Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-19
2004-08-10
Pak, John (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S816000, C514S817000, C514S818000, C514S825000, C514S883000, C514S908000
Reexamination Certificate
active
06774131
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pharmaceutical drug; more specifically, the invention relates to a therapeutic agent for reducing pain in an endothelin-induced disease, such as prostate cancer; a therapeutic agent for ameliorating osteogenic disorders and/or a therapeutic agent for reducing pain involved in osteogenesis; a therapeutic agent for reducing pain involved in the bone metastasis of prostate cancer and/or a therapeutic agent for ameliorating osteogenic disorders due to the bone metastasis of prostate cancer; a therapeutic agent for suppressing the growth of the cancer cell of prostate cancer; or a therapeutic agent for suppressing the progress of prostate cancer.
BACKGROUND OF THE INVENTION
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfoneamide or a salt thereof is described in the International Patent Publication No. 97/22595. The actions thereof to suppress ET-1 binding to endothelin ETA receptor and to suppress ET-1 induced vascular constriction and blood pressure elevation are disclosed therein, indicating that the compound or a salt thereof can be used for treating various diseases primarily including cardiovascular diseases, for which endothelin is responsible.
For the purpose of creating a new therapeutic agent, the present inventors have made more detailed investigations about a possibility of the application of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a salt thereof to the treatment of diseases,
DISCLOSURE OF THE INVENTION
Consequently, the inventors have found that N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a salt thereof is effective for the reduction of pains of endothelin-induced diseases, such as cancer (particularly, prostate cancer, breast cancer, ovarian cancer), arthritis, prostatitis, glioma, peripheral artery occlusion, dysmenorrhea, migraine headache, angina, acute cardiac infarction, cerebral infarction, subarachinoid hemorrhage, diabetic nervous disorders, rheumatoid arthritis, glaucoma, gastric ulcer and labor during delivery. Thus, the invention has been achieved.
It is reported that ET-1 induces pain in humans and experimental animals. For example, ET-1 administered to human brachial artery induces ischemic muscular pain (J.Hypertension,8,811-817,1990). Additionally, it is reported that ET-1 significantly enhances the first and second phases of pain due to formalin in the mouse formalin pain model commonly used as a pain model. (Can.J.Physiol.Pharmacol.,75,596-600,1997). In the model, the first phase means pain due to direct stimulation of sensory nerve, while the second phase means pain due to inflammatory secondary reaction (Pain,38,247-352,1989).
As shown in the following Test Example 1, The effective component of the invention exerted an action to suppress the enhancement of pain induced by ET-1 in the mouse formalin pain model.
Further, the inventors have found that N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a salt thereof is effective for the amelioration of osteogenic disorders and/or the reduction of pain involved in osteogenesis. Thus, the invention has been achieved.
Because bisphosphonates with an action to suppress osteoclast and thereby ameliorate bone metabolism have an effect to ameliorate bone pain involved in the bone metastasis of breast cancer, the amelioration of long-term bone disorders is believed to lead to the amelioration of bone pain. Unlike bread cancer patients with bone metastasis, osteogenic disorders due to bone metastasis are observed in patients with prostate cancer (Semin.,Oncol.,21,630-656,1996), and drugs with an action on osteoblast to thereby ameliorate bone metabolism probably have an effect to ameliorate bone pain involved in the bone metastasis of prostate cancer.
It is reported that ET-1 exerts actions to increase intracellular Ca
2+
concentration and DNA synthesis and to reduce ALP activity through ETA receptors in MC3T3-E1, mouse osteoblast-like cells, and osteoblast primarily cultured from a rat calvaria (Am.J.Physiol.,257,E797-E803,1989/Biochem.Biophys.Res.Commun.,170(3),998-1005,1990/Bone,21(2),143-146,1997).
As shown in the following Test Example 2, The effective component of the invention exerted an action to suppress the ET-1-induced cell response reactions of the MC3T3-E1, mouse osteoblast-like cells.
Further, the inventors have found that N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a salt thereof is effective for the amelioration of osteogenic disorders due to the bone metastasis of prostate cancer and/or the reduction of pain involved in the bone metastasis of prostate cancer. Thus, the invention has been achieved.
It is reported that a human prostate cancer cell line has a potency to generate ET-1 (Nat.Med.,1(9),944-949,1995) and the growth potency is exerted through ETA receptors (Cancer Res. ,56,663-668,1996) and that the plasma ET-1 concentration in prostate cancer patients with bone metastasis is elevated, compared with the ET-1 concentration in prostate cancer patients without bone metastasis (Nat.Med.,1(9),944-949,1995). Taking account of these reports together with the results of Test Examples 1 and 2, the effective component of the invention is believed to be particularly effective for the amelioration of osteogenic disorders due to the bone metastasis in prostate cancer patients and/or the reduction of pain involved in the bone metastasis of prostate cancer patients. Additionally, as shown in the following Test Example 5, the effective component of the invention reduced pain score and use of analgesics in prostate cancer patients, and decreased bone metabolism markers in prostate cancer patients.
Further, the inventors have found that N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a salt thereof is effective for the suppression of the growth of the cancer cell of prostate cancer. Thus, the invention has been achieved.
As shown in the following Test Example 3 and 4, The effective component of the invention suppressed cell growth of hormone-refractory human prostate cancer cell induced by ET-1.
Further, the inventors have found that N-[6-methoxy-5-(2- methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a salt thereof is effective for the suppression of the progress of prostate cancer. Thus, the invention has been achieved.
As shown in the following Test Example 5, The effective component of the invention stabilized or decreased Prostate cancer marker PSA in prostate cancer patients.
In other words, the invention relates to a pharmaceutical composition for reducing pain in endothelin-induced diseases, such as cancer (particularly, prostate cancer, breast cancer, ovarian cancer), arthritis, prostatitis, glioma, peripheral artery occlusion, dysmenorrhea, migraine headache, angina, acute cardiac infarction, cerebral infarction, subarachinoid hemorrhage, diabetic nervous disorders, rheumatoid arthritis, glaucoma, gastric ulcer and labor during delivery; a pharmaceutical composition for ameliorating osteogenic disorders; and/or a pharmaceutical composition for reducing pain involved in osteogenesis, particularly a pharmaceutical composition for ameliorating osteogenic disorders due to the bone metastasis of prostate cancer; and/or a pharmaceutical composition for reducing pain involved in the bone metastasis of prostate cancer, the aforementioned compositions containing N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a pharmaceutically acceptable salt thereof as the effective components.
Additionally, the invention relates to the use of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyri midinyl]-2-phenylethenesulfoneamide or a pharmaceutically acceptable salt thereof for the manufactu
Fujimori Akira
Harada Hironori
Koakutsu Akiko
Mori Mikiko
Sanagi Masanao
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Pak John
Yamanouchi Pharmaceutical Co. Ltd.
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