Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-24
2004-04-06
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S235000
Reexamination Certificate
active
06716863
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a heterocyclic compound which is useful as a growth factor receptor tyrosine kinase (particularly HER2) inhibitor, a method for its production, and a pharmaceutical composition containing it.
BACKGROUND
Growth factor and growth factor receptor genes, known as proto-oncogenes, have play important roles in the pathology of human tumors such as breast cancer (Aronson et al., Science, Vol. 254, pp. 1146-1153, 1991). Having homology to epidermal growth factor (EGF) receptor, the HER2 (human EGF receptor-2) gene encodes transmembrane-type glycoprotein, and this receptor possesses tyrosine kinase activity (Akiyama et al., Science, Vol. 232, pp. 1644-1646, 1986). HER2 is found in human breast cancer and ovarian cancer (Slamon et al., Science, Vol. 244, pp. 707-712, 1989) and is also found in prostate cancer (Lyne et al., Proceedings of the American Association for Cancer Research, Vol. 37, p. 243, 1996) and gastric cancer (Yonemura et al., Cancer Research, Vol. 51, p. 1034, 1991). In addition, the substrate for HER2 tyrosine kinase is found in 90% of cases of pancreatic cancer. Transgenic mice incorporating the HER2 gene develop breast cancer as they grow (Guyre et al., Proceedings of the National Academy of Science, USA, Vol. 89, pp. 10578-10582, 1992).
An antibody against HER2 was shown to suppress in vitro proliferation of cancer cells (McKenzie et al., Oncogene, Vol. 4, pp. 543-548, 1989); in addition, a human monoclonal antibody against HER2 provided encouraging results in a clinical study in breast cancer patients (Baselga et al., Journal of Clinical Oncology, Vol. 14, pp. 737-744, 1996).
These antibodies interfere with growth factors to bind to HER2 and inhibit the activation of tyrosine kinase. Because these antibodies were thus shown to suppress the progression of cancer in breast cancer patients, drugs which directly inhibit HER2 tyrosine kinase were shown to be potentially effective as therapeutic drugs for breast cancer (Hayes, Journal of Clinical Oncology, Vol. 14, pp. 697-699, 1996).
As a compound that inhibits receptor type tyrosine kinases, including HER2, Japanese Patent Unexamined Publication No. 60571/1999 discloses a compound represented by the formula:
wherein R is a is an aromatic heterocyclic group which may be substituted; X is an oxygen atom, an optionally oxidized sulfur atom, —C(═O)— or —CH(OH)—; Y is CH or N; m is an integer from 0 to 10; n is an integer from 1 to 5; the cyclic group:
is an aromatic azole group which may be substituted; Ring A may be further substituted.
And, there is demand for the development of a compound which possesses excellent tyrosine kinase-inhibiting activity, which is of low toxicity, and which is satisfactory as a pharmaceutical.
DISCLOSURE OF INVENTION
The present inventors conducted various investigations on heterocyclic compounds possessing tyrosine kinase-inhibiting activity and succeeded in synthesizing for the first time a compound represented by the formula:
wherein m is 1 or 2;
R
1
is a halogen atom or an optionally halogenated C
1-2
alkyl group;
one of R
2
and R
3
is a a hydrogen atom and the other is a group represented by the formula:
wherein n is 3 or 4; R
4
is a C
1-4
alkyl group substituted by 1 to 2 hydroxy groups (hereinafter also referred to as Compound (I)), which has a chemical structure unique in that phenyl of the phenylethenyl of the skeleton represented by the formula:
wherein the symbols have the same definitions as those shown below is substituted by a halogen or an optionally halogenated C
1-2
alkyl, or a salt thereof, and found that this Compound (I) or a salt thereof possesses an unexpectedly excellent tyrosine kinase-inhibiting activity based on its unique chemical structure. The inventors conducted further investigations based on this finding and developed the present invention.
Accordingly, the present invention relates to:
(1) A compound (I) or a salt thereof;
(2) A compound as defined in (1) above, wherein R
1
is fluoro or trifluoromethyl, or a salt thereof;
(3) A compound as defined in (1) above, wherein R
2
is a group represented by the formula:
and R
3
is a hydrogen atom; or
R
2
is a hydrogen atom and R
3
is a group represented by the formula:
or a salt thereof;
(4) A compound as defined in (1) above, wherein R
2
is a group represented by the formula:
and R
3
is a hydrogen atom, or a salt thereof;
(5) A compound as defined in (1) above, wherein m is 1;
R
1
is 4-trifluoromethyl;
R
2
is a group represented by the formula:
and R
3
is a hydrogen atom, or a salt thereof;
(6) A compound as defined in (1) above, which is 1-(4-{4-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}butyl)-1H-1,2,3-triazole, 1-(3-(3-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}propyl)-1H-1,2,3-triazole, or 3-(1-{4-[4-({2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]butyl}-1H-imidazol-2-yl)-1,2-propanediol, or a salt thereof;
(7) A method for producing Compound (I)or a salt thereof comprising reacting a compound represented by the formula:
wherein, X is a leaving group; the other symbols have the same meanings as defied above, or a salt thereof, with a compound represented by the formula:
wherein the symbols have the same meanings as defied above, or a salt thereof;
(8) A pro-drug of a compound as defined in (1) above;
(9) A pharmaceutical composition containing a compound as defined in (1) above or a salt thereof or a pro-drug thereof;
(10) A pharmaceutical composition as defined in (9) above, which is a tyrosine kinase inhibitor;
(11) A pharmaceutical composition as defined in (9) above, which is an agent for preventing or treating cancer;
(12) A pharmaceutical composition as defined in (11) above, wherein the cancer is breast cancer or prostate cancer;
(13) A pharmaceutical composition as defined in (11) above, wherein the cancer is lung cancer;
(14) A pharmaceutical composition which combines a compound as defined in (1) above or a salt thereof or a pro-drug thereof and other anti-cancer agents;
(15) A pharmaceutical composition which combines a compound as defined in (1) above or a salt thereof or a pro-drug thereof and hormonal therapeutic agents;
(16) The pharmaceutical composition as defined in (15) above, wherein the hormonal therapeutic agent is a LH-RH modulator;
(17) The pharmaceutical composition as defined in (16) above, wherein the LH-RH modulator is LH-RH antagonist;
(18) The pharmaceutical composition as defined in (17) above, wherein the LH-RH antagonist is leuprorelin or a salt thereof;
(19) A method for inhibiting tyrosine-kinase which comprises administering an effective amount of a compound as defined in (1) above or a salt thereof or a pro-drug thereof to mammals;
(20) A method for preventing or treating cancer which comprises administering an effective amount of a compound as defined in (1) above or a salt thereof or a pro-drug thereof to mammals;
(21) A method for preventing or treating cancer which comprises combining [1] administering an effective amount of a compound as defined in (1) above or a salt thereof or a pro-drug thereof to mammals and [2] 1 to 3 selected from the group consisting (i) administering an effective amount of other anti-cancer agents to mammals, (ii) administering an effective amount of hormonal therapeutic agents to mammals and (iii) non-drug therapy;
(22) The method as defined in (21) above wherein non-drug therapy is surgery, hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy, laser cauterization and/or radiotherapy;
(23) A method for preventing or treating cancer which comprises administering in combination of an effective amount of a compound as defined in (1) above or a salt thereof or a pro-drug thereof and an effective amount of other anti-cancer agents to mammals;
(24) A method for preventing or treating cancer which comprises administering in combination
Hitaka Takenori
Matsutani Etsuya
Tasaka Akihiro
Anderson Rebecca
McKane Joseph K.
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
LandOfFree
Heterocyclic compounds their production and use does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Heterocyclic compounds their production and use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Heterocyclic compounds their production and use will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3233260