119413-54-6 Usage
Anticancer drug
Topotecan hydrochloride is a water-soluble derivative of camptothecin, which is the form of hydrochloride of topotecan. It is successfully developed by the SmithKline Beecham US company, and approved by the FDA in the United States in 1996. Its trade name is Hycamtin. It is applied in the treatment of ovarian cancer (OVC) as the second-line therapy.
In 1999 the US Food and Drug Administration (FDA) has approved topotecan hydrochloride as small cell lung cancer (SCLC) therapeutic drug. It has been available in the UK, Germany, France and other dozens of countries and regions. The Ⅲ clinical trials are ongoing for this medicine which is used to treat non-small cell lung cancer, cervical cancer, myelodysplastic syndrome.
Topotecan hydrochloride can enter the blood brain barrier. It has the same effect of oral and intravenous injection. The drug has low toxicity predictable bone marrow suppression, and other minor non-hematologic toxicity. Currently there are manufacturers, for clinical treatment of small cell lung cancer, ovarian cancer and other tumors.
Topotecan hydrochloride inhibits the activity of topoisomerase I, which is required for DNA replication. After intravenous injection, the product is hydrolyzed in the blood, and excreted by urinary. This product has a rapid serum clearance rate, which is 62L/h. It is widely distributed in vivo, and Its half-lifetime is about 2~3h. Preclinical trials have shown that the product has anti-tumor activity on all kinds of types of tumor. In I clinical trial, to patients with ovarian cancer that is cisplatin tolerance, this product also has significant anti-tumor effect.
Clinical studies
In a open randomized trial, 226 cases who used cisplatin or carboplatin invalid or recurrent advanced ovarian cancer women changed to this product, and compared with paclitaxel. In 112 patients who used topotecan hydrochloride, 22 cases were effective, so the effective rate was 20%. In 114 patients treated with paclitaxel, 14 cases were effective, so the effective rate was 12%. Used this product for treatment which has made significant improvement in the average time of 23 weeks, while 14 weeks for paclitaxel. In a non-controlled trial to 111 women patients with refractory advanced ovarian cancer, 16 cases were preferabe after treatment, occupied with 14%, and the curative effect average time was 16-week, and the average survival time was 52-week. In an open trial, 67 cases were ineffective treated with cisplatin and paclitaxel for advanced ovarian cancer. However, 9 cases who changed to this product were effective, and the effective rate was 13%.
The above information is edited by the lookchem of Kui Ming.
Side effects
It can appear toxicity of bone marrow suppression in limited doses, especially it can cause neutropenia. It often induced thrombocytopenia and anemia. Sometimes red blood cell and platelet transfusion is necessary. It can also be nausea, vomiting, hair loss, diarrhea, abdominal pain, gastritis and weakness, but all of them were mild.
Originator
Hycamtin,SmithKline Beecham Pharmaceuticals,UK
Manufacturing Process
Camptothecin (CPT) - a compound isolated from the bark, leaves and fruit of
Camptotheca acuminate (Wall M. E. et al., J. Am. Chem. Soc. 88, 3888,
1966).
10-Hydroxycamptothecin (10-HCPT) was prepared by subjecting CPT (3.2 g
0.0092 mol), 0.8 g of Pt0 (prepared by pre-reduction of 8 g of amorphous
PtO2 in 80 ml of acetic acid for 1.5 h under 1 atm hydrogen pressure) and
acetic acid to 1 atm of H2 for 8.5 h after which theoretical amount of H2
absorbed (slightly more than 0.4 L) and uptake of H2 gets slowed down. The
reaction mixture was degassed under steam of helium and filtered through
celite and washed with acetic acid (20 ml). The resulting solution was treated
immediately with Pb(OAc)4 (6.4 g 0.014 mol) in portions and reaction
mixture, stirred vigorously under helium for 30 min. Gumy residue was
obtained on evaporation of solvent which was triturated with cold water (100
ml) to produce light brown solid. The solid was collected, washed with cold
water and air dried overnight when a mixture of 10-HCPT (44%), acetyl 10-
hydroxycamptothecin (10-AcHCPT, 26%) and unreacted CPT (32%) on HPLC
basis was obtained. This crude mixture was combined with 150 ml of 50%
acetic acid and heated under reflux conditions overnight. The reaction mixture
was cooled, concentrated to 20 ml and treated with cold water (100 ml) to
produce precipitate, which is filtered, washed with more cold water and dried
to afford 2.1 g of solid containing 10-HCPT (70%), 10-AcCPT (1.2%) and CPT
(21.3%) on the basis HPLC. Mixture was triturating with 0.5% aq HCl to
dissolve the water-soluble. When insoluble CPT was removed by filtration.
Water-soluble was extracted with chloroform and crystallized from boiling
solution of 20% of MeOH in CHCl3 by adding EtOAC dropwise until turbidity
appeared to obtain pure yellow 10-(HCPT), melting point 268°-270°C.
10-HCPT (0.364 g 0.01 mmol) and 40% aqueous dimethylamine (12 ml) was
added in dichloromethane (50 ml) in which anhydrous potassium carbonate
(2.17 g, 15 mmol) has been suspended. The reaction mixture was stirred at
room temperature for 5 h, then filtered and solid extracted with ethylacetate
(20 ml). The solvent is evaporated in vacuo giving a residue. The residue was
triturated with 0.5% aq HCl (50 ml) to dissolve the water-soluble adduct.
Water-soluble were partitioned with petroleum ether (3 times 50 ml) and
followed by ethylacetate (3 times 50 ml). The aqueous layer was lyophilized
as an off white hydrochloride salt of 9-[(dimethylamino)methyl]10-
hydroxy(20S)-camptothecin (topotecan hydrochloride) yield 0.236 g (65%).
Therapeutic Function
Antineoplastic
Biological Activity
topotecan hcl（skf104864）is an inhibitor of topoisomerase 1 and semisynthetic analogue of camptothecin [1].topotecan hcl（skf104864）has been reported to have a potent antitumor activity against tumors in murine models. in addition, topotecan hcl has also shown the potent effect against intravenously implanted p388 leukemia and both intravenously and subcutaneously implanted lewis lung carcinoma. topotecan hcl has noted the activity against subcutaneously implanted solid tumors including chemorefractory tumors and human colon carcinoma xenograft ht-29. topotecan hcl has been found to induce regressions in the lung tumor model (lewis lung carcinoma and b16 melanoma), compared to camptothecin and 9-amino-camptothecin. in the preclinical toxicology studies, topotecan hcl has been revealed to have a concentration-dependent, reversible and limited toxoicity to rapidly proliferation tissues such as bone marrow and gastro-intestinal epithelium [1].
Pharmacokinetics
Topotecan elimination is biphasic, with a terminal half-life of 2.0 to 3.5 hours. Lactone hydrolysis is rapid, and binding to serum proteins is limited to between 25 and 40%. CYP3A4-mediated N-dealkylation to mono?and didealkylated metabolites occurs to a limited extent, and the O-glucuronides that form at multiple points along the metabolic path are excreted via the kidney.
Clinical Use
This active camptothecin analogue is used by the IV route in the treatment of ovarian and small cell lung cancer that has not responded to first-line therapy.
references
[1] creemers gj1, lund b, verweij j. topoisomerase i inhibitors: topotecan and irenotecan. cancer treat rev. 1994 jan;20(1):73-96.
Check Digit Verification of cas no
The CAS Registry Mumber 119413-54-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,1,9,4,1 and 3 respectively; the second part has 2 digits, 5 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 119413-54:
(8*1)+(7*1)+(6*9)+(5*4)+(4*1)+(3*3)+(2*5)+(1*4)=116
116 % 10 = 6
So 119413-54-6 is a valid CAS Registry Number.
InChI:InChI=1/C23H23N3O5/c1-4-23(30)16-8-18-20-12(9-26(18)21(28)15(16)11-31-22(23)29)7-13-14(10-25(2)3)19(27)6-5-17(13)24-20/h5-8,27,30H,4,9-11H2,1-3H3/t23-/m0/s1
119413-54-6Relevant articles and documents
Crystalline Polymorphs of Topotecan Hydrochloride and Methods for the Preparation Thereof
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Page/Page column 3, (2009/08/14)
The invention relates to two novel crystalline form of Topotecan hydrochloride (Ia) Herein referred to as forms α and β, characterized by high purity and whose preparation is advantageous from the industrial point of view. Form α can be in fact conveniently prepared starting from 10-hydroxy-camptothecin, whereas form β can be prepared starting from form α.
Crystalline polymorphs of topotecan hydrochloride and methods for the preparation thereof
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Page/Page column 4-5, (2009/07/10)
The invention relates to two novel crystalline form of Topotecan hydrochloride (Ia) Herein referred to as forms α and β, characterized by high purity and whose preparation is advantageous from the industrial point of view. Form α can be in fact conveniently prepared starting from 10-hydroxy-camptothecin, whereas form β can be prepared starting from form α.
PROCESS FOR MAKING TOPOTECAN
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Page/Page column 7-8, (2008/12/08)
A process of making topotecan or a pharmaceutically acceptable salt thereof comprising reacting an iminium salt with 10-hydroxy-camptothecin.
Crystalline forms of topotecan hydrochloride and processes for making the same
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Page/Page column 3, (2008/12/04)
Novel crystalline forms of topotecan hydrochloride and processes of making the same are disclosed.
NOVEL CRYSTALLINE FORMS
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Page/Page column 8, (2008/06/13)
The invention relates to a novel crystalline form of topotecan hydrochloride, and methods of making the same. The characteristic XRPD pattern and FT-IT patterns are shown in Figs. 1 and 2.
PROCESS FOR PREPARING TOPOTECAN
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Page/Page column title page; 7, (2008/06/13)
A process for preparing topotecan.
NOVEL CRYSTALLINE POLYMORPHIC FORM OF A CAMPTOTHECIN ANALOGUE
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Page/Page column 3, (2008/06/13)
The invention relates to a novel crystalline form of topotecan hydrochloride, and methods of making the same. The characteristic XRPD pattern and FT-IT patterns are shown in FIGS. 1 and 2.
PROCESS FOR PREPARING TOPOTECAN FROM 10-HYDROXY-4-(S) CAMPTOTHECIN
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Page 6-7, (2008/06/13)
The present invention relates to the use of dihalomethanes as reagents for the preparation of Topotecan {4-(S)-10 (dimethylamino)-methyl-4-ethyl 4, 9 dihydroxyl-H-pyrano [3'4': 6,7] indolizino-[1,2-b]quinoline-3,14 (4H,12H)dione} from 10-hydroxycamptothecin. The invention discloses the rationale use of dichloromethane under solid-liquid phase transfer catalysis, which can behave both as solvent and a reactant when it serves as a source for C-1 unit for amino-alkylation of 10-hydroxy-4-(S) camptothecin.
Process for preparing Topotecan from 10-hydroxy-4-(S) camptothecin
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Page column 5, (2008/06/13)
The present invention relates to the use of dihalomethanes as reagents for the preparation of Topotecan{4-(S)-10(dimethylamino)-methyl-4-ethyl 4,9 dihydroxyl-H-pyrano[3′4′:6,7]indolizino-[1,2-b]quinoline-3,14(4H,12H)dione} from 10-hydroxycamptothecin. The invention discloses the rationale use of dichloromethane under solid-liquid phase transfer catalysis, which can behave both as solvent and a reactant when it serves as a source for C-1 unit for amino-alkylation of 10-hydroxy-4-(S)camptothecin.
Novel syntheses of camptothecin alkaloids. Part 2. Concise synthesis of (S)-camptothecins
Fortunak, Joseph M.D.,Kitteringham, John,Mastrocola, Antonietta R.,Mellinger, Mark,Sisti, Nicolas J.,Wood, Jeffery L.,Zhuang, Zhi-Ping
, p. 5683 - 5686 (2007/10/03)
A 9-step, convergent total synthesis of (S)-camptothecin alkaloids is described. The intramolecular [4 + 2] cycloaddition of an N-arylimidate with an alkyne is used to prepare the alkaloid ABC ring system. The chiral center is derived utilizing Seebach's chemistry for the diastereoselective Michael addition of a chiral dioxolanone enolate to a methylene malonate acceptor. The total synthesis of non-racemic topotecan is accomplished from (S)-10-hydroxycamptothecin in an additional step.
