Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-04-18
1998-12-01
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514455, 549359, 549458, A61K 3141, C07D31120, C07D31178
Patent
active
058439889
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE
This Application is a 371 of PCT/JP95/02163 filed Oct. 20, 1995.
BACKGROUND OF THE INVENTION
The present invention relates to novel cyclopropachromencarboxylic acid derivatives and pharmaceutically acceptable salts. More specifically, the present invention relates to novel cyclopropachromen-carboxylic acid derivatives and pharmaceutically acceptable salts, which are endowed with antagonistic activity against metabotropic glutamate receptors, and which are effective for ameliorating and treating symptoms of ischemic disorders in the brain such as sequelae of cerebral infarction, sequelae of intracerebral hemorrhage, sequelae of cerebral arteriosclerosis, and so on and symptoms of organic brain disorders such as senile dementia, sequelae of head trauma, sequelae of surgical brain operation, Alzheimer's disease, Parkinson's disease, and so on.
It is generally recognized that the pathogenesis of progressive, delayed death of nerve cells followed by brain injury associated with head trauma or cerebrovascular disorders (e.g. intracerebral hemorrhage, transient ischemic attack, cerebral infarction) involves abnormal activation of glutamate receptors due to excessive release of glutamic acid, i.e. an Pharmacol. Toxicol., 29, 365 (1989); B. Meldrum et al.: Trends Pharmacol. Sci., 11,379 (1990)!. Glutamate receptors are classified into two major types: ionotropic receptors (iGluR), which directly gate ion channels, and metabotropic receptors (mGluR) which are linked to an intracellular and their antagonists are currently under investigation for developing drugs for preventing or inhibiting the death of nerve cells. However, most Pharmacol. Sci., 11, 25 (1990); D. Lodge et al.: ibid. 11, 81(1990)!. With McDonald et al. :J. Neurosci, 13, 4445(1993)! which recently have been al.: Trends Pharmacol. Sci., 14, 13 (1993)! and phenyglycine derivatives
SUMMARY OF THE INVENTION
With the aforementioned background, it is an objective of the present invention to provide novel compounds, which have mGluR antagonistic activity, and which are useful in ameliorating and treating functional and organic disorders in the brain.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors found that cyclopropacromen derivatives protect the brain in a hypoxic state under reduced pressure, and filed a patent application for the resulting invention (please refer to Japanese Patent Application Laid-Open (KOKAI) No.235180/92. Further, the present inventors took particular note of mGluR1, which is an mGluR subtype coupled with (1991)!, and synthesized a series of compounds for screening them in view of an antagonistic activity against intracellular calcium ion elevation, which is induced by glutamic acid, using Chinese hamster ovary (CHO) cells al.: Neuron., 8, 757 (1992)!. The study demonstrated that cyclopropachromencarboxylic acid derivatives have antagonistic activity against mGluR1 and that the derivatives have improved stability as compared with known cyclopropachromen derivatives, and therefore, the present invention has been completed.
The present invention provides, as an mGluR1 antagonist, a cyclopropachromencarboxylic acid derivative and its pharmaceutically acceptable salts represented by the following general formula (1) ##STR2## group having 1 to 5 carbon atoms, or the group .dbd.N--O--(CH.sub.2).sub.n --NR.sup.1 R.sup.2 (where n represents an integer of 2 to 8, and each of R.sup.1 and R.sup.2 independently represents a hydrogen atom or alkyl group having 1 to 5 carbon atoms, respectively); or alkyl group having 1 to 5 carbon atoms) or the group --CONR.sup.4 R.sup.5 (where R.sup.4 and R.sup.5 independently represent a hydrogen atom, alkyl group having 1 to 5 carbon atoms, alkenyl group having 1 to 5 carbon atoms, aminoalkyl group wherein N may be substituted, phenyl group which may be substituted with a halogen atom or hydroxyl group which in turn may be substituted, 2-pyridyl group, or aralkyl group having 7 to 10 carbon atoms, or, R.sup.4 and R.sup.5 taken together with the nitrogen atom to which they
REFERENCES:
patent: 5155129 (1992-10-01), Tatsuoka et al.
Chemical Abstracts 125:33436z (1996) Annoura et al.
Chemical Abstracts, vol. 125(3),abst.No.33,436z,pub.Jul. 15, 1996.
Chemical Abstracts,vol.125,(9),abst.No.114,483q,pub.Aug. 26, 1996.
Annoura Hirokazu
Fukunaga Atsuko
Horikawa Yoshiko
Tatasuoka Toshio
Rotman Alan L.
Suntory Limited
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