Compounds useful for inhibition of farnesyl protein transferase

Details Compounds useful for inhibition of farnesyl protein transferase Compounds useful for inhibition of farnesyl protein transferase

1999-11-23

2001-05-08

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...

C514S228200, C514S232800, C514S253030, C544S058200, C544S058600, C544S126000, C546S093000

Reexamination Certificate

active

06228865

ABSTRACT:

BACKGROUND
WO 95/10516, published Apr. 20, 1995 discloses tricyclic compounds useful for inhibiting famesyl protein transferase.
In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
SUMMARY OF THE INVENTION
This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPT). The compounds of this invention are represented by the formula:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
a represents N or NO—;
R
1
and R
3
are the same or different halo atom;
R
2
and R
4
are selected from H and halo, provided that at least one of R
2
and R
4
is H;
the dotted line
represents an optional bond;
X is N, C when the optional bond is present, or CH when the optional bond is absent;
T is a substituent selected from:
wherein:
A represents —(CH
2
)
b
—;
B represents —(CH
2
)
d
—;
b and d are independently selected from: 0, 1, 2, 3, or 4 such that the sum of b and d is 3 or 4; and
Y is selected from: O, S, SO, or SO
2
;
wherein:
D represents —(CH
2
)
e
—;
E represents —(CH
2
)
f
—;
e and f are independently selected from: 0, 1, 2, or 3 such that the sum of e and f is 2 or 3; and
Z is O:
wherein:
F represents —(CH
2
)
g
—;
G represents —(CH
2
)
h
—;
U represents —(CH
2
)
i
—;
h represents 1, 2, or 3
g and i are independently selected from: 0, 1 or 2 such that the sum of h, g and i is 2 or 3; and
V and W are independently selected from O, S, SO, or SO
2
;
wherein:
the dotted line
represents an optional bound;
k is 1 or 2 such that when the optional bond is present k represents 1, and when the optional double bond is absent then k represents 2;
R
5
, R
6
, R
7
and R
8
are the same alkyl (preferably methyl); or
R
5
and R
7
are the same alkyl (preferably methyl), and R
6
and R
8
are H;
wherein:
the dotted lines
represent optional bonds 1 and 2 such that optional bonds 1 and 2 are both present, or optional bonds 1 and 2 are both absent;
Y represents O, S, SO, or SO
2
;
wherein:
Y represents O, S, SO, or SO
2
;
wherein:
R
9
is selected from: —CN, —CO
2
H, or —C(O)N(R
10
)
2
;
each R
10
is the same or different alkyl group (preferably, methyl);
wherein:
I represents —(CH
2
)
m
—;
m represents 2 or 3;
Y represents O, S, SO, or SO
2
; and
R
11
represents alkyl (preferably ethyl);
The compounds of this invention: (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.
The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit famesyl protein transferase, is useful in the treatment of the cancers described below.
This invention provides a method for inhibiting or treating 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.
This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited or treated 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 adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, breast cancer and prostate cancer.
It is believed that this invention also provides a method for inhibiting or treating 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 or treatment being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a 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, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.
The tricyclic compounds useful in the methods of this invention inhibit or treat the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function 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. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following terms are used as defined below unless otherwise indicated:
MH
+
—represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
Et (or ET)—represents ethyl (C
2
H
5
);
alkyl-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;
halo-represents fluoro, chloro, bromo and iodo;
The following solvents and reagents are referred to herein by the abbreviations indicated: ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoro-acetic anhydride (TFAA); 1-hydroxybenzotrilazole (HOBO; 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC); diisobutylaluminum hydride(DIBAL); and 4-methylmorpholine (NMM).
The positions in the tricyclic ring system are:
Preferred halo atoms for R
1
, R
2
, R
3
, and R
4
in Formula 1.0 are selected from: Br, Cl or I, with Br and Cl being preferred.
Compounds of Formula 1.0 include compounds of the formula:
wherein R
1
and R
3
are the same or different halo. Preferably, for these dihalo compounds, R
1
and R
3
are independently selected from Br or Cl, and more preferably R
1
is Br and R
3
is Cl. Preferably, X is CH or N, with CH being more preferred.
Compounds of Formula 1.0 include compounds of Formulas 1.1 and 1.2:
wherein R
1
, R
3
and R
4
in Formula 1.1 are halo, and R
1
, R
2
and R
3
in Formula 1.2 are halo. Compounds of Formula 1.1 are preferred.
Preferably, in Formula 1.1, R
1
is Br, R
3
is Cl, and R

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