Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-25
2002-02-19
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S236000
Reexamination Certificate
active
06348484
ABSTRACT:
The present invention relates to novel stereoisomeric indole compounds or salts therof, process for the preparation of the compounds and use of the compounds.
PRIOR ART
An indole compound (tartefragin A) of the following formula which is isolated from an extract of seaweed, “Ayanishiki”(Martensia fragilis Harvey) belonging to, Congregatocarpus family is known [Proceedings of Japan Pharmaceutical Society, the 116
th
annual meeting, page 2,215 (1996)].
Further, the above-mentioned indole compound is known to have an anti-oxidative action and to have uses including pharmaceutical ones. However, a synthetic method and stereochemistry of the above-mentioned indole compound was not known.
The inventors of the present invention tried first to synthesize stereoisomers of the above-mentioned compound in order to clarify stereostructure, physiological activities and action mechanisms etc. thereof. As a synthetic route for the stereoisomers of the compound, they noticed a route for synthesizing the following L-tryptophan (2) and a stereoisomeric &agr;-amino acid (3a′) (hereinafter, the stereoisomeric &agr;-amino acid is referred to as homoisoleucine) as intermediates.
(wherein, R, R
1
and R
2
have the meanings shown below, and the symbol ‘*’ represents a position of asymmetric carbon atom.)
Since the stereoisomers of the above-mentioned homoisoleucine are not commercially available compounds, they also established a synthetic route described below for the stereoisomers of the homoisoleucine, and furthermore they succeeded to synthesize a stereoisomeric indole compound (1a′) from the above-mentioned L-tryptophan (2) and a stereoisomeric homoisoleucine (3a′).
Further, from the fact that the synthetic route for the stereoisomeric indole compound (1a′) from the above-mentioned L-tryptophan (2) and the stereoisomeric homoisoleucine (3a′) was established, in the same manner as in the stereoisomeric homoisoleucine, novel indole alkaloids could be synthesized from L-tryptophan and various &agr;-amino acids other than the stereoisomeric homoisoleucine as starting materials for the purpose of searching compounds having stronger physiological activities than those of the above-mentioned compound (1a′), thus many compounds was obtained.
The inventors also have found that a deamino form of the above-mentioned compound (1a′) has higher inhibitory action against lipid peroxidation than any of the four isomers of the above-mentioned Martefragin A, that is (1″S,3″S) form, (1″R,3″S) form, (1″R,3″R) form and (1″S,3″R) form, and also have established synthetic routes thereof.
DISCLOSURE OF THE INVENTION
That is, the present invention relates to stereoisomeric indole compounds of the following formula (1) or salts thereof.
wherein, Y represents the group:
wherein, X represents alkyl group having 1-5 carbon atom(s) (the alkyl group may be optionally substituted with hydroxyl group, carboxyl group, amino group, methylthio group, mercapto group, guanidyl group, imidazolyl group or benzyl group), and R
1
and R
2
represent each independently hydrogen atom, alkyl group, aralkyl group, cycloalkyl group or aryl group, or Y represents the group
R represents hydrogen atom, alkyl group, aralkyl group, cycloalkyl group, aryl group, monovalent metal atom, amine or ammonium; and the symbol ‘*’ represents a position of an asymmetric carbon atom.
Specifically, there may be mentioned the compound of an amino form of the formula (1a):
or salts thereof as well as the compound of a deamino form of the compound of the formula (1a) of the formula (1b) or salts thereof
wherein, R, R
1
, R
2
and X have the same definitions as the formula (1)
In compounds of the above-mentioned formulae (1), (1a) and (1b), specific examples of suitable substituents are as follows.
In addition to the fact that the substituent R represents hydrogen atom, typical substituents R are straight chained or branched alkyl group having 1-12, particularly 1-6, carbon atom(s), such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, tertiary butyl group, pentyl group, hexyl group, octyl group, decyl group and dodecyl group; cycloalkyl group having 5 or 6 ring carbon atoms, such as cyclopentyl group, methylcyclopentyl group, cyclohexyl group and methylcyclohexyl group; aryl group having 6-16 carbon atoms and aralkyl group having 7-16 carbon atoms, such as phenyl group, naphthyl group, benzyl group and phenylethyl group, which may be substituted with halogen atom, hydroxyl group, alkoxy group, amino group and so on. Further, the substituent R may be monovalent metal such as sodium and potassium, amine or ammonium.
Further, suitable substituents R
1
and R
2
are straight chained or branched alkyl group having 1-12, particularly 1-6, carbon atom(s), such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, tertiary butyl group, pentyl group, hexyl group, octyl group, decyl group and dodecyl group; cycloalkyl group having 5 or 6 ring carbon atoms, such as cyclopentyl group, methylcyclopentyl group, cyclohexyl group and methylcyclohexyl group; aryl group having 6-16 carbon atoms and aralkyl group having 7-16 carbon atoms, such as phenyl group, naphthyl group, benzyl group and phenylethyl group, which may be substituted with halogen atom, hydroxyl group, alkoxy group, amino group and so on.
As the salts of the compounds of the formulae (1), (1a) and (1b), there are exemplified salts of inorganic acids and organic acids. However, hydrochloride are particularly preferable.
The indole compounds according to the present invention have one or more asymmetric carbon atom(s), thus form or R form isomers occur depending upon the positions) thereof. For example, in the case of an amino form of the compound (1a′),
it has asymmetric carbon atoms at positions 1″ and 3″. Therefore, the compounds according to the invention have four isomers respectively for their asymmetric carbon atoms, i.e., (1″S,3″S) form, (1″R,3″S) form, (1″R,3″R) form, (1″S,3″R) form. Further, a deamino form (1b)
of the indole compound according to the invention has an asymmetric carbon atom at position 3″. Therefore, the compounds according to the invention have two isomers respectively for their asymmetric carbon atoms, i.e., S form and R form.
The present invention includes all these isomers and mixtures of the isomers.
In the following illustration, the indole compound of the above-mentioned formula (1b) is also referred to as “deaminomartefragin”.
The present invention also relates to a process for preparing the stereoisomeric indole compounds of the following formula (1)
by condensing tryptophan of the following formula (2)
with an acid of the following formula (3)
to obtain a compound of the following formula (4),
and subjecting the compound of the formula (4) to cyclization,
wherein, Y represents the group
wherein, X represents alkyl group having 1-5 carbon atom(s) (the alkyl group may be substituted with hydroxyl group, carboxyl group, amino group, methylthio group, mercapto group, guanidyl group, imidazolyl group or benzyl group), and R
1
and R
2
represent each independently hydrogen atom, alkyl group, aralkyl group, cycloalkyl group or aryl group, or Y represents the group
R represents hydrogen atom, alkyl group, aralkyl group, cycloalkyl group, aryl group, monovalent metal atom, amine or ammonium; and the symbol ‘*’ represents a position of an asymmetric carbon atom.
According to this method, the amino form of the stereoisomeric indole compound of the above-mentioned formula (1a) can be prepared by condensing tryptophan of the above-mentioned formula (2) with an acid of the formula (3a)
to obtain a compound of the following formula (4a),
and subjecting the compound of the formula (4a) to cyclization, and the deamino form of the stereoisomeric indole compound of the above-mentioned formula (1b) can be prepared by condensing tryptophan of the above-mentioned
Fuwa Mihoko
Hasegawa Chika
Matsunaga Takayuki
Mori Masao
Nakagawa Masako
Lead Chemical Co., Ltd.
Oliff & Berridg,e PLC
Stockton Laura L.
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