Inhibitors of the EGF-receptor tyrosine kinase and methods...

Details Inhibitors of the EGF-receptor tyrosine kinase and methods... Inhibitors of the EGF-receptor tyrosine kinase and methods...

1999-03-19

2002-03-12

Gerstl, Robert (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C558S392000

Reexamination Certificate

active

06355678

ABSTRACT:

The excellent technical assistance of Suzy Downes and Ellse Sudbeck in the studies related to this invention is gratefully acknowledged.
BACKGROUND OF THE INVENTION
Breast cancer is the most common form of malignancy in women, representing 32% of all new cancer cases and causing 18% of the cancer related deaths among women in the USA. Although the majority of patients with metastatic breast cancer will experience an initial response, survival is only modestly improved with contemporary chemotherapy programs. Consequently, the development of new anti-breast cancer drugs has become a high priority (Abrams, J. S., et al. M.
Cancer
1994, 84, 1164).
Human epidermal growth factor (EGF) is a 53 amino acid, single-chain polypeptide (Mr 6216 daltons), which exerts biologic effects by binding to a specific cell membrane epidermal growth factor receptor (EGFR/ErbB-1). Many types of cancer cells display enhanced EGFR expression on their cell surface membranes (Khazaie, K., et al. R. B.
Cancer
&
Metasis Reviews
1993, 12, 255). Enhanced expression of the EGFR on cancer cells has been associated with excessive proliferation and metastasis (Mendelsohn, J. and Baselga, J.
Biologic Therapy of Cancer: Principles
&
Practice
1995, 607). Examples include breast cancer, prostate cancer, lung cancer, head and neck cancer, bladder cancer, melanoma, and brain tumors (Khazaie, K., et al. R. B.
Cancer
&
Metasis Reviews
1993, 12, 255).
In breast cancer, expression of the EGFR is a significant and independent indicator for recurrence and poor relapse-free survival (Toi, M., et al.
European J. Cancer
1991, 27, 977; Chrysogelos, S. A. and Dickson, R. B.
Breast Cancer Res. Treat.
1994, 29, 29; Fox, S. B., et al.
Breast Cancer Res. Treat.
1994, 29, 41). Additionally, it has been shown that the EGFR has an essential function for the survival of human breast cancer cells (Uckun, F. M., et al.
Clin. Can. Res.
1998, 4, 901; Moyer, J. D., et al.
Cancer Res.
1997, 57(21), 4838). Therefore, the development of PTK inhibitors which abrogate the enzymatic function of the EGFR tyrosine kinase has become a focal point in drug discovery research programs aimed at designing more effective treatment strategies for metastatic breast cancer (George-Nascimento, et al.
Biochemistry
1988, 27, 797; Khazaie, K., et al. R. B.
Cancer
&
Metasis Reviews
1993, 12, 255; Fry, D. W. and Bridges, A. J.
Curr. Opin. Biotechnol.
1995, 6, 662; Wakeling, A. E., et al.
Breast Cancer Research
&
Treatment
1996, 38, 67).
The primary metabolite of the anti-inflammatory leflunomide N-(4-trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, has been identified as an inhibitor of the EGFR kinase (Parnham, M. J.
Exp. Opin Invest. Drugs
1995, 4, 777; Xu, X., et al.
Biochem. Pharmacol.
1996, 52, 527; Xu, X., et al.
J. Biol. Chem.
1995, 270, 12398; Bertolini, G., et al.
J. Med. Chem.
1997, 40, 2011; Mattar, T., et al. A.
F. E. B. S. Lett.
1993, 334, 161). Despite the identification of this inhibitor of the EGFR kinase, however, there is a continuing need for novel anti-cancer drugs. In particular, there is a need for anti-cancer drugs which are more potent or more selective than existing drugs. There is also a need for anti-cancer drugs that operate by novel mechanisms, and thus, may be useful against cancers that do not respond to, or have developed resistance to, existing therapies.
SUMMARY OF THE INVENTION
Applicants have discovered compounds that selectively inhibit EGFR tyrosine kinase, without affecting the activity of other PTKs. A representative compound of the invention was also found to inhibit the proliferation and in vitro invasiveness of EGFR positive human breast cancer cells at micromolar concentrations. Thus, the compounds of the invention are useful for treating cancer (e.g. breast cancer). The compounds are also useful as pharmacological tools that can be used to further investigate EGFR kinase function, or can be used in competitive binding assays to help identify other agents that may be useful as pharmaceuticals.
Accordingly, the invention provides a compound of the following formula I:
where
R
1
is (C
1
-C
3
)alkyl, (
3
-C
6
)cycloalkyl, phenyl, or NR
a
R
b
;
R
2
is hydroxy, (C
1
-C
6
)alkoxy, or (C
1
-C
6
)alkanoyloxy;
R
3
is cyano, or (C
1
-C
3
)alkanoyl;
R
4
is hydrogen, or (C
1
-C
3
)alkyl;
R
5
is aryl, or heteroaryl;
R
1
and R
b
are each independently hydrogen, or (C
1
-C
3
)alkyl; or R
a
and R
b
together with the nitrogen to which they are attached are pyrrolidino, piperidino, morpholino, or thiomorpholino;
wherein any aryl, or heteroaryl of R
1
and R
5
is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethyl, trifluoromethoxy, (C
1
-C
3
)alkoxy, (C
1
-C
3
)alkyl, (C
1
-C
3
)alkanoyl, —S(O)
2
R
c
, or NR
a
R
b
; wherein R
c
is (C
1
-C
3
)alkyl, or aryl or a pharmaceutically acceptable salt thereof.
Prefereably, if R
5
is phenyl, the phenyl is substituted by —S(O)
2
R
c
, or is substituted by halo and at least one other substituent.
Preferred compounds of formula I include those of formula II:
where R
1
is (C
1
-C
6
)alkyl, optionally substituted by 1, 2, or 3 substituents selected from the group consisting of halo, hydroxy, amino, (C
1
-C
6
)alkoxy, and (C
1
-C
6
)alkanoyloxy; R
2
is hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyloxy; R
3
is cyano, alkanoyl; R
6
is amino, hydroxy, cyano, nitro, (C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, halo(C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyl, or (C
1
-C
6
)alkanoyloxy; and R
7
is H, NH2, CH
3
, OH, CF
3
, or halo, preferably, halo is Br or Cl; or a pharmaceutically acceptable salt thereof.
Particularly compounds of formula I include those of formulae III-VI:
where R
7
is H, NH
2
, CH
3
, OH, CF
3
, or halo. Preferably, halo is Br or Cl.
where R
7
is H, NH
2
, CH
3
, OH, CF
3
, or halo. Preferably, halo is F or Cl.
where R
6
is NH—CH
3
or OCH
3
.
where R
2
is —CH
2
—CH
2
X and X is halo, preferably F; or R
2
is —CH
2
CF
3
; or R
2
is:
The invention also provides a pharmaceutical composition comprising a compound of formula I; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
A particularly useful compound of the invention is LFM 12, having the structural formula:
The invention also provides a therapeutic method for treating diseases in which EGFR is overexpressed, particularly cancers (e.g. breast cancer) comprising administering to a mammal in need of such therapy, a compound of the invention, e.g., of formulae I-VI; or a pharmaceutically acceptable salt thereof.
The invention also provides a compound for use in medical therapy (preferably for use in treating cancer), as well as the use of a compound of formulae I-VI for the manufacture of a medicament for the treatment of a pathological condition or symptom in a mammal, such as a human, which is associated cancer (e.g. breast cancer).
The invention also provides a homology model representing the structure of the EGF-R kinase domain and a docking procedure, which are useful to rationally design compounds predicted to bind favorably to EGF-R and inhibit EGFR-TK activity. Using this model, leflunomide metabolite analogs were designed and found to have potent inhibitory activity against EGFR TK (IC
50
value of 1.7 &mgr;M in EGF-R inhibition assays, killing >99% of human breast cancer cells in vitro by triggering apoptosis). New potent LFM analogs as active inhibitors of the EGF-R tyrosine kinase are designed and confirmed using this model.
The invention also provides processes and novel intermediates, described herein, that are useful for preparing compounds of formulae I, II, IV-VI.


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patent: 4559157 (1985-12-01), Smith et al.
patent: 4608392 (1986-08-01), Jacquet et al.
patent: 4820508 (1989-04-01), Wortzman
patent: 4938949 (1990-07-01), Borch et al.
patent: 4992478 (1991-02-01), Geria
patent: 524096

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