Note: Descriptions are shown in the official language in which they were submitted.
~24~LQ09
-- 1 --
BACKGROUND OF THE INVENTION
-
Field of the Invention
This invention relates to novel chroman compounds,
and to uses of these compounds as antioxidants or
analgesics or precursors for the compounds having
antioxidant activity and/or analgesic activity.
Description of the Prior Art
Recently, vitamin E has become a focus of attention
as a hiqhly safe antioxidant. However, it is relatively
expensive and moreover liable ~o be oxidized and
discolor, and therefore it has not been commonly employed
as an antioxidant yet.
And it is known that compounds having a chroman
skeleton such as 2-(N,N-dimethylamino)ethyl 2-(2,2,5,7,8-
pentamethyl-6-chromanyloxy)isobutyrate, 2-(2,2,5,7,8-
pentamethyl-6-chromanyloxy)isobutyl nicotinate, etc.
have cholesterol lowering activity lJapanese Laid-Open
Patent Publication No. 94382/1980].
An object of the invention is to provide novel
chroman compounds which are either superior in antioxidant
activity to vitamin E or useful as precursors of such
antioxidant-active compounds.
Another object of the invention is to provide novel
chroman compounds which are either analgesic-active or
useful as precursors for such analgesic-active compounds.
A further object of the invention is to provide
uses of the antioxidant-active chroman compounds as
an antioxidant.
A further object of the invention is to provide
uses of the analgesic-active chroman compounds as
an analgesic.
.~ ~
~.
12~10~
These objects as well as other objects and
advantages of the invention will become apparent to
those skilled in the art from the following detailed
description.
SUMMARY OF THE INVENTION
In accordance with this invention, there are
provided a compound of general formula (I)
R
R~ ( CH 2 ) n CH -R __ - ( I)
wherein A is an amino or hydroxyl group, R is a hydrogen
atom or a hydroxymethyl or carboxyl group when A is an
amino group, or a carboxyl group when A is a hydroxyl
group, Rl is a hydrogen atom or a lower alkyl group,
R2 and R3 are the same or different and each is
a hydrogen atom or a lower alkyl or alkoxy group or
R and R3 combinedly represent a -CH=CH-CH=CH- group,
R4 is a hydrogen atom or a protective group and n is
an integer of 0-2, inclusive of the ester and/or salt
form thereof [hereinafter collectively referred to as
"chroman compounds (I)"].
And in accordance with this invention, there are
provided uses of a compound of general formula (I-l)
Rl
R ~ (CH2)n CH-COOH --- (I-l)
wherein A, Rl, R2, R3 and n are as defined above relative
to general formula (I), inclusive of the ester and/or
salt form thereof lhereinafter collectively referred to
as "chroman compounds (I-l)] as an antioxidant.
:~!241 0Q~
-- 3 --
Further in accordance with this invention,
there is also provided a pharmaceutical composition
for analgesic, said composition being composed of (l)
an amount, effective for analgesic, of a compound of
general formula (1-2)
Rl
H ~ CH3 NH2
~2 ~ ~ ( CH2)n CH-R ~ 2)
wherein R, Rl, R2, R3 and n are as defined above relative
to general formula (I), inclusive of the pharmaceutically
acceptable ester and/or salt form thereof [hereinafter
collectively referred to as "chroman compounds (1-2)1,
and (2) a pharmaceutically acceptable diluent or carrier.
DÉTAILED DESCRIPTION OF THE INVENTION
. . . _ .. .
Referring to the above general formula (I), A is
an amino or hydroxyl group. R is a hydrogen atom or
a hydroxymethyl or carboxyl group when A is an amino
group, or a carboxyl group when A is a hydroxyl group.
Rl is a hydrogen atom or a lower alkyl group such as
methyl, ethyl, propyl, butyl, etc. R2 and R3 are the
same or different and each is a hydrogen atom, a lower
alkyl group such as methyl, ethyl, propyl, butyl, etc., or
a lower alkoxy group such as methoxy, ethoxy, propoxy,
butoxy, etc., or R2 and R3 combinedly form a -CH=CH-CH=CH-
group. R4 is a hydrogen atom or a protective group.
Said protective group may be any of conventional
protective groups if only protection of hydroxyl group
can be attained, and may be exemplified by acyl groups
te.g. acetyl, propionyl, butyryl, benzoyl, etc.), methyl,
tert-butyl, triphenylmethyl, benzyl, trimethylsilyl and
so on. n is an integer of 0-2.
~.24100~
-- 4 --
The compound of general formula (I) may be grouped,
according to the substituents A and R, into the
following four classes:
R~ O~(CH2)n CHCO 2H ___ ( I-a)
r' 0~ ( CH2)n CHCH20H --- (I-b)
R2 ~ (CH2)ncH2 --- (I-c)
R40~<(CH2)n CHCC)2H --- (I-d)
The esters and salts of the ~-amino acid of general
formula (I-a) include such ester form as an alkyl ester,
e.g. methyl ester, ethyl ester, propyl ester, butyl ester,
octyl ester, tetradecyl ester, stearyl ester, etc.; and
such salt form as an alkali metal salt, e.g. lithium
salt, sodium salt, potassium salt, etc., or a mineral
acid salt, e.g. hydrochloride, sulfate, nitrate, etc. or
an organic sulfonic acid salt, e.g. p-toluenesulfonate,
methanesulfonate, etc. The esters and salts of the
~-hydroxycarboxylic acid of general formula (I-d) include
~10~
-- 5 --
such ester form as an alkyl ester, e.g. methyl ester,
ethyl ester, propyl ester, butyl ester, octyl ester,
tetradecyl ester, stearyl ester, etc.; and such salt
form as an alkali metal salt, e.g. lithium salt, sodium
salt, potassium salt, etc., or an alkaline earth metal
salt, e.g. magnesium salt, calcium salt, etc., or
an optionally lower alkyl-substituted ammonium salt, e.g.
ammonium salt, methylammonium salt, ethylammonium salt,
trimethylammonium salt, tetra~ethylammonium salt,
tetraethylammonium salt, etc.
The ~-amino acid of general formula (I-a) can be
produced by reacting an aldehyde of general formula
RsO ~ (CH2)ncHO (II)
wherein Rl, R2, R3 and n each have the same meanings
as in general formula (I), and R5 is the same as or
different from R in general formula (I) and represents
a hydrogen atom or a protective group, with
ammonium carbonate and an alkali metal cyanide and then
hydrolyzing the thus-obtained hydantoin of general
formula
o
Rl _C~
R5 0 ~, HN NH
R2 ~~ ( CH 2)n C~IC ~o ( III)
wherein Rl, R2, R3, R5 and n each have the same meanings
as in general formula (II). Said alkali metal cyanide
is, for example, sodium cyanide, potassium cyanide,
lithium cyanide, etc. The reaction of the aldehyde of
1~4~Q~
-- 6 --
general formula (II) with ammonium carbonate and
the alkali metal cyanide can be carried out under
conditions which are generally known to be adequate
for hydantoin syntheses. Thus, for instance, the
aldehyde of general formula (II), about 1-10 moles,
preferably about 1-3 moles, per mole of aldehyde, of
ammonium carbonate and about 1-10 moles, preferably
about 1-3 moles, per mole of aldehyde, of the alkali
metal cyanide are reacted in a solvent such as water,
methanol, ethanol, tetrahydrofuran, etc. at a temperature
between room temperature and 100C, preferably in the
range of 40-60C. The reaction mixture is then
concentrated, a small amount of concentrated hydrochloric
acid is added to the concentrate, and the mixture is
heated at about 80-100C for about 1-10 minutes, whereby
the hydantoin of g~neral formula (III) is obtained.
Hydrolysis of the thus-obtained hydantoin by the
conventional method gives the -amino acid of general
formula tI-a)~ The hydrolysis is carried out, for
example, by reacting the hydantoin and about 1-5 moles,
per mole of hydantoin, of an alkali metal hydroxide
such as sodium hydroxide, potassium hydroxide, etc.
in an aqueous medium at a temperature of 80-150C,
preferably 100-130C, followed by neutralization of
the alkali being in the system with a mineral acid
such as hydrochloric acid, sulfuric acid, etc.
When subjected to the generally known
esterification and/or salt formation reaction,
the a-amino acid of general formula (I-a) is converted
to an ester or salt of said a-amino acid or a salt of
said -amino acid ester. Thus, for example, reacting
the -amino acid of general formula (I-a) with an alkyl
alcohol such as methyl alcohol, ethyl alcohol, propyl
alcohol, butyl alcohol, octyl alcohol, stearyl alcohol,
etc. in the presence of hydrogen chloride, sulfuric acid,
thionyl chloride or the like in an amount at least
~10~
-- 7 --
equivalent to said ~-amino acid at about -20C to +40C,
followed by neutralization of the reaction mixture,
for example, with an aqueous sodium bicarbonate, etc.
gives the corresponding -amino acid ester. The ~-amino
acid of general formula (I-a) or an ester thereof is
converted to the corresponding salt by dissolving said
~-amino acid or ester thereof in water, methy} alcohol,
ethyl alcohol, propyl alcohol, tetrahydrofuran, diethyl
ether or the like and then adding to the solution
an approximately equivalent amount, to the ~-amino acid
or ester thereof, of a mineral acid such as hydrogen
chloride, sulfuric acid, nitric acid, etc., or an organic
sulfonic acid such as p-toluenesulfonic acid,
methanesulfonic acid, etc., or an alkali metal hydroxide
such as lithium hydroxide, sodium hydroxide, potassium
hydroxidej etc.
The ~-amino acid of general formula (I-a) or an ester
thereof, inclusive of salt form, produced in the above
manner can be separated and recovered by any of the
methods generally known for the separation and recovery
of amino acids and esters thereof, and salts thereof.
The ~-hydroxycarboxylic acid of general formula
(I-d) can be produced by reacting the aldehyde of general
formula (II) with a cyanide and then hydrolyzing the
resulting ~-hydroxynitrile of general formula
Rl
R5O ~ CH3 1 (IV)
R2~0 ( CH 2)nC~ICN
R3
wherein Rl, R2, R3, R and n each have the same meanings
as in general formula (II). Said cyanide includes
hydrogen cyanide; an alkali metal cyanide such as sodium
cyanide, potassium cyanide, etc.; an organic aluminum
cyanide such as dimethylaluminum cyanide,
0~
-- 8 --
diethylaluminum cyanide, etc.; and an organic silicon
cyanide such as trimethylsilyl cyanide,
dimethyl-tert-butylsilyl cyanide, etc. The reaction of
the aldehyde of general formula (II) with such cyanide
can be carried out under conditions which are generally
known for cyanohydrin formation. The following are
typical examples of the cyanohydrin formation reaction:
Reaction Example a] Reaction of aldehyde with
hydrogen cyanide
The aldehyde of general formula (II) is reacted
with about 1-10 moles, preferably about 1-3 moles, per
mole of aldehyde, of hydrogen cyanide, preferably
in the presence of a catalytically small amount of
an alkali metal cyanide such as sodium cyanide, potassium
cyanide, etc. in the presence or absence of an inert
solvent such as diethyl ether, methanol, ethanol, benzene,
toluene, dichloroethane, chloroform, etc. with cooling or
under pressure, whereby the ~-hydroxynitrile of general
formula (IV) is produced.
[Reaction Example b] Reaction of aldehyde with alkali
metal cyanide
The aldehyde of general formula (II) is first
reacted with about 1-2 moles, per mole of aldehyde, of
an alkali metal bisulfite such as sodium bisulfite,
potassium bisulfite, etc., for instance, in a mixed
solvent composed of water and ethanol at about 0-50C
to give an aldehyde-alkali metal bisulfite adduct.
The adduct in the reaction mixture is then reacted with
about 1-2 moles, per mole of aldehyde, of an alkali metal
cyanide at about 0-5C to give the ~-hydroxynitrile of
general formula (IV).
[Reaction Example c] Reaction of aldehyde with organic
aluminum cyanide or organic
silicon cyanide
The aldehyde of general formula (II) is reacted
~24~0~9
g
with about 1-3 moles, preferably about 1-2 moles, per
mole of aldehyde, of an organic aluminum cyanide or
an organic silicon cyanide in an inert solvent such as
methylene chloride, dichloroethane, carbon tetrachloride,
tetrahydrofuran, benzene, toluene, etc. at about -50C
to 50C, preferably about -20C to room temperature
to give the ~-hydroxynitrile of general formula ~IV).
The a-hydroxycarboxylic acid of general formula
(I-d) can be produced by hydrolyzing, by the
conventional method, the ~-hydroxynitrile of general
formula (IV) as obtained by the above cyanohydrin
formation reaction. The hydrolysis can be performed,
for example, at room temperature or under heating,
in the presence of a mineral acid such as hydrochloric
acid, sulfuric acid, etc. or an alkali metal hydroxide
such as sodium hydroxide, potass~um hydroxide, etc.,
if necessary in the presence of a high-boiling alcohol
such as glycerol, ethylene glycol, methylcellosolve, etc.
The ~-hydroxycarboxylic acid of general formula
(I-d), when subjected to per se known general
esterification or salt formation reaction, gives
an ester or salt thereof. Thus, for instance, reacting
the ~-hydroxycarboxylic acid of general formula (I-d)
with an equimolar amount to large excess of an alkyl
alcohol such as methyl alcohol, ethyl alcohol, butyl
alcohol, octyl alcohol, stearyl alcohol, etc. in the
presence of an acid catalyst such as p-toluenesulfonic
acid, sulfuric acid, strongly acidic ion exchange resin,
etc. in the presence or absence of an inert solvent
such as benzene, toluene, dichloroethane, etc. at a
temperature of room temperature to the refluxing
temperature, preferably while removing the by-product
water out of the system, whereby the corresponding
~-hydroxycarboxylic acid ester is obtained. When the
~-hydroxycarboxylic acid of general formula (I-d) is
reacted with an equimolar amount of an alkali metal
-- 10 --
hydroxide such as potassium hydroxide, sodium hydroxide,
etc. or ammonia or an amine such as methylamine,
dimethylamine, trimethylamine, triethylamine,
tetramethylammonium hydroxide, etc. in the presence of
water and/or a lower alcohol such as methyl alcohol,
ethyl alcohol, propyl alcohol, etc., the corresponding
salt of said ~-hydroxycarboxylic acid is obtained. The
thus-obtained alkali metal salt of the ~-hydroxycarboxylic
~acid is reacted with an alkaline earth metal halide
such as calcium chloride, magnesium chloride, magnesium
bromide, etc. in the presence of water and/or a lower
alcohol such as methyl alcohol, ethyl alcohol, etc.,
whereby the corresponding alkaline earth metal salt of
the ~-hydroxycarboxylic acid is produced.
The ~-hydroxycarboxylic acid of general formula (I-d)
and an ester thereof as obtained by the above method
can be separated and recovered by the conventional method.
Thus, for example, water is added to the reaction mixture,
followed as necessary by addition of an acid such as
hydrochloric acid, sulfuric acid, etc. so as to make the
mixture weakly acidic, and then the whole mixture is
extracted with diethyl ether or the like. The extract is
washed with water and then dried, the solvent is distilled
off, and the residue is purified by recrystallization or
column chromatography to give the ~-hydroxycarboxylic acid
of general formula (I-d) or an ester thereof. For
separation and recovery of the salt of ~-hydroxycarboxylic
acid of general formula (I-d) from the reaction mixture,
said reaction mixture is concentrated to dryness in the
conventional manner.
When in the salt form, the ~-amino acid of general
formula (I-a) and an ester thereof as well as the
~-hydroxycarboxylic acid of general formula (I-d) are
fairly soluble, so that separation of the salts from
~2~ 3
(
fat-soluble impurities from the reaction process can be
done with ease. The salts deprived of fat-soluble
impurities can be converted to highly pure -amino acids
or ~-hydroxycarboxylic acids by the conventional
neutralization with an acid such as hydrochloric acid,
sulfuric acid, etc. These ~-amino acids or
~-hydroxycarboxylic acids can further be converted to
highly pure esters of said a-amino acids or
~-hydroxycarboxylic acids by subjecting the acids to the
conventional esterification.
The amino alcohol of general formula (I-b) can be
produced by reducing the ~-amino acid of general formula
(I-a), for example, with about 1-3 moles, per mole of
~-amino acid, of lithium aluminium hydride in a solvent
such as tetrahydrofuran, etc. under refluxing. The amino
alcohol of general formula (I-b), when subjected to per
se known general esterification and/or salt formation
reaction, gives an ester or salt of said amino alcohol,
or a salt of the ester. The amino alcohol of general
formula (I-b) and an ester thereof and their salts as
thus obtained can be separated and recovered by the
conventional method.
The amine of general formula (I-c) can be produced
by reacting the aldehyde of general formula (II) with
about 1-2 moles, per mole of aldehyde, of hydroxylamine
in an aqueous alcohol such as methyl alcohol, ethyl
alcohol, etc. at a temperature of 0C to room temperature
and then reducing the thus-obtained oxime of general
formula
R
R$~(CH2)n CH=NOH (
1 2 3 5
wherein R , R , R , R and n each have the same meanings
LQ~S~`~
-- 12 --
as in general formula (II), for example, with about
0.75-2 moles, per mole of oxime, of lithium aluminium
hydride in a solvent such as tetrahydrofuran, etc.
under refluxing. The amine of general formula (I-c),
when subjected to per se known general salt formation
reaction, gives a salt of said amine. The thus-obtained
amine and a salt thereof can be separated and recovered
by the conventional method.
The starting aldehydes of general formula (II) can
be prepared easily by oxidizing alcohols of general
formula (V) given below, which are known compounds,
for example, with chromic anhydride in the presence of
pyridine lcf. Helvetica Chimica Acta, 61, 837-843 (1978)3.
Rl
.2 ~ ( CH 2 ) n C~I 2 OH
R3 Rl
( V) CrO3 . pyridine ~ CH3
-- ~ R2~0 (CH2 ) nC~IO
R3
(n)
Among the chroman compounds (I), the chroman
compounds (I-l) have potent antioxidant activity. The
compounds in which R is a carboxyl group and R4 is
a protective group in general formula (I) can be converted
to the above-mentioned antioxidant-active chroman compounds
(I-l) by replacing the protective group with a hydrogen
atom by the conventional method.
The chroman compounds (I-l) are used as antioxidants
for organic materials sensitive to oxidative factors,
such as oils and fats, waxes, pharmaceutical preparations,
cosmetics and toiletries, rubber products, synthetic
12~ {~3
- 13 -
.
resins, processed foodstuffs, etc. by incorporating
the same chroman compounds to said organic materials.
These antioxidants are preferably incorporated into
such organic materials as the oils and fats and foodstuffs
containing unsaturated fatty acids (e.g. oleic acid,
linoleic acid, linolenic acid, arachidonic acid, etc.)
or esters thereof: and synthetic resins including
polyolefins such as polyethylene, polypropylene,
ethylene-propylene copolymer, etc.; diene polymers such
as polybutadiene, polyisoprene, ethylene-propylene-
diene terpolymer, etc.; styrenic resins such as
polystyrene, styrene-butadiene copolymer, styrene-
acrylonitrile copolymer, methacrylate-styrene-
acrylonitrile copolymerj ABS resin, etc.; halogen-
containing resins such as polyvinyl chloride, poly-
vinylidene chloride, vinyl chloride-vinylidene chloride
copolymer, polychloroprene, chlorinated polyethylene,
etc.: polymers of ~,B-unsaturated acids or derivatives
thereof such as polyacrylates, polyacrylamide, poly-
acrylonitrile, etc.; polymers of unsaturated alcohols
or acyl derivatives thereof such as polyvinyl alcohol,
polyvinyl acetate, styrene-vinyl acetate copolymer,
etc.; polyurethane; aliphatic or aromatic polyamides;
polyimides, poly(amide-imide~; polyacetal; poly-
carbonate; saturated or unsaturated polyesters; epoxy
resins: phenolic resins; polyphenylene oxide; urea
resin; melamine resin; etc. Among the chroman compounds
(I-l), the salts are suitably used as antioxidants
particularly for processed foodstuffs, taking advantage
of their being water-soluble. While the amount of the
antioxidant should vary with the required degree of
stabilization effect sought in the organic material,
it can be selected from the range of about 0.001 to 20
weight percent relative to the organic material. For
the stabilization of a synthetic resin, the antioxidant
00~
- 14 -
can be used advantageously in an amount of from about
0.001 to 5 weight percent based on the resin and when
the organic material is a highly sensitive material
such as a vitamin, the amount of the antioxidant may be
increased to about 20 weight percent.
the chroman compounds (I-l) are used either alone
or in combination with one or more other antioxidants,
particularly phenolic antioxidants such as pentaerythritol
tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate],
octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate,
etc. These phenolic and other antioxidants are generally
used in a proportion of about 10 to 500 weight percent
relative to the chroman compounds (I-1). ~urther, the
chroman compounds (I-l) can be used in combination with
syner~istic auxiliary stabilizers such as calcium stearate,
distearyl thiodipropionate, etc. These auxiliary
stabilizers are used in a proportion of about 50 to 500
weight percent relative to the chroman compounds (I-l).
Thus, the organic composition prepared by
incorporating the chroman compounds (I-l) in an organic
material is very stable against unfavorable effects due to
oxidative factors. The term "unfavorable effects" as used
herein means the degradation, decomposition, etc. of
organic materials. Taking synthetic resins as an example,
the unfavorable effects include the decomposition and
undesirable crosslinking of macromolecules, and other
changes which manifest as aging, brittleness, discoloration,
depression of softening point, etc.
Among the chroman compounds (I), the chroman compounds
(I-2) show excellent analgesic activity. In addition,
these compounds have low toxicity. For example, ~-(2,3-
dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)
alanine hydrochloride has such low acute toxicity that
LD50 value (oral administration) is 2.624 g/kg for male
mice. So, the chroman compounds (1-2) can be used as
:' ~
~ z~oo~
- 15 -
an analgesic.
Among the chroman compounds (I-2), the
pharmaceutically acceptable esters of the compound in
which R in general formula (I-2) is a hydroxymethyl
group include such ester form as a lower fatty acid ester,
e.g. acetic acid ester, propionic acid ester, etc.;
a higher fatty acid ester, e.g. palmitic acid ester,
oleic acid ester, etc.; a phosphoric acid ester, an ester
of monomannosyl phosphate, etc. and the like. And the
pharmaceutically acceptable esters of the compound in
which R in general formula (I-2) is a carboxyl group
include such ester form as an alkyl ester, e.g. methyl
ester, ethyl ester, propyl ester, butyl ester, octyl ester,
tetradecyl ester, stearyl ester, etc.
The pharmaceutically acceptable salts of the compound of
general formula (I-2) include such salt form as an alkali
metal salt, e.g. lithium salt, sodium salt, potassium
salt, etc; hydrochloride, nitrate, methanesulfonate and
the like.
The compounds in which A is an amino group and R4 is
a protective group in general formula (I) can be converted
to the above-mentioned analgesic-active chroman compound
(I-2) by replacing the protective group with a hydrogen
atom by the conventional method.
The pharmaceutical composition of the invention
for analgesic can be formulated into various dosage forms
by using means known per se. For example, the dosage
forms may be those suitable for oral administration
such as tablets, granules, powders, coated tablets, hard
capsules, soft capsules and oral liquid preparations and
those suitable for injection such as suspensions, liquid
preparations, and oily or aqueous emulsions.
The pharmaceutical composition of the invention
may contain various pharmaceutically acceptable liquid
or solid diluents or carriers known per se. Examples of
1;2~1009
- 16 -
such diluents or carriers include syrup, gum arabic,
gelatin, sorbitol, tragacanth, polyvinylpyrrolidone,
magnesium stearate, talc, polyethylene glycol, silica,
lactose, sucrose, corn starch, calcium phosphate, glycine,
potato starch, calcium carboxymethylcellulose, sodium
laurylsulfate, water, ethanol, glycerol, mannitol and
phosphate buffer.
The pharmaceutical composition of the invention
may further include adjuvants conventionally used in
the field of pharmaceutical production, such as coloring
agents, flavors, corrigents, antiseptics, dissolution
aids, suspending agents and dispersing agents.
The pharmaceutical composition of the invention
may be in the form filled in a large dosage container as
well as in a fixed dosage form such as tablets, capsules,
coated tablets, ampoules, etc. exemplified hereinabove.
The pharmaceutical composition of the invention
contains an amount, effective for analgesic, of the
compound of general formula (I-2) and its pharmaceutically
acceptable ester and/or salt. Its dosage can be varied
properly depending upon the condition of the subject,
the purpose of administration, etc. For example, it is
about 50 to about 2,000 mg, preferably about l00 to about
500 mg, per day for an adult.
The pharmaceutical composition of the invention
can be administered through various routes, for example,
orally or by injection (e.g., intravenous, su~cutaneous,
intramuscular). Oral administration and intravenous
injection are especially preferred.
The following examples, test examples and formulation
examples illustrate the invention in more detail. It is
to be noted, however, that these examples, test examples
and formulation examples are by no means limitative of
the invention.
~24~0~'~
Example 1
~~C (NH4)2CNO3 ~ ~ NaOH,
~~C ~ N~H2 Pd/C HO~
~ CO2H HCG ~0 CO2H
(1) To a solution of 3.38 g of 2-(6-benzyloxy-2,3-
dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)-
acetaldehyde in 25 ml of ethanol, there were added 14
ml of water, 4.52 g of ammonium carbonate and 0.98 g of
sodium cyanide, followed-by heating at 50-55C with
stirring for 4 hours. The reaction mixture was
concentrated under reduced pressure, 2 ml of con-
centrated hydrochloric acid was added to the residue,
and the mixture was heated at 90C for 5 minutes. The
reaction mixture was cooled, water was added, and the
resulting precipitate was collected by filtration,
washed with water and diethyl ether, and dried under
reduced pressure to give 3.42 g (83.8% yield) of
5-[(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-
benzopyranyl)methyl]imidazolidine-2,4-dione charac-
terized by the following:
FD mass spectrum: [M~ 408
NMR spectrum (90 MHz) ~DMSO-d6
1.21 ~s, 3H); 1.5-2.7 (m, 15H);
3.26 (s, 2H); 4.0-4.3 (m, lH);
4.6 (s, 2H); 7.25-7.6 (m, 5H)
(2) A mixture of 3.15 g of 5-[(6-benzyloxy-2,3-
dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)methyl]-
imidazolidine-2,4-dione obtained by the above procedure
(1), 1.6 g of sodium hydroxide and 30 ml of water was
12~0~9
- 18 -
heated with stirring in a sealed tube at 120C for 15
hours. Water was then added to the reaction mixture,
the insoluble matter was filtered off, the filtrate was
washed with diethyl ether, and the aqueous layer was
neutralized with diluted hydrochloric acid. The
resulting precipitate was collected by filtration,
washed with water and diethyl ether, and dried under
reduced pressure to give 2.41 g (78.7% yield) of
~-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-
benzopyranyl)alanine characterized by the following:
FD mass spectrum: [M] 383
NMR spectrum (90 MHz): ~DMSO-d6
~ 1.2 (s, 3H); 1.5-2.7 (m, lSH);
3.8-4.1 (m, lH); 4.59 (s, 2H);
7.25-7.57 (m, 5H); 7.6-9.5 (br. s, 3H)
(3) ~-(6-Benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-
benzopyranyl)alanine (2.30 g) obtained ~y the above
procedure (2) was dissolved in 200 ml of ethanol,
followed by addition of 12 ml of 1 N hydrochloric acid
and 2.0 g of 5~ palladium-on-activated carbon. The
mixture was stirred at room temperature in a hydrogen
atmosphere for 2 days. The reaction mixture was
filtered, water was added to the filtrate, and low
boiling components were distilled off under reduced
pressure. The residue was dissolved in ethanol,
followed by recrystallization by addition of diethyl
ether. There was thus obtained 1.21 g (61.2% yield) of
crystalline ~-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-
2H-benzopyranyl)alanine hydrochloride characterized by
the following:
FD mass spectrum: ~M-HCl] 293
NMR spectrum (90 MHz) ~DMsO-d6:
1.5 (s, 3H); 1.6-2.65 (m, 15H);
3.8-4.1 (m, lH); 7.4 (br. s, lH);
8.5 (br. s, 3H)
~4~as
_l9_
Example 2
N>~o >
o~CO2H ~ ~ -CO2 H
NH2 NH3Ce
Using 3.52 g of 3-(6-benzyloxy-2,3-dihydro-2,5,7,8-
tetramethyl-2H-benzopyranyl)propionaldehyde in place of
3.38 g of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-
2H-benzopyranyl)acetaldehyde, the procedure of Example
1-(1) was followed for reaction, separation and
recovery. There was obtained 3.17 g (75.1% yield) of
5-~2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-
benzopyranyl)ethyl]imidazolidine-2,4-dione charac-
terized by the following:
FD mass spectrum: [M] 422
NMR spectrum (90 MHz) ~DMSO-d6
1.13 (s, 3H); 1.3-2.7 (m, 17H);
3.3 (br.s, 2H); 3.85-4.1 ~m, lH);
4.57 (s, 2H); 7.25-7.6 (m, 5H)
The procedure for reaction, separation and
re-covery as described in Example 1-(2) was followed
except that 3.26 g of 5-[2-(6-benzyloxy-2,3-dihydro-
2,5,7,8-tetramethyl-2H-benzopyranyl)ethyl]imidazolidine-
2,4-dione was used in place of 3.15 g of 5-[(6-benzyloxy-
2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)methyl]-
imidazolidine-2,4-dione. There was obtained 2.41 g
(78.6% yield) of 2-amino-4-[2-(6-benzyloxy-2,3-dihydro-
2,5,7,8-tetramethyl-2H-benzopyranyl)]butyric acid
characterized by the following:
FD mass spectrum: [M] 397
NMR spectrum (90 MHz) ~cDsoD:
1.24, 1.28 (s, 3H); 1.6-2.8 (m, 17H);
1241C~Q~
- 20 -
4.1-4.45 (m, lH) 4.68 (s, 2H);
4.73 (s; 3H); 7.2-7.5 (m, 5H)
The procedure for reaction, separation and recovery
as described in Example 1-(3) was followed except that
2.38 g of 2-amino-4-[2-(6-benzyloxy-2,3-dihydro-2,5,7,8-
tetramethyl-2H-benzopyranyl)]butyric acid was used
in place of 2.30 g of ~-(6-benzyloxy-2,3-dihydro-2,5,7,8-
tetramethyl-2H-benzopyranyl)alanine. There was obtained
1.26 g (61.1% yield) of crystalline 2-amino-4-[2-(2,3-
dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)]
butyric acid hydrochloride characterized by the
following:
FD mass spectrum: t~HC1]+ 307
Examples 3 - 10
The procedure for reaction, separation and recovery
as described in Example 1-(1) was follo,wed using
10 millimoles of each aldehyde specifically given in
Table 1 in place of 3.38 g (10 mmol) of 2-(6-benzyloxy-
2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)-
acetaldehyde, to give the corresponding hydantoin. The
results thus obtained are shown in Table 1.
.
.: .j
~4~0~9
-- 21 --
~ ~ o o~ 0 o ~ o o`
a~ 0 O ~ ~
~ ~ +
0
E ~
,~ ~ r o
U .~ ~ 0 0 ~ 0
~o c ~ ~Y~
R . ~ .
~ ~ ~ ~ ~~
~.c O (~ O O
~.~ ~o~ ~O=V
~ o ~
X:Z;
~X410~
- 22 -
The procedure for reaction, separation and
recovery as described in Example 1-(2) was followed
using 7.7 millimoles of each hydantoin specifically
given in Table 2 as obtained by the same method as
above in place of 3.15 g (7.7 mmol) of 5-[(6-benzyloxy-
2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)methyll-
imidazolidine-2,4-dione, to give the corresponding ~-amino
acid. The results thus obtained are shown in Table 2.
1~1009
-- 23 --
E ,~ 5 _ o
E + + + + + + + +
'~' .~ c~
I ~ 1 ~2 ~ ';~
~ C ~ ~
~ . ~ ~ ~ X
a~ o ¦ =7~ ~ ~ ~ ~
~-0 O O
U~ _ 0~ ~ O=V ( 1 r~,U,
~ Z ~ o. o
~1009
- 24 -
The procedure for reaction, separation and recovery as
described in Example 1-(3) was followed using 6 millimoles
of each ~-amino acid specifically given in Table 3 as
obtained by the same method as above in place of 2.30 g
(6 mmol) of B-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-
2H-benzopyranyl)alanine, to give the corresponding a-
amino acid hydrochloride. The results thus obtained
are shown in Table 3.
Table 3
Example Starting ~-amino Product
No.acid ~-Amino acid Yield FD mass
hydrochloride (4) spectrum
3~ ~ C02H ~ C02H H~ 73 ~M-HG~+279
NH2 NH2
~ 02H ~ 02H ~ 81 ~M-HG~+265
8~ ~ OzH ~ C02H.H~ 75 ~M-HG~+279
~ ~ NH~ H0 ~ NH2
9U~0 ~ O~_~Co2H CH30 ~ 0 C02H H~ 72 ~M-HC~+325
CH30 CH30
~ 02H ~ C202H- ~ 76 ~M-HG~+315
. .
4~L0(~9
- 25 -
Example 11
~c, NaHS0~ NaCN
~~ 0 ~I ~ H
~0 CN ~o C0 2H
To a solution of 1.18 g of 2-(6-benzyloxy-3,4-
dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)acetaldehyde
in 13 ml of ethanol was added dropwise an aqueous
solution (2 ml) of 0.73 g of sodium bisulfite. After
precipitation of the sodium bisulfite adduct, an
aqueous solution (l.S ml) containing 0.34 g of sodium
cyanide was added dropwise to the reaction mixture with
vigorous stirring. After dropping, stirring was
continued at room temperature for 4 hours, water was
added to the reaction mixture, and extraction was
performed with diethyl ether. The extract was washed
with water and then low-boiling substances were distilled
off. To the crude cyanohydrin thus obtained, there was
added 20 ml of concentrated hydrochloric acid, followed
by refluxing for an hour. After cooling, water was
added to the reaction mixture, followed by extraction
with diethyl ether. The extract was washed with water
and dried over anhydrous magnesium sulfate, and low
boiling substances were distilled off under reduced
pressure. The concentrate obtained was dissolved in
diethyl ether, and recrystallization was effected by
adding n-hexane. There was thus obtained 0.84 g (81.9~
yield) of 2-hydroxy-3-~2-(3,4-dihydro-6-hydroxy-2,5,7,8-
tetramethyl-2H-benzopyranyl)]propionic acid charac-
terized by the following:
FD mass spectrum: (M] 294
NMR spectrum (90 MHz): ~ CDC13
124~013g
- 26 -
1.28 (s, 3H); 1.7-2.3 (m, 13H);
2.57 (t, J=7Hz, 2H); 4.33-4.57 (m, lH);
6.3 (br. s, 3H)
Example 12
o
lt
CH 3 CC)~, NaHSO3 NaCN
O .
Il
CH3CO~I HCe HO~
CN ~0 CO2H
The procedure for reaction, separation and recovery
as described in Example 11 was followed using 1.01 g of
2-(6-acetoxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-benzo-
pyranyl)acetaldehyde in place of 1.18 g of 2-(6-
benzyloxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-benzo-
pyranyl)acetaldehyde used in Example 11. There was
obtained 0.89 g (86.7% yield) of 2-hydroxy-3-[2-(3,4-
dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)]-
propionic acid.
Examples 13 and 14
NaHSO~ NaCN
O (CH2 ) nCHO ~ ~ ~
-- ~(CH2)nCHCN ~< (CH2)nC~lCO2H
(I')
The procedure for reaction, separation and recovery
as described in Example 11 was followed except that
1.13 g of 2-(6-benzyloxy-3,4-dihydro-2,5,7,8-tetramethyl-
2H-benzopyranyl)carbaldehyde or 1.23 g of 3-(6-benzyloxy-
1~4~V09
_ 27 -
3,4-dihydro-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)propionic
aldehyde was used in place of 1.18 g of 2-(6-benzyloxy-
3,4-dihydro-2 r 5 ~ 7,8-tetramethyl-2H-benzopyranyl)-
acetaldehyde used in Example 11, to give the correspond-
ing 2-hydroxy-2-12-(3,4-dihydro-6-hydroxy-2,5,7,8-tetra-
methyl-2H-benzopyranyl)3acetic acid or 2-hydroxy-4-[2-
(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzo-
pyranyl)]butyric acid, respectively. The results
obtained are shown in Table 4.
Table 4
~-Hydroxycarboxylic acid ~I')
Example Yield FD mass NMR spectrum (90 MHz)
No. n (~) spectrum ~IM S
~ C DCe
1 3 0 7 2.2 ~M~+ 2 8 0 1.2 3 ( s, 3H );
1.7~2.3 (m , 1 l H);
2.6 ( t, J = 7 Hz, 2H);
4.1 2, ~.1 3(s, 1
6.5 ( br.s, 3H)
1 4 2 8 7.5 ~M3+ 3 0 8 1.1 7 ( s , 3 H ) ;
1.5 ~ 2.2 ( m , 1 5 ~I ) ;
2.5 5 ( t , J=7~1z, 2~I);
4.0~4.2(m, lH);
6.2 ( br.s, 3~I)
Examples 15 and 16
The procedure for reaction, separation and recovery
as described in Example 11 was followed using 1.29 g of
2-(6-benzyloxy-3,4-dihydro-7,8-dimethoxy-2,5-dimethyl-
2H-benzopyranyl)acetaldehyde or 1.26 g of 2-(6-benzyloxy-
3,4-dihydro-2,5-dimethyl-2H-naphthopyranyl)acetaldehyde
in place of 1.18 g of 2-(6-benzyloxy-3,4-dihydro-
2,5,7,8-tetramethyl-2H-benzopyranyl)acetaldehyde used
241009
~ 28
in Example 11, to give the corresponding 2-hydroxy-
3-[2-(3,4-dihydro-7,8-dimethoxy-2,5-dimethyl-6-hydroxy-
2H-benzopyranyl)]propionic acid or 2-hydroxy-3-12-[3,4-
dihydro-6-hydroxy-2,5-dimethyl-2H-naphtho[1,2-b]-
pyranyl]]propionic acid, respectively. The results
obtained are shown in Table 5.
Table 5
~-Hydroxycarboxylic acid
Example
Yield FD mass
No. Product (~) spectrum
HO ~, , OH
l S CH30~0~ CO 2H 6 1 ~M~+ 3 2 6
C~I3 0
16 HO~ 7 3 ~M)+3 1 6
CO2H
`~O
Example 17
HO ~ NH3Cl LiAlH4 H ~ NH
~ C2H ~ ~ OH
To a mixture of 0.36 g of lithium aluminium hydride
and 30 ml of tetrahydrofuran was added by portions
2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzo-
pyranyl)alanine hydrochloride under refluxing. The
reaction mixture was poured into a small amount of
water, acidified with hydrochloric acid, and washed by
diethyl ether. The aqueous layer was concentrated under
reduced pressure and the residue was extracted with
ethanol. The ethanol extract was basified with aqueous
sodium bicarbonate and concentrated under reduced pressure.
~- 1241009
- 29 -
(
The resultant residue was extracted with dichloromethane
and the extract was dried and evaporated under reduced
pressure to give 1.05 g of 2-amino-3-[2-(2,3-dihydro-
6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)]-l-
propanol characterized by the following:FD mass spectrum: [M] 279
NMR spectrum ~90 MHZ) ~ DMO:
1.36 (s, 3H); 1.8-2.2 (m, 4H);
2.15, 2.17, 2.22 (each s, 9H);
2.6-2.9 (m, 2H); 3.7-4.1 (m, 3H)
Example 18
NH2OH ~ o ~ NOH
LiAlH4 ~ O ~ NH2
H2 ~ Pd/C HO
HCl ~ NH2-HCl
(1) To a mixture of 3.31 g of hydroxylaminé-- hydrochloride
in 3 ml of water, 2.59 g of sodium carbonate in 6 ml of
water and 50 ml of ethanol, there was added 15.7 g of
2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-
benzopyranyl)acetaldehyde in 100 ml of ethanol on ice
bath, and the resulting mixture was stirred at room
temperature overnight. Saturated aqueous solution of
sodium chloride was added to the reaction mixture, and
the resulting mixture was extracted with diethyl ether.
The ether extract was dried With anhydrous sodium sulfate
and evaporated to give 16.0 g of 2-(6-benzyloxy-2,3-
dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)acetaldoxime.
,
T
124~0~
- 30 -
(2) A solution of 15.0 g of 2-(6-benzyloxy-2,3-
dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)acetaldoxime
obtained by the above procedure (1) in 100 ml of
tetrahydrofuran was added to a mixture of 2.42 g of
lithium aluminium hydride and 100 ml of tetrahydrofuran
under refluxing. After the reaction was completed,
the reaction mixture was poured into ice-water, acidified
with hydrochloric acid, and extracted with dichloromethane.
The extract was dried and evaporated under reduced
pressure. Aqueous solution of sodium hydroxide was added
to the resultant residue, and the resulting mixture was
extracted with diethyl ether. The ether extract was
dried and evaporated to give 2-(6-benzyloxy-2,3-dihydro-
2,5,7,8-tetramethyl-2H-benzopyranyl)ethylamine
characterized by the following:
FD mass spectrum: [M] 339
NMR spectrum (90 MHz) ~CDC13
1.17 (s, 3H~; 1.5-2.0 (m, 4H); 1.92 (s, 3H);
2.07 (s, 3H); 2.14 (s, 3H); 2.3-2.6 (m, 2H);
4.0-4.4 (m, 2H); 4.62 (s, 2H);
7.2-7.5 (m, 5H~
(3) A mixture of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-
tetramethyl-2H-benzopyranyl)ethylamine obtained by the
above procedure (2), 1.0 g of 5% palladium-on-activated
carbon, 20 ml of 2 N hydrochloric acid and 100 ml of
ethanol was stirred at room temperature overnight under
hydrogen atmosphere. After the reaction was completed,
the reaction mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was
dissolved in ethanol, and precipitated by addition of
n-hexane. The precipitate was collected by filtration,
washed with n-hexane and dried to give 8.6 g of 2-(2,3-
dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)
ethylamine hydrochloride characterized by the following:
~100~
- 31 -
(
FD mass spectrum: [M - HCl]+ 249
NMR spectrum (90 MHZ) ~ DMO:
1.24 (s, 3H); 1.6-2.0 (m, 4H);
2.03, 2.06, 2.09 (each s, 9~); 2.4-2.8 (m, 2H);
2.8-3.2 (m, 2H)
Example 19
O ~ NH2OH ~ O ~ NOH
LiAlH4 ~ ~ NH2
H2 ~ Pd/C HO ~
HCl ~ o ~ NH2 HCl
(1) To a mixture of 3.31 g of hydroxy~ne hydrochloride
in 3 ml of water, 2.59 g of sodium carbonate in 6 ml of
water and 50 ml of ethanol, there was added 15 g of
2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-
benzopyranyl)carbaldehyde in 100 ml of ethanol on ice
bath, and the resulting mixture was vigorously stirred
at room temperature overnight. Saturated aqueous solution
of sodium chloride was added to the reaction mixture, and
the resulting mixture was extracted with diethyl ether.
The extract was dried with anhydrous sodium sulfate
and evaporated, and the residue was purified by silica
gel column chromatography to give 14 g of 2-(6-benzyloxy-
2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)-
carbaldoxime.(2) A solution of 14 g of 2-t6-benzyloxy-2,3-dihydro-
2,5,7,8-tetramethyl-2H-benzopyranyl)carbaldoxime obtained
by the above procedure (1) in 100 ml of tetrahydrofuran
was added to a mixture of 2.4 g of lithium aluminium
,:
_r .
12410~9
- 32 -
hydride and 100 ml of tetrahydrofuran under refluxing.
After the reaction was completed, the reaction mixture
was poured into ice-water, acidified with hydrochloric
acid, and extracted with dichloromethane. The extract
was dried and evaporated under reduced pressure. Aqueous
solution of sodium hydroxide was added to the resultant
residue, and the resulting mixture was extracted with
diethyl ether. The ether extract was dried, and hydrogen
chloride was bubbled into the extract. After evaporation
under reduced pressure, the resultant residue was dissolved
in dichloromethane and precipitated by addition of n-hexane.
The precipitate was collected by filtration and dried
to give 7.0 g of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-
tetramethyl-2H-benzopyranyl)methylamine hydrochloride
characterized by the following:
FD mass spectrum: [M - HCl] 325
NMR spectrum (90 MHz) ~ DMMSO d6:
1.24 (s, 3H~; 1.7-2.0 (m, 2H);
2.05, 2.09, 2.12 (each s, 9H);
2.4-2.7 (m, 2H); 2.8-3.1 (m, 2H);
4.61 (s, 2H); 7.3-7.6 (m, 5H)
(3) A mixture of 7.0 g of 2-(6-benzyloxy-2,3-dihydro-
2,5,7,8-tetramethyl-2H-benzopyranyl)methylamine hydrochloride
obtained by the above procedure ~2), 1.0 g of 5% palladium-
on-activated carbon, 20 ml of 2N hydrochloric acid and
100 ml of ethanol was stirred at room temperature overnight
under hydrogen atmosphere. After the reaction was
completed, the reaction mixture was filtered and the
filtrate was concentrated under reduced pressure. The
residue was dissolved in ethanol, and precipitated by
addition of n-hexane. The precipitate was collected by
filtration and dried to give 4.3 g of 2 (2,3-dihydro-
6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)methylamine
hydrochloride characterized by the following:
FD mass spectrum: ~M - HCl] 235
~410~9
- 33 -
NMR spectrum (90 MHz) 6 DMSO-d6
1.27 (s, 3H); 1.6-1.9 (m, 2H); 2.01 (s, 6H);
2.03 (s, 3H); 2.4-2.6 (m, 2H); 2.8-3.1 (m, 2H)
Test Examples 1-16
. .
Inhibition of linoleic acid oxidation
A test solution (10 ml) was prepared by adding
each test compound, in an amount of 0.2~ by weight on
the linoleic acid basis, to a borate buffer (pH 9)
containing 10 2 M sodium linoleate. A 0.2 ml portion
of the test solution was heated at 70C for a specified
period of time. After heating, 4.7 ml of 75% ethanol
and 0.1 ml of 30% ammonium thiocyanate were added to
said test solution, and the mixture was stirred well.
Then, 0.1 ml of a ferrous chloride solution [the
supernatant obtained by adding an aqueous ferrous sulfate
solution (0.6 g/50 ml) and 10 ml of concentrated
hydrochloric acid to an aqueous barium chloride solution
(0.5 g/50 ml), followed by adequate stirring and standing
for a while] was added to said mixture. Exactly
3 minutes later, the resulting solution was measured for
the absorbance at 500 m~. In this way,
the trivalent iron formed by the oxidative action of
sodium linoleate peroxides was assayed and, based on
the assay data, the test compounds were compared with
respect to antioxidant activity ~cf. Shokuhin Kogaku
Jikkensho (Experiments in Food Engineering), vol. I,
edited by the Department of Food Engineering, Faculty
of Agriculture, Kyoto University, pages 634-635]. The
greater the absorbance of the test solution after
heating is, the greater the amount of sodium linoleate
peroxides formed is. The results obtained in the above
manner are shown in Table 6.
2'~0~3'~
- 34 -
(.,
Table 6
Absorbance
Test
Example Test compound
No. Test Solution Solution Solution
solution after 1 after 2 after 3
(No hr. of hrs. of hrs. of
heating) heating heating heating
Blank 0.0 3 0.09 0.2 3 0.29
2 ~-Tocopherol* _ 0.0 7 0.1 9 0.3 0
3 Ascorbic acid - 0.1 0 0.2 1 0.3 0
4 Sodium erYthorbate - 0.11 0.1 7 0.1 8
H0~02H - 0.0 2 0.0 3 0.0 3
6 H0~02H - 0.0 2 0.0 3 0.0 3
~H2
7 HO ~ CO2H . - 0.0 2 0.0 3 0.0 4
8 HO~C02H - 0.0 2 0.0 3 0.0 3
HO~C02H - 0.0 2 0.0 3 0.0 3
HO~C02H - 0.0 2 0.0 3 0.0 4
H0~2
11 CH3 ~ O C02H - 0.0 2 0.0 3 0.0 5
~ `C02H - 0.0 2 0.0 3 0.0 5
oo9
-
Absorbance
Test
Example Te~t compound
No Te~t Solution Solution Solution
solution after 1 after 2 after 3
(No hr. of hrs. of hrs. of
5heating) heating heating heating
HO~ ~ 3 ~
13 ~OJ~co2H - 0.0 2 0.0 3 0.0 4
HO ~" ~2
14 ~O~CO2Na - 0.0 2 0.0 3 0.0 3
HO~ ~ 3 ~
~O~Co2c~ 0.0 2 o o 3 o o 5
HO~, ~3Ce
16 ~O~CO2Cl~H3~ - 3 0.0 4 0.0 7
. .
10* ~or dissolution, an equal amount of a commercial
nonionic surfactant "Tween 20"(trade ~rk) was added.
Test Examples 17-28
To each 100 g of ethyl linoleate was added 0.020 g
of one of the test compounds indicated in Table 7 to
prepare a test solution. A 20 ml portion of each test
solution was exposed to the accelerated conditions of
aeration of 2.33 cc/sec. at 97.8C in an AOM (Antioxygen
Method) tester and the time period till the POV
(peroxide value) reached 100 meq/kg was determined.
The results are presented in Table 7.
. .~ . ~, .
~4~
- 36 -
Table 7
No. Test compound T me (hrs.) t 11
17 No addition 0. 2
18 a-Tocopherol 1. 4
9 HO~CO2H 2. 3
OH
HO~Hco2H 2. 4
21 HO~CO2H 2. 0
OH
22 ~ CO2C 2Hs 2.
23 HO~CO2C2Hs 2. 3
24 HO~,CO2CH3 2.
HO~el~Hco2H 2. 2
2 6 HO ~ Hco2H 2. 3
CH30 ~ Hco2H 2. 2
27 CH30
28 HO ~ Hco2H 1. 9
i24~009
_ 37 -
Test Example 29
Pharmacoloqical tests
B-~2,3-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-
benzopyranyl)alanine hydrochloride was evaluated for
analgesic activity in the writhing test ~cf. Koster et
al., Fed. Proc., 18, 412 (1959)1, local anesthetic
activity in the tail pinch test [cf. Bianchi, C., Brit.
J. Pharmacol., 11, 104 (1956)} and bronchodilator
activity in lung perfusion [cf. Luduena, F. P., Arch.
Int. Pharmacodyn., 111, 392 (1957)]. The results are
shown in Table 8.
B-(2~3-Dihydro-6-hydroxy-2~5~7~8-tetramethyl-2H
benzopyranyl)alanine hydrochloride is active in the
test for analgesic activity causing 84% inhibition of
writhing, and also demonstrated a local anesthetic
activity. An inhibition of isoprenaline-induced
bronchodilation is also observed.
lZ4100~3
-- 38 --
~ ~+
a) , .,
0
~o ~ ~
~ JJ C ~0
.~ ~ ~
~ ~ ~ rl,q n
.~
~ C ~
u~
O ,a O ..
~; o ~
0 0 0 0
E~
_ o
.,, ~al
J~ g,C ~
~ ~ 0
L~ ~8 ~ ~
~ '1
C~ ~ O
o U~~ o o
v
E~ . o o~ o
Cq
~o ~ ~C
C:l oo 0 0
o o o
~ o
~o
~;
U~ l
~l ~ a)
~ ~ C D'
- ,C
3 .~ .C
0 .,~
:- ~ j
12~009
- 39 -
Test Examples 30-33
Analgesic activity testing
~ -(2,3-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-
benzopyranyl)alanine hydrochloride [referred to as
"Compound (1)"], 2-(2,3-dihydro-6-hydroxy-2,5,7,8-
tetramethyl-2H-benzopyranyl)methylamine hydrochloride
[referred to as "Compound (2)"], 2-amino-3-[2-(2,3-
dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)]-
l-propanol [referred to as "Compound (3)"] and Aspirin
were evaluated for analgesic activity.
Male ddY strain mice in groups of ten each were used
for the evaluation of analgesic activity by acetic acid
writhing test [Koster et al., Federation Proc., 18, 412
(1959)1. The results are shown in Table 9.
Table 9
No. Test compound dose (mg/kg, inhibition (~)
:
Aspirin 100 40.8
31 Compound (1) 100 96.1
32 Compound (2) 100 65.6
33 Compound (3) 100 83.7
.
Specific examples of formulating the analgesic
of the invention are shown below. It should be
understood, however, that these examples are not
limitative.
Formulation Example 1
Injectable preparation:-
Compound (1) (100 mg) was dissolved in 3 ml ofphysiological saline and put aseptically in a 3 ml.
ampoule. The ampoule was sealed up by melting and heat
sterilized to form an injectable preparation which was
aseptic and did not contain a pyrogenetic substance.
~24~009
- 40 -
Formulation Example 2
Tablets:-
Compound (1) 100 mg
Corn starch 145 mg
Calcium carboxymethylcellulose 40 mg
Polyvinylpyrrolidone 9 mg
Magnesium stearate 6 mg
The above ingredients were mixed and directly
tableted by a tableting machine to form tablets each
weighing 300 mg.
