Heterocyclic derivative and medicine

Details Heterocyclic derivative and medicine Heterocyclic derivative and medicine

1999-06-16

2001-02-20

Shah, Mukund J. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S135000, C546S139000, C546S141000, C546S294000, C546S297000, C544S239000, C544S241000, C544S242000, C544S298000, C544S326000, C544S330000

Reexamination Certificate

active

06191149

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a heterocyclic derivative which is useful as a medicine.
BACKGROUND ART
Cerebrovascular disease is a condition in which the blood vessels circulating the brain are impaired by, for example, cerebral infarction, cerebral hemorrhage, head trauma, or subarachnoid hemorrage. As the flow of blood to the brain is interrupted or decreased by a cerebrovascular disease and the brain becomes ischemic, the nerve cells are damaged. Even if the patient narrowly escapes death, he or she suffers from sequelae of neuronal death caused by this impairment. Therapeutic agents for cerebrovascular disease may be classified into the agents which act against brain infarction, hemorrhage, etc. and those which inhibit said neuronal death.
It has recently become clear that once the brain tissue is brought into an ischemic state, even if the ischemia is transiently and the complete recovery of regional blood flow reinstates the normal energy metabolism and neural activity once, the final outcome is death of nerve cells. Such pathological changes of nerve cells, which characteristically occur predominantly in the hippocampus, manifest themselves in 3-4 days after ischemia and, therefore, are called delayed neuronal death. Moreover, even in the cerebral region not exposed to reperfusion, there are domains in which the blood flow is not completely interrupted but decreased. It is said that the nerve cells in such domains also succumb to death on prolongation of ischemia. This death of nerve cells could be blocked, the sequelae of a cerebrovascular disease following ischemia could be prevented.
It is known that the cerebral metabolism enhancer, propentofylline is effective against delayed neuronal death but, partly because of its side effects, is not a fully satisfactory medicine.
With therapeutic drugs in this field being the target, much research has been undertaken into inhibitors of excitatory amino acids. This is predicated on the concept of preventing ischemic death of neurons by inhibiting the excessive excitation of neurons following brain ischemia. It is well known that glutamic acid or glutamate is such an excitatory amino acid. As inhibitors of the excitatory amino acid, many glutamate antagonists which would specifically block the receptors of this amino acid and compounds which inhibit the release of glutamate are already known. The glutamate receptors are classified into the N-methyl-D-aspartate (hereinafter referred to as NMDA) receptors and receptors other than said NMDA receptors (hereinafter referred to as non-NMDA receptors). As an NMDA antagonist, MK-801, for instance, is known, while YM-90K, for instance, is known to be a non-NMDA antagonist. As glutamate release inhibitors, 2,4-diamino-5-(2,3,5-trichlorophenyl)pyrimidine and 2,4-diamino-5-(2-chlorophenyl)pyrimidine are known [EP-A 459830; 6th SCI-RSC Medical Chemistry Symposium, Sep. 8-11, 1991].
Meanwhile, it is described in WO 92/04333 that a phenylpyrimidine derivative has learning-and-memory disorder improving activity and finds application in dementia. While various nerve systems have been impaired in dementia, it is known that the impairment of the cholinergic nervous system playing an important role in learning-and-memory is particularly serious. The phenylpyrimidine derivative disclosed in WO 92/04333 acts on the cholinergic nervous system and activates the residual nerve cells to ameliorate the learning-and-memory defects. This learning-and-memory improving action is quite different from the action to inhibit the onset of sequelae of a cerebrovascular disease through inhibition of neuronal death.
In addition to the above-mentioned compounds, a variety of pyrimidine derivatives have so far been reported. For example, Japanese Examined Publication S48-21949 discloses that 4-methyl-2-phenyl-6-[2-(4-phenylpiperazin-1-yl)ethyloxy]pyrimidine, among others, has a-sympatholytic activity (sedation, hypotension, and vasodilation). Moreover, it is reported in CA 100: 209733u and CA 106: 18488r that 4-[2-(N,N-dimethyl-amino)ethyloxy]-6-methyl(or phenyl)-2-phenylpyrimidine and 4-[2-(N,N-dimethylamino)ethylthio]-6-methyl(or phenyl)-2-phenylpyrimidine respectively have the property to amplify the action of phleomycin. Furthermore, it is reported in J. Med. Chem. 31(6), 1231-40 (1988) that 2-(2-dimethylamino)ethylthio-4-methyl(or unsubstituted)-6-phenyl(or aromatic heterocyclyl)-pyrimidine derivatives and 2-[2-(N,N-dimethylamino)ethoxy]-4-thienylpyrimidine derivatives amplify the action of bleomycin.
DISCLOSURE OF INVENTION
The present invention has for its object to provide a pharmaceutical composition having a neuronal death inhibitory action and a novel heterocyclic compound which is an active ingredient of said composition.
To accomplish the above-mentioned object, the inventors of the present invention have synthesized and screened a variety of compounds. In the course, they have discovered that a compound of the following general formula [I] has a protetive activity aginst neuronal death, which is quite different from said learning-and-memory disorder improving action, with low toxicity, and have perfected the present invention. The compound of the present invention exhibits an excellent protective activity against neuronal death particularly in the acute phase of a cerebrovascular disorder and is, therefore, useful for the therapy of a cerebrovasuclar disorder and the inhibition of the onset of its sequelae.
The present invention, in one aspect, relates to a pharmaceutical composition comprising a compound of the following general formula or a salt thereof, or a solvate thereof, as an active ingredient.
wherein R
1
represents an aryl group that may be substituted or a 5- through 10-membered heteroaromatic group that may be substituted. The heteroaromatic group mentioned above is a monocyclic or fused ring system containing at least one hetero-atom selected from the group consisting of nitrogen, oxygen, and sulfur as a ring member. Each of said aryl group and heteroaromatic group may be substituted by 1-3 substitutes, whether the same or different, as selected from the group consisting of hydroxy, halogen, alkyl, haloalkyl, hydroxyalkyl, aralkyl, alkenyl, alkoxy, haloalkyloxy, alkylthio, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkylsulfonyl, sulfamoyl, alkanoyl, amino, monoalkylamino, dialkylamino, carboxy, alkoxycarbonyl, cyano, and nitro.
R
2
represents hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, or phenyl that may be substituted. The phenyl mentioned just above may be substituted by 1-3 same or different substitutes selected from the group consisting of halogen, alkyl, and alkoxy.
R
3
and R
4
may be the same or different and each represents hydrogen or alkyl that may be substituted (this alkyl may be substituted by 1 or 2 same or different substitutes selected from the group consisting of hydroxy, alkoxy, amino, monoalkylamino, and dialkylamino), or R
3
and R
4
taken together with the adjacent N atom represent a 4- through 8-membered cyclic amino group of the formula NR
3
R
4
. This cyclic amino group may contain N, O, or S in addition to said N atom as a ring member and may be substituted by 1-3 substitutes, whether the same or different, as selected from the group consisting of alkyl, alkoxy, hydroxy, oxo, amino, monoalkylamino, dialkylamino, aryl that may be substituted, and pyridyl.
The N atom to which R
3
and R
4
are bound may form an oxide.
The symbol A represents alkylene of 2-10 carbon atoms. The alkylene may be substituted by one or more substitutes selected from the group consisting of alkoxy, hydroxy, and oxo in optional substitutable positions.
E represents O or S.
W represents a single bond, O, S, or (CH
2
)
n
(where CH
2
may be substituted by alkyl; n is an integer of 1 or 2).
X, Y, and Z may be the same or different and each represents CH, CR (where R represents alkyl), or N. Excluded, however, is the case

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