NZ501613A

NZ501613A - Benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl) piperazine derivatives useful as inhibitors of farnesyl-protein transferase

Info

Publication number: NZ501613A
Application number: NZ501613A
Authority: NZ
Inventors: Stuart B Rosenblum; Adriano Afonso; Joseph M Kelly; Jay Weinstein; Ronald L Wolin
Original assignee: Schering Corp
Priority date: 1997-06-17
Filing date: 1998-06-15
Publication date: 2001-11-30
Also published as: AU8253798A; EP0989981A1; KR20010013945A; CA2293549C; JP2002504150A; HUP0003215A2; WO1998057950A1; CA2293549A1; IL133446A0; CN1267292A

Abstract

A compound selected from: 1-(3-Bromo-6,11-dihydro-8,10-dimethoxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; 4-(6,11-Dihydro-10-methoxy-3,8-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(6,11-Dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(7-Chloro-5,6-dihydro-8-methyl-10-methoxy-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-10-hydroxy-8-methyl-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; 4-(5,6-Dihydro-10-methoxy-3,8-dimethyl-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-10-methoxy-8-methyl-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-10-hydroxy-8-methyl-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-7-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)4-( 4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-7,10-dimethyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-6,11-dihydro-8-methoxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (-)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3,10-Dibromo-6,11-dihydro-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3,8-Dibromo-6,11-dihydro-10-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-4-[6,11-Dihydro-3-(1-hydroxy-1-methylethyl)-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-(4-pyridinylacetyl)piperidine N1-oxide; (+)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (-)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-1-(3-Bromo-8-methoxy-10-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; 4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; 4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(methylsulphonyl)piperidine; 4-(3-Ethyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-piperidinylacetyl)piperazine; (+,-)-4-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-piperidinylacetyl-N-carboxamido)piperazine; (+,-)-4-(3-Cyclopropyl-6,11-dihydro-10-methoxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine; (+)-4-(3-Bromo-6,11-dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (-)-4-(3-Bromo-6,11-dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+)-4-(3-Bromo-6,11-dihydro-11-hydroxy-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (-)-4-(3-Bromo-6,11-dihydro-11-hydroxy-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; 4-(3-Bromo-5,6-dihydro-10-bromo-8-methyl-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide or a pharmaceutically acceptable salt thereof is disclosed. A pharmaceutical composition thereof is useful for inhibiting the abnormal growth of cells in a patient such as inhibiting tumour cells expressing an activated ras oncogene.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 501 613 u 50 Ttellectual property office of n7 0 2 OCT 2001 RECEIVED NOVEL PHENYL-SUBSTITUTED TRICYCLIC INHIBITORS OF FARNESYL- PROTEIN TRANSFERASE 5 BACKGROUND Patent application WO 95/00497 published 5 January 1995 under the Patent Cooperation Treaty (PCT) describes compounds which inhibit the enzyme, farnesyl-protein transferase (FTase) and the farnesylation of the 10 oncogene protein Ras. Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-15 transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer. To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, 20 farnesyl protein transferase, have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. Mutated, oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837, 1993). 25 In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be additional compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention. 30 SUMMARY OF THE INVENTION Inhibition of farnesyl protein transferase by tricyclic compounds of this invention has not been reported previously. Thus, described but not claimed is a method for inhibiting farnesyl protein transferase using tricyclic compounds of this invention which: (i) potently inhibit farnesyl protein transferase, but not 35 geranyigeranyl protein transferase I, in vitro: (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranyigeranyl acceptor; (iii) block -1- o 50 161 intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranyigeranyl acceptor; and (iv) block abnormal cell growth) in culture induced by transforming Ras. Also described but not claimed is a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs. Compounds useful in the described methods are represented by Formula 1.0: X (1.0) or a pharmaceutical^ acceptable salt or solvate thereof, wherein: A represents N or N-oxide; X represents N, CH or C, such that when X is N or CH, there is a single bond to carbon atom 11 as represented by the solid line; or when X is C, there is a double bond to carbon atom 11, as represented by the solid and dotted lines; R1 is hydrogen, bromo, chloro, trifluoromethyl, acyl, alkyl, cycloalkyl, amino, acylamino or alkoxy; R2 is hydrogen, halo, trifluoromethyl, alkyl, alkoxy, -OCF3, hydroxy, amino or acylamino; R3 is hydrogen, bromo, chloro, alkoxy, -OCF3 or hydroxy; -2- intellectual property office of n.z. 0 2 OCT 2001 RECEIVED R4 is hydrogen, halo, trifluoromethyl, alkyl or alkoxy; provided that at least one of R2 or R3 or R4 is alkyl or alkoxy and provided that at least two of R1, R2, R3 or R4 are substituents other than hydrogen; Q is hydrogen when there is a single bond to carbon atom 11, or Q is hydrogen or hydroxy when there is a single bond to carbon 11 and X is CH, or Q is not a substituent when there is a double bond to carbon 11; R5, R6, R7 and R8 independently represent hydrogen, alkyl or -CONHR50 wherein R50 can be any of the values represented for R, below ; Z ti Y is -C-R or-S02-R, wherein ; Z is =0 or =S; and R is aryl, aralkyl, cycloalkyi, cycloalkylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl. Preferably in compound (1.0), there is a single bond or a double bond at carbon atom 11; X is N, CH or C; R1 is H, halo, alkyl, cycloalkyi or alkenyl; R2 is H, halo, alkoxy, or alkyl; R3 is H, halo, alkoxy, hydroxy or alkyl; and R4 is H, halo or alkyl; R5, R6, R7 and R8 are hydrogen; Y is -SO2CH3 or -COR wherein R is heteroarylalkyl, preferably pyridinyl N-oxide-methyl or heterocycloalkylalkyl, preferably piperidinyi-methyl. When R1 is other than hydrogen, preferably the halo moiety is bromo, the alkyl is methyl or ethyl, the cycloalkyi is cyclopropyl or the alkenyl is vinyl. When R2 is other than hydrogen, preferably the alkoxy moiety is methoxy, the halo moiety is bromo or the alkyl is methyl. When R3 is other than hydrogen, preferably the alkoxy moiety is methoxy, the halo moiety is bromo or the alkyl is methyl. When R4 is other than hydrogen, preferably the halo moiety is chloro or the alkyl is methyl. -3 (followed by 3a)- intellectual property office of nz. 0 2 OCT 2001 RECEIVED Accordingly, in a first aspect the present invention provides a compound selected from the group consisting of: 1-(3-Bromo-6,11-dihydro-8,10-dimethoxy-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; 4-(6,11-Dihydro-10-methoxy-3,8-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-10-methoxy-8-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(6,11-Dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(7-Chloro-5,6-dihydro-8-methyl-10-methoxy-1 ^ H-benzo[5,6]cyclohepta[1,2-b]- pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-10-hydroxy-8-methyl-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; 4-(5,6-Dihydro-10-methoxy-3,8-dimethyl-11 H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1 -oxide; (+i_)_4-(3-Bromo-10-methoxy-8-methyl-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1 -oxide; (+,-)-4-(3-Bromo-10-hydroxy-8-methyl-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-7-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-7,10-dimethyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-6,11-dihydro-8-methoxy-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; -3a (followed by 3b)- intellectual property office of n.z. 0 2 OCT 2001 RECEIVED 2>iIJ i ' (-)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide, (-) enantiomer; (+)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridiri-11 -yl)-4-(4-pyridinylacetyl)piperazine N4-oxide, (+) enantiomer; (+,-)-1-(3,10-Dibromo-6,11-dihydro-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3,8-Dibromo-6,11-dihydro-10-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-4-[6,11-Dihydro-3-(1-hydroxy-1-methylethyl)-10-methoxy-8-methyl-5H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-(4-pyridinylacetyl)piperidine N1-oxide; (+)-4-(3-Bromo-10-methoxy-8-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (-)-4-(3-Bromo-10-methoxy-8-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine N1-oxide, (-) enantiomer; (+,-)-1 -(3-Bromo-8-methoxy-10-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; 4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; 4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1I2-b]-pyridin-11 -yl)-1 -(methylsulfonyl)piperidine; 4-(3-Ethyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-piperidinylacetyl)piperazine; (+,-)-4-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta[1I2-b]-pyridin-11 -yl)-1 -(4-piperidinylacetyl-N-carboxamido)piperazine; (+.-)-4-(3-Cyclopropyl-6,11-dihydro-10-methoxy-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine; (+)-4-(3-Bromo-6,11-dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-bJ-pyridin-l 1-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (-)-4-(3-Bromo-6,11-dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine N1-oxide, (-) enantiomer; -3b (followed by 3c)- intellectual property office of N.Z. 0 2 OCT 2001 RECEIVED (+)-4-(3-Bromo-6,11-dihydro-11-hydroxy-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (-)-4-(3-Bromo-6,11-dihydro-11-hydroxy-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta-[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (-) enantiomer; 4-(3-Bromo-5,6-dihydro-10-bromo-8-methyl-11 H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; and the pharmaceutically acceptable salts and solvates thereof. Preferred title compounds include those of Examples 1, 2, 3, 6, 7, 8, 10, 16, 18, 19, 21, 22, 24, 26, 27, 29, 33, 34, 35, 36 and 37, preferably those of Examples 3, 21, 22, 24 and 33, disclosed hereinafter. In a further aspect, the present invention provides a pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of "a compound of the invention in combination with a pharmaceutically acceptable carrier. In a still further aspect the present invention provides a use of a compound of the invention in the preparation of a medicament for inhibiting the abnormal growth of cells in a patent in need thereof. * 7") ■ Described by not claimed is a , method for inhibiting the abnoYmal growth of cells, including transformed cells, comprising administering an effective amount of compound (1.0) to a mammal (e.g., a human) in need of such treatment. Abnormal growth of cells refers to 10 cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein ^ is activated as a result of oncogenic mutation in another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation 15 occurs, and (4) benign or malignant cells that are activated by mechanisms other than the Ras protein. Without wishing to be bound by theory, it is believed that these compounds may function either through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and 20 cancer, or through inhibition of ras farnesyl protein transferase, thus making them useful for their antiproliferative activity against ras transformed cells. The cells to be inhibited can be tumor cells expressing an activated ras oncogene. For example, the types of cells that may be inhibited include pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid 25 follicular tumor cells, myelodyspiastic tumor cells, epidermal carcinoma tumor )) cells, bladder carcinoma tumor cells, prostate tumor cells, breast tumor cells or colon tumors cells. Also, the inhibition of the abnormal growth of cells by the treatment with compound (1.0) may be by inhibiting ras farnesyl protein transferase. The inhibition may be of tumor cells wherein the Ras protein is 30 activated as a result of oncogenic mutation in genes other than the Ras gene. Alternatively, compounds (1.0) may inhibit tumor cells activated by a protein other than the Ras protein. Also described but not claimed is a method for inhibiting tumor growth by administering an effective amount of compound (1.0) to a mammal (e.g., a 35 human) in need of such treatment. ] Further described but not claimed is a method for inhibiting the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described 4 - intellectual property office of nz. o 2 OCT 2001 RECEIVED ) compounds. Examples of tumors which may be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon 5 adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, prostate carcinoma and breast carcinoma and epidermal carcinoma. Described by not claimed is '<a method? for inhibiting 10 proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes-i.e., the Ras gene itself is not activated by mutation to an oncogenic form-with said ™ inhibition being accomplished by the administration of an effective amount of the N-substituted urea compounds (1.0) described herein, to a mammal (e.g., a 15 human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, Ick, and fyn), may be inhibited by the N-substituted urea compounds (1.0). Also described but not claimed is a 20 method for inhibiting ras farnesyl protein transferase and the farnesylation of the oncogene protein Ras by administering an effective amount of compound (1.0) to mammals, especially humans. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described above. DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms are used as defined below unless otherwise indicated: 30 M+ -represents the molecular ion of the molecule in the mass spectrum; MH+ -represents the molecular ion plus hydrogen of the molecule in the mass spectrum; Bu-represents butyl; Et-represents ethyl; 35 Me-represents methyl; Ph-represents phenyl; -5- intellectual property office of nz. 0 2 OCT 2001 received WO 98/57950 PCT /U S98/11509 benzotriazol-1-yloxy represents CC- \ o— . r 1 -methyl-tetrazol-5-ylthio represents n-n N I ch3 1 alkyl-(including the alkyl portions of alkoxy, alkylamino and dialkylamino)-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms; for example methyl, ethyl, propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; wherein said alkyl group may be optionally and independently substituted with one, two, three or more of the following: halo (i.e. trifluoromethyl), alkyl, aryl, cycloalkyi, cyano, -cf3, oxy (=0), aryloxy, -OR10 (i.e. hydroxymethyl, hydroxyethyl), -ocf3, heterocycloalkyl, heteroaryl, -NR10R12, -nhso2r10, -S02NH2, -S02NHR1°, -so2r10, -SOR10, -SR10, -NHS02i -N02> -CONR10R12, -NR12COR10, -COR10, -OCOR10, -0C02R10 or-COOR10, wherein R10 and R12 can independently represent hydrogen, alkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyi, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; acylamino- refers to the moiety -CONR10R12 wherein R10 and R12 are defined hereinbefore; alkoxy-an alkyl moiety of one to 20 carbon atoms covalently bonded to an adjacent structural element through an oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like; wherein said alkoxy group may be optionally and independently substituted with alkyl, aryl, cycloalkyi, cyano, -cf3, oxy (=0), aryloxy, -OR10, -ocf3, heterocycloalkyl, heteroaryl, -NR10R12, -NHS02R10, -S02NH2> -S02NHR1°, -S02R10 -SOR10, -SR10, -nhso2, -N02, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -oco2r10 or -COOR10, wherein R10 and R12 are as defined hereinabove; aryl (including the aryl portion of aralkyl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is phenyl), wherein said aryl group optionally can be fused with aryl, cycloalkyi, heteroaryl or heterocycloalkyl rings; and wherein any of the -6- Printed from Mimosa WO 98/57950 PCT/US98/11509 available substitutable carbon and nitrogen atoms in said aryl group and/or said fused ring(s) may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyi, cyano, -cf3, oxy (=0), aryloxy, -OR10, -ocf3, heterocycloalkyl, heteroaryl, -NR10R12, -5 nhso2r10, -so2nh2, -so2nhr10, -S02R10, -SOR10, -SR10, -nhso2, -N02i -CONR10R12, -NR12COR10, -COR10, -OCOR10, -0C02R1° or -COOR10, wherein R10 and R12 are as defined hereinabove; aralkyl - represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one or 10 more aryl groups; wherein said aralkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyi, cyano, -cf3, oxy (=0), aryloxy, -OR10, -ocf3, heterocycloalkyl, heteroaryl, -NR10R12, -nhso2r10, -so2nh2, -so2nhr10 -S02R10, -SOR10, -SR10, -nhso2, -N02, -CONR10R12, -NR12COR10, -COR10, -15 OCOR10, -oco2r10 or -COOR10, wherein R10 and R12 are as defined hereinabove; aryloxy - represents an aryl group, as defined above, wherein said aryl group is covalently bonded to an adjacent structural element through an oxygen atom, for example, phenoxy, wherein said aryl group optionally can be 20 fused with aryl, cycloalkyi, heteroaryl or heterocycloalkyl rings; and wherein any of the available substitutable carbon and nitrogen atoms in said aryloxy group and/or said fused ring(s) may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyi, cyano, -cf3, oxy (=0), aryloxy, -OR10, -ocf3, heterocycloalkyl, heteroaryl, -NR10R12, -25 nhso2r10, -so2nh2, -so2nhr10, -S02R10, -SOR10, -SR10, -NHS02, -N02, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -0C02R1° or -COOR10, wherein R10 and R12 are as defined hereinabove, cycloalkyl-represents saturated carbocyclic rings branched or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms; 30 wherein said cycloalkyi group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyi, cyano, -cf3, oxy (=0), aryloxy, -OR10, -ocf3, heterocycloalkyl, heteroaryl, -NR10R12, -nhso2r10, -so2nh2, -S02NHR10, -S02R10, -SOR10, -SR10, -NHS02, -N02, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -0C02R1° or -COOR10, wherein 35 R10 and R12 are as defined hereinabove; cycloalkylalkyl - represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one -7- Printed from Mimosa WO 98/57950 PCT/US98/11509 or more cycloalkyi groups; wherein said cycloalkylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyi, cyano, -cf3, oxy (=0), aryloxy, -OR10, -OCF3, heterocycloalkyl, heteroaryl, -NR10R12, -nhso2r10, -S02NH2, -S02NHR10, -5 S02R10, -SOR10, -SR10, -NHS02, -N02i -CONR10R12, -NR12COR10, -COR10, -OCOR10, -0C02R10 or -COOR10, wherein R10 and R12 are as defined hereinabove; halo-represents fluoro, chloro, bromo and iodo; heteroalkyl-represents straight and branched carbon chains containing 10 from one to twenty carbon atoms, preferably one to six carbon atoms interrupted by 1 to 3 heteroatoms selected from -O-, -S- and -N-, wherein any of the available substitutable carbon and nitrogen atoms in said heteroalkyl chain may be optionally and independently substituted with one, two, three or more of the following, halo, alkyl, aryl, cycloalkyi, cyano, -cf3, oxy (=0), aryloxy, -OR10, 15 -ocf3, heterocycloalkyl, heteroaryl, -NR10R12, -NHS02R10, -S02NH2, -S02NHR10, -S02R10, -SOR10, -SR10, -NHS02, -N02, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -0C02R1° or-COOR10, wherein R10 and R12 are as defined hereinabove; heteroaryl-represents cyclic groups having at least one heteroatom 20 selected from O, S and N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups containing from 2 to 14 carbon atoms,wherein said heteroaryl group optionally can be fused with one or more aryl, cycloalkyi, heteroaryl or heterocycloalkyl rings; and wherein 25 any of the available substitutable carbon or nitrogen atoms in said heteroaryl group and/or said fused ring(s) may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyi, cyano, -cf3, oxy (=0), aryloxy, -OR10, -ocf3, heterocycloalkyl, heteroaryl, -NR10R12, -NHS02R10, -S02NH2, -S02NHR10, -S02R10, -SOR10, -30 SR10, -NHS02, -N02, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -oco2r10 or -COOR10, wherein R10 and R12 are as defined hereinabove. Representative heteroaryl groups can include, for example, furanyl, imidazoyl, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl N-oxide wherein pyridyl N-oxide can be represented as: -8- Printed from Mimosa WO 98/57950 PCT/US98/11509 b b - b N N N I I O O" o heteroarylalkyl - represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heteroaryl groups; wherein said heteroarylalkyl group may be optionally and 5 independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyi, cyano, -cf3, oxy (=0), aryloxy, -OR10, -ocf3, heterocycloalkyl, heteroaryl, -NR10R12, -nhso2r10, -so2nh2, -so2nhr10 -so2r10, -SOR10, -SR10, -nhso2, -N02, -CONR1QR12, -NR12COR10, -COR10, -OCOR10, -oco2r10 or -COOR10, wherein R10 and R12 are as defined 10 hereinabove; heterocycloalkyl-represents a saturated, branched or unbranched carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 heteroatoms selected from -O-, -S- and -N-, wherein optionally, said ring may contain one or 15 two unsaturated bonds which do not impart aromatic character to the ring; and wherein any of the available substitutable carbon and nitrogen atoms in the ring may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyi, cyano, -cf3, oxy (=0), aryloxy. -OR10, -ocf3, heterocycloalkyl, heteroaryl, -NR10R12, -nhso2r10, -20 S02NH2, -so2nhr10, -S02R10, -SOR10, -SR10, -nhso2, -N02, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -0C02R1° or -COOR10, wherein R10 and R12 are as defined hereinabove. Representative heterocycloalkyl groups can include 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 1-, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 1-, 2- or 3-piperizinyl, 2- or 4-dioxanyl, / \ —<^Vr10 —N S(0\ 25 morpholinyl, > ' or wherein R10 is defined hereinbefore and t is 0, 1 or 2. heterocycloalkalkyl- represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heterocycloalkyl groups; wherein optionally, said ring may contain one or two 30 unsaturated bonds which do not impart aromatic character to the ring; and wherein said heterocycloalkylalkyl group may be optionally and independently -9- Pnnted from Mimosa WO 98/57950 PCT/US98/11509 substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyi, cyano, -CF3, oxy (=0), aryloxy, -OR10, -OCF3, heterocycloalkyl, heteroaryl, -NR10R12, -NHS02R1°, -S02NH2, -S02NHR1°, -S02R1°, -SOR10, -SR10, -NHS02, -N02i -CONR10R12, -NR12COR10, -COR10, -OCOR10, -5 0C02R10 or -COOR10, wherein R10 and R12 are as defined hereinabove. The following solvents and reagents are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH), methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride 10 (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et20); ethyl chloroformate (CIC02Et); lithium di-isopropylamide (LDA) and 1-(3-dimethylaminopropyl)-3-ethyt carbodiimide hydrochloride (EDCI or DEC). Reference to the position of the substituents R1, R2, R3 and R4 is based 15 on the numbered ring structure: (1.0) Certain compounds of the invention may exist in different stereoisomers forms (e.g., enantiomers, diastereoisomers and atropisomers). The invention contemplates all such stereoisomers both in pure form and in mixture, including 20 racemic mixtures. For example, the carbon atom at the C-11 position can be in the S or R stereoconfiguration Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxy! group. These compounds may form pharmaceutically acceptable salts. Examples of such 25 salts may include sodium, potassium, calcium, aluminum, gold and silver salts Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like. -10- Printed from Mimosa WO 98/57950 PCT/US98/11509 10 15 20 Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention. All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purpopses of the invention. Compounds of the present invention can be prepared according to the following Schemes I, II or III wherein Scheme I 1.0a 25 (11, 11 3, 13d, 13.3d, 19, 19 3, 20, 20 3) A, R1, R2, R3, R4, R5, R6, R7, R8, Y, the solid and dotted lines are as defined hereinbefore 1.0b -11 - Printed from Mimosa WO 98/57950 PCT/US98/11509 Z II Y = C- R In Scheme I, compound 1.0 wherein ^ and Z=0 wherein R is defined hereinbefore, can be prepared by acylating compound (11, 11.3), (19, 19.3) or (20, 20.3) with a carboxylic acid of the formula RCOOH (30.0) wherein R is defined hereinbefore, in an aprotic solvent, at temperatures ranging from about 0° to 20°C, using about 1 to 2 moles of carboxylic acid (30.0) per mole of compound (11, 11.3), (19, 19.3) or (20, 20.3). Alternatively, compound 1.0 wherein Y = S02R, can be prepared by reacting compound (11,11.3), (19, 19.3) or (20, 20.3) with a sulfonyl chloride of the formula RSO2CI (20.7) wherein R is as defined before, in a solvent such a pyridine and a base such as 4-dimethylaminopyridine or triethylamine, using 1 to 3 moles of sulfonyl chlonde (20.7) per mole of compound (11, 11.3), (19, 19.3) or (20, 20.3). The amount of base can range from catalytic to about 1.5 moles per mole of compound (11, 11.3), (19, 19.3) or (20, 20.3). The compounds of formula (1.0) wherein A is N-0 (i.e. the N-oxide), can be prepared by treating compound (1.0) wherein A is N with metachloroperbenzoic acid (MCPBA) in an aprotic solvent such as methylene chloride at temperatures ranging from about 0° to 25°C, using 1 to 2 equivalents of MCPBA per mole of compound (1.0). The sulfur-containing compounds of formula (1.0) wherein Z = S, can be treating compounds (1.0) wherein Z=0 with a sulfurating agent such as Lawesson's Reagent in a suitable aprotic solvent such as toluene at about 100°C to give the thioamide (1.0). Alternative sulfurating reagents include bis-(1,5-cyclooctanediarylboryi)sulfide in hexane at -78°C; or phosphorous pentasulfide (P2S5, also of the formula P4S10) in toluene at reflux temperatures, or in THF using ultrasound at 40°C, or bis-(9-Borabicyclo[3.3.1]nonane)sulfide ((9-BBN)2S) in heptane at reflux temperatures. Compounds of formula (1.0) can be isolated from the reaction mixture using conventional procedures, such as, for example, extraction of the reaction mixture from water with organic solvents, evaporation of the organic solvents, followed by chromatography on silica gel or other suitable chromatographic media. Alternatively, compounds (1.0) can be dissolved in a water-miscible solvent, such as methanol, the methanol solution is added to water to precipitate the compound, and the precipitate is isolated by filtration or centrifugation. -12- Printed from Mimosa WO 98/57950 PCT/US98/11509 Compounds of formula 1.0, 1.0a and 1.0b in Scheme I, wherein X is CH or N may be racemates. These racemates can be resolved into their (+) and (-) enantiomers by HPLC procedures on Chiralpak columns (Daicel Chemical 5 Ind.). Alternatively, (+)-lsomers of compounds of formula (19, 19.3, 20, 20.3) wherein X is CH can be prepared with high enantioselectivity by using a process comprising enzyme catalyzed transesterification. Preferably, a racemic compound of formula (19, 19.3, 20, 20.3) , wherein X is C, the double bond is present and X3 is not H, is reacted with an enzyme such as Toyobo LlP-300 10 and an acylating agent such as trifluoroethly isobutyrate; the resultant (+)- amide is then hydrolyzed, for example by refluxing with an acid such as h2so4, to obtain the corresponding optically enriched (+)-isomer wherein X is CH and R3 is not H. Alternatively, a racemic compound of formula (5.0, 6.0 and 10.9), wherein X is C, the double bond is present and R3 is not H, is first reduced to 15 the corresponding racemic compound of formula (19, 19.3, 20, 20.3) wherein X is CH and then treated with the enzyme (Toyobo LIP-300) and acylating agent as described above to obtain the (+)-amide, which is hydrolyzed to obtain the optically enriched (+)-isomer. Compounds of the present invention and preparative starting materials 20 thereof, are exemplified by the following examples, which should not be construed as limiting the scope of the disclosure. Example 1. 1-(3-Bromo-6,11-dihydro-8,10-dimethoxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-4-(4-pyridinylacetyl)piperazine N4-oxide Example 1, Step 1. -13- Pnnted from Mimosa WO 98/57950 PCT/US98/11509 10 15 20 h3co ,ch3 Br O 1 BuLi / i-Pr2NH n nh h3c-j- ch3 h3c CI och3 /^och3 h3co nh h3c-|— ch3 h3c To a solution of diisopropylamine (2.28 ml) in THF (10 ml) at -78°C under a nitrogen atmosphere, 2.5 M Butyl lithium in hexanes (6.5 ml) is added dropwise. After stirring the mixture for 10 mins, a solution of compound A (2.0 g) in THF (10 ml) is added. The resulting purple reaction mixture is stirred for 10 mins before adding a solution of 3,5-dimethoxy benzyl chloride (2.07 g) in THF (10 ml). The reaction mixture is stirred at -78°C for 15 mins, 1 hr at 0°C and then at room temp for 1hr. The pale burgundy color reaction is diluted with ice/water and extracted with dichloromethane. The crude product obtained on evaporation of the organic extract is evaporated and flash chromatographed on silica gel (200ml). Elution with 10% ethylacetate-hexane affords the title compound B as an oil (2.3 g, 75% yield). MS m/e 421, 423(MH), . Example 1, Step 2. h3co och3 Phosphorous oxychloride (12 ml) is added dropwise to a solution of B (2.3g) in toluene (20ml). The mixture is heated in an oil bath (115°C). After one hour a droplet of DMF is added, the solution is heated for an additional 4 hrs and is then cooled to room temp before evaporation under reduced pressure. The residual oil is dissolved in ethylacetate (50 ml) and ice/water (20ml) and stirred while adding 10% sodium hydroxide until the aqueous phase is basic. The basic solution is extracted with ethylacetate, the organic extracts are combined, washed with brine, dried and evaporated. The crude product is dissolved in ethylacetate and filtered through a silica gel plug. The colorless filtrate is -14 Printed from Mimosa WO 98/57950 PCT/U S98/11509 concentrated under reduced pressure and diluted slowly with hexane to afford the title compound C as a crystalline solid (1.62g, 85%): m.p. 106-107°C; MS m/e 347, 349 (MH). Aluminum Chloride (1.0 g) is added in small lots during 10 minutes to a well stirred solution of C (1.16 g) in dichloroethane (100 ml). The pale yellow solution is stirred at room temperature for 1 hr and is then worked up by the 10 addition of ice/water and 10% sodium hydroxide to pH 10. The mixture is extracted several times with dichloromethane, and the crude product obtained on evaporation of the combined extracts is flash chromatographed on silica gel (100ml). Elution with 10% methanol-2% ammonium hydroxide-ethylacetate affords the intermediate imine D (0.89g). Product D of Step 3 is dissolved in 2N hydrochloric acid The solution is heated in an oil bath (120°C) for 1.5hrs, cooled, made basic with 10% sodium 20 hydroxide and extracted with dichloromethane (4 x 50 ml portions). The crude product is obtained by concentration of the combined extract filtered through a silica gel plug, evaporation of the filtrate affords the title ketone E as an amorphous solid (0.81 g, 91%). MS m/e 348, 350 (MH)+. 25 Example 1, Step 4. -15- Printed from Mimosa WO 98/57950 PCT/US98/11509 E F Sodium borohydride (0.09g) is added in portions, with stirring, to a solution of ketone E (0.8 g) in methanol (20 ml) at 0°C. The reaction is then stirred at room temperature for one hour, acidified with acetic acid-water and most of the 5 solvent is removed by evaporation under reduced pressure. The residual mixture is made basic with 10% sodium hydroxide to pH 10 followed by extraction with ethylacetate (4x50ml). The combined extract is filtered through a plug of silica gel and the filtrate is evaporated to afford product F as a resin puff (0.79g). MS m/e 350, 352 (MH). 10 Example 1, Steps 5 and 6 Phosphorous oxychloride (2.0ml) is added dropwise to a solution of product F (0.45 g) in dichloromethane (5 ml) under nitrogen. The reaction mixture is 15 stirred at room temperature for one hour and is then evaporated under reduced pressure at 45°C. The dark residual gum is azeotroped with toluene (2 x10 ml) and is then dissolved in acetonitrile (15 ml) containing piperazine (0.5 g). The reaction mixture is stirred at room temperature for 2 hrs and is worked up by evaporating under reduced pressure and diluting with water followed by 20 addition of 10% sodium hydroxide(5 ml). The product is extracted with dichloromethane (5 x 20 ml) and flash chromatographed on silica gel. Elution with 10% methanol-2% ammonium hydroxide-dichloromethane affords product G as a tan puff (0.22g). MS m/e 418, 420 (MH). 25 Example 1, Step 7. Printed from Mimosa WO 98/57950 PCT/US98/11509 Br ^N^OCH3 OCH3 ArCOOH coupling 95% Br och3 O „ 0K^KJ racemate A solution of product G (0.2 g), 1-hydroxybenzotriazole (0.13 g) and 4-pyridyl acetic acid N-oxide (0.15 g) in dimethylformamide (3.0 ml) is cooled in ice and treated with N-(3-dimethyl aminopropyl)-N'-ethylcarbodiimide hydrochloride 5 (0.18 g) followed by N-methyl morpholine (0.3 ml). The mixture is allowed to warm to room temperature overnight and is then evaporated under reduced pressure. The residual gum is stirred with 10% sodium carbonate and extracted with dichloroethane. The crude product obtained by evaporation of the extract is flash chromatographed on silica gel (30 ml). Elution with 5% methanol-2% 10 ammonium hydroxide-dichloromethane affords product H as a pale tan foam (0.25 g). MS m/e 553, 555 (MH). Example 2. 4-(6,11-dihydro-10-methoxy-3,8-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-15 oxide Example 2, Step 1. h3co h3co B A -17- Printed from Mimosa WO 98/57950 PCT/U S98/11509 10 15 Using similar reaction conditions as described in Step 1, Example 1, reagent A (5-methyl-t-butyl amide) is first treated with di-isopropylamine and butyl lithium, then reacted with benzylbromide 2 to give compound B. Example 2, Step 2. hgco Using similar reaction conditions as described in Step 2, Example 1, the crude product B is reacted with phosphorous oxychloride to afford compound C: m.p. 188-190 °C, MS m/e 301 (MH). Example 2, Step 3. c 2 h2o d Nitnle compound C (1.65g) is added with stirring to cold (0°C) triflic acid (30 ml). The solution is stored overnight at room temperature, diluted with ice/water (50 ml) and heated in an oil bath (120 °C) for 4 hrs. The reaction mixture is then cooled, neutralised with 50% sodium hydroxide and the crude product is extracted with dichloromethane (6 x 50 ml) and flash chromatographed on silica gel (300 ml). Elution with 1.1 ethylacetate-hexane followed by crystallization from ethylacetate-hexane affords compound D (1.54g): MS m/e 302 (MH). Example 2, Step 4. ch3 -18- Printed from Mimosa WO 98/57950 PCT/US98/11509 A solution of E (0.8M, 13.2 ml) in THF is added with stirring under nitrogen to a cold (ice bath) solution of D (1.6g) in THF ( 30ml). The reaction is stirred for 30 min and is then diluted with ice/water followed by extraction with dichlorometrhane (3 x 50 mi). The crude product obtained by evaporation of the 5 extract is flash chromatographed on silica gel (100 ml). The column is first eluted with 10% methanol-dichloromethane to remove impurities; elution with 10% methanol-3% ammonium hydroxidel-dichloromethane affords compound F as an amorphous solid (1.6g): MS m/e 401 (MH). A solution of ethylchloroformate (1.5ml) in toluene (20 ml) is added dropwise during 10 min. with stirring to a solution of compound F (1.5 g) and triethylamine (0.9 ml) in toluene (30 ml) heated in an oil bath at 85° C. The reaction is heated for an additional 45 min and is then cooled and stirred with 15 ice-water, followed by washing with 10% sodium carbonate. The crude product is isolated by extraction with ethylacetate and is flash chromatographed on silica gel to afford compound G. MS m/e 459 (MH). 20 A solution of compound G (1.2g) in ethanol (40ml) and 10% palladium-carbon is hydrogenated in a Parr flask at 50 psi for 6 hrs. The catalyst is removed by filtration and the filtrate is evaporated. The residue is dissolved in ethylacetate and the solution is washed with 10% sodium carbonate. The organic layer is evaporated to afford compound H. 25 Example 2, Step 7. -19- Printed from Mimosa WO 98/57950 PCT/US98/11509 10 15 20 CH3 PPA CH3 COOEt COOEt A paste obtained by combining compound H (0.58g) with poiyphosphoric acid (PPA) (1.5ml) is heated in an oil bath at 100 °C for 30 min. The dark brown liquid is cooled and stirred with ice-water (10 ml), the resulting solution is made basic with 50% sodium hydroxide and then extracted with dichloromethane (5 x 30 ml). The extract is filtered through a plug of silica gel which is then eluted with 10% methanol-dichloromethane. The combined filtrates are evaporated and chromatographed on silica gel (50ml). Elution with 5%methanol-dichloromethane affords compound I as a tan solid. MS m/e 407 (MH). Example 2, Step 8. H3 J L>UULl j A solution of compound I (0.5g) in 4 N hydrochloric acid (20ml) is heated in an oil bath (130°C) for 14 hrs The reaction is cooled and made basic with 50% sodium hydroxide to pH 8 and extracted with dichloromethane. The extract is dried over sodium sulfate and evaporated to dryness to afford compound J. Example 2, Step 9. ? CO x >-vch3 h3° yV a.och3 dibal h XT n fvch3 ~y\J a0ch3 j 1 h k 1 h Dusobutylaluminum hydride (DIBAL H) (1M solution in toluene, 4.8ml) is added dropwise with stirring to a solution of compound J (0.45 g) in dry toluene (10 ml) at 15°C. The reaction mixture is stirred at room temperature for 2 hrs and is then quenched by addition of water (10 ml) and 10% sodium hydroxide. The mixture is extracted with dichloromethane and the crude product is 20- Pnnted from Mimosa WO 98/57950 PCT/US98/11509 chromatographed on silica gel (30ml). Elution with 10% methanol-2% ammonium hydroxide-dichloromethane affords compound J: MS m/e 337 (MH). Example 2, Step 10. 5 racemate A solution of product J (0.2 g), 1-hydroxybenzotriazole (0.13 g) and 4-pyridyl acetic acid N-oxide (0.15 g) in dimethylformamide (3.0 ml) is cooled in ice and treated with N-(3-dimethyl aminopropyl)-N'-ethylcarbodnmide hydrochloride (0.18 g) followed by N-methyl morpholine (0.3 ml). The mixture is allowed to 10 warm to room temperature overnight and is then evaporated under reduced pressure. The residual gum is stirred with 10% sodium carbonate and extracted with dichloromethane. The crude product obtained by evaporation of the extract is flash chromatographed on silica gel (30 ml). Elution with 5% methanol-2% ammonium hydroxide-dichloromethane affords product K as a 15 pale tan foam. MS 471 (CI) 472. Example 3. (+,-)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide 20 racemate H Example 3, Steps 1 & 2. -21 - Printed from Mimosa WO 98/57950 PCT/US98/11509 Br A NHf-Bu H3CO h3co NHf-Bu hgcq Br. N I B NHf-Bu Following the procedures as described in Example 1, Steps 1 and 2, except that reactant 2 is substituted for reactant 2 of Example 1, gives intermediate compounds B and C. Example 3, Step 3. A 0.5M solution of 1 -methyl-4-piperidyl magnesium chloride in THF (28 ml) is added dropwise to a solution of compound C (4.8 g) in THF (60 ml) under argon. The dark color reaction is heated at 55°C for 15 min., cooled in an ice bath, quenched with water and extracted with ethylacetate (4 x 50 ml). The 15 combined extract is dried over sodium sulfate and evaporated under reduced pressure. The resulting intermediate is dissolved in 4N HCI (40 ml) and methanol (20 ml) and the solution is heated on a steam bath for 1 hour, cooled in an ice bath and made basic with 10% NaOH followed by extraction with ethylacetate. The extract is evaporated and flash chromatographed on silica 20 gel. Elution with 10% ethylacetate-hexane affords compound D (2.7g): MS m/e 431 (MH). 10 Br och3 -22- Pnnted from Mimosa WO 98/57950 PCT/US98/11509 Example 3, Step 4. Br CH3 Triflic acid (55 ml) is added with stirring to compound D (2.9 g) and the dark 5 syrupy solution is stored overnight at 4°C. The reaction mixture is worked up by pouring on ice, making basic with 50% NaOH, followed by extraction with dichloromethane (3 x 50ml). The extract is evaporated under reduced pressure and the crude product is flash chromatographed on silica gel. Elution with 5% methanol-dichloromethane affords compound E (1.37g); MS m/e 413 (MH). 10 Example 3, Step 5. Following the procedure as described in Example 2, Step 5 gives intermediate compound F. 15 Example 3, Steps 6 & 7. Following the procedures as described in Example 2, Steps 8 and 9, gives intermediate compounds G and H. Compound H is resolved into its (+) and (-) Br CH3 -23- Printed from Mimosa WO 98/57950 PCT/US98/11509 enatiomers by dissolving 0.580 g in i-propanol/hexane (0.2%dea) containing EtOH with heating on a steambath. The solution is applied to a preparative HPLC chiralpac AD, 5 by 50cm column (Daicel Chemical Ind.), and eluted with i-propanol/hexane (0.2%DEA) with a flow rate at 20 ml/min and collecting 5 500ml fractions. After the first peak is eluted the solvent is changed to 25/75 i-propanol/hexane (0.2%DEA) at a flow rate of 40 ml/min. The (+) enantiomer (0265 g) is obtained in fraction 2. Optical rotation =+2.69 at concentration of (5.2 mg/2ml EtOH) at 20.5 °C. The (-) enantiomer (0.2280 g) is obtained from fractions 7 to 8. Both the (+) and (-) enantiomers are determined pure by 10 analytical HPLC on a chiralpak AD 0.46 cm by 25 cm column. racemate Following the procedures as described in Example 1, Step 7, gives the desired 15 title compound I, a racemate. Example 4. (+,-)-4-(6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine N-1 oxide racemate H -24- Printed from Mimosa WO 98/57950 PCT/US98/11509 COOEt -25- Prmted from Mimosa WO 98/57950 PCT/US98/11509 H COOEt COOEt och3 "V- racemate Following the procedures as described in Example 2, Steps 1-9, except that reactant 2 is substituted for reactant 2>in Example 2, gives intermediate compounds A-K, and the desired title compound L, a racemate. 10 Example 5. (+,-)-4-(7-Chloro-5,6-dihydro-8-methyl-10-methoxy-11H- benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide -26- Printed from Mimosa WO 98/57950 PCT/US98/11509 By substituting 3-methyl-2-chloro-5-methoxybenzylchloride for reagent 2 and 3-methyl-2-t-butyl carboxamidopyridine for compound A in Example 3, Step 1, and by following Example 3, Steps 1-8 but omitting Example 3, Step 7 with DIBALH, the title compound is obtained. Example 6 (+,-)-4-(3-Bromo-10-hydroxy-8-methyl~5,6-dihydro-11H- benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide By starting with 5-bromo-3-methyl-2-t-butyl carboxamido pyridine and by following Example 3, Step 1-6 gives compound A, below. Compound A (500mg,1.34mmol) is stirred in triflic acid (3 ml) at 80°C, for 2 hours, then cooled to room temperature. The reaction mixture is diluted with ice (20 g), basified with 10% sodium carbonate, then extracted with CH2CI2 (2 x 60ml). The organic layer is separated, dried over MgS04i filtered, and evaporated solvent, to yield an oil, which chromatographs on silica gel eluting with 7%(v/v) methanol-methylene chloride containing 2% ammonium hydroxide, yielding Compound B, as a white solid. Using the procedure of -27- Pnnted from Mimosa WO 98/57950 PCT/US98/11509 Example 1, Step 7, substituting an equivalent amount of Compound B for Compound G, gives the title compound. FABS 519 MH. Example 7. 4-(5,6-dihydro-10-methoxy-3,8-dimethyl-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -ylidene)-1 -(4-pyridinylacetyl)piperidine N1-oxide By substituting 3-methyl-5-methoxybenzylghloride for reagent 2 and 3,5-dimethyl-2-t-butyl carboxamidopyridine for compound A in Example 1, Step 1, and by following Example 1, Steps 1-7, the title compound is obtained. Example 8. (+,-)-4-(3-bromo-10-methoxy-8-methyl-5,6-dihydro-11H- benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-(4-pyridinyiacetyl)piperidine N1-oxide By starting with intermediate G of Example 3, Step 6 and by following Example 1, Steps 1-7, the title compound is obtained Example 9. (+,-)-4-(3-Bromo-10-hydroxy-8-methyl--5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine N1 -oxide Br -28- Printed from Mimosa WO 98/57950 PCT/US98/11509 By following the procedure of Example 6, except that the procedure of Example 2, Step 9 is carried out prior to the procedure of Example 1, Step 7, to give the title compound. Example 10. (+,-)-1 -(3-Bromo-10-methoxy-8-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-4-(4-pyridinylacetyl)piperazine N4-oxide By substituting 3-methyl-5-methoxybenzylchloride for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7, the title compound is obtained. Example 14. (+,-)-1-(3-Bromo-7-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide By substituting 2-methylbenzylchloride for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. Example 15. (+,-)-1-(3-Bromo-7,10-dimethyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-4-(4-pyridinylacetyl)piperazine N4-oxide -29- Printed from Mimosa WO 98/57950 PCT/US98/11509 ch3 Br. By substituting 2,5-dimethylbenzyl chloride for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. Example 16. (+,-)-1-(3-Bromo-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-4-(4-pyridinylacetyl)piperazine N4-oxide By substituting 3-methylbenzylchloride for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. Example 17. (+,-)-1-(3-Bromo-6,11-dihydro-8-methoxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-4-(4-pyridinylacetyl)piperazine N4-oxide By substituting 3-methoxybenzylchloride for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. O' O' -30- Printed from Mimosa WO 98/57950 PCT/US98/11509 Example 18. (+,-)-1-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H- benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide By substituting 3,5-dimethylbenzylbromide for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. Example 19. (-)-1 -(3-Bromo-10-methoxy-8-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide, (-) enantiomer The racemic title compound of Example 10 (67 mg) is dissolved into 50/50 i-propanol/hexane containing 0.2% diethylamine and the solution is injected into a preparative high performance liquid chromatography column, chiralpak AD 5 by 50cm column (Daicel Chemical Ind.). Elution with ethanol (EtOH)/Hexane (containing 0.2% diethylamine or DEA) at 20 ml/min for two hours, then changing the eluting phase to 7% EtOH/Hexane (0.2%DEA) and increasing the flow rate to 40 ml/min (500 ml fractions are collected) gives: O' o (-) enantiomer -31 - Printed from Mimosa WO 98/57950 PCT/US98/11509 fractions 10-12, 30.9 mg of title compound of Example 19: [a]o23 -18.8°(c. 0.32, ethanol), mp=111-116°C. Example 20. (+)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-4-(4-pyridinylacetyl)piperazine N4-oxide, (+) enantiomer Following the preparative high performance liquid chromatography procedure described in Example 19, the title compound is obtained: fractions 14-16, the title compound of Example 20- [a]o23 +19.6°(c. 0.28, ethanol), mp=110-117°C. Example 21. (+,-)-1-(3,10-Dibromo-6,11-dihydro-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-4-(4-pyndinylacetyl)piperazine N4-oxide By substituting 3-methyl-5-bromobenzyl bromide for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and o (+) enantiomer O racemate -32- Printed from Mimosa WO 98/57950 PCT/US98/11509 by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. Example 22. (+,-)-1-(3,8-Dibromo-6,11-dihydro-10-methyl-5H-5 benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-4-(4-pyridinylacetyl)piperazine By substituting 3-bromo-5-methyl-benzyl bromide for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and 10 by substituting the procedure of Example 2, Step 3 with heating to 60°C for 4 hours with triflic acid, in place of Example 1, Step 3 and 3a, gives the title compound. Example 23. (+,-)-4-[6,11 -dihydro-3-(1 -hydroxy-1 -methylethyl)-10-methoxy-8-15 methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-(4-pyridinylacetyl)piperidine N1 -oxide N4-oxide o CH, Step 1. -33- Printed from Mimosa I 50161 A nitrogen blanketed solution of the compound A of Example 27, Step 1 (0.4g) in tetrahydrofuran (8 ml) is cooled to -78°C and then treated with 2.5M solution of butyl lithium in hexanes (0.4 ml). After stirring for 5 minutes, acetone (0.4 ml) is added and after 5 minutes the reaction mixture is evaporated under reduced pressure to yield an oil that is flash chromatographed on silica gel (50 ml). Elution with 3% methanol-dichloromethane affords B as white powder (0.13 g). MS(CI) 479. Step 2: CH3 B BOC C H Product B from Step 1 is converted to intermediate C by following the procedures described in Steps 3 and 4, Example 27. Tan powder, MS(CI)381, Step 3: Product C from Step 2 is converted to the title compound D by following the procedure described in Example 1, Step 7. White powder, MS(CI) 516. Example 24. (+)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)*-1 *(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer -34 intellectual property office of nz. o 2 OCT 2001 RECEIVED (+) enantiomer By substituting 3-methyl-5-methoxy-benzylbromide for reagent 2 in Example 3, Step 1, and by following Example 3, Steps 1-8 and using the resolved (+) enantiomer H of Step 7, the title compound is obtained. Optical rotation: +31.9° at concentration of 5.7 mg/2 ml ethanol at 22°C (sodium D line). Example 25. (-)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (-) enantiomer By substituting 3-methyl-5-methoxy-benzylbromide for reagent 2 in Example 3, Step 1, and by following Example 3, Steps 1-8 and using the resolved (-) enantiomer H of Step 7, the title compound is obtained. Optical rotation: -31.6° at concentration of 6.2 mg/2 ml ethanol at 22.4°C (sodium D line). Br O (-) enantiomer intellectual property OFFICE OF N Z. -35- 0 2 OCT 2001 RECEIVED Example 26. (+,-)-1-(3-Bromo-8-methoxy-10-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-4-(4-pyridinylacetyl) piperazine N4-oxide 0" 6 O By substituting 3-methoxy-5-methyl-benzylbromide for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. Example 27. 4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyi)piperidine N-|-Oxide o Step 1. 1,1 -Dimethylethyl-4-(3-bromo-5,6-dihydro-10-methoxy-8-methyl-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -ylidene)-1 -piperidinecarboxylate -36- intellectual property-office of n z 0 2 OCT 2001 Received o 50 Essentially the same procedure is followed as in Example 35, except that the (-) enantiomer elutes second MS (FABS)m/e 599.9(MH) Rotation = -7.3°@20°C, c = 0.1375. Example 37. 4-(3-Bromo-5,6-dihydro-10-bromo-8-methyl-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -ylidene)-1 -(4-pyridinylacetyl)piperidine Ni -Oxide By following procedures used to prepare the title compound of Example 33-steps 6, and 9- from example 2 are omitted, the title compound is obtained. MS (FABS)m/e 582(MH). PREPARATION OF STARTING MATERIALS Starting materials useful in preparing the compounds of the present invention are exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. The pyridyl and phenyl compounds used as starting materials, such as compounds (1, 1.3, 3, 3.5), inorganic and organic bases, and alcohols can be prepared using known methods in the art, such as taught in See J. K. Wong et al., Bioorganic & Medicinal Chemistry Letters, Vol. 3, No. 6, pp. 1073-1078, (1993); U.S. Patents 5,089,496; 5,151,423; 4,454,143; 4,355,036; PCT/US94/11390 (W095/10514); PCT/US94/11391 (WO 95/10515); PCT/US94/11392 (W095/10516); Stanley R. Sandier and Wolf Karo, Organic Functional Group Preparations, 2nd Edition, Academic Press, Inc., San Diego, California, Vol. 1-3, (1983), and in J. March, Advanced Organic Chemistry, Reactions & Mechanisms, and Structure, 3rd Edition, John Wiley & Sons, New York, 1346 pp. (1985). Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art. -45- INTELLECTUAL PROPERTY OFFICE OF NZ. 0 2 OCT 2001 RECEIVED Pharmaceutical Dosage Form Examples EXAMPLE A-Tablets No. Ingredients mg/tablet mg/tablet 1. Active compound 100 500 2. Lactose USP 122 113 3. Corn Starch, Food Grade, as a 10% paste in Purified Water 30 40 4. Corn Starch, Food Grade 45 40 5. Magnesium Stearate _3 _7 Total 300 700 Method of Manufacture Mix Item Nos 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weigh on a suitable tablet machine. EXAMPLE B-Capsules No. Ingredient mg/capsule mg/capsule 1. Active compound 100 500 2. Lactose USP 106 123 3. Corn Starch, Food Grade 40 70 4. Magnesium Stearate NF 7 7 Total 253 700 Method of Manufacture Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine. -55- INTELLECTUAL PROPERTY OFFICE OF NZ. 0 2 OCT 2001 RECEIVED WO 98/57950 PCT/US98/11509 Add di-tert-butyldicarbonate (2.0 g,9.16 mmol) in methylene chloride (5 ml) to a solution of the intermediate compound G of Example 3, Step 6 (1.0 g, 2.51 mmol) in methylene chloride (15 ml) at 20°C, then stir 1hour at room 5 temperature. The solvent is evaporated, and the residual oil is chromatographed on silica gel eluting with 15% (v/v) ethyl acetate-hexanes yielding the product as a white solid (1.1 g, 92%yield). MS (CI) 499, MH. 10 Step 2. 1,1 -Dimethylethyl-4-(3-ethenyl-5,6-dihydro-10-methoxy-8-methyl-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -ylidene)-1 -piperidinecarboxylate. Add tributylvinyltin (3ml,10.26mmol) to a solution of the title compound of Step 1 15 (950 mg, 1.90 mmol), lithium chloride (1.0 g, 23 6 mmol), tris(dibenzylideneacetone)dipalladium (180 mg), and tri-2-furoyl phosphine (90 mg, 0.38 mmol) in toluene (6 ml) at room temperature, then stir at 100°C overnight. The reaction is cooled, extracted with ethyl acetate (100 ml), washed with water (50 ml), dried over magnesium sulfate, filtered and the solvent 20 evaporated, yielding an oil, which chromatographs on silica gel eluting with 40%(v/v) ethylacetate-hexanes yielding the product as a white solid (800 mg, 95% yield). MS (CI) 447,MH. Step 3. 4-(3-Ethenyl-5,6-dihydro-10-methoxy-8-methyl-11H-25 benzo[5,6]cyclohepta[1,2-b]pyridin-11 -ylidene)-1 -piperidine -37- Printed from Mimosa WO 98/57950 PCT/US98/11509 Boc H A 20% solution of trifluoroacetic acid in methylene chloride (10 ml) is added to the title compound of Step 2 (400mg,0.89mmol) at room temperature, then stirred for 1/2 hour at 20°C. Water(20ml), methylene chloride (20ml), and 1N 5 NaOH (3 ml) are added, and the organic layer is separated, dried over MgS04, filtered, and the solvent evaporated, yielding a solid (305 mg, 98% yield) » MS(CI) 347,MH. Step 4 3-Ethenyl-6,11 -Dihydro-10-Methoxy-8-Methyl-11 -(4-Piperidinyl)-5H-10 Benzo[5,6]Cyclohepta[1,2-b]Pyridine A 1 M solution of DIBAL in toluene (3 ml,3 mmol) is added dropwise to a solution of the title compound of Step 3 (310 mg, 0.89 mmol) in toluene(2 ml) at 20°C, then stirred 45 minutes. Water (15 ml), EtOAc (30 ml) and 1N NaOH (5 15 ml) are added The organic layer is separated, dried over MgS04, filtered, and the solvent evaporated to yield an oil, which chromatographs on silica gel eluting with 10% methanol-methylene chloride containing 2% NH4OH, yielding the product as a white solid. (200mg,65% yield), MS (FABS) 349.MH. 20 Step 5 4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H- benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine Dibal h2^ H H N1-Oxide. -38- Pnnted from Mimosa WO 98/57950 PCT/US98/11509 EDCI (50 mg,0.26 mmol),1-hydroxyben2otriazole, monohydrate (40 mg, 0.29 mmol) and 4-methyl morpholine (0.5 ml, 4.5 mmol) are added to a solution of the title compound of Step 4 (50 mg, 0.14 mmol) and 4-pyridyl-N-oxide acetic 5 acid (50 mg, 0.326 mmol) in dimethylformamide (anhydrous,2 ml) at 0°C , then stirred at room temperature overnight. The solvent is evaporated, and the residue extracted with methylene chloride (60 ml), and water (25 ml). The organic layer is separated, washed with saturated sodium carbonate (2 x15ml), dried over MgSC>4, filtered and the solvent evaporated to yield an oil which 10 chromatographs on silica gel eluting with 10% MeOH-MeCl2 containing 2% NH4OH yielding the product as a white solid (55 mg,79% yield), MS (FABS) 484, MH. Example 28. 4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H-15 benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(methylsulfonyl)piperidine Methanesulfonyl chloride (0.5 ml, 6.46 mmol) is added to a solution of the title compound of Example 27, Step 4 (30 mg, 0.086 mmol) in anhydrous pyridine (2 z ml) at 0°C, then 4-dimethylaminopyridine (10 mg, 0.08 mmol) is added, and the 20 solution stirred overnight at 20°C. The solvent is evaporated, water (30 ml) and CH2CI2 (60 ml) are added. The organic layer is separated, dried over MgSC>4, filtered, and solvent evaporated to yield an oil, which chromatographs on silica -39- Printed from Mimosa WO 98/57950 PCT/US98/11509 gel eluting with 70% v/v EtOAC-hexanes yielding the product as a white solid (30 mg, 69% yield), MS(CI) 427, MH. Example 29. 4-(3-Ethyl-6,11 -dihydro-10-methoxy-8-methyl-5H-5 benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine, Ni-Oxide Step 1. 3-Ethyl-6,11-dihydro-10-methoxy-8-methyl-11-(4-piperidinyl)-5H-10 benzo[5,6]cyclohepta[1,2-b]pyridine Ammonium formate (200 mg, 2 08 mmol) and 10% Pd/C(20mg) are added to a solution of the title compound of Example 27, Step 4 (90 mg, 0.258mmol) in methanol (5 ml) at 20°C, then refluxed for 4 hours. Methanol (20 ml) is added, 15 and the reaction is filtered through a celite pad, then washed with methanol (10 ml) and CH2CI2 (3 x 20ml). The filtrate and wash are combined, concentrated, and the residue extracted with CH2CI2 (50 ml) and water (25 ml). The organic layer is separated, dried over MgS04, filtered and solvent removed yielding a white solid (75mg, 84% yield). 20 Step 2. 4-(3-Ethyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine, N1-Oxide -40- Printed from Mimosa WO 98/57950 PCT/US98/11509 H EDCI,HOBT,NMM,DMF °-nCK coo o EDCI (75 mg, 0.39 mmol), HOBT (70mg, 0.51 mmol) and NMM (0.5 ml, 4.5 mmol) are added to a solution of the title compound of Step 1 (75 mg, 0.214 mmol) and 4-pyridyl N-oxide acetic acid (75 mg, 0.48 mmol) in DMF(anhydrous, 3 ml) at 0°C, then stirred at room temperature overnight. The solvent is evaporated, and the residue extracted with CH2CI2 (60 ml) and water (25 ml), the organic layer separated, washed with 10% Na2C03 (2 x 20ml), dried over MgSC>4, filtered, and the solvent evaporated to yield an oil, which chromatographs on silica gel eluting with 7% v/v MeOH:methylene chloride (MeCl2) containing 2% NH4OH yielding product as white solid (75mg,76% yield), MS (FABS) 486(MH). Example 30. (+,-)-4-(3-Bromo-6,11-dihydro-8,10-dimethyI-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-1 -(4-piperidinylacetyl)piperazine By substituting 3,5-dimethylbenzylbromide for reagent 2 and by substituting the corresponding 5-bromo-t-butyl amide for reagent A in Example 1, Step 1, and by following Example 1, Steps 1-6 (except for Steps 3, 3a and 7), and by substituting the procedure of Example 2, Step 3 with heating to 60°C using triflic acid, in place of Example 1, Step 3 and 3a, gives the 8,10-dimethyl analog of Example 1, Step 6, compound G. By following the procedure of Example 1, Step 7, substituting 4-pyridyl acetic acid N-oxide with an equivalent amount of -41 - Printed from Mimosa WO 98/57950 PCT/US98/11509 N-BOC-4-piperidyl acetic acid, then removing the BOC group with trifluoroacetic acid, the title compound is obtained. 10 Example 31. (+,-)-4-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-1 -(4-piperidinylacetyl-N-carboxamido) piperazine Starting with the title compound of Example 30, and treating with 3 equivalents of trimethylsilylisocyanate in methylene chloride at 25°C, then removing the silyl group with excess sodium bicarbonate, the title compound is obtained. 20 Example 32. (+,-)-4-(3-cyclopropyl-6,11-dihydro-10-methoxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine 15 Step 1: ch3 BOC Ethereal diazomethane generated from Diazald (15 g) is added dropwise with stirring to a solution of compound A (0.11 g) from Example 27 (Step 2), and palladium acetate (7 mg) in benzene (1 ml) until a TLC sample showed completion of the reaction. Evaporation under reduced pressure affords compound B as a white powder. MS(CI) 461. •42- Printed from Mimosa WO 98/57950 PCT/US98/11509 procedures described in Steps 3 and 4, Example 27. Tan powder, MS(CI) 362 the procedure described in Example 1, Step 7 White powder, MS(CI) 498. 10 Example 33. (+) 4-(3-Bromo-6,11-dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-1-(4-pyridinylacetyl)piperidine N-|-Oxide 15 By substituting 5-bromo-t-butyl amide for reagent A and 3-methyl-5- bromobenzyl bromide for reagent 2 in Example 2, Step 1 and by following Example 2, Steps 1-10 - except in step 3, the reaction with triflic acid is carried out at 60°C for 4 hours, and by omitting step 6, the title compound is obtained as a racemate. MS(FABS) m/e 584(MH). The racemate is resolved into its -43- Printed from Mimosa WO 98/57950 PCT/US98/11509 enantiomers using a preparative HPLC chiralpak AD column (Daicel Chemical Industries,) and eluting with 30% isopropanol-hexanes (0.2% DEA). The desired (+) enantiomer elutes last. MS (FABS)m/e 584(MH) Rotation = +51.7°@20°C, c = 0.211. 5 Example 34. (-) 4-(3-Bromo-6,11-dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine Ni-Oxide 10 Essentially the same procedure is followed as in Example 33 except that the (-) enantiomer is also collected MS (FABS)m/e 584(MH) Rotation = - 47.5°@20°C, c = 0.2125. Example 35. (+) 4-(3-Bromo-6,11-dihydro-11-hydroxy-10-bromo-8-methyl-5H-15 benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine Ni -Oxide title compound of Example 33,- steps 6,7 and 9, from example 2 are omitted- 20 the title compound is obtained, as a racemate (+,-). FABS MS m/e 599.9(MH). The racemate is resolved using the same procedure as Example 33. The (+)enantiomer elutes first MS (FABS)m/e 599.9(MH), Rotation = +10.4°@20°C, c =0.1155. 25 Example 36. (-) 4-(3-Bromo-6,11-dihydro-11-hydroxy-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine Ni-Oxide -44- Printed from Mimosa WO 98/57950 PCT/US98/11509 Essentially the same procedure is followed as in Example 35, except that the (-) enantiomer elutes second MS (FABS)m/e 599.9(MH) Rotation = -7.3°@20°C, c = 0.1375. 5 Example 37. -(3-Bromo-5,6-dihydro-10-bromo-8-methyl-11H-benzo[5,6]cyclohepta[ 1,2-b]pyridin-11 -ylidene)-1 -(4-pyridinylacetyl)piperidine Ni-Oxide 10 By following procedures used to prepare the title compound of Example 33- steps 6, and 9- from example 2 are omitted, the title compound is obtained. MS (FABS)m/e 582(MH). PREPARATION OF STARTING MATERIALS 15 Starting materials useful in prepanng the compounds of the present invention are exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. The pyridyl and phenyl compounds used as starting materials, such as compounds (1, 1.3, 3, 3.5), inorganic and organic bases, and alcohols can be prepared using known 20 methods in the art, such as taught in See J. K. Wong et al., Bioorganic & Medicinal Chemistry Letters, Vol. 3, No. 6, pp. 1073-1078, (1993); U.S. Patents 5,089,496; 5,151,423; 4,454,143; 4,355,036, PCT /US94/11390 (W095/10514); PCT/US94/11391 (WO 95/10515); PCT/US94/11392 (W095/10516); Stanley R. Sandler and Wolf Karo, Organic Functional Group Preparations, 2nd Edition, 25 Academic Press, Inc., San Diego, California, Vol 1-3, (1983), and in J. March, Advanced Organic Chemistry, Reactions & Mechanisms, and Structure, 3rd Edition, John Wiley & Sons, New York, 1346 pp. (1985). Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art. -45- Printed from Mimosa WO 98/57950 PCT/US98/11509 Scheme n -46- Printed from Mimosa WO 98/57950 PCT/US98/11509 Scheme HI CICOOEt wherein for Schemes II and III, R1, R2, R3, R4, R5, R6, R7 and R8, the solid and dotted lines are as defined hereinbefore. In Schemes II and III, respectively, for Step A, compound 5 and 5.3 is prepared by alkylating compound 1 and 1.3 with an electrophile compound 3 and 3.3 employing a base such as lithium di-isopropylamide (LDA) in an aprotic -47- Printed from Mimosa WO 98/57950 PCT/US98/11509 solvent such as THF, toluene, benzene, ether and the like, at temperatures ranging from about -78° to 20°C, using about 1 to 1.5 moles of electrophile compound 3 per mole of compound 1 and 1.3. In Step B, compound 7 and 7.3 is prepared by treating compound 5 and 5 5.3 with a dehydrating agent such as phosphorus oxychloride (POCI3) or thionyl chloride in an aprotic solvent, at temperatures ranging from about 80° to 120°C, using about 3 to 10 moles of dehydrating agent per mole of compound 5 and 5.3. In Step C, compound 7.5 and 7.53 is prepared by treating compound 7 10 and 7.3 with a Lewis acid such as trifiic acid (CF3SO3H) or aluminum chloride (AICI3). The reaction can be practised neat (i.e. no additional solvents). Optionally, when AICI3 is used, a solvent such as dichloroethane can be employed. The reaction can be conducted at temperatures ranging from about 20° to about 175°C, using about 3 to 10 moles of the Lewis acid per mole of 15 compound 7 and 7.3. In Step D, compound 8 and 8.3 is prepared by treating compound 7.5 and 7.53 with a dilute acid such as aqueous hydrochloric or aqueous sulfuric acid, at temperatures ranging from about 20°C to reflux of the reaction mixture, using about 20 to 100 volumes of the aqueous acid per mole of compound 7.5 and 20 7.53. In Step E, compound 13a and 13.3a is prepared by treating compound 8 and 8.3 with a Grignard reagent 12 derived from N-methyl-4-chloropiperidine in an aprotic solvent, at temperatures ranging from about 0° to 50°C, using about 1 to 1.5 moles of Grignard reagent 12 per mole of compound 8 and 8.3. 25 In Step F, compound 13b and 13.3b is prepared by treating compound 13a and 13 3a with ethylchloroformate in an aprotic solvent, at temperatures ranging from about 60° to 90°C, using 5 to 10 moles of ethylchloroformate per mole of compound 13a and 13.3a. In Step G, compound 13c is prepared by subjecting compound 13b to 30 catalytic hydrogenation at pressures ranging from atmospheric (ambient) to 50 pounds per square inch (psi) using hydrogen (H2) and 10% palladium (Pd)/Carbon (C) as a catalyst. Alternatively, compound 13c can be prepared by treating compound 13b with a hydrogen source such as ammonium formate, using 10% Pd/C as a catalyst at atmospheric pressure, at temperatures ranging 35 from 50° to 70°C, optionally using a protic solvent such as methanol or ethanol. In Step H, compound 15 and 15.3 is prepared by treating compound 13c and 13.3c with an acid such as polyphosphoric acid (PPA). The reaction can -48- Pnnted from Mimosa WO 98/57950 PCT/US98/11509 be practised neat The reaction can be conducted at temperatures ranging from about 60° to 100°C, using about 5 to 10 volumes of polyphosphoric acid per mole of compound 13c and 13.3c. Alternatively, in Step H, compound 13d and 13.3d can be prepared by treating compound 13c and 13.3b with aqueous 5 hydrochloric acid (Hcl) or aqueous sulfuric acid (h2so4) such as 2 N to concentrated hydrochloric acid at temperatures ranging from about 80° to 100°C, using 5 to 10 volumes of the aqueous acid per mole of compound 13c and 13.3b. In Step I, compound 19 and 19.3 is prepared by treating compound 15 and 10 15.3 with an aqueous acid such as 3 N to concentrated hydrochloric acid (HCI), at temperatures ranging from about 80° to 100°C, using 5 to 10 volumes of the aqueous acid per mole of compound 15 and 15.3. In Step J, compound 20 and 20.3 is prepared by treating compound 19 and 19.3 with a reducing agent such as dnsobutyl aluminum hydride (DBAHAI) 15 in an aprotic solvent, at temperatures ranging from about 0° to 20°C, using 1 to 4 moles of reducing agent per moles of compound 19 and 19.3. In Step EE, alcohol compound 9 and 9.3 is prepared by reducing compound 8 and 8.3 with a reducing agent such as as sodium borohydride (NaBH4) in a protic solvent such as methanol, ethanol and acetic acid, at 20 temperatures ranging from 0° to 20°C, using one to three moles of the reducing agent per mole of compound 8 and 8.3. In Step FF, compound 10 and 10.3 is prepared by treating alcohol compound 9 and 9.3 with a chlorinating agent such as thionyl chloride or phosphorous oxychloride (poci3) in an aprotic solvent such as 1,2-25 dichoroethane or methylene chloride, at temperatures ranging from 0° to 25°C, using one to two moles of the chlorinating agent per mole of compound 9 and 93 In Step GG, compound 11 and 11.3 is prepared by reacting compound 10 and 10.3 with a piperazine compound 12 and 12.3 in a solvent such as 30 acetonitrile, toluene or methylene chloride at temperatures ranging from 0° to 60°C, using one to 10 moles of piperazine compound 12 and 12.3 per mole of compound 10 and 10.3. In Step K, the desired compound of formula 1.0 can prepared from compounds (11, 11.3), (13d, 13.3d), (19, 19.3) or (20, 20.3) as described in 35 Scheme I described hereinbefore. -49- Pnnted from Mimosa WO 98/57950 PCT/US98/11509 Scheme IV CH3 vn'N=0 NH;-Bu 13 < , CF3SO3H , R -r- -7-R7 . J R R N R8 CH, 27 (1 0) COOEt wherein for Scheme IV, R1, R2, R3, R4, R5, R6, R7 and R8, the solid and dotted lines are as defined hereinbefore 10 In Scheme IV, in Steps A and B, compounds 5.3 and 7.3 are prepared as described in Scheme III, hereinbefore. In Step L, compound 25 is prepared by reacting compound 7.3 with a Grignard reagent 12 derived from N-methyl-4-chloropiperidine in an aprotic solvent, at temperatures ranging from about 0° to 50°C, using about 1 to 1.5 moles of Grignard reagent 12 per mole of compound 7.3. In Step M, compound 26 is prepared by treating compound 25 with a dilute acid such as aqueous hydrochloric or aqueous sulfuric acid, at temperatures -50- Printed from Mimosa WO 98/57950 PCT/US98/11509 ranging from about 20°C to reflux of the reaction mixture, using about 20 to 100 volumes of the aqueous acid per mole of compound 25. In Step N, compound 27 is prepared by treating compound 25 with a Lewis acid such as triflic acid or aluminum chloride (AICI3). The reaction can 5 be practised neat (i.e. no additional solvents). When triflic acid is used, the reaction can be conducted at temperatures ranging from 0° to 70°C, using 5 to 100 moles of triflic acid per mole of compound 25. Optionally, when AICI3 is used, a solvent such as dichloroethane can be employed. The reaction can be conducted at temperatures ranging from about 20° to about 175°C, using about 10 3 to 10 moles of the Lewis acid per mole of compound 25. In Step O, compound 28 is prepared by treating compound 27 with ethylchloroformate in an aprotic solvent, at temperatures ranging from about 60° to 90°C, using 5 to 10 moles of ethylchloroformate per mole of compound 27. 15 In Step P, compound 29 is prepared by treating compound 28 with an aqueous acid such as 3 N to concentrated hydrochloric acid (HCI), at temperatures ranging from about 80° to 100°C, using 5 to 10 volumes of the aqueous acid per mole of compound 28. In Step Q, compound 30 is prepared by treating compound 29 with a 20 reducing agent such as dnsobutyl aluminum hydride (DIBALH) in an aprotic solvent, at temperatures ranging from about 0° to 20°C, using 1 to 4 moles of reducing agent per moles of compound 29. In Step K, compound 30 is converted to desired compound (1.0) as described in Scheme I, described hereinbefore. -51 - Printed from Mimosa WO 98/57950 PCT/US98/11509 ASSAYS 1. In vitro enzyme assays: FPT IC50 (inhibition of farnesyl protein transferase, in vitro enzyme assay) are determined by the methods disclosed in 5 WO/10515 or WO 95/10516. The data demonstrate that the compounds of the invention are inhibitors of Ras-CVLS farnesylation by partially purified rat brain farnesyl protein transferase (FPT). The data also show that there are compounds of the invention which can be considered as potent (IC50 <10 jiM) inhibitors of Ras-CVLS farnesylation by partially purified rat brain FPT. 10 2. Cell-based assay. COS IC50 values refer to the COS cells activity inhibition of Ras processing, are determined by the methods disclosed in WO/10515 or WO 95/10516. Exampl FPT IC50 Exampl FPT IC50 e (M-M) e (HM) 1 0.0670 21 0.0048 2 0.0340 22 0.0099 3 0.0032 23 >0.200 4 0.1400 24 0.0036 5 >0.2 25 0.2200 6 0.0450 26 0.058 7 0.0600 27 0.0590 8 0.0300 28 0.1320 9 0.1200 29 0 0740 10 0.0160 30 - 14 0.1100 31 0.2000 15 0.1300 32 >0.200 16 0.0640 33 0.0012 17 0.2900 34 >0.016 18 0.0430 35 0.0108 19 0.0042 36 0.0054 20 >0.180 37 0.0054 15 For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 70 percent active ingredient. 20 Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. -52- Printed from Mimosa WO 98/57950 PCT/US98/11509 For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby 5 solidify. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid form preparations may also include solutions for intranasal 10 administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas. Also included are solid form preparations which are intended to be 15 converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols 20 and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate 25 quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg. to 300 mg, according to the particular application. 30 The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased 35 by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. -53- Printed from Mimosa WO 98/57950 PCT/US98/11509 The amount and frequency of administration of the compounds of the invention and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being 5 treated. A typical recommended dosage regimen is oral administration of from 10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to four divided doses to block tumor growth. The compounds are non-toxic when administered within this dosage range. The following are examples of pharmaceutical dosage forms which 10 contain a compound of the invention. The scope of the invention in its pharmaceutical composition aspect is not to be limited by the examples provided. -54- Printed from Mimosa </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 98/57950 PCT/US98/11509 Pharmaceutical Dosage Form Examples EXAMPLE A-Tablets No. Ingredients mg/tablet mg/tablet 1. Active compound 100 500 2. Lactose USP 122 113 3. Corn Starch, Food Grade, as a 10% paste in Purified Water 30 40 4. Corn Starch, Food Grade 45 40 5. Magnesium Stearate _3 7 Total 300 700 Method of Manufacture Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen 5 (e.g.,

1/4", 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weigh on a suitable tablet machine. EXAMPLE B-Capsules No. Ingredient mg/capsule mg/capsule 1. Active compound 100 500

2. Lactose USP 106 123

3. Corn Starch, Food Grade 40 70 4 Magnesium Stearate NF 7 7 Total 253 700 10 Method of Manufacture Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine While the present invention has been described in conjunction with the 15 specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention -55- Printed from Mimosa WHAT WE CLAIM IS: 1. A compound selected from the group consisting of: 1-(3-Bromo-6,11-dihydro-8,10-dimethoxy-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; 4-(6,11-Dihydro-10-methoxy-3,8-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1 -oxide; (+,-)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(6,11-Dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(7-Chloro-5,6-dihydro-8-methyl-10-methoxy-11 H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-10-hydroxy-8-methyl-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; 4-(5,6-Dihydro-10-methoxy-3,8-dimethyl-11 H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-10-methoxy-8-methyl-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-10-hydroxy-8-methyl-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+.-)-1 -(3-Bromo-10-methoxy-8-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-7-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) 4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-7,10-dimethy!-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-6,11-dihydro-8-methoxy-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; -56- INTELLECTUAL PROPERTY OFFICE OF NZ. 0 2 OCT 2001 received ijv 'I (+,-)-1-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta[ir2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (-)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide, (-) enantiomer; (+)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide, (+) enantiomer; (+,-)-1-(3,10-Dibromo-6,11-dihydro-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3,8-Dibromo-6,11-dihydro-10-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+.-)-4-[6,11 -Dihydro-3-(1 -hydroxy-1 -methylethyl)-10-methoxy-8-methyl-5H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-(4-pyridinylacetyl)piperidine N1-oxide; (+)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (-)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (-) enantiomer; (+,-)-1-(3-Bromo-8-methoxy-10-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; 4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; 4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(methylsulfonyl)piperidine; 4-(3-Ethyl-6,11 -dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1 -oxide; (+,-)-4-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-piperidinylacetyl)piperazine; (+,-)-4-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-piperidinylacetyl-N-carboxamido)piperazine; (+,-)-4-(3-Cyclopropyl-6,11-dihydro-10-methoxy-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine; (+)-4-(3-Bromo-6,11 -dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; INTELLECTUAL PROPERTY OFFICE OF NZ. 0 2 OCT 2001 RECEIVED (-)-4-(3-Bromo-6,11 -dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine N1-oxide, (-) enantiomer; (+)-4-(3-Bromo-6,11 -dihydro-11 -hydroxy-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta [1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (-)-4-(3-Bromo-6,11 -dihydro-11 -hydroxy-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta [1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (-) enantiomer; 4-(3-Bromo-5,6-dihydro-10-bromo-8-methyl-11 H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; and the pharmaceutically acceptable salts and solvates thereof. 2. A compound of claim 1 selected from the group consisting of: 1-(3-Bromo-6,11 -dihydro-8,10-dimethoxy-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; 4-(6,11-Dihydro-10-methoxy-3,8-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-10-hydroxy-8-methyl-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; 4-(5,6-Dihydro-10-methoxy-3,8-dimethyl-11 H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-4-(3-Bromo-10-methoxy-8-methyl-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1 -(3-Bromo-8-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (-)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide, (-) enantiomer; -58- INTELLECTUAL PROPERTY OFFICE OF NZ. 0 2 OCT 2001 RECEIVED (+,-)-1-(3,10-Dibromo-6,11-dihydro-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3,8-Dibromo-6,11-dihydro-10-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1I2-b] pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (+,-)-1 -(3-Bromo-8-methoxy-10-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; 4-(3-Ethenyl-6,11 -dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; 4-(3-Ethyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+)-4-(3-Bromo-6,11 -dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (-)-4-(3-Bromo-6,11-dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-pyridinylacetyI)piperidine N1-oxide, (-) enantiomer; (+)-4-(3-Bromo-6,11 -dihydro-11 -hydroxy-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta [1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (-)-4-(3-Bromo-6,11 -dihydro-11 -hydroxy-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta [1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (-) enantiomer; 4-(3-Bromo-5,6-dihydro-10-bromo-8-methyl-11 H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; and the pharmaceutically acceptable salts and solvates thereof. 3. A compound of claim 1 selected from the group consisting of: (+,-)-4-(3-Bromo-10-methoxy-8-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+,-)-1-(3,10-Dibromo-6,11-dihydro-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+,-)-1-(3,8-Dibromo-6,11-dihydro-10-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide; (+)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; -59- INTELLECTUAL PROPERTY office OF NZ. 0 2 OCT 2001 RECEIVED (+)-4-(3-Bromo-6,11 -dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; and the pharmaceutically acceptable salts and solvates thereof.

4. A compound of claim 1 selected from the group consisting of: (+,-)-4-(3-Bromo-10-methoxy-8-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (+)-4-(3-Bromo-6,11 -dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (-)-4-(3-Bromo-6,11 -dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine N1-oxide, (-) enantiomer; (+)-4-(3-Bromo-6,11 -dihydro-11 -hydroxy-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta [1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (-)-4-(3-Bromo-6,11-dihydro-11 -hydroxy-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta [1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (-) enantiomer; 4-(3-Bromo-5,6-dihydro-10-bromo-8-methyl-11 H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide; and the pharmaceutically acceptable salts and solvates thereof.

5. A compound of claim 1 selected from the group consisting of: (+>-)-4-(3-Bromo-10-methoxy-8-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide; (+)-4-(3-Bromo-10-methoxy-8-methyl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (+)-4-(3-Bromo-6,11 -dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine N1-oxide, (+) enantiomer; (-)-4-(3-Bromo-6,11-dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine N1-oxide, (-) enantiomer; and the pharmaceutically acceptable salts and solvates thereof. -60- intellectual property office of nz. 0 2 OCT 2001 received 5016IJ

6. A pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

7. A use of a compound of claim 1 in the preparation of a medicament for inhibiting the abnormal growth of cells in a patient in need thereof.

8. A use of Claim 7 wherein the cells inhibited are tumor cells expressing an activated ras oncogene.

9. A use of Claim 7 wherein the cells inhibited are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodyspastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells or prostate tumor cells, breast tumor cells or colon tumor cells.

10. A use of Claim 7 wherein the inhibition of the abnormal growth of cells occurs by the inhibition of ras farnesyl protein transferase.

11. A use of Claim 7 wherein the inhibition is of tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras protein.

12. A compound as defined in claim 1 substantially as herein described with reference to any example thereof.

13. A pharmaceutical composition as claimed in claim 6 substantially as herein described with reference to any example thereof.

14. A use as defined in claim 7 substantially as herein described with reference to any example thereof. -61- INTELLECTUAL PROPERTY office of nz. 0 2 OCT 2001 RECEIVED </div>