- Dual protein farnesyltransferase-geranylgeranyltransferase-I inhibitors as potential cancer chemotherapeutic agents
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A series of novel diaryl ether lactams have been identified as very potent dual inhibitors of protein farnesyltransferase (FTase) and protein geranylgeranyltransferase I (GGTase-I), enzymes involved in the prenylation of Ras. The structure of the complex formed between one of these compounds and FTase has been determined by X-ray crystallography. These compounds are the first reported to inhibit the prenylation of the important oncogene Ki-Ras4B in vivo. Unfortunately, doses sufficient to achieve this endpoint were rapidly lethal.
- DeSolms, S. Jane,Ciccarone, Terrence M.,MacTough, Suzanne C.,Shaw, Anthony W.,Buser, Carolyn A.,Ellis-Hutchings, Michelle,Fernandes, Christine,Hamilton, Kelly A.,Huber, Hans E.,Kohl, Nancy E.,Lobell, Robert B.,Robinson, Ronald G.,Tsou, Nancy N.,Walsh, Eileen S.,Graham, Samuel L.,Beese, Lorena S.,Taylor, Jeffrey S.
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p. 2973 - 2984
(2007/10/03)
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- Inhibitors of prenyl-protein transferase
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The present invention is directed to azepan-2-one compounds which inhibit prenyl-protein transferase, particularly farnesyl-protein transferase (Ftase), and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.
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- 2-Bromo-3-methoxycyclohex-2-enone, a New Reagent for the α-Arylation of Lactams
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We report efficient syntheses of 2-bromo and 2-chloro-3-methoxycyclohex-2-enone and their use as m-hydroxyphenyl cation synthons for the α-arylation of lactams.The sequence has been used to synthesize the analgesic drug meptazinol.
- Shepherd, Robin G.,White, Alan C.
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p. 2153 - 2156
(2007/10/02)
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- Process for making m-hydroxyphenyl substituted compounds
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m-Hydroxyphenyl substituted compounds of formula STR1 where R is an organic radical and R1 is hydroen or an organic radical are prepared by dehydrohalogenating a compound of formula STR2 (where X is chlorine or bromine, and R and R1 have the above meanings). Preferred novel starting materials of formula (II) are of the formula STR3 (where R1 and X are as above, n is 2,3 or 4, R2 is hydrogen or lower alkyl and R3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl(lower)alkyl or aryl(lower)alkyl).
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- Process for preparing hexahydroazepine, piperidine and pyrrolidine derivatives
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2-Oxo-hexahydroazepine, -piperidine or pyrrolidines of formula STR1 wherein n is 2,3 or 4, R is hydrogen, lower alkyl, aryl(lower)alkyl, loweralkenylmethyl or cycloalkylmethyl, R1 is hydrogen or lower alkyl and R2 is hydrogen, lower alkyl or aryl(lower)alkyl are prepared by a novel process involving reaction of an anion of a lactam of formula STR2 where R3 is lower alkyl, aryl(lower)alkyl, trialkyl-, triaryl- or triarylalkyl-silyl with a benzyne of formula STR3 where R4 is lower alkyl, aryl(lower)alkyl or trialkyl-, triaryl- or triarylalkyl-silyl. The products are useful as intermediates for preparing pharmacologically active 2-unsubstituted -hexahydroazepine, -piperidine and pyrrolidine derivatives.
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- Hexahydroazepine, piperidine and pyrrolidine derivatives
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The invention concerns novel 2-oxo-hexahydroazepine, -piperidine and -pyrrolidine derivatives of formula (I) and their aromatized derivatives of formula (II) STR1 where n is 2, 3 or 4, R is hydrogen, lower alkyl or aryl(lower)alkyl, R2 is hydrogen, lower alkyl or aryl(lower)alkyl and R3 is hydrogen, lower alkyl, aryl(lower)alkyl, lower alkenyl or lower alkynyl. The compounds are useful as intermediates for preparing 3,3-disubstituted -hexahydroazepine, -piperidine and -pyrrolidine compounds having pharmacological activity, particularly analgesic activity.
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