Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-21
2003-08-26
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S336000, C514S340000, C546S256000, C546S262000
Reexamination Certificate
active
06610717
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to new dihydropyridine derivatives and the use of the dihydropyridine derivatives as medicines. The activation of N-type calcium channel is concerned with various diseases, for example, acute stage of ischemic cerebrovascular disorders caused by cerebral infarction or intracerebral bleeding (including subarachnoidal hemorrhage); progressive neurodegenerative diseases such as Alzheimer's disease, AIDS related dementia and Parkinson's disease, dementia due to cerebrovascular disorder and ALS; neuropathy caused by head injury; various pains such as pain caused by spinal injury, diabetes or thromboangiitis obliterans, postoperative pain, migraine and visceral pain; various diseases associated with psychogenic stress such as bronchial asthma, unstable angina and irritable colitis; emotional disorder and withdrawal symptoms after addiction to drugs such as ethanol addiction withdrawal symptoms. The compounds of the present invention can inhibit the activation of the N-type calcium channel and, therefore usable as therapeutic agents for these diseases.
Calcium channels are now classified into subtypes of L, N, P, Q, R and T. Each subtype of calcium channels is organ-specifically distributed. It is known that particularly N-type calcium channel is widely distributed in pars centralis, peripheral nerves and adrenomedullary cells and participates in neuronal cell death, regulation of blood catecholamine level and control of senses such as perception.
It has been confirmed that omega conotoxin GVIA and omega conotoxin MVIIA, which are peptides selectively inhibiting N-type calcium channel, inhibit the release of excitatory neurotransmitters in the sliced brain preparation. It is also confirmed in animal experiments that they inhibit the progress of neuronal necrosis associated with cerebrovascular disorders. It is generally considered that compounds having a N-type calcium channel blocking action are clinically effective in the treatment of acute stage of ischemic cerebrovascular disorders caused by cerebral infarction or intracerebral bleeding (including subarachnoidal hemorrhage); progressive neurodegenerative diseases such as Alzheimer's disease, AIDS related dementia and Parkinson's disease, dementia due to cerebrovascular disorder and ALS; and neuropathy caused by head injury. Further, it is confirmed in animal tests that omega conotoxin MVIIA relieves a pain induced by formaldehyde, hot plate and peripheral neuropathy. Accordingly, omega conotoxin MVIIA is considered to be clinically effective against various pains such as pain caused by spinal injury, diabetes or thromboangiitis obliterans, postoperative pain, migraine and visceral pain. In addition, because omega conotoxin GVIA inhibits the release of catecholamine from cultured sympathetic ganglion cells, catecholamine secretion from canine adrenal medulla and the contraction of the isolated blood vessel by electric stimulation of the perivascular nerve, it is considered that compounds having N-type calcium channel-blocking effects are clinically effective against various diseases related to psychogenic stress such as bronchial asthma, unstable angina and irritable colitis [Neuropharmacol., 32, 1141 (1993)].
Some peptidergic and non-peptidergic compounds which selectively affect N-type calcium channels have been ever disclosed (see, for example, WO 9313128 and WO 9849144). However, none of them was actually used as a medicine. Some of the compounds which affect N-type calcium channels are also effective against various types of calcium channels of other than N-type [British Journal of Pharmacology, 122 (1) 37-42, 1997]. For example, compounds having an antagonistic effect on L-type calcium channels which are very closely related to hypotensive effect, could not be used for diseases for which N-type antagonists will be used (such as cerebral stroke, neuralgia, terminal cancer pain and pain of spinal injury). Under these circumstances, the development of a highly active antagonist selective toward N-type calcium channel has been eagerly demanded.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide new compounds having a selective antagonistic effect on N-type calcium channels.
Another object of the present invention is to provide antagonists to N-type calcium channels.
Still another object of the present invention is to provide a therapeutic agent for any of acute stage of ischemic cerebrovascular disorders caused by cerebral infarction or intracerebral bleeding, Alzheimer's disease, AIDS related dementia, Parkinson's disease, progressive neurodegenerative diseases, neuropathy caused by head injury, pain caused by thromboangiitis obliterans, postoperative pain, migraine, visceral pain, bronchial asthma, unstable angina, irritable colitis and withdrawal symptoms after addiction to drugs.
A further object of the present invention is to provide a pharmaceutical composition.
After synthesizing various dihydropyridine derivatives and examining the N-type calcium channel inhibiting effect (determined by fluorescent dye method) and L-type calcium channel inhibiting effect of the newly synthesized compounds and well-known dihydropyridine derivatives for the purpose of solving the above-described problems, the inventors have found that specified, new dihydropyridine derivatives have an excellent effect of selectively antagonizing N-type calcium channels. The present invention has been completed on the basis of this finding. Namely, the present invention provides dihydropyridine derivatives of the following general formula (1) and pharmaceutically acceptable salts thereof.
wherein
A represents a group of the following general formula (2), or 1-naphthyl, 2-naphthyl, thiophene-3-yl, thiophene-2-yl, furan-3-yl, furan-2-yl, pyridine-4-yl, pyridine-3-yl, pyridine-2-yl, indole-2-yl or indole-3-yl group:
wherein R
1
, R
2
, R
3
, R
4
and R
5
may be the same or different from each other and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, amino group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a lower alkoxycarbonyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl group, a heteroaryl group, an aryl-lower alkoxyl group or an aroyl group,
B represents cyano group, nitro group, acetyl group, tetrazole group, triazole group or a group of the following general formula (3) or (4):
wherein R
6
to R
8
each represent hydrogen atom, a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms, an alkyl group substituted with a cyclic alkyl group which may contain a hetero atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a hydroxy-lower alkyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkenyl group, an aryl-lower alkyl group, an aryl-lower alkenyl group, a heteroaryl-lower alkyl group (excluding pyridine-3-ylpropyl group), a heteroaryl-lower alkenyl group, a cyano-lower alkyl group or a cyano-lower alkenyl group, and the chains of R
6
to R
8
may contain a hetero atom, or R
7
and R
8
may together form a ring which may contain a hetero atom,
C represents hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl group, a halogeno-lower alkyl group (C does not represent these groups listed above when E represents hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl group or a halogeno-lower alkyl group), a substituted or unsubstituted amino-lower alkyl group (the substituent represents hydrogen atom or a lower alkyl group, and if necessary, they may contain a hetero atom in the chain thereof), a
Kajigaya Yuki
Kito Morikazu
Koganei Hajime
Nakajo Akira
Ono Yukitsugu
Ajinomoto Co. Inc.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Seaman D. Margaret
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