- Antifolate chemistry: Synthesis of 4-{N-[(6RS)-2-methyl-4-oxo- 3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoic acid via a (propargyl)Co2(CO)6+ complex
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A new route to compound 3 (4-{N-[(6RS)-2-methyl-4-oxo-3,4,7,8- tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoic acid), a crucial intermediate for the synthesis of potent inhibitors of thymidylate synthase (TS), is described. In this sequence the C6-N10 bond was constructed first, by the reductive amination of 5-acetamido-6-bromoindan-1-one 6 with tert-butyl 4-aminobenzoate, then the cyclopenta[g]quinazolinone ring was formed and the propargyl group was introduced on the N10-position using the (propargyl)Co2(CO)6+ complex as the electrophilic propargyl reagent.
- Bavetsias, Vassilios,Clauss, Rainer,Henderson, Elisa A.
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p. 1943 - 1946
(2007/10/03)
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- Design and synthesis of cyclopenta[g]quinazoline-based antifolates as inhibitors of thymidylate synthase and potential antitumor agents
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Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors
- Bavetsias, Vassilios,Marriott, Jonathan H.,Melin, Camille,Kimbell, Rosemary,Matusiak, Zbigniew S.,Boyle, F. Thomas,Jackman, Ann L.
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p. 1910 - 1926
(2007/10/03)
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- Chemoenzymatic preparation of the novel antifolate thymidylate synthase inhibitor N-(4-{N-[(65)-2-methyl-4-oxo-3, 4, 7, 8-tetrahydro-6-cydopenta[#]quinazolin-6-yl]-Ar-(prop-2-ynyl)amino}-benzoyl)-L- glutamic acid and its glutamyl cleavage product
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5-Aminoindane was converted in six steps to the cyclopenta[g]quinazoline ketone 13. Condensation of 13 with diethyl 4-aminobenzoyl-L-glutamate, followed by in situ reduction, produced the secondary amine 15. W-Propargylation of 15, followed by deprotection, gave the diacid 17 as a mixture of diastereoisomers. Treatment of 17 with the bacterial enzyme carboxypeptidase G2 resulted in removal of the L-glutamic acid residue from (6/J)-17 to give a chromatographically separable mixture of the monoacid 18 and the antifolate 5 [(65)-17], which was assayed as an inhibitor of thymidylate synthase (Kfpp = 3 nM). Treatment of isolated diacid 5 with carboxypeptidase G2 produced the monoacid 19 in ;. 98% enantiomeric excess. The (65) stereochemistry of compound 19 has been established by X-ray crystal structure determination of the amide derivative 24.
- Marriott, Jonathan H.,Neidle, Stephen,Matusiak, Zbigniew,Bavetsias, Vassilios,Jackman, Ann L.,Melin, Camille,Boyle, F. Thomas
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p. 1495 - 1503
(2007/10/03)
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- Anti-cancer compounds
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Cyclopentaquinazoline of the formula (I): STR1 wherein R1 is hydrogen, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl or C1-4 fluoroalkyl; wherein R2 is hydrogen, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, C2-4 hydroxyalkyl, C2-4 halogenoalkyl or C1-4 cyanoalkyl; Ar1 is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, C1-4 alkyl and C1-4 alkoxy; and wherein R3 is a group of the formula: in which A1, A2, Y1 and Ar2 are defined in claim 1; or a pharmaceutically acceptable salt or ester there of are of therapeutic value particularly in the treatment of cancer.
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- Tricyclic compounds with pharmaceutical activity
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The invention relates to tricyclic compounds of formula (I) STR1 wherein R1 is hydrogen, amino, (1-4C)alkyl, (1-4C)alkoxy, hydroxy-(1-4C)alkyl or fluoro-(1-4C)alkyl; R2 is hydrogen, (1-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, hydroxy-(2-4C)alkyl, halogeno-(2-4C)alkyl or cyano-(1-4C)alkyl; Ar is optionally-substituted phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl; and R3 includes a group of the formula --NHCH(CO2 H)--A1 --Y1 wherein A1 is (1-6C)alkylene and Y1 is carboxy, tetrazol-5-yl, N-?(1-4C)alkylsulphonyl!carbamoyl, N(phenylsulphonyl)carbamoyl, tetrazol-5-ylthio, tetrazol-5-ylsulphinyl or tetrazol-5-ylsulphonyl; or pharmaceutically-acceptable salts or esters thereof; to processes for their manufacture; to pharmaceutical compositions containing them; and to their use as anti-cancer agents.
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