Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-13
2002-08-27
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S290000, C544S361000, C546S093000
Reexamination Certificate
active
06440989
ABSTRACT:
BACKGROUND
Patent application WO 95/00497 published Jan. 5, 1995 under the Patent Cooperation Treaty (PCT) describes compounds which inhibit the enzyme, farnesyl-protein transferase (FTase) and the farnesylation of the 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-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, 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).
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.
SUMMARY OF THE INVENTION
Inhibition of farnesyl protein transferase by tricyclic compounds of this invention has not been reported previously. Thus, this invention provides a method for inhibiting farnesyl protein transferase using tricyclic compounds of this invention which: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl 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 geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
This invention provides 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 claimed methods are represented by Formula 1.0:
or a pharmaceutically 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;
R
1
is hydrogen, bromo, chloro, trifluoromethyl, acyl, alkyl, cycloalkyl, amino, acylamino or alkoxy;
R
2
is hydrogen, halo, trifluoromethyl, alkyl, alkoxy, —OCF
3
, hydroxy, amino or acylamino;
R
3
is hydrogen, bromo, chloro, alkoxy, —OCF
3
or hydroxy;
R
4
is hydrogen, halo, trifluoromethyl, alkyl or alkoxy;
provided that at least one of R
2
or R
3
or R
4
is alkyl or alkoxy and provided that at least two of R
1
, R
2
, R
3
or R
4
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;
R
5
, R
6
, R
7
and R
8
independently represent hydrogen, alkyl or —CONHR
50
wherein R
50
can be any of the values represented for R, below;
Z is ═O or ═S; and
R is aryl, aralkyl, cycloalkyl, 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; R
1
is H, halo, alkyl, cycloalkyl or alkenyl; R
2
is H, halo, alkoxy, or alkyl; R
3
is H, halo, alkoxy, hydroxy or alkyl; and R
4
is H, halo or alkyl; R
5
, R
6
, R
7
and R
8
are hydrogen; Y is —SO
2
CH
3
or —COR wherein R is heteroarylalkyl, preferably pyridinyl N-oxide-methyl or heterocycloalkylalkyl, preferably piperidinyl-methyl. When R
1
is other than hydrogen, preferably the halo moiety is bromo, the alkyl is methyl or ethyl, the cycloalkyl is cyclopropyl or the alkenyl is vinyl. When R
2
is other than hydrogen, preferably the alkoxy moiety is methoxy, the halo moiety is bromo or the alkyl is methyl. When R
3
is other than hydrogen, preferably the alkoxy moiety is methoxy, the halo moiety is bromo or the alkyl is methyl. When R
4
is other than hydrogen, preferably the halo moiety is chloro or the alkyl is methyl. Preferred title compounds include those of Examples 1-10 and 14-37, preferably 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, more preferably those of Examples 3, 21, 22, 24 and 33, disclosed hereinafter.
In another embodiment, the present invention is directed toward a pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of compound (1.0) in combination with a pharmaceutically acceptable carrier.
In another embodiment, the present invention is directed toward a method for inhibiting the abnormal 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 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 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 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 follicular tumor cells, myelodysplastic 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 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.
This invention also provides a method for inhibiting tumor growth by administering an effective amount of compound (1.0) to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated Ras oncogene by the administration o
Afonso Adriano
Kelly Joseph M.
Rosenblum Stuart B.
Weinstein Jay
Wolin Ronald L.
Bernstein Robert L.
Huang Evelyn Mei
Schering Corporation
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