2-Hydroxyalkyl-3,4,5-trihydroxy-piperidine compounds, their production and their medicinal use

The invention relates to .alpha.-hydroxyalkyl-3,4,5-trihydroxypiperidines defined by Formula (I), infra, and pharmaceutical compositions and medicaments containing said compounds. Also included in the invention are methods for the use of said compounds, compositions and medicaments as inhibitors of .alpha.-glucoside hydrolases; and intermediates for the compounds of said Formula (I).

The present invention relates to certain new 
2-hydroxyalkyl-3,4,5-trihydroxypiperidine compounds, to processes for 
their production and to their use as medicaments, in particular against 
diabetes, hyperlipoproteinameia, arteriosclerosis and adiposity. 
It has already been disclosed that N-alkyl and N-alkenyl derivatives of 
2-hydroxymethyl-3,4,5-trihydroxypiperidine are potent inhibitors for 
.alpha.-glucoside hydrolases (see European Published Patent Application 
947). 
According to the present invention there are provided compounds which are 
2-hydroxyalkyl-3,4,5-trihydroxypiperidines of the formula 
##STR1## 
in which R.sub.1 denotes a hydrogen atom or a saturated or unsaturated 
optionally substituted aliphatic radical, 
R.sub.2 denotes an optionally substituted alkyl, alkenyl, or aryl radical 
and 
R.sub.3 denotes a hydrogen atom or a sulpho or hydroxyl group. 
The new compounds of the present invention have an increased action on 
.alpha.-glucoside hydrolases. 
According to the present invention there are provided a process for the 
production of a compound of the present invention in which (a) a compound 
of the formula 
##STR2## 
in which R.sub.2 has the abovementioned meaning, 
is reacted with sulphur dioxide to give a compound of the formula (I) in 
which R.sub.1 denotes a hydrogen atom and R.sub.3 denotes an SO.sub.3 H 
group; 
this resulting compound is reacted, if desired, with a base or a basic ion 
exchanger to give a compound of the formula (I) in which R.sub.3 denotes 
an OH group; 
this resulting compound is reduced, if desired, to give a compound of the 
formula (I) in which R.sub.1 and R.sub.3 denote hydrogen atoms; and 
this resulting compound is subjected, if desired, to reductive alkylation 
with an aldehyde or to alkylation with an alkyl halide to give a compound 
of the formula (I) in which R.sub.3 denotes a hydrogen atom and R.sub.1 
has an abovementioned meaning, with the exception of hydrogen, or (b) 
where a compound of formula (I) in which R.sub.1 and R.sub.3 denote 
hydrogen atoms is desired, a compound of the formula 
##STR3## 
in which Bz denotes 
##STR4## 
and Ph denotes a phenyl radical, is reacted with a compound R.sub.2 MgX, 
in which R.sub.2 has the same meaning as in formula (I) and X denotes a 
halogen atom, and reacting the resulting compound of the formula 
##STR5## 
in which Bz, Ph and R.sub.2 have the abovementioned meanings, with sodium 
in liquid ammonia to give the following resulting compound of the formula 
##STR6## 
in which 
R.sub.2 has the abovementioned meaning. 
A process for the production of compounds of the formula (II), using the 
starting compounds shown, is illustrated by the following equation: 
##STR7## 
A benzyloxycarbonyl or acetyl radical, for example, can be used as a 
protective group for the amino group. The compounds of the formula III in 
which R denotes CH.sub.3 or BzO-- are important intermediate compounds for 
the preparation of the compounds of formula (I) of the present invention. 
They are a further subject of the present invention. 
Examples of these novel intermediate compounds and their production are 
given in the preparative Examples. 
Further details of reaction variant (a), now follow. 
The step of reacting compounds of formula (II) with SO.sub.2 with splitting 
off of the isopropylidene group and formation of the piperidine ring is 
generally carried out by a procedure in which an aqueous or 
water-containing alcoholic solution of the compounds of the formula (II) 
is saturated with SO.sub.2 and kept at temperatures between 20.degree. C. 
and 50.degree. C. for several days. The compounds of the formula (I) are 
then obtained as bisulphite adducts (in which R.sub.3 denotes --SO.sub.3 
H), which in most cases crystallise well and from which the compounds of 
the formula (I) (in which R.sub.3 denotes --OH) can be liberated in a 
further step with the aid of, for example, aqueous Ba(OH).sub.2. 
The step of reducing compounds of the formula (I) in which R.sub.3 denotes 
OH to give compounds of the formula (I) in which R.sub.3 denotes a 
hydrogen atom is generally carried out using alkali metal borohydrides, 
alkali metal cyanoborohydrides or dialkylaminoboranes in which each alkyl 
group preferably contains 1 to 4 carbon atoms. It is preferable to use 
sodium cyanoborohydride in aqueous solution or in a water-miscible 
water-containing organic solvent, such as methanol, at room temperature or 
if appropriate elevated temperature. However, the reduction is very 
particularly preferably carried out catalytically with Pt or Pd as the 
catalyst or in the presence of Raney nickel. This procedure is preferably 
carried out in aqueous solution at room temperature. 
Alkali metal cyanoborohydrides, dialkylaminoboranes and alkali metal 
borohydrides may be used as hydrogen donor reducing agents for the 
reductive alkylation step. It is particularly preferable to use sodium 
cyanoborohydride in this process variant. The reaction is in general 
carried out at temperatures between -20.degree. C. and room temperature. 
However, it may also be favourable to heat the mixture to the reflux 
temperature. 
The reductive alkylation step is usually carried out in an inert solvent. 
Although anhydrous aprotic solvents can be employed (for example 
tetrahydrofurane, if the reducing agent is morpholinoborane), a protic 
solvent is nevertheless usually employed. Particularly suitable protic 
solvents are C.sub.1 -C.sub.6 alkanols. However, it is also possible to 
use water or an aqueous C.sub.1 -C.sub.6 alkanol (for example aqueous 
methanol or ethanol) or other aqueous solvent systems, such as aqueous 
dimethylformamide, aqueous hexamethylphosphoric acid triamide, aqueous 
tetrahydrofurane or aqueous ethylene glycol dimethyl ether. 
The reductive alkylation step is usually carried out in a pH range from 1 
to 11, and a pH range from 4 to 7 is preferred. 
The alkylation step is illustrated by the following equation using the 
reactants indicated: 
##STR8## 
"Hal" denotes Br, I, Cl, O-mesyl or O-tosyl "base" denotes K.sub.2 
CO.sub.3, NaOH or KOH 
"solvent" denotes dimethylformamide, dimethylsulphoxide or mixtures thereof 
with H.sub.2 O. 
In reaction variant (b) the aldehyde of formula (IV) employed can be 
prepared by oxidising the corresponding alcohol with 
dicyclohexylcarbodiimide in dimethylsulphoxide in the presence of 
phosphoric acid. 
The two processes for the production of compound IV are illustrated by the 
following equations: 
##STR9## 
Compound IV, the corresponding alcohol and 
N,7-O-Cyclocarbamato-2-hydroxymethyl-3,4,5-trihydroxypiperidine are 
important intermediate compounds for the preparation of the compounds of 
formula I of the present invention. 
These three compounds and their preparation are therefore a further subject 
of the present invention. 
Preferred compounds of formula (I) of the present invention are those in 
which R.sub.1 denotes a hydrogen atom, a C.sub.1 to C.sub.10 alkyl, 
C.sub.3 to C.sub.6 alkenyl or C.sub.5 to C.sub.10 alkadienyl radical which 
is optionally substituted by hydroxyl or C.sub.1 to C.sub.4 alkoxy, or a 
radical of the general formula 
##STR10## 
in which R.sub.4 denotes a hydrogen or halogen (preferably fluorine, 
chlorine or bromine) atom or a 
C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, nitro or cyano 
radical, 
R.sub.2 denotes a C.sub.1 to C.sub.10 alkyl, C.sub.2 to C.sub.6 alkenyl or 
C.sub.4 to C.sub.10 alkadienyl radical which is optionally substituted by 
hydroxyl, C.sub.1 to C.sub.4 alkoxy or phenyl, which can in turn be 
substituted by C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, 
halogen (preferably fluorine, chlorine or bromine), nitro or cyano, or 
denotes a phenyl radical which is optionally substituted by C.sub.1 to 
C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, halogen, (preferaably fluorine, 
chlorine or bromine), nitro, or cyano, and R.sub.3 has the above-mentioned 
meaning. 
Particularly preferred compounds of formula (I) of the present invention 
are those in which R.sub.1 denotes a hydrogen atom or a C.sub.1 to 
C.sub.10 alkyl, hydroxyethyl, phenoxyethyl, allyl, but-2-enyl, 
penta-2,4-dienyl, hexa-2,4-dienyl, hepta-2,4-dienyl or 
##STR11## 
radical, R.sub.2 denotes a C.sub.1 to C.sub.6 alkyl, allyl, benzyl or 
phenyl radical, and R.sub.3 has the abovementioned meaning. 
Very particularly preferred compounds of formula (I) of the present 
invention are those in which R.sub.1 denotes a hydrogen atom or a methyl, 
ethyl, propyl, hexyl, allyl, 2-propen-1-yl, 2,4-hexadien-1-yl, cinnamyl or 
2-phenoxyethyl radical, R.sub.2 denotes a methyl or ethyl radical and 
R.sub.3 denotes a hydrogen atom, or R.sub.1 denotes a hydrogen atom, 
R.sub.2 denotes a methyl radical and R.sub.3 denotes a sulpho or hydroxyl 
radical. 
The inhibitors according to the invention are suitable as therapeutic 
agents for the following indications in warm-blooded animals: prediabetes, 
gastritis, constipation, caries, infections of the gastro-intestinal 
tract, meteorism, flatulence, hypertension and, in particular, 
arteriosclerosis, adiposity, diabetes and hyperlipoproteinaemia. 
The combining of inhibitors for glycoside hydrolases which complement one 
another in their action may be recommended to broaden the action spectrum, 
these being either combinations of the inhibitors according to the 
invention with one another or combinations of the inhibitors according to 
the invention with inhibitors which are already known. 
In some cases, combinations of the inhibitors according to the invention 
with known oral antidiabetic agents (.beta.-cytotropic sulphonylurea 
derivatives and/or biguanides which have an action on the blood sugar 
level) and with active compounds which lower the blood lipid level, such 
as, for example, clofibrate, nicotinic acid, cholestyramine and others, 
are also advantageous. 
The compounds can be administered without dilution, for example as powders 
or in a gelatin casing, or in a pharmaceutical composition in combination 
with an excipient. 
As stated above, the invention also relates to the use in medicine of the 
compounds of the invention. 
The present invention provides pharmaceutical compositions containing as 
active ingredients a compound of the invention in admixture with an inert 
pharmaceutical carrier, e.g. a solid or liquefied gaseous diluent, or in 
admixture with a liquid diluent other than a solvent of a molecular weight 
less than 200 (preferably less than 350) except in the presence of a 
surface active agent. 
The invention further provides pharmaceutical compositions containing as 
active ingredients a compound of the invention in the form of a sterile 
and/or physiologically isotonic aqueous solution. 
The invention also provides medicaments in dosage unit form comprising a 
compound of the invention. 
The invention also provides medicaments in the form of tablets (including 
lozenges and granules), dragees, capsules, pills, ampoules or 
suppositories comprising a compound of the invention. 
"Medicament" as used in this Specification means physically discrete 
coherent portions suitable for medical administration. "Medicament in 
dosage unit form" as used in this Specification means physically discrete 
coherent units suitable for medical administration each containing a daily 
dose or a multiple (up to four times) of submultiple (down to a fortieth) 
of a daily dose of the compound of the invention in association with a 
carrier and/or enclosed within an envelope. Whether the medicament 
contains a daily dose or, for example, a half, a thrid or a quarter of a 
daily dose will depend on whether the medicament is to be administered 
once or, for example, twice, three times or four times a day respectively. 
The pharmaceutical composition according to the invention may, for example, 
take the form of suspensions, solutions and emulsions of the active 
ingredient in aqueous or non-aqueous diluents or syrups. 
The pharmaceutical compositions according to the invention generally 
contain from 0.1% to 99.5% of the active ingredient by weight of the total 
composition. 
In addition to a compound of the invention, the pharmaceutical compositions 
and medicaments according to the invention can also contain other 
pharmaceutically active compounds. They may also contain a plurality of 
compounds of the invention. 
Any diluent in the medicaments of the present invention may be any of those 
mentioned above in relation to the pharmaceutical compositions of the 
present invention. Such medicaments may include solvents of molecular 
weight less than 200 as sole diluent. 
The discrete coherent portions constituting the medicament according to the 
invention will generally be adapted by virtue of their shape or packaging 
for medical administration and may be, for example, any of the following: 
tablets (including lozenges and granulates), pills, dragees, capsules, 
suppositories and ampoules. Some of these forms may be made up for delayed 
release of the active ingredient. Some, such as capsules, include a 
protective envelope which renders the portions of the medicament 
physically discrete and coherent. 
The preferred dialy dose for administration of the medicaments of the 
invention is 25 mg to 500 mg of active ingredient. 
The product of the above-mentioned pharmaceutical compositions and 
medicaments is carried out by any method known in the art, for example, by 
mixing the active ingredient(s) with the diluent(s) to form a 
pharmaceutical composition (e.g. a granulate) and then forming the 
composition into the medicament (e.g. tablets). 
This invention further provides a method of combating the above-mentioned 
diseases in warm-blooded animals, which comprises administering to the 
animals a compound of the invention alone or in admixture with a diluent 
or in the form of a medicament according to the invention. 
In general it has provided advantageous to administer amounts of from 0.05 
mg to 10 mg/kg of body weight per day, usually at all the main meal times 
and secondary meal times during the day, to achieve effective results. 
Nevertheless, it can at times be necessary to deviate from those dosage 
rates, and in particular to do so as a function of the nature and body 
weight of the warm-blooded animal subject to be treated, the individual 
reaction of this subject to the treatment, the type of formulation in 
which the active ingredient is administered and the mode in which the 
administration is carried out, and the point in the progress of the 
disease or interval at which it is to be administered. Thus it may in some 
case suffice to use less than the above-mentioned minimum dosage rate, 
whilst other cases the upper limit mentioned must be exceeded to achieve 
the desired results. Where larger amounts are administered it can be 
advisable to divide these into several individual administrations over the 
course of the day. 
The compounds according to the invention are formulated and administered in 
the same manner as that described in European Published Patent Application 
947.

The following examples illustrate processes for the production of compounds 
of the present invention. 
EXAMPLE 1 
(a) 
5-Acetamido-3-O-benzyl-5-desoxy-1,2-O-isopropylidene-6-O-triphenylmethyl-. 
alpha.-D-glucofuranose 
551 g of 
5-amino-5-desoxy-3-O-benzyl-1,2-O-isopropylidene-6-O-triphenylmethyl-.alph 
a.-D-glucofuranose (see S. Inouye, T. Tsurnoka, T. Ito and T. Nidda, 
Tetrahedron 24, 2125-2144 (1968)), 400 ml of methylene chloride, 400 ml of 
pyridine and 200 ml of acetic anhydride were brought together at 
0.degree.-20.degree. C. and the mixture was stirred at room temperature 
for 24 hours. The methylene chloride was then stripped off in vacuo, 300 g 
of ice were added to the residue and the mixture was stirred for 30 
minutes. It was extracted three times with 300 ml of chloroform each time 
and the extract was washed twice with water and twice with sodium 
bicarbonate solution, dried over sodium sulphate and concentrated in vacuo 
at a bath temperature of 40.degree. C. Yield: 600 g. 
(b) 
5-Acetamido-3-O-benzyl-5-desoxy-1,2-O-isopropylidene-.alpha.-D-glucofurano 
se 
600 g of crude 
5-acetamido-5-desoxy-3-O-benzyl-1,2-O-isopropylidene-6-O-triphenylmethyl-. 
alpha.-D-glucofuranose were dissolved in 1.5 ml of glacial acetic acid, 600 
ml of water were added and the mixture was stirred at 70.degree. C. for 2 
hours and at 20.degree. C. overnight. The reaction was followed by thin 
layer chromatography (chloroform/ethyl acetate 3:1 and chloroform/methanol 
10:1). The precipitate was filtered off, washed with glacial acetic 
acid/water 1:1 and discarded. The comined filtrates were evaporated at 
50.degree. C. in vacuo. The residue was taken up in 1 liter of ethyl 
acetate, insoluble constituents were filtered off and the ethyl acetate 
phase was washed with water and with sodium bicarbonate solution until 
neutral, dried over sodium sulphate and evaporated in vacuo. The resulting 
oil crystallised from methanol/water, yield: 101 g of melting point 
84.degree.-88.degree. C. The mother liquor was evaporated, the residue was 
taken up in a little ether, the mixture was discharged onto a silica gel 
column and the column was eluted successively with 6 liters of ether, 5 
liters of ethyl acetate and 2.5 liters of methanol. The ether eluate was 
discarded, the ethyl acetate eluate and the methanol eluate were each 
evaporated and the residue was crystallised from methanol/water. A total 
of 214 g (61%) of melting point 84.degree.-88.degree. C. was obtained. 
(c) 
5-Acetamido-3-O-benzyl-5-desoxy-1,2-O-iso-propylidene-.alpha.-D-glucofuran 
ose 
51 g of 
5-acetamido-6-O-acetyl-3-O-benzyl-5-desoxy-1,2-O-isopropylidene-.alpha.-D- 
glucofuranose (see H. Saeki et al, Chem. Pharm. Bull 26, 2477 (1968)), 160 
ml of methanol and 0.2 g of sodium methylate were stirred at room 
temperature overnight. The batch was then neutralised with CO.sub.2 (dry 
ice) and evaporated in vacuo, the residue was taken up in ethyl acetate, 
the ethyl acetate mixture was washed twice with water, dried over sodium 
sulphate and evaporated in vacuo and the residue was crystallised from 
ether/petroleum ether. Yield: 43 g (94% of theory) of melting point 
88.degree. C. 
(d) 
5-Acetamido-3-O-benzyl-5-desoxy-1,2-O-isopropylidene-.alpha.-D-gluco-hexod 
ialdo-1,4-furanose: 
21 g of 
5-acetamido-3-O-benzyl-5-desoxy-1,2-O-isopropylidene-.alpha.-D-glucofurano 
se, 54 ml of dimethylsulphoxide. 15 ml of benzene, 3 g of phosphoric acid 
and 37.5 g of dicyclohexylcarbodiimide were brought together, whilst 
cooling with ice, and the mixture was stirred at 20.degree.-25.degree. C. 
for 3 hours. For working up, 12 g of oxalic acid were slowly added, the 
mixture was stirred for 30 minutes, the precipitate was filtered off and 
washed with ethyl acetate, the filtrate was washed with 50 ml of saturated 
sodium bicarbonate solution and the aqueous phase was washed three times 
with 50 ml of ethyl acetate each time. The combined ethyl acetate extracts 
were dried over sodium sulphate, washed twice with saturated sodium 
chloride solution, dried twice over sodium sulphate and evaporated at 
20.degree. C. in vacuo. The resulting crude product (19 g) was immediately 
reacted further. 
(e) 
5-Acetamido-3-O-benzyl-5,7-didesoxy-1,2-O-isopropylidene-D(L)-glycero-.alp 
ha.-D-glucohepto-1,4-furanose: 
39 ml of methyl iodide in 300 ml of anhydrous ether were added dropwise to 
16.7 g of magnesium filings in 50 ml of anhydrous ether such that the 
ether simmered, and the mixture was then boiled under refux for 30 
minutes. 19 g of crude 
acetamido-3-O-benzyl-5-desoxy-1,2-O-isopropylidene-.alpha.-D-gluco-hexodia 
ldo-1,4-furanose in 200 ml of anhydrous ether were added dropwise to this 
solution at 20.degree.-25.degree. C. and the mixture was stirred overnight 
at room temperature. 500 ml of 20% strength ammonium chloride solution 
were then carefully added, whilst cooling with ice, the ether phase was 
separated off and three extractions were carried out with 100 ml of ethyl 
acetate each time. The combined organic phases were washed with sodium 
bicarbonate solution, dried over sodium sulphate and evaporated in vacuo 
and the residue was recrystallised from isopropanol. Yield: 3.5 g of 
melting point 179.degree.-181.degree. C. 
(f) 
5-Amino-3-O-benzyl-5,7-didesoxy-1,2-O-isopropylidene-D(L)-glycero-.alpha.- 
D-glucohepto-1,4-furanose: 
2.4 g of 
5-acetamido-3-O-benzyl-5,7-didesoxy-1,2-O-isopropylidene-D(L)-glycero-.alp 
ha.-D-glucohepto-1,4-furanose, 40 ml of ethylene glycol, 8 ml of water and 
2 g of potassium hydroxide were heated to 150.degree. C. for 3 hours. 
After cooling, the reaction mixture was neutralised with CO.sub.2 and 
evaporated under a high vacuum, the residue was digested with hot ethanol, 
the solution was evaporated and the residue was purified by column 
chromatography on 250 g of silica gel using ammonia-saturated 
chloroform/ethanol 10:1. 1.9 g of the desired compound were obtained as an 
oil. 
(g) 
5-Acetamido-5,7-didesoxy-1,2-O-isopropylidene-D(L)-glycero-.alpha.-D-gluco 
hepto-1,4-furanose: 
20 g of 
5-acetamido-3-O-benzyl-5,7-didesoxy-1,2-O-isopropylidene-D(L)-glycero-.alp 
ha.-D-glucohepto-1,4-furanone were dissolved in 80 ml of methaol and 50 ml 
of glacial acetic acid and were hydrogenated on 15 g of 5% strength 
palladium-on-charcoal under 3.5 atmospheres at 30.degree. C. for 8 hours. 
The batch was then filtered, the filtrate was concentrated in a rotary 
evaporator, the residue was taken up in ethyl acetate and the ethyl 
acetate mixture was washed with sodium hydroxide solution until neutral, 
dried and concentrated in a rotary evaporator. 13.7 g of an oil were 
obtained. 
(h) 
5-Amino-5,7-didesoxy-1,2-O-isopropylidene-D(L)-glycero-.alpha.-D-glucohept 
o-1,4-furanose: 
13 g of 
5-acetamido-5,7-didesoxy-1,2-O-isopropylidene-D(L)-glycero-.alpha.-D-gluco 
hepto-1,4-furanose, 24.7 g of Ba(OH).sub.2 .times.8H.sub.2 O and 180 ml of 
water were boiled under reflux overnight. 18 g of ammonium bicarbonate 
were then added, the mixture was stirred at room temperature for 2 hours, 
the precipitate was filtered off and washed with water, the filtrate was 
concentrated, the residue was discharged onto a column containing 250 ml 
of a strongly basic ion exchanger (Lewatit n 500) and the column was 
eluted with water. After concentrating the eluate in a rotary evaporator, 
the residue was recrystallised from chloroform. Yield: 8.5 g, melting 
point: 127.degree.-131.degree. C. 
(i) 
5-Amino-5,7-didesoxy-1,2-O-isopropylidene-D(L)-glycero-.alpha.-D-glucohept 
o-1,4-furanose: 
4 g of sodium were added to 1.9 g of 
6-amino-3-O-benzyl-5,7-didesoxy-1,2-O-isopropylidene-D(L)-glycero-.alpha.- 
D-glucohepto-1,4-furanose in 100 ml of liquid ammonia and the mixture was 
stirred at -70.degree. C. overnight. 6 g of ammonium chloride and 250 ml 
of methanol were then added, the mixture was allowed to warm to room 
temperature, the salts were filtered off, the filtrate was evaporated and 
the residue was chromatographed on 80 g of silica gel with a mixture of 
ethyl acetate/methanol/concentrated aqueous ammonia 100:60:2. The eluate 
was evaporated, the residue was taken up in hot isopropanol, the 
isopropanol mixture was filtered and the product was precipitated with 
three times the amount of petroleum ether. Yield: 0.6 g. 
(j) Bisulphite adduct of 5-amino-5,7-didesoxy-D(L)-glycero-D-glucoheptose: 
Sulphur dioxide was passed into a solution of 320 mg of 
5-amino-5,7-didesoxy-1,2-O-isopropylidene-D(L)-glycero-.alpha.-D-glucohept 
o-1,4-furanose in 2 ml of water at room temperature for 20 hours and then 
at 40.degree. C. for 20 hours. 20 ml of methanol were subsequently added, 
whereupon the desired product crystallised out. Yield 200 mg of melting 
point 128.degree.-130.degree. C. 
(k) 5-Amino-5,7-didesoxy-D(L)-glycero-O-glucoheptose: 
120 mg of the bisulphite adduct of 
5-amino-5,7-didesoxy-D(L)-glycero-D-glucoheptose were dissolved in 5 ml of 
water, strongly basic ion exchangers were added, the mixture was stirred 
for 30 minutes and filtered, the residue was washed with water and the 
filtrate was evaporated in vacuo at 20.degree. C. Yield: 70 mg. 
(l) 1,5,7-Tridesoxy-1,5-imino-D(L)-glycero-D-glucoheptitol: 
120 mg of the bisulphite adduct of 
5-amino-5,7-didesoxy-D(L)-glycero-D-glucoheptose were dissolved in 15 ml 
of water, 173 mg of barium hydroxide.times.8 H.sub.2 O and 400 mg of Raney 
nickel were added and hydrogenation was carried out at room temperature 
under 3 atmospheres for 7 hours. The reaction mixture was then filtered, 
the filtrate was evaporated in vacuo and the residue was purified by 
column chromtography on 20 g of silica gel with 
ether/methanol/concentrated aqueous ammonia (5:6:2). Yield 40.7 mg of an 
oil which crystallised within a few hours. Melting point: 
165.degree.-6.degree. C. 
(m) 1,5,7-Tridesoxy-1,5-imino-N-methyl-D(L)-glycero-D-glucoheptitol: 
32 mg (0.18 mole) of 
1,5,7-tridesoxy-1,5-imino-D(L)-glycero-D-gluco-heptitol were dissolved in 
2 ml of methanol, 20 mg of sodium cyanoborohydride, 0.05 ml of formalin 
solution (40% strength) and 0.02 ml of glacial acetic acid were added and 
the reaction mixture was stirred at room temperature for 4 hours. It was 
then evaporated, the residue was dissolved in 0.5 ml of 1 N HCl and 0.5 ml 
of methanol, the solution was discharged onto a column containing a 
strongly acid ion exchanger (Lewatit TSW 40) and the column was washed 
with water and methanol/water 10:1 and eluted with 
methanol/water/concentrated aqueous ammonia 10:1:0.2. The eluate was 
evaporated in vacuo. Yield: 25 mg. 
(n) N-Ethyl-1,5,7-tridesoxy-1,5-imino-D(L)-glycero-D-glucoheptitol: 
500 mg of 1,5,7-tridesoxy-1,5-imino-D(L)-glycero-D-glucoheptitol were 
dissolved in 20 ml of methanol, 170 mg of acetaldehyde, 315 mg of sodium 
cyanoborohydride and 350 .mu.l of glacial acetic acid were added and the 
mixture was stirred at room temperature overnight and boiled under reflux 
for 2 hours. For working up, 5 ml of 1 N hydrochloric acid were added, the 
batch was concentrated, the residue was discharged onto 30 ml of a 
strongly acid ion exchanger (Lewatit TSW 40) and the ion exchanger was 
washed with water and methanol/water 10:1 and eluted with 
methanol/water/ammonia 10:1:1. After concentration the eluate in a rotary 
evaporator, 500 mg of the desired compound were obtained. Mass spectrum: 
m/e=160(100%, M.sup.+ --CH.sub.3 --CH--OH). 
EXAMPLE 2 
The following N-alkyl derivatives of 
1,5,7-tridesoxy-1,5-imino-D(L)-glycero-D-glucoheptitol were prepared in an 
analogous manner to Example 1, the acetaldehyde in the reaction being 
replaced by the aldehyde indicated: 
(a) 1,5,7-Tridesoxy-1,5-imino-N-propyl-D(L)-glycero-D-glucoheptitol, 
aldehyde used: propionaldehyde. Mass spectrum: m/e=174 (100%, M.sup.+ 
--CH.sub.3 --CHOH). 
(b) 1,5,7-Tridesoxy-1,5-imino-N-hexyl-D(L)-glycero-D-glucoheptitol, 
aldehyde used: hexanal. Mass spectrum: m/e=216 (M.sup.+ --CH.sub.3 CHOH). 
(c) 
1,5,7-Tridesoxy-1,5-imino-N-(2-propen-1-yl)-D(L)-glycero-D-glucoheptitol, 
aldehyde used: acrolein. Mass spectrum: m/e=172 (60%, M.sup.+ --CH.sub.3 
--CHOH), 41 (100%, CH.sub.2 --CH.dbd.CH.sub.2). 
(d) 
N-(2-Buten-1-yl)-1,5,7-tridesoxy-1,5-imino-D(L)-glycero-D-glucoheptitol, a 
ldehyde used: crotonaldehyde. Mass spectrum: m/e=186 (70%, M.sup.+ 
--CH.sub.3 --CHOH), 55 (100%, CH.sub.2 --CH.dbd.CH--CH.sub.3). 
(e) 
1,5,7-Tridesoxy-1,5-imino-N-(2,4-hexadien-1-yl)-D(L)-glycero-D-glucoheptit 
ol, aldehyde used: sorbaldehyde. Mass spectrum: m/e=212 (70%, M.sup.+ 
--CH.sub.3 --CHOH), 81 (100%, CH.sub.2 CH.dbd.CH--CH--CH.sub.3). 
(f) N-Cinnamyl-1,5,7-tridesoxy-1,5-imino-D(L)-glycero-D-glycoheptitol, 
aldehyde used: cinnamaldehyde. Mass spectrum: m/e=248 (30%, M.sup.+ 
--CH.sub.3 CH--OH), 117 (100%, CH.sub.2 --CH.dbd.CH--C.sub.6 H.sub.5). 
(g) 
1,5,7-Tridesoxy-1,5-imino-N-(2-phenoxyethyl)-D(L)-glycero-D-glucoheptitol, 
aldehyde used: phenoxyacetaldehyde. 
(h) 1,5,7-Tridesoxy-N-ethyl-1,5-imino-D(L)-glycero-D-glucoheptitol, 
aldehyde used: acetaldehyde. Mass spectrum: m/e=160 (100%, M.sup.+ 
--CH.sub.3 CHOH). 
(i) N-Butyl-1,5,7-tridesoxy-1,5-imino-D(L)-glucero-D-glucoheptitol, 
aldehyde used: butanal. Mass spectrum: m/e=188 (100%, M.sup.+ --CH.sub.3 
--CHOH). 
(j) 
1,5,7-Tridesoxy-1,5-imino-N-(2-phenylethyl)-D(L)-glycero-D-glucoheptitol, 
aldehyde used: phenyl-acetaldehyde. Mass spectrum: m/e=250 (100%, M.sup.+ 
--CH.sub.3 --CHOH), 188 (30%), 146 (30%). 
(k) N-Cinnamyl-1,5,7-tridesoxy-1,5-imino-D(L)-glycero-D-glucoheptitol: 
500 mg of 1,5,7-tridesoxy-1,5-imino-D(L)-glycero-D-glucoheptitol, 5.2 ml of 
dimethylformamide, 600 mg of potassium carbonate and 770 mg of cinnamyl 
bromide were stirred at room temperature for 3 hours. The salts were then 
filtered off, 10 ml of water were added to the filtrate and the mixture 
was extracted twice with ether. The aqueous phase was concentrated in a 
rotary evaporator, the residue was extracted by stirring with acetone, the 
precipited was separated off, the filtrate was evaporated and the residue 
was purified by column chromatograhy on 100 g of silica gel with 
chloroform/methanol 8:2. 
The following compounds were prepared in an analogous manner: 
1,5,7-tridesoxy-1,5-imino-N-(2,4-hexadien-1-yl)-D(L)-glycero-D-glucoheptit 
ol, using sorbyl bromide, and 
N-(2-buten-1-yl)-1,5,7-tridesoxy-1,5-imino-D(L)-glycero-D-glucoheptitiol, 
using crotonyl bromide. 
EXAMPLE 3 
(a) 2-.alpha.-Hydroxyethyl-3,4,5-trihydroxypiperidine 
##STR12## 
2.0 g of 
N-benzoyl-2-.alpha.-hydroxyethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypiperi 
dine in 6 ml of absolute tetrahydrofurane were slowly added dropwise to a 
solution of 2.0 g of sodium in 13.5 ml of liquid ammonia and 5 ml of 
absolute tetrahydrofurane at -70.degree. C. The mixture was stirred at 
-70.degree. C. for 4 hours and at -40.degree. C. for 1 hour. 5 g of 
NH.sub.4 Cl were then added and the ammonia was evaporated off overnight. 
The residue was extracted by stirring with ethanol, the salts were 
filtered off and the solution was concentrated to dryness. The residue was 
chromatographed over a column filled with silica gel. The column was 
eluted first with CHCl.sub.3 /CH.sub.3 OH 4:1 and then with ether/CH.sub.3 
OH/25% strength NH.sub.3 5:6:2. 150 mg of crude product were obtained. For 
further purification, this product was discharged onto a column filled 
with Amberlite IR 120 (H.sup..sym. form). The column was eluted first 
with water and then with 2% strength ammonia. Yield: 100 mg of 
2-.alpha.-hydroxyethyl-3,4,5-trihydroxypiperidine as a resin. 
(b) 
N-Benzoyl-2-.alpha.-hydroxyethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypiperi 
dine 
##STR13## 
2.6 g of N-benzoyl-3,4,5-tri-O-benzyl-3,4,5-dihydroxy-piperidine-2-aldehyde 
in 25 ml of ether were added dropwise to a Grignard solution of 1.03 g of 
Mg filings and 2.26 ml of CH.sub.3 I in 5 ml of absolute ether at room 
temperature. The mixture was warmed under reflux for 2 hours. It was then 
reacted with NH.sub.4 Cl solution and acidified with dilute HCl. The ether 
phase was separated off and the mixture which remained was extracted 3 
time with ether. The combined ether solutions were dried and concentrated. 
The residue was chromatographed over a silica gel column using chloroform 
as the mobile phase. Yield: 2 g of 
N-benzoyl-2-.alpha.-hydroxyethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypiperi 
dine as a resin. 
(c) N-Benzoyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypiperidine-2-aldehyde 
##STR14## 
2.685 g of 
N-benzoyl-2-hydroxymethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypiperidine 
and 0.25 g of crystalline orthophosphoric acid were added to 3.125 g of 
dicyclohexylcarbodiimide in 4.4 ml of absolute dimethylsulphoxide and 2.5 
ml of benzene at 20.degree. C., whilst stirring. The temperature was kept 
at room temperature and the mixture was subsequently stirred for 3 hours. 
1 g of oxalic acid was then added, and after 30 minutes 25 ml of ethyl 
acetate were added. The precipitate was separated off and rinsed with 
ethyl acetate. The combined ethyl acetate solutions were washed first with 
saturated NaHCO.sub.3 solution and then with saturated sodium chloride 
solution. The ethyl acetate solution was dried over MgSO.sub.4 and the 
solvent was removed. 2.6 g of 
N-benzoyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypiperidine-2-aldehyde were 
obtained as a resin. 
(d) N-Benzoyl-2-hydroxymethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypiperidine 
##STR15## 
1.84 g of 
N,7-O-cyclocarbonato-2-hydroxymethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypi 
peridine in 25 ml of absolute tetrahydrofurane were added dropwise to a 
Grignard solution of 10.3 g of Mg filings and 6.28 g of bromobenzene in 5 
ml of absolute tetrahydrofurane and the mixture was stirred at 40.degree. 
C. for 2 hours. It was then poured onto 100 ml of ice-water and rendered 
neutral with NH.sub.4 Cl and dilute HCl. The mixture was extracted with 
CHCl.sub.3 and the chloroform solution was dried and concentrated. For 
crystallisation, ether was added to the residue. Yield: 1.2 g of 
N-benzoyl-2-hydroxymethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypiperidine of 
melting point: 104.degree.-106.degree. C. 
(e) N-Benzoyl-2-hydroxymethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypiperidine 
28 g of 
N-benzoyl-7-O-trityl-3,4,5-tri-O-benzyl-2-hydroxymethyl-3,4,5-trihydroxypi 
peridine were dissolved in 200 ml of 80% strength acetic acid and the 
solution was heated to 60.degree.-70.degree. C. for 4 hours. After 
cooling, triphenylcarbinol which had precipitated was filtered off. The 
mother liquor was concentrated in vacuo and methanol was added to the 
residue. The triphenylcarbinol which had precipitated was filtered off and 
the mother liquor was again concentrated to dryness. The residue was 
chromatographed over a column filled with silica gel. The column was 
eluted first with CHCl.sub.3 and then with CHCl.sub.3 /MeOH 98:2. Yield: 
11.3 g of 
N-benzoyl-2-hydroxymethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypiperidine of 
melting point 106.degree. C. 
(f) 
N,7-O-Cyclocarbamato-2-hydroxymethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypi 
peridine 
##STR16## 
9.8 g of KOH powder and 2.9 g of 
N,7-O-cyclocarbamato-2-hydroxymethyl-3,4,5-trihydroxypiperidine in 100 ml 
of dimethylsulphoxide were heated to 60.degree. C. for 30 minutes, whilst 
stirring. 17.6 ml of benzyl chloride were then added dropwise at 
60.degree. C. The mixture was stirred at 60.degree. for a further 30 
minutes. The dimethylsulphoxide was then distilled off using an oil pump. 
The residue was introduced into ice-water and the aqueous phase was 
rendered neutral with concentrated HCl. The mixture was then extracted 
with chloroform. The chloroform solution was dried and concentrated. The 
residue was chromatographed over a column filled with silica gel (eluting 
agent: CHCl.sub.3 /MeOH 40:1). Yield: 4.6 g of 
N,7-O-cyclocarbamato-2-hydroxymethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypi 
peridine. The substance became crystalline on trituration with cyclohexane 
or with a little methanol. Melting point: 104.degree.-105.degree. C. 
(g) N,7-O-Cyclocarbamato-2-hydroxymethyl-3,4,5-trihydroxypiperidine 
##STR17## 
2.58 ml of chloroformic acid ethyl ester were slowly added dropwise to a 
mixture of 2.4 g of 1-desoxynojirimicin and 3.2 g of finely powdered 
K.sub.2 CO.sub.3 in 50 ml of absolute dimethylformamide at 15.degree. C., 
whilst stirring. The mixture was stirred at room temperature for 1 hour 
and was then warmed to 100.degree. C. for 3 hours. The salts were then 
filtered off, the dimethylformamide solution was concentrated in vacuo and 
the residue was crystallised with ethanol. Yield: 2 g of 
N,7-O-cyclocarbamato-2-hydroxymethyl-3,4,5-trihydroxypiperidine. 
For further purification, the substance could be recrystallised from 
ethanol/a little water. Melting point: 218.degree. C. 
(h) 
N-Benzoyl-7-O-trityl-2-hydroxymethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypi 
peridine 
##STR18## 
1.35 g of 80% pure NaH were stirred with 50 ml of n-hexane. The n-hexane 
was decanted off and replaced by 50 ml of absolute dimethylsulphoxide. The 
mixture was then warmed to 60.degree.-70.degree. C. under N.sub.2 for 1 
hour. After cooling, 5.1 g of 
N-benzoyl-7-O-trityl-2-hydroxymethyl-3,4,5-trihydroxypiperidine in 30 ml 
of absolute dimethylsulphoxide were added dropwise and the mixture was 
stirred at room temperature for 1 hour. 4.2 g of benzyl chloride in 25 ml 
of dimethylsulphoxide were then added dropwise and the mixture was stirred 
overnight. 300 ml of CH.sub.2 Cl.sub.2 were added to the reaction mixture 
and the mixture was extracted by shaking with 200 ml of H.sub.2 O. The 
CH.sub.2 Cl.sub.2 phase was washed twice more with water, dried over 
Na.sub.2 SO.sub.4 and concentrated in vacuo. Yield: 6.5 g of crude 
N-benzoyl-7-O-trityl-2-hydroxymethyl-3,4,5-tri-O-benzyl-3,4,5-trihydroxypi 
peridine. The crude product was employed in the next reaction stage. 
(i) N-Benzoyl-7-O-trityl-2-hydroxymethyl-3,4,5-trihydroxypiperidine 
##STR19## 
63.9 g of N-benzoyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine and 79.9 g 
of trityl chloride in 250 ml of absolute pyridine were stirred at room 
temperature for 24 hours. A further 80 g of trityl chloride were then 
added and the mixture was stirred once again for 48 hours. The precipitate 
was filtered off and the mother liquor was concentrated in vacuo. The 
residue was dissolved in CHCl.sub.3 and the chloroform solution was washed 
with H.sub.2 O. The chloroform phase was dried with Na.sub.2 SO.sub.4 and 
concentrated in vacuo. The residue was then taken up in a little toluene. 
The reaction product was precipitated by adding the toluene solution 
dropwise to a large excess of cyclohexane. The precipitate was filtered 
off and dried. Yield: 90 g of crude 
N-benzoyl-7-O-trityl-2-hydroxymethyl-3,4,5-trihydroxypiperidine. The crude 
product could be further purified by trituration with ether or by 
recrystallisation from a little toluene. Melting point: 
185.degree.-187.degree. C. 
(j) N-Benzoyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine 
##STR20## 
27 ml of benzoyl chloride in 300 ml of ethyl acetate were added dropwise to 
a solution of 30 g of 1-desoxynojirimicin in 120 ml of H.sub.2 O, 350 ml 
of CH.sub.3 OH and 30 ml of triethylamine at 30.degree.-35.degree. C. The 
mixture was subsequently stirred at room temperature for 1 hour and a 
further 15 ml of triethylamine and 13.5 ml of benzoyl chloride in 150 ml 
of ethyl acetate were then added dropwise at 30.degree.-35.degree. C. 
After stirring for 1 hour, the reaction mixture was evaporated to dryness 
in vacuo. The residue was taken up in water and the aqueous mixture was 
extracted with ether. The aqueous phase was again concentrated to dryness 
in vacuo and the residue was stirred with acetone. The triethylamine 
hydrochloride which has precipitated was filtered off. Residual 
triethylamine hydrochloride was separated off by again concentrating the 
acetone solution and taking up the residue in a little acetone. After 
removal of the solvent, the product was obtained as a resin. After 
thorough drying, this resin could be employed in the next stage. Yield: 56 
g of crude N-benzoyl-3,4,5-trihydroxypiperidine. After standing for a 
relatively long period, the compound crystallised from acetone. Melting 
point: 159.degree. C. 
The following were prepared analogously to Examples 3a and 3b: 
EXAMPLE 4 
(with ethyl-magnesium iodide at room temperature) 
2-.alpha.-Hydroxypropyl-3,4,5-trihydroxypiperidine 
##STR21## 
The non-crystalline product was characterised by a proton nuclear magnetic 
resonance spectrum at 250 MHz. 
Rf value: 0.52 
Rf value for 1-desoxynojirimicin: 0.31 
[Pre-coated thin layer chromatography plates, Silica gel 60 F 254, Merck 
(Darmstadt); mobile phase: CHCl.sub.3 /MeOH/25% strength NH.sub.3, 4:3:1]. 
EXAMPLE 5 
(with n-butyl-lithium at -70.degree. C.) 
2-.alpha.-Hydroxypentyl-3,4,5-trihydroxypiperidine 
##STR22## 
Rf value: 0.65 (chromatography conditions as in Example 4). 
EXAMPLE 6 
(with phenyl-magnesium bromide at -20.degree. C.) 
2-.alpha.-Hydroxybenzyl-3,4,5-trihydroxypiperidine 
##STR23## 
Rf value: 0.82 (chromatography conditions as in Example 4). 
The present invention also comprises pharmaceutically acceptable 
bioprecursors of the active compounds of the present invention. 
For the purpose of this specification the term `pharmaceutically acceptable 
bioprecursors` of an active compound of the invention means a compound 
having a structural formula different from the active compound but which 
nonetheless, upon administration to a warm-blooded animal is converted in 
the patient's body to the active compound.