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Cimicoxib

UR-8880,
CAS 265114-23-6,
Molecular Formula: C16H13ClFN3O3S
Molecular Weight: 381.809123

Uriach (Originator)

4-[4-Chloro-5-(3-fluoro-4-methoxyphenyl)-1H-imidazol-1-yl]benzenesulfonamide

 

IN PHASE 2

Cimicoxib (trade name Cimalgex) is a non-steroidal anti-inflammatory drug (NSAID) used in veterinary medicine to treat dogs for pain and inflammation associated with osteoarthritis and for the management of pain and inflammation associated with surgery.[1] It acts as a COX-2 inhibitor.

Cimicoxib is a selective COX-2 inhibitor being developed by Affectis as a treatment for depression and schizophrenia. If approved, Cimicoxib would be the first drug in decades to treat depression by a new mechanism of action

Cimicoxib, an imidazole derivative, is a selective cyclooxygenase-2 (COX-2) inhibitor. The product was in phase II development at Affectis Pharmaceuticals for the oral treatment of major depression, however, no recent development have been reported. Originally developed by Uriach, the compound was acquired by Palau Pharma, a spin-off created by Uriach in November 2006.

In 2007, Palau Pharma licensed global rights to cimicoxib to Affectis Pharmaceuticals for all CNS indications. Palau had been clinically evaluating the compound for the treatment of osteoarthritis, pain and rheumatoid arthritis, however, no recent development has been reported for these indications. The compound holds potential for the treatment of schizophrenia.

Chemical structure for CID 213053

 

 

Treatment of 4-(acetylamino)phenylsulfonyl chloride (I) with tert-butylamine yields sulfonamide (II), which on deprotection with potassium hydroxide gives amine (III). Reaction of compound (III) with 4-methoxy-3-fluorobenz-aldehyde gives imine (IV), which is cyclized with tosylmethyl isocyanide to afford imidazole (V). Regioselective chlorination of compound (V) with N-chlorosuccinimide (NCS) to afford the chloroimidazole (VI) and then deprotection of the sulfonamide group of (VI) yields cimicoxib in 40% overall yield.

EP 1122243; JP 2002527508; WO 0023426, ES 2184633; WO 0316285

……………………………….

http://www.google.com/patents/EP1424329A1?cl=en

EXAMPLE 1

4-Amino-N- tert -butylbenzenesulfonamide Method A:

  • [0031]

a) N-tert-Butyl-4-nitrobenzenesulfonamide

  • [0032]
    To a solution of tert-butylamine (0.47 L, 6.4 mol) in THF (0.55 L) is slowly added, at 0 °C, a solution of 4-nitrobenzenesulfonyl chloride (50 g, 0.23 mol) in THF (0.55 L) and the resulting mixture is stirred for 24 h at room temperature. The solvent is removed and the residue is taken up in a CHCl3/0.5 N HCl mixture, the layers are separated and the aqueous phase is extracted with CHCl3. The combined organic extracts are washed with H2O and brine and dried over MgSO4. The solvent is removed, yielding 56.3 g of a yellowish solid which is directly used in the next reaction (yield: 97%).
    Mp: 105-109°C; 1H-NMR (300 MHz, CDCl3) δ (TMS): 1.29 (s, 9 H), 5.07 (s, 1 H), 8.13 (d, J = 9 Hz, 2 H), 8.39 (d, J = 9 Hz, 2 H).

b) Title compound

  • [0033]
    A solution of N-tert-butyl-4-nitrobenzenesulfonamide (10.0 g, 39 mmol) in EtOH (100 mL) is stirred for 48 h under a H2 atmosphere in the presence of 10% Pd/C (1.50 g). The resulting mixture is filtered and concentrated to give the desired product as a slightly-coloured solid (8.7 g, yield: 98%).
    Mp: 127 °C; 1H-NMR (300 MHz, CDCl3 + CD3OD) δ (TMS): 1.19 (s, 9 H), 3.74 (s, CD3OD + 1 H), 6.93 (d, J = 9 Hz, 2 H), 7.66 (d, J = 9 Hz, 2 H).

Method B:

  • [0034]

a) 4-Acetylamino-N-tert-butylbenzenesulfonamide

  • [0035]
    To a suspension of 4-acetylaminobenzenesulfonyl chloride (10 g, 43 mmol) in DME (103 mL) is added, at 0 °C, tert-butylamine (9 mL, 86 mmol) in DME (103 mL). Next, the reaction mixture is stirred for 4 h at reflux. The solvent is removed and CHCl3 is added. The resulting suspension is filtered and the solid is washed with CHCl3, H2O and Et2O. The solid obtained is dried in vacuo to give 8.0 g of the product as a white solid (yield: 68%).
    Mp: 200-201 °C; 1H-NMR (300 MHz, CDCl3 + CD3OD) δ (TMS): 1.15 (s, 9 H), 2.12 (s, 3 H), 4.21 (s, 2H + CD3OD), 7.66 (d, J = 9 Hz, 2 H), 7.75 (d, J = 9 Hz, 2 H).

b) Title compound

  • [0036]
    A solution of 4-acetylamino-N-tert-butylbenzenesulfonamide (8.0 g, 29.6 mmol), KOH (8.30 g, 148 mmol), H2O (6 mL) and MeOH (24 mL) is heated at 100°C for 2 h. H2O (24 mL) is added and the mixture is heated for two more hours. It is allowed to cool, H2O is added and it is brought to pH 8 with 1N HCl. It is then extracted with EtOAc, dried over Na2SO4 and the solvent is removed, to give 6.0 g of the product as a white solid (yield: 89%).

EXAMPLE 2 N- tert -Butyl-4-[(3-fluoro-4-methoxybenzylidene)amino]benzenesulfonamide

  • [0037]
  • [0038]
    A mixture of 4-amino-N-tert-butylbenzenesulfonamide (52.3 g, 0.23 mol, obtained in example 1), 3-fluoro-4-methoxybenzaldehyde (35.3 g, 0.23 mol) and toluene (2.5 L) is heated at reflux in a Dean-Stark for 24 h. The solvent is removed, yielding 83.5 g of the title compound (yield: quantitative).
    Mp: 129-131 °C; 1H-NMR (300 MHz, CDCl3) δ (TMS): 1.23 (s, 9 H), 3.98 (s, 3 H), 4.65 (s, 1 H), 7.04 (t, J = 8.1 Hz, 1 H), 7.21 (d, J = 6.7 Hz, 2 H), 7.58 (m, 1 H), 7.73 (dd, JH-F = 11.8 Hz, J = 2 Hz, 1 H), 7.90 (d, J = 6.7 Hz, 2 H), 8.33 (s, 1 H).

EXAMPLE 3 N-tert-Butyl-4-[5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide

  • [0039]
  • [0040]
    A mixture of N-tert-butyl-4-[(3-fluoro-4-methoxybenzylidene)amino]benzenesulfonamide (41.5 g, 114 mmol, obtained in example 2), tosylmethylisocyanide (33.22 g, 171 mmol), K2CO3 (31.1 g, 228 mmol), DME (340 mL) and MeOH (778 mL) is heated at reflux for 3 h. The solvent is removed and the residue is taken up in a CHCl3/H2O mixture and the layers are separated. The aqueous phase is extracted with CHCl3 and the combined organic extracts are dried over MgSO4 and concentrated. A crude product is obtained, which is washed with Et2O several times to give 41.40 g of a creamy solid that is directly used in the next reaction (yield: 90%).
    Mp: 229-232°C; 1H-NMR (300 MHz, CDCl3) δ (TMS): 1.24 (s, 9 H), 3.89 (s, 3 H), 4.51 (s, 1 H), 6.90 (m, 3 H), 7.23 (s, 1 H), 7.29 (d, J = 8.7 Hz, 2 H), 7.73 (s, 1 H), 7.94 (d, J = 8.7 Hz, 2 H).

EXAMPLE 4 N-tert-Butyl-4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide

  • [0041]
  • [0042]
    A mixture of N-tert-butyl-4-[5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (41.40 g, 103 mmol, obtained in example 3) and acetonitrile (840 mL) is heated at reflux and acetonitrile is added until complete dissolution (200 mL more). Next, N-chlorosuccinimide (15.0 g, 113 mmol) is added and the mixture is refluxed for 24 h. The solvent is removed and the residue is suspended in EtOAc and 1N HCl and is stirred for 10 min. The solid obtained is filtered and washed directly in the filter with 1N HCl, 1N NaOH, saturated NH4Cl solution, H2O and Et2O. A solid is obtained, which is dried in vacuo to give 37.0 g of the product as a creamy solid (yield: 82%).
    Mp: 208-210 °C; 1H-NMR (300 MHz, CDCl3) δ (TMS): 1.24 (s, 9 H), 3.89 (s, 3 H), 4.51 (s, 1 H), 6.90 (m, 3 H), 7.23 (d, J = 8.7 Hz, 2 H), 7.63 (s, 1 H), 7.92 (d, J = 8.7 Hz, 2 H).

EXAMPLE 5 4-[4-Chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide

  • [0043]
  • [0044]
    A mixture of N-tert-butyl-4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (37.0 g, 85 mmol, obtained in example 4), concentrated HCl (200 mL) and H2O (200 mL) is heated at reflux for 3 h. The mixture is allowed to cool and is brought to pH 6 with 6N NaOH. A white precipitate appears, which is collected by filtration and washed with plenty of H2O and then with CHCl3. 31 g of the title compound of the example is obtained (yield: 97%), which are recrystallized from acetonitrile.
    Mp: 211-212 °C;
  • 1H-NMR (300 MHz, CDCl3 + CD3OD) δ (TMS): 3.90 (s, 3 H), 4.16 (s, CD3OD + 2 H), 6.93 (m, 3 H), 7.30 (d, J = 8.6 Hz, 2 H), 7.73 (s, 1 H), 7.95 (d, J = 8.7 Hz, 2 H).

 

References

  1. “European Public Assessment Report: Cimalgex (cimicoxib)”. European Medicines Agency.
9-1-2013
Detection and quantification of cimicoxib, a novel COX-2 inhibitor, in canine plasma by HPLC with spectrofluorimetric detection: development and validation of a new methodology.
Journal of pharmaceutical and biomedical analysis
6-1-2013
Efficacy and safety of cimicoxib in the control of perioperative pain in dogs.
The Journal of small animal practice
4-5-2007
NO-donor COX-2 inhibitors. New nitrooxy-substituted 1,5-diarylimidazoles endowed with COX-2 inhibitory and vasodilator properties.
Journal of medicinal chemistry
10-21-2004
New water-soluble sulfonylphosphoramidic acid derivatives of the COX-2 selective inhibitor cimicoxib. A novel approach to sulfonamide prodrugs.
Journal of medicinal chemistry
7-31-2003
Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.
Journal of medicinal chemistry
4-15-2005
Compositions of a cyclooxygenase-2 selective inhibitor and a serotonin-modulating agent for the treatment of central nervous system damage
4-8-2005
Compositions of a cyclooxygenase-2 selective inhibitor and an IKK inhibitor for the treatment of ischemic mediated central nervous system disorders or injury
1-9-2009
Process for the Preparation of 4-(imidazol-1-yl)benzenesulfonamide Derivatives
9-5-2008
Medicament that is Intended for Oral Administration, Comprising a Cyclooxygenase-2 Inhibitor, and Preparation Method Thereof
4-2-2008
Method of preparing 4-(imidazol-1-yl)benzenesulphonamide derivatives
6-29-2007
Compositions of a cyclooxygenase-2 selective inhibitor administered under hypothermic conditions for the treatment of ischemic mediated central nervous system disorders or injury
7-8-2005
Compositions of a cyclooxygenase-2 selective inhibitor and a neurotrophic factor-modulating agent for the treatment of central nervous system mediated disorders
5-27-2005
Compositions of a cyclooxygenase-2 selective inhibitor administered under hypothermic conditions for the treatment of ischemic mediated central nervous system disorders or injury
5-13-2005
Compositions of a cyclooxygenase-2 selective inhibitior and a non-NMDA glutamate modulator for the treatment of central nervous system damage
4-22-2005
Compositions of a cyclooxygenase-2 selective inhibitor and a low-molecular-weight heparin for the treatment of central nervous system damage
4-22-2005
Mediated central nervous system compositions of a cyclooxygenase-2 selective inhibitor and a corticotropin releasing factor antagonist for the treatment of ischemic disorders or injury

 


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DR ANTHONY CRASTO

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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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