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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Cefditoren pivoxil
Cefditoren pivoxil
ME-1207, Spectracef, Meiact
117467-28-4
- (-)-(6R,7R)-2,2-dimethylpropionyloxymethyl 7-((Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido)-3-((Z)-2-(4-methylthiazol-5-yl)ethenyl)-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylate
- 7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-(2-(4-methylthiazol-5-yl)ethenyl)cephem-4-carboxylic acid pivaloyloxymethyl ester
- CDTR-PI
- cefditoren pivoxil
- ME 1207
- ME-1207
- Spectracef
Novel crystalline form of cefditoren pivoxil (first disclosed in EP175610). Represents Yungjin Pharma’s first interest in this API, which was developed and launched by Meiji Seika and previous licensee TAP Pharmaceuticals, and now marketed by Merus Labs, for treating chronic bronchitis and community acquired pneumonia caused by bacterial infections
Cefditoren is a third-generation cephalosporin antibiotic for oral use. It is commonly marketed under the trade name Spectracef by Vansen Pharma Inc.
Cefditoren is also marketed under the name Meiact by Meiji Seika Pharma Co., Ltd.[1]
Spectrum of bacterial susceptibility
Cefditoren has a broad spectrum of activity and has been used to treat bacterial infections of the skin and respiratory tract, including bronchitis, pneumonia, and tonsillitis. The following represents MIC susceptibility data for a few medically significant microorganisms.
- Haemophilus influenzae: ≥0.063 – 0.25 μg/ml
- Staphylcoccus aureus: 0.25 – >128 μg/ml (includes MRSA)
- Streptococcus pyogenes: ≤0.004 – 2 μg/ml[2]
Cefditoren is a broad-spectrum antibiotic against Gram-negative and Gram-positive bacteria, but does not have antibacterial activity against Pseudomonas aeruginosa.[3]
Clinical use
Indications
Cefditoren is used to treat uncomplicated skin and skin structure infections, community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, pharyngitis, and tonsillitis.
Formulations
Cefditoren is available as 200- and 400-mg tablets. It can be formulated as the prodrug cefditoren pivoxil.
Chemical structure of cefditoren pivoxil
References
- Meiact Full Description
- http://www.toku-e.com/Assets/MIC/Cefditoren%20sodium.pdf
- “Disease relevance of Cefditoren”. Retrieved June 24, 2014.
- Chem Pharm Bull 1992,39(9),2433
- J Antibiot 1990,43(8),1047
Synthesis Reference
Kiyoshi Yasui, Masahiro Onodera, Masamichi Sukegawa, Tatsuo Watanabe, Yuichi Yamamoto, Yasushi Murai, Katsuharu Iinuma, “Crystalline substance of cefditoren pivoxyl and the production of the same.” U.S. Patent US6294669, issued March, 1986.
| Patent | Submitted | Granted |
|---|---|---|
| Therapy for Treating Resistant Bacterial Infections [US2009275552] | 2009-11-05 | |
| Process for the preparation of thiazole intermediate [US6833459] | 2003-10-30 | 2004-12-21 |
| Nanoparticulate and Controlled Release Compositions Comprising Cefditoren [US8119163] | 2008-11-13 | 2012-02-21 |
External links
 |
|
| Systematic (IUPAC) name | |
|---|---|
| (7R)-7-((Z)-2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((Z)-2-(4-methylthiazol-5-yl)vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | |
| Clinical data | |
| Trade names | Spectracef |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a605003 |
| Legal status |
?
|
| Identifiers | |
| CAS number | 104145-95-1  |
| ATC code | J01DD16 |
| PubChem | CID 9870843 |
| DrugBank | DB01066 |
| ChemSpider | 8046534  |
| UNII | 81QS09V3YW |
| Chemical data | |
| Formula | C19H18N6O5S3 |
| Mol. mass | 506.58 g/mol |
WO-2014189308, Yungjin Pharmaceutical Co Ltd
I did not run away from a NaCN Exotherm
DELTAMETHRIN
DID NOT RUN AWAY FROM NACN ie sodium cyanide EXOTHERM
ALMOST VIRTUAL ACCIDENT AT ISAGRO.RPG LIFESCIENCES (SEARLE) PANOLI GUJARAT INDIA 1999-2000
DELTAMETHRIN PROJECT, 1999-2000 Panoli Gujarat India
ww were trying to add acid chloride into an aldehyde at zero degrees cent using PTC conditions and one of ingredient was sodium cyanide, cooling was done by brine
We Did not run away when instead of adding acid chloride in 2 hrs the operator added it on 10 min…………..I waited at the reactor and controlled an exotherm in plant by switching off brine supply to other reactors,
The reaction got controlled at 59 deg cent and luckily was ok…………the exotherm was fearful. This extreme tension is experienced in a lifetime when everyone runs away and no one to help, FEARFUL, In this case the ‘I’ worked not the ‘we’
Despite all odds God saves us
MAKE IN INDIA
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THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D
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I was paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my familyJanssen seeks FDA approval for Yondelis (Trabectedin) drug to treat advanced STS
ET-743, Yondelis (trabectedin)
Trabectedin, Ecteinascidin 743, NSC-684766, ET-743, Yondelis, ID0YZQ2TCP
cas 114899-77-3
(-)-(1’R,6R,6aR,7R,13S,14S,16R)-5-Acetoxy-6′,8,14-trihydroxy-7′,9-dimethoxy-4,10,23-trimethyl-1′,2′,3′,4′,6a,7,12,13,14,16-decahydro-6H-spiro[6,16-(epithiopropanoxymethano)-7,13-epimino-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1′-isoquinolin]-19-one
Janssen seeks FDA approval for Yondelis drug to treat advanced STS
Janssen Research & Development is seeking approval from US Food and Drug Administration (FDA) for its Yondelis (trabectedin) to treat patients with advanced soft tissue sarcoma (STS).
http://www.pharmaceutical-technology.com/news/newsjanssen-yondelis-sts-4451060?WT.mc_id=DN_News
Trabectedin, also referred as ET-743 during its development, is a marine derived antitumoral agent discovered in the Carribean tunicate _Ecteinascidia turbinata_ and now produced synthetically. Trabectedin has a unique mechanism of action. It binds to the minor groove of DNA interfering with cell division and genetic transcription processes and DNA repair machinery.It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas. The European Commission and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and ovarian cancer.
Trabectedin (also known as ecteinascidin 743 or ET-743) is an anti-tumor drug. It is sold by Zeltia and Johnson and Johnson under the brand name Yondelis. It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas. The European Commission and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and ovarian cancer.
Discovery and development
The ecteinascidins (herein abbreviated ETs) are exceedingly potent antitumor agents isolated from the marine tunicate Ecteinascidia turbinata. Several ecteinascidins have been reported previously in the patent and scientific literature. See, for example U.S. Pat. No. 5,089,273, which describes novel compounds of matter extracted from the tropical marine invertebrate Ecteinascidia turbinata, and designated therein as ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and/or antitumor agents in mammals. U.S. Pat. No. 5,478,932 describes other novel ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo antitumor activity against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX- I human lung and MX- 1 human mammary carcinoma xenografts.
One of the ETs, ecteinascidin 743 (ET-743), is a tetrahydroisoquinoline alkaloid with considerable in vitro and in vivo antitumor activity in murine and human tumors, and potent antineoplastic activity against a variety of human tumor xenografts grown in athymic mice, including melanoma, ovarian and breast carcinoma.
ET-743 is a natural compound with the following structure:
ET-743 is also known with the generic name trabectedin and the trademark Yondelis®, and it is currently approved in Europe for the treatment of soft tissue sarcoma. The clinical development of trabectedin continues in phase 11/ III clinical trials in breast, ovarian and prostate cancer. A clinical development program of ET-743 in cancer patients was started with phase I studies investigating 1- hour, 3-hour, 24-hour, and 72-hour intravenous infusion schedules and a 1 hour daily x 5 (dx5) schedule. Promising responses were observed in patients with sarcoma, breast and ovarian carcinoma.
Therefore this new drug is currently under intense investigation in several phase 11/ III clinical trials in cancer patients with a variety of neoplastic diseases. Further information regarding the dosage, schedules, and administration of ET-743 for the treatment of cancer in the human body, either given alone or in combination is provided in WO 00/69441 , WO 02/36135, WO 03/39571 , WO 2004/ 105761 , WO 2005/039584, WO 2005/049031 , WO 2005/049030, WO 2005/049029, WO 2006/046080, WO 2006/005602, and PCT/US07/98727, which are incorporated by reference herein in their entirety.
A review of ET-743, its chemistry, mechanism of action and preclinical and clinical development can be found in Kesteren, Ch.
Van et al., Anti-Cancer Drugs, 2003, 14 (7), 487-502: “ET-743 (trabectedin, ET-743): the development of an anticancer agent of marine origin”, and references therein.
During the past 30 years medical oncologists have focused to optimise the outcome of cancer patients and it is just now that the new technologies available are allowing to investigate polymorphisms, gene expression levels and gene mutations aimed to predict the impact of a given therapy in different groups of cancer patients to tailor chemotherapy. Representative examples include the relationship between the Thymidylate Synthase (TS) mRNA expression and the response and the survival with antifolates, beta tubulin III mRNA levels and response to tubulin interacting agents, PTEN gene methylation and resistance to CPT- I l and, STAT3 over expression and resistance to Epidermal Growth Factor (EGF) interacting agents.
A molecular observation of potential clinical impact relates to the paradoxical relation between the efficiency of the Nucleotide Excision Repair (NER) pathway and the cytotoxicity of ET-743. In fact, tumour cells that are efficient in this DNA repair pathway appear to be more sensitive to ET-743. This evidence is in contrast with the pattern noted with platin based therapeutic regimens which are highly dependent on the lack of activity of this repair pathway (ie. an increase in ERCCl expression has been associated to clinical resistance to platinum-based anti-cancer therapy).
There are evidences on the key role of NER pathways on the cytotoxicity of ET-743 in cell lines. ET-743 binds to G residues in the minor groove of DNA forming adducts that distort the DNA helix structure and they are recognised by NER mechanisms (Pourquier, P. et al., 2001 , Proceedings of the American Association for Cancer Research Annual Meeting, Vol. 42, pp. 556. 92nd Annual Meeting of the American Association for Cancer Research. New Orleans, LA, USA. March 24-28, 2001. ISSN: 0197-016X). Takebayasi et al. (Nature Medicine, 2001 , 7(8), 961-966) have proposed that the presence of these DNA adducts in transcribed genes, blocks the Transcription Coupled NER (TC-NER) system by stalling the cleavage intermediates and producing lethal Single Strand Breaks (SSBs). It is known from Grazziotin et al (Proc.Natl.Acad.Sic.USA, 104: 13062- 13067) that the DNA adducts formed by exposure to ET-743 are transformed into double strand DNA breaks.
The fact that NER mediates ET-743 ‘s cytotoxicity has also been found in the yeast Saccharomyces cerevisae by Grazziotin et al. (Biochemical Pharmacology, 2005, 70, 59-69) and in the yeast Schizosaccharomyces pombe by Herrero et al. (Cancer Res. 2006, 66(16), 8155-8162).
In addition, Bueren et al. (Proceedings AACR Annual Meeting 2007, Abstract no. 1965) have been shown that ET-743 induces double-strand breaks in the DNA in early S phase that are detected and repaired by the Homologous Recombination Repair (HRR) pathway. In addition, Erba et al (Eur. J. Cancer, 2001 , 37(1), 97- 105) and Bueren et al (Proceedings AACR Annual Meeting 2007, Abstract no. 1965) have shown that inactivation/ mutations of genes related to the Double Strand Break detection such as DNA-PK, ATM and ATR and of genes related to Homologous Recombination Repair pathway, such as Fanconi Anemia genes, BRCAl , BRCA2 and RAD51 make cells more sensitive to trabectedin. Such unique finding is the opposite to the pattern with conventional DNA interacting agents, like in the case of microtubule poisons such as taxanes and vinorelbine.
Finally, pharmacogenomic studies prior have demonstrated that increased expression of the NER genes ERCCl and XPD in the tumor tissue does not impact the outcome of patients treated with
ET-743. However, the low expression of BRCAl in the tumor tissue is correlated with a better outcome in cancer patents treated with
ET-743. Further information can be found in WO 2006/005602, which is incorporated by reference herein in its entirety.
Three rare, autosomal recessive inherited human disorders are associated with impaired NER activity: xeroderma pigmentosum (XP), Cockayne Syndrome (CS), and trichothiodystrophy (Bootsma et al. The Genetic Basis of Human Cancer. McGraw-Hill, 1998, 245- 274). XP patients exhibit extreme sensitivity to sunlight, resulting in a high incidence of skin cancers (Kraemer et al. Arch. Dermatol. 123, 241-250, and Arch. Dermatol. 130, 1018- 1021). About 20% of XP patients also develop neurologic abnormalities in addition to their skin problems. These clinical findings are associated with cellular defects, including hypersensitivity to killing and mutagenic effects of UV, and inability of XP cells to repair UV-induced DNA damage (van Steeg et al. MoI. Med. Today, 1999, 5, 86-94).
Seven different NER genes, which correct seven distinct genetic XP complementation groups (XPA-XPG), have been identified (Bootsma et al. The Genetic Basis of Human Cancer. McGraw-Hill, 1998, 245-274). The human gene responsible for XP group G was identified as ERCC5 (Mudgett et al. Genomics, 1990, 8, 623-633; O’Donovan et al. Nature, 1993, 363, 185- 188; and Nouspikel et al. Hum. MoI. Genet. 1994, 3, 963-967). The XPG gene codes for a structure-specific endonuclease that cleaves damaged DNA ~5 nt 3′ to the site of the lesion and is also required non-enzymatically for subsequent 5’ incision by the XPF/ ERCCl heterodimer during the NER process (Aboussekhra et al. Cell, 1995, 80, 859-868; Mu et al. J. Biol. Chem. 1996, 271 , 8285-8294; and Wakasugi et al. J. Biol. Chem. 1997, 272, 16030- 16034). There is also evidence suggesting that XPG is also involved in transcription-coupled repair of oxidative DNA lesions (Le Page et al. Cell, 101 , 159- 171).
Takebayashi et al. (Cancer Lett., 2001 , 174: 1 15- 125) have observed an increase in heterozygosity loss and microsatellite instability in a substantial percentage of samples of ovarian, lung and colon carcinoma. Le Moirvan et al, (Int.J. Cancer, 2006,1 19: 1732- 1735) have described the presence of polymorphisms in the XPG gene in sarcoma patients. It is also known from Takebayashi et al. (Proceedings of the American Association forCancer Research Annual Meeting, March, 2001 , Vol. 42, pp. 813.92nd Annual Meeting of the American Association for Cancer
Research. New Orleans, LA, USA. March 24-28, 2001) that cells deficient in the NER system are resistant to treatment with ET-743 (Zewail-Foote, M. et al., 2001 , Chemistry and Biology, 8: 1033- 1049 and Damia, G. et al., 2001 , Symposium AACR NCI EORTC) and that the antiproliferative effects of ET-743 require a functional XPG gene.
Since cancer is a leading cause of death in animals and humans, several efforts have been and are still being undertaken in order to obtain an antitumor therapy active and safe to be administered to patients suffering from a cancer. Accordingly, there is a need for providing additional antitumor therapies that are useful in the treatment of cancer.
Trabectedin is a tetrahydroisoquinoline, a novel marine-derived antitumor agent isolated from the colonial tunicate Ecteinascidia turbinate. The drug binds to the minor groove of the DNA, bending the DNA towards the major groove, blocking the activation of genes in a unique way via several pathways, including selective inhibition of the expression of key genes (including oncogenes) involved in cell growth and drug resistance, inhibition of genetic repair pathways and inhibition of cell cycle progression leading to p53-independent programmed cell death.
In July 2003, the European Committee of Proprietary Medicinal Products (CPMP) recommended against granting marketing authorization to trabectedin for soft tissue sarcoma. PharmaMar appealed the decision in September 2003. Later that year, the CPMP rejected the company’s appeal. In 2006, the company filed another regulatory application for this indication and, finally, in 2007, a positive opinion was received in the E.U. for the treatment of metastatic soft tissue sarcoma. First commercialization of the product in the E.U. took place in October 2007 in the U.K. and Germany.
The compound is also available in several other countries. In 2008, the compound was filed for approval in the U.S. and the E.U. for the treatment of relapsed advanced ovarian cancer in combination with liposomal doxorubicin, and in 2009 approval was received in both countries. Trabectedin is available in several European countries, including the U.K. and Germany. Also in 2009 the drug candidate was approved in Philippines for the ovarian cancer indication.
The compound had been in phase II development by Johnson & Johnson for the treatment of prostate cancer; however, no recent development has been reported for this research. PharmaMar is evaluating the compound in phase II trials for the treatment of breast cancer. Additional early clinical trials are ongoing at the National Cancer Institute (NCI) to evaluate trabectedin for potential use in the treatment of advanced, persistent or recurrent uterine leiomyosarcomas and solid tumors.
In 2011, a regulatory application that had been filed in the U.S. seeking approval for the treatment of relapsed advanced disease in combination with liposomal doxorubicin was withdrawn by the company based on the FDA’s recommendation that an additional phase III study be conducted to obtain approval. In 2014, Janssen Research & Development, LLC submitted an NDA for trabectedin to the FDA for the treatment of patients with advanced soft tissue sarcoma (STS), including liposarcoma and leiomyosarcoma subtypes, who have received prior chemotherapy including an anthracycline.
Trabectedin was developed by PharmaMar, a subsidiary of Zeltia. The drug was being codeveloped and comarketed in partnership with Ortho Biotech, a subsidiary of Johnson & Johnson pursuant to an agreement signed in 2001. However, in 2008 the license agreement between the two companies was terminated.
The compound was granted orphan drug designation for the treatment of soft tissue sarcoma and for the treatment of ovarian cancer by the FDA and the EMEA. In 2011, orphan drug designation was granted in Japan for the treatment of malignant soft tissue tumor accompanied with chromosomal translocation. In 2009, the product was licensed to Taiho by PharmaMar in Japan for the treatment of cancer.
During the 1950s and 1960s, the National Cancer Institute carried out a wide ranging program of screening plant and marine organism material. As part of that program extract from the sea squirt Ecteinascidia turbinata was found to have anticancer activity in 1969.[1] Separation and characterisation of the active molecules had to wait many years for the development of sufficiently sensitive techniques, and the structure of one of them, Ecteinascidin 743, was determined by KL Rinehart at the University of Illinois in 1984.[2] Rinehart had collected his sea squirts by scuba diving in the reefs of the West Indies.[3]
Recently, the biosynthetic pathway responsible for producing the drug, has been determined to come from Candidatus Endoecteinascidia frumentensis, a microbial symbiont of the tunicate.[4] The Spanish company PharmaMar licensed the compound from the University of Illinois before 1994 and attempted to farm the sea squirt with limited success.[3]
Yields from the sea squirt are extremely low – it takes 1 tonne of animals to isolate 1 gram of trabectedin – and about 5 grams were believed to be needed for a clinical trial[5] so Rinehart asked the Harvard chemist E. J. Corey to search for a synthetic method of preparation. His group developed such a method and published it in 1996.[6] This was later followed by a simpler and more tractable method which was patented by Harvard and subsequently licensed to PharmaMar.[3] The current supply is based on a semisynthetic process developed by PharmaMar starting from Safracin B, an antibiotic obtained by fermentation of the bacterium Pseudomonas fluorescens.[7] PharmaMar have entered into an agreement with Johnson and Johnson to market the compound outside Europe.
Trabectedin was first dosed in humans in 1996.In 2007, the EMEA gave authorisation for the marketing of trabectedin, under the trade name Yondelis, for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. The agency’s evaluating committee, the CHMP observed that trabectedin had not been evaluated in an adequately designed and analyzed randomized trial against current best care, and that the clinical efficacy data was mainly based on patients with liposarcoma and leiomyosarcoma. However the pivotal study did show a significant difference between two different trabectedin treatment regimens, and due to the rarity of the disease the CHMP considered that marketing authorisation could be granted under exceptional circumstances.[8] As part of the approval PharmaMar agreed to conduct a further trial to identify whether any specific chromosomal translocations could be used to predict responsiveness to trabectedin.[9] Trabectedin is also approved in South Korea[10] and Russia.
In 2008 the submission was announced of a registration dossier to the European Medicines Agency (EMEA) and the FDA for Yondelis when administered in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer. In 2011, Johnson&Johnson voluntarily withdrew the submission in the United States following a request by the FDA for an additional Phase III study to be done in support of the submission.[11]
Trabectedin is also in phase II trials for prostate, breast and paediatric cancers.[12]
Structure
Trabectedin is composed of 3 tetrahydroisoquinoline moieties, 8 rings including one 10-membered heteocyclic ring containing a cysteine residue, and 7 chiral centers.
Biosynthesis
The biosynthesis of Trabectedin in Candidatus Endoecteinascidia frumentensis starts with a fatty acid loading onto the acyl-ligase domain of the EtuA3 module. A cysteine and glycine are then loaded as canonical NRPS amino acids. A tyrosine residue is modified by the enzymes EtuH, EtuM1, and EtuM2 to add a hydroxyl at the meta position of the phenol, and adding two methyl groups at the para-hydroxyl and the meta carbon position. This modified tyrosine reacts with the original substrate via a Pictet-Spangler reaction, where the amine group is converted to an imine by deprotonation, then attacks the free aldehyde to form a carbocation that is quenched by electrons from the methyl-phenol ring. This is done in the EtuA2 T-domain. This reaction is done a second time to yeid a dimer of modified tyrosine residues that have been further cyclized via Pictet-spangler reaction, yielding a bicyclic ring moiety. The EtuO and EtuF3 enzymes continue to post-translationally modify the molecule, adding several functional groups and making a sulfide bridge between the original cysteine residue and the beta-carbon of the first tyrosine to form ET-583, ET-597, ET-596, and ET-594 which have been previously isolated.[4] A third o-methylated tyrosine is added and cyclized via Pictet-Spangler to yield the final product.[4]
Proposed biosynthetic scheme for the biosynthesis of Trabecteden (ET-743)
Synthesis
The total synthesis by E.J. Corey used this proposed biosynthesis to guide their synthetic strategy. The synthesis uses such reactions as the Mannich reaction, Pictet-Spengler reaction, the Curtius rearrangement, and chiral rhodium-based diphosphine–catalyzed enantioselective hydrogenation. A separate synthetic process also involved the Ugi reaction to assist in the formation of the pentacyclic core. This reaction was unprecedented for using such a one pot multi-component reaction in the synthesis of such a complex molecule.
Org Lett 2000,2(7),993
The previously reported synthesis of 139221 (scheme 13922101a) has been investigated in order to find a more efficient, reproducible and economical route to work in the mutikilogram scale. Herein it is reported a new process which is simpler and proceeds with an overall yield of 54% (the original process, 35%). The condensation of intermediate aminolactone (I) (scheme 13922101a, intermediate (VII)) with acid (XLII) (the acid derived from scheme 13922101a, intermediate ester (IX)) by means of 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), and 1-hydroxy-7-azabenzotriazole (HOAt) in THF/dichloromethane gives the coupling product (XLIII), which is allylated with allyl bromide (XLIV) and Cs2CO3 in DMF yielding the allyl ether (XLV). The reduction of the lactone group of (XLV) with LiAlH2(OEt)2 in ethyl ether affords the lactol (XLVI), which is desilylated with KF in methanol to provide the phenolic compound (XLVII). The opening of the lactol ring of (XLVII) with simultaneous cyclization by means of Tf-OH in water/trifluoroethanol gives the hexacyclic intermediate (XLVIII), which is finally reductocondensed with KCN by means of LiAlH2(OEt)2 in THF to furnish the previously reported pentacyclic intermediate (XI) (scheme 13922101a, intermediate (XI)).
……………………………………………
Reaction of cyanosafracin B (I) with Boc2O in ethanol gives the amino-protected compound (II), which is treated with methoxymethyl bromide (MOM-Br), DIEA and DMAP in acetonitrile yielding the O-protected compound (III). The demethylation of (III) with NaOH in methanol affords the hydroxyquinone (IV), which is reduced with H2 over Pd/C and cyclized with bromochloromethane and Cs2CO3 in hot DMF to provide compound (V). Reaction of (V) with allyl bromide (VI) and Cs2CO3 in DMF gives the allyl ether (VII), which first is treated with TFA, phenyl isothiocyanate and HCl to yield the primary amine (VIII) and then protected at the free NH2 group with Troc-Cl and pyridine, to afford the amino protected compound (IX).Org Lett 2000,2(16),2545
……………………………….
Reaction of (IX) with MOM-Br and DIEA as before affords the ether (X), which is treated with Zn/HOAc in order to regenerate the primary amino group giving (XI). The reaction of (XI) with NaNO2 and HOAc eliminates the NH2 group, affording the primary alcohol (XII), which is esterified with the protected (S)-cysteine (XIII) by means of EDC and DMAP in dichloromethane furnishing the cysteine ester (XIV). Reaction of (XIV) with Bu3SnH and PdCl2(PPh3)2, followed by oxidation with (PhSeO)2O in dichloromethane gives the hydroxyketone (XV), which is cyclized with Tf2O and Ac2O yielding the heptacyclic compound (XVI). Elimination of the MOM protecting group with TMSCl and NaI in CH3CN/CH2Cl2 affords the phenolic compound (XVII).
…………………….
Intermediate (XVII) by a treatment with Zn and HOAc eliminates the Troc protecting group, giving the primary amine (XVIII). This compound by treatment with 4-formyl-1-methylpyridinium iodide (NMPC), DBU and oxalic acid in order to convert the nitrile group into an alcohol, provides compund (XIX), which is finally cyclized with 2-(3-hydroxy-4-methoxyphenyl)ethylamine (XX) by means of SiO2 / EtOH, followed treatment with and AgNO3 in acetonitrile/water.
……………………….
The reaction of cyanosafracin B (I) with Boc2O in ethanol gives the amino protected compound (II), which is treated with Mom-Br, DIEA and DMAP in acetonitrile yielding the O-protected compound (III). The demethylation of (III) with NaOH in methanol affords the hydroxyquinone (IV), which is reduced with H2 over Pd/C and cyclized with bromochloromethane and Cs2CO3 in hot DMF providing the methylenedioxy compound (V). The reaction of (V) with acetyl chloride and pyridine in dichloromethane gives the acetate (VI), which is treated with TFA, phenyl isothiocyanate and HCl yielding the primary amine (VII). Finally, this compound is treated with phthalic anhydride (VIII) and CDI in dichloromethane to afford the target phthalimide (phthalascidin Pt-650)
………………………………
http://pubs.acs.org/doi/abs/10.1021/ol0056729
Enantioselective Total Synthesis of Ecteinascidin 743
Ecteinascidins are a group of marine alkaloid having antineoplasticity which is isolated from the extracted products from the marine tunicate habitat of the Caribbean sea by a very small amount. Arming the ecteinascidins, Et 743 has a very strong antineoplastic activity, studies to put it into practical use as a carcinostatic agent are limited, and the phase II clinical tests are now being carried out in ten countries in Europe and America. It is known that Et 743 has an effect of depressing the proliferation of cancer cells by 10 to 100 times more potent than (IC50=0.1-1 nM) Toxol, Camptotesin, Adriamycin or Mitomycin which are currently used carcinostatic agents.
From the background mentioned above, various studies for synthesis were carried out; however, the complete synthesis was only reported by Prof. E. J. Corey of Harvard University in the U.S.A. (J. Am. Chem. Soc. 1996, 118, 9202-9203, reference document A).
In the process of the total synthesis disclosed in Document A (refer to page 9202), the main feature of the process is that Et 743 is synthesized from the analogous compound to the compound represented by general formula 1 of the present invention via intermediates 4 and 8. That is, according to said process, the C4 site of ring B (regarding the location of rings, and the sites of atoms comprising the 6 membered ring, refer to general formula 1), which composes a 6 membered ring, is formed from the intermediate 4 at the first step. Since the atom C4 composing the ring B of the 6-membered ring H, which lacks reactivity, is bonded, it becomes necessary to perform an oxidation reaction at the C4 site on the B ring. This oxidation reaction is not effective and is carried out under harsh conditions; therefore production on an industrial scale is difficult, and also the yield is not good. Further, since the atom N12 site of the synthesized intermediate is substituted by an alkyl group which lacks reactivity, in this case substituted by a methyl group, it is not suited to the synthesis of various compounds. Although total synthesis was reported, the supplying source of Et 743 still depends on the natural sample whose supply is very scarce. Therefore, the establishment of the method for a large scale production of Et 743 is desired and requires accomplishing an effective synthesizing process.
Since ET 743 is known as a medicine having high antineoplasticity, and phthalascidin induced from the intermediate product at the synthesis of Et 743 displays the same activity to ET 743, the establishment of an effective and mild method for synthesis of ET 743 and analogous compounds thereof is strongly desired.
Therefore, the subject of the present invention is to accomplish the effective method for total synthesis of Et 743, and further, to provide not only Et 743 but also analogous compounds.
To dissolve the subject, the present invention uses retrosynthetic analysis for easy synthesis. It will be possible to form a B ring by a ring forming reaction at the ortho position of phenol, which binds an A ring to inner molecular aldehyde in a compound generated by the 4-8 reaction. Further, the present invention contemplates that the generated compound by the 4-8 reaction can be synthesized based on the polycondensation reaction of general formula 4, and general formula 5 via a compound of general formula 3. Then the total synthesis of Et 743, which is the aimed compound, can be accomplished by way of the compounds represented by general formulae 5, 4, 3, 2 and 1 and the specific structure of general formulae 1 and 2. This synthetic route provides for the analogous compounds of Et 743.
Mechanism of action
The biological mechanism of action is believed to involve the production of superoxide near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis. The actual mechanism is not yet known, but is believed to proceed from reduction of molecular oxygen into superoxide via an unusual auto-redox reaction on a hydroxyquinone moiety of the compound following. There is also some speculation the compound becomes ‘activated’ into its reactive oxazolidine form.
Schematic of the unique and complex mode of action of trabectedin. The antitumor effects of trabectedin are due to multiple mechanisms involving DNA binding in the minor groove, interactions with DNA repair mechanisms, modulation of transcription regulation, and induction of microenvironment changes.
References
- Lichter et al. Worthen LW, ed. “Food-drugs from the sea. Proc: Aug 20–23, 1972.” 173. Marine Tech Soc. pp. 117–127.
- Rinehart KL (January 2000). “Antitumor compounds from tunicates”. Med Res Rev 20 (1): 1–27. doi:10.1002/(SICI)1098-1128(200001)20:1<1::AID-MED1>3.0.CO;2-A. PMID 10608919.
- “Potent cancer drugs made — Sea squirts provide recipe”.
- Rath CM et al (November 2011). “Meta-omic characterization of the marine invertebrate microbial consortium that produces the chemotherapeutic natural product ET-743”. ACS Chemical Biology 6 (11): 1244–56. doi:10.1021/cb200244t. PMC 3220770. PMID 21875091.
- “New Scientist”.
- E. J. Corey, David Y. Gin, and Robert S. Kania (1996). “Enantioselective Total Synthesis of Ecteinascidin 743”. J. Am. Chem. Soc. 118 (38): 9202–9203. doi:10.1021/ja962480t.
- C. Cuevas et al. (2000). “Synthesis of ecteinascidin ET-743 and phthalascidin PT-650 from cyanosafracin”. B. Org. Lett. 2: 2545–2548.
- “CHMP evaluation”.
- “PharmaMar website”.
- S.Korea approves Zeltia cancer drug Yondelis, Reuters.com, May 8, 2008
- Grogan, Kevin (3 May 2011). “J&J pulls submission for Zeltia’s Yondelis”. PharmaTimes Magazine (London, England). Online PharmaTimes. Archived from the original on 7 May 2011. Retrieved 7 May 2011.
- “PharmaMar website”.
 |
|
| Systematic (IUPAC) name | |
|---|---|
| (1′R,6R,6aR,7R,13S,14S,16R)-6′,8,14-trihydroxy-7′,9-dimethoxy-4,10,23-trimethyl-19-oxo-3′,4′,6,7,12,13,14,16-octahydrospiro[6,16-(epithiopropano-oxymethano)-7,13-imino-6aH-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1′(2′H)-isoquinolin]-5-yl acetate | |
| Clinical data | |
| AHFS/Drugs.com | International Drug Names |
| Licence data | EMA:Link |
| Legal status | |
| Routes | Intravenous |
| Pharmacokinetic data | |
| Bioavailability | Not applicable (IV only) |
| Protein binding | 94 to 98% |
| Metabolism | Hepatic (mostly CYP3A4-mediated) |
| Half-life | 180 hours (mean) |
| Excretion | Mostly fecal |
| Identifiers | |
| CAS number | 114899-77-3 |
| ATC code | L01CX01 |
| PubChem | CID 108150 |
| IUPHAR ligand | 2774 |
| DrugBank | DB05109 |
| ChemSpider | 16736970 |
| UNII | ID0YZQ2TCP |
| Chemical data | |
| Formula | C39H43N3O11S |
| Mol. mass | 761.84 g/mol |
……..
1 Corey, “Enantioselective Total Synthesis of Ecteinascidin 743“, J. Am. Chem. Soc. 1996, vol. 118, 9202-9203.
| 2 | * | Endo, “Synthetic Study on Ecteinascidin 743 Starting From D-Glucose“, Synlett 1999, No. 7, 1103-1105. |
| 3 | * | Endo, “Total Synthesis of Ecteinascidin 743“, J. Am. Chem. Soc. 2002, vol. 124, 6552-6554. |
| 4 | * | Hinterding, “Synthesis and In Vitro Evaluation of the Ras Farnesyltransferase Inhibitor Pepticinnamin E“, Angew. Chem. Int. Ed. 1998, 37, No. 9 1236-1239. |
| 5 | * | Tohma, “Synthesis of Optically Active alpha-Arylglycines: Stereoselective Mannich-Type Reaction with a New Chiral Template“, Synlett 2001, No. 7, 1179-1181.Hamprecht, D.W.; Berge, J.M.; Copley, R.C.B.; Eggleston, D.S.; Houge-Frydrych, C.S.V.; Jarvest, R.L.; Mensah, L.M.; O’Hanlon, P.J.; Pope, A.J.; Rittenhouse, S. Derivatives of the natural product SB-219383 and synthetic analogues: Potent inhibitors of bacterial tyrosyl tRNA synthetase 16th Int Symp Med Chem (September 18-22, Bologna) 2000, Abst PA-155Cuevas, C.; Perez, M.; Martin, M.J.; et al. Synthesis of ecteinascidin ET-743 and phathalascidin Pt-650 from cyanosafracin B Org Lett 2000, 2(16): 2545
|
| Patent | Submitted | Granted |
|---|---|---|
| Assay for identifying biological targets of polynucleotide-binding compounds [US2008096201] | 2008-04-24 | |
| Compounds of the saframycin-ecteinascidin series, uses, and synthesis thereof [US6936714] | 2004-07-01 | 2005-08-30 |
| Method For Total Synthesis Of Ecteinascidins And Intermediate Compounds Thereof [US7807833] | 2009-08-06 | 2010-10-05 |
| Method For Total Synthesis Of Ecteinascidins And Intermediate Compounds Thereof [US7820838] | 2009-02-05 | 2010-10-26 |
| Assay for identifying biological targets of polynucleotide-binding compounds [US7183054] | 2004-12-09 | 2007-02-27 |
KEBUZONE…….An antirheumatic agent.
Kebuzone (or ketophenylbutazone) is a non-steroidal anti-inflammatory drug.
Structural formula
4-(3-oxobutyl)-1,2-diphenylpyrazolidine-3,5-dione
- BRN 0308507
- Chebutan
- Chepirol
- Chetazolidin
- Chetil
- Copirene
- EINECS 212-715-7
- Hichillos
- Kebuzone
- Kebuzonum
- Kebuzonum [INN-Latin]
- Keobutane-jade
- Ketason
- Ketazone
- Ketophenylbutazone
- Ketophenylbutazonum
- KPB
- Pecnon
- Quebuzona
- Quebuzona [INN-Spanish]
- Recheton
- UNII-4VD83UL6Y6
Anti-inflammatory agents that are non-steroidal in nature. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions.They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects.
UV – range
 |
||||
| Conditions : Concentration – 1 mg / 100 ml | ||||
| The solvent designation graphics | Methanol |
Water |
0.1М HCl |
0.1M NaOH |
|---|---|---|---|---|
| Maximum absorption | 244 nm | – | 237 nm | 262 nm |
 |
448 | – | 404 | 617 |
| e | 14440 | – | 13020 | 19890 |
IR – spectrum
| Wavelength (μm) |
|---|
 |
| Wave number (cm -1 ) |
Reference
-
UV and IR Spectra. H.-W. Dibbern, R.M. Muller, E. Wirbitzki, 2002 ECV
-
NIST/EPA/NIH Mass Spectral Library 2008
-
Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman. Academic Press, 2000.
-
Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.
Brief background information
| Salt | ATC | Formula | MM | CAS |
|---|---|---|---|---|
| – | M01AA06 | C 19 H 18 N 2 O 3 | 322.36 g / mol | 853-34-9 |
| 4-(3-oxobutyl)-1,2-di(phenyl)pyrazolidine-3,5-dione | |
| Clinical data | |
|---|---|
| Legal status |
?
|
| Identifiers | |
| CAS number | 853-34-9 |
| ATC code | M01AA06 |
| PubChem | CID 3824 |
| ChemSpider | 3692 |
| UNII | 4VD83UL6Y6 |
| KEGG | D01567 |
| ChEBI | CHEBI:31749 |
| Chemical data | |
| Formula | C19H18N2O3 |
| Mol. mass | 322.35782 g/mol |
Application
-
anti-inflammatory
-
antirheumatic
-
Synthesis pathway
| Synthesis of a) |
|---|
   |
| Synthesis b) |
 |
Trade names
| Country | Trade name | Manufacturer |
|---|---|---|
| Germany | Kebuzon | Steiner |
| France | Ketazon | Beytout |
| Italy | Chetopir | Sarm |
| Ukraine | no | no |
Formulations
-
ampoules of 1 g / 5 ml;
-
250 mg capsule
Reference
-
Synthesis of a)
-
Denss, R. et al .: Helv. Chim. Acta (HCACAV) 40, 402 (1957).
-
material:
-
Kühn, M .: J. Prakt. Chem. (JPCEAO) 156 (II), 103 (1940).
-
-
-
Synthesis b)
-
AT 198 263 (Synfarma; appl. 1955).
-
References: Prepn: Deuss et al., US 2910481 (1959 to Geigy).
Review of pharmacology: Horakova et al.,Pharmacotherapeutica 1950-1959, 335-350 (1963), C.A. 60, 6072g (1964).
Metabolism: Nemecek et al., Arzneim.-Forsch. 16,1339 (1966); Queisnerova, Nemecek, Cesk. Farm. 20, 55 (1971), C.A. 75, 47077u (1971).
Herrenknecht, Christine; Guernet-Nivaud, Elisabeth; Lafont, Olivier; Guernet, Michel; Gueutin, Claire
Canadian Journal of Chemistry, 1988 , v. 66, pg. 1199 – 1202
Cizmarik; Lycka
Pharmazie, 1988 , v. 43, 11 pg. 794 – 795
Gueutin-Pelinard, Claire; Nivaud, Elisabeth; Boucly, Patrick; Guernet, Michel
Canadian Journal of Chemistry, 1981 , v. 59, pg. 759 – 762
Denss et al.
Helvetica Chimica Acta, 1957 , v. 40, pg. 402,406
Patent: CS124279 , 1965 ;Chem.Abstr., 1968 , v. 69, 52134r
SPOFA; United Pharmaceutical Work Patent: FR1500627 , 1965 ;Chem.Abstr., 1968 , v. 69, 96715k
Nippon Shinyaju Co., Ltd. Patent: US5811547 A1, 1998 ;
Fisnerova,L. et al. Collection of Czechoslovak Chemical Communications, 1974 , v. 39, pg. 624 – 633
NETOGLITAZONE
NETOGLITAZONE, isaglitazone
- 5-((6-((2-fluorophenyl)methoxy)-2-naphthalenyl)methyl)-2,4-thiazolidinedione
- MCC 555
- MCC-555
- netoglitazone
- RWJ-241947
Netoglitazone (MCC-555) is a hypoglycemic agent.
Synthesis
US 5594016
http://www.google.co.in/patents/US5594016
Reaction of aldehyde (III) with 2-fluorobenzyl alcohol (VIII) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF furnishes 6-(2-fluorobenzyloxy)naphthalene-2-carbaldehyde (IX) , which is then reduced with NaBH4 in ethanol/THF to give the naphthalenemethanol derivative (X). Halogenation of (X) by means of iodide, triphenylphosphine and imidazole in THF yields the naphthylmethyl iodide derivative (XI), which is finally condensed with thiazolidine-2,4-dione (IV) by means of HMPA and butyl lithium in THF.
Ueno, H.; Oe, T.; Suehiro, I.; Nakamura, F. (Mitsubishi Chemical Corp.); Naphthalene derivs.. EP 0604983; JP 1994247945; US 5594016 .
http://www.google.co.in/patents/EP0604983B1?cl=en
References
Sorbera, L.A.; Castañer, J.; Del Fresno, M.; Silvestre, J. (2002). “Netoglitazone”. Drugs of the Future 27 (2): 132.doi:10.1358/dof.2002.027.02.657482.
 |
|
| Systematic (IUPAC) name | |
|---|---|
| 5-[(6-[(2-fluorophenyl)methoxy]naphthalen-2-yl)methyl]-1,3-thiazolidine-2,4-dione | |
| Clinical data | |
| Legal status |
|
| Identifiers | |
| CAS number | 161600-01-7 |
| ATC code | ? |
| PubChem | CID 204109 |
| UNII | QOV2JZ647A |
| KEGG | D05150 |
| Chemical data | |
| Formula | C21H16FNO3S |
| Mol. mass | 381.420 g/mol |
| Pharmaceutical composition comprising a glitazone and a 4-oxobutanoic acid, and the use thereof for treating diabetes [US2005085489] | 2005-04-21 | |
| Compositions of a cyclooxygenase-2 selective inhibitor and a peroxisome proliferator activated receptor agonist for the treatment of ischemic mediated central nervous system disorders [US2005107387] | 2005-05-19 | |
| Pharmaceutical composition comprising an ACAT inhibitor and an insulin resistance reducing agent [US2005119314] | 2005-06-02 | |
| Medical devices to treat or inhibit restenosis [US2005149174] | 2005-07-07 | |
| Medicinal compositions containing diuretic and insulin resistance-improving agent [US2005288339] | 2005-12-29 | |
| Crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione [US2006149075] | 2006-07-06 | |
| Concomitant drug as therapeutic agent for inflammatory bowel disease [US2006177444] | 2006-08-10 | |
| Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes [US2004167178] | 2004-08-26 | |
| Crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione [US2003158241] | 2003-08-21 | |
| Pharmacological method for treatment of neuropathic pain [US2007249561] | 2007-10-25 |
| Patent | Submitted | Granted |
|---|---|---|
| Medicinal composition containing diabetes remedy [US7943584] | 2008-02-14 | 2011-05-17 |
| Medicinal compositions containing diuretic and insulin resistance-improving agent [US7199139] | 2004-03-18 | 2007-04-03 |
| Crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione [US6541493] | 2003-04-01 | |
| Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes [US6756360] | 2004-06-29 | |
| Roflumilast for the Treatment of Diabetes Mellitus [US8017633] | 2008-09-04 | 2011-09-13 |
| Combination of FBPase Inhibitors and Insulin Sensitizers for the Treatment of Diabetes [US2008004226] | 2008-01-03 | |
| Pharmaceutical Composition Comprising Ppar Regulator [US2008153882] | 2008-06-26 | |
| Pharmaceutical combination comprising vitamin k [US2009137614] | 2009-05-28 | |
| Pharmaceutical Composition Containing PPARgamma Agonist [US2009137626] | 2009-05-28 | |
| Pharmaceutical agent comprising insulin resistance improving agent [US2009124626] | 2009-05-14 | |
| ROFLUMILAST FOR THE TREATMENT OF DIABETES MELLITUS [US2011269750] | 2011-11-03 | |
| Combination treatment for diabetes mellitus [US2010179131] | 2010-07-15 | |
| Therapeutic agent for diabetes containing insulin resistance improving agent [US2007049515] | 2007-03-01 | |
| PHARMACEUTICAL COMBINATION COMPRISING VITAMIN K [US2011028499] | 2011-02-03 | |
| RESPIRATORY DISEASE TREATMENT [US8236786] | 2011-03-03 | 2012-08-07 |
NAVEGLITAZAR (LY519818)
NAVEGLITAZAR
2(S)-Methoxy-3-[4-[3-(4-phenoxyphenoxy)propoxy]phenyl]propionic acid
476436-68-7
C25 H26 O6, 422.4703
- CCRIS 9448
- LY 519818
- LY 9818
- LY519818
- LY9818
- Naveglitazar
- UNII-Y995M7GM0G
http://clinicaltrials.gov/search/intervention=NAVEGLITAZAR
Naveglitazar, a peroxisome proliferator-activated receptor (PPAR) modulator, had been in phase II clinical trials for the once-daily oral treatment of type 2 diabetes, however, no recent development for this indication has been reported. The compound was originally discovered through an ongoing research collaboration between Lilly and Ligand, but, in 2006, Lilly discontinued the development program.
Naveglitazar [LY519818; benzenepropanoic acid, alpha-methoxy-4-[3-(4-phenoxyphenoxy)propoxy], (alpha-S)-] is a nonthiozolidinedione peroxisome proliferator-activated receptor alpha-gamma dual, gamma-dominant agonist that has shown glucose-lowering potential in animal models and in the clinic.
Studies have been conducted to characterize the disposition, metabolism, and excretion of naveglitazar in mice, rats, and monkeys after oral and/or i.v. bolus administration.
………………………………
Martín JA, Brooks DA, Prieto L, González R, Torrado A, Rojo I, López de Uralde B, Lamas C, Ferritto R, Dolores Martín-Ortega M, Agejas J, Parra F, Rizzo JR, Rhodes GA, Robey RL, Alt CA, Wendel SR, Zhang TY, Reifel-Miller A, Montrose-Rafizadeh C, Brozinick JT, Hawkins E, Misener EA, Briere DA, Ardecky R, Fraser JD, Warshawsky AM.
Bioorg Med Chem Lett. 2005 Jan 3;15(1):51-5.
………………………………………..
http://www.google.im/patents/US20050020684?cl=un
EXAMPLE 153
′2-Methoxy-3-{3-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acid
The title compound was prepared from 3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester from Example 152, Step D with 4-(3-bromopropoxy)1-phenoxybenzene in a manner analogous as in Example 152, Step E. MS (ES) for C25H26O6[M+NH4]+: 440.2, [M+Na]+: 445.2. 1H-NMR (CDCl3, 200.15 MHz): 7.33-7.17 (m, 3H), 7.07-6.78 (m, 10H), 4.15 (dt, 4H, J=1.9, 6.2), 4.03 (dd, 1H, J=7.3, 4.3), 3.40 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.98 (dd, 1H, J=14.0, 7.5), 2.25 (qui, 2H, J=5.9)ppm.
DENAGLIPTIN
DENAGLIPTIN
(2S,4S)-1-[(2S)-2- amino-3,3-bis(4-fluorophenyl)propionyl]-4-fluoropyrrolidine-2-carbonitrile, (2S,4S)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile
1-[2(S)-Amino-3,3-bis(4-fluorophenyl)propionyl]-4(S)-fluoropyrrolidine-2(S)-carbonitrile
GSK-823093, 823093
811432-66-3 CAS TOSYLATE
483369-58-0 (free base)
Denagliptin (GSK-823093) having the structural formula D below is (2S,4S)-1-[(2S)-2- amino-3,3-bis(4-fluorophenyl)propionyl]-4-fluoropyrrolidine-2-carbonitrile, also named (2S,4S)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile
(D) – A –
Denagliptin is specifically disclosed in US Patent No. 7,132,443 and in WO 03/002531. In one embodiment, denagliptin is in the form of its hydrochloride salt as disclosed in Example 2 of WO 03/002531 or its tosylate salt as disclosed in WO 2005/009956. A class of this embodiment refers to denagliptin tosylate. Crystalline anhydrous denagliptin tosylate is disclosed in WO 2005/009956.
Denagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor which entered phase III clinical trials in 2006 for the treatment of type 2 diabetes at GlaxoSmithKline. Development of this compound was put on hold due to unfavorable preliminary data from preclinical long-term toxicity trials.
………………………
………………………..
http://www.google.com/patents/US7132443
Example 2
(2S,4S)-1-[(2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride
A. 3,3-Bis(4-fluorophenyl)-3-hydroxypropanoic acid.
To an anhydrous THF (80 mL) solution of n-butyl lithium (46 mL of 2.5 M, 115 mmol) at 0° C. was added dropwise diisopropylamine (11.13 g, 115 mmol) and the solution stirred for 10 minutes. Keeping the solution at 0° C., acetic acid (2.64 g, 44 mmol) was added dropwise and the mixture stirred for 10 min and it was then heated 50° C. After 30 min a heavy precipitate had formed and the solution was allowed to cool. A solution of 4,4′-diflurobenzophenone (9.6 g, 0.044 mol) in THF (50 mL, anhydrous) was added at 0° C., and the solution stirred at room temperature overnight. Water (100 mL) and diethyl ether (100 mL) were added and the aqueous layer was separated and acidified with 1M HCl to pH 3. The organics were extracted with ethyl acetate (3×200 mL) followed by drying over MgSO4. Filtration and removal of the solvent in vacuo yielded a crude white solid that could be washed with cold CHCl3 to remove trace amounts of the benzophenone. The solid was dried under high vacuum yielding 5.63 g (20.2 mmol, 46% yield) of compound A as a white solid.
1H NMR (d6-DMSO) 400 MHz δ 12.4 (s(br), 1H), 7.48–7.39 (m, 4H), 7.19–7.02 (m, 4H), 5.91 (s(br), 1H), 3.25 (s, 2H) ppm.
B. 3,3-Bis(4-fluorophenyl)acrylic acid.
To a 20% solution of sulfuric acid in acetic acid (50 mL, V/V) was compound A (5.6 g, 20.2 mmol) and the mixture stirred for 30 minutes at RT. To this solution was added H2O (500 mL) and the organics were extracted with ethyl acetate (3×150 mL) followed by drying over MgSO4. Filtration and removal of the solvent in vacuo yielded a white solid. The solid was dried under high vacuum yielding 4.97 g (19.1 mmol, 95% yield) of compound B as a white solid.
1H NMR (CDCl3) 400 MHz δ 7.27–7.21 (m, 2H), 7.19–7.13 (m, 2H), 7.10–6.95 (m, 4H), 6.26 (s, 1H) ppm.
C. 3,3-Bis(4-fluorophenyl)propanoic acid.
To a solution of compound B (2.5 g, 9.61 mmol) in ethyl acetate (250 mL) was added 10% palladium on carbon (50% w/w) and hydrogenated at 1 atmosphere of hydrogen for 12 hours. The heterogeneous solution was filtered through celite and concentrated in vacuo to provide a yellow oil. The oil was dried under high vacuum yielding 2.40 g (9.16 mmol, 95% yield) of compound C as a yellow oil.
1H NMR (d6-DMSO) 400 MHz δ 12.08 (brs, 1H), 7.40–7.30 (m, 4H), 7.15–7.05 (m, 4H), 4.45 (t, 1H, J=8.1 Hz), 3.05(d, 2H, J=8.1 Hz) ppm.
D. (4S,5R)-3-[3,3-Bis(4-fluorophenyl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one.
To a THF (50 mL, anhydrous) containing compound C (2.0 g, 7.63 mmol) was added N,N-diisopropylethylamine (1.18 g, 9.16 mmol) and then the solution cooled to −78° C. To this solution was added trimethylacetyl chloride (0.97 g, 8.01 mmol) and the solution warmed to 0° C. over 1 hour. The cloudy mixture was filtered and the filtrate added slowly over 10 min to a solution of the lithiated (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone at −78° C., which was prepared by the dropwise addition of n-butyl lithium (3.0 mL of 2.5 M, 7.63 mmol) to a THF (50 mL) solution of (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (1.35 g, 7.63 mmol) at −78° C. which had stirred for 10 min to provide the lithiated (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone. The yellow mixture was warmed to 0° C. and quenched with H2O (50 mL) and extracted with diethyl ether (3×250 mL) followed by drying over MgSO4. Filtration and removal of the solvent in vacuo yielded a solid. Flash chromatography (silica gel, 20% ethyl acetate/hexanes) provided compound D. The white solid was dried under high vacuum yielding 2.31 g (5.49 mmol, 72% yield) as a white solid.
1H NMR (d6-DMSO) 400 MHz δ 7.40–7.25 (m, 9H), 7.18–7.02 (m, 4H), 5.76 (d, 1H, J=7.6 Hz), 4.65 (m, 1H), 4.58 (t, 1H, J=7.6 Hz), 3.72 (dd, 1H, J=16.8, 7.0 Hz) 3.57 (dd, 1H, J=16.8, 7.0 Hz), 0.58 (d, 3H, J=6.7 Hz) ppm.
E. (4S,5R)-3-[(2S)-2-Azido-3,3-bis(4-fluorophenyl)propanoyl]-4-methyl-5-[(1E,3Z)-1-methylhexa-1,3,5-trienyl]-1,3-oxazolidin-2-one.
To a THF (50 mL anhydrous) solution containing compound D (2.0 g, 4.75 mmol) at −78° C. was added dropwise potassium bis(trimethylsilyl)amide (10.0 mL of 0.5 M toluene solution, 4.98 mmol). After stirring for 10 min 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide) (1.84 g, 5.94 mmol) in THF (10 mL, anhydrous) was added in one portion. After 3 minutes acetic acid was added (1.31 g, 21.8 mmol) at −78° C. and then the reaction quickly warmed to 30° C. and stirred for 1 hr at that temperature generating a light yellow solution. To this solution was added H2O (100 mL) and the organics were extracted with ethyl acetate (500 mL). After washing with sat NaHCO3 (100 mL) and drying over MgSO4 the solvent was reomved in vacuo yielding a yellow oil. Column chromatography (ethyl acetate/hexanes 1:9) provided compound E as a white solid. HPLC showed a single diastereoisomer. The white solid was dried under high vacuum yielding 1.71 g (3.70 mmol, 78% yield) as a white solid.
1H NMR (CDCl3) 400 MHz δ 7.42–7.35 (m, H), 7.25–7.18 (m, H), 7.10–7.06 (m, 2H), 7.05–6.92 (m, 2H), 5.95 (d, 1H, J=10.8 Hz), 5.05 (d, 1H, J=7.1 Hz), 4.60 (d, 1H, J=10.8 Hz), 4.38 (m, 1H), 0.95 (d, 3H, J=6.8 Hz) ppm.
F. (2S)-2-Azido-3,3-bis(4-fluorophenyl)propanoic acid.
To a THF/H2O (4:1, 50 mL) solution of compound E (1.5 g, 3.25 mmol) at 0° C. was added a solution of lithium hydroxide (0.272 g, 6.49 mmol) in hydrogen peroxide (1.50 mL of 30% soln in H2O, 48.75 mmol). The mixture was stirred at 0° C. for 1 hr and then quenched with Na2SO4 (6.3 g, 50 mL of 1.0 M solution in H2O). The THF was removed in vacuo and the solution acidified to pH 1 with 6.0 M HCl at 0° C. The organics were extracted with ethyl acetate (2×200 mL) followed by drying over MgSO4. Filtration and removal of the solvent in vacuo yielded a clear oil. Column chromatography (EtOAc/hexanes/acetic acid 50:50:1) provided compound F as a white solid. The solid was dried under high vacuum yielding 0.78 g (2.60 mmol, 80% yield) as a white solid.
1H NMR (CDCl3) 400 MHz δ 9.60(s(br), 1H), 7.25–7.10 (m, 4H), 7.10–6.95 (m, 4H), 4.50 (d, 2H, J=8.6 Hz) ppm.
G. (2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoic acid.
To an ethyl acetate (250 mL) solution of compound F (1.5 g, 4.95 mmol) was added 10% palladium on carbon (10% w/w) and hydrogenated at 1 atmosphere of hydrogen for 12 hr. The heterogeneous solution was filtered through celite (1 g) and the filtrate concentrated in vacuo to provide a clear oil. The oil was dried under high vacuum yielding 1.30 g (4.70 mmol, 95% yield) of compound G as a white solid.
1H NMR (d6-DMSO) 400 MHz δ 10.2(s(br), 1H), 7.38–7.27(m, 4H), 7.08–6.98 (m, 4H), 4.25 (d, 1H, J=8.3 Hz), 3.95 (d, 1H, J=8.3 Hz) ppm.
H. (2S)-2-[(tert-Butoxycarbonyl)amino]-3,3-bis(4-fluorophenyl)propanoic acid.
To a CH2Cl2 (150 mL) solution containing compound G (1.30 g, 4.69 mmol) was added triethylamine (2.37 g, 23.4 mmol) and di-tert-butyl dicarbonate (1.23 g, 5.63 mmol). After stirring for 12 hr H2O (50 mL) and CH2Cl2 (300 mL) were added and the solution acidified to pH 3 with 1.0 M HCl. Separation of the ethyl acetate layer followed by drying over MgSO4 and removal of the solvent in vacuo yielded a clear oil. The oil was dried under high vacuum yielding 1.68 g (4.4 mmol, 95% yield) of compound H as a white solid.
1H NMR (d6-DMSO) 400 MHz δ 12.4 (s(br), 1H), 7.35–7.22 (m, 4H), 7.15–6.95 (m, 4H), 4.78 (t, 1H, J=8.9 Hz), 4.25 (d, 1H, J=8.9 Hz), 3.05 (m, 1H), 1.20 (s, 3H), 1.15 (s, 6H) ppm.
I. (2S,4S)-1-[(2S)-2-(tert-Butoxycarbonyl)amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile.
To a DMF solution (25 mL anhydrous) was compound H (1.0 g, 2.65 mmol) and HATU (1.0 g, 2.65 mmol). To this solution was added N,N-diisopropylethylamine (0.462 mL, 2.65 mmol) and after 30 min (2S, 4S)-4-fluoro-2-pyrrolidinecarbonitrile 4-methylbenzenesulfonate (0.619 g, 2.12 mmol) and additional N,N-diisopropylethylamine (0.37 mL 2.12 mmol) were added. This solution was allowed to stir at RT for 12 hr and then saturated sodium bicarbonate (100 mL) was added. The resulting gummy mixture was extracted with ethyl acetate (3×100 mL) and the organics were washed with saturated NaCl (50 mL) followed by drying over MgSO4. Filtration and removal of the solvent in vacuo yielded a clear oil. The oil was chromatographed on silica gel (hexanes/EtOAc 4:1) to provide a white solid. The solid was dried under high vacuum yielding 815 mg (1.72 mmol, 65% yield) of compound I as a white solid.
1H NMR (CDCl3) 400 MHz δ 7.38–7.32 (m, 2H), 7.21–7.15 (m, 2H), 7.12–6.98(m, 4H), 5.15 (d, 1H, J=51 Hz), 5.03 (d, 1H, J=8.9 Hz, 4.89 (d, 1H, J=11.2 Hz), 4.86 (d, 1H, J=8.9 Hz), 4.40 (d, 1H, J=11.2 Hz), 3.83 (ddd, 1H, J=36.8, 12.1, 3.7 Hz), 3.05 (d, 1H, J=12.2 Hz), 2.62 (t, 1H, J=15.3 Hz), 2.25 (m, 1H), 1.38 (s, 9H) ppm.
J. (2S,4S)-1-[(2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride.
To compound I (0.5 g, 1.05 mmol) was added 4.0 N HCl in 1,4-dioxane (10 mL, 40 mmol) and after 3 hr diethyl ether (100 mL) was added. The resulting precipitate was collected by filtration and after drying under high vacuum 0.41 g (1.0 mmol, 95% yield) of compound J was obtained as a white solid.
1H NMR (d6-DMSO) 400 MHz δ 8.42 (s(br), 3H), 7.72–7.66 (m, 2H), 7.38–7.32 (m, 2H), 7.25–7.19 (m, 2H), 7.06–7.0 (m, 2H), 5.38 (d, 1H, J=51 Hz), 4.91 (d, 2H, J=8.8 Hz), 4.82 (d, 1H, J=11.3 Hz), 4.41 (d, 1H, J=11.3 Hz), 3.86 (ddd, 1H, J=39.2, 12.4, 3.1 Hz), 3.45 (q, 1H, J=12.4 Hz), 2.38–2.20 (m, 2H) ppm.
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PAPER
http://pubs.acs.org/doi/full/10.1021/op900178d
A recent paper from workers at GSK describes improvements to the synthesis of Denagliptin (12). The final chemical step is Boc deprotection of (11) with p-toluenesulphonic acid (p-TSA) in isopropanol (IPA). Some isolated batches of final product contained impurities 12A (~1%), 12B (~1%), and 12C (~0.3%). Investigation showed that these three impurities were not produced during the reaction but were produced in the dryer if there was any excess p-TSA in the filter cake during drying. These impurities could be avoided by washing the filter cake with 2 volumes of IPA prior to drying.
D.E. Paterson,* J.D. Powers, M. LeBlanc, T. Sharkey, E. Boehler, E. Irdam, and M.H. Osterhout (GlaxoSmithKline), Org. Process. Res. Dev.,2009, 13(5), 900-906.
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http://www.google.com.ar/patents/US7462641?cl=pt-PT
(2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt
EXAMPLE 1Preparation of (2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt, Form 1a) Preparation of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide
A reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline (130 g, 1 wt, 1 eq.), dichloromethane (520 mL, 4 vol), pyridine (55 mL, 0.4 vol, 1.2 eq), and Boc-anhydride (145 g, 1.1 wt, 1.2 eq.). The reaction solution was stirred at approximately 20° C. for 2 hours. The reactor was charged with ammonium bicarbonate (62 g, 0.5 wt, 1.44 eq), and was stirred at approximately 20° C. overnight. The reaction was filtered over a bed of celite (130 g, 1 wt), and the filter cake was washed with dichloromethane (260 mL, 2 vol). The filtrate was concentrated to a volume of 3 volumes, heptane (520 mL, 4 vol) was added, and again concentrated to a final volume of 3 volumes. Heptane (390 mL, 3 vol) was added, and the reaction was cooled to approx. 5° C. for 30 min.
The solid was collected by filtration, washed with heptane (260 mL, 2 vol), and then dried under vacuum at approximately 50° C. to constant weight. Yield: 88-90%.
b) Preparation of (2S,4S)-4-fluoropyrrolidine-2-carbonitrile para-toluenesulfonic acid
The reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide (116 g, 1 wt, 1 eq.), isopropyl acetate (578 mL, 5 vol), and pyridine (88 mL, 0.8 vol, 2.2 eq). The resulting slurry was stirred at approx. 20° C. Trifluoroacetic anhydride (77 mL, 1.0 wt, 1.1 eq.) was added over at least 30 minutes, maintaining the temperature at approx. 20° C. The reaction solution was stirred an additonal 1 hour at approx. 20° C. Water (578 mL, 5 vol) was added slowly, and the reaction mixture was stirred for 15 minutes. The stirring was stopped, the layers were allowed to separate, and the aqueous (lower) layer was discarded. The organic layer was concentrated under vacuum at a jacket temperature of approximately 50° C. to half volume. The reaction was diluted back up to 5 volumes with isopropyl acetate. The reactor contents were cooled to 20° C., and the reactor was charged with p-toluenesulfonic acid (94 g, 0.8 wt, 1 eq). The reaction was stirred for 2 hours, and GC analysis at this point should show complete consumption of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide. The reaction was concentrated to 3 volumes under full vacuum at a jacket temperature of approximately 50° C. and 2 volumes of isopropyl alcohol were added. The reaction was concentrated to a final volume of 4 volumes. The reaction was cooled to 0° C. and held for 30 minutes. The solids were collected by filtration, washed with isopropyl alcohol (1 vol), and then dried under vacuum at approx. 50° C. to constant weight. Yield: 68-71%.
c) Preparation of tert-Butyl{(1S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamate
A reactor was charged with N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-β-(4-fluorophenyl)-L-phenylalanine (400 g, 1 wt, 1 eq.), (2S,4S)-4-fluoropyrrolidine-2-carbonitrile para-toluenesulfonic acid (307.7 g, 0.77 wt, 1.01 eq.), O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexaflurophosphate [i.e. HATU] (408 g, 1.02 wt, 1.01 equiv.), and DMF (2.8L, 7 vol). The mixture was cooled to approximately 0° C. Hunig’s base (376 mL, 0.94 vol, 2.04 equiv.) was added over at least 30 minutes. The mixture was heated to approximately 25° C. and was stirred at this temperature until the reaction was complete (ca. 3 hours). MTBE (2.8L mL, 7 vol) was added, followed by water (2L, 5 vol) over at least 30 minutes to quench the reaction. The aqueous phase was extracted with MTBE (1.2L, 3 vol). The combined organic phases were washed with water (2L, 5 vol). The organic phase was concentrated under vacuum to 3 volumes, and ethanol (1.6L, 4 vol) was added. The reaction was further concentrated under vacuum to 3 volumes, and ethanol (1.6 L, 4 vol) was added. The reaction was further concentrated under vacuum to 3 volumes. Added ethanol (2L, 5 vol). The ethanol solution of tert-Butyl {(1 S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamatewas used directly in the next step.
d) Preparation of (2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt. Form 1
A 10L reactor equipped with overhead stirring was charged with a slurry of tert-Butyl {(1S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamate (500 g, 1 wt, 1 eq) in ethanol (3.5L, 7 vol). To this solution was added para-toluenesulfonic acid (403g, 0.806 wt, 2 eq). This solution was heated to 60° C., and was allowed to stir at this temperature for 12 hours. The reaction mixture was cooled to 5° C. and was stirred at this temperature for 30 minutes. The solids were collected by filtration, washed with ethanol (2×1 L), and dried to constant weight in a 50° C. vacuum oven. Yield: 70-80% over 2 steps.
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Augustyns, K. et al., “The Unique Properties of Dipeptidyl-Peptidase IV (DPP IV/CD26) and the Therapeutic Potential of DPP IV Inhibitors,” Current Medicinal Chemistry, V6, N4, 1999, pp. 311-327.
| US7132443 * | 26 Jun 2002 | 7 Nov 2006 | Smithklinebeecham Corporation | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
| WO2003002531A2 | 26 Jun 2002 | 9 Jan 2003 | Curt Dale Haffner | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
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DIABETES
MURAGLITAZAR(CAS-No. 331741-94-7), ROSIGLITAZONE (CAS-NO. 122320-73-4), PIOGLITAZONE (CAS-No. 111025-46-8), RAGAGLITAZAR(CAS-No. 222834-30-2), FARGLITAZAR(CAS-No. 196808-45-4), TESAGLITAZAR(CAS-No. 251565-85-2), NAVEGLITAZAR(CAS-No. 476-436-68-7), NETOGLITAZONE (CAS-NO. 161600-01-7), RIVOGLITAZONE (CAS-No. 185428-18-6), K-111 (CAS-No. 221564-97-2), GW-677954 (CAS-No. 622402-24-8), FK-614 (CAS-No 193012-35-0) and (−)-Halofenate (CAS-No. 024136-23-0).
| TABLE 1 | |
| INN or Research | |
| Code | Structure/Chemical Name |
| BIM-51077 | L-histidyl-2-methylalanyl-L-glutamyl-glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L- |
| aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-glutamyl-glycyl-L-glutaminyl-L-alanyl-L- | |
| alanyl-L-lysyl-L-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L- | |
| lysyl-2-methylalanyl-L-argininamide | |
| EXENATIDE | L-histidylglycyl-L-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-aspartyl-L-leucyl- |
| L-seryl-L-lysyl-glutaminyl-L-methionyl-L-glutamyl-L-glutamyl-L-glutamyl-L-alanyl-L-valyl-L- | |
| arginyl-L-leucyl-L-phenylalanyl-L-isoleucyl-L-glutamyl-L-tryptophyl-L-leucyl-L-lysyl-L- | |
| asparaginylglyclglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L- | |
| serinamide | |
| CJC-1131 | L-histidyl-D-alanyl-L-alpha-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha- |
| aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-alpha-glutamylglycyl-L-glutaminyl-L-alanyl-L- | |
| alanyl-L-lysyl-L-alpha-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl- | |
| L-lysylglycyl-L-arginyl-N6-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- | |
| yl)propionamido]ethoxy]ethoxy]acetyl]-L-lysin-amide | |
| LIRAGLUTIDE | L-histidyl-L-alanyl-L-glutamyl-glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-aspartyl-L- |
| valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-glutamyl-glycyl-L-glutaminyl-L-alanyl-L-alanyl-Nepsilon- | |
| (Nalpha-hexadecanoyl-gamma-L-glutamyl)-L-lysyl-L-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl- | |
| L-tryptophyl-L-leucyl-L-valyl-L-arginyl-glycyl-L-arginyl-glycine | |
| ZP-10 | H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe- |
| Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2 | |
| TOLBUTAMIDE |
 |
| TOLAZAMIDE |
 |
| GLIPIZIDE |
 |
| CARBUTAMIDE |
 |
| GLISOXEPIDE |
 |
| GLISENTIDE |
 |
| GLIBORNURIDE |
 |
| GLIBENCLAMIDE |
 |
| GLIQUIDONE |
 |
| GLIMEPIRIDE |
 |
| GLICLAZIDE |
 |
| METFORMIN |
 |
| ACARBOSE |
 |
| MIGLITOL |
 |
| VOGLIBOSE |
 |
| MURAGLITAZAR |
 |
| ROSIGLITAZONE |
 |
| PIOGLITAZONE |
 |
| RAGAGLITAZAR |
 |
| FARGLITAZAR |
 |
| TESAGLITAZAR |
 |
| NAVEGLITAZAR |
 |
| NETOGLITAZONE |
 |
| RIVOGLITAZONE |
 |
| K-111 |
 |
| GW-677954 |
 |
| FK-614 |
 |
| (−)-Halofenate |
 |
| REPAGLINIDE |
 |
| NATEGLINIDE |
 |
| MITIGLINIDE |
 |
| SITAGLIPTIN |
 |
| SAXAGLIPTIN |
 |
| VILDAGLIPTIN |
 |
| DENAGLIPTIN |
 |
| P32/98 |
 |
| NVP-DPP-728 |
 |
| SILDENAFIL |
 |
| VARDENAFIL |
 |
| TADALAFIL |
 |
| PRAMLINTIDE | L-lysyl-L-cysteinyl-L-asparaginyl-L-threonyl-L-alanyl-L-threonyl-L-cysteinyl-L-alanyl-L-threonyl- |
| L-glutaminyl-L-arginyl-L-leucyl-L-alanyl-L-asparaginyl-L-phenylalanyl-L-leucyl-L-valyl-L-histidyl- | |
| L-seryl-L-seryl-L-asparaginyl-L-asparaginyl-L-phenylalanylglycyl-L-prolyl-L-isoleucyl-L-leucyl-L- | |
| prolyl-L-prolyl-L-threonyl-L-asparaginyl-L-valylglycyl-L-seryl-L-asparaginyl-L-threonyl-L- | |
| tyrosinamide, cyclic (2−>7)disulfide | |
| ETOMOXIR |
 |
| HMR-1426 |
 |
| CETILISTAT |
 |
| SIBUTRAMINE |
 |
Additional information with regard to the preparation, suitable dosage forms and dose ranges of the glucagon-like-peptide-1 receptor agonists listed in Table 1 can be found in the following patents/patent applications: WO0334331, EP0981611, EP1180121, WO9808871 and WO0104156.
Zifaxaban, TY-602, Zhifeishaban 知非沙班……Tianjin Institute of Pharmaceutical Research China
Zifaxaban
Zifaxaban
cas 1378266-98-8
rotation (-)
C20 H16 Cl N3 O4 S
C20H16ClN3O4 S, M = 429.87
Tianjin Institute of Pharmaceutical Research
Deep vein thrombosis; Lung embolism
Factor Xa antagonist
TY-602; zhifeishaban; zifaxaban
Chinese J Struc Chem. 2014, 33 (7), 1091-1095.
(S) -5- chloro -N- ((2- oxo _3_ (4_ (2_ oxo _2H_-1-yl) phenyl) oxazolidin-5 -1,3_ yl) methyl) thiophene-2-carboxamide
5-Chloro-N-(5S)-2-oxo-3-[4-(2-oxopyridin-1(2H)-yl)phenyl]oxazolidin-5-ylimethyllthiophene-2-carboxamide]
The title compound(zifaxaban 2, C20H16ClN3O4 S, Mr = 429.87) was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. Zifaxaban crystallizes in monoclinic, space group P21 with a = 5.7900(12), b = 13.086(3), c = 12.889(3) A, β = 100.86(3)°, V = 959.1(3) A3, Z = 2, Dc = 1.489 g/cm3, F(000) = 444, μ = 0.342 mm-1, the final R = 0.0320 and wR = 0.0640 for 2717 observed reflections(I > 2σ(I)).
The absolute configuration of the stereogenic center in the title compound was confirmed to be S by single-crystal X-ray diffraction. Four existing intermolecular hydrogen bonds help to stabilize the lattice and the molecule in the lattice to adopt an L-shape conformation.
Zifaxaban was slightly more active than rivaroxaban 1 in in vitro assay against human FXa and therefore is promising as a drug candidate.
zifaxaban (first disclosed in CN102464658), useful for treating thromboembolic disorders. Zifaxaban, a factor Xa antagonist, is being developed by Tianjin Institute of Pharmaceutical Research, for treating deep vein thrombosis and pulmonary embolism (preclinical, as of November 2014). In May 2014, an IND was filed in China. In June 2014, the institute was seeking to outlicense this product.
In vivo within the cardiovascular, blood coagulation or blood analysis some have formed out of the process of forming a solid mass with the aggregation, called thrombosis, the formation of a solid mass called a thrombus blocks. Thrombosis is an abnormal flow of blood coagulation status due to platelet activation and coagulation factors are activated in accordance therewith.
The blood coagulation was originally a protective mechanism of the organism, there is a mutual antagonism in blood coagulation system and the anti-clotting system. Under physiological conditions, blood clotting factors continue to be activated to produce thrombin, fibrin formation trace, calm on the vascular endothelium, but these traces of fibrin and constantly being activated fibrinolytic system dissolution, while being activated coagulation factors are constantly mononuclear phagocyte system swallowed. The dynamics of the coagulation system and fibrinolysis system, which ensures the blood coagulation potential can also always ensure that the fluid state of the blood.
Sometimes, however, in certain factors can promote the coagulation process, breaking the above dynamic balance triggered the coagulation process, the blood can form a thrombosis or embolism, such as leading to myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism and other thromboembolic disease.
Thromboembolic disease is cardiovascular disease against the most serious diseases, is the first killer of human health. In China, with the improvement and increased aging of the population’s living standards, the incidence of such diseases, mortality, morbidity is increasing every year.
The existing anti-thromboembolic diseases into anti-platelet drugs, anticoagulants and fibrinolytic drugs. Among them, the anti-clotting drugs are the main contents of antithrombotic therapy, mainly thrombin inhibitors and vitamin K antagonists. Heparin and low molecular weight heparin, represented by the presence of oral thrombin inhibitor invalid, non-selective inhibition and high risk of bleeding and other shortcomings. Although warfarin is representative of vitamin K antagonists can be administered orally, but there are narrow therapeutic index, high risk of bleeding and other shortcomings.
Studies have shown that the coagulation process is usually divided into intrinsic coagulation pathway and the extrinsic coagulation pathway. Coagulation process involves a lot of coagulation factors, coagulation factor activated are each the next inactive clotting factor precursor is converted into the activated form. Endogenous, exogenous pathway final summary, the blood coagulation factor X is converted to Xa.
Therefore, theoretically, the direct inhibition of ¾ factor activity should produce effective anti-clotting effect, without the side effects of thrombin inhibitors with. As direct inhibition) (a factor activity on normal hemostasis reaction / adjustment process produces minimal impact. For example, platelets remain low catalytic activity of thrombin on the ability to respond to, and thus does not affect the formation of platelet thrombi, so bleeding integrated minimize the risk of the levy.
research also proved this point. Recently reported a variety of compounds can selectively inhibit efficient Xa, which play a preventive and / or treatment of thromboembolic disease effect (W003000256A1; CN00818966; US2007259913A1; US2007259913A1). Among them, rivaroxaban (Rivaroxaban) was listed in 2008 for hip or knee replacement surgery prophylaxis and treatment of venous thrombosis, with oral, fixed dose and other advantages.
rivaroxaban drawback is the high price of raw materials, low yield preparation, purification of the product is difficult, high production costs. Patent CN00818966 8 reported rivaroxaban synthetic routes as follows:
4
where the first reaction (Preparation of 4- (4-morpholino-3-yl) nitrobenzene) yield of only 17.6%, and rivaroxaban difficult purification.
………………………………
Patent
http://www.google.com/patents/CN103232446A?cl=en
(S) -5- chloro -N- ((2- oxo-3- (4- (2_ oxo -2H- pyridin-1-yl) phenyl) -1, 3_ oxazolidine -5 – yl) methyl) thiophene-2-carboxamide.
[0011] Meanwhile, patent CN201110337461.4 described formula (I) Preparation of the compound:
[0012]
……………………………………..
Patent
CN102464658
http://www.google.com/patents/CN102464658B?cl=en
Example 1
[0046] (S) -5- chloro -N- ((2- oxo-3- (4_ (2_ Batch oxo _2H_ piperidinyl) phenyl) _1,3_ oxazolidin-5-yl) methyl ) thiophene-2-carboxamide (II)
[0048] A, 1- (4- amino-phenyl) -IH- pyridin _2_ -one (Compound VII) is
[0049] The reaction flask was charged with 104g of pyridine -2 (IH) – one (Compound IX), 200g of iodoaniline (compound VIII), 26gCuI, 151g of potassium carbonate, 18g8- hydroxyquinoline, 500mlDMF, nitrogen, heated to reflux, Insulation reaction was stirred 10h. Filtered hot, the filtrate evaporated under reduced pressure to make the solvent, the residue was added ethyl acetate, IL, 0 ° C incubated with stirring lh, filtered and the solid dried, 2L acetonitrile and purified to give 98g dark red solid. Refined liquor was concentrated to 500ml, the ice bath was stirred lh, filtered to give a dark red solid 19g. Total product were 117g, yield 68.9%.
[0050] 1H-NMR (DMSO-Cl6), δ (ppm):… 5 306 (s, 2H), 6 236 (d, 1H), 6 406 (d, 1H), 6 601 (d,. 2H), 6. 977 (d, 2H), 7. 459 (m, 2H).
[0051] B, (R) -2- (2- hydroxy-3- ((2-oxo–2H- pyridin-1-yl) phenyl) amino) propyl) isoindoline-1,3- -dione (Compound V) is
[0052] The reaction flask was added 40gl_ (4- aminophenyl) -IH- pyridin-2-one (Compound VII), 45g (S) _N_ glycidyl phthalimide (Compound VI), 300ml95% ethanol, heating to reflux, the gradual emergence of solid insulation mixing IOh, cooled to room temperature, filtered, and the filter cake washed with ethanol (150ml X 2), and dried to give an off-white solid 38g.
[0053] The mother liquor was taken, evaporated to dryness under reduced pressure, was added 15g (Q-N_ glycidyl phthalimide (Compound VII), 150ml95% ethanol, heated to reflux, stirred incubated 10h, concentrated under reduced pressure, cooled to room temperature , stirred at room temperature for 2h, washed with ethanol and dried to give an off-white solid 33g.
[0054] A total of an off-white solid 71g, yield of 84.8%, without purification, was used directly in the next step.
[0055] 1H-NMR (DMS0_d6), δ (ppm):… 3 053 (m, 1H), 3 194 (m, 1H), 4 644 (m, 2H), 4 020 (m, 1H). , 5. 168 (d, 1H), 5. 851 (t, 1H), 6. 230 (m, 1H), 6. 404 (d, 1H), 6. 665 (d, 2H), 7. 041 ( d, 2H), 7. 435 (m, 1H), 7. 537 (m, 1H), 7. 855 (m, 4H).
[0056] C, ⑶-2- ((2- oxo-3- (4- (2_ oxo _2H_ pyridyl) phenyl) oxazolidin _5_ -1,3_ yl) methyl ) Preparation of isoindoline-1,3-dione (Compound IV) of the
[0057] The reaction flask was charged 50g Compound V, 27gN, N’- carbonyldiimidazole (⑶I), 4_ catalytic amount of dimethylaminopyridine (DMAP), 150mlN, N- dimethylformamide (DMF), stirred for 90 temperature ° C, the reaction was kept for 8 hours to make the solvent was evaporated under reduced pressure, added to IL of water, stirred and dispersed, filtered, washed with water (150mlX “, washed with ethanol (100ml X 1), dried to give a white solid 48g, yield of 90%.
[0058] 1H-NMR (DMSo-CI6), δ (ppm):…. 3 984 (m, 3H), 4 251 (t, 1H), 4 968 (m, 1H), 6 301 (m, 1H), 6. 459 (d, 1H), 7. 423 (d, 2H), 7. 514 (m, 1H), 7. 615 (m, 3H), 7. 892 (m, 4H).
[0059] D, (S) -5- (aminomethyl) -3- (4- (2_ oxo _2H_-1-yl) phenyl) oxazolidin _2_ -1,3_ one hydrochloride (compound III) Synthesis of
[0060] The reaction flask was charged 50g compound IV, 200ml of ethanol, 60ml aqueous methylamine (40%), heated to reflux, stirred incubated 2h, cooled, evaporated under reduced pressure to make the solvent to give a sticky solid.
[0061] added to 300ml of ethanol, 20ml of hydrochloric acid, heated to reflux, stirred incubated lh, cooled to room temperature, incubated with stirring 2h, filtered, washed with ethanol, and dried to obtain;. 34 5g of white solid, yield 88.7%.
1H-NMR (DMS0_d6), δ (ppm):…. 3 240 (m, 2H), 3 980 (m, 1H), 4 255 (m, 1H), 5 028 (m, 1H) , 6. 321 (m, 1H), 6. 475 (d, 1H), 7. 504 (m, 3H), 7. 634 (m, 3H), 8. 561 (s, 1H).
Ε, (S) -5- chloro -N – ((2- oxo-3- (4- (2-oxo–2Η- pyridin-1-yl) phenyl) oxazolidin _1,3_ 5-yl) methyl) thiophene-2-carboxamide Preparation of thiophene (II) of
The reaction flask was charged 15g Compound III, 200ml of tetrahydrofuran, 40ml of water was added with stirring 6. 2g of sodium carbonate was added dropwise 10g5- chloro-thiophene-2-carbonyl chloride (Compound II-1) in tetrahydrofuran IOOml, 30~35 ° C insulation stirred 5h, point board to control the reaction was complete.
to make the solvent was distilled off under reduced pressure, 50ml of water was added, stirring was filtered, the filter cake washed with water and dried to give 18. 5g of white solid.
200ml of acetic acid and purified room temperature overnight, filtered, and the filter cake washed with ethanol and dried to give a white solid 16g, 80% yield.
Melting point: 204 8 ~205 8 ° C;
1H-NMR (DMSo-CI6), δ (ppm):…. 3 623 (t, 2H), 3 893 (m, 1H), 4 230 (t, 1H), 4 871 (m, 1H), 6. 308 (t, 1H), 6. 468 (d, 1H), 7. 193 (d, 1H), 7. 426 (m, 2H), 7. 500 (m, 1H), 7. 637 (m, 4H), 8. 967 (t, 1H);
MS (ESI): m / z = 430 (M + H);
HPLC: rt (%) = 14. 38 (99. 62);
[a] 20d = -37 6 ° (c 0. 3004, DMS0);
WO-2014183667Acetic acid solvate of oxazolidinone derivative, preparation method for the solvate, and application thereof
WO-2014183665Oxazolidinone derivative crystal form I and preparation method and use thereof
WO-2014183666Oxazolidinone derivate crystal form II, preparation method therefor, and application thereo
SEE ABAN SERIES AT…………http://organicsynthesisinternational.blogspot.in/p/aban-series.html
/////////
TORCETRAPIB Revisted
Torcetrapib (CP-529,414, Pfizer) was a drug being developed to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease. Its development was halted in 2006 when phase III studies showed excessive all-cause mortality in the treatment group receiving a combination of atorvastatin (Lipitor) and torcetrapib.
Medical uses
Torcetrapib has not been found to affect either cardiovascular disease or risk of death in those already taking a statin.[1]
Mechanism
Torcetrapib acts (as a CETP inhibitor) by inhibiting cholesterylester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol to very low density or low density lipoproteins (VLDL or LDL). Inhibition of this process results in higher HDL levels (the “good” cholesterol-containing particle) and reduces LDL levels (the “bad” cholesterol).[vague][citation needed]
Development
The first step in the synthesis was a recently created reaction of amination to p-chlorotrifluoryltoluene, a reaction that was created by Dr. Stephen Buchwald at MIT.[2]
Development of the drug began around 1990; it was first administered in humans in 1999, and manufacturing at production scale began in Ireland in 2005.[3]
Pfizer had previously announced that torcetrapib would be sold in combination with Pfizer’s statin, atorvastatin (Lipitor); however, following media and physician criticism, Pfizer had subsequently planned for torcetrapib to be sold independently of Lipitor.[4]
Clinical trials
A 2004 trial (19 subjects, non-randomised) showed that torcetrapib could increase HDL and lower LDL with and without an added statin.[5]
Nine phase III studies were completed.[6][7][8][9][10][11][12][13][14][15]
Early termination of study
On December 2, 2006 Pfizer cut off torcetrapib’s phase III trial because of “an imbalance of mortality and cardiovascular events” associated with its use.[16] This was a sudden and unexpected event and as late as November 30, 2006 Jeff Kindler, Pfizer’s chief executive, was quoted, “This will be one of the most important compounds of our generation.”[16] In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone.[17] Pfizer recommended that all patients stop taking the drug immediately.[18]
Six studies were terminated early.[6] One of the completed studies found it raised systolic blood pressure and concluded “Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.”[19]
The drug cost $800m+ to bring into Phase III development.[20]
| A Concise Asymmetric Synthesis of Torcetrapib�, M. Guino, P. H. Phua, J-C. Caille and K. K. Hii, J. Org. Chem., 2007, 72, 6290-6293.doi:10.1021/jo071031gAbstract: Optically active torcetrapib was synthesized in seven steps from achiral precursors without the need for protecting groups, utilizing an enantioselective aza-Michael reaction to achieve asymmetry. |
Example 9 Anhydrous, (-)-(2R,4S)-4-[(3,5-Bιs-trιfluoromethyl-benzyl)-methoxycarbonyl-amιnol-2- ethyl-6-trιfluoromethyl-3,4-dιhydro-2H-quιnolιne-1 -carboxylic acid ethyl ester.
A 2.6g portion of 4(S)-[(3,5-bιs-tπfluoromethyl-benzyl)-methoxycarbonyl-amιno]-2(R)- ethyl-6-tπfluoromethyl-3,4-dιhydro-2H-quιnolιne-1 -carboxylic acid ethyl ester (a mixture of predominantly amorphous material with traces of ethanolate crystalline form; the title compound was also prepared in an analogous manner starting from pure amorphous or pure ethanolate material) was charged to 13 milliliters of hexanes and heated to effect a solution at about 60°C The heat was removed and the reaction was allowed to cool to ambient over a one hour period The reaction was seeded with anhydrous (-)-(2R,4S)-4-[(3,5-bιs-tπfluoromethyl-benzyl)- methoxycarbonyl-amιno]-2-ethyl-6-trιfluoromethyl-3,4-dιhydro-2H-quιnolιne-1 – carboxylic acid ethyl ester and granulated for eighteen hours under ambient conditions. Alternately, the anhydrous crystals may be prepared from hexanes without seeding. The product was collected by filtration and air dried. The isolated product X-ray pattern matched the calculated powder pattern. Density: 1.406 Crystal System: Trigonal
Microscopy: Well formed rods and equant (fractured rods) crystals demonstrating high birefringence when viewed across the C axis. Being in the Trigonal crystal system the crystals do not demonstrate birefringence when viewed down the C axis. The crystals demonstrate a cleavage plane perpendicular to the C axis Fusion Microsocopy In Type A oil dissolution at 50°C.
Dry — clear melt at 86°C.
NMR: No trace of ethanolate
Degree of crystallmity: Highly crystalline Hygroscopicity. Non-hygroscopic at 100% relative humidity over 48 hours.
Appearance: Free flowing white powder
References
- Clark, RW; Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, Cosgrove PG, Sand TM, Wester RT, Williams JA, Perlman ME, Bamberger MJ (January 22, 2004). “Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib”. Arteriosclerosis, Thrombosis, and Vascular Biology 24 (3): 490–497. doi:10.1161/01.ATV.0000118278.21719.17. PMID 14739125. Retrieved 2006-12-03.
- Clark, RW; Ruggeri RB; Cunningham D; Bamberger MJ (March 2006). “Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action”. Journal of Lipid Research 47 (3): 537–552. doi:10.1194/jlr.M500349-JLR200. PMID 16326978. Retrieved 2006-12-03.
- Davidson, MH; McKenny JM; Shear CL; Revkin JH (November 7, 2006). “Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels”. Journal of the American College of Cardiology 48 (9): 1774–1781. doi:10.1016/j.jacc.2006.06.067.PMID 17084249. Retrieved 2006-12-03.
- McKenny, JM; Davidson MH; Shear CL; Revkin JH (November 7, 2006). “Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels on a background of atorvastatin”. Journal of the American College of Cardiology 48 (9): 1782–1790.doi:10.1016/j.jacc.2006.06.066. PMID 17084250. Retrieved 2006-12-03.
Notes
- Keene, D; Price, C; Shun-Shin, MJ; Francis, DP (Jul 18, 2014). “Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients.”. BMJ (Clinical research ed.) 349: g4379. PMID 25038074.
- Buchwald, Stephen (July 23, 2004). “Research Projects”. Retrieved 2007-10-04.
- “Pfizer Begins Production at Torcetrapib/Atorvastatin Manufacturing Facility” (Press release). Pfizer. June 22, 2005. Retrieved 2006-12-03.
- Berenson, Alex (July 26, 2006). “Heart Pill to Be Sold by Itself”. Business (The New York Times). Retrieved 2006-12-03.
- Brousseau, ME; Schaefer EJ; Wolfe ML; Bloedon LT; Digenio AG; Clark RW; Mancuso JP; Rader DJ (April 8, 2004). “Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol” (abstract). New England Journal of Medicine 350 (15): 1505–1515. doi:10.1056/NEJMoa031766. PMID 15071125. Retrieved 2006-12-03.
- http://clinicaltrials.gov/ct2/results?term=torcetrapib
- http://clinicaltrials.gov/ct2/show/NCT00139061 Phase III Assess HDL-C Increase And Non-HDL Lowering Effect Of Torcetrapib/Atorvastatin Vs. Fenofibrate
- http://clinicaltrials.gov/ct2/show/NCT00134511 Phase III Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder
- http://clinicaltrials.gov/ct2/show/NCT00134485 Phase III Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia
- http://clinicaltrials.gov/ct2/show/NCT00134498 Phase III Study Comparing The Efficacy & Safety Of Torcetrapib/Atorvastatin And Atorvastatin In Subjects With High Triglycerides
- http://clinicaltrials.gov/ct2/show/NCT00267254 Phase III Clinical Trial Comparing Torcetrapib/Atorvastatin To Simvastatin In Subjects With High Cholesterol
- http://clinicaltrials.gov/ct2/show/NCT00138762 Phase III Study of Torcetrapib/Atorvastatin vs Atorvastatin Alone or Placebo in Patients With High Cholesterol
- http://clinicaltrials.gov/ct2/show/NCT00134173 Phase III Coronary IVUS Study to Compare Torcetrapib/Atorvastatin to Atorvastatin Alone in Subjects With Coronary Heart Disease (ILLUSTRATE)
- http://clinicaltrials.gov/ct2/show/NCT00137462 Phase III Lipitor Trial To Study The Effect Of Torcetrpib/Atorvastatin To Atorvastatin Alone.
- http://clinicaltrials.gov/ct2/show/NCT00136981 Phase III Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrpib/Atorvastatin to Atorvastatin Alone. (RADIANCE 1)
- Berenson, Alex (December 3, 2006). “Pfizer Ends Studies on Drug for Heart Disease”. The New York Times. Retrieved 2006-12-03. (registration required)
- Theresa Agovino (Associated Press) (December 3, 2006). “Pfizer ends cholesterol drug development”. Yahoo! News. Retrieved 2006-12-03.[dead link] Each study arm (torcetrapib + atorvastatin vs. atorvastatin alone) had 7500 patients enrolled; 51 deaths were observed in the atorvastatin alone arm, while 82 deaths occurred in the torcetrapib + atorvastatin arm. (Link dead as of 15 January 2007)
- Associated Press (December 2, 2006). “Pfizer cuts off cholesterol drug trials”. Yahoo! News (Yahoo.com). Retrieved 2006-12-03.[dead link] (Link dead as of 15 January 2007)
- Bots et al.; Visseren, Frank L; Evans, Gregory W; Riley, Ward A; Revkin, James H; Tegeler, Charles H; Shear, Charles L; Duggan, William T et al. (July 2007). “Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial”. The Lancet 370 (9582): 153–160. doi:10.1016/S0140-6736(07)61088-5.
- Cutler, D. M. (2007-03-29). “The Demise of the Blockbuster?”. The New England Journal of Medicine (Massachusetts Medical Society) 356 (13): 1292–1293. doi:10.1056/NEJMp078020.ISSN 1533-4406. PMID 17392299. Retrieved 2007-04-23.
External links
Troglitazone (Romglizone) an antidiabetic Revisted
Troglitazone, GR-92132X, CI-991, CS-045, Romozin, Prelay, Rezulin, Noscal
CAS 97322-87-7
- CI 991
- CS 045
- Depotox
- GR 92132X
- Noscal
- Rezulin
- Romglizone
- Troglitazone
Withdrawn – 2000
Crystals, m.p. 184-6 °C
Daiichi Sankyo Co., Ltd. INNOVATOR
Troglitazone
Type-II diabetes mellitus (DM) is characterized by insulin resistance, glucose intolerance, increased hepatic glucose production, and decreased pancreatic insulin secretion. In the past, the drug classes used for type-II DM have targeted the last three of these abnormalities. Sulfonylurea agents bind to ATP-dependent potassium efflux channels to stimulate pancreatic insulin secretion at b-islet cells. The biguanides decrease hepatic glucose production, and thea-glucosidase inhibitors delay carbohydrate digestion to improve glucose tolerance. Until the recent advent of the thiazolidinedione drugs (ciglitazone was first synthesized in 1982), there was no therapy specifically targeting insulin resistance. Drugs of this class all share a common thiazolidine-2-4-dione structure. Marketed drugs of this class include pioglitazone, rosiglitazone, and troglitazone [Figure 1] – the first to reach the market.
The “glitazones” act to reduce insulin resistance and also correct hyperglycemia, hyperinsulinemia, and hypertriglyceridemia. Thiazolidinediones bind to the gisoform of the peroxisome proliferator-activated receptor (PPARg), a nuclear transcription factor that regulates the expression of several insulin-responsive genes involved in glucose and lipid metabolism, and the differentiation of fibroblasts into adipose tissue. The net effect is to reduce insulin resistance, mostly through increased glucose uptake by muscle tissue; however, the exact biochemical mechanism is unclear. Effects on lipid metabolism include decreased triglycerides and free fatty acids, and a slight increase or no change in high-density lipoprotein, low-density lipoprotein, and total cholesterol. There also appear to be acute increases in insulin-stimulated glucose uptake that are PPAR-independent. This effect is too rapid to occur via gene transcription, and in the case of troglitazone may result from action of its quinone metabolite. Troglitazone also decreases production of various inflammatory mediators and may antagonize TNFa.
Troglitazone�s most common adverse effect is fluid retention, which may increase preload and induce cardiac hypertrophy. Troglitazone is contraindicated in congestive heart failure, and cases of pulmonary edema have been reported. Troglitazone induces colon polyps in murine models and is therefore contraindicated for patients with familial polyposis coli. Troglitazone and pioglitazone (but not rosiglitazone) induce cytochrome P450 (CYP) 3A4. This enzyme induction can result in decreased drug levels or drug effects with estradiol, terfenadine, cyclosporine, simvistatin, tacrolimus, and other drugs metabolized by CYP 3A4. A small fraction of troglitazone is metabolized by CYP (not 3A4) to an active quinone metabolite, but it is mostly conjugated to sulfate and glucuronide. Troglitazone enhances the anticoagulant effect of warfarin, probably through competitive serum protein binding, and has other drug interactions at the PPAR level. Troglitazone interferes with gemfibrozil’s binding to PPARa, and may decrease NSAID effectiveness by competing for PPARg.
Rezulin� (tradename troglitazone by Parke-Davis) was FDA approved January 29, 1997, and was first marketed in March 1997. Over 600,000 American patients received troglitazone, with an additional 200,000 in Japan. Pre-marketing studies showed 1.9% of patients on troglitazone developed serum alanine aminotransferase levels in excess of three times the upper limit of normal, vs. 0.6% with placebo. Such hepatotoxicity was typically asymptomatic and reversible. A few patients developed overt liver injury, and two liver biopsies among these patients showed hepatocellular injury pattern. It was estimated that only 1 patient in 50,000 to 60,000 would die from liver failure or require liver transplantation. On November 3, 1997, the FDA released a warning regarding 150 adverse events with troglitazone, 35 with acute liver injury, and 3 deaths in Japan from liver failure. The warnings and restrictions about troglitazone were extended in December 1997, July 1998, and June 1999. Troglitazone was voluntarily withdrawn from the US market on March 21, 2000, after it had been demonstrated that Rezulin� was more toxic than either Avandia� (rosiglitazone) or Actos�(pioglitazone).
Troglitazone hepatotoxicity appears to be idiosyncratic. The onset is typically delayed, usually 2-5 months after initiating therapy, although one case was reported after only four doses. Although hypersensitivity has been suggested in several cases, the hallmarks of immune mechanisms, fever, rash, and eosinophilia, are usually absent. Histologic specimens usually show hepatocellular injury, bridging fibrosis and necrosis, intracanalicular cholestasis, and lack of regenerative activity. Samples vary in the amount of WBC infiltration (with or without eosinophils) and steatosis.
Idiosyncratic (or host-dependent) drug reactions are either due to hypersensitivity or to metabolic aberrations. It is not clear whether troglitazone hepatotoxicity is caused by hypersensitivity. Proposed metabolic aberrations include oxidation/reduction reactions with the a-tocopherol moiety on troglitazone (although it is usually considered an antioxidant), reactions from the quinone metabolite (similar to acetaminophen’s quinone metabolite), and genetic variations in cytokines and their receptors, the apoptosis cascade, mitochondrial respiration, and regenerative response. It is unlikely that CYP polymorphisms play a major role, as the incidence of troglitazone hepatotoxicity is too low. Two cases of hepatic toxicity associated with rosiglitazone have also been reported. Although the patients had co-morbidities, exposures to other drugs, and one case may have been due to shock, these cases suggest that hepatotoxicity may be an emerging “class-effect” of thiazolidinediones.
Troglitazone (Rezulin, Resulin, Romozin, Noscal) is an antidiabetic and anti-inflammatory drug, and a member of the drug class of the thiazolidinediones. It was prescribed for patients with diabetes mellitus type 2.[1] It was developed by Daiichi Sankyo Co.(Japan). In the United States, it was introduced and manufactured by Parke-Davis in the late 1990s, but turned out to be associated with an idiosyncratic reaction leading to drug-induced hepatitis. One F.D.A. medical officer evaluating troglitazone, John Gueriguian, did not recommend its approval due to potential high liver toxicity,[2] but a full panel of experts approved it in January 1997.[3] Once the prevalence of adverse liver effects became known, troglitazone was withdrawn from the British market in December 1997, from the United States market in 2000, and from the Japanese market soon afterwards. It didn’t get approval in the rest of Europe.
Approval history
Troglitazone was developed as the first anti-diabetic drug having a mechanism of action involving the enhancement of insulin sensitivity. At the time it was widely believed that such drugs, by addressing the primary metabolic defect associated with Type 2 diabetes, would have numerous benefits including avoiding the risk of hypoglycemia associated with insulin and earlier oral antidiabetic drugs. It was further believed that reducing insulin resistance would potentially reduce the very high rate of cardiovascular disease that is associated with diabetes.[4][5]
Parke-Davis/Warner Lambert submitted the diabetes drug Rezulin for U.S. Food and Drug Administration (F.D.A.) review on July 31, 1996. The medical officer assigned to the review, Dr. John L. Gueriguian, cited Rezulin’s potential to harm the liver and the heart and he questioned its viability in lowering blood sugar for patients with adult-onset diabetes, recommending against the drug’s approval. After complaints from the drugmaker, Gueriguian was removed on November 4, 1996 and his review was purged by the F.D.A.[6][7]Gueriguian and the company had a single meeting, at which Gueriguian used “intemperate” language; The company said it’s objections were based on inappropriate remarks made by Gueriguian.[8] Parke-Davis said at the advisory committee that the risk of liver toxicity was comparable to placebo and that additional data of other studies confirmed this.[9] According to Peter Gøtzsche, when the company provided these additional data one week after approval, they showed a substantial greater risk for liver toxicity.[10]
The F.D.A. approved the drug on January 29, 1997, and it appeared in pharmacies in late March. At the time Dr. Solomon Sobel, a director at the F.D.A., overseeing diabetes drugs, said in a New York Times interview that adverse effects of troglitazone appeared to be rare and relatively mild.[11]
Glaxo Wellcome P.L.C. received approval from the British Medicines Control Agency (MCA) to market troglitazone, as Romozin, in July 1997.[12] After reports of sudden liver failure in patients receiving the drug, the Parke-Davis and the FDA added warnings to the drug label requiring monthly monitoring of liver enzyme levels.[13] Glaxo removed troglitazone from the market in Britain on December 1, 1997.[6] Glaxo had licensed the drug from Sankyo Company of Japan and had sold it in Britain from October 1, 1997.[14][15]
On May 17, 1998, a 55-year old patient named Audrey LaRue Jones died of acute liver failure after taking troglitazone. Importantly, she had been monitored closely by physicians at the National Institutes of Health as a participant in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) diabetes prevention study.[16][17] This called into question the efficacy of the monitoring strategy. The N.I.H. responded on June 4 by dropping troglitazone from the study.[7][18] Dr. David J. Graham, an F.D.A. epidemiologist charged with evaluating the drug, warned on March 26, 1999 of the dangers of using it and concluded that patient monitoring was not effective in protecting against liver failure. He estimated that the drug could be linked to over 430 liver failures and that patients incurred 1,200 times greater risk of liver failure when taking Rezulin.[7][19] Dr. Janet B. McGill, an endocrinologist who had assisted in the Warner–Lambert’s early clinical testing of Rezulin, wrote in a March 1, 2000 letter to Sen. Edward M. Kennedy (D-Mass.): “I believe that the company . . . deliberately omitted reports of liver toxicity and misrepresented serious adverse events experienced by patients in their clinical studies.”[20]
On March 21, 2000, the F.D.A. withdrew the drug from the market.[21] Dr. Robert I. Misbin, an F.D.A. medical officer, wrote in a July 3, 2000 letter to the House Energy and Commerce Committee of strong evidence that Rezulin could not be used safely, after having been threatened by the FDA with dismissal in March 2000.[6][22] By that time the drug had been linked to 63 liver-failure deaths and had generated sales of more than $2.1 billion for Warner-Lambert.[19] The drug cost $1,400 a year per patient in 1998.[15] Pfizer, which had acquired Warner-Lambert in February 2000, reported the withdrawal of Rezulin cost $136 million.[23]
Lawsuits
In 2009 Pfizer Inc. resolved all but three of 35,000 claims over its withdrawn diabetes drug Rezulin for a total of about $750 million. Pfizer, which acquired rival Wyeth for almost $64 billion, paid about $500 million to settle Rezulin cases consolidated in federal court in New York, according to court filings. The company also paid as much as $250 million to resolve state-court suits. In 2004, it set aside $955 million to end Rezulin cases.[24]
Mode of action
Troglitazone, like the other thiazolidinediones (pioglitazone and rosiglitazone), works by activating peroxisome proliferator-activated receptors (PPARs).
Troglitazone is a ligand to both PPARα and – more strongly – PPARγ. Troglitazone also contains an α-tocopheroyl moiety, potentially giving it vitamin E-like activity in addition to its PPAR activation. It has been shown to reduce inflammation:[25] troglitazone use was associated with a decrease of nuclear factor kappa-B (NF-κB) and a concomitant increase in its inhibitor (IκB). NFκB is an important cellular transcription regulator for the immune response.
rosiglitazone, ciglitazone, darglitazone, englitazone, rosiglitazone, pioglitazone, rosiglitazone, troglitazone
| Systematic (IUPAC) name | |
|---|---|
| (RS)-5-(4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl)thiazolidine-2,4-dione | |
| Clinical data | |
| Legal status |
?
|
| Pharmacokinetic data | |
| Half-life | 16-34 hours |
| Identifiers | |
| CAS number | 97322-87-7 |
| ATC code | A10BG01 |
| PubChem | CID 5591 |
| IUPHAR ligand | 2693 |
| DrugBank | DB00197 |
| ChemSpider | 5389 |
| UNII | I66ZZ0ZN0E |
| KEGG | D00395 |
| ChEBI | CHEBI:9753 |
| ChEMBL | CHEMBL408 |
| Chemical data | |
| Formula | C24H27NO5S |
| Mol. mass | 441.541 g/mol |
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A new synthesis of [14C]-labeled CS-045 has been reported: The condensation of 5-acetoxy-2-hydroxy-3,4,6-trimethylacetophenone (I) with phenoxyacetone (II) by means of morpholine and p-toluenesulfonic acid in refluxing benzene gives 6-acetoxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-3,4-dihydro-2H-benzo[b]pyran-4-one (III), which is reduced with NaBH4 in methanol to the corresponding carbinol (IV). The dehydration of (IV) by means of p-toluenesulfonic acid in refluxing benzene affords 2-acetoxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-2H-benzo[b]pyran (V), which is hydrogenated with H2 over Pd/C in methanol to give the corresponding 3,4-dihydro derivative (VI). The hydrolysis of (VI) with NaOH in methanol yields the corresponding phenol (VII), which is chloromethylated with paraformaldehyde and dry HCl in dioxane to afford 2-[4-(chloromethyl)phenoxymethyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[b]pyran-6-ol (VIII). The protection of (VIII) with chloromethyl methyl ether by means of potassium tert-butoxide in THF gives the corresponding 6-(methoxymethoxy) derivative (IX), which is condensed with [5-14C]-thiazolidine-2,4-dione (X) by means of butyllithium in THF-HMPT to yield 5-[4-[6-(methoxymethoxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[b]pyran-2-ylmethoxy]benzyl]-[5-14C]-thiazolidine-2,4-dione (XI). Finally, this compound is deprotected with concentrated HCl in ethylene glycol monomethyl ether at 130 C.
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A new short synthesis of troglitazone has been described: Condensation of the bromoacetal (I) with 4-hydroxybenzaldehyde (II) by means of K2CO3 and NaI in refluxing acetone gives the unsaturated ether (III), which is cyclized with trimethylhydroquinone (IV) by means of bis(trifluoromethylsulfonyl)imide in dichloromethane to yield the 6-hydroxybenzopyran (V). Acylation of (V) with acetic anhydride and DMAP in THF affords the expected acetoxybenzopyran (VI), which is condensed with thiazolidine-2,4-dione (VII) by means of piperidine in toluene to provide the 6-benzylidene-thiazolidine (VIII). The hydrogenation of (VIII) with H2 over Pd/C in methanol gives the corresponding benzyl derivative (IX), which is finally deacetylated with AcOH/HCl/water (3:1:1) in MeOH.
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European Journal of Medicinal Chemistry, 51, 206-215; 2012
http://www.sciencedirect.com/science/article/pii/S0223523412001353
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see Indian Journal of Heterocyclic Chemistry, 15(4), 407-408; 2006
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Bioorganic & Medicinal Chemistry Letters, 14(10), 2547-2550; 2004
http://www.sciencedirect.com/science/article/pii/S0960894X04003038
(a) t-Butyldimethylsilyl chloride, imidazole, DMF; (b) LAH, rt, 3 h (75.9%, two steps); (c) 4-fluorobenzaldehyde, KtOBu, DMF, 80 °C, 8 h; (d) 2,4-thiazolidinedione, AcOH, piperidine, toluene, reflux, 4 h (37%, two steps); (e) HCl, MeOH, 15 min; (f) CoCl2, DMG (84%).
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Patent
http://www.google.co.in/patents/US5700820
EXAMPLE-1
A mixture of 70 g of ethyl-3- 4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl!-2-chloropropionate, 13.12 g of thiourea and 80.2 ml of sulpholane was reacted for 80 min., under a nitrogen stream at 115°-120° C. Subsequently, a 656.2 ml Acetic acid, 218.7 ml conc. hydrochloric acid and 109.4 ml water was added to this and the resulting mixture was further heated for 12 hrs at 85°-90° C. The reaction mixture was cooled to room temperature and 196.8 g of sodium bicarbonate was added and once the evolution of carbondioxide had ceased, the solvent was distilled off applying high vacuum. A 10:1 by volume mixture of benzene and ethyl acetate was added to the residue and the crude product was washed with a mixture of equal volumes of a saturated aq. sodium bicarbonate solution & water. The organic layer was dried over anhydrous sodium sulphate and the solvent was distilled off. The resulting crude product was quickly eluted from a silica gel column with 50% ethylacetate-hexane to furnish 40 g of the required 5-{4-(6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-yl-methoxy) benzyl) thiazolidine-2,4-dione (Troglitazone) with a HPLC purity of ˜67-70%. The elution of column was continued further to yield 5- 4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl!2-iminothiazolidine-4-one with HPLC purity of ˜70%.
Lit References:
Oral hypoglycemic agent which improves insulin sensitivity and decreases hepatic glucose production. Prepn: JP Kokai 85 51189; T. Yoshioka et al., US 4572912 (1985, 1986 both to Sankyo); T. Yoshioka et al.,
J. Med. Chem. 32,421 (1989).
Mechanism of action studies: T. P. Ciaraldi et al., Metabolism 39, 1056 (1990); M. Kellerer et al., Diabetes 43, 447 (1994).
Clinical evaluation: T. Kuzuya et al., Diabetes Res. Clin. Pract. 11, 147 (1991).
Clinical metabolic effects: S. L. Suter et al., Diabetes Care 15, 193 (1992).
References
- Fisher, Lawrence (4 November 1997). “Adverse Diabetes Drug News Sends Warner-Lambert Down”. The New York Times. Retrieved 12 December 2012.
- Retired Drugs: Failed Blockbusters, Homicidal Tampering, Fatal Oversights, wired.com
- Cohen, J. S. (2006). “Risks of troglitazone apparent before approval in USA”.Diabetologia 49 (6): 1454–5. doi:10.1007/s00125-006-0245-0. PMID 16601971.
- Henry RR (September 1996). “Effects of troglitazone on insulin sensitivity”. Diabet. Med.13 (9 Suppl 6): S148–50. PMID 8894499.
- Keen H (November 1994). “Insulin resistance and the prevention of diabetes mellitus”. N. Engl. J. Med. 331 (18): 1226–7. doi:10.1056/NEJM199411033311812. PMID 7935664.
- Willman, David (20 December 2000). “NEW FDA: Rezulin Fast-Track Approval and a Slow Withdrawal”. The Los Angeles Times. Retrieved 12 December 2012.
- Willman, David (4 June 2000). “The Rise and Fall of the Killer Drug Rezulin”. The Los Angeles Times. Retrieved 12 December 2012.
- “Report: FDA Removes Medical Officer”.
- Avorn, J (2005). Powerful medicines. New York: Vintage books.
- Gøtzsche, Peter (2013). Deadly medicines and organised crime : how big pharma has corrupted healthcare. London [u.a.]: Radcliffe Publ. p. 185. ISBN 9781846198847.
- Leary, Warren (31 January 1997). “New Class of Diabetes Drug Is Approved”. The New York Times. Retrieved 12 December 2012.
- Sinclair, Neil (31 July 1997). “Glaxo Wellcome gets approval for Romozin”. ICIS News. Retrieved 12 December 2012.
- “www.accessdata.fda.gov”.
- British Broadcasting Corporation (1 December 1997). “Diabetes drug withdrawn from sale”. BBC. Retrieved 12 December 2012.
- Fisher, Lawrence (17 January 1998). “Drug Makers at Threshold of a New Therapy; With a Dose of Biotechnology, Big Change Is Ahead in the Treatment of Diabetes”. The New York Times. Retrieved 12 December 2012.
- Diabetes Prevention Research Group (April 1999). “Design and methods for a clinical trial in the prevention of type 2 diabetes”. Diabetes Care 22 (4): 623–634.doi:10.2337/diacare.22.4.623. Retrieved 12 December 2012.
- Diabetes Prevention Program Research Group (7 February 2002). “Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin”. The New England Journal of Medicine 346 (6): 393–403. doi:10.1056/NEJMoa012512.PMC 1370926. PMID 11832527. Retrieved 12 December 2012.
- Gale, Edwin (January 2006). “Troglitazone: the lesson that nobody learned?”.Diabetologia 49 (1): 1–6. doi:10.1007/s00125-005-0074-6.
- Willman, David (16 August 2000). “FDA’s Approval and Delay in Withdrawing Rezulin Probed”. The Los Angeles Times. Retrieved 12 December 2012.
- Willman, David (10 March 2000). “Fears Grow Over Delay in Removing Rezulin”. The Los Angeles Times. Retrieved 12 December 2012.
- U.S. Food and Drug Administration. “2000 Safety Alerts for Human Medical Products”. U.S. Food and Drug Administration. Retrieved 12 December 2012.
- Willman, David (March 17, 2000). “Physician Who Opposes Rezulin Is Threatened by FDA With Dismissal”. Los Angeles Times.
- Pfizer. “Pfizer Annual Report 2001”. Pfizer. Retrieved 12 December 2012.
- Feeley, Jef (March 31, 2009). “Pfizer Ends Rezulin Cases With $205 Million to Spare”.Bloomberg. Retrieved 6 April 2014.
- Aljada A, Garg R, Ghanim H, et al. (2001). “Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action?”. J. Clin. Endocrinol. Metab. 86 (7): 3250–6.doi:10.1210/jc.86.7.3250. PMID 11443197.
External links
- Diabetes Monitor article on troglit
| US4316849 * | 11 Jul 1980 | 23 Feb 1982 | Blasinachim S.P.A. | Process for preparing a crystalline polymorphous type of chenodeoxycholic acid |
| US4572912 * | 28 Aug 1984 | 25 Feb 1986 | Sankyo Company Limited | Treatment of hyperlipemia and hyperglycemia |
| US5248699 * | 13 Aug 1992 | 28 Sep 1993 | Pfizer Inc. | Hydrochloride salt, antidepressant, anorectic |
| US5319097 * | 11 Dec 1991 | 7 Jun 1994 | Imperial Chemical Industries Plc | Pharmaceutical agents |
| AU3255984A * | Title not available | |||
| EP0014590A1 * | 7 Feb 1980 | 20 Aug 1980 | Eli Lilly And Company | Crystalline forms of N-2-(6-methoxy)benzothiazolyl-N’-phenyl urea and process for their preparation |
| EP0022527A1 * | 4 Jul 1980 | 21 Jan 1981 | BLASCHIM S.p.A. | Process for preparing a solvent-free crystalline polymorphous form of chenodeoxycholic acid |
| EP0490648A1 * | 11 Dec 1991 | 17 Jun 1992 | Zeneca Limited | Pharmaceutical agents |
New Drug Approvals