New Drug Approvals

Home » DIABETES » CIGLITAZONE

CIGLITAZONE

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Recent Posts

Blog Stats

  • 3,476,086 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,614 other followers

add to any

Share

Ciglitazone.svg

Ciglitazone

U-63287, ADD-3878

  • Molecular FormulaC18H23NO3S
  • Average mass333.445 Da
  • 74772-77-3 [RN]

(±)-5-[4-(1-Methylcyclohexylmethoxy)benzyl]thiazolidine-2,4-dione2,4-Thiazolidinedione, 5-[[4-[(1-methylcyclohexyl)methoxy]phenyl]methyl]-5-[4-(1-methylcyclohexylmethoxy) benzyl]-thiazolidine-2,4-dione

Ciglitazone (INN) is a thiazolidinedione. Developed by Takeda Pharmaceuticals in the early 1980s, it is considered the prototypical compound for the thiazolidinedione class.[1][2][3][4]

Ciglitazone was never used as a medication, but it sparked interest in the effects of thiazolidinediones. Several analogues were later developed, some of which—such as pioglitazone and troglitazone—made it to the market.[2]

Ciglitazone significantly decreases VEGF production by human granulosa cells in an in vitro study, and may potentially be used in ovarian hyperstimulation syndrome.[5] Ciglitazone is a potent and selective PPARγ ligand. It binds to the PPARγ ligand-binding domain with an EC50 of 3.0 μM. Ciglitazone is active in vivo as an anti-hyperglycemic agent in the ob/ob murine model.[6] Inhibits HUVEC differentiation and angiogenesis and also stimulates adipogenesis and decreases osteoblastogenesis in human mesenchymal stem cells.[7]

SYN

T. Sohda, K. Mizuno, E. Imamiya, Y. Sugiyama, T. Fujita, and Y. Kawamatsu, Chem. Pharm. Bull., 30, 3580 (1982).

File:Ciglitazone synthesis.svg

SYN

Ciglitazone (CAS NO.: ), with other name of , 5-((4-((1-methylcyclohexyl)methoxy)phenyl)methyl)-, (+-)-, could be produced through many synthetic methods.

Following is one of the reaction routes:

Synthesis of Ciglitazone

The reaction of 1-methylcyclohexylmethanol (II) with 4-chloronitrobenzene (III) by means of NaH in hot DMSO gives 4-(1-methylcyclohexylmethoxylnitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 4-(1-methylcyclohexylmethoxylaniline (IV). Diazotation of (IV) with NaNO2 and HCl in water affords a solution of the corresponding diazonium chloride (V), which is condensed with methyl acrylate (VI) by means of Cu2O affording methyl 2-chloro-3-[4-(1-methylcyclohexylmethoxyl)phenyl]propionate (VII). The cyclization of (VII) with thiourea (VIII) by means of sodium acetate in hot 2-methoxyethanol gives 2-imino-5-[4-(1-methylcyclohexylmethoxy)benzyl]thiazolidin-4-one (IX), which is finally hydrolyzed with HCl in refluxing 2-methoxyethanol – water.

Syn

Chem Pharm Bull 1982,30(10),3580

The reaction of 1-methylcyclohexylmethanol (II) with 4-chloronitrobenzene (III) by means of NaH in hot DMSO gives 4-(1-methylcyclohexylmethoxylnitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 4-(1-methylcyclohexylmethoxylaniline (IV). Diazotation of (IV) with NaNO2 and HCl in water affords a solution of the corresponding diazonium chloride (V), which is condensed with methyl acrylate (VI) by means of Cu2O affording methyl 2-chloro-3-[4-(1-methylcyclohexylmethoxyl)phenyl]propionate (VII). The cyclization of (VII) with thiourea (VIII) by means of sodium acetate in hot 2-methoxyethanol gives 2-imino-5-[4-(1-methylcyclohexylmethoxy)benzyl]thiazolidin-4-one (IX), which is finally hydrolyzed with HCl in refluxing 2-methoxyethanol – water.

By cyclization of (VIII) with methyl 2-(methanesulfonyloxy)-3-[4-(1-methylcyclohexylmethoxy)phenyl]propionate (X) by means of sodium acetate in hot 2-methoxyethanol, followed by hydrolysis with HCl in ethanol water.

paper

Vijay Kumar Sharma , Anup Barde & Sunita Rattan (2020): A short review on synthetic strategies toward glitazone drugs, Synthetic Communications, DOI: 10.1080/00397911.2020.1821223

Experimental process for synthesis of ciglitazone is fairly robust, albeit pyrophorophic NaH as base is utilized for synthesis of 15.

Scheme 4. Reagents and conditions for the preparation of (R)-ciglitazone 24 (a) (S)-1-phenylethan-1- amine 19 (0.9 mol. equiv.), EtOH, RT, 4 h; (b) 1 N HCl (2 vol.), diethyl ether, RT, 10 min; (c) CH2N2 in diethyl ether (ca. 3% w/w), diethyl ether, 0 C-RT, 30 min; (d) KSCN (1.5 mol. equiv.), DMSO, 90 C, 2 h; (e) 2 N HCl (10 vol.), and EtOH, reflux 4 h.

Chiral synthesis Racemic-ciglitazone 17 was resolved with optically active a-methylbenzylamine (PEA) 19 through asymmetric transformation of optical lability at the C-5 position of TZD ring. 2-chloro-3-(4-((1-methylcyclohexyl)methoxy)phenyl)propanoic acid 18 was resolved using (S)-()-1-Phenylethylamine 19 to isolate (S)-2-chloro-3-(4-((1- methylcyclohexyl) methoxy)phenyl)propanoicacid 21. Esterification followed by substitution with KSCN provided methyl (R)-3-(4-((1-methylcyclohexyl)methoxy)phenyl)-2- thiocyanatopropan-oate 23 which was then hydrolyzed to isolate (R)-ciglitazone 24. Similarly, S-isomer was also isolated with (R)-(þ)-1-phenylethylamine (Scheme 4).

[30]Sohda, T.; Mizuno, K.; Kawamatsu, Y. Studies on Antidiabetic Agents. VI. Asymmetric Transformation of (þ/-)-5-[4-(1-Methylcyclohexylmethoxy)Benzyl]-2,4- Thiazolidinedione (Ciglitazone) with Optically Active 1-Phenylethylamines. Chem. Pharm. Bull. 1984, 32, 4460–4465. DOI: 10.1248/cpb.32.4460.

References

  1. ^ Pershadsingh HA, Szollosi J, Benson S, Hyun WC, Feuerstein BG, Kurtz TW (June 1993). “Effects of ciglitazone on blood pressure and intracellular calcium metabolism”Hypertension21 (6 Pt 2): 1020–3. doi:10.1161/01.hyp.21.6.1020PMID 8505086.
  2. Jump up to:a b Hulin B, McCarthy PA, Gibbs EM (1996). “The glitazone family of antidiabetic agents”Current Pharmaceutical Design2: 85–102.
  3. ^ Imoto H, Imamiya E, Momose Y, Sugiyama Y, Kimura H, Sohda T (October 2002). “Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives”Chem. Pharm. Bull50 (10): 1349–57. doi:10.1248/cpb.50.1349PMID 12372861.
  4. ^ Sohda T, Kawamatsu Y, Fujita T, Meguro K, Ikeda H (November 2002). “[Discovery and development of a new insulin sensitizing agent, pioglitazone]”Yakugaku Zasshi (in Japanese). 122 (11): 909–18. doi:10.1248/yakushi.122.909PMID 12440149.
  5. ^ Shah DK, Menon KM, Cabrera LM, Vahratian A, Kavoussi SK, Lebovic DI (April 2010). “Thiazolidinediones decrease vascular endothelial growth factor (VEGF) production by human luteinized granulosa cells in vitro”Fertil. Steril93 (6): 2042–7. doi:10.1016/j.fertnstert.2009.02.059PMC 2847675PMID 19342033.
  6. ^ Willson, T.M.; Cobb, J.E.; Cowan, D.J.; et al. (1996). “The structure-activity relationship between peroxisome proliferator-activated receptor γ agonism and the antihyperglycemic activity of thiazolidinediones”. J Med Chem39 (3): 665–668. doi:10.1021/jm950395aPMID 8576907.
  7. ^ Xin, X.; et al. (1999). “Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo;”J. Biol. Chem274 (13): 9116–21. doi:10.1074/jbc.274.13.9116PMID 10085162.
Clinical data
ATC codenone
Identifiers
IUPAC name[show]
CAS Number74772-77-3 
PubChem CID2750
IUPHAR/BPS2711
DrugBankDB09201 
ChemSpider2648 
UNIIU8QXS1WU8G
KEGGD03493 
ChEMBLChEMBL7002 
CompTox Dashboard (EPA)DTXSID0040757 
ECHA InfoCard100.220.474 
Chemical and physical data
FormulaC18H23NO3S
Molar mass333.45 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]O=C1NC(=O)SC1Cc3ccc(OCC2(C)CCCCC2)cc3
InChI[hide]InChI=1S/C18H23NO3S/c1-18(9-3-2-4-10-18)12-22-14-7-5-13(6-8-14)11-15-16(20)19-17(21)23-15/h5-8,15H,2-4,9-12H2,1H3,(H,19,20,21) Key:YZFWTZACSRHJQD-UHFFFAOYSA-N 

/////////ciglitazone, U 63287, ADD 3878, DIABETES


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,614 other followers

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

Personal Links

View Full Profile →

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: