Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-05
2003-11-04
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...
C544S133000, C548S151000, C548S303100
Reexamination Certificate
active
06642264
ABSTRACT:
This application is a 371 of PCT/JP00/02199 Apr. 5, 2000.
TECHNICAL FIELD
This invention relates to novel thiazolobenzoimidazole derivatives or salts thereof. The compounds of the invention are useful as medicaments, particularly as a metabotropic glutamate receptor ligand.
It further relates to pharmaceutical compositions which comprise the thiazolobenzoimidazole derivatives or salts thereof as an active ingredient and to intermediates for the synthesis of the compounds of the invention.
BACKGROUND ART
Glutamic acid acts as a neurotransmitter in the mammalian central nervous system (Mayer M. L. and Westbrook G. L.,
Prog. Neurobiol.,
28 (1987) 197-276). By the recent studies, importance of glutamic acid in the higher order cranial nerve function has been revealed. Glutamic acid is released from the nerve ending and regulates activity of nerve cells or release of a neurotransmitter, via glutamate receptors which are present in the postsynaptic membrane or nerve ending. Based on various pharmacological and physiological studies, glutamate receptors are currently classified roughly into two categories. One of them is ionotropic receptor and the other is metabotropic receptor (Hollmann M and Heinemann S.,
Annu. Rev. Neurosci.,
17 (1994) 31-108).
Based on the molecular biological studies, it has been reported that the metabotropic glutamate receptor (to be referred to as mGluR hereinafter) exists so far in at least eight different subtypes of from mGluR1 to mGluR8. The mGluR is classified into a group of receptors (mGluR1 and mGluR5) which accelerate production of inositol triphosphate (IP3) and incorporation of calcium ions into cells, by coupling with phospholipase C via G protein, and another group of receptors (mGluR2, mGluR3, mGluR4, mGluR6, mGluR7 and mGluR8) which inhibit production of cAMP by coupling with Gi protein. These receptors show different intracerebral distributions from one another, for example, mGluR6 does not exist in the brain but exists only on the retina, so that it is considered that each receptor is taking each own deferent physiological role. (Nakanishi S.,
Neuron,
13 (1995) 1031-1037).
Compounds which are selective for the mGluR in comparison with the ionotropic receptor have so far been reported (Hayashi Y. et al.,
Br. J. Phamacol.,
107 (1992) 539-543; Hayashi Y. et al.,
J. Neurosci.,
14 (1995) 3370-3377), and relationships between the mGluR and various morbid states have been reported as the following cases (1) to (4), based on the studies carried out using these compounds.
(1) Epilepsy is induced by the administration of an mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (to be referred to as (1S,3R)-ACPD hereinafter) (Tizzano J. P. et al.,
Neurosci. Lett.,
162 (1993) 12-16; McDonald J. W. et al.,
J. Neurosci.,
13 (1993) 4445-4455). In addition, the efficacy of (S)-4-carboxy-3-hydroxyphenylglycine (to be referred to as (S)-CHPG hereinafter), which is an antagonist of mGluR1 and also an agonist of mGluR2, in various epilepsy models has been reported (Dalby, N. O. & Thomsen, C. J.,
J. Pharmacol. Exp. Ther.,
276 (1996) 516-522).
(2) Participation of mGluR in the transmission of pain sensation into spinal posterior horn nerve cells has been confirmed by electro-physiological tests (Young, M. R. et al.,
Neuropharmacology,
33 (1994) 141-144; ibid., 34 (1995) 1033-1041). Also, it has been reported that (S)-CHPG has an action to delay avoiding reaction of thermal and mechanical pain sensation stimulation (Young, M. R. et al.,
Br. J. Pharmacol.,
114 (1995) 316P).
(3) It has been reported that when (1S,3R)-ACPD or (RS)-3,5-dihydroxyphenylglycine (to be referred to as 3,5-DHPG hereinafter) is administered in a trace amount or systemically to the cerebral parenchyma of mouse or rat, it causes nerve cell death accompanied by spasm (Lipartit, M. et al.,
Life Sci.,
52 (1993) PL 85-90; McDonald, J. W. et al.,
J. Neurosci.,
13 (1993) 4445-4455; Tizzano, J. P. et al.,
Neuropharmacology,
34 (1995) 1063-3067). It is considered that this is a result of the activation of mGluR1 and mGluR5.
(4) It is well known that chronic administration of benzodiazepine forms its dependency. It has been reported that metabolic turnover of inositol-phospholipid increases by (1S,3R)-ACPD via mGluR, on the second day and third day after 7 days of continuous administration of benzodiazepine, and it has been suggested that mGluR is taking a role in the expression of benzodiazepine withdrawal syndrome (Mortensen, M. et al.,
J. Pharmacol. Exp. Ther.,
274 (1995) 155-163).
That is, these reports show that compounds which act upon mGluR1 are useful in epilepsy, pain, nerve cell death inhibition and benzodiazepine withdrawal syndrome.
On the other hand, thiazolobenzoimidazole derivatives have been disclosed in
J. Org. Chem.,
29 (4) 865-869 (1964);
Can. J. Chem.,
45 (23) 2903-2912 (1967),
Khim. Geterotsikl. Soedin.,
7 (3) 393-396 (1971);
Indian J. Exp. Biol.,
10 (1) 37-40 (1972),
Khim. Geterotsikl. Soedin
., (6) 778-783 (1974);
Synthesis
, (3) 189 (1976);
Tetrahedron Lett
., (3) 275-278 (1977);
Bull. Chem. Soc. Jpn.,
61 (4) 1339-1344 (1988);
J. Prakt. Chem.,
330 (3) 338-348 (1988);
Bull. Pol. Acad. Sci. chem.,
37 (5-6) 185-191 (1989); Chem. Pap., 48 (2) 108-110 (1994),
Tetrahedron,
52 (31) 10485-10496 (1996) and the like. However, among these reports,
Indian J. Exp. Biol.,
10 (1) 37-40 (1972) and
Bull. Pol. Acad. Sci. Chem.,
37 (5-6) 185-191 (1989) describe that thiazolobenzoimidazole derivatives have antibacterial actions but do not disclose about their use as a medicament, and there is no disclosure or suggestion regarding the action of these thiazolobenzoimidazole derivatives upon metabotropic glutamate receptors.
Regarding compounds having a function as a metabotropic glutamate receptor ligand, on the other hand, a compound having an amino acid or peptide structure (cf. JP-A-7-267908; the term “JP-A” as used herein means an “unexamined published Japanese patent application”), a compound having a thieno[2,3-b]indole structure (cf. WO 95/25110), a cyclopropachromenecarboxylic acid derivative (cf. JP-A-8-169884), a 3-vinylindole derivative (cf. WO 97/05109), a pyridino[2,3-b]indole derivative (cf. WO 97/05137) and an imidazobenzothiazole derivative (cf. WO 98/06724) have so far been reported, but thiazolobenzoimidazole derivatives are not known.
Though these compounds and the like are known as metabotropic glutamate receptor ligand, their actions are still insufficient, so that a compound having more excellent action upon metabotropic glutamate receptors is expected.
The objects of the invention is to provide a thiazolobenzoimidazole derivative which has a novel basal skeleton and shows excellent action upon metabotropic glutamate receptors, and salts thereof, and to further provide a medicament which contains the same.
DISCLOSURE OF THE INVENTION
The present inventors have conducted intensive studies and accomplished the invention by finding that a thiazolobenzoimidazole derivative exerts strong action upon metabotropic glutamate receptors and is useful as a medicament.
Accordingly, the invention relates to a thiazolobenzoimidazole derivative represented by the following general formula (I) or a salt thereof and a pharmaceutical composition which uses the compound as an active ingredient.
A thiazolobenzoimidazole derivative represented by the following general formula (I) or a salt thereof
(wherein each of the symbols means as follows;
R
1
:
(1) —A
1
—CO—N(R
6
)—R
7
,
(2) —A
1
—CO—A
2
—R
8
,
(3) —A
1
—CO—A
3
—N(R
6
)—R
7
,
(4) —A
1
—O—A
2
—R
9
,
(5) —A
1
—N(R
6
)—R
7
,
(6) —A
1
—N(R
6
)—CO—R
7
, or
(7) —N(R
10
)—CO—O—R
11
,
A
1
: the same or different from each other and each represents a bond or a lower alkylene group which may be substituted by hydroxyl group(s),
A
2
: the same or different from each other and each represents a bond, a lower alkylene or lower alkenylene group,
R
6
and R
7
: the same or different from each other and each represents hydrogen, —N(R
15
)—R
16
, a lower alkyl which may be substi
Hayashibe Satoshi
Itahana Hirotsune
Kamikubo Takashi
Kohara Atsuyuki
Maeno Kyoichi
Small Andrea D.
Yamanouchi Pharmaceutical Co. Ltd.
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