Heterocyclic compounds, their production and use

Details Heterocyclic compounds, their production and use Heterocyclic compounds, their production and use

1998-11-18

2001-04-03

Gerstl, Robert (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S365000, C514S367000, C548S202000, C548S217000, C548S235000

Reexamination Certificate

active

06211215

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a heterocyclic compound useful as the growth factor receptor tyrosine kinase (especially HER2) inhibiting agent, a method of producing the compound, and a medicinal composition comprising the compound.
BACKGROUND ART
Genes of cell growth factor and growth factor receptors are called proto-oncogene and play important roles in behavior of human tumors including breast cancer (Arronson et al., Science Vol.254, pp.1141-1153, 1991). HER2 (Human EGF Receptor-2 genes having homology with the receptor of epidermal growth factor EGF are those of transmembrane receptor glycoprotein, and this receptor has tyrosine kinase activity (Akiyama et al., Science Vol.232, pp.1644-1656, 1986). HER2 is observed in human breast cancer and ovarian cancer (Slamon et al., Science, Vol.244, pp.707-712, 1989), which is further observed in prostate cancer (Lyne et al., Proceedings of American Association for Cancer Research Vol.37, p.243, 1996) or gastric cancer (Yonemura et al., Cancer Research Vol.51, p.1034, 1991). Further, the substrate of HER2-tyrosine kinase is observed in 90% of pancreatic cancers. Transgenic mice carrying HER2 gene develop mammary cancers as they grow (Guy et al., Proceedings of National Academy of Science U.S.A., Vol.89, pp.10578-10582, 1992).
It is disclosed that antibodies specific for HER2 suppress in vitro proliferation of tumor cells (Mckenzie et al. Oncogene Vol.4, pp.543-548, 1989) and humanized monoclonal antibody demonstrated prospective results in the clinical tests of patients suffering from breast cancer (Baselga et al., Journal of Clinical Oncology, Vol.14, pp.737-747, 1996).
These antibodies hinder the binding of growth factor with HER2 receptor and inhibit activation of tyrosine kinase. As the result, since it was shown that the advance of breast cancer was suppressed, it was shown that the drug directly inhibiting tyrosine kinase of HER2 was possibly effective as a medicine for the therapy of breast cancer (Hayes, Journal of Clinical Oncology, Vol.14, pp.697-699, 1996).
While several low molecular weight compounds inhibiting receptor-type tyrosine kinase containing HER2 have been reported, most of them are styrene-like compounds analogous to tyrosine itself having hydroxylated aromatic ring. For example, erbstatin inhibits proliferation of human epidermal carcinoma cell line A431 (Journal of Antibiotics, Vol.39, p.170, 1986), and it is reported that tyrphostin has antitumor activity in vivoon nude mice bearing the well-characterized human squamous cell carcinoma MH-85 (Cancer Research, Vol.51, p.4430, 1991). And, it it reported that sulfonylbenzoyl-nitrostyrene derivatives have antitumor activities in vivo in nude mice carrying A431 cell line. Further, it has been known that indole derivatives inhibit EGF receptor type tyrosine kinase and inhibit in vivo the growth of A431 cell line (International Application No. PCT/US93/7272, Japanese Patent Application under PCT laid-open under Kohyo No.Toku-Hyo-Hei 8-503450).
And, it has been known that triazole and diazole derivatives, although they are not tyrosine kinase inhibiting compounds, have the activity of inhibiting the signal transduction of cell proliferation due to growth factor (U.S. Pat. No. 5,482,954).
DISCLOSURE OF INVENTION
The object of this invention is to provide a compound having an action of inhibiting tyrosine kinase, being useful as an antitumor agent with less toxicity.
The present inventors conducted various studies on heterocyclic compounds having a tyrosine kinase inhibiting action, and, as a result, they synthesized, for the first time, a heterocyclic compound represented by the general formula (I) having a terminal aromatic azole group,
wherein R stands for an optionally substituted aromatic heterocyclic group;
X stands for oxygen atom, an optionally oxidized sulfur atom, —C(═O)— or —CH(OH)—;
Y stands for CH or N;
m denotes an integer of 0 to 10;
n denotes an integer of 1 to 5; and
the cyclic group
 stands for an optionally substituted aromatic azole group, and the ring A may optionally further be substituted (hereinafter simply called “compound (I)”), or a salt thereof, and found that this compound (I) or a salt thereof has, unexpectedly, an excellent suppressing action of tyrosine kinase based on the specific chemical structure. Based on this finding, the present invention has been accomplished.
More specifically, the present invention is to provide
(1) the heterocyclic compound (I) or a salt thereof;
(2) a medicinal composition comprising the heterocyclic compound (I) or a pharmaceutically acceptable salt thereof;
(3) use of the heterocyclic compound (I) or a pharmaceutically acceptable salt thereof, for a preparation of a medicinal agent for prophylaxis or treatment for cancer;
(4) a method comprising administering an effective amount of the heterocyclic compound (I) or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier to provide a prophylactic or therapeutic action for cancer; and
(5) a method of producing the heterocyclic compound (I) or a salt thereof.
In the present specification, as the heterocyclic group in the optionally substituted aromatic heterocyclic group shown by R, mention is made of, for example, (1) a 5- or 6-membered aromatic monocyclic heterocyclic group containing as the ring-forming atoms, besides carbon atoms, 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfur atom, and (2) an aromatic condensed heterocyclic group formed by condensation of (i) a 5- or 6-membered aromatic monocyclic heterocyclic group containing, as the ring-forming atoms, besides carbon atoms, 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfur atom with (ii) a 5- or 6-membered aromatic or non-aromatic heterocyclic group containing, as the ring-forming atoms, besides carbon atoms, 1 to 2 nitrogen atoms, benzene ring or a 5-membered aromatic or non-aromatic heterocyclic group containing, as the ring-forming atoms, besides carbon atoms, one sulfur atom.
Specific examples of these aromatic heterocyclic groups include pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g. 2-pyrazinyl), pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isoxazolyl, isothiazolyl, thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), oxadiazolyl (e.g. 1,2,4-oxadiazolyl such as 1,2,4-oxadiazol-5-yl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g. 1,2,4-triazolyl such as 1,2,4-triazol-1-yl, 1,2,4-triazol-5-yl, 1,2,4-triazolyl such as 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g. tetrazol-1-yl, tetrazol-5-yl), benzimidazolyl (e.g. benzimidazol-1-yl, benzimidazol-2-yl), indolyl (e.g. indol-1-yl, indol-3-yl), indazolyl (e.g. 1H-indazol-1-yl, 1H-indazol-3-yl), pyrrolopyrazinyl (e.g. 1H-pyrrolo[2,3-b]pyrazinyl), pyrrolopyridyl (e.g. 1H-pyrrolo[2,3-b]pyridyl), imidazopyridyl (e.g. 1H-imidazo[4,5-b]pyridyl, 1H-imidazo[4,5-c]pyridyl, imidazopyrazinyl (e.g. 1H-imidazo[4,5-bpyrazinyl), pyrrolopyridazinyl (e.g. pyrrolo[1,2-b]pyridazinyl), pyrazolpyridyl (e.g. pyrazolo[1,5-a]pyridyl), imidazopyridyl (e.g. imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl), imidazopyridazinyl (e.g. imidazo[1,2-b]pyridazinyl), imidazopyrimidinyl (e.g. imidazo[1,2-a]pyrimidinyl), furyl, thienyl, benzofuranyl, benzothienyl (e.g. benzo[b]thienyl), benzoxazolyl, benzthiazolyl, quinolyl, isoquinolyl and quinazolinyl. Preferable examples include a 5-membered cyclic aromatic azole group such as oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazolyl and thiadiazolyl, an aromatic condensed azole group formed by c

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