Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ketone doai
Reexamination Certificate
2000-02-14
2001-05-08
Vollano, Jean F. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ketone doai
C568S377000, C568S378000
Reexamination Certificate
active
06228893
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a cyclohexenone long-chain alcohol having excellent neurite growth stimulating effects which is useful as preventive and/or therapeutic for cerebral diseases typified by dementia, and also as a medicament containing the same.
BACKGROUND ART OF THE INVENTION
Nerve growth factors (which will hereinafter be abbreviated as “NGF”s), many of which exist primarily in the hippocampus and cerebral cortex, are neurotrophic factors which stimulate differentiation or growth of neurocytes and are therefore essential for maintenance of function and survival. They act on catecholamine activating neurons in the peripheral nervous system, as well as on cholinergic neurons in the brain. Alzheimer's disease is thought to have, as its main lesion, degeneration and defluxion of cholinergic neurons. Therefore there has been an attempt to administer NGFs into the brain for the treatment of Alzheimer's disease. NGFs, however, cannot pass through the blood-brain barrier because they are proteins having molecular weights as high as 12,000. Therefore such treatment has not proven practical as a therepeutic method for humans. If there existed a low-molecular-weight compound which exhibited NGF-like effects and could pass through the blood-brain barrier or a compound capable of enhancing NGF synthesis in the brain, such a compound would likely be therapeutically useful for treating Alzheimer's disease. Based on this idea, substances exhibiting NGF-like effects have been sought. As a result, it has been shown that long-chain alcohols such as n-hexacosanol induce in vitro production of NGFs in gliacytes, thereby promoting neurite growth. In addition they can pass through the blood-brain barrier in vivo (Japanese Patent Application Laid-Open No. HEI 4-502167).
Effects of n-hexacosanol, however, have not been satisfactory yet.
An object of the present invention is therefore to provide a medicament comprising a compound which can be orally administered, which readily transfers into the brain, and which permits neurite growth in the brain even at low concentrations compared with those of the above-described long-chain alcohols such as n-hexacosanol.
DISCLOSURE OF THE PRESENT INVENTION
Focusing on the skeletal structure of cyclohexenone, the present inventors synthesized a number of cyclohexane derivatives. As a result, it has been found that a cyclohexenone long-chain alcohol represented by the below-described formula (1) is useful as a medicament for the prevention and treatment of cerebral diseases such as dementia because it has excellent neurite growth promoting effects even at lower concentrations compared with those of n-hexacosanol and has the effect of acting directly on the neurite, thereby stimulating neurite growth without inducing NGF production in gliacytes, leading to the completion of the present invention.
In one aspect of the present invention, there is thus provided a cyclohexenone long-chain alcohol represented by the following formula (1):
wherein R
1
, R
2
and R
3
each independently represents a hydrogen atom or a methyl group and X represents a C
10-18
alkylene or alkenylene group.
In another aspect of the present invention, there is also provided a medicament comprising as an effective ingredient the compound represented by the formula (1).
In a further aspect of the present invention, there is also provided a neurite growth stimulating agent comprising the compound represented by the formula (1) as an effective ingredient.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising the compound represented by the formula (1) and a pharmaceutically acceptable carrier.
In a further aspect of the present invention, there is provided use of the compound represented by the formula (1) as a medicament.
In a further aspect of the present invention, there is provided a method for the treatment of dementia comprising administering to a patient an effective amount of the compound represented by the formula (1).
BEST MODES FOR CARRYING OUT THE INVENTION
In the formula (1), among the C
10-18
alkylene and alkenylene groups represented by X, preferred are C
10-18
alkylene groups, with C
10-16
alkylene groups being more preferred. For the alkylene or alkenylene group, either linear or branched one can be employed, with the linear one being more preferred. R
1
, R
2
and R
3
each independently represents a hydrogen atom or a methyl group, with the case where at least one of them represents a methyl group being more preferred.
The compound of the present invention may exist in the form of a hydrate. The compound of the present invention has various isomers and these isomers are also embraced by the present invention.
The compound (1) of the present invention can be prepared, for example, in accordance with the following reaction processes A or B.
[Process A]
wherein R
1a
, R
2a
and R
3a
each independently represents a hydrogen atom or a methyl group, with the proviso that at least one of them represents a methyl group, Ph represents a phenyl group and R1, R2 and R3 have the same meanings as defined above.
Described specifically, the invention compound (1) can be obtained by reacting cyclohexenone (2) or methyl-substituted-2-cyclohexen-1-one (3) with a benzenesulfinic acid salt in the presence of an acid to obtain Compound (4), reacting the resulting Compound (4) with ethylene glycol to obtain its ketal derivative (5), reacting the resulting derivative (5) with a &ohgr;-halogenoalkanol or &ohgr;-halogenoalkenol to obtain Compound (6), followed by subjecting Compound (6) to an acid treatment to eliminate the protective group.
The methyl-substituted-2-cyclohexen-1-one (3) used here as a raw material is available by reacting methyl-substituted cyclohexanone with a trialkylsilyl halide in the presence of butyl lithium, followed by oxidation in the presence of a palladium catalyst.
In the above reaction, the reaction between cyclohexanone (2) or methyl-substituted-2-cyclohexen-1-one (3) and a benzenesulfinic acid salt, for example, benzenesulfinic acid sodium is preferably effected in the presence of an acid such as hydrochloric acid, sulfuric acid or phosphoric acid at 0 to 100° C. for 5 to 40 hours.
The reaction between Compound (4) and ethylene glycol is preferably carried out in the presence of a condensing agent such as paratoluenesulfonic anhydride at 50 to 120° C. for 1 to 10 hours.
As a &ohgr;-halogenoalkanol to be reacted with the ketal derivative (5), a &ohgr;-bromoalkanol is preferred. It is desirable that the reaction between the ketal derivative (5) and a &ohgr;-bromoalkanol be carried out in the presence of a metal compound such as butyl lithium under low-temperature conditions.
The elimination of the phenylsulfonyl and ketal-protective groups from Compound (6) is preferably effected by reacting Compound (6) with an acid such as paratoluenesulfonic acid.
[Process B]
wherein X1 represents C
9-17
alkylene group or C
9-17
alkenylene group, Ac represents an acyl group, R
1
, R
2
, R
3
and Ph have the same meanings as defined above.
Described specifically, compound (7) (obtained, for instance, through the method described in
Synthesis,
1996, November) is reacted with &ohgr;-bromoalcohol to obtain compound (9), subsequently the phenylsulphonyl group of the resulting compound being eliminated to give compound (10), followed by protection of the hydroxy group of compound (10) to yield compound (11). The resulting compound is subsequently oxidized to obtain compound (12), and the hydroxy-protective group of the resulting compound is then eliminated to obtain compound (12).
The reaction between compound (7) and compound (8) is preferably carried out at low temperatures in the presence of a metal compound such as butyl lithium.
The elimination of the phenylsulphonyl group from compound (9) may be conducted by reacting the compound and a phosphate in the presence of sodium amalgam.
As a hydroxy-protective group of compound (10), the acetyl group is preferred, the pro
Junges-Girlanda Celine
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Vollano Jean F.
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