Glucosylmoranoline derivatives and use thereof for inhibiting increase in blood sugar levels

Compounds of formula I are useful in the prophylaxis or treatment of hyperglycemic symptoms ##STR1## wherein R is alkyl substituted by one or more hydroxy.

The present invention is directed to compounds of formula (I) 
##STR2## 
in which R is alkyl substituted by one or more hydroxyl moieties. 
Compounds (I) are useful as agents that inhibit blood sugar level 
increase. 
Moranoline, which is represented by the formula (II) below, has been 
isolated from Mori Cortex, which is a crude drug of natural origin (cf. 
Yagi, et al., Nippon Nogei Kagaku Kaishi, volume 50, page 571, 1976 and 
Japanese published patent application No. 52-83951): 
##STR3## 
Moranoline (II) has also been manufactured by fermentation using 
microorganisms belonging to the genus Streptomyces (cf. Japanese published 
patent application No. 54-84094). 
While moranoline (II) exhibits inhibitory action against blood sugar 
increase in animals loaded with sugar, and it is useful in the treatment 
of diabetes mellitus, derivatives having an improved effect have been 
proposed, namely 4-(alpha-D-glucosyl)-moranoline and 
4-(alpha-D-glucosyl)-N-lower alkylmoranolines represented by the following 
structural formula (III), (cf. Japanese published patent application Nos. 
54-159417 and 55-76838): 
##STR4## 
(where R.sup.1 represents H or lower alkyl) 
The compounds (I) of the invention have a stronger inhibitory action 
against blood sugar increase with less toxicity than moranoline (II) and 
the moraniline derivitives (III) and hence are useful in the treatment of 
diabetes mellitus. 
The characteristic feature of the compounds (I) of the present invention is 
the hydroxy-substituted alkyl group located at the nitrogen atom in the 
ring. There does not appear to be any limitation on the number of hydroxy 
substituents, and generally from about 1 to about 8, preferably from about 
1 to about 4, hydroxy groups will be present. Similarly, there does not 
appear to be any limitation on the number of carbon atoms in the alkyl 
moiety, and generally from about 1 to 8, preferably from about 1 to about 
4, carbon atoms will be present. The term "alkyl" as used herein includes 
both straight and branched chain alkyl. 
Representative compounds (I) of the present invention include: 
4-O-alpha-D-Glucopyranosyl-N-(2-hydroxyethyl)moranoline; 
4-O-alpha-D-Glucopyranosyl-N-(2-hydroxypropyl)moranoline; 
4-O-alpha-D-Glucopyransoyl-N-(3-hydroxypropyl)moranoline; and 
4-O-alpha-D-Glucopyranosyl-N-(2,3-dihydroxypropyl)moranoline. 
Compounds (I) are basic and, accordingly, form salts with various types of 
acids. The present invention includes compounds (I) and pharmaceutically 
acceptable salts thereof. 
Compounds (I) may be prepared by treating 
4-O-alpha-D-glucopyranosylmoranoline, i.e. compound III in which R' is 
hydrogen, with an epoxide in an inert solvent; or with a beta-halohydrin 
in a polar solvent; or with an alpha-haloketone followed by reduction to 
provide the hydroxy group or groups. 
Alternatively, compounds (I) can be prepared by reacting N-hydroxyalkyl 
moranoline (IV) 
##STR5## 
in solution with cyclodextrin or soluble starch, followed by reaction with 
cyclodextringlycosyltransferase to give the oligoglucosylmoranoline 
derivative (V) 
##STR6## 
wherein R is as defined above and n is an integer from zero to about 15. 
Compound (V) may be isolated from the reaction mixture by any suitable 
means, such as column chromatography. If desired, the reaction solution 
containing compound (V) may be used as such in the next reaction step, 
wherein compound (V) is reacted with a glucoamylase to provide compound 
(I). Glucoamylase available in the market may be used. After the reaction, 
compound (I) may be isolated by, for example, a column chromatography. 
Compound (I) may be purified by a conventional column chromatographic 
technique such as with Sephadex G-15. 
The inhibitory action of compounds (I) of the present invention against 
blood sugar level increase was confirmed by the following tests. 
Starch (soluble starch; Kanto Kagaku KK) (2 g/kg) was given orally to four 
male beagles (26 months of age; 11-14 kg body weight) and the inhibitory 
effect of the present invention compound given orally at the same time 
against blood sugar level increase was tested. Starch (20 g) was added to 
100 ml of water followed by heating to dissolve the starch and 10 ml of 
the solution per 1 kg of body weight was administered. Blood was taken 
from the artery of front and central part of the forepaw at predetermined 
time intervals and 25 microliters of blood was placed in an YS-1 
glucoanalyzer (model 23A) (manufactured by K. K. Nikkaki) to determine the 
blood sugar level. The group administered with starch only and that with 
water (10 ml/kg body weight) only were named control and basal, 
respectively, and the test compound was administered orally to the animals 
in doses of 1, 3, and 10 mg/kg together with starch. During the test, four 
beagles were kept at a constant temperature ( 23.degree..+-.2.degree. C.) 
and a constant humidity (55.+-.5%) with a dark-bright cycle every 12 hours 
and, in the evening, 300 g of dog food (CD-1, manufactured by Nippon Kurea 
K.K.) was given daily. The results of four examples of each test group is 
given in Table 1. The values therein is (average value).+-.(standard 
deviation). 
It is apparent from the result that the compounds (I) of the present 
invention exhibit an inhibitory action against blood sugar level increase. 
TABLE 1 
______________________________________ 
Compound + Dose 
(Example Number) 
Blood Sugar Level (mg/dl) 
(mg/kg) 0 min 15 min 30 min 45 min 
______________________________________ 
.circle.1 
Basal 56 .+-. 2 
57 .+-. 3 
55 .+-. 2 
56 .+-. 2 
.circle.2 
Control 56 .+-. 2 
87 .+-. 12 
113 .+-. 13 
116 .+-. 6 
.circle.3 
1 (1) 56 .+-. 1 
77 .+-. 8 
94 .+-. 3 
94 .+-. 6 
.circle.4 
1 (3) 54 .+-. 2 
69 .+-. 5 
77 .+-. 8 
86 .+-. 6* 
.circle.5 
1 (10) 56 .+-. 2 
68 .+-. 3 
73 .+-. 5* 
69 .+-. 2* 
.circle.6 
2 (1) 57 .+-. 2 
63 .+-. 2 
106 .+-. 5 
118 .+-. 6 
.circle.7 
2 (3) 56 .+-. 1 
84 .+-. 12 
104 .+-. 4 
100 .+-. 6 
.circle.8 
2 (10) 55 .+-. 2 
60 .+-. 2 
71 .+-. 6* 
81 .+-. 7* 
______________________________________ 
Blood Sugar Level (mg/dl) 
60 min 75 min 90 min 120 min 180 min 
______________________________________ 
.circle.1 
56 .+-. 1 54 .+-. 1 
55 .+-. 2 
52 .+-. 2 
50 .+-. 1 
.circle.2 
114 .+-. 6 
90 .+-. 8 
68 .+-. 6 
53 .+-. 3 
52 .+-. 2 
.circle.3 
86 .+-. 6* 
87 .+-. 6 
80 .+-. 4 
66 .+-. 1 
53 .+-. 3 
.circle.4 
82 .+-. 4** 
81 .+-. 4 
77 .+-. 2 
65 .+-. 4 
53 .+-. 2 
.circle.5 
68 .+-. 3*** 
72 .+-. 3 
65 .+-. 1 
65 .+-. 4 
50 .+-. 3 
.circle.6 
113 .+-. 11 
98 .+-. 9 
82 .+-. 4 
60 .+-. 3 
51 .+-. 2 
.circle.7 
92 .+-. 5* 
78 .+-. 3 
69 .+-. 2 
65 .+-. 52 .+-. 2 
.circle.8 
87 .+-. 5* 
78 .+-. 5 
74 .+-. 1 
64 .+-. 3 
52 .+-. 1 
______________________________________ 
* P &lt; 0.05, ** P &lt;0.01, *** P &lt; 0.001 
When the present invention compounds (Examples 1 and 2) were orally given 
to mice at 5 g/kg for checking the toxicity, there was no case of death. 
When the present invention compounds (Examples 1 and 2) were administered 
at 400 mg/kg to rats for consecutive five days by intraperitoneal route, 
there was no abnormal observation in clinical state, biochemical values of 
serum, and hematological data at all. Thus, the toxicity of the present 
invention compounds is very little. 
The present invention provides a pharmaceutical composition for prophylaxis 
or treatment of hyperglycemic symptoms, which comprises an amount of 
compound (I) effective to inhibit the increase of blood sugar, together 
with a pharmaceutically acceptable non-toxic, inert diluent or carrier 
therefor. 
The present invention also provides a method for the prophylaxis or 
treatment of hyperglycemic symptoms in humans and animals, which comprises 
administering to a human or animal in need thereof an amount of compound I 
effective to inhibit the increase of blood sugar. 
Compounds (I) are used in the same manner as known inhibitors of blood 
sugar level increase, such as the known moranoline derivatives. 
Compounds (I) can be administered as such or in the form of the above 
pharmaceutical composition containing, for example, 0.1 to 99.5% or 
preferably 0.5 to 90% of compound (I) and a pharmaceutically acceptable 
non-toxic inert carrier. The carrier may be one or more solid, semisolid 
or liquid diluent, filler or auxiliary agent used for pharmaceutical 
preparations. The pharmaceutical composition is preferably administered in 
a form of unit dose. 
Compounds (I) may be administered orally, parenterally, topically or by 
rectum. Oral administration is especially preferred. 
Suitable dosages for diabetes mellitus will be determined by taking into 
account the state of the patient (e.g. age, body weight, etc.), 
administration route, type and degree of the disease, and the like. 
Usually it is preferred that the daily dose range from about 10 to 2000 mg 
and, more preferably from about 100 to about 600 mg. In some cases, a 
smaller dose may be sufficient while, in other cases, a larger dose may be 
necessary. It may also preferred that the daily dose is divided when given 
to the patient.

The present invention is further illustrated by the following Examples. 
EXAMPLE 1A 
4-O-alpha-D-Glucopyranosylmoranoline (10 g) was dissolved in 150 ml of hot 
dimethyl sulfoxide and 16 g of potassium carbonate was added thereto. 
Ethylene bromohydrin (18 g) was added thereto with stirring and the 
mixture was made to react at 100.degree.-110.degree. C. for 3 hours. After 
the reaction, the mixture was filtered to remove the insoluble matter, 
then 150 ml of water was added, and the mixture was gently stirred. This 
was passed through 300 ml of strongly acidic ion exchange resin (Dowex 
50W.times.2 (H+)) so that the object compound was adsorbed therein. The 
column was well washed with water, eluted with 0.5N ammonia water, the 
eluate was concentrated in vacuo, then treated with an activated carbon, 
and concentrated to dryness in vacuo. To this was added acetone and the 
matter which was soluble in acetone was removed. The acetone-insoluble 
matter was dissolved in suitable amount of hot water and was crystallized 
using ethanol. Crystals were collected by filtration and were similarly 
recrystallized and 6.0 g of the final product, i.e. 
4-O-alpha-D-glucopyranosyl-N-(2-hydroxyethyl)moranoline was obtained. 
M.p. 98.degree.-101.degree. C. 
[.alpha.].sub.D.sup.24 =+76.7.degree. (1%, water) 
Example 1B. 
Manufacture of the same compound as in Example 1A utilizing enzymes, is 
disclosed in this example. 
Culture of Bacillus mascerans 
A culture liquid (100 ml; pH 7) containing 1% corn steep liquor, 1% soluble 
starch, 0.5% ammonium sulfate and 0.5% calcium carboante was placed in a 
500 ml Erlenmeyer flask and sterilized by heating at 120.degree. C. for 15 
minutes. Three platinum loops of Bacillus macerans IFO 3490 strain fully 
grown on a slant medium of 1% peptone, 0.5% yeast, 0.3% glucose, 1.5% 
glycerol, 0.3% sodium chloride, 2.5% liver powder (OXOID-trademark), and 
1.5% agar were inoculated thereupon and subjected to a shake culture at 
37.degree. C. for 3 days. The culture liquid (600 ml) was inoculated on 18 
liters of the medium of the same composition in a 30 liter jar fermentor 
and cultured at 37.degree. C. for 3 days with full aeration and stirring 
to give an enzyme solution of 130 to 150 units as a supernatant liquid 
after centrifugation. 
Unit of activity of cyclodextrin glycosyltransferase 
In 0.05M acetate buffer (pH 5.5) was dissolved 0.7% of soluble starch (for 
biochemical study; manufactured by Nakarai Chemical Co) to prepare a 
substrate solution. To 950 microliters of this substrate solution was 
added 50 microliters of enzyme solution, the mixture was made to react at 
40.degree. C. for 10 minutes, and the reaction was made stopped by 
addition of 0.5 ml of 0.5N acetic acid. After the reaction, 100 
microliters of the reaction solution was taken out and 3 ml of water and 
0.8 ml of iodine solution (in 0.25M potassium iodide solution was added 
iodine to make its concentration 0.01M) were added thereto. The mixture 
was stirred and the extinction at 660 nm was measured (an AT value). 
Similarly, to 950 microliters of the substrate solution were added 50 
microliters of water and 0.5 ml of 0.5N acetic acid and 100 microliters of 
the resulting mixture was treated with the iodide solution and the 
extinction at 660 nm was measured (an AR value). 
EQU One unit=[(AR-AT)/AR].times.100.times.2 
This one unit is an activity causing a decrease of 1% extinction of the 
enzyme solution at 40.degree. C. for 1 minute. 
Preparation of the crude enzyme solution 
The culture liquid of B. macerans IFO 3490 is centrifuged to give a 
supernatant liquid. This was lyophilized, dissolved in small quantities of 
water, and a concentrated enzyme solution was obtained. This was well 
dialyzed at 5.degree. C. to water and the inner solution free from low 
molecular substances was used as an enzyme solution. If necessary, it was 
lyophilized and the resulting powder was used. 
N-(2-Hydroxyethyl)moranoline (5 g) was dissolved in small amount of water, 
the solution was adjusted to pH 5.7 with 3N hydrochloric acid, and made 25 
ml with water. alpha-Cyclodextrin (80 g) was dissolved in 3975 ml of crude 
enzyme solution (250 units/ml), N-(2-hydroxyethyl)moranoline solution was 
added thereto, and the mixture was readjusted to pH 5.7. This was shaken 
at 40.degree. C. for 3 days to cause a reaction. The reaction solution was 
centrifuged, the supernatant liquid was passed through a column (200 ml) 
of Dowex 5oW.times.2 (H.sup.+), strongly acidic ion exchange resin, so 
that basic substances were adsorbed. The column was well washed with 
water, eluted with 0.5N ammonia water, the eluate was concentrated to 
dryness in vacuo, and 14.8 g of mixture of 
oligoglucosyl-N-(2-hydroxyethyl)moranolines was obtained. 
This was analyzed by a high-speed liquid chromatography and was found to be 
a mixture of 15% of N-(2-hydroxyethyl)moranoline and 85% of 
oligoglucosyl-N-(2-hydroxyethyl)moranoline. The conditions for said 
high-speed liquid chromatography were as follows. 
Sumipax R741 (Nucleosil 5NH.sub.2, 5 micrometers, 4 mm ID.times.25 cm). 
Solvent: acetonitrile-water (65/35). Rate of liquid flow: 1 ml/min. RI 
Detection (Elmer Optical Co., ERC-7510). Data processor (manufd by Hitachi 
Ltd., 655-60). 
The oligoglucosyl-N-(2-hydroxyethyl)moranoline mixture (10 g) obtained 
hereinabove was dissolved in 50 ml of water and the solution was adjusted 
to pH 5.1. Water was added thereto to make the total volume 100 ml and 250 
ml of glucoamylase (Glucozyme AF-6, manufd by Nagase Sangyo Co) was added. 
The mixture was made to react at 50.degree. C. for 24 hours, the reaction 
was ceased by heating at 80.degree. C., and cooled to ambient temperature. 
The reaction solution was centrifuged, the supernatant liquid was passed 
through a column (200 ml resin volume) of strongly acidic ion exchange 
resin, and the column was well washed with water. The column was then 
eluted with 0.5N ammonia water and the eluate was concentrated to dryness 
in vacuo to give 5.6 g of powder. 
This was subjected to an analysis by a high-speed chromatography the same 
as before and found to be a mixture of 28.8% of 
N-(2-hydroxyethyl)moranoline, 71.0% of 
4-O-alpha-D-glucopyranosyl-N-(2-hydroxyethyl)moranoline, and 0.2% of 
4-O-alpha-D-maltosyl-N-(2-hydroxyethyl)moranoline. 
EXAMPLE 1C 
Soluble starch (8 g) was dissolved in 50 ml of hot water 1 g of 
N-(2-hydroxyethyl)moranoline was dissolved therein. The solution was 
cooled to 40.degree. C., adjusted to pH 5.7, and 50 ml of a crude enzyme 
solution (4000 units/ml) was added thereto. This was readjusted to 5.7 
and made to react at 40.degree. for 3 days with shaking. The reaction was 
ceased by heating at 80.degree. C. for 20 minutes, cooled to 50.degree. 
C., adjusted to pH 5.1, 500 ml of glucoamylase (Glucozyme AF-6, manufd by 
Nagase Industry Co) was added thereto, and the mixture was made to react 
at 50.degree. C. for 24 hours. The reaction was ceased by heating at 
80.degree. C. for 20 minutes, cooled to ambient temperature, and 
centrifuged. The supernatant liquid was passed through a column (100 ml of 
resin) of strongly acidic ion exchange resin Dowex 50W.times.2 (H.sup.+) 
to make basic substances adsorbed. The column was well washed with water, 
eluted with 0.5N ammonia water, and the eluate was concentrated to dryness 
in vacuo to give 1.8 g of powder. 
This was analyzed by a high-speed liquid chromatography and found to be a 
mixture of 29% of N-(2-hydroxyethyl)moranoline, 70% of 
4-O-alpha-D-glucopyranosyl-N-(2-hydroxyethyl)moranoline, and 1% of 
4-O-alpha-D-maltosyl-N-(2-hydroxyethyl)moranoline. The high-speed liquid 
chromatographic condition was the same as above with an exception that the 
developer was a mixture of acetonitrile and water (70:30). 
The above mixture powder (1.5 g) was dissolved in small amount of water, 
the solution was passed through a column (48 mm diameter.times.850 mm) of 
Sephadex G-15 and the column was developed with distilled water wherefrom 
each 5 ml of fraction was collected. 
Each fraction was analyzed by a high-speed liquid chromatography to collect 
desired fractions were combined and concentrated to dryness in vacuo. The 
resulting powder was recrystallized from aqueous ethanol to give 550 mg of 
4-O-alpha-D-glucopyranosyl-N-(2-hydroxyethyl)moranoline. M.p. 
99.degree.-102.degree. C. [.alpha.].sub.D.sup.25 =+76.5.degree. (1%, 
water). 
Example 2A 
4-O-alpha-D-Glucopyranosylmoranoline (10 g) was dissolved in 150 ml of hot 
dimethyl sulfoxide and 16 g of potassium carbonate was added thereto. 
Epibromohydrin (20 g) was added thereto with stirring and the mixture was 
made to react at 100.degree.-110.degree. C. for 3 hours. After the 
reaction, the mixture was filtered to remove the insoluble matter. Water 
(150 ml) was added thereto and the mixture was gently stirred. This was 
passed through a column of 300 ml of strongly acidic ion exchange resin 
(Dowex 50W.times.2 (H.sup.+)) and the object compound was adsorbed 
therein. The column was well washed with water, eluted with 0.5N ammonia 
water, the eluate was refluxed with stirring at 80.degree. C. for 3 hours, 
concentrated in vacuo, treated with an activated carbon, passed through a 
column of 200 ml of Diaion HP-200, and washed with water. The passed 
solution and washing solution were combined, the mixture was concentrated 
in vacuo, the concentrate was dissolved in methanol, the methanolic 
solution was treated with 3 liters of Sephadex LH-20, the column was 
developed with methanol, fractions containing the object compound were 
collected, then methanol was evaporated therefrom, the residue was 
dissolved in suitable quantity of hot water, and crystallized with 
ethanol. Crystals were collected by filtration and similarly 
recrystallized to give 5.0 g of the final product, i.e. 
4-O-alpha-D-glucopyranosyl-N-(2,3-dihydroxypropyl)moranoline. m.p. 
83.degree.-85.degree. C. [.alpha.].sub.D.sup.24 =+73.7.degree. (1%, water) 
EXAMPLE 2B 
Manufacture of the same compound as in Example 2A utilizing enzymes, is 
disclosed in this example. 
Soluble starch (8 g) was dissolved in 50 ml of hot water and 1 g of 
N-(2,3-dihydroxypropyl)moranoline was dissolved therein. The solution was 
cooled to 40.degree. C., adjusted to pH 5.7, and 50 ml of crude enzyme 
solution (4000 units/ml) was added thereto. The solution was readjusted to 
pH 5.7 and made to react at 40.degree. C. for 3 days with shaking. Then 
this was treated by similar manner as Example 2 to give 1.6 g of mixture 
of 31% of N-(2,3-hydroxypropyl)moranoline, 68% of 
4-O-alpha-D-glucopyranosyl-N-(2,3-dihydroxypropyl)moranoline, and 1% of 
4-O-alpha-D-maltosyl-N-(2,3-dihydroxypropyl)moranoline. 
This mixture powder (1.5 g) was dissolved in small amount of waer, the 
solution was passed through a column (48 mm diameter.times.850 mm) of 
Sephadex G-15, developed with distilled water, and each 5 ml of fraction 
was collected. Each fraction was analyzed by a high-speed liquid 
chromatography to collect object fractions and concentrated to dryness in 
vacuo. The resulting powder was recrystallized from aqueous ethanol to 
give 505 mg of 
4-O-alpha-D-glucopyranosyl-N-(2,3-dihydroxypropyl)moranoline. M.p. 
83.degree.-86.degree. C. [.alpha.].sub.D.sup.25 =+72.3.degree. (1%, 
water). 
EXAMPLE 3 
L-Arabinose tetraacetate (Wolfrom, et al.: J. Am. Chem. Soc. 63, 201, 1941) 
was reduced and brominated to give 2,3,4,5-tetra-O-acetylpentyl-1-bromide. 
This substance (11.8 g) and 5 g of 4-O-alpha-D-glucopyranosylmoranoline 
were dissolved in 50 ml of dimethylformamide, the solution was added to 
6.4 g of anhydrous potassium carbonate, and the mixture was made to react 
at 100.degree. C. for 5 hours. The reaction solution was filtered and the 
solvent was evaporated therefrom. The residue was dissolved in water and 
passed through a column of 100 ml of strongly acidic ion exchange resin 
[Dowex 50W.times.2 (H.sup.+)]. The column was well washed with water and 
eluted with 1N ammonia water. The eluate was heated at 70.degree. C. for 1 
hour to deacetylate and the solvent was evaporated in vacuo. The residue 
was dissolved in water and the solution was passed through a column of 100 
ml of strongly acidic ion exchange resin [Dowex 50W.times.2 (H.sup. +)]. 
The column was well washed with water and eluted with 0.5N ammonia water. 
The solvent was evaporated therefrom. The residue was dried, dissolved in 
methanol, 4.5 g of p-toluenesulfonic acid monohydrate was added to make it 
crystallized. After filtration, the crystals were dried and 3.4 g of 
4-O-alpha-D-glucopyranosyl-N-(2,3,4,5-tetrahydroxy-n-pentyl)moranoline 
p-toluenesulfonate was obtained. M.p. 195.degree.-198.degree. C. 
[.alpha.].sub.D.sup.24 =+139.2.degree. (c=1%, water). 
EXAMPLE 4 
4-O-alpha-D-Glucopyranosylmoranoline (5 g) was dissolved in 50 ml of 
dimethylformamide. To this was added 10 ml of cyclohexene oxide and the 
mixture was stirred by heating at 110.degree. C. for 20 hours. Then the 
mixture was diluted with water to wash n-hexane. This was passed through a 
column of 100 ml of strongly acidic ion exchange resin [Dowex 50W.times.2 
(H.sup.+)] to make the object compound adsorbed and washed well with 
water. The column was eluted with 0.5N ammonia water, the solvent was 
evaporated therefrom, dried, then dissolved in methanol, and 4.5 g of 
p-toluenesulfonic acid monohydrate was added to make it crystallized. The 
mixture was filtered and dried to give 5.8 g of 
4-O-alpha-D-glucopyranosyl-N-(2-hydroxycyclohexyl)moranoline. M.p. 
105.degree.-108.degree. C. [.alpha.].sub.D.sup.24 =+85.0.degree. (c=1%, 
water) 
Compounds (IV) can be prepared in the same manner as compounds (I), namely 
by treating moranoline (II) with an epoxide in an inert solvent, or with a 
beta-halohydrin in a polar solvent, or with an alpha-haloketone followed 
by reduction to provide the hydroxy group or groups. See Japanese 
published patent application No. 54-106,477.