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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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Methotripremazine


Methotrimeprazine

Methotripremazine

Levomepromazine.svg
  • CL 36467
  • CL 39743
  • N05AA02
  • RP 7044
  • RP-7044
  • SK&F 5116
  • XP-03
  • XP03

Product Ingredients

INGREDIENTUNIICASINCHI KEY
Methotrimeprazine hydrochloride42BB1Y25861236-99-3ODLGFPIWRAEFAN-PFEQFJNWSA-N
Methotrimeprazine maleate5KN5Y9V01K7104-38-3IFLZPECPTYCEBR-VIEYUMQNSA-N

Methotrimeprazine 
CAS Registry Number: 60-99-1 
CAS Name: (bR)-2-Methoxy-N,N,b-trimethyl-10H-phenothiazine-10-propanamine 
Additional Names: (-)-10-(3-dimethylamino-2-methylpropyl)-2-methoxyphenothiazine; levomepromazine; 2-methoxytrimeprazine; levomeprazine 
Manufacturers’ Codes: RP-7044 
Trademarks: Sinogan-Debil; Tisercin (EGYT); Neozine (Rh>e-Poulenc); Nirvan; Nozinan (Rh>e-Poulenc); Levoprome (Lederle) 
Molecular Formula: C19H24N2OS 
Molecular Weight: 328.47 
Percent Composition: C 69.47%, H 7.36%, N 8.53%, O 4.87%, S 9.76% 
Literature References: Prepn: Courvoisier et al.,C.R. Seances Soc. Biol. Ses Fil.151, 1378 (1957); Jacob, Robert, US2837518 (1958 to Rhône-Poulenc).Optical Rotatory Power, -17, Conc: 5 g/100mL; Solv: chloroform; Wavlen: 589.3 nm; Temp: 20 °C 
Derivative Type: Maleate 
CAS Registry Number: 7104-38-3 
Trademarks: Minozinan; Milezin (Spofa); Neuractil; Neurocil (Bayer); Sofmin (Dainippon); Veractil 
Molecular Formula: C19H24N2OS.C4H4O4 
Molecular Weight: 444.54 
Percent Composition: C 62.14%, H 6.35%, N 6.30%, O 18.00%, S 7.21% 
Properties: Crystals, darkened by light. Dec about 190°. Sparingly sol in water (0.3% at 20°) and in ethanol (0.4%). pH of a 0.3% aq soln is 4.3. The free base is levorotatory: [a]D20 -17° (c = 5 in chloroform). 
Optical Rotation: [a]D20 -17° (c = 5 in chloroform) 
Therap-Cat: Analgesic. 
Keywords: Analgesic (Non-Narcotic).

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Methotrimeprazine is a phenothiazine used in the management of psychosis, particular those of schizophrenia, and manic phases of bipolar disorder.

A phenothiazine with pharmacological activity similar to that of both chlorpromazine and promethazine. It has the histamine-antagonist properties of the antihistamines together with central nervous system effects resembling those of chlorpromazine. (From Martindale, The Extra Pharmacopoeia, 30th ed, p604)

Levomepromazine, also known as methotrimeprazine, is a phenothiazine neuroleptic drug. Brand names include Nozinan, Levoprome, Detenler, Hirnamin, Levotomin and Neurocil. It is a low-potency antipsychotic (approximately half as potent as chlorpromazine) with strong analgesichypnotic and antiemetic properties that are primarily used in palliative care.[1][2]

Serious side effects include tardive dyskinesiaakathisiaabnormalities in the electrical cycle of the heartlow blood pressure and the potentially fatal neuroleptic malignant syndrome.[1][2]

As is typical of phenothiazine antipsychotics, levomepromazine is a “dirty drug“, that is, it exerts its effects by blocking a variety of receptors, including adrenergic receptorsdopamine receptorshistamine receptorsmuscarinic acetylcholine receptors and serotonin receptors.[1][2]

Medical uses

It can be used as an analgesic for moderate to severe pain in non-ambulant patients (the latter being because of its strong sedative effects).[3]

Levomepromazine is also used at lower doses for the treatment of nausea and insomnia.[1]

Levomepromazine is frequently prescribed and valued worldwide in palliative care medicine for its multimodal action, to treat intractable nausea or vomiting, and for severe delirium/agitation in the last days of life. Palliative care physicians will commonly prescribe it orally or via subcutaneous syringe drivers in combination with opioid analgesics such as hydromorphone.[1][2]

Levomepromazine is used for the treatment of psychosis, particularly those of schizophrenia, and manic phases of bipolar disorder. It should only be used with caution in the treatment of agitated depressions, as it can cause akathisia as a side effect, which could worsen the agitation.[1][2] A 2010 systematic review compared the efficacy of levomepromazine with atypical antipsychotic drugs:

 

Adverse effects

The most common side effect is akathisia.[2] Levomepromazine has prominent sedative and anticholinergic/sympatholytic effects (dry mouth, hypotensionsinus tachycardia, night sweats) and may cause weight gain.[2] These side effects normally preclude prescribing the drug in doses needed for full remission of schizophrenia, so it has to be combined with a more potent antipsychotic.[2] In any case, blood pressure and EKG should be monitored regularly.[2]

A rare but life-threatening side effect is neuroleptic malignant syndrome (NMS).[2] The symptoms of NMS include muscle stiffness, convulsions and fever.[2]

PAPER

Bulletin de la Societe de Pharmacie de Bordeaux (1964), 103(4), 224-30.

The authors define an extn. equil. const., pKe.  When a basic mol., A, in an org. solvent (immiscible with water) is shaken with an aq. acid, part of A passes into the aq. phase in the equil. A + H+ .rdblhar. AH+, and Ke and pKe are defined by the equations Ke = [A]org[H+]H2O/[AH+]H2O and pKe = pKa -log ([A]org/[A]H2O), resp.  Values of pKe are reported for levomepromazine, properidiazine, thioridazine, chlorpromazine, alimenazine, propiomazine, promethazine, and aminopromazine.  Where 2 C atoms sep. the 2 N chain atoms, pKe is of the order of 5, and if 3, the value is near 4.3.

PATENT

JP 40009030

A soln. of 10.5 g.  l-3-dimethylamino-2-methylpropanol in xylene is added a suspension of 2.5 g. Na in xylene and a soln. of 18 g. p-tosyl chloride in xylene is dropped in to give l-3-dimethylamino-2-methylpropanol tosylate (I), hydrochloride m. 98-100%.  I is treated with 18 g. 2-methoxyphenothiazine and NaNH2 (prepd. from 1.85 g. Na) to give 80% l-3-(2-methoxy-10-phenothiazinyl)-2-methyl-1-dimethylaminopropane, m. 125-6° (hexane).  Similarly are prepd. l-3-(3-ethyl-10-phenothiazinyl)-2-methyl-1-dimethylaminopropane (maleate m. 136°) and l-3-(10-phenothiazinyl)-2-methyl-1-dimethylaminopropane (maleate m. 174-5°).  The products are tranquilizers.

PATENT

HU 152208

HU 157158

PL 66636

PAPER

Bulletin de la Societe Chimique de France (1968), (8), 3220-2.

Folia medica (1970), 12(1), 88-9

Journal of pharmaceutical sciences (1987), 76(7), 541-4.

SYN

IN201203390

Deprotonation of 2-methoxyphenothiazine by means of KOH in refluxing touene/DMSO, followed by condensation of resulting pottasium salt with N-(3-chloro-2-methylpropyl)-N,N-dimethylamine  in refluxing toluene leads to racemic levomepromazine , which upon finally resolution using (-)-dibenzoyl-L-tartaric acid in acetone or using di-p-toluoyl-L-tartaric acid and, optionally, HCOOH in EtOH at 60 °C affords the target levomepromazine

SYN

References

  1. Jump up to:a b c d e f Brayfield A, ed. (13 December 2013). “Levomepromazine”Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 12 May 2014.
  2. Jump up to:a b c d e f g h i j k Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
  3. ^ “Levomepromazine”Farmacotherapeutisch Kompas (in Dutch). Retrieved 5 October 2016.
  4. Jump up to:a b Sivaraman P, Rattehalli RD, Jayaram MB (October 2010). “Levomepromazine for schizophrenia”The Cochrane Database of Systematic Reviews10 (10): CD007779. doi:10.1002/14651858.CD007779.pub2PMC 3283151PMID 20927765.
Clinical data
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
Only if clearly needed
Routes of
administration
Oral, seldom IM
Drug classTypical antipsychotic
ATC codeN05AA02 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability~50–60%
MetabolismHepatic
Elimination half-life~20 hours
ExcretionIn feces and urine (metabolites), unchanged drug only 1%
Identifiers
showIUPAC name
CAS Number60-99-1 
7104-38-3 (maleate),
1236-99-3 HCl)
PubChem CID72287
IUPHAR/BPS7603
DrugBankDB01403 
ChemSpider65239 
UNII9G0LAW7ATQ
KEGGD00403 
ChEBICHEBI:6838 
ChEMBLChEMBL1764 
CompTox Dashboard (EPA)DTXSID1023289 
ECHA InfoCard100.000.450 
Chemical and physical data
FormulaC19H24N2OS
Molar mass328.47 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (what is this?)  (verify)

///////////methotripremazine, L 36467, CL 39743, N05AA02, RP 7044, RP-7044, SK&F 5116, XP-03, XP03

O(c2cc1N(c3c(Sc1cc2)cccc3)C[C@H](C)CN(C)C)C

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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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