N,N-substituted cyclic amine derivatives

Details N,N-substituted cyclic amine derivatives N,N-substituted cyclic amine derivatives

2001-01-29

2004-05-18

Raymond, Richard L. (Department: 1609)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S218000, C514S252140, C514S255060, C544S358000, C544S359000, C544S399000, C544S403000, C540S575000

Reexamination Certificate

active

06737425

ABSTRACT:

INDUSTRIAL FIELD OF THE APPLICATION
The present invention relates to novel N,N-substituted cyclic amine compounds useful as a calcium antagonist, particularly as a nerve-selective calcium antagonist, specifically as an agent for treating and improving the diseases against which an inhibitory action on P/Q type calcium channels or an inhibitory action on N type calcium channels is effective, more specifically as an agent for inhibiting the death of nerve cells or for protecting cerebral nerve cells, and further specifically as an agent for treating and improving nerve diseases, and most specifically as an agent for preventing, treating or improving acute ischemic stroke, cerebral apoplexy, cerebral infarction, head trauma, cerebral nerve cell death, Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, Huntington disease, cerebral circulatory metabolism disturbance, cerebral function disturbance, pain, spasm, schizophrenia, migraine, epilepsy, maniac-depressive psychosis, nerve degenerative diseases, cerebral ischemia, AIDS dementia complications, edema, anxiety disorder (generalized anxiety disorder) and diabetic neuropathy.
BACKGROUND OF THE INVENTION
In Japan, the number of patients with cerebral apoplexy is about 1.4 million or more per year, and the medical expenses therefor are estimated to be about two billion yen. Cerebral apoplexy is the second cause of death next to malignant tumor and is the biggest cause for bedridden man often suffering from severe secondary diseases. A key to the treatment of cerebral apoplexy is to deal with the acute stage, and the treatment at the acute stage influences the life and function prognosis of the patient and significantly influences secondary diseases.
For the purpose of improving blood stream, several drugs such as ozagrel sodium (thromboxane synthase inhibitor), argatroban (anti-thrombin agent) as an agent for treatment of chronic arterial occlusion, t-PA (alteplase: tissue plasminogen activator which should be used within 3 hours after the onset) as thrombolytic agent etc. are now approved of, or in off lavel use.
In the treatment with these drugs, the following complicated techniques and cautious judgement based on adequate knowledge and experience by a medical specialist are required.
(1) In the case of thrombus-type cerebral infarction, respiratory control, blood pressure control and blood transfusion control are first conducted.
(2) Blood gas and blood pressure are periodically measured.
(3) At the acute stage, reactive high blood pressure is observed, but if complications in the heart and kidney are not observed, treatment for decreasing blood pressure is not conducted.
(4) Then, in the early-acute stage case with no low absorption range observed in CT, the thrombus-lytic agent “urokinase” is used.
(5) In the case where these agents are not applicable or in the case where 24 hours or more has elapsed after the onset, “ozagrel sodium” is administered. Or “argatroban” is administered. However, argatroban is not applicable to lacuna infarction.
(6) To prevent the development of cerebral edema, “glycerin” or “mannitol” is administered at a suitable dosage.
However, the therapeutic effects of the drugs used heretofore are not satisfactory and further there is the danger that bleeding is often accompanied by their pharmacological effect.
Accordingly, there is the problem that it is difficult for those except of skilled medical specialists to use these drugs.
JP 62-167762-A (EP 229623), JP 2-506694-A (WO 90/13539), DE 4404249, JP 10-95758-A (EP 805147) etc. disclose compounds having piperazine compounds being completely different in structure from the N,N-substituted cyclic amine compounds of the present invention.
BRIEF SUMMARY OF THE INVENTION
The present inventors sought a highly safe drug, which causes no bleeding, and is highly effective in treating and improving the acute ischemic stroke against which no useful drugs have been developed. The inventors focused their attention on nerve-selective, voltage-dependent calcium channel antagonist which directly acts on nerve cells to prevent the development of infarction volume, and they made extensive studies thereon.
As a result, they have found that novel N,N-substituted cyclic amine compounds having the following formula, or pharmacologically acceptable salts thereof, possess an excellent action on inhibition of the death of nerve cells and on protection of cerebral nerve cells, based on inhibitory action on P/Q type calcuim channels or N-type calcium channels. These N,N-substituted cyclic amine compounds are superior in safety and can solve the problems described above, and the present invention has been thereby completed.
DETAILED DESCRIPTION OF THE INVENTION
The N,N-substituted cyclic amine compounds according to the present invention are represented by the following formula (VIII):
wherein
A represents an aryl group which may be substituted, a heteroaryl group which may be substituted, an aralkyl group which may be substituted or a heteroaryl alkyl group which may be substituted;
E represents a group represented by the formula —CO— or a group represented by the formula —CHOH—;
G represents an oxygen atom, a sulfur atom, and a group represented by the formula —NR
10
— (wherein R
10
represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl, a lower acyl group or a lower alkyl sulfonyl group), a group represented by the formula —CO—, a group represented by —COO—, a group represented by the formula —OOC—, a group represented by the formula —CONR
11
— (wherein R
11
represents a hydrogen atom or a lower alkyl group), a group represented by the formula —NR
12
CO— (wherein R
12
represents a hydrogen atom or a lower alkyl group), a group represented by the formula —SO—, a group represented by the formula —SO
2
—, a group represented by the formula —SONR
13
— (wherein R
13
represents a hydrogen atom or a lower alkyl group) a group represented by the formula —NR
14
SO— (wherein R
14
represents a hydrogen atom or a lower alkyl group), a group represented by the formula —SO
2
NR
15
— (wherein R
15
represents a hydrogen atom or a lower alkyl group), a group represented by the formula —NR
16
SO
2
— (wherein R
16
represents a hydrogen atom or a lower alkyl group), a group represented by the formula >C═N—OR
17
(wherein R
17
represents a hydrogen atom or a lower alkyl group), a group represented by the formula —NHCONH—, a group represented by the formula —NHCSNH—, a group represented by the formula —C(═NH)NH—, a group represented by the formula —NHC(═NH)—, a group represented by the formula —OCOS—, a group represented by the formula —SCOO—, a group represented by the formula —OCOO—, a group represented by the formula —NHCOO—, a group represented by the formula —OCONH—, a group represented by the formula —CO(CH
2
)
s
O—, a group represented by the formula —CHOH— or a group represented by the formula —CHOH(CH
2
)
s
O— (wherein s represents 0 or an integer of 1 to 6);
J represents an aryl group which may be substituted or a heteroaryl group which may be substituted;
R
1
represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, a hydroxy lower alkyl group, a lower alkoxyalkyl group, a cyano-lower alkyl group, a halogenated lower alkyl group, an optionally N-substituted amino-lower alkyl group, a group represented by the formula —NR
18
R
19
(wherein R
18
and R
19
may be the same as or different from each other and each represents a hydrogen atom or a lower alkyl group), an aralkyl group, a morpholinyl group, a thiomorpholinyl group, a piperidyl group, a pyrrolidinyl group or a piperazinyl group;
Alk represents a linear or branched lower alkylene group; and
n, v, w, x and y are independent of each other and each represents 0 or 1, and p represents 2 or 3.
The invention includes a pharmacologically acceptable salt of the compound.
Herein, particular examples of the aryl group which may be substituted are phenyl group, naphthyl group etc., or those f

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