219989-84-1 Usage
Uses
Used in Oncology:
Ixabepilone is used as an anti-tumor agent for the treatment of patients suffering from solid tumors, such as metastatic breast cancer. It is particularly effective in cases where the cancer is resistant to taxanes.
Used in Antineoplastic and Antimitotic Applications:
Ixabepilone is used as an antineoplastic and antimitotic agent, stabilizing and inducing the polymerization of microtubules, and inducing cell cycle arrest during mitosis. This leads to mitotic arrest and apoptosis, making it effective against a panel of cancer cell lines.
Used in Combination Therapy:
Ixabepilone is used in combination with capecitabine for the treatment of metastatic or locally advanced breast cancer in patients who have previously failed treatment with an anthracycline such as doxorubicin and a taxane such as paclitaxel.
Used as Monotherapy:
Ixabepilone is also approved as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.
General Description:
Ixabepilone has been approved for the treatment of metastatic breast cancer that is resistant to taxanes. It is the first member of the epothilone family of anticancer agents to be approved. The most common adverse reactions associated with ixabepilone as monotherapy or in combination with capecitabine include peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The most common hematologic abnormalities include neutropenia, leukopenia, anemia, and thrombocytopenia. Ixabelipone in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 ULN (upper limit of normal) or bilirubin >1 ULN due to increased risk of toxicity and neutropenia-related death.
Synthesis
The synthesis is described in the scheme, and was initiated by treating epothilone B (56) with sodium azide,
tetrabutylammonium chloride, ammonium chloride, trimethylphosphine
and tris-(dibenzylideneacetone)-dipalladium(0)
chloroform which gave the ring-opened amino acid 57 in
96% yield. It has been proposed that this reaction proceeds
via initial ring-opening -allyl palladium complex formation
followed by trapping with azide and subsequent reduction to
the desired amine. Lactamization of the acyclic amino
carboxylic acid 57 by reaction with K2CO3, HOBt and EDCI
provided ixabepilone (VIII) in 93% yield. Re-crystallization
from cyclohexane/ethyl acetate afforded ixabepilone in 56%
overall yield from epothilone B.
in vitro
in a large panel of tumor cell lines, bms-247550 was as active as epothilone b in inducing cytotoxicity. of the 21 cells lines tested, the ic50 values were in the range of 1.4–34.5 nm. bms-247550 almost completely blocked cells in mitosis as early as 8 h after the initiation of drug exposureat a concentration close to the ic90 (7.5 nm, clonogenic cytotoxicity assay) [2].
in vivo
bms-247550 has clearly demonstrated antitumor activity that is superior to paclitaxel in both paclitaxel-sensitive and -resistant tumors. bms-247550 was more efficacious than paclitaxel in all five paclitaxel-resistant tumors such as the clinically derived paclitaxel resistant pat-7 ovarian carcinoma, the a2780tax ovarian carcinoma that is resistant to paclitaxel because of tubulin mutations, the hct116/vm46 mdr colon carcinoma, the clinically derived paclitaxel-resistant pat-21 breast carcinoma, and the murine fibrosarcoma m5076. bms-247550 produced antitumor activity equivalent to paclitaxel against three paclitaxel-sensitive human tumor xenografts such as a2780 human ovarian carcinoma, hct116, and ls174t human colon carcinoma [2].
references
[1]. lee fy1, borzilleri r,fairchild cr, kim sh, long bh, reventos-suarez c, vite gd, rose wc, kramer ra.bms-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. clin cancer res.2001 may;7(5):1429-37[2]. denduluri n, low j a, lee j j, et al. phase ii trial of ixabepilone, an epothilone b analog, in patients with metastatic breast cancer previously untreated with taxanes[j]. journal of clinical oncology, 2007, 25(23): 3421-3427.[3]. shannon puhalla, adam brufsky. ixabepilone: a new chemotherapeutic option for refractory metastatic breast cancer. biologics. 2008 sep; 2(3): 505–515.
Check Digit Verification of cas no
The CAS Registry Mumber 219989-84-1 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,1,9,9,8 and 9 respectively; the second part has 2 digits, 8 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 219989-84:
(8*2)+(7*1)+(6*9)+(5*9)+(4*8)+(3*9)+(2*8)+(1*4)=201
201 % 10 = 1
So 219989-84-1 is a valid CAS Registry Number.
InChI:InChI=1/C27H42N2O5S/c1-15-9-8-10-27(7)22(34-27)12-20(16(2)11-19-14-35-18(4)28-19)29-23(31)13-21(30)26(5,6)25(33)17(3)24(15)32/h11,14-15,17,20-22,24,30,32H,8-10,12-13H2,1-7H3,(H,29,31)/b16-11+/t15-,17+,20-,21-,22-,24-,27+/m0/s1
219989-84-1Relevant articles and documents
A novel application of a Pd(0)-catalyzed nucleophilic substitution reaction to the regio- and stereoselective synthesis of lactam analogues of the epothilone natural products
Borzilleri,Zheng,Schmidt,Johnson,Kim,DiMarco,Fairchild,Gougoutas,Lee,Long,Vite
, p. 8890 - 8897 (2000)
Several lactam analogues of the epothilones were prepared using a concise semisynthetic approach starting with the unprotected natural products. Highlighted in this strategy is a novel regio- and stereoselective Pd(0)-catalyzed azidation reaction of a macrocyclic lactone. Subsequent reduction and macrolactamization of the resulting azide acid intermediates provided the desired macrolactams in satisfactory overall yields. The entire three-step sequence was streamlined into a 'one-pot' process for the epothilone B-lactam, BMS-247550, which is currently undergoing phase I clinical trials. An initial total synthesis route to prepare the lactam analogue of epothilone C was completed and compared to the more direct semisynthesis approach. All of the lactam analogues were evaluated in vitro and the results are discussed.
PROCESS FOR THE PREPARATION OF (1S,3S,7S,10R,11S,12S,16R)-7,11-DIHYDROXY-8,8,10,12,16-PENTAMETHYL-3-[(1E)-1-METHYL-2-(2-METHYL-4-THIAZOLYL)ETHENYL]-17-OXA-4-AZABICYCLO[14.1.0]HEPTADECANE-5,9-DIONE AND INTERMEDIATES THEREOF
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Page/Page column 62, (2015/06/25)
The present invention relates to an improved process for the preparation of (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2- methyl-4-thiazolyl)ethenyl]- 17-oxa-4-azabicyclo[ 14.1.0]heptadecane-5,9-dione represented by the following structural formula I and intermediates thereof. The present invention also provides novel intermediate compounds useful for the preparation of compound of formula I and its intermediates.
PROCESS FOR IXABEPILONE, AND INTERMEDIATES THEREOF
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Paragraph 0288-0289; sheet 10; 20, (2014/09/29)
The present invention relates to a novel process of making ixabepilone, ixabepilone derivatives and analogues, and intermediates thereof.
PROCESS FOR PREPARATION OF IXABEPILONE AND INTERMEDIATES USEFUL IN SAID PROCESS.
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Page/Page column 11, (2013/11/19)
The present invention describes a process for preparation of Ixabepilone and intermediates useful in said process.
SOLID STATE FORMS OF IXABEPILONE
-
, (2011/12/14)
Crystalline forms of Ixabepilone are described in the present application and processes for preparing the crystalline forms. The present invention also includes pharmaceutical compositions of such crystalline forms of Ixabepilone.
On the interactivity of complex synthesis and tumor pharmacology in the drug discovery process: Total synthesis and comparative in vivo evaluations of the 15-Aza epothilones
Stachel,Chul Bom Lee,Spassova,Chappell,Bornmann,Danishefsky,Chou,Guan
, p. 4369 - 4378 (2007/10/03)
The total syntheses of 12,13,15-desoxy-15(S)-aza-epothilone B (aza-dEpoB; dEpoB-lactam) and 12,13,15-desoxy-15(R)-aza-epothilone B (15-epi-aza-dEpoB; 15-epi-dEpoB-lactam) have been accomplished via a highly convergent strategy. We have also successfully oxidized 12,13,15-desoxy-15(S)-aza-epothilone B to aza-epothilone B (aza-EpoB; EpoB-lactam). Aza-epothilone B has been advanced to phase I clinical trials by the Bristol-Myers Squibb group. Our synthesis is efficient and was amenable to the production of significant quantities of these lactams. Using our fully synthetically derived lactams, in vitro and in vivo studies were conducted in comparison with advanced clinical candidates, 12,13-desoxyepothilone B and 12,13-desoxyepothilone F, also derived by total synthesis.
