Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-07
2002-05-21
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S298000, C549S299000, C549S458000, C514S458000, C514S473000
Reexamination Certificate
active
06392059
ABSTRACT:
BACKGROUND TECHNOLOGIES
Himbacine is a piperidine alkaloid, which was isolated from Galbulimima baccata being one species of pinaceous plant and the structure of which was determined in 1956, and, as the structural characteristics thereof, three points of condensation of 5-membered lactone ring to thermodynamically stable transdecalin ring in cis configuration, eight asymmetric centers including four internuclear hydrogens, and further binding of 3-cyclic portion with piperidine ring via trans double bond can be mentioned.
In recent years, the senile dementia represented by Alzheimer type dementia has posed a significant problem socially and a substantial therapeutic drug therefore is desired earnestly. As one of approaches, from a phenomenon of decreased function of central cholinergic nerve in demential patients, development of therapeutic drugs based on so-called “choline hypothesis” is being advanced actively. Roughly classifying them, it is possible to divide into four below. Namely, they are (1) inhibitor of taking-in of choline, (2) inhibitor of acetylcholinesterase, (3) activator for synthesizing choline acetyltransferase and (4) compound acting on muscarine receptor (muscarine M
1
against or M
2
receptor antagonist). It has become clear recently that the himbacine exhibits potent and selective antagonistic action on M
2
receptor that is considered to suppress the release of nerve terminal acetylcholine, hence the potential as an antidemential drug has been found.
As described, the himbacine is a globally noteworthy compound from two points of potent activity and interesting chemical structure and, in recent years, its syntheses are reported by some groups. Thereamong, overall syntheses having intramolecular Diels-Alder reaction as a key reaction in all cases have been accomplished by groups of Kozikowski et al and Chackalamannil et al (Kozikowski, A. P. et al, J. Am. Chem. Soc., 1995, 117, 9369. Chackalamannil, S. et al, J. Am. Chem. Soc., 1996, 118, 9812). With these processes using intramolecular Diels-Alder reaction, however, there are problems of not only necessity for passing through troublesome processes in the synthesis of its skeleton, but also difficult synthesis of affinous compounds that become important for aiming at improved activity and decreased side effect. While, if using intermolecular Diels-Alder reaction, required constitutional units can be synthesized separately and each can be combined arbitrarily to react, thereby leading to easy synthesis of affinous compounds. However, its is the status quo that the synthesis of himbacine having such intermolecular Diels-Alder reaction as a key reaction has not yet been accomplished.
DISCLOSURE OF THE INVENTION
As a result of diligent studies in view of the subjects aforementioned, the inventors have found that the following inventive compounds are useful as the intermediates in the preparation of himbacine using the intermolecular Diels-Alder reaction as a key reaction, leading to the completion of the invention.
Namely, the invention provides hydronaphtho[2,3-c]furan derivatives represented by a following general formula (1)
(wherein R
1
denotes a lower alkyl group or substituted or unsubstituted aralkyl group, R
2
denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group, R
3
and R
4
unitedly denote an oxygen atom or methylene group, or R
3
denotes a hydrogen atom and R
4
denotes a hydroxyl group, lower alkoxy group, substituted or unsubstituted aralkyloxy group or lower acyloxy group, R
5
and R
6
unitedly denote an oxygen atom, or R
5
denotes a hydrogen atom and R
6
denotes a hydroxyl group, lower alkoxy group, substituted or unsubstituted aralkyloxy group or lower acyloxy group, and, in the case of broken lines accompanied, one denotes single bond and the other denotes double bond, or both denote single bonds), hydronaphtho[2,3-c]furan derivatives represented by a following general formula (1-1)
(wherein R
1
denotes a lower alkyl group or substituted or unsubstituted aralkyl group, R
2
denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group, R
3
and R
4
unitedly denote an oxygen atom or methylene group, or R
3
denotes a hydrogen atom and R
4
denotes a hydroxyl group, lower alkoxy group, substituted or unsubstituted aralkyloxy group or lower acyloxy group, and in the case of broken lines accompanied, one denotes single bond and the other denotes double bond, or both denote single bonds), hydronaphtho[2,3-c]furan derivatives represented by a following general formula (1-2)
(wherein R
1
denotes a lower alkyl group or substituted or unsubstituted aralkyl group, R
2
denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group, R
3
and R
4
unitedly denote an oxygen atom or methylene group, or R
3
denotes a hydrogen atom and R
4
denotes a hydroxyl group, lower alkoxy group, substituted or unsubstituted aralkyloxy group or lower acyloxy group, and R
7
denotes a hydrogen atom, lower alkyl group, substituted or unsubstituted daralkyl group or lower acyl group), hydronaphtho[2,3-c]furan derivatives represented by a following general formula (2)
(wherein R
1
denotes a lower alkyl group or substituted or unsubstituted aralkyl group, R
2
denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group, R
7
denotes a hydrogen atom, lower alkyl group, substituted or unsubstituted aralkyl group or lower acyl group), and R
8
denotes a hydrogen atom or protective group of hydroxyl group), and hydronaphtho[2,3-c]furan derivatives represented by a following general formula (3)
(wherein R
1
denotes a lower alkyl group or substituted or unsubstituted aralkyl group, R
2
denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group, and, in the case of broken line accompanied, it denotes single bond or double bond), and a process for preparing compounds represented by a following general formula (3a)
(wherein R
1
denotes a lower alkyl group or substituted or unsubstituted aralkyl group, and R
2
denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group), characterized by reacting compounds represented by a following general formula (4)
(wherein R
1
denotes a lower alkyl group or substituted or unsubstituted aralkyl group), with compounds represented by a following general formula (5)
(wherein R
2
denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group).
In the invention, for “lower alkyls”, straight chain or branched ones with carbon atoms of 1 to 6 such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl and 2-methylpropyl are mentioned and it doesn't matter whether saturated or unsaturated. For “aralkyl groups”, benzyl group, 1-phenylethyl group, etc. are mentioned and, as substituents, lower alkyl group, lower alkoxy group, halogen atom, cyano group, nitro group, etc. are mentioned. For “lower alkoxy group”, straight chain or branched ones with carbon atoms of 1 to 6 such as methoxy, ethoxy, 1-methylethoxy, 1,1-dimethylethoxy, propoxy and 2-methylpropoxy are mentioned and it doesn't matter whether saturated or unsaturated. For “aralkyloxy groups”, benzyloxy group, 1-phenylethoxy group, etc. are mentioned and, as substituents, lower alkyl group, lower alkoxy group, halogen atom, cyano group, nitro group, etc. are mentioned. For “lower acyl groups”, ones with carbon atoms of 1 to 6 such as formyl group, acetyl group, propionyl group and 2,2-dimethylpropionyl group are mentioned, and, for “lower acyloxy groups”, ones with carbon atoms of 1 to 6 such as formyloxy group, acetoxy group, propionyloxy group and 2,2-dimethylpropionyl group are mentioned. Moreover, for the protective groups of hydroxyl group, trialkylsilyl groups such as trimethylsilyl group and t-butyldimethylsilyl group, arylmethyl groups such as benzyl group and diphenylmethyl group, acyl groups such as acetyl group and propionyl group, lower alkoxymeth
Ishiwata Akihiro
Katoh Tadashi
Takadoi Masanori
Terashima Shiro
Higel Floyd D.
Saeed Kamal
Sagami Chemical Reasearch Center
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