193276-49-2Relevant academic research and scientific papers
Process for producing (8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-B]pyridin-11-YL)-1-piperdine
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Page column 6, (2008/06/13)
A process for producing compounds of the formula: is disclosed. The compound of formula 1.0 is produced by: (1) separating the atropisomers of ?to obtain the atropisomers (2) heating the atropisomer of formula 2.0B at a suitable temperature in a suitable solvent to obtain a mixture of atropisomers of formulas 2.0A and 2.0B; (3) separating the atropisomers of formulas 2.0A and 2.0B of step (2); and (4) reducing the atropisomer of formula 2.0A to obtain a compound of formula 1.0. Preferably, R1is Br, R2is Cl and R3is Br. Also disclosed is the (+)-atropisomer of formula 2.0 wherein R1is Br, R2is Cl and R3is Br.
BENZO(5,6)CYCLOHEPTA(1,2B)PYRIDINE DERIVATIVES USEFUL FOR INHIBITION OF FARNESYL PROTEIN TRANSFERASE
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Page 29, (2010/02/08)
Novel compounds of formula: (1.0) or a pharmaceutically acceptable salt or solvate thereof, wherein: a represents N or NO; R and R are the same or different and each represents halo; R and R are each independently selected from H and halo, provided that at least one of R and R is H; each dotted line (---) represents an optional bond; X is N, C when the optional bond to X is present, or CH when the optional bond to X is absent; T is a substituent selected from (A) or (B): Z represents O or S; R represents -C(O)N(R)2, -CH2C(O)N(R), -SO2R, -SO2N(R)2, -C(O)R, -C(O)-O-R, alkyl, aryl, aralkyl, cycloalkyl, heterocycloalkyl or heteroaryl; R represents alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, OR, NRH, SH, SR, SOR (where R is not H) or SO2R (where R is not H); and each R independently represents H, alkyl, aryl, or aralkyl; R is alkyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl; R is selected from H, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, or heterocycloalkyl. Also disclosed are methods of inhibiting farnesyl protein transferase and methods for treating tumor cells.
BENZO(5,6)CYCLOHEPTA(1,2-B)PYRIDINE DERIVATIVES USEFUL FOR INHIBITION OF FARNESYL PROTEIN TRANSFERASE
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Page 38, (2010/02/08)
Novel compounds of formula (1.0) are disclosed. In Formula (1.0) a represents N or NO, R and R are halo, R and R are independently H or halo provided that at least one is H, X is C, CH or N, and T represents a five or six membered heterocycloalkyl ring having one or two heteroatoms selected from S or O. Also disclosed are methods of inhibiting farnesyl protein transferase and methods for treating tumor cells.
COMPOUNDS USEFUL FOR INHIBITION OF FARNESYL PROTEIN TRANSFERASE
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Page 78, (2010/02/09)
Novel compounds of formula (1.0) are disclosed. Compounds of formula (1.0) are represented by the compounds of formula (1.4) or (1.5) wherein R, R and R are each independently selected from halo. Also disclosed are methods of inhibiting farnesyl protein transferase and the growth of abnormal cells, such as tumor cells.
TRICYCLIC INHIBITORS OF FARNESYL PROTEIN TRANSFERASE
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Page 44, (2010/02/09)
Novel compounds of formula (1.0) are disclosed. Compounds of formula (1.0) are represented by the compounds of formulas (1.4) or (1.5) wherein R, R and R are each independently selected from halo. Also disclosed are methods of inhibiting farnesyl
A novel enantioselective alkylation and its application to the synthesis of an anticancer agent
Kuo, Shen-Chun,Chen, Frank,Hou, Donald,Kim-Meade, Agnes,Bernard, Charles,Liu, Jinchu,Levy, Stacy,Wu, George G.
, p. 4984 - 4987 (2007/10/03)
A novel enantioselective alkylation of double benzylic substrates with secondary electrophiles is reported. A simple norephedrine-based chiral ligand was synthesized that gives alkylation product in 95% yield and 95% ee. A unique water effect on the enantioselectivity was unveiled. Good to excellent ee values were obtained with a number of double benzylic substrates and secondary electrophiles. This novel reaction has been applied to the synthesis of a promising anticancer agent.
Enzymatic kinetic resolution of piperidine atropisomers: Synthesis of a key intermediate of the farnesyl protein transferase inhibitor, SCH66336
Morgan, Brian,Zaks, Aleksey,Dodds, David R.,Liu, Jinchu,Jain, Rama,Megati, Sreeni,Njoroge, F. George,Girijavallabhan, Viyyoor M.
, p. 5451 - 5459 (2007/10/03)
The resolution of secondary amines via enzyme-catalyzed acylation is a relatively rare process. The kinetic resolution of a series of intermediates of SCH66336 (1), by either enzymatic acylation of the pendant piperidine (4, 5) or hydrolysis of the corresponding carbamate 3, was investigated. In the case of 4, the molecule exists as a pair of enantiomers due to atropisomerism about the exocyclic double bond. The enzymatic acylation of (±)-4 was optimized in terms of acylating agent, solvent, and moisture content. The use of lipase, Toyobo LIP-300, and trifluoroethyl isobutyrate as acylating agent resulted in isobutyrylation of the (+)-enantiomer, which is easily separated from the unwanted (-)-4. Hydrolysis of the isobutyramide 6c yielded the desired (+)-4 in high enantiomeric excess. (-)-4 may be recovered from the resolution step, racemized, and resubjected to enzymatic acylation to increase material throughput.
(+)-4-[2-[4-(8-chloro-3,10-dibromo-6,11-dihydro-5H- benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1- piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent
George Njoroge,Taveras, Arthur G.,Kelly, Joseph,Remiszewski, Stacy,Mallams, Alan K.,Wolin, Ronald,Afonso, Adriano,Cooper, Alan B.,Rane, Dinananth F.,Liu, Yi-Tsung,Wong, Jesse,Vibulbhan, Bancha,Pinto, Patrick,Deskus, Jeffrey,Alvarez, Carmen S.,Del Rosario, Joycelyn,Connolly, Michael,Wang, James,Desai, Jagdish,Rossman, Randall R.,Robert Bishop,Patton, Robert,Wang, Lynn,Kirschmeier, Paul,Bryant, Mathew S.,Nomeir, Amin A.,Lin,Liu, Ming,McPhail, Andrew T.,Doll, Ronald J.,Girijavallabhan, Viyyoor M.,Ganguly, Ashit K.
, p. 4890 - 4902 (2007/10/03)
We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3- bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.
