| Revision as of 11:52, 20 February 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 460077547 of page Zosuquidar for the Chem/Drugbox validation project (updated: 'CAS_number'). |
Latest revision as of 09:08, 15 June 2024 edit 2.101.54.127 (talk) Synthesis update |
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{{Short description|Chemical compound}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}} |
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{{Drugbox |
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{{Drugbox |
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| verifiedrevid = 477869670 |
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| IUPAC_name = (2''R'')-1-{4-cyclopropa annulen-6-yl}-3-(quinolin-5-yloxy)propan-2-ol |
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| verifiedrevid = 431677972 |
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| IUPAC_name = (2''R'')-​1-​{4-​​cyclopropa​​​annulen-​6-​yl}-​3-​(quinolin-​5-​yloxy)​propan-​2-​ol |
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| image = Zosuquidar.svg |
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| image = Zosuquidar.svg |
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| width = 250px |
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| width = 200px |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| tradename = |
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| tradename = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category = |
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| pregnancy_category = |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
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| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> |
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| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| legal_status = |
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| legal_status = Investigational |
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| routes_of_administration = |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data--> |
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| bioavailability = |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| synonyms = LY-335979 |
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| CAS_number_Ref = {{cascite|correct|CAS}} |
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| CAS_number = <!-- blanked - oldvalue: 167354-41-8 --> |
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| CAS_number = 167354-41-8 |
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| ATC_prefix = none |
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| ATC_prefix = None |
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| ATC_suffix = |
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| ATC_suffix = |
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| PubChem = 153997 |
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| PubChem = 153997 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| DrugBank = DB06191 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 24599682 |
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| ChemSpiderID = 24599682 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = AB5K82X98Y |
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| UNII = AB5K82X98Y |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D06387 |
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| KEGG = D06387 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 444172 |
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| ChEMBL = 444172 |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| C=32 | H=31 | F=2 | N=3 | O=2 |
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| C=32 | H=31 | F=2 | N=3 | O=2 |
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| molecular_weight = 527.61 g/mol |
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| smiles = Cl.Cl.Cl.FC4(F)3c1ccccc1C(c2c(cccc2)34)N5CCN(CC5)C(O)COc7c6cccnc6ccc7 |
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| smiles = Cl.Cl.Cl.FC4(F)3c1ccccc1C(c2c(cccc2)34)N5CCN(CC5)C(O)COc7c6cccnc6ccc7 |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = IHOVFYSQUDPMCN-DBEBIPAYSA-N |
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| StdInChIKey = IHOVFYSQUDPMCN-DBEBIPAYSA-N |
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}} |
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'''Zosuquidar''' (development code '''LY-335979''') is an experimental ] ].<ref>{{cite web | url = https://www.cancer.gov/publications/dictionaries/cancer-drug/def/zosuquidar-trihydrochloride | title = Zosuquidar trihydrochloride | work = NCI Drug Dictionary | publisher = ] | access-date = 2024-05-27 | archive-date = 2023-02-10 | archive-url = https://web.archive.org/web/20230210204825/https://www.cancer.gov/publications/dictionaries/cancer-drug/def/zosuquidar-trihydrochloride | url-status = live }}</ref> Zosquidir ] ]s.<ref name=Cripe>{{cite journal | vauthors = Cripe LD, Uno H, Paietta EM, Litzow MR, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Luger S, Tallman MS | display-authors = 6 | title = Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999 | journal = Blood | volume = 116 | issue = 20 | pages = 4077–4085 | date = November 2010 | pmid = 20716770 | pmc = 2993615 | doi = 10.1182/blood-2010-04-277269 }}</ref> Other drugs with this mechanism include ] and ]. P-glycoproteins are trans-membrane ]s that pump foreign substances out of cells in an ] dependent fashion. Cancers overexpressing P-glycoproteins are able to pump out therapeutic molecules before they are able to reach their target, effectively making the cancer multi-drug resistant. Zosuquidar inhibits P-glycoproteins, inhibiting the efflux pump and restoring sensitivity to chemotherapeutic agents.<ref name=Cripe/> |
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Zosuqidar was initially characterized by Syntex Corporation, which was acquired by ] in 1990. Roche licensed the drug to ] in 1997. It was granted ] by the FDA in 2006 for AML. In 2010, it was announced that a ] for the treatment of ] (AML) and ] did not meet its primary endpoint<ref>{{ClinicalTrialsGov|NCT00046930|Daunorubicin & Cytarabine +/- Zosuquidar inTreating Older Patients With Newly Diagnosed Acute Myeloid Leukemia or Refractory Anemia}}</ref> and Eli Lilly discontinued its development.<ref>{{cite web | url = https://adisinsight.springer.com/drugs/800005159 | title = Zosuquidar - Kanisa Pharmaceuticals | work = Adis Insight | publisher = Springer Nature Switzerland AG | access-date = 2024-05-27 | archive-date = 2023-02-10 | archive-url = https://web.archive.org/web/20230210204825/https://adisinsight.springer.com/drugs/800005159 | url-status = live }}</ref> |
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==Synthesis== |
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When dibenzosuberone (1) is treated with difluorocarbene (generated in situ from lithium chlorodifluoroacetate), a cyclopropanation occurs to give 10,11-difluoromethanodibenzosuberone (2). Reduction of the ketone with borohydride proceeds to afford the derivative wherein the fused cyclpropyl and alcohol are on the same side of the seven-membered ring to give 1,1-Difluorocyclopropane Dibenzosuberol & (3). This is halogenated with 48% HBr to give the product where both groups are now positioned anti (4). Displacement of the bromide with pyrazine gives the quat (5). Sodium borohydride was able to reduce the aromaticity in the sidechain giving the corresponding piperazine, i.e. Fb= HCl=PC9799090 (6). |
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The reaction of 5-hydroxyquinoline (7) with (R)-glycidyl nosylate (8) affords (R)-1-(5-Quinolinyloxy)-2,3-epoxypropane (8). The convergent synthesis between 6 & 9 gives Zosuquidar in good yield. |
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== References == |
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{{Reflist}} |
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