&bgr;-amyloid protein production/secretion inhibitors

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...

Reexamination Certificate

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C564S171000

Reexamination Certificate

active

06586475

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel amine derivative having an excellent inhibiting effect for the production and/or secretion of amyloid-&bgr; protein and production thereof.
BACKGROUND ART
Alzheimer's disease is a neurodegenerative disease, which is characterized by the degeneration and loss of neuronal cells accompanied by the formation of senile plaques and neurofibrillary tangles. Senile plaques that are the most characteristic in Alzheimer's disease consist of essentially amyloid-&bgr; protein (hereinafter, sometimes, abbreviated to A&bgr;) [see Biochem. Biophys. Res. Commun., 122, 1311 (1984)] and other intracerebral components. It is known that A&bgr; is composed of 40 or 42 amino acids (hereinafter abbreviated to A&bgr;
1-40
and A&bgr;
1-42
, respectively) and is toxic to neurons and induces neurofibrillary changes.
Some patients with familial Alzheimer's disease are known to have APP (Amyloid Precursor Protein) gene mutation, and it is well known that the cells transfected with such mutated gene produce and secrete an increased amount of A&bgr; [for example, see Nature, 360, 672 (1992); Science, 259, 514 (1993); Science, 264, 1336 (1994), etc.].
Based on this information, medicines which inhibit the production and/or secretion of A&bgr; are useful for preventing and/or treating diseases caused by A&bgr; (e.g., Alzheimer's disease, Down's syndrome, etc).
In particular, for patients who are highly susceptible to the diseases, hereditarily, such as patients with familial Alzheimer's disease, etc., medicines which inhibit production and/or secretion of A&bgr; are especially useful for the prevention of such diseases.
On the other hand, the secreted form of APP is reported to have a neurotrophic factor like property (Neuron, 10, 243-254,1993). Example of neurotrophic factor like properties are given as, 1) survival and preserving effect to the neuronal cell; 2) stimulating the synapse formation; 3) protection of neuronal cell death; and 4) long term potentiation in hippocampus. By the above-mentioned properties, drugs which stimulate the secretion of the secreted form of APP are also useful in preventing and treating 1) neurodegenerative diseases (e.g., Alzheimer's disease, Down's syndrome, senile dementia, Parkinson's disease, Creutzfeldt-Jacob disease, amyotrophic sclerosis on lateral fasciculus, diabetic neuropathy, Huntington's disease, multiple sclerosis, etc.), 2) neurological disorders involved in cerebrovascular disorders (e.g., cerebral infarction, encephalorrhagia, etc.), a head injury or an injury of spinal cord, and so forth.
EP-A-652009 discloses peptide derivatives which are protease inhibitors exhibiting an A&bgr; production inhibiting effect in in vitro experiments using cell lines.
JP-A-2-91052 discloses a cholinesterase inhibitor comprising a substituted amine of the formula:
wherein R
1
and R
2
are independently hydrogen atom or a hydrocarbon group which may be substituted, or they form, together with the adjacent nitrogen atom, a fused heterocyclic group; R
3
and R
4
are such that, when R
3
is hydrogen atom, or a hydrocarbon group or an acyl group each or which may have substituent(s), R
4
is hydrogen atom, or R
3
and R
4
are bound to each other to form —(CH
2
)
m
—CO—, —CO— (CH
2
)
m
— or —(CH
2
)
m+1
— (wherein m is 0, 1 or 2); A is —(CH
2
)
1
—(wherein 1 is 0, 1 or 2) or —CH═CH—; X is one or more substituents and n is an integer of 4 to 7, or a salt thereof.
JP-A-2-73069 discloses a thiazole derivative having monoamine oxidase inhibitory activity.
WO98/38156 discloses a compound having a fused ring skeleton of a benzene ring and a 4- to 8-membered ring and having an inhibitory activity for the production and/or secretion of amyloid-&bgr; protein.
JP-A-5-239005 discloses N—(2-aminoethyl)benzamides useful for the treatment of senile dementia. However, this does not disclose an inhibitory activity of production and/or secretion of amyloid-&bgr; protein.
WO95/17183 discloses a compound having a phospholipase A
2
inhibitory activity and utility for treating senile dementia, etc. However, this does not disclose an inhibitory activity for the production and/or secretion of amyloid-&bgr; protein.
WO98/06691 discloses amine derivatives having an inhibitory activity of aggregation and/or accumulation of amyloid-&bgr; protein and useful for preventing and treating Alzheimer's disease. However, this does not disclose an inhibitory activity for the production and/or secretion of amyloid-&bgr; protein.
WO91/19697 discloses pyridine derivatives having angiotensin II antagonistic activity.
JP-A-3-142277 discloses amine compounds to be used for recording materials.
WO93/23040 discloses 17-ether and thioether of 4-azasteroid having 5&agr;-reductase inhibitory activity.
It is desired to develop a compound which is different from the above known compounds in its chemical structure and which has an excellent inhibitory activity for the A&bgr; production and/or secretion and is therefore satisfactorily used in medicines.
DISCLOSURE OF INVENTION
The present inventors have studied various compounds having an inhibitory activity for the A&bgr; production and/or secretion and, as a result, have found that a compound of the formula:
wherein Ar represents an aromatic group which may be substituted; X and Y are the same or different and each is a bivalent group selected from —O—, —S—, —CO—, —SO—, —SO
2
—, —NR
8
—, —CONR
8
—, SO
2
NR
8
and —COO— (wherein R
8
is hydrogen atom, a hydrocarbon group which may be substituted or acyl), or a bivalent C
1-6
aliphatic hydrocarbon group which may contain one or two above bivalent groups; R
1
and R
2
are hydrogen atom or C
1-6
alkyl which may be substituted, or R
1
and R
2
may form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring which may be substituted; and ring A is a monocyclic aromatic ring which may be further substituted, or a salt thereof has an unexpected excellent inhibitory activity for the production and/or secretion of amyloid-&bgr; protein. On the basis of this finding, the present inventors have further studied and completed the present invention.
That is, the present invention provides:
1. An amyloid-&bgr; protein production and/or secretion inhibitor which comprises a compound of the formula:
wherein Ar is an aromatic group which may be substituted; X and Y are the same or different and each is a bivalent group selected from —O—, —S—, —CO—, —SO—, —SO
2
—, —NR
8
—, —CONR
8
—, SO
2
NR
8
and —COO— (wherein R
8
is hydrogen atom, a hydrocarbon group which may be substituted or acyl), or a bivalent C
1-6
aliphatic hydrocarbon group which may contain one or two above bivalent groups; R
1
and R
2
are hydrogen atom or C
1-6
alkyl which may be substituted, or R
1
and R
2
may form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring which may be substituted; and ring A is a monocyclic aromatic ring which may be further substituted, or a salt thereof;
2. The inhibitor according to the above 1, wherein Ar is:
(1) a monovalent monocyclic aromatic group formed by removing any one of hydrogen atoms from a benzene ring or a 5- or 6-membered aromatic heterocyclic ring having, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom,
(2) an aromatic ring assembly group formed by removing any one of hydrogen atoms from an aromatic ring assembly of 2 or 3 rings of [1] C
6-14
monocyclic or bi- or tricyclic aromatic hydrocarbon aromatic ring or [2] 5- to 14-membered aromatic heterocyclic ring having, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, or rings formed by the aromatic heterocyclic ring fused together with 1 or 2 benzene rings, said rings being bound to each other directly through a single bond, and the number of the bonds which bind the rings directly being smaller than the number of the rings by 1, or
(3) a monov

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