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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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Etosalamide, этосаламид , إيتوسالاميد , 依托柳胺 ,


img

Image result for Etosalamide

Etosalamide

ethosalamide

Cas 15302-15-5
Chemical Formula: C11H15NO3
Molecular Weight: 209.245

o-(2-Ethoxyethoxy)benzamide

1585
1PU994YJUH
этосаламид [Russian] [INN]
إيتوسالاميد [Arabic] [INN]
依托柳胺 [Chinese] [INN]

Etosalamide, also known as Ethosalamide, is an antipyretic and analgesics agent

SYN

str1

OR

str1

CAS:592-55-2, 2-Bromoethyl ethyl ether

Cas, 611-20-1, 2-Hydroxybenzonitrile

PATENT

DE 1013643

PATENT

GB 774635

PATENT

US2822391

78 – 79 MP

PAPER

Journal of Chemical and Engineering Data (1962), 7, 265-6

70 – 71.5 MP

PATENT

WO 2004003198

US 20100226943

/////////Etosalamideэтосаламид إيتوسالاميد 依托柳胺 ethosalamide

O=C(N)C1=CC=CC=C1OCCOCC

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KETOROLAC


KetorolacKetorolac.svg

Ketorolac

  • Molecular FormulaC15H13NO3
  • Average mass255.269 Da
1H-Pyrrolizine-1-carboxylic acid, 5-benzoyl-2,3-dihydro-
413572 [Beilstein]
5-(Phenylcarbonyl)-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
5-Benzoyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid
74103-06-3 [RN]
 Ketorolac
CAS Registry Number: 74103-06-3
CAS Name: 5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
Additional Names: 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid
Manufacturers’ Codes: RS-37619
Molecular Formula: C15H13NO3
Molecular Weight: 255.27
Percent Composition: C 70.58%, H 5.13%, N 5.49%, O 18.80%
Literature References: Prostaglandin biosynthesis inhibitor. Prepn and separation of isomers: BE 856681; J. M. Muchowski, A. F. Kluge, US 4089969 (both 1978 to Syntex). Alternate processes: J. M. Muchowski, R. Greenhouse, US 4347186 (1982 to Syntex); F. Franco et al., J. Org. Chem. 47, 1682 (1982); J. B. Doherty, US 4496741 (1985 to Merck & Co.). Absolute configuration: A. Guzman et al., J. Med. Chem. 29, 589 (1986). Structure-activity relationships: J. M. Muchowski et al., ibid. 28, 1037 (1985). Pharmacology and analgesic, anti-inflammatory profile of ketorolac and its tromethamine salt: W. H. Rooks et al., Agents Actions12, 684 (1982); eidem, Drugs Exp. Clin. Res. 11, 479 (1985). Clinical comparison with acetaminophen in post-operative pain: H. J. McQuay et al., Clin. Pharmacol. Ther. 39, 89 (1986).
Properties: Crystals from ethyl acetate + ether, mp 160-161°. uv max in methanol: 245, 312 nm (e 7080, 17400). pKa 3.49 ±0.02. LD50 orally in mice: ~200 mg/kg (Rooks).
Melting point: mp 160-161°
pKa: pKa 3.49 ±0.02
Absorption maximum: uv max in methanol: 245, 312 nm (e 7080, 17400)
Toxicity data: LD50 orally in mice: ~200 mg/kg (Rooks)
Derivative Type: (±)-Form tromethamine salt
CAS Registry Number: 74103-07-4
Trademarks: Acular (Allergan); Dolac (Syntex); Lixidol (Farmitalia); Tarasyn (Syntex); Toradol (Syntex); Toratex (Syntex)
Molecular Formula: C19H24N2O6
Molecular Weight: 376.40
Percent Composition: C 60.63%, H 6.43%, N 7.44%, O 25.50%
Derivative Type: (+)-Form
Properties: Crystals from hexane + ethyl acetate, mp 174° (Guzman); also reported as mp 154-156° (Muchowski, Kluge). [a]D+173° (c = 1 in methanol).
Melting point: mp 174° (Guzman); mp 154-156° (Muchowski, Kluge)
Optical Rotation: [a]D +173° (c = 1 in methanol)
Derivative Type: (-)-Form
Properties: Crystals from hexane + ethyl acetate, mp 169-170° (Guzman); also reported as mp 153-155° (Muchowski, Kluge). [a]D-176° (c = 1 in methanol).
Melting point: mp 169-170° (Guzman); mp 153-155° (Muchowski, Kluge)
Optical Rotation: [a]D -176° (c = 1 in methanol)
Therap-Cat: Analgesic; anti-inflammatory.
Keywords: Analgesic (Non-Narcotic); Anti-inflammatory (Nonsteroidal); Arylcarboxylic Acids.

Ketorolac, sold under the brand name Toradol among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain.[1]Specifically it is recommended for moderate to severe pain.[2] Recommended duration of treatment is less than six days.[1] It is used by mouth, by injection into a vein or muscle, and as eye drops.[1][2] Effects begin within an hour and last for up to eight hours.[1]

Common side effects include sleepiness, dizziness, abdominal pain, swelling, and nausea.[1] Serious side effects may include stomach bleedingkidney failureheart attacksbronchospasmheart failure, and anaphylaxis.[1] Use is not recommended during the last part of pregnancy or during breastfeeding.[1] Ketorolac works by blocking cyclooxygenase 1 and 2 (COX1 and COX2) thereby decreasing prostaglandins.[1][3]

Ketorolac was patented in 1976 and approved for medical use in 1989.[4][1] It is avaliable as a generic medication.[2] In the United Kingdom it costs the NHS less than a £ per injectable dose as of 2019.[2] In the United States the wholesale cost of this amount is about 1.50 USD.[5] In 2016 it was the 296th most prescribed medication in the United States with more than a million prescriptions.[6]

Medical uses

Ketorolac is used for short-term management of moderate to severe pain.[7]It is usually not prescribed for longer than five days.[8][9][10][11] Ketorolac is effective when administered with paracetamol to control pain in neonates because it does not depress respiration as do opioids.[12] Ketorolac is also an adjuvant to opioid medications and improves pain relief. It is also used to treat dysmenorrhea.[11] Ketorolac is used to treat idiopathic pericarditis, where it reduces inflammation.[13]

Ketorolac is used for short-term pain control not lasting longer than five days, and can be administered orally, by intramuscular injection, intravenously, and by nasal spray.[8] Ketorolac is initially administered by intramuscular injection or intravenously.[7] Oral therapy is only used as a continuation from the intramuscular or intravenous starting point.[8][12]

Ketorolac is used during eye surgery help with pain.[14] Ketorolac is effective in treating ocular itching.[15] The ketorolac ophthalmic formulation is associated with a decreased development of macular edema after cataract surgery and is more effective alone rather than as an opioid/ketorolac combination treatment.[16][17] Ketorolac has also been used to manage pain from corneal abrasions.[18]

During treatment with ketorolac, clinicians monitor for the manifestation of adverse effects and side effects. Lab tests, such as liver function tests, bleeding time, BUNserum creatinine and electrolyte levels are often used and help to identify potential complications.[8][9]

Contraindications

Ketorolac is contraindicated in those with hypersensitivity, allergies to the medication, cross-sensitivity to other NSAIDs, prior to surgery, history of peptic ulcer disease, gastrointestinal bleeding, alcohol intolerance, renal impairment, cerebrovascular bleeding, nasal polypsangioedema, and asthma.[8][9] Recommendations exist for cautious use of ketorolac in those who have experienced cardiovascular disease, myocardial infarction, stroke, heart failurecoagulation disorders, renal impairment, and hepatic impairment.[8][9]

Adverse effects

Though uncommon, potentially fatal adverse effects are strokemyocardial infarctionGI bleedingStevens-Johnson Syndrometoxic epidermal necrolysis and anaphylaxis. A less serious and more common (>10%) side effect is drowsiness. Infrequent (<1%) side effects are paresthesia, prolonged bleeding timeinjection site pain, purpurasweatingabnormal thinking, increased production of tearsedemapallordry mouthabnormal tasteurinary frequencyincreased liver enzymesitching and others. Ketorolac can cause premature constriction of the ductus arteriosis in an infant during the third trimester of pregnancy.[8][9] Platelet function is decreased related to the use of ketorolac.[19]

The practice of restricting treatment with ketorolac is due to its potential to cause kidney damage.[20]

Interactions

Ketorolac can interact with other medications. Probenecid can increase the probability of having an adverse reaction or experiencing a side effect when taken with ketorolac. Pentoxifylline can increase the risk of bleeding. When aspirin is taken at the same time as ketorolac, the effectiveness is decreased. Problematic GI effects are additive and become more likely if potassium supplements, aspirin, other NSAIDS, corticosteroids, or alcohol is taken at the same time. The effectiveness of antihypertensives and diuretics can be lowered. The use of ketorolac can increase serum lithium levels to the point of toxicity. Toxicity to methotrexate is more likely if ketorolac is taken at the same time. The risk of bleeding increases with the concurrent medications clopidogrelcefoperazonevalproic acidcefotetaneptifibatidetirofiban, and copidine. Anticoagulants and thrombolytic medications also increase the likelihood of bleeding. Medications used to treat cancer can interact with ketorolac along with radiation therapy. The risk of toxicity to the kidneys increases when ketorolac is taken with cyclosporine.[8][9]

Interactions with ketorolac exist with some herbal supplements. The use of Panax ginsengclovegingerarnicafeverfewdong quaichamomile, and Ginkgo biloba increases the risk of bleeding.[8][9]

Mechanism of action

The primary mechanism of action responsible for ketorolac’s anti-inflammatory, antipyretic and analgesic effects is the inhibition of prostaglandin synthesis by competitive blocking of the enzyme cyclooxygenase (COX). Ketorolac is a non-selective COX inhibitor.[21] Ketorolac has been assessed to be a relatively higher risk NSAID when compared to aceclofenac, celecoxib, and ibuprofen.[13] It is considered a first-generation NSAID.[19]

History

In the US, ketorolac was the only widely available intravenous NSAID for many years; an IV form of paracetemol, which is not an NSAID, became available in Europe in 2009 and then in the US.[12]

The Syntex company, of Palo Alto, California developed the ophthalmic solution Acular around 2006.[citation needed]

In 2007, there were concerns about the high incidence of reported side effects. This led to restriction in its dosage and maximum duration of use. In the UK, treatment was initiated only in a hospital, although this was not designed to exclude its use in prehospital care and mountain rescue settings.[7] Dosing guidelines were published at that time.[22]

Concerns over the high incidence of reported side effects with ketorolac trometamol led to its withdrawal (apart from the ophthalmic formulation) in several countries, while in others its permitted dosage and maximum duration of treatment have been reduced. From 1990 to 1993, 97 reactions with a fatal outcome were reported worldwide.[23]

The eye-drop formulation was approved by the FDA in 1992.[24] An intranasal formulation was approved by the FDA in 2010[25] for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level.

Synthesis

DOI: 10.1021/jo00348a014

Image result for Ketorolac SYNTHESIS

1H-Pyrrolizine-1-carboxylic acid, 2,3-dihydro-5-benzoyl-, (+-)-, could be produced through many synthetic methods.

Following is one of the reaction routes:

Synthesis of Ketorolac

2-Methylthiopyrrole (I) is benzoylated with N,N-dimethylbenzamide (II) to produce 5-benzoyl-2-methylthiopyrrole (III) in the presence of POCl3 in refluxing CH2Cl2, and the yielding product is condensed with spiro[2.5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione (IV) in the presence of NaH in DMF giving compound (V). The oxidation of (V) with m-chloroperbenzoic acid in CH2Cl2affords the sulfone (VI), which is submitted to methanolysis with methanol and HCl giving 1-(3,3-dimethoxycarbonylpropyl)-2-methanesulfonyl-5-benzoylpyrrole (VII). The cyclization of (VII) with NaH in DMF yields dimethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (VIII), which is finally hydrolyzed and decarboxylated with KOH in refluxing methanol.Compound (III) can be oxidized with m-chloroperbenzoic acid as before giving 2-methanesulfonyl-5-benzoylpyrrole (IX), which is then condensed with spiro compound (IV) as before to afford compound (VI), already obtained.

SYN

DE 2731678; ES 460706; ES 470214; FR 2358406; FR 2375234; GB 1554075

The condensation of dimethylacetone-1,3-dicarboxylate (X) with ethanolamine (XI) yields methyl 3-(methoxycarbonylmethyl)-3-(2-hydroxyethylamino)acrylate (XII), which is cyclized with bromoacetaldehyde diethylacetal (XIII) affording methyl 1-(2-hydroxyethyl)-3-methoxycarbonylpyrrol-2-acetate (XIV). Acylation of (XIV) with methanesulfonyl chloride (XV) and triethylamine in CH2Cl2 yields the corresponding mesylate (XVI), which by treatment with methyl iodide in refluxing acetonitrile is converted into methyl 1-(2-iodoethyl)-3-methoxycarbonylpyrrole-2-acetate (XVII). The cyclization of (XVII) with NaH in DMF yields dimethyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (XVIII), which is hydrolyzed with KOH in refluxing methanol – water to the corresponding diacid (XIX). Partial esterification of (XIX) with isopropanol and HCl gives isopropyl 1,2-dihydro-3H-7-carboxypyrrolo[1,2-a]pyrrole-1-carboxylate (XX), which is decarboxylated by heating at 270 C affording isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXI). Benzoylation of (XXI) with N,N-dimethylbenzamide (XXII) and POCl3 in refluxing CH2Cl2 yields isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXIII), which is finally hydrolyzed with K2CO3 or NaOH in methanol – water.

SYN2

The benzoylation of 2-methylthiopyrrole (I) with N,N-dimethylbenzamide (II) by means of POCl3 in refluxing CH2Cl2 gives 5-benzoyl-2-methylthiopyrrole (III), which is condensed with spiro[2.5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione (IV) by means of NaH in DMF yielding compound (V). The oxidation of (V) with m-chloroperbenzoic acid in CH2Cl2 affords the sulfone (VI), which is submitted to methanolysis with methanol and HCl giving 1-(3,3-dimethoxycarbonylpropyl)-2-methanesulfonyl-5-benzoylpyrrole (VII). The cyclization of (VII) with NaH in DMF yields dimethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (VIII), which is finally hydrolyzed and decarboxylated with KOH in refluxing methanol. Compound (III) can be oxidized with m-chloroperbenzoic acid as before giving 2-methanesulfonyl-5-benzoylpyrrole (IX), which is then condensed with spiro compound (IV) as before to afford compound (VI), already obtained.

References

  1. Jump up to:a b c d e f g h i “Ketorolac Tromethamine Monograph for Professionals”Drugs.com. American Society of Health-System Pharmacists. Retrieved 13 April 2019.
  2. Jump up to:a b c d British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 1144, 1302–1303. ISBN 9780857113382.
  3. ^ “DailyMed – ketorolac tromethamine tablet, film coated”dailymed.nlm.nih.gov. Retrieved 14 April 2019.
  4. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 521. ISBN 9783527607495.
  5. ^ “NADAC as of 2019-02-27”Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
  6. ^ “The Top 300 of 2019”clincalc.com. Retrieved 22 December 2018.
  7. Jump up to:a b c Mallinson, Tom (2017). “A review of ketorolac as a prehospital analgesic”Journal of Paramedic Practice9 (12): 522–526. doi:10.12968/jpar.2017.9.12.522. Retrieved 2 June 2018.
  8. Jump up to:a b c d e f g h i Vallerand, April H. (2017). Davis’s Drug Guide for Nurses. Philadelphia: F.A. Davis Company. p. 730. ISBN 9780803657052.
  9. Jump up to:a b c d e f g Physician’s Desk Reference 2017. Montvale, New Jersey: PDR, LLC. 2017. pp. S–474–5. ISBN 9781563638381.
  10. ^ “Ketorolac-tromethamine”The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  11. Jump up to:a b Henry, p. 291.
  12. Jump up to:a b c Martin, Lizabeth D; Jimenez, Nathalia; Lynn, Anne M (2017). “A review of perioperative anesthesia and analgesia for infants: updates and trends to watch”F1000Research6: 120. doi:10.12688/f1000research.10272.1ISSN 2046-1402PMC 5302152PMID 28232869.
  13. Jump up to:a b Schwier, Nicholas; Tran, Nicole (2016). “Non-Steroidal Anti-Inflammatory Drugs and Aspirin Therapy for the Treatment of Acute and Recurrent Idiopathic Pericarditis”Pharmaceuticals9 (2): 17. doi:10.3390/ph9020017ISSN 1424-8247PMC 4932535PMID 27023565.
  14. ^ Saenz-de-Viteri, Manuel; Gonzalez-Salinas, Roberto; Guarnieri, Adriano; Guiaro-Navarro, María Concepción (2016). “Patient considerations in cataract surgery – the role of combined therapy using phenylephrine and ketorolac”Patient Preference and Adherence10: 1795–1801. doi:10.2147/PPA.S90468ISSN 1177-889XPMC 5029911PMID 27695298.
  15. ^ Karch, Amy (2017). Focus on nursing pharmacology. Philadelphia: Wolters Kluwer. p. 272. ISBN 9781496318213.
  16. ^ Lim, Blanche X; Lim, Chris HL; Lim, Dawn K; Evans, Jennifer R; Bunce, Catey; Wormald, Richard; Wormald, Richard (2016). “Prophylactic non-steroidal anti-inflammatory drugs for the prevention of macular oedema after cataract surgery”Cochrane Database Syst Rev11: CD006683. doi:10.1002/14651858.CD006683.pub3PMID 27801522.
  17. ^ Sivaprasad, Sobha; Bunce, Catey; Crosby-Nwaobi, Roxanne; Sivaprasad, Sobha (2012). “Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery”. Cochrane Database Syst Rev (2): CD004239. doi:10.1002/14651858.CD004239.pub3PMID 22336801.
  18. ^ Wakai A, Lawrenson JG, Lawrenson AL, Wang Y, Brown MD, Quirke M, Ghandour O, McCormick R, Walsh CD, Amayem A, Lang E, Harrison N (2017). “Topical non-steroidal anti-inflammatory drugs for analgesia in traumatic corneal abrasions”. Cochrane Database Syst Rev5: CD009781. doi:10.1002/14651858.CD009781.pub2PMID 28516471.
  19. Jump up to:a b Henry, p. 279.
  20. ^ Henry, p. 280.
  21. ^ Lee, I. O.; Seo, Y. (2008). “The Effects of Intrathecal Cyclooxygenase-1, Cyclooxygenase-2, or Nonselective Inhibitors on Pain Behavior and Spinal Fos-Like Immunoreactivity”. Anesthesia & Analgesia106 (3): 972–977, table 977 contents. doi:10.1213/ane.0b013e318163f602PMID 18292448.
  22. ^ MHRA Drug Safety Update October 2007, Volume 1, Issue 3, pp 3-4.
  23. ^ Committee on the Safety of Medicines, Medicines Control Agency: Ketorolac: new restrictions on dose and duration of treatment. Current Problems in Pharmacovigilance:June 1993; Volume 19 (pages 5-8).
  24. ^ “Ketorolac ophthalmic medical facts from”. Drugs.com. Retrieved 2013-10-06.
  25. ^ “Sprix Information from”. Drugs.com. Retrieved 2013-10-06.

Bibliography

External links

Ketorolac
Ketorolac.svg
Ketorolac ball-and-stick.png
Clinical data
Trade names Toradol, Acular, Sprix, others
Synonyms Ketorolac tromethamine
AHFS/Drugs.com Monograph
MedlinePlus a693001
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration
By mouth, IMIV, eye drops
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 100% (All routes)
Metabolism Liver
Elimination half-life 3.5 h to 9.2 h, young adults;
4.7 h to 8.6 h, elderly (mean age 72)
Excretion Kidney: 91.4% (mean)
Biliary: 6.1% (mean)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.110.314 Edit this at Wikidata
Chemical and physical data
Formula C15H13NO3
Molar mass 255.27 g/mol g·mol−1
3D model (JSmol)
Chirality Racemic mixture

//////////Ketorolac,

Cefamandole, セファマンドール ,цефамандол , سيفاماندول , 头孢孟多 ,


Cefamandole

Cefamandole.svg

ChemSpider 2D Image | Cefamandole | C18H18N6O5S2

Image result for Cefamandole

Cefamandole

セファマンドール

цефамандол [Russian] [INN]
سيفاماندول [Arabic] [INN]
头孢孟多 [Chinese] [INN]
CAS Registry Number: 34444-01-4
CAS Name: (6R,7R)-7-[[(2R)-Hydroxyphenylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Additional Names: 7-mandelamido-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-D-mandelamido-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-3-cephem-4-carboxylic acid; 7-D-mandelamido-3-(1-methyl-1,2,3,4-tetrazole-5-thiomethyl)-D3-cephem-4-carboxylic acid; CMT
Manufacturers’ Codes: compd 83405
Molecular Formula: C18H18N6O5S2
Molecular Weight: 462.50
Percent Composition: C 46.74%, H 3.92%, N 18.17%, O 17.30%, S 13.87%
Literature References: Broad-spectrum semi-synthetic cephalosporin antibiotic. Prepn: C. W. Ryan, DE 2018600idem, US3641021 (1970, 1972 to Lilly); J. M. Greene, DE 2312997idem, US 3840531 (1973, 1974 to Lilly). Biological properties: W. E. Wick, D. A. Preston, Antimicrob. Agents Chemother. 1, 221 (1972). Antibacterial activity: S. Eykyn et al., ibid. 3, 657 (1973); H. C. Neu, ibid. 6, 177 (1974); A. D. Russell, J. Antimicrob. Chemother. 1, 97 (1975). Pharmacologic studies: B. R. Meyers et al.,Antimicrob. Agents Chemother. 9, 140 (1976); R. S. Griffith et al., ibid. 10, 814 (1976). Comprehensive description: R. H. Bishara, E. C. Rickard, Anal. Profiles Drug Subs. 9, 125-154 (1980).
Derivative Type: Nafate
CAS Registry Number: 42540-40-9
Trademarks: Bergacef (Bergamon); Cedol (Tiber); Cefam (Magis); Cefiran (Poli); Cemado (Francia); Cemandil (SIT); Fado (Errekappa); Kefadol (Lilly); Kefandol (Lilly); Lampomandol (AGIPS); Mandokef (Lilly); Mandol (Lilly); Mandolsan (San Carlo); Neocefal (Metapharma); Pavecef (IBP)
Molecular Formula: C19H17N6NaO6S2
Molecular Weight: 512.49
Percent Composition: C 44.53%, H 3.34%, N 16.40%, Na 4.49%, O 18.73%, S 12.51%
Properties: White, odorless needles, mp 190° (dec). uv max (H2O): 269 nm (e 10800). pKa 2.6-3.0. Sol in water, methanol. Practically insol in ether, chloroform, benzene, cyclohexane.
Melting point: mp 190° (dec)
pKa: pKa 2.6-3.0
Absorption maximum: uv max (H2O): 269 nm (e 10800)
Therap-Cat: Antibacterial.
Keywords: Antibacterial (Antibiotics); ?Lactams; Cephalosporins.
  • Use:antibiotic
  • Chemical name:[6R-[6α,7β(R*)]]-7-[(hydroxyphenylacetyl)amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  • Formula:C18H18N6O5S2
  • MW:462.51 g/mol
  • CAS-RN:34444-01-4
  • InChI Key:OLVCFLKTBJRLHI-AXAPSJFSSA-N
  • InChI:InChI=1S/C18H18N6O5S2/c1-23-18(20-21-22-23)31-8-10-7-30-16-11(15(27)24(16)12(10)17(28)29)19-14(26)13(25)9-5-3-2-4-6-9/h2-6,11,13,16,25H,7-8H2,1H3,(H,19,26)(H,28,29)/t11-,13-,16-/m1/s1
  • EINECS:252-030-0

Derivatives

Formate monosodium salt (nafate)

  • Formula:C19H17N6NaO6S2
  • MW:512.50 g/mol
  • CAS-RN:42540-40-9
  • EINECS:255-877-4
  • LD50:3915 mg/kg (M, i.v.);
    2562 mg/kg (R, i.v.)

Cefamandole (INN, also known as cephamandole) is a second-generation broad-spectrumcephalosporinantibiotic. The clinically used form of cefamandole is the formateestercefamandole nafate, a prodrug which is administered parenterally. Cefamandole is no longer available in the United States.

The chemical structure of cefamandole, like that of several other cephalosporins, contains an N-methylthiotetrazole (NMTT or 1-MTT) side chain. As the antibiotic is broken down in the body, it releases free NMTT, which can cause hypoprothrombinemia (likely due to inhibition of the enzymevitamin K epoxide reductase)(vitamin K supplement is recommended during therapy) and a reaction with ethanol similar to that produced by disulfiram (Antabuse), due to inhibition of aldehyde dehydrogenase.

Cefamandole has a broad spectrum of activity and can be used to treat bacterial infections of the skin, bones and joints, urinary tract, and lower respiratory tract. The following represents cefamandole MIC susceptibility data for a few medically significant microorganisms.

  • Escherichia coli: 0.12 – 400 μg/ml
  • Haemophilus influenzae: 0.06 – >16 μg/ml
  • Staphylococcus aureus: 0.1 – 12.5 μg/ml

[1]

CO2 is generated during the normal constitution of cefamandole and ceftazidime, potentially resulting in an explosive-like reaction in syringes.[2]

SYNTHESIS

US 3641021

US 3840531 US 3974153 US 3903278 US 2018600 US 2065621 DE 2018600 DE 2065621 DE 2730579

DE 2312997

Image result for Cefamandole

SYN

The formylation of 7-aminocephalosporanic acid (I) by the usual techniques produces 7-formamidocephalosporanic acid (II), which is then treated with the sodium salt of 1-methyl-1H-tetrazole-5-thiol (III) to yield 7-formamido-3-(1-methyl-1H-tetrazol-5-ylthio)methyl-3-cephem-4-carboxylic acid (IV). The resulting product (IV) is deformylated affording 7-amino-3-(1-methyl-1H-tetrazol-5-ylthio)methyl-3-cephem-4-carboxylic acid (V), which is finally acylated with anhydro-O-carboxymandelic acid (VI) using the usual techniques.

References

  1. ^ http://www.toku-e.com/Assets/MIC/Cefamandole%20sodium%20salt.pdf
  2. ^ Stork CM (2006). “Antibiotics, antifungals, and antivirals”. In Nelson LH, Flomenbaum N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA. Goldfrank’s toxicologic emergencies. New York: McGraw-Hill. p. 847. ISBN 0-07-143763-0. Retrieved 2009-07-03.
    • US 3 641 021 (Lilly; 8.2.1972; appl. 18.4.1969).
    • DE 2 018 600 (Lilly; appl. 17.4.1970; USA-prior. 18.4.1969).
    • DAS 2 065 621 (Lilly; appl. 17.4.1970; USA-prior. 18.4.1969).
    • US 3 840 531 (Lilly; 8.10.1974; appl. 21.3.1972).
    • US 3 903 278 (Smith Kline Corp.; 2.9.1975; prior. 4.11.1971).
    • DOS 2 730 579 (Pierrel S.p.A.; appl. 6.7.1977; GB-prior. 10.7.1976).
  • preparation and/or purification via the trimethylsilyl-derivatives:

    • DOS 2 711 095 (Lilly; appl. 14.3.1977; USA-prior. 17.3.1976).
  • purification:

    • US 4 115 644 (Lilly; 19.9.1978; appl. 19.9.1978).
    • DOS 2 839 670 (Lilly; appl. 12.9.1978; USA-prior. 19.9.1977).
  • crystalline sodium salt:

    • US 4 054 738 (Lilly; 18.10.1977; appl. 22.12.1975).
    • US 4 168 376 (Lilly; 18.9.1979; appl. 5.6.1978).
  • lithium salt:

    • GB 1 546 757 (Lilly; appl. 10.4.1975; valid from 7.4.1976).
  • O-formyl-derivative:

    • US 3 928 592 (Lilly; 23.12.1975; appl. 21.2.1974).
    • GB 1 493 676 (Lilly; appl. 20.2.1975; USA-prior. 22.2.1974).
    • GB 1 546 898 (Lilly; appl. 7.4.1976; USA-prior. 11.4.1975).
    • DOS 2 506 622 (Lilly; appl. 17.2.1975; USA-prior. 22.2.1974).
  • crystalline sodium salt of O-formylcefamandole:

    • US 4 006 138 (Lilly; 1.2.1977; appl. 11.4.1975).
  • complex of cefamandole sodium with 1,4-dioxane and water:

    • US 3 947 414 (Lilly; 30.3.1976; appl. 23.12.1974).
  • complex of cefamandole sodium with ethyl l-(–)-lactate:

    • US 3 947 415 (Lilly; 30.3.1976; appl. 23.12.1974).
Cefamandole
Cefamandole.svg
Clinical data
Trade names former Mandol
AHFS/Drugs.com Micromedex Detailed Consumer Information
MedlinePlus a601206
Pregnancy
category
Routes of
administration
Intramuscularintravenous
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
  • US: Discontinued
Pharmacokinetic data
Protein binding 75%
Elimination half-life 48 minutes
Excretion Mostly renal, as unchanged drug
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.047.285 Edit this at Wikidata
Chemical and physical data
Formula C18H18N6O5S2
Molar mass 462.505 g/mol g·mol−1
3D model (JSmol)
/////////////Cefamandole, セファマンドール  ,цефамандол سيفاماندول 头孢孟多 

Tegaserod, テガセロド


Tegaserod structure.svg

ChemSpider 2D Image | Tegaserod | C16H23N5O

Tegaserod

  • Molecular FormulaC16H23N5O
  • Average mass301.387 Da
  • テガセロド
145158-71-0 cas
HTF 919 / HTF-919 / SDZ HTF 919 / SDZ-HTF-919
N’-[(E)-[(5-methoxy-1H-indol-3-yl)methylidene]amino]-N-pentylguanidine
(2E)-2-[(5-Methoxy-1H-indol-3-yl)methylene]-N-pentylhydrazinecarboximidamide [ACD/IUPAC Name]
(2E)-2-[(5-methoxy-1H-indol-3-yl)methylidene]-N’-pentylhydrazinecarboximidamide
(2E)-2-[(5-methoxy-1H-indol-3-yl)methylidene]-N-pentylhydrazinecarboximidamide
145158-71-0 [RN]
7606
Hydrazinecarboximidamide, 2-[(5-methoxy-1H-indol-3-yl)methylene]-N-pentyl-, (2E)

Sundaram Venkataraman, Srinivasulu Gudipati, Brahmeshwararao Mandava Venkata Naga, Goverdhan Banda, Radhakrishna Singamsetty, “Process for preparing form I of tegaserod maleate.” U.S. Patent US20050272802, issued December 08, 2005.US20050272802

2D chemical structure of 189188-57-6

Tegaserod maleate [USAN]
189188-57-6

Tegaserod
CAS Registry Number: 145158-71-0
CAS Name: 2-[(5-Methoxy-1H-indol-3-yl)methylene]-N-pentylhydrazinecarboximidamide
Molecular Formula: C16H23N5O
Molecular Weight: 301.39
Percent Composition: C 63.76%, H 7.69%, N 23.24%, O 5.31%
Literature References: Selective serotonin 5HT4-receptor partial agonist. Prepn: R. K. A. Giger, H. Mattes, EP 505322eidem, US5510353 (1992, 1996 both to Sandoz); K.-H. Buchheit et al., J. Med. Chem. 38, 2331 (1995). Clinical pharmacology: S. Appel et al., Clin. Pharmacol. Ther. 62, 546 (1997); and pharmacokinetics: idem et al., J. Clin. Pharmacol. 37, 229 (1997). Clinical trial in irritable bowel syndrome: S. A. Müller-Lissner et al., Aliment. Pharmacol. Ther. 15, 1655 (2001); in female patients: J. Novick et al.,ibid. 16, 1877 (2002). Review of clinical efficacy: B. W. Jones et al., J. Clin. Pharm. Ther. 27, 343-352 (2002); of mechanism of action, efficacy and safety: M. Corsetti, J. Tack, Expert Opin. Pharmacother. 3, 1211-1218 (2002).
Properties: mp 155°.
Melting point: mp 155°
Derivative Type: Maleate
CAS Registry Number: 189188-57-6
Manufacturers’ Codes: SDZ-HTF-919
Trademarks: Zelmac (Novartis); Zelnorm (Novartis)
Molecular Formula: C16H23N5O.C4H4O4
Molecular Weight: 417.46
Percent Composition: C 57.54%, H 6.52%, N 16.78%, O 19.16%
Therap-Cat: Gastroprokinetic; in treatment of irritable bowel syndrome.
Keywords: Gastroprokinetic; Serotonin Receptor Agonist.

Tegaserod is a 5-HT4 agonist manufactured by Novartis and sold under the names Zelnorm and Zelmac for the management of irritable bowel syndrome and constipation.[1] Approved by the FDA in 2002, it was subsequently removed from the market in 2007 due to FDA concerns about possible adverse cardiovascular effects. Before then, it was the only drug approved by the United States Food and Drug Administration to help relieve the abdominal discomfort, bloating, and constipation associated with irritable bowel syndrome. Its use was also approved to treat chronic idiopathic constipation.[2]

In 2000, originator Novartis established an alliance with Bristol-Myers Squibb for the codevelopment and copromotion of tegaserod maleate, which is now available in more than 55 countries worldwide for the treatment of IBS with constipation. In 2015, Zelnorm was acquired by Sloan Pharma from Novartis.

Novartis’ brand name Zelnorm (tegaserod) had originally received approval from the US FDA in 2002 for the treatment of irritable bowel syndrome with constipation (IBS-C) [58]. It was, however, voluntarily withdrawn from widespread use in the US market in 2007 after concerns arose over the possibility that tegaserod could potentially cause dangerous cardiovascular events in patients [5,8]. Since then, closer evaluations of the original data suggesting such cardiovascular risk have resulted in the limited reintroduction or ‘re-approval’ of tegaserod for treatment of IBS-C specifically in female patients less than 65 years of age and whom are considered to be at a lower risk of a cardiovascular event than the broader population . Zelnorm (tegaserod) by Sloan Pharma subsequently gained re-approval in April of 2019 [5]. Nevertheless, tegaserod remains un-approved in certain regions [7].

Despite the relative complications involved in its history of regulatory approval, ever since its first introduction in 2002 tegaserod remains the only therapy for IBS-C that possesses the unique mechanism of action of acting on serotonin-4 (5-HT(4)) receptors in smooth muscle cells and in the gastrointestinal wall to facilitate actions like esophageal relaxation, peristaltic gut movement, and natural secretions in the gut, among others

Mechanism of action

The drug functions as a motility stimulant, achieving its desired therapeutic effects through activation of the 5-HT4 receptors of the enteric nervous system in the gastrointestinal tract. It also stimulates gastrointestinal motility and the peristaltic reflex, and allegedly reduces abdominal pain.[3] Additionally, tegaserod is a 5-HT2B receptor antagonist.[4]

Withdrawal from market

On 30 March 2007, the United States Food and Drug Administration requested that Novartis withdraw Zelnorm from shelves.[5] The FDA alleges a relationship between prescriptions of the drug and increased risks of heart attack or stroke. An analysis of data collected on over 18,000 patients demonstrated adverse cardiovascular events in 13 of 11,614 patients treated with Zelnorm (a rate of 0.11%) as compared with 1 of 7,031 patients treated with placebo (a rate of 0.01%). Novartis alleges all of the affected patients had preexisting cardiovascular disease or risk factors for such, and further alleges that no causal relationship between tegaserod use and cardiovascular events has been demonstrated.[6] On the same day as the FDA announcement, Novartis Pharmaceuticals Canada announced that it was suspending marketing and sales of the drug in Canada in response to a request from Health Canada.[7] In a large cohort study based on a US health insurance database, no increase in the risk of cardiovascular events were found under tegaserod treatment.[8] Currently, tegaserod may only be used in emergency situations only with prior authorization from the FDA.[9]

Paper

The serotonin 5-HT4 receptor. 2. Structure-activity studies of the indole carbazimidamide class of agonists
J Med Chem 1995, 38(13): 2331

https://pubs.acs.org/doi/abs/10.1021/jm00013a010

PATENT

US 5510353

WO 2005105740

WO 2007119109

WO 2007126889

CN 103467358

WO 2006116953

Syn

PATENT

https://patents.google.com/patent/US20090306170A1/en

Image result for tegaserod synthesis

  • In a preferred embodiment of the first aspect of the present invention, the process of preparing tegaserod or a salt thereof comprises the steps of:
    • (a) coupling S-methyl-isothiosemicarbazide or a salt thereof and 5-methoxy-indole-3-carboxaldehyde to form 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemicarbazide:
  • Figure US20090306170A1-20091210-C00002
  • and
    • (b) reacting the 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemicarbazide with n-pentyl amine to form tegaserod:
  • Figure US20090306170A1-20091210-C00003
  • [0013]
    The skilled person will appreciate that:
      • S-methyl-isothiosemicarbazide and salts thereof exist in two tautomeric forms:
  • Figure US20090306170A1-20091210-C00004
      • 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemicarbazide exists in four tautomeric forms:
  • Figure US20090306170A1-20091210-C00005
      • tegaserod exists in four tautomeric forms:
  • Figure US20090306170A1-20091210-C00006
  • [0017]
    It is to be understood that where tautomeric forms occur, the present invention embraces all tautomeric forms and their mixtures, i.e. although S-methyl-isothio-semicarbazide and 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemi-carbazide are mostly defined for convenience by reference to one isothiosemicarbazide form only, and although tegaserod is mostly defined for convenience by reference to one guanidino form only, the invention is not to be understood as being in any way limited by the particular nomenclature or graphical representation employed.
  • [0018]
    When an S-methyl-isothiosemicarbazide salt is used in the process of the present invention, this may be an acid addition salt with acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulfuric or phosphoric acid), or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene-2-sulfonic or camphorsulfonic acid) or amino acids (for example, ornithinic, glutamic or aspartic acid). Preferably the S-methyl-isothiosemicarbazide salt is a hydrohalide (such as the hydrofluoride, hydrochloride, hydrobromide, or hydroiodide) or a sulfonate (such as the methanesulfonate, benzenesulfonate, or p-toluenesulfonate). Preferably the S-methyl-isothiosemicarbazide salt is S-methyl-isothiosemicarbazide hydroiodide.
    • The following synthetic scheme demonstrates a preferred process of the present invention.
    • Figure US20090306170A1-20091210-C00007
    • [0032]
      The invention is now demonstrated by the following non-limiting illustrative example.

EXAMPLE Step 1: Schiff’s Base Formation of 5-methoxy-indole-3-carboxaldehyde and S-methyl-isothiosemi-carbazide hydroiodide

    • [0033]
      5-Methoxy-indole-3-carboxaldehyde (1.5 g, 1 eq) and S-methyl-isothiosemicarbazide hydroiodide (3.99 g, 2 eq) in methanol (15 ml, 10 vol) were stirred in the presence of triethylamine (3 ml, 2 vol) at 25-30° C. for 2 hours. After completion of the reaction, the methanol was removed by distillation under reduced pressure at 45-50° C. and ethyl acetate (10.5 ml, 7 vol) was added to the residue to precipitate out the product. The product, 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemi-carbazide, was separated by filtration, washed with ethyl acetate (3 ml, 2 vol) and dried under vacuum at 45-50° C. The yield was almost quantitative (˜100%).

Step 2: Conversion of 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemicarbazide to 1-((5-methoxy-1H-indol-3-yl)methyleneamino)-3-pentyl-guanidine (Tegaserod)

    • [0034]
      A solution of 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemicarbazide (8.0 g, 1 eq) and n-pentyl amine (2.65 g, 1 eq) was refluxed in methanol (8 ml, 1 vol) at 66° C. for 4 hours. After completion of the reaction, the methanol was removed by distillation under reduced pressure at 45-50° C. to obtain tegaserod free base as a yellowish brown solid. Yield=97%. HPLC purity=95%.

Step 3: Conversion of 1-((5-methoxy-1H-indol-3-yl)methyleneamino)-3-pentyl-guanidine (Tegaserod) to Tegaserod Maleate

  • [0035]
    1-((5-Methoxy-1H-indol-3-yl)methyleneamino)-3-pentyl-guanidine (55 g, 1 eq) was taken in methanol (357.5 ml, 6.5 vol) and stirred. To this reaction mixture was added at room temperature a solution of maleic acid (74.15 g, 3.5 eq) in water (137.5 ml, 2.5 vol) and the reaction mixture stirred for one hour at room temperature. The solid obtained was then filtered through a Buchner funnel and dried at 700 mmHg and 500° C. Yield=36.8 g, 48.42%. HPLC purity=99.45%.

Polymorphs

WO 2007084697

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007084697

EXAMPLES

PXRD:

EV 320 251 655 US Powder X-ray diffraction (“PXRD”) analysis using a SCINTAG powder X-ray diffϊactometer model X’TRA equipped with a solid-state detector. Copper radiation of λ=1.5418 A was used. The sample was introduced using a round standard aluminum sample holder with round zero background quartz plate in the bottom.
Thermal Gravimetric Analysis TTGA):
TGA/SDTA 85 r, Mettler Toledo , Sample weight 7-15 mg.
Heating rate: 100C/ min., in N2 stream: flow rate: 50 ml/min

Example 1 : Preparation of Tegaserod maleate Form B
To a mixture of 90 g MICHO and 63 g NaOH [47 %] was added a solution of 212 g AGPΗI dissolved in 566 mL of water at room temperature. The resultant reaction mixture was heated to 400C. After 3 hours, 522 mL of ethyl acetate was added and the reaction mixture was stirred for an additional hour. The organic phase was washed with water (3 x 450 mL), and vacuum filtered. After addition of 211 mL ethyl acetate and 870 mL of n-propanol, the mixture was heated to 600C and a solution of maleic acid (86.5 g in 180 mL water), at the same temperature, was added to the reaction mixture and stirred at the same temperature. After 2 hours the reaction mixture was cooled to about 100C and stirred for an additional hour. The resulting solid was filtered off, washed with n-propanol, and dried in a vacuum oven over night to give 195.8 g of tegaserod maleate Form B.

6
EV 320251 655 US

PATENT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=0DB6F8E3A17F95B3E74D6454382AF545.wapp1nC?docId=WO2007084761&tab=PCTDESCRIPTION&maxRec=1000

Tegaserod maleate is an aminoguanidine indole 5HT4 agonist for the treatment of irritable bowel syndrome (IBS). Tegaserod maleate has the following structure:

According to the prescribing information (Physician’s Desk Reference, 57th Ed., at Page 2339), tegaserod as the maleate salt is a white to off-white crystalline powder and is slightly soluble in ethanol and very slightly soluble in water. Tegaserod maleate is available commercially as ZELNORM®, in which it is present as crystalline form.
Tegaserod maleate is disclosed in US patent No. 5,510,353 and in its equivalent EP 0 505 322 (example 13), and is reported to have a melting point of 1900C (table 1 example 13).
The literature (Buchheit K.H, et al., J.Med.Chem., 1995, 38, 2331) describes a general method for the condensation of amino guanidines with indole-3-carbadehydes in methanol in the presence of HCl (pH 3-4). The product obtained after solvent evaporation maybe converted to its hydrochloride salt by treatment of the methanolic solution with diethylether/HCl followed by recrystallization from
methanol/diethylether. Tegaserod base prepared according to this general method is characterized solely by a melting point of 155 0C (table 3 compound 5b). Additional Tegaserod maleate characterization was done by 1H and 13C-NMR according to the literature (Jing J. et. al., Guangdong Weiliang Yuansu Kexue, 2002, 9/2, 51).
WO 04/085393 discloses four crystalline forms of tegaserod maleate. The search report for WO 04/085393 further identifies WO 00/10526, and Drugs Fut. 1999, 24(1) which provides an overview for tegaserod maleate. Additional crystalline forms of tegaserod maleate are provided in WO 2005/058819, one of which is characterized by an X-ray Diffraction pattern having peaks at 15.7, 16.9, 17.2, 24.1, 24.6 and 25.2±0.2 two theta (designated as Form B in that PCT publication).
The solid state physical properties of tegaserod salt may be influenced by controlling the conditions under which tegaserod salt is obtained in solid Form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient’s stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally- administered active ingredient may reach the patient’s bloodstream. The rate of dissolution is also a consideration in
formulating syrups, elixirs and other liquid medicaments. The solid state Form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic Form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic Form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and may be used to distinguish some polymorphic forms from others. A particular polymorphic Form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state C NMR spectrometry and infrared spectrometry.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
The polymorphic forms may further help in purification of tegaserod, particularly if they possess high crystallinity. In the event of metastability, a metastable polymorphic form may be used to prepare a more stable polymorph.
Hence, discovery of new polymorphic forms and new processes help in advancing a formulation scientist in preparation of tegaserod as an active pharmaceutical ingredient in a formulation.
The present invention provides an additional polymorphic form of a maleate salt of tegaserod.

Example 1 : Preparation of sesqui-tefiaserod maleate Foπn H2 through tegaserod base

To a mixture of AGPΗI (112.7 g) in 283 mL of water was added 5-MICHO (45 g) followed by NaOH (52.8 g, 47%) and stirred at room temperature. After three hours, 522 mL of ethyl acetate were added and the mixture stirred for an additional four hours. After phase separation at 400C the organic phase was washed with water (3 x 218 ml), and filtrated under vacuum. The resulting solution was heated to 60 0C and a solution of maleic acid (14.4 g) in 45 mL water was dropped during half hour, and the reaction mixture stirred at the same temperature for an additional two hours. The mixture was cooled to 100C during one hour, kept under stirring at the same temperature for 12 hrs and then filtered under vacuum. The wet product was washed twice with 65 ml of ethyl acetate and dried in a vacuum oven at 45°C for 16 hours to give 85% of the product.

Example 2: Preparation of sesqui-tegaserod maleate Form H2
45 gr MICHO were added to a 1 L reactor at RT. A solution of 112.7 gr of AGP HI and 283 ml water was added to the reactor. 52.8 gr of NaOH 47% were added to the mixture while stirring. The mixture was heated to 400C and stirred for 12 hrs. 522 ml of Ethyl Acetate were added and the mixture was stirred for 4 hrs.
After phase separation at 400C the organic phase was washed with water (3 x 218 ml), and filtrated under vacuum.
The mixture was heated to 600C and a mixture o 14.4 gr of Maleic Acid in 45 ml water was dropped during 5 min.
The mixture was stirred at 600C for 2 hrs.
The mixture was cooled to 100C during 1 hour, stirred at 100C for 13 hrs and then filtered under vacuum. The wet product was washed twice with 65 ml of n-Propanol. The wet product was dried in a vacuum oven at 45°C.
Yield: 71.2%

Example 3: Preparation of Tegaserod maleate Form B from Sesqui-tegaserod maleate Form H2
6.9 g of maleic acid were added to a slurry of Sesqui-Tegaserod maleate Form H2 (41.5 g) in 208 ml n-propanol at room temperature. The mixture was stirred for 5 hours at the same temperature, filtered and washed with n-propanol. After drying on vacuum oven at 450C for 15 hours the product was analyzed by XRD and found to be Form B (89% yield).

PATENT

https://patents.google.com/patent/WO2005058819A2/en

Figure imgf000010_0001
Figure imgf000011_0001
PATENT

 The formation of hydrazones is catalyzed by both general acids and general bases. General base catalysis of dehydration of the tetrahedral intermediate involves nitrogen deprotonation concerted with elimination of hydroxide ion as shown in the Scheme (Sayer J.M., et al. J. Am. Chem. Soc. 1973, 95, 4277). R fast O I H h° NH2R’ R- -NHR’ R R

Figure imgf000005_0001

In many cases, the equilibrium constant for their formation in aqueous solution is high. The additional stability may be attributed to the participation of the atom adjacent to the nitrogen in delocalized bonding. – + RRC = N – NH2 ~*→- RRC – N = NH2

In order to obtain only the maleic salt, the product when using an acid halide (HA) or other acids has to first be converted into the free base, before the addition of maleic acid (Path a), which results in an additional step to the synthesis. On the other hand, the reaction of the present invention in the presence of organic or inorganic base results in the formation of tegaserod free base which gives only the maleate salt after the addition of maleic acid (Path b).

Figure imgf000006_0001
Figure imgf000006_0002

TGS

Figure imgf000006_0003

TGS-MA

 EXAMPLES

HPLC method for detecting the level of the impurities:

Column: Atlantis dcl8(150*4.6),

Mobile phase: A.80% KH2PO4(0.02M) pH=5, 20% acetonitrile(ACN), B.100% ACN. Gradient: time 0= A: 100 B: 0, time 25 min= A:50%, B:50%, time 30 min= A:50%, B:50%, + 10 minutes of equilibration time. Wavelength= 225 nm

Sample concentration: 0.5 mg/mL

Temperature = 25°C

Example 1- Preparation of Tegaserod maleate in water with HCl.

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL water was added 5-MICHO (3.50 g, 0.02 mol) followed by HCl (37%) until pH 4. The mixture was heated to reflux for 1 hour and then cooled to room temperature. To the resulting slurry was added a solution of NaHCO3 (10%) until pH 9, and heated to 65°C for 20 minutes. After cooling, 100 mL of EtOAc were added, and the organic phase washed with water. A solution of maleic acid (3.48 g, 0.03 mol) in 100 mL EtOAc was added, and the resulting solid was filtered off and washed with EtOAc to give 6.27 g of crude tegaserod maleate with a purity of 99.70% (by HPLC).

Example 2- Preparation of Tegaserod maleate in water with HCl in two steps. a. Preparation of Tegaserod free base.

To a mixture of AGP-HI (163.3 g, 0.6 mol) in 375 mL water was added 5-MICHO (52.5 g, 0.3 mol) followed by HCl (37%) until pH 4. The mixture was heated to reflux for 1 hour and then cooled to room temperature. To the resulting slurry was added a liter of a solution of NaHCO (10%) until pH 9, and heated to 65 °C for one hour. After cooling, 1500 mL of EtOAc were added, and the organic phase washed with water. The remaining organic phase was evaporated to dryness to give tegaserod free base with a purity of 87.42 % (by HPLC). b. Preparation of Tegaserod maleate. To a solution of 2 g of tegaserod free base in MeOH was added a solution of maleic acid (1.28 g, 0.011 mol) in 10 mL MeOH. The resulting solid was filtered off and washed with MeOH to give 1.09 g of crude tegaserod maleate with a purity of 96.81 % (by HPLC).

Example 3- Preparation of Tegaserod maleate in water with TEA.

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 100 mL water was added 5-MICHO (3.50 g, 0.02 mol) followed by TEA (11.0 mL, 0.08 mol) and stirred at room temperature. After one hour, 25 mL of EtOAc was added, and the organic phase washed with water. A solution of maleic acid (3.48 g, 0.03 mol) in 100 mL EtOAc was added, and the resulting solid was filtered off and washed with EtOAc to give 7.92 g of crude tegaserod maleate with a purity of 94 % (by HPLC).

Example 4- Preparation of Tegaserod maleate in water with NaHCO3. To a mixture of AGP-HI (10.88 g, 0.04 mol) in 100 mL water was added 5-MICHO (3.50 g, 0.02 mol) followed by NaHCO3 (6.72 g, 0.08 mol) and heated to reflux for 1 hour. After cooling, 50 mL of EtOAc was added, and the organic phase washed with water. A solution of maleic acid (3.48 g, 0.03mol) in 100 mL EtOAc was added, and the resulting solid was filtered off and washed with EtOAc to give 6.71 g of crude tegaserod maleate with a purity of 98 % (by HPLC) .

Example 5- Preparation of Tegaserod maleate in water with NaHCO3 in two steps. a. Preparation of Tegaserod free base. To a mixture of AGP-HI (32.66 g, 0.12 mol) in 300 mL water was added 5-MICHO (10.51 g, 0.06 mol) followed by NaHCO3(20.16 g, 0.24 mol) and heated to reflux for 1 hour. After cooling, 150 mL of EtOAc was added, and the organic phase washed with water and evaporated to dryness to give 20.4 g of tegaserod free base (91.55%) purity by HPLC). b. Preparation of Tegaserod maleate.

To a solution of 2g of the resulting tegaserod free base in 8 mL MeOH was added a solution of maleic acid (1.28 g, 0.011 mol) in 5 mL MeOH. The resulting solid was filtered off and washed with MeOH to give 2.1 g of crude tegaserod maleate with a purity of 99.63 % (by HPLC).

Example 6- Preparation of Tegaserod maleate in water with Na2CO3. To a mixture of AGP-HI (10.88 g, 0.04 mol) in 100 mL water was added 5-MICHO (3.50 g, 0.02 mol) followed by Na2CO3 (4.24 g, 0.04 mol) and heated to reflux for 1 hour. After cooling, 50 mL of EtOAc was added, and the organic phase washed with water. A solution of maleic acid (3.48 g, 0.03 mol) in 100 mL EtOAc was added, and the resulting solid was filtered off and washed with EtOAc to give 6.48 g of crude tegaserod maleate with a purity of 98.2 % (by HPLC).

Example 7- Preparation of Tegaserod maleate in MeOH with TEA in two steps. a. Preparation of tegaserod free base

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL MeOH was added 5-MICHO (3.50 g, 0.02 mol) followed by triethylamine (11.0 mL, 0.08 mol). After 1 h at room temperature the mixture was evaporated to dryness, and washed with water, giving 5.79 g of tegaserod free base (86.90 % purity by HPLC). b. Preparation of tegaserod maleate

To a solution of 2 g of the resulting tegaserod free base in 10 mL MeOH was added a solution of maleic acid (1.16 g, 0.01 mol) in water. The resulting solid was filtrated and washed with water to give 1.45 g of crude tegaserod maleate as a white solid (94.60 % purity by HPLC). Crystallization in MeOH improved the purity to 98.94% by HPLC.

Example 8- Preparation of Tegaserod maleate in IPA with K2CO3.

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL IPA was added 5-MICHO (3.50 g, 0.02 mol) followed by K2CO3 (5.53g, 0.04 mol). After 22 h at room temperature the mixture was washed with brine. The organic phase was treated with a solution of maleic acid (3.48 g, 0.03 mol) in IPA. The resulting solid was filtrated and washed with IPA to give 3.26 g of a white solid (98.97% purity by HPLC).

Example 9- Preparation of Tegaserod maleate in TEA.

To a mixture of AGP-HI (10.88 g, 0.04 mol) and 5-MICHO (3.50 g, 0.02 mol) was added 11 mL of TEA (0.08 mol). After 2 h at room temperature 25 mL of EtOAc were added and the mixture was stirred for 1 h. The resulting solid was filtrated and washed with 25 mL EtOAc, to give 5.7 g of crude.

2 g of the residue was dissolved in 13 mL MeOH and treated with 7 mL of a solution of maleic acid (2.7 g, 0.023 mol) in water. The resulting solid was filtered and washed with water to give 1.5 g of tegaserod maleate (99.26 % purity by HPLC). Crystallization of the solid in MeOH improved the purity to 99.89%) by HPLC.

Example 10- Preparation of Tegaserod maleate in toluene/water with NaHCO3. a. Preparation of tegaserod free base To a mixture of AGP-HI (10.88 g, 0.04 mol) in 200 mL of water/toluene 1:1 was added 5-MICHO (3.50 g, 0.02 mol) followed by NaHCO3 (6.72 g, 0.08 mol) and heated to reflux for 1 hour. After cooling, the solid was filtrated out of the mixture and washed with water. After drying 6.25 g of tegaserod free base was obtained (93.8 % purity by HPLC). b. Preparation of tegaserod maleate To a solution of 3 g of the product in 10 mL MeOH was added a solution of maleic acid (2.31 g, 0.02 mol) in 10 mL water. The resulting solid was filtered off and washed with a solution of MeOH / water to give 2.50 g of crude tegaserod maleate with a purity of 96.6 % (by HPLC).

Example 11- Preparation of Tegaserod maleate in water with NaOH. a. Preparation of tegaserod free base

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL of water was added 5-MICHO (3.50 g, 0.02 mol) followed by NaOH (2 g, 0.05 mol) and stirred at room temperature. After 3 hours 50 mL of EtOAc was added, and the organic phase washed with water and evaporated to dryness to give 5.6 g of tegaserod free base (98.80% purity by HPLC). b. Preparation of Tegaserod maleate.

To a solution of 1.6 g of tegaserod free base in 15 mL ethyl acetate was added a solution of maleic acid (0.7 g, 0.006 mol) in 5 mL ethyl acetate. The resulting solid was filtered off and washed with ethyl acetate to give 1.65 g of crude tegaserod maleate, with a purity of 99.87 % (by HPLC)

Example 12- Preparation of Tegaserod maleate in water with maleic acid. To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL of water was added 5-MICHO (3.50 g, 0.02 mol) followed by maleic acid (9.3 g, 0.08 mol) and heated to reflux for 1 hour. After cooling, the solid was filtrated out of the mixture and washed with water. After drying 6.92 g of tegaserod maleate crude was obtained (92.4 % purity by HPLC).

Example 13- Preparation of Tegaserod maleate in methanol with maleic acid.

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL of methanol was added 5- MICHO (3.50 g, 0.02 mol) followed by maleic acid (9.29 g, 0.08 mol) and heated to reflux for 2 hours. After cooling, the solid was filtrated out of the mixture and washed with water. After drying 6.51 g of tegaserod maleate crude was obtained (97.4 % purity by HPLC).

Example 14- Preparation of Tegaserod maleate in water with NaOH in one pot. To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL of water was added 5-MICHO (3.50 g, 0.02 mol) followed by NaOH (2 g, 0.05 mol) and stirred at room temperature. After 4 hours a solution of maleic acid (4.35 g, 0.0375 mol) in 25 mL water was added, and the reaction mixture was stirred overnight. The resulting solid was filtered off and washed with water to give 7.87 g of crude tegaserod maleate (99.16% purity by HPLC).

Example 15- Preparation of Tegaserod maleate in water with NaOH in one pot.

To a mixture of AGP-HI (174.2 g, 0.64 mol) in 362 mL of water was added 5-MICHO (56.2 g, 0.32 mol) followed by NaOH (68.1 g, 47%) and stirred at room temperature. After 4.5 hours, 640 mL of EtOAc was added, and the organic phase washed with water, treated with active carbon and filtrated through hyper flow bed. A solution of maleic acid (44.57 g, 0.38 mol) in 415 mL ethyl acetate / water 97:3 was added, and the reaction mixture was heating to 65 °C and stirrer overnight. The resulting solid was filtered off and washed with water and ethyl acetate to give 121.4 g of crude tegaserod maleate (up to 99.88 % purity by HPLC).

Example 16- Preparation of Tegaserod maleate (from Tegaserod acetate).

To a solution of 8.2 g of tegaserod acetate in 15 mL ethyl acetate heated to 65 °C was added a solution of 3.3 g maleic acid in 5 ml ethyl acetate/water 95:5, and the mixture was stirred at the same temperature for an additional 2 hours, followed by cooling to room temperature and stirring overnight. The resulting solid was filtered off and washed with ethyl acetate/water 95:5. After drying on vacuum oven at 45 °C for 15 hours, 9.18 g of tegaserod maleate were obtained. Tegaserod acetate is prepared according to Examples 19, 20 and 21 of U.S. Appl. No. 11/015,875 and PCT/US04/42822.

Example 19 of U.S. Appl. No. 11/015,875 reads as follows: A slurry of tegaserod base amorphous (6 g) in 50 mL ethyl acetate was stirred at 20- 30 °C for 24 hours. The solid was filtrated and washed with 15 mL of same solvent and dried in a vacuum oven at 40 °C for 16 hours.

Example 20 of U.S. Appl. No. 11/015,875 reads as follows:

A slurry of tegaserod base amorphous (6 g) in 50 mL ethyl acetate was stirred at reflux for 24 hours. The solid was filtrated and washed with 15 mL of same solvent and dried in a vacuum oven at 40 °C for 16 hours.

Example 21 of U.S. Appl. No. 11/015,875 reads as follows:

To a slurry of tegaserod maleate Form A (15 g) in EtOAc (210 mL) and water (210 mL) was added 38.4 g of NaOH 47%. The mixture was stirred overnight and the resulting white solid was isolated by filtration and washed with 100 mL of water. Drying in vacuum oven at 40 °C for 16 hours gives 12.38 g (90% yield). Tegaserod acetate was characterized by H and C-NMR.

Example 17: General method for the preparation of Tegaserod maleate Form A from crystallization.

Tegaserod maleate (1 g) was combined with the appropriate solvent (5 mL), and heated to reflux. Then, additional solvent was added until complete dissolution. After the compound was dissolved, the oil bath was removed and the solution was cooled to room temperature. The solid was filtrated and washed with 5 mL of the same solvent and dried in a vacuum oven at 40 C for 16 hours.

Figure imgf000022_0001
Figure imgf000023_0001

Example 18: Preparation of Tegaserod maleate in water with p-TSOH.

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL water was added 5-MICHO (3.50 g, 0.02 mol) followed by para-toluenesulfonic acid monohydrate (0.45 g, 0.0024 mol). The mixture was heated to reflux for 4 hour and then cooled to room temperature. The resulting solid was filtered off and washed with water to give 8.32 g of a white solid (84.74 % purity by HPLC).

Example 19: Preparation of Tegaserod maleate from Tegaserod Hemi-maleate hemihydrate

To a solution of 1.72 g of Tegaserod Hemi-maleate hemihydrate in 20 mL ethyl acetate at room temperature was added a solution of 0.134 g maleic acid in 5 ml ethyl acetate/water 95:5, and the mixture was stirred at the same temperature for overnight. The resulting solid was filtered off and washed with ethyl acetate/water 95:5. After drying on vacuum oven at 45°C for 15 hours, 1.68 g of tegaserod maleate were obtained. Tegaserod Hemi-maleate hemihydrate was prepared according to Example 23 of U.S. Appl. No. 11/015,875 and PCT/US04/42822. Example 23 of U.S. Appl. No. 11/015,875 and PCT/US04/42822 reads as follows: A solution of maleic acid (2.32 g in 22 mL ethyl acetate/water 97:3) was added to a mixture of tegaserod base in ethyl acetate, and the reaction mixture was heated to 65 °C and stirrer overnight. The resulting solid was filtered off and washed with water and ethyl acetate. Drying in vacuum oven at 40 °C for 16 hours gives 12.19 g of Tegaserod hemi-maleate hemihydrate. Depending on the base polymorph used a solution or slurry is obtained. When using amorphous tegaserod base, a solution is obtained, while when using any other base polymorph of tegaserod, a slurry is obtained.

PATENT

https://patents.google.com/patent/WO2009063247A1/en

Tegaserod, chemically named 2-[(5-methoxy-liϊ-indol-3-yl)methylene]-IV-pentylhydrazine- carboximidamide, is a selective serotonin 4 (5-HT4) receptor agonist, which can be used to treat gastrointestinal disorders such as heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudoobstruction, irritable bowel syndrome and gastro-oesophageal reflux. Tegaserod as the maleate salt is marketed for the short-term treatment of irritable bowel syndrome in women whose primary bowel symptom is constipation.

Tegaserod, represented by the formula (I), was first described in US 5 510 353 as well as processes for its preparation. The maleate salt of tegaserod is also disclosed, but interestingly a method of manufacturing tegaserod maleate is not disclosed. The only characterizing data is the melting point which is disclosed as 1900C for the maleate salt and 124°C for the tegaserod base.

Figure imgf000002_0001

WO 2006/116953 describes crystalline forms of the hydrobromide, dihydrogen phosphate and oxalate salts of tegaserod. Also claimed is a process for preparing the hydrochloride, hydrobromide, dihydrogen phosphate, tartrate, citrate, lactate, mesylate, oxalate, succinate, glutarate, adipate, salicylate, sulfate, mandelate, camphor sulfonate and hydrogen sulfate salts of tegaserod from a specific crystalline form of tegaserod base. Another process described is a method of preparing the dihydrogen phosphate, maleate, tartrate, citrate, mesylate, lactate, succinate, oxalate, hydrochloride, salicylate, glutarate, adipate, hydrobromide, sulfate and hydrogen sulfate from a hydrogen halide salt of tegaserod.

There are often major hurdles to overcome before an active pharmaceutical ingredient (API) can be formulated into a composition that can be marketed. For example, the rate of dissolution of an API that has poor aqueous solubility is often problematic. The aqueous solubility is a major influence on the bioavailability of the API such that a poorly soluble API can mean the API is not available to have a pharmaceutical effect on the body. The API can also cause problems during manufacture of a pharmaceutical composition. For example, flowability, compactability and stickiness are all factors affected by the solid state properties of an API.

It has thus always been an aim of the pharmaceutical industry to provide many forms of an API in order to mitigate the problems described above. Different salts, crystalline forms also known as polymorphs, solvates and amorphous forms are all forms of an API that can have different physiochemical and biological characteristics. Indeed, it has been discovered that the tegaserod maleate product on the market, Zelnorm , has been linked to an increase in heart problems in a proportion of individuals. One possible reason is that the maleate moiety reacts with the tegaserod, resulting over time in the production of a toxic impurity.

This impurity could be a contributor to the heart problems seen in some patients.

PATENT

https://patents.google.com/patent/WO2004085393A1/en

Figure 1 is a x-ray powder diffraction pattern of tegaserod maleate Form I. Figure 2 is a x-ray powder diffraction pattern of tegaserod maleate Form II. Figure 3 is a x-ray powder diffraction pattern of tegaserod maleate Form III. Figure 4 is a x-ray powder diffraction pattern of tegaserod maleate Form IV. x-Ray powder diffraction spectrum was measured on a Siemens D5000 x- ray powder diffractometer having a copper-Kα radiation.

The following examples further illustrate the invention.

Example 1 Tegaserod free base (10 gm) is dissolved in acetone (100 ml). Maleic acid (4 gm) is added to the solution and the contents are maintained for 1 hour at 25°C. The separated solid is filtered to give 12.5 gm of tegaserod maleate Form I.

Example 2 Tegaserod maleate Form II (5 gm) and acetone (70 ml) are mixed and refluxed for 1 hour and cooled to 25°C and filtered to give 4.8 gm of tegaserod maleate Form I.

Example 3 Tegaserod maleate Form I (10 gm) is dissolved in methanol (100 ml). Acetonitrile (150 ml) is added to the solution and the contents are heated to reflux. The contents are then cooled to 25°C and maintained for 30 minutes. The separated crystals are collected by filtration to give 9 gm of tegaserod maleate Form II.

Example 4 Tegaserod free base (10 gm) is dissolved in methanol (100 ml) and maleic acid (4 gm) is added to the solution. Then the contents are maintained for 30 minutes at 25°C. Then the separated solid is filtered to give 13 gm of tegaserod maleate Form III.

Example 5

Tegaserod maleate (5 gm) is dissolved in methanol (50 ml) and the solution is maintained at 25°C for 30 minutes. The separated crystals are collected by filtration to give 4.8 gm of tegaserod maleate Form III. Example 6 Tegaserod free base (10 gm) is dissolved in methanol (50 ml), maleic acid (4 gm) is added and the contents are refluxed for 30 minutes and then the resulting solution is cooled to 25°C. Methylene dichloride (200 ml) is added and the contents are maintained for 30 minutes at 25°C. The separated solid is collected by filtration to give 13 gm of tegaserod maleate Form IV.

Example 7 Maleic acid (4 gm) is added to a solution of tegaserod free base (10 gm) in methanol (50 ml). The contents are maintained for 30 minutes at 25°C and isopropyl alcohol (150 ml) is mixed and contents are maintained for 30 minutes at 25°C. The separated solid is collected by filtration to give 12.5 gm of tegaserod maleate Form IV

CLIP

References

  1. ^ “New Data for Zelnorm”. Archived from the original on December 9, 2007. Retrieved March 30, 2007.
  2. ^ “FDA approves first treatment for women with irritable-bowel syndrome”. Archived from the original on February 5, 2007. Retrieved March 30, 2007.
  3. ^ Rossi, S. (2004). Australian Medicines Handbook. Adelaide: Health Communication Network. ISBN 0-9578521-4-2.
  4. ^ Beattie DT, Smith JA, Marquess D, et al. (November 2004). “The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo”Br. J. Pharmacol143 (5): 549–60. doi:10.1038/sj.bjp.0705929PMC 1575425PMID 15466450.
  5. ^ “FDA Announces Discontinued Marketing of GI Drug, Zelnorm, for Safety Reasons”. FDA Press Release. 30 March 2007.
  6. ^ “Zelnorm” (PDF)Novartis. Archived from the original (PDF) on 2007-04-10. Retrieved 2007-03-30.
  7. ^ “Novartis suspends Canadian marketing and sales of Zelnorm in response to request from Health Canada”. Retrieved 2007-03-30.
  8. ^ Loughlin J, Quinn S, Rivero E, Wong J, Huang J, Kralstein J, Earnest DL, Seeger JD (2010). “Tegaserod and the Risk of Cardiovascular Ischemic Events: An Observational Cohort Study”. J Cardiovasc Pharmacol Ther15 (2): 151–7. doi:10.1177/1074248409360357PMID 20200325.
  9. ^ http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103223.htm
  1. Beattie DT, Smith JA, Marquess D, Vickery RG, Armstrong SR, Pulido-Rios T, McCullough JL, Sandlund C, Richardson C, Mai N, Humphrey PP: The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo. Br J Pharmacol. 2004 Nov;143(5):549-60. Epub 2004 Oct 4. [PubMed:15466450]
  2. Talley NJ: Irritable bowel syndrome. Intern Med J. 2006 Nov;36(11):724-8. doi: 10.1111/j.1445-5994.2006.01217.x. [PubMed:17040359]
  3. Borman RA, Tilford NS, Harmer DW, Day N, Ellis ES, Sheldrick RL, Carey J, Coleman RA, Baxter GS: 5-HT(2B) receptors play a key role in mediating the excitatory effects of 5-HT in human colon in vitro. Br J Pharmacol. 2002 Mar;135(5):1144-51. doi: 10.1038/sj.bjp.0704571. [PubMed:11877320]
  4. Vickers AE, Zollinger M, Dannecker R, Tynes R, Heitz F, Fischer V: In vitro metabolism of tegaserod in human liver and intestine: assessment of drug interactions. Drug Metab Dispos. 2001 Oct;29(10):1269-76. [PubMed:11560869]
  5. FDA approves the reintroduction of Zelnorm™ (tegaserod) for Irritable Bowel Syndrome with Constipation (IBS-C) in women under 65 [Link]
  6. Tegaserod 2019 FDA Label [File]
  7. EMA Refusal Assessment Report for Zelnorm (Tegaserod) [File]
  8. FDA Joint Meeting of the Gastrointestinal Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee Briefing Document for Zelnorm (tegaserod maleate) [File]

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Tegaserod
Tegaserod structure.svg
Tegaserod ball-and-stick model.png
Clinical data
Trade names Zelnorm, Zelmac
AHFS/Drugs.com Monograph
Pregnancy
category
  • AU: B3
  • US: B (No risk in non-human studies)
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • US: Usage requires authorization from the FDA
Pharmacokinetic data
Bioavailability 10%
Protein binding 98%
Metabolism Gastric and hepatic
Elimination half-life 11 ± 5 hours
Excretion Fecal and renal
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C16H23N5O
Molar mass 301.39 g/mol g·mol−1
3D model (JSmol)

References

    • Buchheit, K.-H. et al.: J. Med. Chem. (JMCMAR) 38, 2331 (1995).
    • US 5 510 353 (Novartis; 23.4.1996; GB-prior. 22.3.1991).
    • EP 505 322 (Sandoz; GB-prior. 22.3.1991).
  • Preparation of 5-methoxyindole:

    • Tsuji, Y. et al.: J. Org. Chem. (JOCEAH) 55 (2), 580 (1990).
    • Jones, G.B. et al.: J. Org. Chem. (JOCEAH) 58 (20), 5558 (1993).
    • Kondo, Y. et al.: J. Org. Chem. (JOCEAH) 62 (19), 6507 (1997).
    • JP 3 024 055 (Kawaken Fine Chemicals; 1.2.1991; J-prior. 21.6.1989).

/////////Tegaserod, HTF 919,  HTF-919SDZ HTF 919SDZ-HTF-919, テガセロド  , Sloan Pharma,  Novartis,
CCCCCNC(=N)N\N=C\C1=CNC2=C1C=C(OC)C=C2

BMS 986236


JXMPVWXEDGELMJ-UHFFFAOYSA-N.png

BMS-986236

CAS  2058035-15-5

MW C22 H25 N9 O

MF 431.49

1-(5-(4-(3-Hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile

1H-Pyrazolo[3,4-b]pyridine-5-carbonitrile, 1-[5-[4-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl]-4-[(1-methylethyl)amino]-2-pyridinyl]-

1-[5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]-4-(propan-2-ylamino)pyridin-2-yl]pyrazolo[3,4-b]pyridine-5-carbonitrile

The present invention generally relates to heteroaryl substituted aminopyridine compounds useful as kinase inhibitors, including the modulation of IRAK-4. Provided herein are heteroaryl substituted aminopyridine compounds, compositions comprising such compounds, and methods of their use. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to kinase modulation and methods of inhibiting the activity of kinases, including IRAK-4 in a mammal.
      Toll/IL-1 receptor family members are important regulators of inflammation and host resistance. The Toll like receptor (TLR) family recognizes molecular patterns derived from infectious organisms including bacteria, fungi, parasites, and viruses (reviewed in Kawai, T. et al., Nature Immunol., 11:373-384 (2010)). Ligand binding to the receptor induces dimerization and recruitment of adaptor molecules to a conserved cytoplasmic motif in the receptor termed the Toll/IL-1 receptor (TIR) domain. With the exception of TLR3, all TLRs recruit the adaptor molecule MyD88. The IL-1 receptor family also contains a cytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewed in Sims, J. E. et al., Nature Rev. Immunol., 10:89-102 (2010)).
      Members of the IRAK family of serine/threonine kinases are recruited to the receptor via interactions with MyD88. The family consists of four members. Several lines of evidence indicate that IRAK4 plays a critical and non-redundant role in initiating signaling via MyD88 dependent TLRs and IL-1R family members. Structural data confirms that IRAK4 directly interacts with MyD88 and subsequently recruits either IRAK1 or IRAK2 to the receptor complex to facilitate downstream signaling (Lin, S. et al., Nature, 465:885-890 (2010)). IRAK4 directly phosphorylates IRAK1 to facilitate downstream signaling to the E3 ubiquitin ligase TRAF6, resulting in activation of the serine/threonine kinase TAK1 with subsequent activation of the NFκB pathway and MAPK cascade (Flannery, S. et al., Biochem. Pharmacol., 80:1981-1991 (2010)). A subset of human patients was identified who lack IRAK4 expression (Picard, C. et al.,Science, 299:2076-2079 (2003)). Cells from these patients fail to respond to all TLR agonists with the exception of TLR3 as well as to members of the IL-1 family including IL-113 and IL-18 (Ku, C. et al., J. Exp. Med., 204:2407-2422 (2007)). Deletion of IRAK4 in mice results in a severe block in IL-1, IL-18 and all TLR dependent responses with the exception of TLR3 (Suzuki, N. et al., Nature, 416:750-754 (2002)). In contrast, deletion of either IRAK1 (Thomas, J. A. et al., J. Immunol., 163:978-984 (1999); Swantek, J. L. et al., J. Immunol., 164:4301-4306 (2000) or IRAK2 (Wan, Y. et al., J. Biol. Chem., 284:10367-10375 (2009)) results in partial loss of signaling. Furthermore, IRAK4 is the only member of the IRAK family whose kinase activity has been shown to be required for initiation of signaling. Replacement of wild type IRAK4 in the mouse genome with a kinase inactive mutant (KDKI) impairs signaling via all MyD88 dependent receptors including IL-1, IL-18 and all TLRs with the exception of TLR3 (Koziczak-Holbro, M. et al., J. Biol. Chem., 282:13552-13560 (2007); Kawagoe, T. et al., J. Exp. Med., 204:1013-1024 (2007); and Fraczek, J. et al., J. Biol. Chem., 283:31697-31705 (2008)).
      As compared to wild type animals, IRAK4 KDKI mice show greatly reduced disease severity in mouse models of multiple sclerosis (Staschke, K. A. et al., J. Immunol., 183:568-577 (2009)), rheumatoid arthritis (Koziczak-Holbro, M. et al., Arthritis Rheum., 60:1661-1671 (2009)), atherosclerosis (Kim, T. W. et al., J. Immunol., 186:2871-2880 (2011) and Rekhter, M. et al., Biochem. Biophys. Res. Comm., 367:642-648 (2008)), and myocardial infarction (Maekawa, Y. et al., Circulation, 120:1401-1414 (2009)). As described, IRAK4 inhibitors will block all MyD88 dependent signaling. MyD88 dependent TLRs have been shown to contribute to the pathogenesis of multiple sclerosis, rheumatoid arthritis, cardiovascular disease, metabolic syndrome, sepsis, systemic lupus erythematosus, inflammatory bowel diseases including Crohn’s disease and ulcerative colitis, autoimmune uveitis, asthma, allergy, type I diabetes, and allograft rejection (Keogh, B. et al., Trends Pharmacol. Sci., 32:435-442 (2011); Mann, D. L., Circ. Res., 108:1133-1145 (2011); Horton, C. G. et al., Mediators Inflamm., Article ID 498980 (2010), doi:10.1155/2010/498980; Goldstein, D. R. et al., J Heart Lung Transplant., 24:1721-1729 (2005); and Cario, E., Inflamm. Bowel Dis., 16:1583-1597 (2010)). Oncogenically active MyD88 mutations in diffuse large B cell lymphomas have been identified that are sensitive to IRAK4 inhibition (Ngo, V. N. et al., Nature, 470:115-121 (2011)). Whole genome sequencing also identified mutations in MyD88 associated with chronic lymphatic leukemia suggesting that IRAK4 inhibitors may also have utility in treating leukemia (Puente, X. S. et al., Nature, 475:101-105 (2011)).
      In addition to blocking TLR signaling, IRAK4 inhibitors will also block signaling by members of the IL-1 family. Neutralization of IL-1 has been shown to be efficacious in multiple diseases including gout; gouty arthritis; type 2 diabetes; auto-inflammatory diseases including Cryopyrin-Associated Periodic Syndromes (CAPS), TNF Receptor Associated Periodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), adult onset stills; systemic onset juvenile idiopathic arthritis; stroke; Graft-versus-Host Disease (GVHD); smoldering multiple myeloma; recurrent pericarditis; osteoarthritis; emphysema (Dinarello, C. A., Eur. J. Immunol., 41:1203-1217 (2011) and Couillin, I. et al., J Immunol., 183:8195-8202 (2009)). In a mouse model of Alzheimer’s disease, blockade of IL-1 receptor improved cognitive defects, attenuated tau pathology and reduced oligomeric forms of amyloid-β (Kitazawa, M. et al., J. Immunol., 187:6539-6549 (2011)). IL-1 has also been shown to be a critical link to adaptive immunity, driving differentiation of the TH17 effector T cell subset (Chung, Y. et al., Immunity, 30:576-587 (2009)). Therefore, IRAK4 inhibitors are predicted to have efficacy in TH17 associated diseases including multiple sclerosis, psoriasis, inflammatory bowel diseases, autoimmune uveitis, and rheumatoid arthritis (Wilke, C. M. et al., Trends Immunol., 32:603-661 (2011)).
      WO2013/106612, WO2013/106614, WO2013/106641, WO2014/074657, and WO2014/074675 disclose substituted pyridyl compounds useful as kinase inhibitors, including the modulation of IRAK4.
      In view of the conditions that may benefit by treatment involving modulation of protein kinases, it is immediately apparent that new compounds capable of modulating protein kinases such as IRAK-4 and methods of using these compounds could provide substantial therapeutic benefits to a wide variety of patients.
      The present invention relates to a new class of heteroaryl substituted aminopyridine compounds found to be effective inhibitors of protein kinases including IRAK-4. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.

PATENT

US2018186799

https://patentscope.wipo.int/search/en/detail.jsf?docId=US222843237&tab=PCTDESCRIPTION&maxRec=1000

 (MOL) (CDX)

PATENT

Gardner, D. S.Santella, J. B.Paidi, V. R.Wu, H.Duncia, J. V.Nair, S. K.Hynes, J. (BMS, USA). Heteroaryl Substituted Aminopyridine Compounds. PCT Int. Appl. WO/2016/210034 A12016.

https://patents.google.com/patent/WO2016210034A1/en

Clip

https://pubs.acs.org/doi/10.1021/acs.oprd.9b00023

Development of a Scalable Synthesis for the Potent Kinase Inhibitor BMS-986236; 1-(5-(4-(3-Hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile

 Department of Discovery SynthesisBiocon Bristol-Myers Squibb Research CenterBiocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore-560 099, India
 Discovery ChemistryBristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-4000, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.9b00023
Abstract Image

A scalable route to 1-(5-(4-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (1BMS-986236) was developed by incorporating an alternate azide intermediate following safety-driven processes. The newly developed process involved mitigating safety hazards and eliminating the column chromatography purification. The issue of trace metal contamination in the final API observed in the first-generation synthesis has been overcome.

1 (92.5 g, 73% yield, 99.5% purity by HPLC) as a cream-colored solid.

1H NMR (400 MHz, DMSO-d6) δ = 9.21–8.86 (m, 2H), 8.66 (s, 1H), 8.45–8.24 (m, 2H), 7.49 (s, 1H), 6.57 (d, J = 7.5 Hz, 1H), 4.33 (s, 1H), 3.83 (d, J = 7.0 Hz, 1H), 2.91–2.72 (m, 2H), 1.97–1.68 (m, 2H), 1.24 (d, J = 6.5 Hz, 12H).

13C NMR (100 MHz, DMSO) δ = 151.7, 150.8, 149.8, 147.9, 147.7, 143.7, 136.8, 136.3, 122.9, 118.9, 117.6, 116.0, 102.8, 99.4, 68.4, 43.6, 42.7, 29.2, 21.7, 20.2.

HRMS [M + H]+ calcd for C22H25N9O 432.2255, found 432.2259.

//////// BMS-986236, BMS 986236

CC(C)(O)CCc1cn(nn1)c2cnc(cc2NC(C)C)n4ncc3cc(cnc34)C#N

Acefylline


Acefylline

Skeletal formula of acefylline

Acefylline

  • Molecular FormulaC9H10N4O4
  • Average mass238.200 Da
(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetic acid
1,2,3,6-Tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-acetic Acid
1,3-Dimethylxanthine-7-acetic acid
211-490-2 [EINECS]
652-37-9 [RN]
7-(Carboxymethyl)theophylline
7H-Purine-7-acetic acid, 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-
CAS Registry Number: 652-37-9
CAS Name: 1,2,3,6-Tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-acetic acid
Additional Names: carboxymethyltheophylline; 7-theophyllineacetic acid
Molecular Formula: C9H10N4O4
Molecular Weight: 238.20
Percent Composition: C 45.38%, H 4.23%, N 23.52%, O 26.87%
Literature References: Prepn: DE 352980 (1922 to E. Merck); Frdl. 14, 1320; S. M. Ride et al., Pharmazie 32, 672 (1977). Prepn of salts: J. Baisse, Bull. Soc. Chim. Fr. 1949, 769; M. Milletti, F. Virgili, Chimica 6, 394 (1951), C.A. 46, 8615h (1952). GC determn in urine: J. Zuidema, H. Hilbers, J. Chromatogr. 182, 445 (1980). HPLC determn in serum and pharmacokinetics: S. Sved et al.,Biopharm. Drug Dispos. 2, 177 (1981).
Properties: Crystals from water, mp 271°.
Melting point: mp 271°
Derivative Type: Sodium salt
CAS Registry Number: 837-27-4
Molecular Formula: C9H9N4NaO4
Molecular Weight: 260.18
Percent Composition: C 41.55%, H 3.49%, N 21.53%, Na 8.84%, O 24.60%
Properties: Silky needles, mp >300°.
Melting point: mp >300°
Derivative Type: Compd with piperazine
Additional Names: Acefylline piperazine; acepifylline
Trademarks: Dynaphylline (Welcker-Lyster); Etaphylline (Delalande); Etafillina (Delalande)
Properties: Undefined mixture of the 1:1 and 2:1 salts; contains 75-78% theophylline acetic acid and 22-25% anhydrous piperazine.
Therap-Cat: Bronchodilator.
Keywords: Bronchodilator; Xanthine Derivatives.

Acefylline (INN),[1] also known as acetyloxytheophylline, is a stimulant drug of the xanthine chemical class. It acts as an adenosine receptor antagonist. It is combined with diphenhydramine in the pharmaceutical preparation etanautine to help offset diphenhydramine induced drowsiness.[2]

Synthesis

DE 352980 (1922 to E. Merck); Frdl. 14, 1320; S. M. Ride et al., Pharmazie 32, 672 (1977).

File:Acefylline synthesis.svg

Acefylline

  • Use:cardiotonic, diuretic, antispasmodic, bronchodilator
  • Chemical name:1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-acetic acid
  • Formula:C9H10N4O4
  • MW:238.20 g/mol
  • CAS-RN:652-37-9
  • EINECS:211-490-2
  • LD50:1180 mg/kg (M, i.p.); 2733 mg/kg (M, p.o.)
Acepifylline
  • Use:
  • Chemical name:1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-acetic acid compd. with piperazine
  • Formula:C9H10N4O4 • xC4H10N2
  • MW:unspecified
  • CAS-RN:18833-13-1
  • EINECS:242-614-3
Acefylline heptaminol
  • Use:
  • Chemical name:1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-acetic acid compd. with 6-amino-2-methyl-2-heptaminol (1:1)
  • Formula:C9H10N4O3 • C8H19NO
  • MW:367.45 g/mol
  • CAS-RN:59989-20-7
  • EINECS:262-012-4
References
  1. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 21” (PDF). World Health Organization. Retrieved 29 December 2016.
  2. ^ Zuidema, Jan. (1978). “Biofarmaceutische en farmacokinetische aspecten van theofylline en acefylline”. Thesis (doctoral)–Universiteit van Amsterdam. References
Baisse, J.: Bull. Soc. Chim. Fr. (BSCFAS) 1949, 769.
DE 352 980 (E. Merck; 1922).
Acefylline
Skeletal formula of acefylline
Ball-and-stick model of the acefylline molecule
Clinical data
ATC code
Identifiers
CAS Number
PubChemCID
ChemSpider
UNII
ChEMBL
ECHA InfoCard 100.010.447 Edit this at Wikidata
Chemical and physical data
Formula C9H10N4O4
Molar mass 238.20 g/mol g·mol−1
3D model (JSmol)

////////Acefylline

DESLORATADINE, デスロラタジン


Desloratadine.svg

Desloratadine

  • Molecular FormulaC19H19ClN2
  • Average mass310.821 Da
100643-71-8 [RN]
5H-Benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-(4-piperidinylidene)-
7817
Desloratadine, Descarboethoxyloratadine, Sch-34117, DCL, Denosin, Clarinex RediTabs, Allex, Desalex, Opulis, Clarinex, Neoclarityn, Aerius, MK-4117

Desloratadine (trade name Clarinex and Aerius) is a tricyclic H1-antihistamine that is used to treat allergies. It is an active metaboliteof loratadine.

It was patented in 1984 and came into medical use in 2001.[1]

Medical uses

Desloratadine is used to treat allergic rhinitisnasal congestion and chronic idiopathic urticaria (hives).[2] It is the major metabolite of loratadine and the two drugs are similar in safety and effectiveness.[2] Desloratadine is available in many dosage forms and under many trade names worldwide.[3]

An emerging indication for desloratadine is in the treatment of acne, as an inexpensive adjuvant to isotretinoin and possibly as maintenance therapy or monotherapy.[4][5]

Side effects

The most common side-effects are fatiguedry mouth, and headache.[2]

Interactions

A number of drugs and other substances that are prone to interactions, such as ketoconazoleerythromycin and grapefruit juice, have shown no influence on desloratadine concentrations in the body. Desloratadine is judged to have a low potential for interactions.[6]

Pharmacology

Pharmacodynamics

Desloratadine is a selective H1antihistamine which functions as an inverse agonist at the histamine H1 receptor.[7]

At very high doses, is also an antagonist at various subtypes of the muscarinic acetylcholine receptors. This effect is not relevant for the drug’s action at therapeutic doses.[8]

Pharmacokinetics

Desloratadine is well absorbed from the gut and reaches highest blood plasma concentrations after about three hours. In the bloodstream, 83 to 87% of the substance are bound to plasma proteins.[6]

Desloratadine is metabolized to 3-hydroxydesloratadine in a three-step sequence in normal metabolizers. First, n-glucuronidation of desloratadine by UGT2B10; then, 3-hydroxylation of desloratadine N-glucuronide by CYP2C8; and finally, a non-enzymatic deconjugation of 3-hydroxydesloratadine N-glucuronide.[9] Both desloratadine and 3-hydroxydesloratadine are eliminated via urine and feces with a half-life of 27 hours in normal metabolizers.[6][10]

3-Hydroxydesloratadine, the main metabolite

It exhibits only peripheral activity since it does not readily cross the blood-brain barrier; hence, it does not normally cause drowsiness because it does not readily enter the central nervous system.[11]

Desloratadine does not have a strong effect on a number of tested enzymes in the cytochrome P450 system. It was found to weakly inhibit CYP2B6CYP2D6, and CYP3A4/CYP3A5, and not to inhibit CYP1A2CYP2C8CYP2C9, or CYP2C19. Desloratadine was found to be a potent and relatively selective inhibitor of UGT2B10, a weak to moderate inhibitor of UGT2B17UGT1A10, and UGT2B4, and not to inhibit UGT1A1UGT1A3UGT1A4UGT1A6UGT1A9UGT2B7UGT2B15UGT1A7, and UGT1A8.[9]

Pharmacogenomics

2% of Caucasian people and 18% of people from African descent are desloratadine poor metabolizers. In these people, the drug reaches threefold highest plasma concentrations six to seven hours after intake, and has a half-life of about 89 hours. However, the safety profile for these subjects is not worse than for extensive (normal) metabolizers.[6][10]

Clip

https://www.beilstein-journals.org/bjoc/articles/9/265

The value of substituted 3-picoline precursors is illustrated in the synthesis of clarinex (1.22, Desloratadine, Scheme 5), a dual antagonist of platelet activating factor (PAF) and of histamine used in the treatment of allergies. This compound consists of a highly functional tricyclic core with an unsaturated linkage to a pendant piperidine ring. The picoline derivative 1.23 is first treated with two equivalents of n-butyllithium (n-BuLi) followed by alkylation with benzyl chloride to give the chain elongated adduct [27]. The tert-butylamide 1.24 is then dehydrated with phosphorous oxychloride at elevated temperatures to yield the nitrile derivative 1.25. Introduction of the piperidine ring is achieved by utilisation of the appropriately substituted Grignard reagent 1.26. A Friedel–Crafts type acylation promoted by either triflic acid or polyphosphoric acid (PPA) furnishes the tricyclic structure 1.28 which upon N-demethylation affords clarinex (1.22).

CLIP

Image result for desloratadine

FTIR

Image result for desloratadine

SYN

Alcoholysis of 3-methylpyridine-2-carbonitrile (I) with hot tert-butanol and H2SO4 gives the N-tert-butylcarboxamide (II), which is alkylated with 3-chlorobenzyl chloride (III) and BuLi in THF, yielding N-tert-butyl-3-[2-(3-chlorophenyl)ethyl]pyridine-2-carboxamide (IV). The reaction of (IV) with refluxing POCl3 and then with NaOH affords the corresponding nitrile (V), which is condensed with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF to give the ketone (VII). Cyclization of (VII) by means of either BF3 in HF or trifluoromethanesulfonic acid yields 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII), which is reacted with cyanogen bromide in benzene to give the N-cyano compound (IX). Finally, this compound is treated with HCl in refluxing acetic acid/water. Alternatively, 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII) is treated with ethyl chloroformate in hot toluene, affording the carbamate (X) (2), which is finally decarboxylated with KOH or NaOH in refluxing ethanol/water.

SYN

Condensation of ethyl nicotinate (XI) with 3-chlorophenylacetonitrile (XII) by means of sodium ethoxide in ethanol gives 2-(3-chlorophenyl)-3-oxo-3-(3-pyridyl)propionitrile (XIII), which by refluxing with concentrated HBr yields 2-(3-chlorophenyl)-1-(3-pyridyl)ethanone (XIV). The reduction of (XIV) with hydrazine hydrate and NaOH in diethylene glycol at 235-40 C affords 3-(2-phenylethyl) pyridine (XV), which is oxidized with H2O2 in hot acetic acid to provide the corresponding N-oxide (XVI). Reaction of (XVI) with NaCN and dimethyl sulfate in water affords the previously described 3-(2-phenylethyl)pyridine-2-carbonitrile (V), which can be worked up as previously described or cyclized with polyphosphoric acid (PPA) at 180 C to give 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (XVII). The condensation of (XVII) with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF yields the corresponding carbinol (XVIII), which is dehydrated with PPA at 170 C to afford the previously reported 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII).

SYN

Condensation of ethyl nicotinate (XI) with 3-chlorophenylacetonitrile (XII) by means of sodium ethoxide in ethanol gives 2-(3-chlorophenyl)-3-oxo-3-(3-pyridyl)propionitrile (XIII), which by refluxing with concentrated HBr yields 2-(3-chlorophenyl)-1-(3-pyridyl)ethanone (XIV). The reduction of (XIV) with hydrazine hydrate and NaOH in diethylene glycol at 235-40 C affords 3-(2-phenylethyl) pyridine (XV), which is oxidized with H2O2 in hot acetic acid to provide the corresponding N-oxide (XVI). Reaction of (XVI) with NaCN and dimethyl sulfate in water affords the previously described 3-(2-phenylethyl)pyridine-2-carbonitrile (V), which can be worked up as previously described or cyclized with polyphosphoric acid (PPA) at 180 C to give 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (XVII). The condensation of (XVII) with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF yields the corresponding carbinol (XVIII), which is dehydrated with PPA at 170 C to afford the previously reported 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII).

Syn

2) By reaction of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (III) with the Grignard reagent (IV) to give the tertiary carbinol (V), which is dehydrated with 85% H2SO4 affording 8-chloro-11-piperidinylidene derivative (VI). Finally, cornpound (VI) is treated with ethyl chloroformate (II) in toluene.

SYN

1) By carboxylation of 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyctohepta[1,2-b]pyridine (I) with ethyl chloroformate (II) in refluxing benzene.

SYN

The condensation of S-methylisothiourea (I) with trans-4-(aminomethyl)cyclohexanecarboxylic acid (II) by means of NaOH in water gives trans-4-(guanidinomethyl)cyclohexanecarboxylic acid (III) (I), which is esterified with benzyl salicylate (IV) by means of dicyclohexylcarbodiimide (DCC) or SOCl2 yielding 2-benzyloxycarbonylphenyl trans-4-(guanidinomethyl)cyclohexanecarboxylate (V). Finally, this compound is treated with cyclodextrin in aqueous solution to afford the corresponding complex.

SPECTROSCOPY

Figure CN103755682AD00061

[0052] Table 1, desloratadine sample IH-NMR data of the DMS0_d6

Figure CN103755682AD00062

[0055] The desloratadine 1H spectra of the samples were assigned:
[0056] (I) 1H spectra show that there are 10 groups of hydrogen from low field to high field integral hydrogen ratio was 1: 1: 1: 1: 1: 1: 2: 4:
2: 4, and desloratadine structure match.
[0057] (2) δ 8.334 处 hydrogen as a set of double doublet, number of protons is I, attributed to two hydrogen;
[0058] (3) δ 7.560 处 hydrogen as a set of double doublet, number of protons is I, attributed to four hydrogen;
[0059] (4) δ 7.282 处 doublet hydrogen as a group, the number of protons is I, 12 attributed to hydrogen.
[0060] (5) δ 7.198 处 hydrogen as a set of double doublet, number of protons is I, 14 attributed to hydrogen;
[0061] (6) δ 7.174 处 hydrogen as a set of double doublet, number of protons is I, attributed to three hydrogen;
[0062] (7) δ 7.064 处 doublet hydrogen as a group, the number of protons is I, 15 attributed to hydrogen;
[0063] (8) δ 3.314 处 hydrogen as a group multiplet, 2 protons attributable to 10 hydrogen;
[0064] (9) δ 2.831,2.554 hydrogen groups at multiplet, protons of 4, 18, 20, the home position is hydrogen;
[0065] (10) δ 2.819 处 hydrogen as a group multiplet, 2 protons attributable to 11 hydrogen;
[0066] (11) δ 2.108 处 hydrogen as a single peak, the number of protons is I, home to 19 active hydrogen;
[0067] (12) δ 2.205, 2.002 处 two hydrogen multiplet, protons of 4, 17, 21 bits attributed to hydrogen; [0068] From the foregoing, 1H-NMR spectrum data and the resulting product in this embodiment is of he will be loratadine same structure as the target product.

 http://www.google.com/patents/CN103755682A?cl=en

References

  1. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 549. ISBN 9783527607495.
  2. Jump up to:a b c See S (2003). “Desloratadine for allergic rhinitis”Am Fam Physician68 (10): 2015–6. PMID 14655812.
  3. ^ Drugs.com Desloratadine entry at drugs.com international Page accessed May 4, 2015
  4. ^ Lee HE, Chang IK, Lee Y, Kim CD, Seo YJ, Lee JH, Im M (2014). “Effect of antihistamine as an adjuvant treatment of isotretinoin in acne: a randomized, controlled comparative study”. J Eur Acad Dermatol Venereol28 (12): 1654–60. doi:10.1111/jdv.12403PMID 25081735.
  5. ^ Layton AM (2016). “Top Ten List of Clinical Pearls in the Treatment of Acne Vulgaris”. Dermatol Clin34 (2): 147–57. doi:10.1016/j.det.2015.11.008PMID 27015774.
  6. Jump up to:a b c d “Aerius: EPAR – Product Information” (PDF)European Medicines Agency. 2017-06-07.
  7. ^ Canonica GW, Blaiss M (2011). “Antihistaminic, anti-inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a review of the evidence”World Allergy Organ J4 (2): 47–53. doi:10.1097/WOX.0b013e3182093e19PMC 3500039PMID 23268457.
Desloratadine
Desloratadine.svg
Desloratadine 3D ball-and-stick.png
Clinical data
Trade names Clarinex (US), Aerius, Dasselta, Deslordis (EU), others
AHFS/Drugs.com Monograph
MedlinePlus a602002
License data
Pregnancy
category
  • AU: B1
  • US: C (Risk not ruled out)
Routes of
administration
Oral (tablets, solution)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Rapidly absorbed
Protein binding 83 to 87%
Metabolism UGT2B10CYP2C8
Metabolites 3-Hydroxydesloratadine
Onset of action within 1 hour
Elimination half-life 27 hours
Duration of action up to 24 hours
Excretion 40% as conjugated metabolites into urine
Similar amount into the feces
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.166.554 Edit this at Wikidata
Chemical and physical data
Formula C19H19ClN2
Molar mass 310.82 g/mol g·mol−1
3D model (JSmol)

//////////Desloratadine, Descarboethoxyloratadine, Sch-34117, DCL, Denosin, Clarinex RediTabs, Allex, Desalex, Opulis, Clarinex, Neoclarityn, Aerius, MK-4117

E 2212


str1

C25 H23 F3 N6 O, 480.48

CAS 1123197-68-1

(+) -2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

  • (+)-5,6,7,8-Tetrahydro-2-[(1E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)-3-pyridinyl]ethenyl]-8-[2-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyridine
  • (+)-2-[(E)-2-[5-Methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]ethenyl]-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Figure

E2212

CAS 1123197-82-9

  • C25 H23 F3 N6 O . 3/2 C4 H6 O6
  • [1,2,4]Triazolo[1,5-a]pyridine, 5,6,7,8-tetrahydro-2-[(1E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]ethenyl]-8-[2-(trifluoromethyl)phenyl]-, (8S)-, (2S,3S)-2,3-dihydroxybutanedioate (2:3)

PATENT

https://patents.google.com/patent/US9453000B2/en

Examples 394 and 395 Synthesis of (+) and (−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

Figure US09453000-20160927-C00296

230 mg of the racemic title compound was obtained from 1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (343 mg) and (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid (500 mg) by the same method as in Examples 194 and 195. The racemic title compound (220 mg) was separated by CHIRALPAK™ IC manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: methanol) to obtain the title optically active compound with positive optical rotation and a retention time of 16 minutes (92 mg) and the title optically active compound with negative optical rotation and a retention time of 19 minutes (79 mg).

The property value of the title optically active compound with a retention time of 16 minutes is as follows.

ESI-MS; m/z 481 [M++H].

The property values of the title optically active compound with a retention time of 19 minutes are as follows.

ESI-MS; m/z 481 [M++H]. 1H-NMR (CDCl3) δ (ppm): 1.90-2.01 (m, 1H), 2.10-2.35 (m, 2H), 2.29 (s, 3H), 2.43-2.52 (m, 1H), 3.95 (s, 3H), 4.27-4.41 (m, 2H), 4.69 (dd, J=6.0, 8.4 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.08 (d, J=16.4 Hz, 1H), 7.40 (dd, J=7.6, 7.6 Hz, 1H), 7.44-7.53 (m, 4H), 7.73 (d, J=8.0 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 8.34 (s, 1H).

PATENT

WO2009028588

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=D6AD22B6CC7302560AE1ADCED305CDCE.wapp2nC?docId=WO2009028588&tab=FULLTEXT&queryString=%28PA%2Feisai%29%2520&recNum=93&maxRec=725
(+)および(-)-2-{(E)-2-[5-メトキシ-6-(4-メチル-1H-イミダゾール-1-イル)ピリジン-3-イル]ビニル}-8-(2-トリフルオロメチルフェニル)-5,6,7,8-テトラヒドロ-[1,2,4]トリアゾロ[1,5-a]ピリジンの合成
[化221]

実施例194および実施例195と同様の方法により、1-アミノ-3-(2-トリフルオロメチルフェニル)ピペリジン-2-オン(343mg)および(E)-3-[5-メトキシ-6-(4-メチル-1H-イミダゾール-1-イル)ピリジン-3-イル]アクリル酸(500mg)から、ラセミ体の表題化合物を230mg得た。ラセミ体の表題化合物(220mg)をダイセル製CHIRALPAK TM IC(2cm×25cm:移動相;メタノール)にて分取し、(+)の旋光性を有する保持時間16分の表題光学活性化合物(92mg)および(-)の旋光性を有する保持時間19分の表題光学活性化合物(79mg)を得た。
保持時間16分の表題光学活性体の物性値は以下の通りである。
ESI-MS;m/z 481[M +H].
保持時間19分の表題光学活性体の物性値は以下の通りである。
ESI-MS;m/z 481[M +H]. H-NMR(CDCl )δ(ppm):1.90-2.01(m,1H),2.10-2.35(m,2H),2.29(s,3H),2.43-2.52(m,1H),3.95(s,3H),4.27-4.41(m,2H),4.69(dd,J=6.0,8.4Hz,1H),7.02(d,J=8.0Hz,1H),7.08(d,J=16.4Hz,1H),7.40(dd,J=7.6,7.6Hz,1H),7.44-7.53(m,4H),7.73(d,J=8.0Hz,1H),8.13(d,J=1.6Hz,1H),8.34(s,1H).

Example 394 and Example 395
(+) and (−)-2-{(E) -2- [5-methoxy-6- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl] Synthesis of vinyl} -8- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine [Formula
221]

Example 194 and By a method similar to Example 195, 1-amino-3- (2-trifluoromethylphenyl) piperidin-2-one (343 mg) and (E) -3- [5-methoxy-6- (4-methyl-) 1 H-Imidazol-1-yl) pyridin-3-yl] acrylic acid (500 mg) gave 230 mg of the racemic title compound. Racemic title compound (220 mg) a Daicel CHIRALPAK TM IC (2 cm × 25 cm: mobile phase; methanol) was collected by min (+) title optically active compound of the retention time of 16 minutes with a optical rotation of (92 mg) The title optically active compound (79 mg) having a polarizability of (−) and a retention time of 19 minutes was obtained.
The physical property values of the title optically active substance with a retention time of 16 minutes are as follows.
ESI-MS; m / z 481 [M + + H].
The physical property values of the title optically active substance with a retention time of 19 minutes are as follows.
ESI-MS; m / z 481 [M + + H]. 1 H-NMR (CDCl 3)) Δ (ppm): 1.90 to 2.01 (m, 1 H), 2.10 to 2.35 (m, 2 H), 2.29 (s, 3 H), 2.43 to 2.52 (m) , 1 H), 3.95 (s, 3 H), 4.27-4. 41 (m, 2 H), 4.69 (dd, J = 6.0, 8.4 Hz, 1 H), 7.02 (d , J = 8.0 Hz, 1 H), 7.08 (d, J = 16.4 Hz, 1 H), 7.40 (dd, J = 7.6, 7.6 Hz, 1 H), 7.44-7. 53 (m, 4H), 7.73 (d, J = 8.0 Hz, 1 H), 8.13 (d, J = 1.6 Hz, 1 H), 8.34 (s, 1 H).

PATENT

https://patents.google.com/patent/WO2010098490A1/it

str1

As a novel compound that has an effect of reducing the production of Aβ40 and

42 and is expected as a therapeutic or prophylactic agent for Alzheimer’s disease or the like, the present inventors have found a compound represented by the following formula (1) (compound

(D): [Formula 1]

and filed a patent application for the invention (PCT/JP08/065365).

Generally, properties of salts of compounds and those crystals that are useful as pharmaceuticals are highly important for the development of pharmaceuticals, because the properties greatly affect bioavailability of drugs, purity of drug substances, formulation of preparations, and the like. Therefore, it is necessary to research which salts and crystal forms of the compound of the formula (1) are most excellent as pharmaceuticals. Specifically, since their properties depend on the character of the individual compounds, it is generally difficult to estimate salts and crystal forms for drug substances having excellent properties and it is demanded to actually make various studies for each compound.

EXAMPLES [0023] The present invention will be described in detail below with reference to reference examples and examples; however, the present invention is not limited to these reference examples and examples. [0024]

The following abbreviations are used in the following reference examples and examples.

DMF: N,N’-dimethylformamide

THF: Tetrahydrofuran

EDC: lrEmyl-S-β-dimemylammopropytycarbodiimide hydrochloride HOBT: 1-Hydroxybenzotriazole IPEA: Diisopropylethylamine [0025]

In powder X-ray diffractometry of the crystals produced in the following examples, the resulting crystals were placed on a sample stage of a powder X-ray diffractometer and analyzed under the following conditions. [0026] Measurement conditions

Sample holder: Aluminum Target: Copper

Detector: Scintillation counter Tube voltage: 50 kV Tube current: 300 mA

Slit: DS 0.5 mm (Height limiting slit 2 mm), SS Open, RS Open Scanning rate : 5 °/min

Sampling interval: 0.02° Scan range: 5 to 35° Goniometer: Horizontal goniometer [0027] Reference Example 1

Svnmesis ofr8SV2-(fE)-246-memoxy-5-(4-memyl-lH-imidazol-l-vnpyridin-2-yllvmvU-8-(2-trifluoromethylphenyl)-5,6J,8-tetrahvdro-[1.2,41triazolo[l.,5-a]pyridine

[Formula 2]

Synthesis of l-amino-3-(2-trifluoromemylphenyl)piperidin-2-one Thionyl chloride (2.72 mL) was added to a solution of 2-trifluoromethylphenylacetic acid (1.9 g) in methanol (38 mL), followed by stirring at room temperature for three hours. The reaction solution was concentrated under reduced pressure. The resulting residue was diluted with DMF. Sodium hydride (containing 40% mineral oil, 410 mg) was added under ice-cooling, followed by stirring for 10 minutes. The reaction solution was further stirred for 30 minutes and then ice-cooled again. l-Chloro-3-iodopropane (1.02 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was diluted with ethanol (26.6 mL). Hydrazine monohydrate (7.6 mL) was added, and the reaction solution was stirred at room temperature for two hours and then at 60°C for further three hours. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 1.68 g of the title compound. The property values of the compound are as follows.

ESI-MS; m/z 259 [M+H-H]. 1H-NMR (CDCl3) δ (ppm): 1.82-2.10 (m, 3H), 2.18-2.26 (m, IH), 3.58-3.76 (m, 2H), 4.07 (dd, J = 10.0, 5.6 Hz, IH), 4.60 (s, 2H), 7.24 (d, J = 7.6 Hz, IH), 7.35 (t, J = 7.6 Hz, IH), 7.51 (t, J = 7.6 Hz, IH)5 7.66 (d, J = 7.6 Hz, IH). [0028] Synthesis of (EV3-[6-methoxy-5-(4-methyl- 1 H-imidazol- 1 -yl)pyridin-2-yl]-N-f2-oxo-3 -(2-trifluoromethylphenyl)piperidin- 1 -yl]acrylamide

EDC (834 mg), HOBT (588 mg) and IPEA (2.03 mL) were added to a suspension of (E)-3-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridm-2-yl]acrylic acid trifluoroacetate (1.42 g) and l-amήio-3-(2-trifluoromethylphenyl)piperidin-2-one (750 mg) in DMF (30 mL). After stirring at room temperature for 14 hours, a saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system) to obtain 1.23 g of the title compound. The property values of the compound are as follows. ESI-MS; m/z 500 [M1H-HJ. [0029]

Synthesis of r8S>-2-(fEV2-r6-methoxy-5-r4-methyl-lH-imidazol-l-vnpyridm’2-vnvinvU-8-(2-trifluoromethvlphenvD-5.6.7.8-tetrahvdro-ri.2.41triazoloπ.5-a1pvridine Phosphorus oxychloride (24.2 mL) was added to (E)-3~[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]-N-[2-oxo-3-(2-trifluoromethylphenyl)piperidin-l-yl]acrylamide (1.2 g). The reaction solution was stirred at 1000C for one hour and then concentrated under reduced pressure. Subsequently, the residue was diluted with acetic acid (24.2 mL) and then ammonium acetate (1.9 g) was added, followed by stirring at 1500C for two hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution and ethyl acetate were added to the resulting residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain a racemate of the title compound (750 mg). The resulting racemate (410 mg) was separated by CHIRALP AK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm x 25 cm, mobile phase: hexane:ethanol = 8:2, flow rate: 10 mL/min) to obtain the title compound with a retention time of 33 minutes and negative optical rotation (170 mg) as crystals. The property values of the title compound are as follows.

1H-NMR (CDCl3) δ (ppm): 1.90-2.01 (m, IH), 2.10-2.35 (m, 2H), 2.29 (d, J = 1.2 Hz, 3H), 2.42-2.51 (m, IH), 4.03 (s, 3H), 4.28-4.41 (m, 2H), 4.70 (dd, J = 8.4, 6.0 Hz, IH), 6.92 (d, J = 8.0 Hz, IH), 6.95 (t, J = 1.2 Hz, IH), 7.01 (d, J = 7.6 Hz, IH), 7.39 (t, J = 7.6 Hz5 IH), 7.44 (d, J = 16.0 Hz, IH), 7.45 (d, J = 8.0 Hz, IH), 7.49 (t, J = 7.6 Hz, IH), 7.63 (d, J = 16.0 Hz5 IH), 7.72 (d, J = 7.6 Hz, IH), 7.76 (d, J = 1.2 Hz, IH). [0030]

(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-lH-imidazol-l-yl)ρyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine synthesized according to the above reference example was used for the following synthesis of salts. [0031] Example 1

Synthesis of r8SV2-{rEV2-[6-methoxy-5-(4-methyl-lH-imidazol-l-vπpyridin-2-vnvinvU-8-f2-trifluoromethylphenyl)-5.6.7.8-tetrahvdro-fl,2,4]triazolo[l.,5-a]pyridine 1.5 D-tartrate

(8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine (33.70 mg) was dissolved in 285 μL of a D-tartaric acid-ethanol solution (110.92 mg/3 mL) with stirring at room temperature. The oil was precipitated when 1 mL of heptane was added. Accordingly, the oily substance was dissolved by adding 1 mL of ethanol. Further, 0.5 mL of heptane was added, and the mixture was transferred to a low temperature laboratory at about 50C (under shading) and continuously stirred for 24 hours. Thus, partial gelation occurred. Thereafter, the mixture was brought back to room temperature and continuously stirred, resulting in precipitation of a solid. The solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 21.25 mg of the title compound as white solid crystals. 1H-NMR (600 MHz, DMSOd6) δ (ppm): 1.96 (m, IH), 2.14 (s, 3H), 2.16 (m, 2H), 2.29 (m, IH), 3.98 (s, 3H), 4.28 (m, 2H), 4.29 (s, 3H), 4.51 (dd, J = 9, 6 Hz, IH), 7.22 (s, IH), 7.25 (brd, J = 8 Hz, IH), 7.27 (d, J = 8 Hz, IH), 7.32 (d, J = 16 Hz, IH)5 7.46 (d, J = 16 Hz, IH), 7.49 (brdd, J = 8 Hz, IH), 7.61 (brdd, J = 8 Hz5 IH), 7.77 (brd, J = 8 Hz, IH), 7.78 (d, J = 8 Hz, IH), 7.91 (s, IH). [0032] Example 2

Synthesis of (8SV2-l(Ε)-2-f6-methoxy-5-(4-methyl-lH-imidazol-l-vnpyridm-2-yllvinyl>-8-f2-trifluoromethylphenylV5,6J,8-tetrahvdro-[l ,2,4]triazolo[l ,5-a]pyridine di-D-tartrate

(8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,657,8-tetrahydro-[l ,2,4]triazolo[l ,5-a]ρyridine (810.18 mg) was dissolved in 8 mL of a D-tartaric acid-ethanol solution (751.13 mg/10 mL) with stirring at room temperature. The oil was precipitated when 2 mL of heptane was added. Accordingly, the oily substance was dissolved by ultrasonic treatment to prepare a clear solution. Several mg of crystals of the 1.5 D-tartrate prepared according to Example 1 were added, followed by stirring at room temperature. Stirring for about one hour resulted in gelation and subsequent precipitation of a solid. Further, stirring was continued while gradually adding 14 mL of heptane. A part of the suspension (2 mL) was separated and the solid was collected by filtration through a glass filter. The solid was dried under reduced pressure at room temperature to obtain 71.14 mg of the title compound as white solid crystals. 1H-NMR (400 MHz, DMSOd6) δ (ppm): 1.97 (m, IH), 2.15 (s, 3H), 2.16 (m, 2H), 2.30 (m, IH), 3.98 (s, 3H), 4.28 (m, 2H), 4.29 (s, 4H), 4.51 (dd, J = 9, 6 Hz, IH), 7.22 (brs, IH), 7.25 (brd, J = 8 Hz, IH), 7.27 (d, J = 8 Hz, IH), 7.32 (d, J = 16 Hz, IH), 7.46 (d, J = 16 Hz, IH), 7.49 (brdd, J – 8 Hz, IH), 7.61 (brdd, J = 8 Hz, IH), 7.77 (brd, J = 8 Hz, IH), 7.78 (d, J = 8 Hz, IH), 7.91 (brs, IH). [0033] Example 3

Synthesis of r8SV2-(rE)-2-r6-methoxy-5-r4-methyl-lH-imidazol-l-vnpyridin-2-yl1vinvU-8-α-trifluoromethylphenyl)-5,6J,8-tetrahydro-[1.2,4]triazolo[l,5-a]pyridine disulfate

Concentrated sulfuric acid (11.5 μL) was added to a solution of (8S)-2-{(E)-2-[6- methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-txifluoromethylphenyl)-5,6,7,8-tetrahydro-[l52,4]triazolo[l55-a]pyridine (98.09 mg) in ethanol (1 mL), and 1 mL of ethyl acetate was added with stirring at room temperature. Since the oily portion was confirmed on the bottom of the recovery flask, the oily substance was dissolved by ultrasonic treatment. Stirring at room temperature under shading for about 30 minutes resulted in precipitation of a solid. The solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 127.94 mg of the title compound as white solid crystals. 1H-NMR (400 MHz, DMSOd6) δ (ppm): 1.97 (m, IH), 2.17 (m, 2H), 2.30 (m, IH), 2.34 (brd, J = 1 Hz, 3H), 4.01 (s, 3H), 4.29 (m, 2H), 4.52 (dd, J = 9, 6 Hz, IH)5 7.25 (brd, J = 8 Hz, IH), 7.37 (d, J = 16 Hz, IH), 7.40 (d, J = 8 Hz, IH), 7.50 (brdd, J = 8 Hz, IH), 7.55 (d, J = 16 Hz, IH), 7.61 (brdd, J = 8 Hz, IH), 7.77 (m, IH), 7.78 (m, IH), 8.00 (d, J = 8 Hz, IH), 9.36 (d, J = 2 Hz, IH). [0034] Example 4 Synthesis of (8SV2-((E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-ylN)ρyridin-2-yllvinvU-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahvdiO-[1.2,41triazolo[l,5-a]pyridine dihydrobromide

Concentrated hydrobromic acid (24.8 μL) was added to a solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,84etrahydro-[l,254]triazolo[l55-a]pyridine (51.42 mg) m ethanol (1 mL), and 1 mL of heptane was added with stirring at room temperature. After several minutes, 1 mL of heptane was further added to the solution and stirring was continued. The solution was stirred at room temperature for one hour and then further stirred at about 50C for 20 minutes. The precipitated solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 49.24 mg of the title compound as white solid crystals. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.99 (m, IH), 2.17 (m, 2H), 2.30 (m, IH), 2.34 (brd, J = 1 Hz5 3H), 4.01 (s, 3H), 4.30 (m, 2H), 4.52 (dd, J = 9, 6 Hz5 IH), 7.25 (brd, J = 8 Hz5 IH), 7.37 (d, J = 16 Hz, IH), 7.40 (d, J = 7 Hz, IH)57.50 (brdd, J = 8 Hz, IH), 7.55 (d, J = 16 Hz, IH), 7.61 (brdd, J = 8 Hz5 IH), 7.77 (m, IH)5 7.78 (m, IH), 8.00 (d, J = 7 Hz, IH), 9.37 (d, J = 2 Hz, IH). [0035] Example 5

Synthesis of r8SV2-((Ε)-2-r6-methoxy-5-r4-methyl-lH-imidazol-l-yl)ρyridin-2-vnvinyl}-8-r2-trifluoromethylphenyl)-5,6J,8-tetrahvdro-[1.2,41triazolo[1.5-alpyridine hydrochloride

Concentrated hydrochloric acid (3.6 μL) was added to a solution of (8S)-2-{(E)- 2-[6-methoxy-5-(4-metiiyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylplienyl)-5,6,7,8-te1xahydro-[l,2,4]triazolo[l,5-a]pyridme (19.80 mg) in 2-propanol (1 mL), and a total of 4 mL of heptane was added in 1 mL portions with stirring at room temperature. The solution was stirred at room temperature under shading for five days. The precipitated solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 7.45 mg of the title compound as white solid crystals. 1H-NMR (400 MHz, DMSOd6) δ (ppm): 1.97 (m, IH), 2.17 (m, 2H)5 2.30 (m, IH), 2.30 (s, 3H), 4.00 (s, 3H), 4.30 (m, 2H)5 4.52 (dd, J = 9, 6 Hz5 IH), 7.25 (brd, J – 8 Hz5 IH), 7.36 (d, J = 16 Hz5 IH), 7.37 (d5 J = 8 Hz, IH), 7.50 (brt, J = 8 Hz5 IH)5 7.53 (d, J = 16 Hz5 IH)5 7.61 (brt, J = 8 Hz5 IH)5 7.66 (brs, IH), 7.77 (brd, J = 8 Hz, IH)5 7.96 (d, J = 8 Hz5 IH), 9.06 (brs, IH). [0036] Example 6

Synthesis of (8S)-2-((ΕV2-r6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl1vinvU-8-(2-trifluoromethylphenyl)-5.6,7,8-tetrahvdro-[l,2,4]triazolo[L5-a1pyridine hydrochloride Concentrated hydrochloric acid (14.3 μL) and heptane (7 mL) were added to a solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,657,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine (79.77 mg) in 2-propanol (3 mL). A small amount of the crystals obtained in Example 5 were added as seed crystals with stirring at room temperature. The mixture was transferred to a low temperature laboratory at about 50C and stirred for one hour. Thereafter, 1 mL of heptane was further added, followed by stirring for several minutes. When the precipitated solid was collected by filtration through a glass filter, the solid was precipitated in the filtrate. The precipitated solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 38.02 mg of the title compound as white solid crystals. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.97 (m, IH), 2.17 (m5 2H), 2.29 (m, IH), 2.32 (brd, J = 1 Hz, 3H), 4.00 (s, 3H), 4.30 (m, 2H), 4.52 (dd, J = 9, 6 Hz, IH), 7.25 (brd, J = 8 Hz, IH), 7.37 (d, J = 16 Hz5 IH), 7.38 (d, J = 8 Hz, IH), 7.50 (brdd, J = 8 Hz, IH)5 7.54 (d, J = 16 Hz, IH), 7.61 (brdd, J = 8 Hz, IH), 7.72 (brs, IH), 7.77 (brd, J = 8 Hz, IH), 7.98 (d, J = 8 Hz5 IH)5 9.24 (brs, IH). [0037] Example 7

SvnJhesis off8SV2-f(E>2-r6-memoxy-5-(4-mefovπ trifluoromethylt>henylV5,6,7,8-tetrahvdro-[l,2,4]triazolo[l,5-a]pyridine mesylate

Mesylic acid (0.8 μL) was added to a mixed solution of (8S)-2-{(E)-2-[6- methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphen^ tetrahydro-[l52,4]triazolo[l,5-a]pyridine (50 mg) in t-butyl methyl ether (0.8 mL)-ethaαol (0.1 mL). The mixture was solidified as a result of stirring at room temperature for two hours. The solid was collected by filtration through a glass filter. The solid was washed with t-butyl methyl ether-ethanol (8:1) and then dried under reduced pressure at room temperature to obtain 51.9 mg of the title compound as pale yellow solid crystals.

1H-NMR (DMSO-d6) δ (ppm): 1.90-2.05 (m, IH)3 2.10-2.22 (m, 2H), 2.28-2.40 (m, IH), 2.31 (s, 3H), 2.35 (s, 3H)5 4.02 (s, 3H)5 4.25-4.39 (m, 2H), 4.50-4.55 (m, IH), 7.27 (d5 J = 8.0 Hz5 IH)5 7.38 (d, J = 16.0 Hz5 IH)5 7.41 (d, J = 8.0 Hz, IH)5 7.51 (t5 J = 8.0 Hz5 IH)5 7.55 (d, J = 16.0 Hz5 IH), 7.63 (t, J = 8.0 Hz5 IH)5 7.78 (d, J = 8.0 Hz5 IH)5 7.79 (s, IH), 8.01 (d, J = 8.0 Hz5 IH), 9.37 (s, IH). [0038] Example 8 Synthesis of (8S)-2-((ΕV2-r6-methoxy-5-(4-methyl-lH-imidazol-l-vnpyridin-2-vnvinvn-8-r2-trifluoromethylphenyl)-5.6,7,8-tetrahydro-[l.,2,4|triazolo[l,5-a]pyridine diphosphate

A solution of phosphoric acid (52.8 mg) in acetonitrile (0.2 mL) was added to a solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-mτidazol-l-yl)ρyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5565758-tetrahydro-[l5254]triazolo[l,5-a]pyridine (100 mg) in acetonitrile (0.8 mL) at room temperature. The precipitated oil was solidified as a result of stirring with spatula. The solid was collected by filtration through a glass filter. The solid was washed with ice-cold acetonitrile, air-dried at room temperature for 10 minutes and then dried under reduced pressure at room temperature to obtain 120 mg of the title compound as white solid crystals. 1H-NMR (DMSO-d6) δ (ppm): 1.90-2.05 (m, IH), 2.11-2.20 (m, 2H), 2.15 (s, 3H), 2.25-2.35 (m, IH), 3.99 (s, 3H)5 4.24-4.39 (m, 2H), 4.50-4.55 (m, IH)5 7.23 (s, IH), 7.26 (d, J = 7.0 Hz, IH), 7.28 (d, J = 8.0 Hz, IH), 7.33 (d, J = 16.0 Hz5 IH), 7.47 (d, J = 16.0 Hz5 IH), 7.51 (t, J = 7.0 Hz, IH), 7.63 (t, J = 7.0 Hz, IH), 7.78 (d, J = 7.0 Hz, IH), 7.79 (d, J = 8.0 Hz, IH), 7.90 (s, IH). [0039] Example 9 Svnmesis of(8SV2-{(E)-2-[6-memoxy-5-(4-methyl-lH-irnidazol-l-yl)pyridin-2-yl1vinvU-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahvdro-[l .2.41triazolo[l .5-a]pyridine diphosphate

A solution of phosphoric acid (13.2 mg) in ethanol (0.05 mL) was added to a mixed solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[l,2!,4]triazolo[l,5-a]pyridme (50 mg) in heptane (0.6 mL)-ethanol (0.15 mL) at room temperature. The reaction solution was stirred at room temperature, and the precipitated solid was collected by filtration through a glass filter. The solid was washed with heptane-ethanol (3:1) and then dried under reduced pressure at room temperature to obtain 37.6 mg of the title compound as white solid crystals. 1H-NMR (DMSOd6) δ (ppm): 1.90-2.05 (m, IH), 2.11-2.20 (m, 2H), 2.15 (s, 3H), 2.25-2.35 (m, IH), 3.99 (s, 3H), 4.24-4.39 (m, 2H), 4.50-4.55 (m, IH), 7.23 (s, IH), 7.26 (d, J = 7.0 Hz, IH), 7.28 (d, J = 8.0 Hz, IH), 7.33 (d, J = 16.0 Hz, IH), 7.47 (d, J = 16.0 Hz, IH), 7.51 (t, J = 7.0 Hz, IH), 7.63 (t, J = 7.0 Hz, IH), 7.78 (d, J = 7.0 Hz, IH), 7.79 (d, J = 8.0 Hz, IH), 7.90 (s, IH).

CLIP

Development of an Efficient Manufacturing Process for E2212 toward Rapid Clinical Introduction

 API Research Japan, Pharmaceutical Science & Technology, CFU, Medicine Development CenterEisai Co. Ltd.5-1-3-Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
 API Research Japan, Pharmaceutical Science & Technology, CFU, Medicine Development CenterEisai Co. Ltd.22-Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan
§ Neurology Tsukuba Research Department, Discovery, Medicine Creation, NBGEisai Co. Ltd.5-1-3-Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
 Integrated ChemistryEisai AiM Institute4 Corporate Drive, Andover, Massachusetts 01810, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00444
This article is part of the Japanese Society for Process Chemistry special issue.
Abstract Image

Process studies of E2212 (1) toward rapid clinical introduction are described. Through comprehensive route-finding studies and optimization of key condensation and cyclization steps, a racemate-based manufacturing route was established and successfully scaled-up to the hundred kilogram scale. For the rapid delivery of a drug substance containing the Z isomer for preclinical safety studies, the successful scale-up of the photoisomerization of an olefin in a flow system is also presented.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00444

E2212 (1) (18.0 kg, 92.5% yield) as a white solid. Mother liquor 3 were recycled according to the procedure described below. FTIR (cm–1, KBr) 3461, 3173, 2956, 1734, 1584, 1536, 1476, 1309, 1130, 835, 765, 752; 1H NMR (600 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.77 (br d, J = 8.4 Hz, 1H), 7.61 (br dd, J = 7.8, 7.8 Hz, 1H), 7.49 (br dd, J = 7.8, 7.8 Hz, 1H), 7.46 (d, J= 15.6 Hz, 1H), 7.32 (d, J = 15.6 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.25 (br d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 4.51 (dd, J = 9.0, 6.0 Hz, 1H), 4.29 (s, 3H), 4.28 (m, 2H), 3.98 (s, 3H), 2.29 (m, 1H), 2.14 (s, 3H), 2.16 (m, 2H), 1.96 (m, 1H); 13C NMR (150 MHz, DMSO-d6) δ 173.3, 159.3, 155.4, 155.0, 150.1, 141.1, 137.1, 136.9, 133.6, 132.9, 131.0, 130.5, 127.6, 127.1 (q, JC–F = 30 Hz), 125.8 (q, JC–F = 5.6 Hz), 124.7 (q, JC–F = 270 Hz), 122.2, 120.7, 117.2, 116.5, 72.3, 53.7, 47.0, 37.6, 30.7, 21.3, 13.6; HRMS (ESI+) calcd for C25H23F3N6O ([M + H]+) 481.1958, found 481.1953.

 E/Z mixture of E2212 (196.0 g (containing residual n-PrOH), E:Z = 61.8:37.4 by UV (271 nm), 1.3:1.0 by 1H NMR) as an orange oil. HPLC conditions to monitor the isomerization conversion and E/Z ratio: XBridge-Shield-RP18 (5 μm, 4.6 mm × 250 mm), 1.0 mL/min, oven temperature = 40 °C, mobile phase A = 900:100:1 v/v/w H2O/MeCN/AcONH4, mobile phase B = 100:900:1 v/v/w H2O/MeCN/AcONH4, gradient (time (min)/B conc (%)) = 0/5 → 5/45 → 35/45 → 50/100 → 55/100 → 55.01/5 → 65/5 → 65.01/stop, RRT of Z form = 0.73.
From this mixture, a small portion was purified by silica gel column chromatography to give the Zisomer in free form. FTIR (cm–1, KBr) 3416, 2952, 1586, 1500, 1487, 1313, 1161, 1114, 1036, 966, 858, 769; 1H NMR (600 MHz, CDCl3) δ 7.90 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 1.2 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 7.6, 7.4 Hz, 1H), 7.37 (dd, J = 7.7, 7.6 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 6.93 (dd, J = 1.2, 1.0 Hz, 1H), 6.73 (d, J = 13.3 Hz, 1H), 6.64 (d, J = 13.3 Hz, 1H), 4.63 (dd, J = 9.3, 5.9 Hz, 1H), 4.34 (br ddd, J = 13.0, 5.6, 4.1 Hz, 1H), 4.28 (ddd, J = 13.0, 9.9, 4.9 Hz, 1H), 3.92 (s, 3H), 2.45 (dddd, J = 13.2, 6.5, 6.5, 2.6 Hz, 1H), 2.29 (d, J= 1.0 Hz, 3H), 2.28 (m, 1H), 2.15 (m, 1H), 1.94 (dddd, J = 12.9, 11.4, 8.3, 2.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 159.4, 155.2, 154.4, 150.8, 140.2, 138.3, 136.6, 133.2, 131.9 131.6, 129.9, 128.5 (q, JC–F = 29.8 Hz), 127.2, 126.2 (q, JC–F = 5.6 Hz), 124.4 (q, JC–F = 274.0 Hz), 121.8, 120.1, 118.4, 116.0, 53.6, 47.3, 37.9, 31.0, 21.7, 13.6; HRMS (ESI+) calcd for C25H24F3N6O ([M + H]+) 481.1958, found 481.1960.

///////////E2212, E 2212

Certolizumab pegol, セルトリズマブペゴル (遺伝子組換え)


Image result for certolizumab pegol

>Amino acid sequence of the light chain
DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASFLYSGVPY
RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPLTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Amino acid sequence of the heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGYVFTDYGMNWVRQAPGKGLEWMGWINTYIGEPIY
ADSVKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCARGYRSYAMDYWGQGTLVTVSSAS
TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCAA

Certolizumab pegol

CAS: 428863-50-7

セルトリズマブペゴル (遺伝子組換え)

CDP 870 / CDP-870 / CDP870 / PHA-738144

Formula
C2115H3252N556O673S16
Cas
428863-50-7
Mol weight
47748.8128

Reducing signs and symptoms of Crohn’s disease and treatment of moderately to severely active rheumatoid arthritis (RA).

Certolizumab pegol is a recombinant Fab’ antibody fragment against tumor necrosis factor alpha which is conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). Polyethylene glycol helps to delay the metabolism and elimination of the drugs. Chemically, the light chain is made up of 214 amino acid residues while the heavy chain is composed of 229 amino acid residues. The molecular mass of the Fab’ antibody fragment itself is 47.8 kDa. It is used for the treatment of rheumatoid arthritis and Crohn’s disease. FDA approved on April 22, 2008

Certolizumab pegol (CDP870, tradename Cimzia) is a biologic medication for the treatment of Crohn’s disease,[1][2] rheumatoid arthritispsoriatic arthritis and ankylosing spondylitis. It is a fragment of a monoclonal antibody specific to tumor necrosis factor alpha(TNF-α) and is manufactured by UCB.[3][4][5]

Image result for certolizumab pegol

Medical uses

Crohn’s Disease
On April 22, 2008, the U.S. FDA approved Cimzia for the treatment of Crohn’s disease in people who did not respond sufficiently or adequately to standard therapy.[4][6][7]
Rheumatoid arthritis
On June 26, 2009, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion recommending that the European Commission grant a marketing authorisation for Cimzia for the treatment of rheumatoid arthritis only – the CHMP refused approval for the treatment of Crohn’s disease. The marketing authorisation was granted to UCB Pharma SA on October 1, 2009.[8]
Psoriatic arthritis
On September 27, 2013, the U.S. FDA approved Cimzia for the treatment of adult patients with active psoriatic arthritis.[9]

Method of action

Certolizumab pegol is a monoclonal antibody directed against tumor necrosis factor alpha. More precisely, it is a PEGylated Fabfragment of a humanized TNF inhibitor monoclonal antibody.[10]

Clinical trials

Crohn’s disease
Positive results have been demonstrated in two phase III trials (PRECiSE 1 and 2) of certolizumab pegol versus placebo in moderate to severe active Crohn’s disease.[1][10][11][12]
Axial spondyloarthritis
In 2013, a phase 3 double blind randomized placebo-controlled study found significantly positive results in patient self-reported questionnaires, with rapid improvement of function and pain reduction, in patients with axial spondyloarthritis.[13]
Rheumatoid arthritis
Certolizumab appears beneficial in those with rheumatoid arthritis.[14]

Side effects

Significant side effects occur in 2% of people who take the medication.[14]

References

  1. Jump up to:a b Sandborn WJ, Feagan BG, Stoinov S, et al. (July 2007). “Certolizumab pegol for the treatment of Crohn’s disease”N. Engl. J. Med357 (3): 228–38. doi:10.1056/NEJMoa067594PMC 3187683PMID 17634458.
  2. ^ Goel, Niti; Sue Stephens (2010). “Certolizumab pegol”mAbs2 (2): 137–147. doi:10.4161/mabs.2.2.11271PMC 2840232PMID 20190560.
  3. ^ Kaushik VV, Moots RJ (April 2005). “CDP-870 (certolizumab) in rheumatoid arthritis”. Expert Opinion on Biological Therapy5 (4): 601–6. doi:10.1517/14712598.5.4.601PMID 15934837.
  4. Jump up to:a b index.cfm?fuseaction=Search.Label_ApprovalHistory “Cimzia Label and Approval History” Check |url= value (help)Drugs@FDAU.S. Food and Drug Administration(FDA). Retrieved 2009-11-15.
  5. ^ “Cimzia Prescribing Information” (PDF). US Food and Drug Administration (FDA). April 2016. Retrieved 2016-08-21.
  6. ^ UCB press release – Cimzia Approved in the US for the Treatment of Moderate to Severe Crohn’s Disease. Retrieved April 22, 2008.
  7. ^ Waknine, Yael (May 1, 2008). “FDA Approvals: Patanase, Actonel, Cimzia”Medscape. Retrieved 2008-05-01.
  8. ^ “Cimzia European Public Assessment Report”European Medicines Agency. Retrieved November 15, 2009.
  9. ^ “Cimzia (certolizumab pegol) approved by the U.S. FDA for treatment of adult patients with active psoriatic arthritis”. Archived from the original on October 1, 2013. Retrieved October 1, 2013.
  10. Jump up to:a b Schreiber S. et al., Certolizumab pegol, a humanised anti-TNF pegylated FAb’ fragment, is safe and effective in the maintenance of response and remission following induction in active Crohn’s disease: a phase 3 study (precise), Gut, 2005, 54, suppl7, A82
  11. ^ Sandborn et al., Certolizumab pegol administered subcutaneously is effective and well tolerated in patients with active Crohn’s disease: results from a 26-week, placebo-controlled Phase 3 study (PRECiSE 1), Gastroenterology, 2006, 130, A107
  12. ^ “New Analysis Shows Cimzia (Certolizumab Pegol) Maintained Remission and Response in Recent Onset Crohn’s Disease” (Press release). UCB. October 23, 2006. Retrieved 2009-11-15.
  13. ^ Sieper J, Tubergen A, Coteur G, Woltering F, Landewe R (May 2013). “PMS50 – Rapid Improvements In Patient-Reported Outcomes With Certolizumab Pegol In Patients With Axial Spondyloarthritis, Including Ankylosing Spondylitis And Non-Radiographic Axial Spondyloarthritis: 24-Week Results Of A Phase 3 Double Blind Randomized Placebo-Controlled Study”. Value in Health16 (3): A227. doi:10.1016/j.jval.2013.03.1150.
  14. Jump up to:a b Ruiz Garcia, V; Jobanputra, P; Burls, A; Vela Casasempere, P; Bort-Marti, S; Bernal, JA (Sep 8, 2017). “Certolizumab pegol (CDP870) for rheumatoid arthritis in adults”(PDF)The Cochrane Database of Systematic Reviews9: CD007649. doi:10.1002/14651858.CD007649.pub4PMID 28884785.

External links

FDA approves treatment Cimzia (certolizumab pegol) for patients with a type of inflammatory arthritis

March 28, 2019

Release

The U.S. Food and Drug Administration today approved Cimzia (certolizumab pegol) injection for treatment of adults with a certain type of inflammatory arthritis called non-radiographic axial spondyloarthritis (nr-axSpA), with objective signs of inflammation. This is the first time that the FDA has approved a treatment for nr-axSpA.

“Today’s approval of Cimzia fulfills an unmet need for patients suffering from non-radiographic axial spondyloarthritis as there has been no FDA-approved treatments until now,” said Nikolay Nikolov, M.D., associate director for rheumatology of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Nr-axSpA is a type of inflammatory arthritis that causes inflammation in the spine and other symptoms. There is no visible damage seen on x-rays, so it is referred to as non-radiographic.

The efficacy of Cimzia for the treatment of nr-axSpA was studied in a randomized clinical trial in 317 adult patients with nr-axSpA with objective signs of inflammation, indicated by elevated C-reactive protein (CRP) levels and/or sacroiliitis (inflammation of the sacroiliac joints) on MRI. The trial measured the improvement response on the Ankylosing Spondylitis Disease Activity Score, a composite scoring system that assesses disease activity including patient-reported outcomes and CRP levels. Responses were greater for patients treated with Cimzia compared to patients treated with placebo. The overall safety profile observed in the Cimzia treatment group was consistent with the known safety profile of Cimzia.

The prescribing information for Cimzia includes a Boxed Warning to advise health care professionals and patients about the increased risk of serious infections leading to hospitalization or death including tuberculosis (TB), bacterial sepsis (infection in the blood steam), invasive fungal infections (such as histoplasmosis, an infection that affects the lungs), and other infections. Cimzia should be discontinued if a patient develops a serious infection or sepsis. Health care providers are advised to perform testing for latent TB and, if positive, to start treatment for TB prior to starting Cimzia. All patients should be monitored for active TB during treatment, even if the initial latent TB test is negative. The Boxed Warning also advises that lymphoma (cancer in blood cells) and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, of which Cimzia is a member. Cimzia is not indicated for use in pediatric patients. Cimzia must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Cimzia was originally approved in 2008 and is also indicated for adult patients with Crohn’s disease, moderate-to-severe rheumatoid arthritis, active ankylosing spondylitis (AS) and moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

The FDA granted the approval of Cimzia to UCB.

Certolizumab pegol
Syringe with Certolizumab pegol-1800.jpg

Syringe with 200mg Certolizumab pegol
Monoclonal antibody
Type Fab’ fragment
Source Humanized (from mouse)
Target TNF alpha
Clinical data
Trade names Cimzia
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a608041
License data
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration
Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life about 11 days
Excretion Renal (PEG only)
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C2115H3252N556O673S16
Molar mass 47,750 g/mol g·mol−1

///////////////FDA 2019, Cimzia, certolizumab pegol, inflammatory arthritis, UCB

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634671.htm?utm_campaign=032819_PR_FDA%20approves%20treatment%20for%20patients%20with%20a%20type%20of%20inflammatory%20arthritis&utm_medium=email&utm_source=Eloqua

Cevimeline, セビメリン


Cevimeline.svg

Cevimeline

セビメリン

  • Molecular FormulaC10H17NOS
  • Average mass199.313 Da
cis-2′-Methylspiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxathiolane]
Evoxac [Trade name]
Spiro[1-azabicyclo[2.2.2]octane-3,5′-[1,3]oxathiolane], 2′-methyl-, (2’R,3R)-
Cevimeline
CAS Registry Number: 107233-08-9
CAS Name: (2¢R,3R)-rel-2¢-Methylspiro[1-azabicyclo[2.2.2]octane-3,5¢-[1,3]oxathiolane]
Additional Names: (±)-cis-2-methylspiro[1,3-oxathiolane-5,3¢-quinuclidine]
Molecular Formula: C10H17NOS
Molecular Weight: 199.31
Percent Composition: C 60.26%, H 8.60%, N 7.03%, O 8.03%, S 16.09%
Literature References: Muscarinic M1 and M3 receptor agonist. Prepn: A. Fisher et al., JP Kokai 61 280497eidemUS 4855290; (1986, 1989 both to State of Israel). Improved process: K. Hayashi et al., US 5571918 (1996 to Ishihara Sangyo Kaisha). Sialogogic effect in animals: H. Masunaga et al., Eur. J. Pharmacol. 339, 1 (1997). General pharmacology: H. Arisawa et al., Arzneim.-Forsch. 52, 14, 81 (2002). Clinical experience in Sjögren’s syndrome dry eye: M. Ono et al., Am. J. Ophthalmol. 138, 6 (2004); in dry mouth: K. Suzuki et al., Pharmacology 74, 100 (2005). Review of clinical pharmacokinetics and efficacy in Sjögren’s syndrome: H. Yasuda, H. Niki, Clin. Drug Invest. 22, 67-73 (2002).
Derivative Type: Hydrochloride hemihydrate
CAS Registry Number: 153504-70-2; 107220-28-0 (anhydrous)
Manufacturers’ Codes: AF-102B; SNI-2011
Trademarks: Evoxac (Daiichi)
Molecular Formula: C10H17NOS.HCl.½H2O
Molecular Weight: 244.78
Percent Composition: C 49.07%, H 7.82%, N 5.72%, O 9.80%, S 13.10%, Cl 14.48%
Properties: White to off white crystalline powder, mp 201-203°. Freely sol in alcohol, chloroform; very sol in water. Virtually insol in ether.
Melting point: mp 201-203°
Therap-Cat: Sialagogue.
Keywords: Sialagogue.

Cevimeline hydrochloride

    • Synonyms:AF-102B, SNI-2011, SNK-508, Evoxac
    • ATC:N07
  • Use:cognition disorder, treatment of Sjogren’s syndrome, muscarinic M3-receptor agonist
  • Chemical name:(2′R,3R)-rel-2′-methylspiro[1-azabicyclo[2.2.2]octane-3,5′-[1,3]oxathiolane] hydrochloride hydrate (2:2:1)
  • Formula:C10H17NOS • HCl • 1/2H2O
  • MW:489.57 g/mol
  • CAS-RN:153504-70-2
  • InChI Key:SURWTGAXEIEOGY-GHXDPTCOSA-N
  • InChI:InChI=1S/C10H17NOS.ClH/c1-8-12-10(7-13-8)6-11-4-2-9(10)3-5-11;/h8-9H,2-7H2,1H3;1H/t8-,10-;/m1./s1

Derivatives

base

  • Formula:C10H17NOS
  • MW:199.32 g/mol
  • CAS-RN:107233-08-9

anhydrous hydrochloride

  • Formula:C10H17NOS • HCl
  • MW:235.78 g/mol
  • CAS-RN:107220-28-0

Cevimeline is cis-2′-methylspiro {1-azabicyclo [2.2.2] octane-3, 5′ -[1,3] oxathiolane} hydro-chloride, hydrate (2:1). Its empirical formula is C10H17NOS•HCl•½ H2O, and its structural formula is:

Image result for Cevimeline STRUCTURECevimeline has a molecular weight of 244.79. It is a white to off white crystalline powder with a melting point range of 201 to 203°C. It is freely soluble in alcohol and chloroform, very soluble in water, and virtually insoluble in ether. The pH of a 1% solution ranges from 4.6 to 5.6. Inactive ingredients include lactose monohydrate, hydroxypropyl cellulose, and magnesium stearate.

Image result for Cevimeline STRUCTURE

Image result for Cevimeline STRUCTURE

Cevimeline hydrochloride [USAN]
RN: 153504-70-2

 (+-)-cis-2-Methylspiro(1,3-oxathiolane-5,3′-quinuclidine) hydrochloride, hemihydrate

Cevimeline (trade name Evoxac) is a parasympathomimetic and muscarinic agonist,[1] with particular effect on M1 and M3 receptors. It is used in the treatment of dry mouth and especially associated with Sjögren’s syndrome.

Mechanism of action

By activating the M3 receptors of the parasympathetic nervous system, cevimeline stimulates secretion by the salivary glands, thereby alleviating dry mouth.

Side effects

Known side effects include nauseavomitingdiarrhea, excessive sweatingrashheadacherunny nosecoughdrowsinesshot flashesblurred vision, and difficulty sleeping.[2]

Contraindications include asthma and angle closure glaucoma.

Clip

https://www.sciencedirect.com/science/article/abs/pii/S0731708515302260

Image result for cevimeline

Image result for cevimeline

Image result for cevimeline

CLIP

https://www.sciencedirect.com/science/article/pii/S0040403913005042

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Image result for cevimeline

CLIP

CLIP

  • Reaction of quinuclidin-3-one (I) with trimethylsulfoxonium iodide and NaH in DMSO gives epoxide (II), which is opened with SH2 in NaOH/water, yielding 3-hydroxy-3-(sulfanylmethyl)quinuclidine (III). The cyclization of compound (III) with acetaldehyde (IV) catalyzed by boron trifluoride ethearate or by SnCl4, POCl3, H3PO4 or p-toluenesulfonic acid affords a mixture of two diastereomeric spiroracemates, the (?-trans (V) and (?-cis (cevimeline). This mixture is separated by fractional recrystallization in acetone or by TLC chromatography, and treated with hydrochloric acid. The (?-trans-compound (V) can be isomerized to cevimeline by treatment with an acidic catalyst such as an organic sulfonic acid (trifluoromethanesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid), a Lewis acid (SnCl4, FeCl3, BF3 or AlCl3) or sulfuric acid in refluxing toluene, hexane or CHCl3. Cevimeline hydrochloride hemihydrate is obtained from the above mentioned hydrochloride by a complex work-up using water, isopropanol and n-hexane.
  • Synthesis of Cevimeline Hydrochloride (EN:134916): Reaction of quinuclidin-3-one (I) with trimethylsulfoxonium iodide and NaH in DMSO gives epoxide (II), which is opened with SH2 in NaOH/water, yielding 3-hydroxy-3-(sulfanylmethyl)quinuclidine (III) (1,2). The cyclization of compound (III) with acetaldehyde (IV) catalyzed by boron trifluoride ethearate (1) or by SnCl4, POCl3, H3PO4 or p-toluenesulfonic acid (2) affords a mixture of two diastereomeric spiro-racemates, the (?-trans (V) and (?-cis (cevimeline). This mixture is separated by fractional recrystallization in acetone or by TLC chromatography, and treated with hydrochloric acid (1,2). The (?-trans-compound (V) can be isomerized to cevimeline by treatment with an acidic catalyst such as an organic sulfonic acid (trifluoromethanesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid), a Lewis acid (SnCl4, FeCl3, BF3 or AlCl3) or sulfuric acid in refluxing toluene, hexane or CHCl3 (2,3). Cevimeline hydrochloride hemihydrate is obtained from the above mentioned hydrochloride by a complex work-up using water, isopropanol and n-hexane (4).(Scheme 13491601a) Description M.p. 203 C (4). Sources Discovered by Israel Institute for Biological Research, Ness-Ziona (IL) and licensed to Snow Brand Milk Products Co. Ltd. (JP). In the U.S., comarketed by Snow Brand Milk Products and Daiichi Pharmaceutical Co., Ltd. In Japan, codeveloped with Nippon Kayaku Co. Ltd. Ishihara Sangyo Co., Ltd. (JP) is the bulk supplier. References 1. Fisher, A., Heldman, E., Grunfeld, Y., Karton, I., Levy, A. (Israel Institute for Biological Research); Derivs. of quinuclidine; EP 0205247, JP 1986280497, US 4855290. 2. Hayashi, K., Tokumoto, S., Yoshizawa, H., Isogai, T. (Ishihara Sangyo Kaisha, Ltd.); Method for producing 2-methylspiro(1,3-oxathiolan-5,3′)quinuclidine; EP 0683168, US 5571918. 3. Haga, T., Koyanagi, T., Hara, K., Maeda, M., Shigehara, I. (Ishihara Sangyo Kaisha, Ltd.); Method for isomerization of trans-form 2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine or acid addition salts thereof; EP 0298491, US 4861886. 4. Saito, K., Ono, T., Honda, N. (Snow Brand Milk Products Co., Ltd.); Preparation method of cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine hydrochloride.1/2 hydrate capable of disgregating easily; JP 1992108792.

PATENT

https://patents.google.com/patent/US8080663B2/en

The present invention refers to a novel, industrially advantageous process for the preparation of an intermediate useful for the preparation of Cevimeline hydrochloride (1, cis-2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine, Scheme 1). This pharmaceutical is useful for the treatment of diseases of the central nervous system due to disturbances of central cholinergic function and autoimmune system (Sjörgen’s syndrome) and is marketed as Evoxac®.

U.S. Pat. No. 4,855,290 describes a process for preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1). The process comprises the preparation of the epoxide of 3-methylenequiniclidine, which is subsequently reacted with hydrogen sulfide to produce 3-hydroxy-3-mercaptomethylquiniclidine and condensed with acetaldehyde in the presence of a Lewis acid (boron trifluoride etherate) to provide 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine. This process is depicted in Scheme I.

Figure US08080663-20111220-C00001

This process suffers from major disadvantages when transiting to industrial scale. These include the use of the highly hazardous and difficult to handle hydrogen sulfide gas. Also, boron trifluoride etherate is employed during the condensation step with acetaldehyde. The boron trifluoride etherate reagent is an air and moisture sensitive Lewis acid which has to be used under anhydrous conditions, thus creating a serious disadvantage in industrial settings. Another drawback of this process is the use of sodium hydride. U.S. Pat. Nos. 5,571,918 and 4,861,886 relate to the isomerization of the trans- to cis-form of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine but do not describe methods for its preparation. Thus, an industrially acceptable and cost-effective method for the preparation of Cevimeline hydrochloride which overcomes the deficiencies of the prior art is required.

Further and other objects of the invention will be realized by those skilled in the art from the following Summary of the Invention and Detailed Description of Preferred Embodiments of the Invention thereof.

According to one aspect of the invention, a novel process is provided for the preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1). The process is industrially practical, efficient, safe and economical, as well as being environmentally friendly. The general method is shown in the Scheme II.

Figure US08080663-20111220-C00002


wherein R is selected from C1 to C6 alkyl and aryl groups, most preferably a methyl, ethyl or propyl group; Ris hydrogen or a C2 to C7 alkyl or aryl carbonyl group; Ris a C1 to C6 alkyl group, preferably methyl, ethyl, propyl, or butyl group.

Figure US08080663-20111220-C00003

EXAMPLE I Preparation of the Epoxide of 3-methylenequiniclidine (3)

A mixture of the hydrochloric salt of 3-quiniclidinone (2, 120 g, 795.7 mmol) and trimethylsulfoxonium iodide (219 g, 993.3 mmol) in dimethylsulfoxide (91.0 g, 0.63 mol) was cooled to 0-5° C. in an ice/water bath under nitrogen atmosphere. A solution of potassium tert-butoxide (201 g, 1789.1 mmol) in dimethylsulfoxide (500 mL) was added dropwise over 45 minutes. The mixture was warmed gradually to room temperature and stirred for an additional 16 hours at room temperature. After cooling to 0-5° C. (ice/water bath) the mixture was poured into an ice/water mixture (500 g) and then sodium chloride (300 g) was added. The mixture was stirred for 30 minutes and extracted with toluene (3×400 mL). The toluene phase was dried over sodium sulfate, filtered and evaporated to furnish the epoxide of 3-methylenequiniclidine (60 g, 431.7 mmol, 54% yield) as a yellow oil. The product could be used in the next step neat or as toluene solution after the extraction without further purification.

1H NMR (400 MHz, CDCl3): δ=3.10 (d, 1H, J=14.6 Hz); 2.98-2.77 (m, 5H); 2.74 (d, 1H, J=4.8 Hz); 2.70 (d, 1H, J=4.8 Hz); 1.96-1.89 (m, 1H); 1.79-1.62 (m, 2H); 1.60-1.54 (m, 1H); 1.38-1.36 (m,1H).

LRMS (ES+): 140.0 (100, M+H+).

EXAMPLE II Preparation of the Thiolacetic Acid Salt of 3-hydroxy-3-acetoxymercaptomethylquiniclidine (4)

A solution of the epoxide of 3-methylenequiniclidine (3, 54 g, 388.5 mmol) in toluene (200 mL) was cooled to 0-5° C. (ice/water bath). Thiolacetic acid was added dropwise over 10-15 minutes. The mixture was stirred at 0-5° C. for 30 minutes and then allowed to come to room temperature. After stirring at room temperature for 2 hours the formed precipitate was filtered and washed with toluene (2×100 mL) to give the 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein Ris H and R is methyl, 77 g, 264.6 mmol, 68%) as a light yellow solid. The product was used in the next step without any further purification.

1H NMR (400 MHz CD3OD): δ=3.47 (d, 1H, J=14.1 Hz); 3.37-3.18 (m, 7H); 2.40 (s, 3H); 2.38 (s, 3H); 2.36-2.27 (m, 1H), 2.14-2.05 (m, 2H); 2.03-1.93 (m, 1H); 1.81-1.78 (m, 1H).

LRMS (ES+): 216.1 (100, M−[SCOCH3]+H+).

EXAMPLE III Preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine using p-toluenesulfonic acid (1)

To a solution of 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein Ris H and R is methyl, 3 g, 10.3 mmol) in iso-propanol (50 mL) was added p-toluenesulfonic acid monohydrate (5.9 g, 30.9 mmol) and the mixture was heated to reflux for 3.5 hours. The mixture was cooled to room temperature and acetaldehyde diethyl acetal (6.1 g, 51.5 mmol) was added. The mixture was heated to reflux and stirred for an additional 3 hours. The solvent was evaporated and the residue was dissolved in dichloromethane (50 mL). The mixture was cooled to 0-5° C. and a 25% aqueous solution of sodium hydroxide (80 mL) was added. The mixture was stirred for 10-15 minutes and the phases were separated. The aqueous phase was extracted with dichloromethane (3×50 mL). The organic phases were combined and extracted with 5% aqueous solution of sulfuric acid (3×50 mL). The acidic aqueous phases were combined and the pH was adjusted to 12 with a 25% aqueous solution of sodium hydroxide. The aqueous phase was extracted with heptane (3×50 mL) and the organic phases were combined, dried over sodium sulfate and the solvent was evaporated to give 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1.8 g, 9.2 mmol, 89% yield) as a 3:1 cis/trans ratio mixture of diastereomers (determined by 1H NMR).

LRMS (ES+): 200.1 (100, M+H+).

EXAMPLE IV Preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1) using racemic camphorsulfonic acid

In a similar experiment as Example III, racemic camphorsulfonic acid (7.2 g, 30.9 mmol) was added to a solution of 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein Ris H and R is methyl, 3 g, 10.3 mmol) in iso-propanol (50 mL). The mixture was refluxed for 5 h, cooled to room temperature and acetaldehyde diethyl acetal (6.1 g, 51.5 mmol) was added. The mixture was refluxed for an additional an 8 hours and processed according to Example III to give 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1.32 g, 6.63 mmol, 64% yield) in a 3.5:1 cis/trans ratio mixture of diastereomers (determined by 1H NMR).

EXAMPLE V Preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1) using phenyl sulfonic acid

In a similar experiment as Example III, to a solution of 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein Ris H and R is methyl, 3 g, 10.3 mmol) in iso-propanol (50 mL) was added phenyl sulfonic acid (4.9 g, 30.9 mmol) and the mixture was refluxed 5 h, cooled to room temperature and acetaldehyde diethyl acetal (6.1 g, 51.5 mmol) was added. The mixture was refluxed for an additional 8 hours and worked up in a manner similar to Example III to furnish 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1.6 g, 8.2 mmol, 80% yield) as a 2.5:1 cis/trans ratio mixture of diastereomers (determined by 1H NMR).

EXAMPLE VI Preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1) using p-toluenesulfonic acid in butanol

To a solution of 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein Ris H and R is methyl, 3 g, 10.3 mmol) in butanol (100 mL) was added of p-toluenesulfonic acid monohydrate (5.9 g, 30.9 mmol) and the mixture was refluxed for 3 hours with a Dean-Stark apparatus attached to the flask. The reaction mixture was cooled to room temperature and acetaldehyde diethyl acetal (6.1 g, 51.5 mmol) was added. The mixture was heated to 80° C. for an additional 8 h and worked up according to Example III to afford 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1.8 g, 9.2 mmol, 89% yield) as a 3:1 cis/trans ratio mixture of diastereomers (determined by 1H NMR).

References

  1. ^ Ono M, Takamura E, Shinozaki K, et al. (July 2004). “Therapeutic effect of cevimeline on dry eye in patients with Sjögren’s syndrome: a randomized, double-blind clinical study”Am. J. Ophthalmol138 (1): 6–17. doi:10.1016/j.ajo.2004.02.010PMID 15234277.
  2. ^ [1] MedicineNet: Cevimeline. Accessed 10/12/2007
      • US 4 855 290 (Israel Institute for Biological Research; 8.8.1989; IL-prior. 10.5.1985).
      • US 4 876 260 (Israel Institute for Biological Research; 24.10.1989; USA-prior. 28.10.1987).
      • EP 683 168 (Ishihara Sangyo Kaisha; appl. 19.5.1995; J-prior. 19.5.1994).
    • Method for isomerization of trans-isomer:

      • US 4 861 886 (Ishihara Sangyo Kaisha; 29.8.1989; J-prior. 10.7.1987).
    • Method of separation:

      • IL 81 652 (Israel Institute for Biological Research; 12.5.1991; appl. 23.2.1987).
      • JP 01 290 680 (Ishihara Sangyo Kaisha; 22.11.1989; J-prior. 18.5.1988).
    • Synthesis of enantiomerically pure (S)-3-hydroxy-3-mercaptomethylquinuclidine (S)-II:

      • Bos, M.; Canesso, R.: Heterocycles (HTCYAM) 38 (8), 1889 (1994).
    • Synthesis of 3-quinuclidone:

      • Sternbach, L.H.; Kaiser, S.: J. Am. Chem. Soc. (JACSAT) 74, 2215 (1952).

External links

Cevimeline
Cevimeline.svg
Cevimeline 3D.png
Clinical data
Trade names Evoxac
AHFS/Drugs.com Monograph
MedlinePlus a608025
Pregnancy
category
  • C
Routes of
administration
By mouth (capsules)
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding <20%
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C10H17NOS
Molar mass 199.31308 g/mol g·mol−1
3D model (JSmol)

/////////// Cevimeline, AF-102B, SNI-2011, SNK-508, Evoxac, セビメリン

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