Chalcone derivatives and process for producing the same

Chalcone derivatives having at least one tetrahydropyranyloxy group is disclosed. Typically, the compounds are represented by general formula (I) ##STR1## wherein X and X' each represent a tetrahydropyranyl group, R and R', which are then same or different, each represent an alkyl group or a hydrogen atom, n and n' each are an integer of from 0 to 5, m and m' each are integers of from 0 to 5, provided that n+n' is 1 or more, and that n+m is an integer of from 0 to 5 and n'+m' is an integer of from 0 to 5. Also, disclosed are processes for producing the chalcone derivatives starting from acetophenone or its derivative and benzaldehyde or its derivative at least one of which has at least one tetrahydropyranyloxy group. Further, disclosed is 2,3,4,2',4'-pentahydroxychalcone.

BACKGROUND OF THE INVENTION 
The present invention relates to novel chalcone derivatives, which are 
intermediates for the production of hydroxychalcones, and also to 
processes for producing hydroxychalcones using such chalcone derivatives. 
Chalcone series compounds include chalcone, which can be produced by 
Claisen condensation reaction of acetophenone, and benzaldehyde and 
derivatives of chalcone. These chalcone compounds are known to have 
various pharmacological activities. 
For example, Japanese Patent Application (Kokai) No. Sho 60-178815 
describes examples in which chalcone compounds are used as active 
ingredients of antitumor drugs. Also, there is reported in Japanese Patent 
Publication (Kokoku) No. Sho 48-8485 that isoliquiritigenin (or 
4,2',4'-trihydroxychalcone) is contained in extract of licorice root, 
exhibits antiulcer activity and is used in the therapy of gastric ulcer. 
Furthermore, it is known that isoliquiritigenin has antiallergic activity 
and is effective for the therapy, treatment and prophylaxis of asthma, 
allergic dermatitis, allergic rhinitis, urticaria, food allergy, and the 
like (Japanese Patent Application (Kokai) No. Sho 62-2027212). It is also 
known that isoliquiritigenin is also effective as a drug for the therapy, 
treatment and prophylaxis of kidney diseases such as kidney lesion caused 
by antitumor drugs, acute nephritis, chronic nephritis, Rehpus nephritis, 
and the like, and effective as a drug for the therapy, treatment and 
prophylaxis of liver diseases such as liver lesion caused by antitumor 
drugs, acute hepatitis, chronic hepatitis and the like (WO87-7835). 
It is already known that isoliquiritigenin can be produced by reacting 
2,4-dihydroxyacetophenone with 4-hydroxybenzaldehyde under alkaline 
conditions according to the following reaction scheme. 
##STR2## 
However, the yield of isoliquiritigenin obtained by the above reaction is 
about 20%, and in addition, chalcone compounds having a hydroxyl group at 
the 2-position of the acetophenone skeleton are obtained generally in low 
yield. Therefore, improvement for increasing the yield of chalcone 
compounds has been desired. 
SUMMARY OF THE INVENTION 
Therefore, the present invention provides a chalcone compound having at 
least one tetrahydropyranyloxy group in the chalcone skeleton. 
The present invention also provides a process for producing a chalcone 
compound having at least one tetrahydropyranyloxy group. 
Further, the present invention provides a novel hydroxychalcone derivative. 
Also, the present invention provides a process for producing a 
hydroxychalcone by hydrolyzing a chalcone compound having at least one 
tetrahydropyranyloxy group in the chalcone skeleton. 
The hydroxychalcone derivatives having at least one tetrahydropyranyloxy 
group are useful for producing hydroxychalcones which are useful as 
therapeutic agents. 
According to the present invention, chalcone derivatives having at least 
one tetrahydropyranyloxy group can be obtained in high yield from starting 
compounds, and such chalcone derivatives can be decomposed with water or 
alcohols to release hydroxychalcones also in high yield, resulting in that 
the yield of hydroxychalcones can be increased as high as, e.g., 80% and 
about 4 times as high as the yield attained by direct synthesis of the 
hydroxychalcones using the corresponding starting compounds whose hydroxyl 
group(s) is or are not substituted with tetrahydropyranyloxy group. The 
present invention can provide process for producing chalcone derivatives 
at low cost, which assures easy obtention of intermediates for the 
production of hydroxychalcones and thus permits production of 
hydroxychalcones in high yield and at low cost. 
DETAILED DESCRIPTION OF THE INVENTION 
The novel chalcone derivatives having at least one tetrahydropyranyloxy 
group which the present invention provides, for example, those compounds 
in which at least one hydroxyl group in the hydroxychalcone is substituted 
with a tetrahydropyranyloxy group, include compounds represented by 
general formula (I) below. 
##STR3## 
wherein X and X' each represent a tetrahydropyranyl group, R and R', which 
are the same or different, each represent an alkyl group or a hydrogen 
atom, n and n' each are an integer of from 0 to 5, m and m' each are 
integers of from 0 to 5, provided that n+n' is 1 or more, and that n+m is 
an integer of from 0 to 5 and n'+m' is an integer of from 0 to 5. 
Preferred examples of the chalcone compounds are those in which n, n', m, 
and m' each are an integer of from 1 to 3, provided that n+m and n'+m' 
each are an integer of from 1 to 3. In this case, combinations of n and n' 
being an integer of from 1 to 3 and m and m' each being 0 may also be 
possible. 
As specific compounds included in the above-described preferred examples, 
there can be cited, for example, the following compounds. 
##STR4## 
Also, compounds can be used which have a hydroxyl group at the 2-position 
of acetophenone skeleton and are represented by general formula (II) 
below. 
##STR5## 
wherein X and X' each represent a tetrahydropyranyl group, R and R', which 
are the same or different, each represent an alkyl group or a hydrogen 
atom, n is an integer of from 0 to 2, n' is an integer of from 0 to 3, m 
is an integer of from 0 to 2, and m' is an integer of from 0 to 3, 
provided that n+n' is 1 or more, and that n+m is an integer of from 0 to 3 
and n'+m' is an integer of from 1 to 3. 
Specific compounds embraced by general formula (II) include the following 
compounds. 
##STR6## 
In the present invention, in order to produce chalcone derivatives having 
at least one tetrahydropyranyloxy group in the chalcone skeleton, 
acetophenone having at least one tetrahydropyranyloxy group or its 
derivative is reacted by Claisen condensation with benzaldehyde or its 
derivative, or alternatively acetophenone or its derivative is reacted by 
Claisen condensation with benzaldehyde having at least one 
tetrahydropyranyloxy group or its derivative. The tetrahydropyranyloxy 
group or groups is or are substituted with one or more hydroxyl groups, if 
any, attached to acetophenone (or its derivative) or benzaldehyde (or its 
derivative), thus increasing the yield of chalcone derivatives by Claisen 
condensation reaction. 
The acetophenone having at least one tetrahydropyranyloxy group or its 
derivatives includes compounds represented by general formula (III) below 
##STR7## 
wherein X represents a tetrahydropyranyl group, R represents an alkyl 
group or a hydrogen atom, n and m each are an integer of from 0 to 5. 
The benzaldehyde having at least one tetrahydropyranyloxy group or its 
derivatives include compounds represented by general formula (IV) below 
##STR8## 
X' represents a tetrahydropyranyl group, R' is an alkyl group or a 
hydrogen atom, and n' and m' each are an integer of from 0 to 5. 
In general formulae (III) and (IV), n and n' may be an integer of from 0 to 
3, and m and m' may also be an integer of from 0 to 3. 
The chalcone derivatives of the present invention represented by general 
formula (II) above can also be produced by using compounds represented by 
general formula (III') below 
##STR9## 
wherein X represents a tetrahydropyranyl group, R represents an alkyl 
group or a hydrogen atom, n is an integer of from 0 to 2, and m is an 
integer of from 0 to 3, and those represented by general formula (IV') 
below. 
##STR10## 
wherein X' represents a tetrahydropyranyl group, R' represents an alkyl 
group or a hydrogen atom, m' and n' each are an integer of from 0 to 3. 
The acetophenone derivatives which have at least one tetrahydropyranyloxy 
group can be obtained, for example, by reacting acetophenone having one or 
more hydroxyl groups (OH) with dihydropyran in an organic solvent in the 
presence of an acid catalyst. For example, substitution of hydroxyl group 
at the 4-position of 2,4-dihydroxyacetophenone with a tetrahydropyranyloxy 
group proceeds as follows. 
##STR11## 
As for the acid catalyst, there can be cited mineral acids such as 
hydrochloric acid, sulfuric acid and the like, organic acids such as 
acetic acid, p-toluenesulfonic acid and the like, H.sup.+ type ion 
exchange resins, and salts thereof that are acidic, etc. For example, 
pyridinium p-toluenesulfonate is preferred when substituting, with 
tetrahydropyranyloxy group, one or more hydroxyl groups attached to those 
compounds having plural hydroxyl groups such as acetophenone or its 
derivative, or benzaldehyde or its derivative, having one or more hydroxyl 
groups in addition to the hydroxyl group at the respective 2-positions of 
these compounds. 
As for the organic solvent, there can be used those other than alcohols, 
water, dimethylformamide and dimethyl sulfoxide. For example, aromatic and 
aliphatic hydrocarbons, ketones, esters, ethers, halogenated hydrocarbons, 
and the like can be used. 
Generally, the reaction temperature and reaction time may vary depending on 
the kind and amount of the catalyst to be used as well as the kind of the 
solvent to be used. When the reaction is allowed to proceed in a solvent 
such as methylene chloride in the presence of a catalyst such as 
pyridinium p-toluenesulfonate, it is preferred that hydroxyacetophenone 
and the acid catalyst are charged in methylene chloride or the like 
solvent and dihydropyran is dropped at a temperature of from 0.degree. to 
40.degree. C. in from 1 to 2 hours, followed by agitation for from 2 to 3 
hours. 
The reaction product is neutralized with a base such as caustic soda 
(sodium hydroxide), caustic potasse (potassium hydroxide), potassium 
carbonate, sodium bicarbonate, etc., and filtered, followed by 
concentration of the filtrate after removing excess amount of the base. 
The concentration is carried out preferably under reduced pressure. In 
this manner, acetophenone derivatives having one or more 
tetrahydropyranyloxy groups can be obtained as oily products. 
The formation of them can be confirmed by various analytical methods such 
as infrared absorption spectrum (IR), nuclear magnetic resonance spectrum 
(NMR), mass spectrum, and the like. 
The benzaldehyde compounds having at least one tetrahydropyranyloxy group 
can be produced and identified in a manner similar to that for the 
above-described acetophenone derivatives. For example, 
4-hydroxybenzaldehyde can be produced as follows. 
##STR12## 
Although the acetophenone and benzaldehyde compounds each having at least 
one tetrahydropyranyloxy group may be produced separately as described 
above, one or more tetrahydropyranyloxy groups can be introduced in the 
skeletons of both acetophenone and benzaldehyde at the same time by mixing 
acetophenone having one or more hydroxyl groups with benzaldehyde having 
one or more hydroxyl groups, and then subjecting the mixture to a reaction 
for introducing tetrahydropyranyloxy groups as described above. 
The reaction between acetophenone or its derivative and benzaldehyde or its 
derivative is performed by Claisen condensation reaction. It is preferred 
to use a basic catalyst, particularly hydroxides of alkaline earth metals. 
As for the hydroxides, there can be used, for example, hydroxides of 
magnesium, calcium, strontium, barium, or their hydrates. Of these, barium 
hydroxide and its hydrate is preferred. In this case, it is preferred to 
use as the solvent lower alcohols such as methanol, ethanol, isopropanol 
and n-propanol, water, and mixtures thereof. 
Concretely, a reaction components such as acetophenone derivative and 
benzaldehyde derivative each having one or more tetrahydropyranyloxy 
groups are dissolved in a solvent together with the above-described 
catalyst, and the mixture is agitated at a temperature of from 30.degree. 
to 60.degree. C. for from 6 to 12 hours to perform Claisen condensation 
reaction. For example, when the above-described tetrahydropyranyloxylated 
acetophenone and benzaldehyde derivatives are used, the reaction proceeds 
as follows. 
##STR13## 
to obtain 2'-hydroxy-4,4'bis(tetrahydropyranyloxy)chalcone. 
The resulting mixture is cooled to room temperature and to this is added 
oil-soluble solvent such as methylene chloride and then mineral acid such 
as hydrochloric acid, followed by separation to an oil layer and a water 
layer. In this case, it is preferred to adjust pH value of the water layer 
to a value of from 6 to 7 by dropping slowly 5% hydrochloric acid with ice 
cooling (0.degree. to 5.degree. C.). After the separation, the water layer 
is extracted several times with an oil-soluble solvent such as methylene 
chloride, and the extracts are combined, dehydrated with a dehydrating 
agent such as anhydrous magnesium sulfate, and the solvent for extraction 
is distilled off to obtain a chalcone derivative having 
tetrahydropyranyloxy group of a color of from yellow to brown. 
The chalcone derivatives having one or more tetrahydropyranyloxy groups can 
be converted into hydroxychalcone derivatives by decomposition with water 
or alcohols to unprotect the tetrahydropyranyloxy group(s). For example, 
in the case of 2'-hydroxy-4,4'-bis(tetrahydropyranyloxy)chalcone (compound 
(II-3) above) obtained as described above, 4,2',4'-trihydroxychalcone can 
be obtained. 
##STR14## 
The removal of the protective group is carried out in the presence of an 
acid catalyst. As for the acid catalyst, there can be used, for example, 
p-toluenesulfonic acid, formic acid, acetic acid, hydrochloric acid, 
sulfuric acid, and the like. The solvent which can be used preferably 
includes water, lower alcohols such as methanol, ethanol, propanol, and 
the like, and mixtures thereof. Water is added to the resulting 
hydrolysate to crystalize the reaction product or the reaction product is 
extracted with an organic solvent such as ethyl acetate to obtain 
hydroxychalcone. 
In this way, various hydroxychalcones can be obtained through the chalcone 
derivatives having at least one tetrahydropyranyloxy group according to 
the present invention. Concrete examples thereof are shown in Table 1 
below. 
In Table 1, "--OH" represents a hydroxyl group, "THPO" a 
tetrahydropyranyloxy group, and "Me" a methyl group, and "Kind" indicates 
the type of general formula under which the chalcone derivatives of the 
present invention fall. 
TABLE 1 
__________________________________________________________________________ 
Chalcone Derivative of Invention 
Hydroxychalcone 
Kind 
Chemical Structure Chemical Structure 
__________________________________________________________________________ 
I-1 3,4,3'-Tris(THPO)chalcone 
3,4,3'-Tri(OH)chalcone 
I-2 3,4,4'-Tris(THPO)chalcone 
3,4,4'-Tri(OH)chalcone 
II-1 
2'-OH-3,4-Bis(THPO)chalcone 
3,4,2'-Tri(OH)chalcone 
II-2 
2'-OH-4'-(THPO)chalcone 
2',4'-Di(OH)chalcone 
II-3 
2'-OH-4,4'-Bis(THPO)chalcone 
4,2',4'-Tri(OH)chalcone 
II-4 
2'-OH-3,4,4'-Tris(THPO)chalcone 
3,4,2',4'-Tetra(OH)chalcone 
II-5 
2'-OH-4,4'-Bis(THPO)-3-OMe-chalcon 
4,2',4'-Tri(OH)-3-OMe-chalcone 
II-6 
2'-OH-3,4'-Bis(THPO)-4-OMe-chalcone 
3,2',4'-Tri(OH)-4-OMe-chalcone 
II-7 
2'-OH-2,3,4,4'-Tetrakis(THPO)chalcone 
2,3,4,2',4'-Penta(OH)chalcone 
II-8 
2'-OH-3,4,5,4'-Tetrakis(THPO)chalcone 
3,4,5,2',4'-Penta(OH)chalcone 
II-9 
2'-OH-4',6'-Bis(THPO)chalcone 
2',4',6'-Tri(OH)chalcone 
II-10 
2'-OH-4,4',6'-Tris(THPO)chalcone 
4,2',4',6'-Tetra(OH)chalcone 
II-11 
2'-OH-3,4,4',6'-Tetrakis(THPO)chalcone 
3,4,2',4',6'-Penta(OH)chalcone 
__________________________________________________________________________ 
Thus, when the compounds described in the right hand column are derived 
from the corresponding compounds described in the left hand column the 
respective yields can be improved about 4 times as high as in the cases 
where the former compounds are prepared directly from acetophenone 
compounds and benzaldehyde derivatives. This is because the yield of the 
reaction in which hydroxyl groups of acetophenone and benzaldehyde are 
substituted with tetrahydropyranyloxy groups can be made as high as, for 
example, 90% or more, and the yield of Claisen condensation products 
derived from the derivatives after the thus-performed protection of 
hydroxyl groups by the substitution can also be made as high as, for 
example, 90% or more. The latter factor is believed to give greater 
contribution to improvement in the yield of hydroxychalcones. 
The process of producing hydroxychalcone derivatives according to the 
present invention is economically advantageous since the protection 
reaction of hydroxyl groups for the introduction of tetrahydropyranyl 
groups can be carried out by using acid catalysts, Claisen condensation 
reaction by using basic catalysts, and the reaction for the elimination of 
tetrahydropyranyl groups to unprotect hydroxyl groups by using acid 
catalysts, and the respective reactions can be performed in generally 
employed solvents. 
The thus-obtained hydroxychalcones as listed in the right hand column in 
Table 1 are known to have pharmacological activities. For example, the 
pharmacological activities of the hydroxychalcone compound described in 
Table 1 under type number II-3 are as described hereinbefore, the 
corresponding compounds described in the left hand side column are useful 
as intermediates for producing such hydroxychalcones. 
The above-described processes for the production of chalcone derivatives 
having a hydroxyl group and a tetrahydropyranyloxy group, and for the 
decomposition of them with water or alcohols can also be applied to those 
chalcone derivatives starting from acetophenone or its derivatives and 
benzaldehyde or its derivatives which reactants each have substituents 
other than hydroxyl groups. As for the other substituents, there can be 
cited, for example, a nitro group, an amino group, a halogen atom, an 
alkyl group, an alkenyl group, an aryl group, an aryloxy group, and the 
like. The chalcone derivatives may have one or more of these substituents.