneThiophene, 2,5-dichloro- 

SYN 
Synthesis of lornoxicam (DE2838851)

File:Lornoxicam synthesis.svg

The sulfonation of 2,5-dichlorothiophene (I) with ClSO3H -SOCl2 gives 2,5-dichlorothiophene-3-sulfonic acid chloride (II), which by reaction with methylamine in CHCl3 yields the corresponding methylamide (III). The carboxylation of (III) with butyllithium and CO2 in ether affords 5-chloro-3-(N-methylsulfamoyl)thiophene-2-carboxylic acid (IV), which is esterified with PCl5 and methanol to the methyl ester (V). The condensation of (V) with methyl iodoacetate (VI) by means of NaH in DMF gives 5-chloro-3-[N-(methoxycarbonylmethyl)-N-methylsulfamoyl]thiophene-2-carboxylic acid methyl ester (VII), which is cyclized with sodium methoxide in methanol yielding 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxylic acid methyl ester 1,1-dioxide (VIII). Finally, this compound is treated with 2-aminopyridine (IX) in refluxing xylene.

Lornoxicam is an NSAID indicated in the treatment of mild to moderate pain, as well as rheumatoid arthritis and osteoarthritis.

Lornoxicam, also known as chlortenoxicam, is a nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class with analgesic (pain relieving), anti-inflammatory and antipyretic (fever reducing) properties. It is available in oral and parenteral formulations.

It was patented in 1977 and approved for medical use in 1997.[1] Brand names include Xefo and Xefocam among others.

Lornoxicam (chlortenoxicam) is a new nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class with analgesic, anti-inflammatory and antipyretic properties. Lornoxicam differs from other oxicam compounds in its potent inhibition of prostaglandin biosynthesis, a property that explains the particularly pronounced efficacy of the drug. Lornoxicam is approved for use in Japan.

Medical uses

Lornoxicam is used for the treatment of various types of pain, especially resulting from inflammatory diseases of the joints, osteoarthritis, surgery, sciatica, and other inflammations.[2]

Non‐Steroidal Anti‐Inflammatory Drugs (NSAIDs) in Metal Complexes and Their Effect at the Cellular Level - Banti - 2016 - European Journal of Inorganic Chemistry - Wiley Online Library

Contraindications

The drug is contraindicated in patients who must not take other NSAIDs, possible reasons including salicylate sensitivity, gastrointestinal bleeding and bleeding disorders, and severe impairment of heart, liver or kidney function. Lornoxicam is not recommended during pregnancy and breastfeeding and is contraindicated during the last third of pregnancy.[2]

Adverse effects

Lornoxicam has side effects similar to other NSAIDs, most commonly mild ones like gastrointestinal disorders (nausea and diarrhea) and headache. Severe but seldom side effects include bleeding, bronchospasms and the extremely rare Stevens–Johnson syndrome.[2]

Interactions

Interactions with other drugs are typical of NSAIDs. Combination with vitamin K antagonists like warfarin increases the risk of bleeding. Combination with ciclosporin can lead to reduced kidney function, and to acute kidney injury in rare cases. Lornoxicam can also increase the adverse effects of lithiummethotrexate and digoxin and its derivatives. The effect of diureticsACE inhibitors and angiotensin II receptor antagonists can be reduced, but this is only relevant in patients with special risks like heart failure. As with piroxicamcimetidine can increase plasma levels but is unlikely to cause relevant interactions.[3]

PAPER

https://www.mdpi.com/2218-0532/71/4/303

str1

PATENT

CN 113480561

The present invention relates to the prepn. of high purity loroxicam.  In particular, the prepn. method comprises a step of taking 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-Me thiazinecarboxylate-1,1-dioxide and 2-amino pyridine is used as the raw material and xylene is used as the solvent undergoes distn. reaction with solid acid catalyst, mixed gas obtained by the distn. reaction is condensed to obtain a condensate and solid acid catalyst is used to adsorb methanol in the condensate and the adsorbed condensate is recycled, filtering and refining to obtain loroxicam.  The present inventive method distills out the methanol produced by the reaction to promote the pos. progress of the reaction and then catalyzes the absorption of methanol by H2SO4/MxOy solid super acid, so that the xylene returned to the reaction system does not contain methanol, which reduces the coking of the reaction, thereby improving product quality and yield.  The prepd. lornoxicam has high purity, which can reach more than 99.9%, reduces the amt. of solvent and also suitable for industrial prodn.

PATENT

CN 112592356

The present invention relates to the prepn. of lornoxicam.  In particular, the prepn. method comprises a step of taking 6-chloro-4-hydroxy-2-methyl-2-H-thieno[2,3-e]-1,2-thiazidecarboxylic acid Me ester-1,1-dioxide and 2-aminopyridine as raw materials, xylene is used as solvent, adding stabilizer, and carrying out aminolysis reaction, the solvent was removed by concn. under reduced pressure, adding org. solvent to make the slurry, filtering and refining to obtain lornoxicam.  The inventive method uses p-toluene sulfonic acid as a stabilizer, while lowering the reaction temp., it promotes the reaction to proceed forward, and improve the product quality and yield; at the same time reduce the amt. of industrial solvents, the post-treatment process is optimized and the cost of the three wastes treatment is reduced.

PATENT

IN 2014CH02116

Example: 1Preparation of 6-chloro-4-hydroxy-l,l-dioxo-l,2-dihydro-lX6-thieno [2,3-e][l,2] thiazine-3-carboxylic acid methyl ester To the mixture of methanol ( 1000 ml) and 5-chloro-3-(methoxy carbonyl methyl sulfamoyl)-thiophene-2-carboxylicacid methyl ester ( 100 g ,0.305 moles), added sodium methoxide solution (200 ml ) at 25-30°C over a period of 30-45 min. The resulting mixture was stirred for 60 min at same temperature; allowed to heat at 65-75°C and stirred for 10-12 hrs. After completion of reaction, methanol was distilled out under reduced pressure to obtained titled residual product which is directly used to next step

(Example-2). Example: – 2:Preparation of 6-chloro-4-hydroxy-2-methyl-l,l-dioxo-l,2-dihydro-U6- thieno[2,3-e][l,2] thiazine-3-carboxylic acid methyl ester 6-chloro-4-hydroxy-1,1 -dioxo-1,2-dihydro-1 X,6-thieno [2,3-e][ 1,2] thiazine-3-carboxylic acid methyl ester was suspended in DM water (500 ml) and cooled to 10-15° C, dimethyl sulphate ( 70 g) was slowly added to the mixture at 10-15°C in 30 min. The reaction mixture was raised to 25-30°C and maintained for 2-3 hours at same temperature. After completion of reaction, mixture was cooled to 10-15°C, methylene dichloride (1600 ml) was added, reaction mixture pH was adjust to 1.0 -2.0 with hydrochloric acid at 10-15° C, stir reaction mixture to separate the layers. The methylene dichloride layer was distilled out completely at below 30°C to get an residue, followed by addition of methanol (60 ml) and distilled out methanol completely under vacuum at below 50°C to get an residue; further it was crystallized by addition of methanol 190 ml and stirred for 30 min at 50-55°C; cooled the reaction mixture at 25-30°C and stirred for 60 min at same temperature. The resultant solid was filtered, washed with methanol (40 ml) and dried at 50-55°C for 4 – 6 hrs to obtain the titled product

Example: 3Preparation of 6-Chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazine-3-carboxamide 1,1-dioxide (Lornoxicam) 6-chloro-4-hydroxy-2-methyl-l, 1 -dioxo-1,2-dihydro-l X.6-thieno[2,3-e][l ,2] thiazine-3-carboxylic acid methyl ester ( 50 g 0.161 moles) was suspended in O-xylene (500 ml) and allow to stirred at 70-75°C to obtained clear solution. To this clear solution slowly added the mixture of THF ( 50 ml) solution of 2-Amino pyridine ( 14 g ) and ethyl magnesium bromide 2 molar solution (100 ml) at 70-75°C and allow to stirred for 3-4 hrs at same temperature. After completion of reaction, the dilute hydrochloric acid was added to the mixture at 10-15°C and stirred for 60 min. The resultant solid was filtered, washed with water (100 ml) to obtain crude Lornoxicam.

Example: 4Preparation of 6-Chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e)-l,2-thiazine-3-carboxamide 1,1-dioxide (Lornoxicam) 6-chloro-4-hydroxy-2-methyl-l,l-dioxo-l,2-dihydro-R6-thieno[2,3-e][l,2] thiazine-3-carboxylic acid methyl ester ( 50 g 0.161 moles) was suspended in O-xylene (500 ml) and allow to stirred at 70-75°C to obtained clear solution. To this clear solution slowly added the mixture of THF ( 50 ml) solution of 2-Amino pyridine ( 14 g ) and isopropyl magnesium bromide 2 molar solution (100 ml) at 70-75°C and allow to stirred for 3-4 hrs at same temperature. After completion of reaction, the dilute hydrochloric acid was added to the mixture at 10-15°C and stirred for 60 min. The resultant solid was filtered, washed with water (100 ml) to obtain crude Lornoxicam.

Example: 5Purification of Lornoxicam.The crude Lornoxicam was suspended in methanol (500 ml) and cooled to 5-10°C, resulting suspension was basified to pH 11-13 by using sodium hydroxide solution to get clear solution; followed by filtration through hyflo bed; the obtain filtrate was acidified to pH 4.5 – 5.0 with dil. HC1 (1:1) at 5-10°C; stirred the slurry for 30 min. at 5-10°C. The resultant solid was filtered, washed with DM water (100 ml) and dried at 50-55°C to obtained pure Lornoxicam.

PATENT

.EXAMPLES:Preparation of Lornoxicam crudeExample ITo 1200ml o-xylene, 20gm Methyl-6-chloro-4-hydroxy-2-methyl-2//-thieno [2, 3-e] [1, 2] thiazine-3- carboxyate 1,1-dioxide and 6.44gm 2-aminopyridine was added. The reaction mass was stirred under nitrogen atmosphere. Temperature was raised to 140-145°C and maintained for 6hrs. The reaction mass was cooled to 30-35°C and nitrogen was removed. Reaction mass was further stirred for 3hrs- Filtered and washed twice with 50ml of o-xylene. 19.8gm of crude Lornoxicam was obtained. Purification of Lornoxicam crude

Example 219.8gm of crude Lornoxicam was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and methanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around Ihr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C, til! the reaction mass reached pH of 2-3, and then stirred for around I hi*. The reaction mass was cooled to room temperature, filtered, and then washed with 1:1 mixture of methanol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 19.1 gm of pure Lornoxicam was obtained. (HPLC purity- 99.95%)

Example 3!7.9gm of crude Lornoxicam (prepared as per example 1) was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and methanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution, and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around Ihr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C till the reaction mass reached pH of 2-3, and then stirred for around Ihr. The reaction mass was cooled to room temperature, filtered and then washed with 1:1 mixture of methanol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 17.2 gm of pure Lornoxicam was obtained. (HPLC purity- 99.9%) clear solution and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around lhr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C, till the reaction mass reached pH of 2-3, and then stirred for around lhr. The reaction mass was cooled to 30-35°C, filtered and then washed with 1:1 mixture of isopropyl alcohol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 4.85 gm of pure Lornoxicam was obtained. (HPLC purity- 99.8%)

Example 55 gm of crude Lornoxicam (prepared as per example 1) was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and ethanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution, and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around lhr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C, til! the reaction mass reached pH of 2-3 and then stirred for around lhr. The reaction mass was cooled to 30-35°C and filtered, washed with 1:1 mixture of ethanol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 4.8 gm of pure Lornoxicam was obtained. (HPLC purity- 99.8%)

Example 619.4 gm of crude Lornoxicam (prepared as per example I) was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and methanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution, and 20% activated charcoal was further added. The reaction mass was stirred for around lhr at room temperature followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added till the reaction mass reached pH of 2-3 and then stirred for around 1 hr. The reaction mass was * filtered and washed with 1:1 mixture of methanol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 18.9 gm of pure Lornoxicam was obtained. (HPLC purity- 99.3%).

PATENT

https://www.sciencedirect.com/science/article/abs/pii/S0968089603007624?via%

PATENT

https://patents.google.com/patent/WO2002000167A2/en

References

  1. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 519. ISBN 9783527607495.
  2. Jump up to:a b c Haberfeld H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. Xefo Filmtabletten. ISBN 978-3-85200-196-8.
  3. ^ Klopp T, ed. (2010). Arzneimittel-Interaktionen (in German) (2010/2011 ed.). Arbeitsgemeinschaft für Pharmazeutische Information. ISBN 978-3-85200-207-1.
Clinical data
Trade namesXefo, Xefocam others
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
Not recommended; contraindicated in months 7–9
Routes of
administration
By mouthparenteral
ATC codeM01AC05 (WHO)
Legal status
Legal statusIn general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability90–100%
Protein binding99%
MetabolismCYP2C9
Elimination half-life3–4 hours
Excretion2/3 liver, 1/3 kidney
Identifiers
showIUPAC name
CAS Number70374-39-9 
PubChem CID5282204
DrugBankDB06725 
ChemSpider10442760 
UNIIER09126G7A
KEGGD01866 
ChEBICHEBI:31783 
CompTox Dashboard (EPA)DTXSID6046133 
ECHA InfoCard100.158.646 
Chemical and physical data
FormulaC13H10ClN3O4S2
Molar mass371.81 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (what is this?)  (verify)
hidevteNonsteroidal anti-inflammatory drugs (NSAIDs) (primarily M01A and M02A, also N02BA)
Pyrazolones /
Pyrazolidines
AminophenazoneAmpyroneAzapropazoneClofezoneDifenamizoleFamprofazoneFeprazoneKebuzoneMetamizoleMofebutazoneMorazoneNifenazoneOxyphenbutazonePhenazonePhenylbutazonePropyphenazoneSulfinpyrazoneSuxibuzone
SalicylatesAspirin (acetylsalicylic acid)#AloxiprinBenorylateCarbasalate calciumDiflunisalDipyrocetylEthenzamideGuacetisalMagnesium salicylateMethyl salicylateSalsalateSalicinSalicylamideSalicylic acid (salicylate)Sodium salicylate
Acetic acid derivatives
and related substances
AceclofenacAcemetacinAlclofenacAmfenacBendazacBromfenacBumadizoneBufexamacDiclofenacDifenpiramideEtodolacFelbinacFenclozic acidFentiazacIndometacinIndometacin farnesilIsoxepacKetorolacLonazolacMofezolacOxametacinProdolic acidProglumetacinSulindacTiopinacTolmetinZomepirac
OxicamsAmpiroxicamDroxicamIsoxicamLornoxicamMeloxicamPiroxicamTenoxicam
Propionic acid derivatives
(profens)
AlminoprofenBenoxaprofenCarprofenDexibuprofenDexketoprofenFenbufenFenoprofenFlunoxaprofenFlurbiprofenIbuprofen#IbuproxamIndoprofenKetoprofenLoxoprofenMiroprofenNaproxenOxaprozinPiketoprofenPirprofenSuprofenTarenflurbilTepoxalinTiaprofenic acidVedaprofenZaltoprofenCOX-inhibiting nitric oxide donatorNaproxcinod
N-Arylanthranilic acids
(fenamates)
AzapropazoneClonixinEtofenamateFloctafenineFlufenamic acidFlunixinGlafenineMeclofenamic acidMefenamic acidMorniflumateNiflumic acidTolfenamic acidFlutiazin
CoxibsApricoxibCelecoxib (+tramadol)CimicoxibDeracoxibEtoricoxibFirocoxibLumiracoxibMavacoxibParecoxibRobenacoxibRofecoxibValdecoxib
OtherAminopropionitrileBenzydamineChondroitin sulfateDiacereinFluproquazoneGlucosamineGlycosaminoglycanHyperforinNabumetoneNimesulideOxaceprolProquazoneSuperoxide dismutase/OrgoteinTenidap
CombinationsIbuprofen/famotidineIbuprofen/hydrocodoneIbuprofen/oxycodoneIbuprofen/paracetamolMeloxicam/bupivacaineNaproxen/diphenhydramineNaproxen/esomeprazole
Items listed in bold indicate initially developed compounds of specific groups. #WHO-EM Withdrawn drugsVeterinary use medications.

//////////LORNOXICAM, Ro-13-9297, TS-110, Anti-inflammatory, analgesic, chlortenoxicam, CCRIS 8589

CN1C(C(=O)NC2=CC=CC=N2)=C(O)C2=C(C=C(Cl)S2)S1(=O)=O

General References

  1. Balfour JA, Fitton A, Barradell LB: Lornoxicam. A review of its pharmacology and therapeutic potential in the management of painful and inflammatory conditions. Drugs. 1996 Apr;51(4):639-57. [Article]
  2. Vane JR: Introduction: mechanism of action of NSAIDs. Br J Rheumatol. 1996 Apr;35 Suppl 1:1-3. [Article]
  3. Radhofer-Welte S, Rabasseda X: Lornoxicam, a new potent NSAID with an improved tolerability profile. Drugs Today (Barc). 2000 Jan;36(1):55-76. [Article]
  4. Skjodt NM, Davies NM: Clinical pharmacokinetics of lornoxicam. A short half-life oxicam. Clin Pharmacokinet. 1998 Jun;34(6):421-8. [Article]
  5. Olkkola KT, Brunetto AV, Mattila MJ: Pharmacokinetics of oxicam nonsteroidal anti-inflammatory agents. Clin Pharmacokinet. 1994 Feb;26(2):107-20. [Article]
  6. Hitzenberger G, Radhofer-Welte S, Takacs F, Rosenow D: Pharmacokinetics of lornoxicam in man. Postgrad Med J. 1990;66 Suppl 4:S22-7. [Article]
  7. Pruss TP, Stroissnig H, Radhofer-Welte S, Wendtlandt W, Mehdi N, Takacs F, Fellier H: Overview of the pharmacological properties, pharmacokinetics and animal safety assessment of lornoxicam. Postgrad Med J. 1990;66 Suppl 4:S18-21. [Article]
  8. Bonnabry P, Leemann T, Dayer P: Role of human liver microsomal CYP2C9 in the biotransformation of lornoxicam. Eur J Clin Pharmacol. 1996;49(4):305-8. [Article]
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(Heavy chain)
QVQLVQSGAE VKKPGASVKV SCKASGYTFT NYGLSWVRQA PGQGLEWMGW ISANNGDTNY
GQEFQGRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARDS SSSWARWFFD LWGRGTLVTV
SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ
SSGLYSLSSV VTVPSSSLGT KTYTCNVDHK PSNTKVDKRV ESKYGPPCPS CPAPEFLGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV YTLPPSQEEM
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ
EGNVFSCSVM HEALHNHYTQ KSLSLSLGK
(Light chain)
SYVLTQPPSV SVAPGKTARI TCGGNIIGSK LVHWYQQKPG QAPVLVIYDD GDRPSGIPER
FSGSNSGNTA TLTISRVEAG DEADYYCQVW DTGSDPVVFG GGTKLTVLGQ PKAAPSVTLF
PPSSEELQAN KATLVCLISD FYPGAVTVAW KADSSPVKAG VETTTPSKQS NNKYAASSYL
SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS
(Disulfide bridge: H22-H96, H149-H205, H263-H323, H369-H427, H228-H’228, H231-H’231, L22-L87, L136-L195, H136-L213)

Tralokinumab

トラロキヌマブ (遺伝子組換え)

FormulaC6374H9822N1698O2014S44
CAS1044515-88-9
Mol weight143873.2167

EU APPROVED, Adtralza, 2021/6/17

Antiasthmatic, Anti-inflammatory, Anti-IL-13 antibody

Tralokinumab is a human monoclonal antibody which targets the cytokine interleukin 13,[1] and is designed for the treatment of asthma and other inflammatory diseases.[2] Tralokinumab was discovered by Cambridge Antibody Technology scientists, using Ribosome Display, as CAT-354[3] and taken through pre-clinical and early clinical development.[4] After 2007 it has been developed by MedImmune, a member of the AstraZeneca group, where it is currently in Ph3 testing for asthma and Ph2b testing for atopic dermatitis.[5][6] This makes it one of the few fully internally discovered and developed drug candidates in AstraZeneca’s late stage development pipeline.

Discovery and development

Tralokinumab (CAT-354) was discovered by Cambridge Antibody Technology scientists[7] using protein optimization based on Ribosome Display.[8] They used the extensive data sets from ribosome display to patent protect CAT-354 in a world-first of sequence-activity-relationship claims.[7] In 2004, clinical development of CAT-354 was initiated with this first study completing in 2005.[9] On 21 July 2011, MedImmune LLC initiated a Ph2b, randomized, double-blind study to evaluate the efficacy of tralokinumab in adults with asthma.[10]

In 2016, MedImmune and AstraZeneca were developing tralokinumab for asthma (Ph3) and atopic dermatitis (Ph2b) while clinical development for moderate-to-severe ulcerative colitis and idiopathic pulmonary fibrosis (IPF) have been discontinued.[9] In July of that year AstraZeneca licensed Tralokinumab to LEO Pharma for skin diseases.[11]

A phase IIb study of Tralokinumab found that treatment was associated with early and sustained improvements in atopic dermatitis symptoms and tralokinumab had an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with atopic dermatitis.[12]

On 15 June 2017, Leo Pharma announced that they were starting phase III clinical trials with tralokinumab in atopic dermatitis.[13]

Society and culture

Legal status

On 22 April 2021, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Adtralza, intended for the treatment of moderate‑to‑severe atopic dermatitis.[14]

The applicant for this medicinal product is LEO Pharma A/S.

References

  1. ^ Kopf M, Bachmann MF, Marsland BJ (September 2010). “Averting inflammation by targeting the cytokine environment”. Nature Reviews. Drug Discovery9 (9): 703–18. doi:10.1038/nrd2805PMID 20811382S2CID 23769909.
  2. ^ “Statement On A Nonproprietary Name Adopted By The USAN Council: Tralokinumab” (PDF). American Medical Association.
  3. ^ Thom G, Cockroft AC, Buchanan AG, Candotti CJ, Cohen ES, Lowne D, et al. (May 2006). “Probing a protein-protein interaction by in vitro evolution” [P]. Proceedings of the National Academy of Sciences of the United States of America103 (20): 7619–24. Bibcode:2006PNAS..103.7619Tdoi:10.1073/pnas.0602341103PMC 1458619PMID 16684878.
  4. ^ May RD, Monk PD, Cohen ES, Manuel D, Dempsey F, Davis NH, et al. (May 2012). “Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma”British Journal of Pharmacology166 (1): 177–93. doi:10.1111/j.1476-5381.2011.01659.xPMC 3415647PMID 21895629.
  5. ^ “Pipeline”MedImmune. Retrieved 11 June 2013.
  6. ^ “Studies found for CAT-354”ClinicalTrials.gov. Retrieved 11 June 2013.
  7. Jump up to:a b Human Antibody Molecules for Il-13, retrieved 2015-07-26
  8. ^ Jermutus L, Honegger A, Schwesinger F, Hanes J, Plückthun A (January 2001). “Tailoring in vitro evolution for protein affinity or stability”Proceedings of the National Academy of Sciences of the United States of America98 (1): 75–80. Bibcode:2001PNAS…98…75Jdoi:10.1073/pnas.98.1.75PMC 14547PMID 11134506.
  9. Jump up to:a b “Tralokinumab”Adis Insight. Springer Nature Switzerland AG.
  10. ^ Clinical trial number NCT01402986 for “A Phase 2b, Randomized, Double-blind Study to Evaluate the Efficacy of Tralokinumab in Adults With Asthma” at ClinicalTrials.gov
  11. ^ “AstraZeneca enters licensing agreements with LEO Pharma in skin diseases”.
  12. ^ Wollenberg A, Howell MD, Guttman-Yassky E, Silverberg JI, Kell C, Ranade K, et al. (January 2019). “Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb”The Journal of Allergy and Clinical Immunology143 (1): 135–141. doi:10.1016/j.jaci.2018.05.029PMID 29906525.
  13. ^ “LEO Pharma starts phase 3 clinical study for tralokinumab in atopic dermatitis”leo-pharma.com. AstraZeneca. 1 July 2016.
  14. ^ “Adtralza: Pending EC decision”European Medicines Agency. 23 April 2021. Retrieved 23 April 2021.
Tralokinumab Fab fragment bound to IL-13. From PDB 5L6Y​.
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetIL-13
Clinical data
ATC codeD11AH07 (WHO)
Identifiers
CAS Number1044515-88-9 
ChemSpidernone
UNIIGK1LYB375A
KEGGD09979
Chemical and physical data
FormulaC6374H9822N1698O2014S44
Molar mass143875.20 g·mol−1
  (what is this?)  (verify)

/////////Tralokinumab, Adtralza, EU 2021, APPROVALS 2021, Antiasthmatic, Anti-inflammatory, Anti-IL-13 antibody, MONOCLONAL ANTIBODY, PEPTIDE, トラロキヌマブ (遺伝子組換え) ,

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крисаборол , كريسابورول , Crisaborole, AN 2728


 

Crisaborole

Treatment for Inflammatory Skin Diseases, including Atopic Dermatitis and Psoriasis

C14H10BNO3, Average mass251.045 Da

4-[(1-Hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile ,

4-((1-Hydroxy-1,3-dihydrobenzo(c)(1,2)oxaborol-6-yl)oxy)benzonitrile

 CAS 906673-24-3, AN-2728

Benzonitrile, 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]-

1,3-Dihydro-1-hydroxy-5-(4-cyanophenoxy)-2,1-benzoxaborole

5-(4-Cyanophenoxy)-l, 3-dihydro-l-hydroxy-2, 1-benzoxaborole

crisaborol, crisaborole, Crisaborole, crisaborolum

UNII-Q2R47HGR7P

крисаборол

كريسابورول

In phase 3  for treatment of mild to moderate atopic dermatitis……Anacor Pharmaceuticals, Inc.

Psoriasis is a chronic skin disorder caused by inflammatory cell infiltration into the dermis and epidermis, and is accompanied by keratinocyte hyperproliferation. Once triggered, a strong T-cell response is mounted, and a cascade of cytokine and chemokine production is induced.

Down-regulation of certain cytokines and chemokines is considered to be a good approach to treatment, and indeed, the biologics targeting TNF-α demonstrate the effectiveness of this approach.However, biologics have intrinsic challenges, such as limited administration route, side effects, quality control and production cost.

Small molecule approaches to treat psoriasis include systemic or topical steroids, cyclosporine, psoralen plus UVA (PUVA), retinoids, methotrexete, and vitamin D3 analogs.Atopic dermatitis is an allergic skin disorder, which is typically treated with topical steroids, antihistamines, and calcineurin inhibitors.

However, there is still a need for new treatment with improved safety profile. Recently phosphodiesterase 4 (PDE4) inhibitors have been in development for such skin diseases. CC-10004 is in development as an oral treatment for psoriasis and atopic dermatitis. AWD-12-281 was, until recently, in development for the topical treatment of atopic dermatitis. In addition, roflumilast is under Phase 1 development for both diseases.

PDE4 inhibitors aiming at skin inflammatory diseases.

Figure 1.

PDE4 inhibitors aiming at skin inflammatory diseases.

 

Anacor’s lead product candidate is crisaborole, an investigational non-steroidal topical PDE-4 inhibitor in development for the potential treatment of mild-to-moderate atopic dermatitis and psoriasis

crisaborole is an investigational topical antiinflammatory drug in phase III clinical development by Anacor Pharmaceuticals for the treatment of mild to moderate atopic dermatitis and in phase II clinical trials in mild to moderate psoriasis

A novel boron-containing small molecule, Crisaborole inhibits the release of pro-inflammatory cytokines including TNF-alpha, IL-12, and IL-23, known mediators of the inflammation associated with psoriasis.

Synthesis

AN3

CKICK ON IMAGE FOR CLEAR VIEW

 

 

 

Originator
Therapeutic Claim
Class
Mechanism of action
WHO ATC code(s)
EPhMRA code(s)
Clinical trial(s)
Conditions Phases Interventions Status
Dermatitis, Atopic Phase 3 AN-2728 Active, not recruiting
Psoriasis Phase 2 AN-2728 Completed
Plaque-Type Psoriasis Phase 1 AN-2728 Completed

PAPER

Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis
Bioorg Med Chem Lett 2009, 19(8): 2129

http://www.sciencedirect.com/science/article/pii/S0960894X09002996

 

  • Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA

A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. This compound is now in clinical development for the topical treatment of psoriasis and being pursued for the topical treatment of atopic dermatitis

Image for unlabelled figure

Reagents and conditions: (a) ethylene glycol, p-TsOH, toluene, reflux, 6h ...

Scheme 1.

Reagents and conditions: (a) ethylene glycol, p-TsOH, toluene, reflux, 6 h (quant.); (b) K2CO3, DMF, 100 °C, overnight (82–96%); (c) 3 M HCl, THF, reflux, 2 h (80–100%); (d) NaBH4, MeOH, rt, 1 h (quant.); (e) 3,4-dihydro-2H-pyran, camphorsulfonic acid, CH2Cl2, rt, 2 h (quant.); (f) (i-PrO)3B, n-BuLi, THF, −78 °C to rt, 3 h; (g) 6 M HCl, THF, rt, 3 h (37–44%); (h) 6 M NaOH, MeOH, 1,4-dioxane, reflux, 6 days (79%); (i) diethylamine (for 5f) or morpholine (for 5g), EDCI, HOBt, DMAP, DMF, rt, overnight (41–70%).

PATENT

http://www.google.co.in/patents/WO2006089067A2?cl=en

4.2. q 5-(4-Cyanophenoxy)-l, 3-dihydro-l-hydroxy-2, 1-benzoxaborole (C17) [0264] 1H-NMR (300 MHz,

Figure imgf000077_0001

δ ppm 4.95 (s, 2H), 7.08 (dd, J= 7.9, 2.1 Hz, IH), 7.14 (d, J= 8.8 Hz, IH), 7.15 (d, J= 2.1 Hz, IH), 7.78 (d, J= 7.9 Hz, IH), 7.85 (d, J= 9.1 Hz, 2H), 9.22 (s, IH).

 

PATENT

 

EXAMPLE 15

http://www.google.com/patents/WO2007095638A2?cl=en

4-(4-Cvanophenoxy)phenylboronic acid (C97)

Figure imgf000097_0002

(a) (4-cyanophenyl) (4-bromophenyl) ether. Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 1000C for 16 h and then filtered. After rotary evaporation, the residue was dissolved in ethyl acetate and washed with IN NaOH solution to remove unreacted phenol. The organic solution was dried and passed through a short silica gel column to remove the color and minor phenol impurity. Evaporation of the solution gave (4-cyanophenyl)(4- bromophenyl)ether (13.82 g, yield 87.2%) as a white solid. 1H NMR (300 MHz, DMSO-de): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.

(b) 4-(4-cyanophenoxy)phenylboronic acid. The procedure described in Example 2d was used for the synthesis of 4-(4-cyanophenoxy)phenylboronic acid using (4-cyanophenyl)(4-bromophenyl)ether as starting material. The title compound was obtained as a white solid. M.p.l94-198°C. MS: m/z = 239 (M+), 240 (M+ 1) (ESI+) and m/z = 238 (M-I) (ESI-). HPLC: 95.3% purity at 254 nm and 92.1% at 220 nm. 1H NMR (300 MHz, DMSO-d6 + D2O): δ 7.83-7.76 (m, 4H), 7.07 (d, 2H) and 7.04 (d, 2H) ppm.

FURTHER METHOD

Figure imgf000048_0003

 

2-Bromo-5-(4-cvanophenoxy)benzyl Alcohol

1H-NMR (300 MHz, CDCl3) δ (ppm) 2.00 (br s, IH), 4.75 (s, 2H), 6.88 (dd, J= 8.5, 2.9 Hz, IH), 7.02 (d, J= 8.8 Hz, IH), 7.26 (d, J= 2.6 Hz, IH), 7.56 (d, J = 8.5 Hz, IH), 7.62 (d, J= 8.8 Hz, 2H).

 

 

PATENT

http://www.google.im/patents/EP1976536A2?cl=en

2.2.a 2-Bromo-5-(4-cyanophenoxy)benzyl Alcohol

1H-NMR (300 MHz, CDCl3) δ (ppm) 2.00 (br s, IH), 4.75 (s, 2H), 6.88 (dd, J= 8.5, 2.9 Hz, IH), 7.02 (d, J= 8.8 Hz, IH), 7.26 (d, J- 2.6 Hz, IH), 7.56 (d, J = 8.5 Hz, IH), 7.62 (d, J= 8.8 Hz, 2H).

2.2.b 2-Bromo-4-(4-cyanophenoxγ)benzyl Alcohol

1H NMR (300 MHz, DMSO-d6): δ 7.83 (d, 2H), 7.58 (d, IH), 7.39 (d, IH), 7.18 (dd, IH), 7.11- (d, 2H), 5.48 (t, IH) and 4.50 (d, 2H) ppm.

2.2.c 5- (4-Cyanophenoxy) -1 -Indanol

M.p.50-53°C. MS (ESI+): m/z = 252 (M+l). HPLC: 99.7% purity at 254 nm and 99.0% at 220 nm. 1H NMR (300 MHz, DMSOd6): δ 7.80 (d, 2H), 7.37 (d, IH), 7.04 (d, 2H), 6.98-6.93 (m, 2H), 5.27 (d, IH)5 5.03 (q, IH), 2.95-2.85 (m, IH), 2.75-2.64 (m, IH), 2.39-2.29 (m, IH) and 1.85-1.74 (m, IH) ppm.

2.2. d 2-Bromo-5-(tert-butyldimethylsiloxy)benzyl Alcohol [0429] 1H-NMR (300 MHz, CDCl3) δ (ppm) 0.20 (s, 6H), 0.98 (s, 9H), 4.67 (br s,lH), 6.65 (dd, J= 8.2, 2.6 Hz, IH), 6.98 (d, J= 2.9 Hz, IH), 7.36 (d, J= 8.8 Hz, IH).

3.2.k 2-Bromo-5-(2-cyanophenoχy)-l-(methoxymethoxymethyl)benzene [0443] 1H-NMR (300 MHz, CDCl3) δ (ppm) 3.41 (s, 3H), 4.64 (s, 2H), 4.76 (s, 2H), 6.8-6.9 (m, 2H), 7.16 (td, J= 7.6, 0.9 Hz, IH), 7.28 (d, J= 2.9 Hz, IH), 7.49 (ddd, J= 8.8, 7.6, 1.8 Hz, IH)5 7.56 (d, J= 8.5 Hz, IH), 7.67 (dd, J= 7.9, 1.8 Hz, IH).

EXAMPLE 32

Alternative Preparation of C17 -Intermediate

Figure imgf000223_0001

The procedure described in Example II I was followed for 1H NMR characterization of the current alcohol-borate intermediate. 1H NMR determination indicated there were 72.7 mol% of the desired alcohol-borate intermediate [2-bromo- 5-(4-cyanophenoxy)benzyl] diisopropyl borate, 20.7 mol% of an unknown intermediate and 6.5 mol% of unreacted alcohol. 1H NMR (CDCl3, 300 MHz) of [2- bromo-5-(4-cyanophenoxy)benzyl] diisopropyl borate: δ= 7.61 (d, J= 9.0 Hz, 2H), 7.52 (d, J= 8.4 Hz, IH), 7.15 (d, J= 3.0 Hz, IH), 7.03 (d, J= 8.7 Hz, 2H), 6.84 (dd, J= 8.7 Hz, J= 3.0 Hz, IH), 4.85 (s, 2H), 4.35 (septet, J= 6.1 Hz, 2H), 1.11 (d, J= 6.1 Hz, 12H) ppm.

PATENT

http://www.google.com/patents/US20090291917

    Example 154-(4-Cyanophenoxy)phenylboronic acid (C97)

  • Figure US20090291917A1-20091126-C00195
  • (a) (4-cyanophenyl)(4-bromophenyl)ether. Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 100° C. for 16 h and then filtered. After rotary evaporation, the residue was dissolved in ethyl acetate and washed with 1N NaOH solution to remove unreacted phenol. The organic solution was dried and passed through a short silica gel column to remove the color and minor phenol impurity. Evaporation of the solution gave (4-cyanophenyl)(4-bromophenyl)ether (13.82 g, yield 87.2%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.
  • (b) 4-(4-cyanophenoxy)phenylboronic acid. The procedure described in Example 2d was used for the synthesis of 4-(4-cyanophenoxy)phenylboronic acid using (4-cyanophenyl)(4-bromophenyl)ether as starting material. The title compound was obtained as a white solid. M.p. 194-198° C. MS: m/z=239 (M+), 240 (M+1) (ESI+) and m/z=238 (M−1) (ESI−). HPLC: 95.3% purity at 254 nm and 92.1% at 220 nm. 1H NMR (300 MHz, DMSO-d6+D2O): δ 7.83-7.76 (m, 4H), 7.07 (d, 2H) and 7.04 (d, 2H) ppm.

see

http://www.google.co.in/patents/WO2006089067A2?cl=en

see

http://www.google.com/patents/US20090291917

US5688928 * Jun 7, 1995 Nov 18, 1997 Prolinx, Inc. Phenylboronic acid complexing reagents derived from aminosalicylic acid
US5880188 * May 26, 1995 Mar 9, 1999 Zeneca Limited Oxaboroles and salts thereof, and their use as biocides
US5962498 * Dec 2, 1994 Oct 5, 1999 Procyon Pharmaceuticals, Inc. Protein kinase C modulators. C. indolactam structural-types with anti-inflammatory activity
US6369098 * Oct 4, 2000 Apr 9, 2002 Bethesda Pharmaceuticals, Inc. Dithiolane derivatives
US20030032673 * Jul 19, 2002 Feb 13, 2003 Isis Innovation Limited Therapeutic strategies for prevention and treatment of alzheimer’s disease
US20050239170 * Jul 16, 2001 Oct 27, 2005 Hedley Mary L Alpha-MSH related compounds and methods of use
US20060009386 * May 12, 2005 Jan 12, 2006 The Brigham And Women’s Hospital, Inc. Use of gelsolin to treat infections
Methods of treating anti-inflammatory conditions through the use of boron- containing small molecules are disclosed.
… Francisco, CA Mar. 6-10, 2009. 6, “AN2728 … Francisco, CA Mar. 6-10, 2009. 7 , “AN2728 … Kyoto, Japan, May 14-18, 2008. 10, “AN2728 …
AN2728, 5-(4-cyanophenoxy)-2,3- dihydro-1-hydroxy-2,1- …. UK-500,001, AN2728, DE-103, Tofisopam, Dextofisopam, Levotofisopam (USAN).
… Dermatology Annual Meeting, San Francisco, CA Mar. 6-10, 2009. 6, “AN2728 … 7, “AN2728 … Francisco, CA May 6-10, 2009. 10, “AN2728 …
… from the group consisting of AN-2728, AN-2898, CBS- 3595, apremilast, ELB- 353, KF-66490, K-34, LAS-37779, IBFB-211913, AWD-12-281, …
AN2728” is the compound 4-(l-hydroxy-l,3-dihydro-2 … GSK256066, oglemilast, tetomilast, apremilast, AN2728, Compound A, Compound B, …
AN2728, 5-(4-cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1- …. UK-500,001, AN2728, DE-103, Tofisopam, Dextofisopam, Levotofisopam (USAN).
85.用于治疗疼痛的UK-500,001。 85. for the treatment of pain UK-500,001. 86.用 于治疗疼痛的AN2728。 86. for the treatment of pain AN2728.

 

 

see full series on boroles

http://apisynthesisint.blogspot.in/p/borole-compds.html

http://apisynthesisint.blogspot.in/p/borole-compds.html

http://apisynthesisint.blogspot.in/p/borole-compds.html

do not miss out

 

 

 

 

 

 

///////////crisaborole, AN 2728, PHASE 3, Anti-inflammatory, Phosphodiesterase, Oxaborole, Psoriasis, Atopic dermatitis, borole

Synthesis, biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors


STR4

COMPD HAS  cas no 1616882-93-9

MF……….C18 H11 F3 N2 O2
[1]​Benzopyrano[4,​3-​c]​pyrazol-​4(1H)​-​one, 3-​methyl-​1-​[4-​(trifluoromethyl)​phenyl]​-

 3-Methyl-1-(4-(trifluoromethyl)phenylchromeno[4,3-c]pyrazol-4(1H)-one

image

Synthesis, biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors

DOI: 10.1016/j.bmcl.2014.08.050

Jagdeep Grover, Vivek Kumar, M. Elizabeth Sobhia, Sanjay M. Jachak

http://www.sciencedirect.com/science/article/pii/S0960894X14008944

 Abstract

As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds (3ad, 3h, 3k and 3q) were identified as potential and selective COX-2 inhibitors (COX-2 IC50’s in 1.79–4.35 μM range; COX-2 selectivity index (SI) = 6.8–16.7 range). Compound 3b emerged as most potent (COX-2 IC50 = 1.79 μM; COX-1 IC50 >30 μM) and selective COX-2 inhibitor (SI >16.7). Further, compound 3b displayed superior anti-inflammatory activity (59.86% inhibition of edema at 5 h) in comparison to celecoxib (51.44% inhibition of edema at 5 h) in carrageenan-induced rat paw edema assay. Structure–activity relationship studies suggested that N-phenyl ring substituted with p-CF3 substituent (3b, 3k and 3q) leads to more selective inhibition of COX-2. To corroborate obtained experimental biological data, molecular docking study was carried out which revealed that compound 3b showed stronger binding interaction with COX-2 as compared to COX-1.


Authors

  • a Department of Natural Products, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar (Mohali) 160062, Punjab, India
  • b Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar 160062, Punjab, India

Sanjay Corresponding author. Tel.: +91 172 2214683; fax: +91 172 2214692.

 CLICK……….

Cyclooxygenase (COX) or prostaglandin endoperoxide synthase (PGHS), catalyzes the conversion of arachidonic acid to inflammatory mediators such as prostaglandins (PGs), prostacyclins and thromboxanes. COX exists in mainly two isoforms: COX-1 and COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs), widely used for relief of fever, pain and inflammation, act by inhibiting COX catalyzed biosynthesis of inflammatory mediators.

However, the therapeutic use of classical NSAIDs is associated with well-known side effects at the gastrointestinal level (mucosal damage, bleeding) and, less frequently, at the renal level.

Two decades after the discovery of COX isoforms, it was recognized that selective inhibition of COX-2 might be endowed with improved anti-inflammatory properties and reduced gastrointestinal toxicity profiles than classical NSAIDs.

Overall, these selective COX-2 inhibitors (coxibs) have fulfilled the hope of possessing reduced risk in gastrointestinal events, but unfortunately cardiovascular concerns regarding the use of these agents have emerged that led to the withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the market in 2004 and 2005, respectively.

Ongoing safety concerns pertaining to the use of non-selective NSAIDs have spurred development of coxibs with improved safety profile.

……………………………………………………………………………………………..
STR4

cas no 1616882-93-9

mf……….C18 H11 F3 N2 O2
[1]​Benzopyrano[4,​3-​c]​pyrazol-​4(1H)​-​one, 3-​methyl-​1-​[4-​(trifluoromethyl)​phenyl]​-

 3-Methyl-1-(4-(trifluoromethyl)phenylchromeno[4,3-c]pyrazol-4(1H)-one

Full-size image (21 K)

Scheme 1.

Reagent and conditions: (a) Piperidine, rt, 20 min; (b) ArNHNH2, EtOH, reflux, 5 h; (c) K2CO3, acetone, reflux, 24 h.

COMPD IS

3b R1=H R2= H 4-CF3-C6H4 90
3-Methyl-1-(4-(trifluoromethyl)phenylchromeno[4,3-c]pyrazol-4(1H)-one (3b):
White solid; yield 90%; mp: 224–225 °C;
1H NMR (CDCl3, 400 MHz): δ ppm 7.89 (d, 2H, J = 8.32 Hz, Ar-H), 7.73 (d, 2H, J = 8.24 Hz, Ar-H), 7.45–7.52 (m, 2H, H-6, H-7), 7.16 (dd, 1H, J = 1.4, 8.2 Hz, H-9), 7.10 (td, 1H, J = 1.56, 7.38 Hz, H-8), 2.69 (s, 3H, CH3);
13C NMR (CDCl3, 100 MHz): δ ppm 157.7, 153.3, 151.5, 142.3, 141.8, 131.9, 127.2, 127.1, 127.0, 124.0, 122.2, 118.3, 111.5, 107.1, 12.8;
HRMS (ESI) m/z: Calcd for C18H11F3N2O2Na [M + Na]+ 367.0670; found 367.0676.

Synthetic Communications (2014), 44(13), 1914-1923

DOI:
10.1080/00397911.2013.879184

Jagdeep Grovera, Somendu Kumar Roya & Sanjay Madhukar Jachaka*

pages 1914-1923

http://www.tandfonline.com/doi/abs/10.1080/00397911.2013.879184#.VCI5f0DgXXM

http://www.tandfonline.com/doi/suppl/10.1080/00397911.2013.879184/suppl_file/lsyc_a_879184_sm8537.pdf

Abstract

Unprecedented cyclization was observed during N-sulfonylation of 3-[1-(phenylhydrazono)-ethyl]-chromen-2-one in pyridine, affording 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones. To avoid use of noxious pyridine, reaction was tried in different basic conditions and the best results were obtained with potassium carbonate in acetone. A wide range of substrates bearing either electron-donating or electron-withdrawing substituents on phenylhydrazine ring were compatible with the developed methodology. Rapid access of starting material, 3-acetylcoumarin, excellent yields of products, and use of environmentally benign base and solvent for the cyclization make this strategy an efficient and convenient method for synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones.

STR4

Methyl-1-(4-(trifluoromethyl)phenylchromeno[4,3-c]pyrazol-4(1H)-one (4b):
Whitesolid;
yield 90%; mp: 224–225 °C;
1H NMR (CDCl3, 400 MHz):δppm 2.69 (s, 3H, CH3),
7.10(td, 1H,J= 1.56, 7.38 Hz, H-8),
7.16 (dd, 1H,J= 1.4, 8.2 Hz, H-9),
7.45–7.52 (m, 2H, H-6, H-7),
7.73 (d, 2H,J= 8.24 Hz, Ar-H),
7.89 (d, 2H,J= 8.32 Hz, Ar-H);
13C NMR (CDCl3, 100MHz):
δppm 12.8, 107.1, 111.5, 118.3, 122.2, 124.0,
127.0, 127.1, 127.2, 131.9, 141.8, 142.3,
151.5, 153.3, 157.7;
HRMS (ESI)m/z: Calcd for C18H11F3N2O2Na [M + Na]+367.0670; found367.0676.
 3-Methyl-1-(4-(trifluoromethyl)phenylchromeno[4,3-c]pyrazol-4(1H)-one

STR4

SEE BELOW  1H NMR, 13CNMR, AND MASS SPEC

STR2STR2

STR3

References
1. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. J. Mol. Biol. 1997, 267, 727.
2. Bernstein, F. C.; Koetzle, T. F.; Williams, G. J. B.; Meyer, E. F.; Brice, M. D.; Rodgers, J. R.; Kennard, O.; Shimanouchi, T.; Tasumi, M. J. Mol. Biol. 1977, 112, 535.

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