JPS635012B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to agents containing novel amino-sugar derivatives, particularly agents for treating diabetes, steatosis and hyperglycemia. Many actinomycetes, particularly the Actinoplanaceae, produce oligosaccharide-like inhibitors of α-glucosidase. High molecular weight compounds are highly inhibitors of α-amylase activity and low molecular weight compounds are
It is a powerful sucrose enzyme inhibitor that inhibits the digestion of starch in vivo to a surprisingly high degree. These inhibitors have the general formula In the above formula, p and q represent numbers from 0 to 8, and p and q
has a value of 1 to 8 (DE 2347782 and DE P 26143931). The present invention is based on the general formula provides an amino sugar derivative of n
and m each independently represent a number from 0 to 8, and the sum n+m has a value from 0 to 8, and X is -
OR, -SH, -SR, _-NH2 , -NHR or-
NRR ₁ , where R represents an optionally substituted alkyl, alkenyl, cycloalkyl, aralkyl, aryl or heterocyclic group,
and R ₁ is optionally substituted alkyl,
It represents a cycloalkyl, aralkyl or aryl group, or R and R ₁ together with the nitrogen atom to which they are attached form a heterocyclic ring. Compounds of formula () are highly active inhibitors of digestive glucoside hydrolase. If R is alkyl, it is a straight-chain or branched alkyl having 1 to 30, especially 1 to 18 carbon atoms. Examples that may be mentioned are methyl,
Ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-hexyl, n-octyl,
Octyl-2, dodecyl, lauryl, cetyl and stearyl. Alkyl group R is 1 or more, preferably 1 to 5
may have the same or different substituents. Examples of substituents that may be mentioned are: hydroxyl or alkoxy preferably having 1 to 4 carbon atoms, especially methoxy and ethoxy; amino or monoalkyl preferably having 1 to 4 carbon atoms per alkyl group. Amino and dialkylamino, especially monomethylamino, monoethylamino, dimethylamino and diethylamino; mercapto or alkylthio preferably having 1 to 4 carbon atoms, especially methylthio and ethylthio; halogen, preferably fluorine, chlorine and bromine; per alkyl group Preferably 1-4
Alkylcarbonyl having carbon atoms; and carboxyl, nitro, cyano, aldehyde groups and sulfonic acid groups. Groups derived from sugar derivatives, such as polyalcohols or sugar acids, are of particular interest within the scope of this specification for R in the sense of substituted alkyl groups. When R is alkenyl, it may bear substituents, such as, for example, hydroxyl, alkoxy with 1 to 4 carbon atoms, mercapto, alkylthio with 1 to 4 carbon atoms, halogen or nitro. Preference is given to straight-chain or branched alkenyls having 2 to 6 carbon atoms. When R is cycloalkyl, it is preferably an optionally substituted carbocyclic group having 3 to 7 carbon atoms, but possible substituents include In the case of hydrogen group R, these are the groups and atoms mentioned above. When R is aryl, it is preferably an optionally substituted aromatic group having 6 to 10 carbon atoms in the aryl moiety, especially phenyl. An aryl or alkyl group can carry one or more, preferably from 1 to 3, identical or different substituents. Examples of substituents that may be mentioned are: alkyl having 1 to 10 carbon atoms, which may also be substituted, for example by chlorine, nitro or cyano; optionally substituted 1 to 10 alkenyl groups having carbon atoms; hydroxyl or alkoxy preferably having 1 to 4 carbon atoms; monoalkylamino and dialkylamino preferably having 1 to 4 carbon atoms per amino or alkyl group; mercapto or preferably 1 to 4 carbon atoms and carboxyl or carboxy with preferably 1 to 4 carbon atoms; sulfonic acid groups, preferably alkylsulfonyl and arylsulfonyl with 1 to 4 carbon atoms, preferably phenylsulfonyl; 1 per aminosulfonyl or alkyl group Alkylaminosulfonyl and dialkylaminosulfonyl preferably having ~4 carbon atoms; preferably methylaminosulfonyl and dimethylaminosulfonyl; nitro, cyano or aldehyde groups; alkylcarbonylamino preferably having 1 to 4 carbon atoms; and 1 to 4 carbon atoms alkylcarbonyl, benzoyl, benzylcarbonyl and phenylethylcarbonyl having, while alkyl, phenyl, benzyl and phenylethyl groups in the last-mentioned substituents,
For example, it may be substituted once more by chlorine, nitro or hydroxy, as well as groups derived from sugars. If R is aralkyl, it preferably has from 6 to 10, especially 6, carbon atoms in the aryl moiety and 1 to 1 in the alkyl moiety, as for example in benzyl and phenylethyl.
It is preferred to have ˜4, especially 1 or 2 carbon atoms. Possible substituents for the aryl part of the aralkyl group are preferably the substituents listed above for R of the aryl group. If R is a heterocyclic group, it represents a 5- or 6-membered hetero-paraffinic, hetero-aromatic or hetero-olefinic ring, preferably having 1 to 3 identical or different heteroatoms. It is preferable to have. Heteroatoms are oxygen, sulfur or nitrogen. These ring systems may further contain other substituents, such as hydroxyl, amino or
It may have a C ₁ -C ₄ -alkyl group or a benzene nucleus or another heterocyclic ring of the type mentioned above, preferably 6-membered, may be fused thereto. In this case, the bonding of the heterocyclic radical R takes place via a carbon atom of the heterocyclic system or of the fused benzene nucleus. Particularly suitable heterocyclic groups are derived from, for example, furan, pyran, prolidine, piperidine, pyrazole, imidazole, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyridine, benzimidazole, quinoline, isoquinoline or purine. It is to be understood that a heterocyclic group also includes those attached to the outside of the ring by a --CH ₂ -- bond, such as a furfuryl group. R ₁ is preferably a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or a benzyl or phenyl group; for the above groups, preferably an alkoxy group having 1 to 4 carbon atoms; , amino, _C1 - _C4 -monoalkylamino and _C1 - _C4 -dialkylamino, nitro, halogen, cyano, hydroxyl, mercapto, _C1
Substitution by ~ _C4 -thioalkyl or carboxyl or sulfonic acid groups and, if _R1 represents phenyl, furthermore by _C1 - _C4 -alkyl is possible. As above, for R and R ₁ jointly and including the nitrogen atom to which they are attached,
It is also possible to form heterocyclic rings. This ring can be saturated or unsaturated and contains 1 to 3 further (preferably 1) oxygen, sulfur or nitrogen atoms and, as a hetero group, an SO ₂ group or an N-alkyl group. However, it is preferred that the alkyl of this N-alkyl group contains 1 to 4, especially 1 or 2 carbon atoms. Alkyl includes methyl, ethyl, n- and i-propyl and n-, i-propyl
- and t-butyl. Heterocyclic rings are 5-7, preferably 5- or 6-membered. Preferably, the 6-membered heterocyclic ring has a hetero atom or a hetero group at the para position to the nitrogen atom. Examples of heterocyclic rings that may be mentioned are pyrrolidine, piperidine, piperazine, hexamethyleneimine, morpholine and n-methylpiperazine. Particularly valuable inhibitors of the invention are those where n is 1 or 2; among them, formula (),
Of particular interest are the amino-sugar derivatives of () and (). X has the following particularly preferred meaning; X is -OR, -SH, -SR, _-NH2 , -NHR
or -NRR ₁ , in which R is 1 to 5 hydroxyl or C ₁ to _{C 4} -
1, which may be substituted with an alkoxy group;
an alkyl group having ~18 carbon atoms; optionally 1
-3 _C1 - _C4 -alkyl, OH, _C1 - _C4 -alkoxy, amino, C1 _{-C4 -} alkylamino, _C1-
C ₄ -dialkylamino, carboxyl, methoxycarbonyl, nitro, glucopyranyl, benzoyl, p-hydroxyphenylethylcarbonyl, C ₁ -C ₄ -alkylaminosulfonyl or
by a _C1 - _C4 -dialkylaminosulfonyl group or by one group, a phenyl group, a benzyl group, or a 2-benzothiazolyl group substituted with;
and R ₁ is represented by C ₁ -C ₄ -alkyl, or R
Together with, it forms a morpholine or piperidine ring. Surprisingly, the compounds according to the invention have α
-Exhibits a higher inhibitory effect on glucosidases than the pre-inducible parent substance and therefore strengthens the whole range of drugs available today. Furthermore, the present invention provides formula (1) In the above formula, m' and n' independently represent numbers from 0 to 8, and the sum n'+m' has a value from 0 to 8, and Ac is a group.

[Formula], where R″ represents an optionally substituted alkyl, alkenyl, cycloalkyl, aralkyl or aryl group, and R′ represents hydrogen or a group Ac as described above, and Y represents halogen ( An acylhalogen derivative of the formula H-X () in which X has the meaning given above (or substituted by H metal, preferably Na or K) (a salt thereof) optionally in the presence of an acid binding agent (in this embodiment, an O-acylhalogen compound in which R′ is hydrogen, i.e., a derivative of formula ( ) and R″ is C ₁ to C ₆ -acyl group or aroyl group,
or (2) an ortho-ester (acyl halide compound () of the formula ()) of the formula HOR ₂ , where R ₂ is from 1 to
alkyl or phenyl having 6 carbon atoms,
(preferably methyl or t-butyl) In the above formula, AC, m′, n′, R′, R ₂ and R″ have the above meanings, is reacted with a compound of formula () (e.g.
Kochetkov [RLWistler and JHBeMiller.
Methods of Carbohydrate Chemistry, Vol. 480, Academic Press, New York and London]); or (3) compounds of formula () (from acylhalogen compounds (), H ₂ O, H ₂ S, NH ₃ or _{NH2R1 ,}
where R ₁ has the above meaning, and can be obtained by the reaction) In the above formula, m', n', Ac and R' have the above meanings, and Y' is -OH, -SH, -NH ₂ or -NHR ₁
, where the meaning of R ₁ is as described above, and the formula Z−R ₃ () In the above formula, R ₃ has the meaning of R, or represents aryl-N=N-, and Z is an acid group, preferably for example -Cl, -
Br, -I, _-HSO4 or _-SO3H ,
(This embodiment is particularly suitable for the preparation of thioethers); The ester or amide can be prepared by known methods, for example using a catalytic amount of sodium in methanol [G.
Zemplen, Ber, 56 , 1705 (1923)] or by oxidation with an aqueous solution of an alkali metal hydroxide); or formula (4) In the above formula, m′, n′, Ac and R′ have the above-mentioned meanings, and an amino derivative, preferably an O-amyl derivative, of the compound of formula ()

or (5) consisting of reacting the parent substance of formula () with a compound of formula (), possibly in the presence of an acid catalyst, with elimination of water. , provides a method for preparing a compound of formula () according to the present invention. The method for preparing starting compounds of the formula () in which p=0 and q=1 to 7 is known (DE 2347782). Starting compounds of the formula () in which p and q are numbers from 0 to 8 and the sum n+m takes a value from 1 to 8 are the subject of West German patent specification P 26143931. The compounds listed here belong to the order Actinomycetes.
Actinomycetales, in particular strains of microorganisms of the family Actinoplanceae, are cultured by known methods and the individual compounds are then separated and isolated, also by known methods. Therefore, it can be manufactured. Although the compounds of each formula used as starting materials have not yet been clarified, they can be produced by routine methods in sugar chemistry. For example, Y=Br, Ac=acetyl, R'=H
To prepare a compound of formula (), an O-acetyl compound of formula (XI) is diluted with -10 in glacial acetic acid.
at a temperature of from °C to room temperature, preferably 0 °C,
React with HBr. Reaction time is 15 minutes to 4 hours.
Preferably it is about 1 hour. The reaction product is isolated by diluting the reaction mixture with chloroform, washing with water to remove the acetic acid, drying the chloroform phase, and then evaporating the solution to dryness under reduced pressure in a rotary evaporator. . The crude product thus obtained, ie the acetobromo compound, can be used for the abovementioned reaction without further purification. The compound of formula (XI) is obtained from the compound of formula (),
by known methods, for example by reaction with carboxylic acid chlorides or carboxylic acid anhydrides,
can be obtained. In the case of O-acetylation, reaction with acetic anhydride/pyridine for 12 to 48 hours at room temperature has been found to be suitable. A compound of formula (XI) in which m′=0, n′=0, R′ represents hydrogen or Ac, and Ac represents an acetyl group is, for example, a compound of formula (XII) can be obtained by acetolysis of amino-sugar derivatives of In this method, the amino-sugar derivative (XII) is heated with acetic anhydride/glacial acetic acid (1:1) in the presence of a catalytic amount of sulfuric acid, resulting in the degradation of two glucose units and the remaining sugar Simultaneous acylation of the derivative occurs. The ortho ester of formula () is new.
However, these can be easily prepared from a compound of formula () and an alcohol of formula (R ₂ OH). The alcohol R ₂ OH is preferably used in excess. This reaction can be carried out with or without a diluent;
Preferably, nitromethane is used as the diluent. Preferably, 2,6-lutidine is used as the acid binder. This reaction is preferably carried out at room temperature and under normal pressure. The compound of formula () in which Y′ represents a mercapto group can be prepared by a known method [M. Cerny, D.
Zorchystalova and J.Pacak, Collection
Czechoslov.Chem.Communs. 26 , 2206 (1961)]
From an acetobromo compound of formula (),
Reaction with thiourea in acetone and subsequent reaction of the reaction product in a slightly alkaline medium (H ₂ O/CHCl ₃
It can be obtained by hydrolysis in NaHCO ₃ /NaHSO ₃ ). Alcohols, polyalcohols with general formula (),
Sugar derivatives, phenols, mercaptans, thiophenols and amines are already known. Some of the compounds of formula () will be described in detail later as examples. In the case of the compounds mentioned here, the polyfunctional compounds can optionally also be used in the reaction in the form of suitable partially protected derivatives. In that case, the protecting group must be chosen appropriately so that it can be removed again from the reaction product without the glucosidic bond or double bond being attacked thereby. As examples of compounds of the formula, the following may be mentioned: methanol, ethanol, propanol, isopropanol, t-butanol, n
-Butanol, allyl alcohol, cyclopentanol, n-hexanol, n-octyl alcohol, octanol-2, lauryl alcohol,
Cetyl alcohol, 1-dimethylamino-propanol-2, benzyl alcohol, furfuryl alcohol, trichloroethanol, ethylene glycol, ethylene glycol monomethyl ether, butane-1,4-diol, D-glucose, D-sorbitol, meso-inositol, phenol , p-nitrophenol, m-chlorophenol, 2,4-dichlorophenol, 6-chloro-3-hydroxy-toluene, 4-hydroxy-1-t-butylbenzene, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid , salicylic acid, resorcinol, hydroquinone, phloroglucinol,
p-acetamidophenol, diethylstilbestrol, phloretin, phlorizin, 8-hydroxy-quinoline, methyl mercaptan, ethyl mercaptan, n-propyl mercaptan, iso-
Propyl mercaptan, n-hexyl mercaptan, cyclohexyl mercaptan, benzyl mercaptan, 1,3-dimercaptopropane, thiophenol, m-thio-klenol, p-bromothiophenol, β-thionaphthol, thiohydroquinone, methylamine, dimethylamine , ethylamine, propylamine, dipropylamine,
Isopropylamino, t-butylamino, N-ethyl-N-propylamine, n-hexylamine, dodecylamine, stearylamine, allylamine, ethylene-diamine, putrescine, 3
-amino-1-dimethylaminopropane, 2-amino-ethanol, 2-methylaminoethanol, bis-(2-hydroxy-ethyl)amine,
Ethyl 3-amino-propyl ether, 4-amino-2-butanol, cyclohexylamine, benzylamine, pyrrolidine, piperidine, morpholine, piperazine, aniline, N-methylaniline, p-toluidine, o-chloroaniline, m-
Anisidine, p-nitraniline, m-aminophenol, 4-chloro-3-nitroaniline, p-
Phenylene diamine, 3-trifluoromethylaniline, α-naphthylamine, benzidine, furfurylamine, 3-aminosulfolane, benzimidazole, hyboxanthin, adenine, uradyl, cytosine and 2-desoxystoptoamine. The reaction of a compound of formula with a compound of formula can be carried out with or without a diluent. Preferably it is carried out under the conditions of the Könitzhik-Nor reaction or one of the more recent modification methods. Diluents that can be used are all inert solvents, such as benzine, chloroform, ether or nitromethane, or
Also basic solvents, such as pyridine or quinoline. The reaction is optionally carried out in the presence of an acid binder, a Lewis acid and a drying agent. Preference is given to using silver or mercury salts and dryerites. This reaction is generally carried out at a temperature of 0 DEG to 100 DEG C., preferably at room temperature, preferably under normal pressure. In this reaction, equimolar amounts of the compound and also the silver or mercury salt can be used; however, large excesses of the compound can also be used.
This reaction is moderately favorable. This reaction can also be carried out using a metal salt of the compound, such as an alkali metal salt of the compound. Silylated derivatives of compounds may also, in some cases,
can be used. However, in some cases, this reaction
It can also be carried out in protic solvents, such as, for example, alcohol, water or water/acetone mixtures. This embodiment is particularly suitable when the compound of formula is a phenol. In this case, it is preferable to use an alkali metal hydroxide or an alkali metal carbonate as the acid binder. If the preparation of the compound of formula is carried out according to the second method, when R ₂ is methyl, nitromethane is used as a solvent in the reaction of the ortho ester with the compound of formula, and mercury bromide ()
It is preferred to use as catalyst. R ₂ is t
-butyl, it is preferred to use chlorobenzene as the solvent and 2,6-rutidinium verchlorate as the catalyst. The reaction is preferably carried out under normal pressure and at the boiling point, and the shift of the equilibrium towards the desired reaction product is effected by distilling off the volatile reaction product. When the compound of the formula is prepared according to embodiment (3) via the intermediate product (), the compound ()
The reaction of with a compound of formula () can be carried out, for example, in the following solvents: acetone, dimethylformamide, dioxane, tetrahydrofuran, alcohol, water, chloroform, benzene,
Acetic acid or mixtures of these solvents. Preference is given to using alkali metal carbonates or alkali metal hydroxides as binders in this reaction. This reaction can be carried out using an equimolar amount of the compound (), but in some cases an excess of () may be used. This reaction is carried out at a temperature of 0 to 140°C, preferably 20 to 80°C, and preferably at normal pressure. The reaction of a compound of formula (XI) with a compound of formula () can be carried out with or without a diluent. A preferred embodiment of this process is the reaction of a compound of (XI) with a phenol of formula () in the melt, optionally using an excess of phenol. This reaction can be catalytically promoted by protic or Lewis acids.
A suitable catalyst is p-toluenesulfonic acid or
_ZnCl2 . This reaction is carried out at a temperature of 60-200°C, preferably 80-140°C. an amine of formula (), preferably an aromatic amine;
The reaction between and the compound of formula (XI) is preferably carried out using a lower alcohol as a solvent with the addition of acetic acid and optionally also using an excess of amine. This reaction is carried out at 20-80°C, preferably at room temperature, preferably at normal pressure. The reaction of a compound of formula () with a compound of formula () can be carried out with or without the use of a diluent. A preferred embodiment of this process is the reaction of compound () with an excess of lower anhydrous alcohol of formula () using a mineral acid or a cation exchange resin as catalyst. This reaction is preferably carried out at the boiling point of the alcohol, but in some cases it can also be carried out at a lower temperature. When the compound of formula ( ) is an amine, preferably an aromatic amine, the reaction with the compound of formula ( This is preferably carried out by heating at pH=3 to 4. This reaction can also be carried out by heating both components without the presence of a diluent. This reaction is carried out at a temperature of 25-200°C, preferably 60-120°C. In most of these methods, compounds of formula () are first obtained as O-acyl derivatives. Separation of the acyl protecting group is carried out by transesterification under basic catalysis, e.g. with catalytic amounts of sodium in methanol or triethylamine in methanol, by saponification with alkali metal hydroxides in alcohol/water. Alternatively, it is preferably carried out by reaction with an amine, such as ammonia in methanol. The individual reactions for the preparation of novel amino-sugar derivatives are illustrated below: As starting materials n-butanol and Y
When using a compound of formula () in which Br, m' is 0, n' is 2, Ac is acetyl and R' is H, the reaction course according to embodiment (1) can be expressed as the following formula (R.
H. Whistler and JNBeMiller, Modified Koenitzhiknol Synthesis, Methods of Carbohydrate Chemistry, Vol. 474, Academic Press, New York and London]. When the reactant in formula () is phenol,
The reaction is carried out using AqO and dryerite as auxiliaries and quinoline as a solvent,
Embodiment (1), or the embodiment using acetone/H ₂ O as reaction medium and KOH as acid binding agent, is preferred. When using 1,2-,5,6-di-O-isopropylidene-α-D-glucopyranose as the alcohol component of formula () and following the procedure according to embodiment (2), the reaction is For example, it can be expressed by the following formula [RLWhistler and JN
Kochetkov's Method by BeMiller, Methods in Carbohydrate Chemistry, Volume 480, Academic Press, New York and London]. For example, Y is Br, m′ is 0,
n' is 2, Ac is acetyl, and R' is H
From a compound of formula () which is, according to the method of embodiment (3), -X is, for example,

The process for preparing a compound of formula () which is [Formula] can be represented by the following formula [Cerny's method by M.Corney and J.Pacak, Collection Czechoslov.Chem.Communs 24 ,
2566 (1959) and M. Cerny, J. Vrkoe and H.
Stanek, ibid., 24 , 64 (1959)]. If X is an aryl, e.g.

For the preparation of a compound of formula () which is
Method (3), in the third reaction step the S-H compound is reacted with an aryldiazonium salt, such as phenyldiazonium chloride, resulting in O-acylation of () by elimination of HCl and evolution of _N2 . [M. Cerny, D. Zochysta-lova and J.
Cerny's Method, Collection, by Pacak
Czechoslov.Chem.Communs. 26 , 2206 (1961)]. In the reaction for the preparation of compounds of formula (), O-acyl derivatives of formula (XI) are used as starting materials, for example m'=0, n'=2, Ac=acetyl,
When using a compound with R′=H and p-toluidine, the course of the reaction can be represented by the following formula: When the starting material of formula () is a phenol, the following reaction embodiment is preferred [B.
by Helberich and E. Schmitz-Hillebrecht
Helberich's Method, Ber. 66 , 378 (1933)]. In reactions for the preparation of compounds of formula (), compounds of formula () as described in German Patent Application No. 2347782, such as those in which m is 0 and n is 1, and, for example,
When MeOH is used as starting material, the reaction course follows the following formula [Fischer's method by E. Fischer, Ber. 28 , 1151 (1895)]: When a compound in which m is 1 and n is 2 is chosen as the starting material of formula () and p-toluidine is chosen as the starting material of formula (), the reaction course follows the following formula: This reaction is carried out at 0 to 100°C, preferably at room temperature, and under normal pressure. This crude active compound () is suitably purified by column chromatography. Chromatography on cellulose using a butanol/ethanol/water mixture as eluent is preferred. In particular, new active compounds which may be mentioned are: C≡4,6-dideoxy-4[1S-(1,4,
6/5)-4,5,6-trihydroxy-3-hydroxy-methylcyclohex-2-ene-1-
ylamino]-α-D-glucopyranosyl, phenyl-4,6-deoxy-4-[1S-
(1,4,6/5)-4,5,6-trihydroxy-3-hydroxy-methylcyclohexy-2-
En-1-ylamino]-β-D-glucopyranoside, phenyl-4,6-dideoxy-4[1S-
(1,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-cyclohexy-2-
en-1-ylamino]-β-D-thioglucopyranoside, methyl-4,6-dideoxy-4[1S-(1,
4,6/5)-4,5,6-trihydroxy-3
-Hydroxymethyl-cyclohex-2-ene-
1-ylamino]-α-D-glucopyranoside, ethyl-O-{C}-(1→4)-β-D-glucopyranoside, methyl-O-{C}-(1→4)-α-D-glucopyranoside , benzyl-O-{C}-(1→4)-β-D-
Glucopyranoside, phenyl-O-{C}-(1→4)-β-D-
Glucopyranoside, p-nitrophenyl-O-{C}-(1→4)
-β-D-thioglucopyranoside, N-p-tolyl-O-{C}-(1→4)-D
-Glucopyranosylamine, phenyl-O-{C}-(1→4)-O-α-
D-Glcp-(1→4)-β-D glucopyranoside, p-carbomethoxyphenyl-O-{C}-
(1→4)-O-α-D-Glcp-(1→4)-β
-D glucopyranoside, p-carboxyphenyl-O-{C}-(1→
4) -O-α-D-Glcp-(1→4)-β-D
-Glucopyranoside, m-carbomethoxyphenyl-O-{C}-
(1→4)-O-α-D-Glcp-(1→4)-β
-D-glucopyranoside, m-carboxyphenyl-O-{C}-(1→
4) -O-α-D-Glcp-(1→4)-β-D
-Glucopyranoside, p-hydroxyphenyl-O-{C}-(1→
4) -O-α-D-Glcp-(1→4)-β-D
-Glucopyranoside, m-hydroxyphenyl-O-{C}-(1→
4) -O-α-D-Glcp-(1→4)-β-D
-Glucopyranoside, p-nitrophenyl-O-{C}-(1→4)
-O-α-D-Glcp-(1→4)-β-D-glucopyranoside, p-butylphenyl-O-{C}-(1→4)
-O-α-D-Glcp-(1→4)-β-D-glucopyranoside, Methyl-O-{C}-(1→4)-O-α-D
-Glcp-(1→4)-β-D-glucopyranoside, ethyl-O-{C}-(1→4)-O-α-D
-Glcp-(1→4)-α-D-glucopyranoside, n-butyl-O-{C}-(1→4)-O-α
-D-Glcp-(1→4)-β-D-glucopyranoside, benzyl-O-{C}-(1→4)-O-α-
D-Glcp-(1→4)-β-D glucopyranoside, n-octyl-O-{C}-(1→4)-O-
α-D-Glcp-(1→4)-β-D-glucopyranoside, n-hexadecyl-O-{C}-(1→4)-
O-α-D-Glcp-(1→4)-β-D-glucopyranoside, m-dimethylaminophenyl-O-{C}-
(1→4)-O-α-D-Glcp-(1→4)-β
-D-glucopyranoside, p-dimethylaminosulfonylphenyl-O-
{C}-(1→4)-O-α-D-Glcp-(1→
4) -β-D-glucopyranoside, p-benzoylphenyl-O-{C}-(1→
4) -O-α-D-Glcp-(1→4)-β-D
-Glucopyranoside, phenyl-O-{C}-(1→4)-O-α-
D-Glcp-(1→4)-β-D-glucopyranoside, o-aminophenyl-O-{C}-(1→4)
-O-α-D-Glcp-(1→4)-β-D-thioglucopyranoside, benzyl-O-{C}-(1→4)-O-α-
D-Glcp-(1→4)-β-D-thioglucopyranoside, n-butyl-O-{C}-(1→4)-O-α
-D-Glcp-(1→4)-β-D-thioglucopyranoside, carboxymethyl-O-{C}-(1→4)-
O-α-D-Glcp-(1→4)-β-D-thioglucopyranoside, N-phenyl-O-{C}-(1→4)-O-
α-D-Glcp-(1→4)-D-glucopyranocyamine, N-p-tolyl-O-{C}-(1→4)-O
-α-D-Glcp-(1→4)-D-glucopyranosylamine, N-methyl-N-phenyl-O-{C}-(1
→4) -O-α-D-Glcp-(1→4)-D-
Glucopyranosylamine, N-p-hydroxyphenyl-O-{C}-
(1→4)-O-α-D-Glcp-(1→4)-D
-Glucopyranosylamine, N-propyl-O-{C}-(1→4)-O-
α-D-Glcp-(1→4)-D-glucopyranosylamine, O-{C}-(1→4)-O-α-D-Glcp
-(1→4)-D-glucopyranosylpiperidine, O-{C}-(1→4)-O-α-D-Glcp
-(1→4)-D-glucopyranosylmorpholine, p-aminophenyl-O-{C}-(1→4)
-O-α-D-Glcp-(1→4)-β-D-glucopyranoside, m-aminophenyl-O-{C}-(1→4)
-O-α-D-Glcp-(1→4)-β-D-glucopyranoside, Naringenin dihydrochalcone-2′-β-D-
Glucopyranoside-4′-[O-{C}-(1→
4) - [O-α-D-GLcp-(1→4)-β-
D-glucopyranoside], diethylstilbestrol-4'-[O-
{C}-(1→4)-O-α-D-Glcp-(1→
4)-β-D-glucopyranoside], D-solpitol-4-[O-{C}-(1→
4)-α-D-glucopyranoside], O-{C}-(1→4)-O-β-D-Glcp
-(1→6)-D-glucopyranose, O-{C}-(1→4)-O-α-D-Glcp
-(1→4)-O-β-D-Glcp-(1→6)
-D-glucopyranose, p-nitrophenyl-O-{4,4-dideoxy-4-[1S-(1,4,6/5)-4,5,
6-trihydroxy-3-hydroxymethyl-4
-O-α-D-glucopyranosyl-(1→4)-
cyclohex-2-en-1-ylamino〕-α
-D-glucopyranosyl}-(1→4)-OD
-Glcp-(1→4)-β-D-glucopyranoside, phenyl-O-{4,6-dideoxy-4-
[1S-(1,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-4-O-α-
D-glucopyranosyl-(1→4)-cyclohexyl-2-en-1-ylamino]-α-D-glucopyranosyl}-(1→4)-O-α-D-
Glcp-(1→4)-β-D-thioglucopyranoside, N-p-tolyl-O-{4,6-dideoxy-
4-[1S-(1,4,6/5)-4,5,6-
Trihydroxy-3-hydroxymethyl-4-O
-α-D-glucopyranosyl-(1→4)-cyclohex-2-en-1-ylamino]-α-D
-Glucopyranosyl}-(1→4)-O-α-D
-Glcp-(1→4)-D-glucopyranosylamine, p-nitrophenyl-O-{C}-(1→4)
-O-α-D-Glcp-(1→4)-O-α-D
-Glcp-(1→4)-β-D-glucopyranoside, phenyl-O-{C}-(1→4)-O-α-
D-Glcp-(1→4)-O-α-D-Glcp-
(1→4)-β-D-thio-glucopyranoside, p-nitrophenyl-O-{4,6-dideoxy-4-[1S-(1,4,6/5)-4,5,
6-trihydroxy-3-hydroxymethyl-4
-(O-α-D-Glcp-(1→4)-O-α-
D-glucopyranosyl)-(1→4)-cyclohex-2-en-1-ylamino]-α-D-glucopyranosyl}-(1→4)-O-α-D-
Glcp-(1→4)-β-D-thioglucopyranoside, p-nitrophenyl-O-{4,6-dideoxy-4-[1S-(1,4,6/5)-4,5,
6-trihydroxy-3-hydroxymethyl-4
-(O-α-D-Glcp(1→4)-O-α-D-
Glcp-(1→4)-O-α-D-glucopyranosyl)-(1→4)-cyclohex-2-ene-
ylamino]-α-D-glucopyranosyl}-
(1→4)-O-α-D-Glcp-(1→4)-β
-D-glucopyranoside, O-{C}-(1→4)-O-α-D-Glcp
-(1→4)-D-glucopyranosylamine, and O-{C}-(1→4)-O-α-D-Glcp
-(1→4)-1-thio-D-glucopyranose. The compounds according to the invention are inhibitors of glucoside hydrolases and are thus suitable for the treatment of diseases in which inhibition of these enzymes would be desirable. In animals and humans, after ingestion of carbohydrate-containing foods and beverages, such as cereal starches, potato starches, fruits, fruit juices, beer, and thiocholate, glucoside hydrolases (e.g., salivary and pancreatic Hyperglycemia occurs as a result of rapid degradation of carbohydrates by the enzymes amylase, maltase, and sucrose.

Table: In the case of diabetes, these hyperglycemias are of a particularly strong and long-lasting and pronounced nature. In patients with steatosis, dietary hyperglycemia often leads to particularly severe secretion of insulin, while it leads to an increase in fat content and a decrease in lipogenesis. Such hyperglycemia is often followed by hypoglycemia in obese individuals with healthy metabolism. Both hypoglycemia and food sludge remaining in the stomach promote the production of gastric juices, which in turn causes or predisposes to the production of gastritis or gastric or duodenal ulcers. It is also known that carbohydrates, especially sucrose, are degraded by microorganisms in the oral cavity, thereby promoting the formation of dental caries. Pathological absorption of carbohydrates, for example as a result of a deficiency of intestinal sucrose enzymes, causes diarrhea. Appropriate administration of glucosidase inhibitors influences synthetic pathological absorption and is thus suitable for counteracting constipation. The inhibitory factors according to the invention are thus suitable for use as therapeutic agents for the following indications: steatosis, hyperlipidemia, atherosclerosis, diabetes, prediabetes, hypoglycemia, gastritis,
Constipation and dental caries. In order to widen the spectrum of activity, it is desirable to use inhibitors for glucoside hydrolase whose activities complement each other in combination, and the combination is a combination of inhibitors according to the present invention with each other, or with inhibitors according to the present invention. It is either a combination of an inhibitory factor and a known inhibitory factor. In some cases, the inhibitory factor according to the invention is combined with known oral antidiabetic agents (cytotropic sulfonylurea derivatives and/or piguanides with action on blood sugar) and blood lipid-lowering active compounds, such as clofibrat, nicotinic acid, cholesterol. Combinations with tyramine and others are also advantageous. The compounds of the invention can be administered undiluted, for example as a powder or in a gelatin casing, or in combination with excipients in pharmaceutical compositions. The present invention can be used as a mixture with a solid or liquefied gas diluent or with a liquid diluent other than a solvent having a molecular weight of less than 200 (preferably less than 350) except in the presence of a surfactant. Pharmaceutical compositions containing the compounds of the invention as active ingredients are provided as mixtures. The invention further provides pharmaceutical compositions containing as active ingredient a compound of the invention in the form of a sterile or isotonic aqueous solution. The present invention also provides medicaments in dosage unit form containing the compounds of the present invention. The present invention further provides medicaments in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories containing the compounds of the present invention. "Drug" as used herein refers to physically separate, associated moieties suitable for medical administration. As used herein, "drug in dosage unit form" refers to a daily or unit dose of a compound of the invention, respectively, in combination with a carrier and/or enclosed within an outer package. Physically separate bonded parts suitable for medical administration containing double the amount (up to 4 times) or the same amount (at least 40 times the amount). Whether the drug contains a daily dose or, for example, one-half, one-third or one-fourth of the daily dose, the drug should be administered once a day, respectively. Or, for example, depending on whether two, three or four doses are administered. Pharmaceutical compositions according to the invention can take the form of, for example, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granules or powders. Diluents to be used in pharmaceutical compositions adapted to form tablets, dragees, capsules and pills (e.g. granules) include: (a) fillers and extenders; For example, starch, sugar,
mannitol, and silicic acid: (b) binders, such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate. and sodium bicarbonate; (e) dissolution retardants, such as paraffin; (f) absorption enhancers, such as quaternary ammonium compounds; (g) surfactants, such as cetyl alcohol, glycerol monostearate:
(h) Sorptive carriers such as kaolin and bentonite; (i) Lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols. Tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the present invention may have conventional coatings, envelopes and protective matrices, and they may contain opacifying agents. They can be configured to release the active ingredient only in, or preferentially in, certain parts of the intestinal tract, preferably over a period of time;
The outer envelope and the protective matrix can, for example, consist of a polymeric material or a wax. The active ingredient can also be placed in microcapsule form with one or more of the diluents mentioned above. Diluents to be used in pharmaceutical compositions adapted for formation as suppositories include, for example, polyethylene glycols and fatty acids such as cocoa oil and higher esters [such as _C14
- esters with fatty acids]) or mixtures of these diluents. Pharmaceutical compositions that are solutions and emulsions may, for example, be prepared using the usual diluents (with the above exclusion of solvents having a molecular weight lower than 200, unless of course in the presence of surfactants) may contain, for example, solvents, solubilizers and emulsifiers; specific examples of such diluents include water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene. Glycol, 1,3-
Fatty acid esters of butylene glycol, dimethylformamide, fats and oils (eg peanut oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitol, or mixtures thereof. For oral administration, solutions and emulsions must be sterile and, if necessary, blood isotonic. Pharmaceutical compositions that are suspensions can be prepared using conventional diluents such as liquid diluents such as water, ethyl alcohol, propylene glycol, surfactants (such as ethoxylated isostearyl alcohol, polyoxyethylene sorbite and sorbitan esters), microorganisms, etc. It may contain cristane cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures thereof. All pharmaceutical compositions according to the invention generally contain 0.9 to 99.5% by weight of the total composition, usually 0.5 to 95% by weight.
Contains active ingredients. In addition to the compounds of the invention, the pharmaceutical compositions and medicaments according to the invention can also contain other pharmaceutically active compounds. They may also contain more than one compound of the invention. The diluent in the medicament of the invention can be any of those already mentioned for the pharmaceutical composition of the invention. Such agents may include a solvent having a molecular weight of less than 200 as the sole diluent. The separate joined parts constituting the medicament according to the invention are generally adapted by their shape or packaging for medical administration and can be, for example, any of the following:
Tablets (including lozenges and granules), pills, dragees,
Capsules, suppositories and ampoules. Some of these forms can be tailored to provide delayed release of the active substance. Some, such as capsules, have a protective outer envelope that physically separates and keeps the portions of the drug together. The above pharmaceutical compositions and medicaments may be manufactured by any known method, e.g., by mixing the active ingredient(s) with diluent(s) to form a pharmaceutical composition (e.g. granules); This is accomplished by forming the composition into a drug (eg, a tablet). The present invention further provides a method for treating the aforementioned diseases in human and non-human animals, comprising administering to the animal a compound of the invention, alone or in a mixture with a diluent or in the form of a medicament according to the invention. provide ways to combat (including prevention, mitigation and treatment) These active compounds are expected to be administered orally, parenterally (eg, intramuscularly, intraperitoneally or intravenously) or rectally. Therefore, preferred pharmaceutical compositions and agents are those adapted for such administration. In general, to achieve effective results, 1
It has been found advantageous to administer amounts of 30 to 3×10 ⁵ AIU and 1 to 1×10 ⁴ SIU per kg of body weight per day. However, deviations from these dosage rates may sometimes be necessary, particularly depending on the type and weight of the human or animal subject to be treated, the type of formulation in which the active ingredient is administered and the mode of administration, and the nature of the disease. The need arises depending on the point of progression or the interval at which the administration is to take place. Thus, in some cases it may be sufficient to use lower doses than the above-mentioned minimum dosage rate, while in other cases the above-mentioned upper limit may have to be exceeded to obtain the desired result. be. When administering a relatively large amount,
It may be desirable to divide it into several individual doses over the course of the day. Pharmaceutical compositions to be administered orally, such as solutions, syrups and elixirs, can be prepared in dosage units so that each dose of the formulation contains a specific amount of active substance. Syrups are prepared by dissolving the active compound in an aqueous solution containing a suitable flavour; elixirs can be obtained with a non-toxic, alcoholic carrier. Suspensions can be made by dispersing the active substances in non-toxic carrier materials. Solvents and emulsifiers, such as ethoxylated isostearyl alcohol and polyoxyethylene sorbite esters, preservatives, flavor improvers, such as corn oil or saccharin, can also be added. The dosage formulation can be in capsules. In this case, the release of the active substance can be delayed, for example by incorporating the active substance in a polymeric substance, wax or the like, in order to ensure a suitable dosage. In addition to the above-mentioned pharmaceutical compositions, food products containing these active substances, such as sugar, bread, potato products, fruit juices, beer, tyokolate and other fruits, as well as preserved foods, such as diyam, are produced. These products may then contain a pharmaceutically active amount of at least one inhibitor of the invention. Furthermore, the inhibitory factor according to the invention has a highly effective effect on the ratio between the proportion of undesirable fat and the proportion of meat with a desirable low fat content in animals, in favor of low fat meat. It has the property of This is of particular importance for the breeding of agricultural livestock animals, for example in the fattening of pigs, but is also of considerable importance for the breeding of other domestic animals and companion animals.
Moreover, the use of inhibitors results in a great rationalization of animal feeding, both in terms of time, quantity and quality. Inhibitors cause a definite retardation of digestion, thereby prolonging the residence time of nutrients in the gastrointestinal tract, thereby making it possible to feed in arbitrary quantities with reduced costs. Moreover, in many cases, the use of the inhibitor according to the invention results in considerable savings in expensive protein feed. The active compounds of the invention can thus be used in almost all sectors of animal nutrition, as drugs for reducing the formation of fat layers and for saving feed protein. The degree of activity of the active compound is in this case largely independent of the species and sex of the animal. It has been recognized that the active compounds are of particular value in animal species that generally have a tendency to accumulate relatively large amounts of fat or are prone to do so during certain stages of life. As examples of animals in which inhibitors can be used to reduce the formation of fat layers and/or to conserve feed protein, mention may be made of the following domestic animals and companion animals: warm-blooded animals, such as cattle,
Pigs, horses, sheep, goats, cats, dogs, rabbits, fur animals such as mink and chinchillas, and other companion animals such as rats and hamsters, laboratory and zoo animals such as rats, mice, monkeys, etc. , poultry such as chickens, chickens, ducks, turkeys and pigeons, cows and canaries, and cold-blooded animals such as fish such as carp and reptiles such as snakes. In view of the advantageous properties of the active compounds of the invention, the amount of active compound to be administered to achieve the desired effect can vary substantially. Approximately 0.5 mg to 2.5 g, particularly 10 to 100 mg per kg of feed is preferred. The period over which the active compound is administered can range from hours or days to years. The appropriate amount of active compound and the appropriate period of time for carrying out the administration are closely related to the subject of care.
In particular, it concerns the species, age, sex and health condition of the animal, as well as the method of animal care, which can be readily determined by a person skilled in the art. The active compounds according to the invention are administered to animals in a conventional manner. The method of administration is particularly dependent on the type of animal,
Depends on behavior and general condition. It is thus possible to carry out administration once or several times a day orally at regular or irregular intervals. In most cases, oral administration is preferred for reasons of convenience, especially during the animal's feed and/or drink intake cycle. The active compound can be administered as a pure substance or in a compounded form, but this compounded form can be administered as a premix, i.e. mixed with non-toxic, inert excipients of any desired kind, and As part of the total feed in the form of supplementary feed,
It should be understood that this includes both of the following: and as a component of the mixture of the mixed feed itself. Administration of appropriate formulations using drinking water is also included. The active compounds may optionally be combined in combination with other nutrients and active compounds in suitable forms, such as inorganic salts, trace elements, vitamins, proteins, energy carriers (for example starches, sugars or fats). , dyes and/or flavors, or other feed additives such as growth promoters. The active compound can be administered before, during or after feeding. Oral administration along with the feed and/or drinking water is preferred, in which case the active compound can be added to the feed and/or drinking water in its entirety or only in part, if desired. The active compound can be prepared as a pure substance by conventional methods.
Feed and feed products are prepared by simple mixing, preferably in finely ground form or in a formulated form mixed with edible non-toxic excipients, or optionally in the form of premixes or feed concentrates. /or can be added to drinking water. The feed and/or drinking water may, for example, contain about 0.001 to 5.0% of the active compound according to the invention, in particular
It can be contained at a concentration of 0.02-2.0% (by weight). The optimal level of the concentration of the active compound in the feed and/or drinking water depends, inter alia, on the feed and/or drinking water intake of the animal and can be easily determined by a specialist. The type of feed and its composition are not important in this case. It is possible to use all the commonly available feeds or special feeds, but it is necessary for balanced nutrition,
It is preferred to have a normal balance of energy substances and proteins, including vitamins and mineral substances. The feed can be, for example, vegetable matter, such as shredded oil cake, shredded grain and grain by-products, as well as hay, ensiled feed, beets, etc.
Other dietary sources of plant and animal matter, such as meat and fish products, bone meal, fats and vitamins, such as A, D, E, K and B-complex, and special protein sources, such as yeast and certain It can consist of amino acids, as well as inorganic substances and trace elements, such as phosphorus and iron, zinc, manganese, copper, cobalt, iodine, etc. The premix may contain about 0.1 to 50%, especially 0.5 to 5.0%, in addition to any desired edible excipients and/or inorganic salts, such as carbonated feed lime.
% (by weight) of an active compound of formula () and can be prepared by conventional mixing methods. The mixed feed contains, in addition to the usual raw material components of mixed feeds, such as shredded grain or grain by-products, shredded oil cake, animal protein, minerals, trace elements and vitamins, preferably from 0.001 to 5.0%.
Preferably it contains from 0.02 to 2.0% (by weight) of active compound of formula (). They can be produced by conventional mixing thereof. It is desirable that the active compounds in premixes and mixed feeds be suitably protected from air, light and/or moisture by suitable materials covering their surfaces, such as non-toxic wax or gelatin. The following is an example of the composition of a finished mixed feed for poultry containing the active compound of the invention: 200 g of wheat, 340 g of corn,
360.3g coarse soybean flour, 60g beef tallow, 15g dicalcium phosphate, 10g calcium carbonate, 4g sodium iodide chloride, 7.5g vitamin/mineral mixture and 3.2g active compound premixes, after careful mixing, 1Kg feed. Vitamins/minerals consist of:
6000I.U. of vitamin A, 1000I.U. of vitamin _D3 ,
10mg vitamin E, 1mg vitamin _K3 , 3mg riboflavin, 2mg pyridoxine, 20mg vitamin _B12 , 5mg calcium pantothenate, 30mg
nicotinic acid, 200mg choline chloride, 200mg
_MnSO4 · _H2O , 140mg _ZnSO4 · _7H2O , 100mg
_FeSO4 · _7H2O and 20 mg _CuSO4 · _5H2O . The active compound premix contains, for example, the desired amount, e.g. 1600 mg, of the active compound from Examples 1, 8 and, in addition, enough soy flour to produce 1 g of DL-methionine and 3.2 g of the premix. are doing. The following is an example of the composition of a mixed feed for pigs containing an active compound of formula (): 630 g
of shredded grain feed (consisting of 200 g shredded corn, 150 g shredded barley, 150 g shredded oats and 130 g shredded wheat), 80
g of fish meal, 60 g of coarse soybean flour, 58.8 g of tapioca flour, 38 g of brewer's yeast, 50 g of vitamins for pigs/
mineral mixture (the composition of which is the same as, for example, chicken feed), 30 g of flaxseed meal, 30 g of corn gluten feed, 10 g of soybean oil, 10 g of cane molasses and 2 g of active compound premix (the composition of which is the same as, for example, chicken feed). The same as in the feed) is given 1 Kg of feed after careful mixing. Each of the above feed mixtures preferably comprises:
For the breeding and fattening of chickens and pigs, which, in the same or different composition,
It can also be used for breeding and fattening other animals. In vitro α-amylase inhibition test The in vitro α-amylase inhibition test evaluates the activity of α-amylase from pig pancreas, which is available commercially, in the presence of an inhibitor and in the presence of an inhibitor. By comparing with the case where the enzyme is not used (so-called 100% value), it is possible to determine the enzyme inhibitory activity of the sample. For this, soluble starch is used as a substrate;
Quantification of enzyme activity is based on colorimetric determination of reducing groups using dinitrosalicylic acid. One amylase inhibitory unit (AIU) is defined as the inhibitory activity that reduces a given starch-degrading activity in a defined test batch by 1 unit (amylase unit = AU); , splitting 1 μmol of glucosidic bonds,
Thus, the production of 1 μmol of reducing groups is defined as the leading enzyme activity. A 200μ solution of α-amylase from pig pancreatic secretions (crystal suspension “Behringer”) in 20mM sodium glycerophosphate buffer at PH 6.9, with a concentration of 1mM in _CaCl2 , 0.05 in 10μ ~
Sample solution diluted to contain 0.15AJU
10μ and the mixture at 37°C.
Preincubate for 10 minutes. Amylase solution is 2.0~
Should be adjusted to 2.5 AU/ml. Next, PH6.9
of starch (“Merck 1257”) in sodium glycerophosphate buffer at a concentration of 5%, CaCl ₂
The starch decomposition reaction was started by adding 200μ of the solution at a concentration of 1mM and
After an incubation period of 1 minute, add 0.5 ml of dinitrosalicylic acid reagent (S.P.COLOWICK + N.O.KAPLAN.
ed. Meth. Enzymol. 1 (1955) 149). To develop the color, mix the mixture
Heat to 100° C. for 5 minutes, then dilute with 2.5 ml H ₂ O and photometrically measure at 540 nm against a blank solution (no yeast). To calculate the activity of the enzyme in the presence and absence of the inhibitor, standards are set by 1 and 2 μmol maltose in 400μ sodium glycerophosphate buffer; 1 μmol from the difference in absorbance between both standards. The absorbance for the reducing group is obtained.
This value can be used to calculate the enzyme activity (in amylase units) in a known manner. The specific inhibitory activity of an inhibitor, expressed in amylase inhibitory units per gram (AIU/g), is the activity between batches with and without inhibitor, taking into account the amount of inhibitor used. It can be found from the difference between In vitro sucrose enzyme inhibition test The in vitro sucrose enzyme inhibition test evaluates the activity of solubilized intestinal disaccharide degrading enzyme complex in the presence and absence of an inhibitor (so-called 100% value).
The enzyme inhibitory activity of the sample can be quantified by comparing the enzyme activity. In this case, sutucarose containing almost no glucose (<100 ppm) is used as substrate, which determines the specificity of the inhibition test. Enzyme activities include glucose oxidase, peroxidase and 2,2-azino-di[3-ethyl-benzthiazoline-6-sulfonate] (=
ABTS) based on colorimetric determination of released glucose. One sucrose enzyme inhibitor unit (SIU) is defined as the inhibitory activity that reduces a given sucrose degrading activity in a defined test batch by 1 unit (sucrose enzyme unit = SU): Under conditions of 1 μmole of sucrose is split per minute and 1 μmole of each is quantified in the test.
It is defined as the enzyme activity that leads to the release of glucose and fructose, which is not detected in the test. The disaccharide-degrading enzyme complex in the intestine is derived from pig small intestine mucosa, tribucin digestion, and 66% ethanol.
Obtained by precipitation at 20° C., dissolution of the precipitate in 100 mM phosphate buffer, pH 7.0, and finally dialysis against the same buffer. A 100μ diluted solution of intestinal disaccharide degrading enzyme in 0.1M maleate buffer at PH6.25 was added to the test batch at least 10% lower than the 100% value, but
10μ of the sample solution, previously diluted to give an extinction coefficient not lower than 25%, is added and the mixture is pre-incubated for 10 minutes at 37°C. The dilution of disaccharide degrading enzyme should be adjusted to an activity of 0.05 SU/ml. For sucrose degradation, sucrose (“Zerva”) in 0.1 M maleate buffer at PH 6.25 was then
35579”) and after a 20 min incubation time at 37°C, 1 ml of
GOD/POD/ABTS reagent (0.5M in 100ml of PH7.0)
50 mg GOD in Tris buffer, purity, “Peminger” + 30 mg POD, purity, Boehminger,
Stop by addition of +2 g of ABTS (“Boehminger”). To develop the color, mix the mixture
Incubate for 30 minutes at 37°C, then dilute with 2 ml of Tris buffer and test at 420 nm against a blank solution (containing enzyme but no sucrose).
Measure the photointensity at When calculating the inhibitory activity of an inhibitory factor, even slight changes in the test system can cause slight changes from measurement to measurement.
The difficulty is made considerably by the fact that the 100% value has a non-negligible influence on the test results. Such problems can be avoided by simultaneously using a standard in each measurement; i.e. with a specific inhibitory activity of 68000 SIU/g and when using amounts of 5-10 mg. to cause the above-mentioned degree of suppression in the test,
A compound of formula () with m=0 and n=2 is used as standard. When the difference in absorbance at 420 nm between the 100% value and the batch inhibited by the standard is known, the specific inhibitory activity of the inhibitor, expressed in sucrose enzyme inhibitor units per gram (SIU/g), is , can be calculated in a known manner from the difference in absorbance between the 100% value and the batches inhibited by the sample solution, taking into account the amount of inhibitor used. In Vitro Methods for Inhibition of Glucose Absorption Inhibition of glucose absorption by compounds of the invention has been described by Crane and Mandelstam [Biochem.
Biophys. Acta 45 (1960) 460-476],
This can be demonstrated by modified test procedures. The upper part of the small intestine of a fasted male Wistar rat is folded and cut into rings approximately 3 mm wide. 10 of these rings (~150 mg wet weight)
D-Glucose- ¹⁴ C(U) (10mg/ml, 0.2μCi/
ml) and active compound were added in 5 ml of Krebs-Ringer bicarbonate buffer (PH 7.4).
Incubate for 2 minutes at 37°C. The washed and dried intestinal rings were weighed and dissolved in 5 ml of digestive medium (Merck)/isopropanol (1:1);
The radioactivity absorbed into the tissue is then measured by a liquid scintillation counter. All values are corrected using tissue absorbed radioactivity as D-mannitol- ^1-14C . Results: In vitro inhibition of glucose absorption by several selected compounds (10 mg/ml):

TABLE The in vivo activity of the compounds was tested for several examples using the experimental procedure described below. Oral administration of starch or sucrose causes an increase in blood sugar in humans and animals if the carbohydrates are enzymatically degraded to monosaccharides in the small intestine.
Inhibition of enzymatic hydrolysis by glucosidase inhibitors reduces the extent of blood glucose increase. To detect the effects of glucosidase inhibitors, six fasted rats were orally administered 1 g/Kg of boiled starch or 2.5 g/Kg of sucrose as an aqueous suspension or solution. (starch and sucrose control samples, respectively). Equal numbers of rats are given a defined amount of glucosidase inhibitor along with the same amount of the relevant carbohydrate. A further 6 rats (controls) are administered orally with the same volume of physiological sodium chloride solution. After administration of carbohydrates ± glucosidase inhibitors, changes in postprandial blood glucose were measured at specified time intervals by WSHoffmam (J.biol.Chem 120 , 51
(1937)] in blood from the retroorbital venous plexus. This shows that the active compounds according to the invention are highly active inhibitors of the digestion of starch and sucrose and have a high activity and a long duration of action even at low doses. Shown. Table 2 shows the results of the starch donation test, and Table 3 shows the results of the sucrose donation test.

【table】

[Table] Production of starting compounds 30 g (wet weight) of Dowex in 0.001 NHCl to a column with a diameter of 1.5 cm.
Fill with 50W x 4, (H ⁺ ), 200-400 meshes. Next, the West German patent application publication specification
500 ml of the mixed desorption product (400000 SIU/, PH 2.5, 60% acetone) obtained according to Example 10, Table, Serial No. 7 of No. 2347782 was pumped into the column for about 1 hour and then 500 ml of
Wash the column with 0.001NHCl. Under these conditions, only traces of activity flow out. The product is then desorbed using 0.0125NHCl and the conductivity or refractive index of the column eluate is recorded. The active fractions 74-100 were combined, neutralized by addition of Amberlite IRA410OH ^- , then concentrated to 5 ml and digested with 5 ml of methanol and the product was added dropwise to 200 ml of acetone. Twist and precipitate. After washing with acetone and ether, the product is dried under vacuum. Yield: containing 65000 SIU/g, p+q=2
1 g of a compound with Compounds with p+q=3-8 glucose units are obtained from the elution and active pre-fraction. Unlike alkaline desorption, this acidic desorption method allows the fractionation of each amino-sugar derivative of this series. To separate isomeric compounds with 3 glucose units, 10 g of the isomer mixture dissolved in water was washed with water on a column packed with Dowex 50W x 4 (H ⁺ ) until the eluate was neutral. , then elute using 0.025N hydrochloric acid. Fractions of 3 ml were collected and examined by thin layer chromatography. Thin layer chromatography was performed on silanized gel plates (Merck, West Germany) at 100:
60:40:2 ethyl acetate + methanol + water + 25%
This is done with three developments using concentrated ammonia. A compound with p=0 and q=3 migrates a longer distance from the starting compound than a compound with p=1 and q=2. p=1 and q=2
Fractions 215-272 containing 6 g of the isomer with p
Fractions 288-294 containing 600 mg of the isomer with = 0 and q = 3 were combined to give Amberlite
After neutralizing with IRA-410 (OH ^- ), concentrate. p=0 and q= isolated by this method
The in vitro sucrose inhibitory activity of the isomer with 3 is 190000 SIU/g. Preparation of another starting compound is described in Example 8, 23 ;
25; 9, 26 ; 9, 27 and 9, 28 . Production examples for amino-sugar derivatives of the present invention Example 1 p-nitrophenyl-O-{C}-(1→4)
-O-α-D-Glcp-(1→4)-β-D-glucopyranoside C≡4,6-dideoxy-4-[1S-(1,
4,6/5)-4,5,6-trihydroxy-3
-Hydroxymethyl-cyclohex-2-ene-
1-ylamino]-α-D-glucopyranosyl 1 5g Drierite, 1.2g (8.6 mmol)
of p-nitrophenol and 1 g (4.3 mmol) of silver oxide are added to 40 ml of anhydrous quinoline and the mixture is stirred for 30 minutes with exclusion of moisture. 10 g of compound 26 from Example 9 are then added and the mixture is slowly brought to room temperature while stirring vigorously. The reaction mixture was stirred for an additional hour at room temperature,
Add 300 ml of chloroform and separate the undissolved residue. The chloroform solution was washed with ice-cooling, first with 5% hydrochloric acid, then with sodium carbonate, and finally with water.
dry. The residue was dissolved in 100 ml of absolute methanol.
A solution of 400 mg of sodium is added and the mixture is stirred at room temperature for 2 hours. It is then diluted with 100 ml of water and neutralized using a weakly acidic ion exchanger (H ⁺ form), the ion exchanger is separated off and the solution is evaporated to dryness in a rotary evaporator. Take up the residue in a small amount of dimethylformamide/water and add cellulose (Avicel, Merck)
Flow onto a column (length 70 cm, diameter 2.6 cm) packed with The column is eluted with water-saturated butanol and the individual fractions are examined by thin layer chromatography. 3 g of amorphous compound 1 with a light absorption value α _D =88.8° (H ₂ O; C=1%) are obtained. Furthermore, for chelactylation, a small amount of the compound is acetylated in acetic anhydride/pyridine at room temperature and the mass spectrum of the resulting dodecaacetate salt is recorded. Molecular weight measured by mass spectrometry: 1270
_{( C55H72N2O32 ) .} The following compound was produced in the same manner: 2 Phenyl-O-{C}-(1→4)-O-α
-D-Glcp-(1→4)-β-D-glucopyranoside Mass spectra of acetylated compounds and
N ¹ -NMR and C ¹³ NMR spectra were measured. 3 m-hydroxyphenyl-O-{C}-(1
→4)-O-α-D-Glcp-(1→4)-β
-D-glucopyranoside (O-acetylresorcinol was used as starting compound) α _D =100.2° (H ₂ O; c=1%). Molecular weight of the acetylated compound measured by mass spectrometry: 1283 (C ₅₇ H ₇₃ NO ₃₂ ) 4 m-carbomethoxyphenyl-O-{C}-
(1→4)-O-α-D-Glcp-(1→4)-
β-D-glucopyranoside Molecular weight _of the acetylated compound determined by mass spectrometry: 1283 ( _C57H73NO32 ) _. 5 m-carboxyphenyl-O-{C}-(1
→4)-O-α-D-Glcp-(1→4)-β
-D-glucopyranoside 5 was prepared by saponifying 4 using 10% strength sodium hydroxide solution at room temperature. α _D = 91.7° (H ₂ O; c = 1%) 6 p-carbomethoxyphenyl-O-{C}-
(1→4)-O-α-D-Glcp-(1→5)-
β-D-glucopyranoside Molecular weight _of the acetylated compound determined by mass spectrometry: 1283 ( _C57H73NO32 ) _. 7 p-carboxyphenyl-O-{C}-(1
→4)-O-α-D-Glcp-(1→4)-β
-D-glucopyranoside 7 was prepared by saponifying 6 with 10% strength sodium hydroxide at room temperature. α _D = 85.9° (H ₂ O; c = 1%) 8 p-hydroxyphenyl-O-{C}-(1
→4)-O-α-D-Glcp-(1→4)-β
-D-glucopyranoside (O-benzoyl-hydroquinone was used as starting compound) Molecular weight of the acetylated compound determined by mass spectrometry _{: 1283} ( _C57H73NO32 ). 9 pt-butylphenyl-O-{C}-(1
→4)-O-α-D-Glcp-(1→4)-β
-D-glucopyranoside _Molecular weight of the acetylated compound determined by mass _spectrometry : 1281 ( _C59H79NO30 ). 10 Diethylstilbostrol-4′-[O-
{C}-(1→4)-O-α-D-Glcp-(1
→4)-β-D-glucopyranoside] Upon acetylation, this compound was characterized by mass spectrometry. 11 Naringenin dihydrochalcone-2′-β-
Glucopyranoside-4′-[O-{C}-(1→
4) -O-α-D-Glcp-(1→4)-β-
D-glucopyranoside] (Florhidine was used as starting compound) C ₄₆ H ₆₅ NO ₂₇ (1064.0) Calculated: C51.9 H6.2 N1.3 O40.6 Analyzed: C51.6 H7.1 N0.8 O38.5. 12 p-Nitrophenyl-O-{4,6-dideoxy-4[1S-(1,4,6/5)-4,5,
6-trihydroxy-3-hydroxymethyl-
4-O-α-D-glucopyranosyl-(1→
4)-cyclohex-2-en-1-ylamino]-α-D-glucopyranosyl}-(1→
4) -O-α-D-Glcp-(1→4)-β-
D-glucopyranoside The product was characterized by C ¹³ -NMR spectroscopy and mass spectrometry of the acetylated compound. 13 4-formyl-phenyl-O-{C}-(1
→4)-O-α-D-Glcp-(1→4)-β
-D-glucopyranoside Molecular weight _of the acetylated compound determined by mass spectrometry: 1253 ( _C56H71NO31 ) _. 14 4-(β-cyanoethenyl)-phenyl-O
-{C}-(1→4)-O-α-D-Glcp-
(1→4)-β-D-glucopyranoside Molecular weight of acetylated compound: 1276
_{( C58H72N2O30 ) .} 15 4-cyclohexyl-phenyl-O-{C}
-(1→4)-O-α-D-Glcp-(1→4)
-β-D-glucopyranoside 16 3-(β-cyanoethenyl)-phenyl-O
-{C}-(1→4)-α-D-Glcp-(1
→4) -β-D-glucopyranoside Similar to Production Example 1 3-dimethylamino-phenyl-O-{C}-
(1→4)-O-α-D-Glcp-(1→4)-β
-D-Glucopyranoside 17 α _D =73.22° (H ₂ O; c=1%) Molecular weight of the acetylated compound determined by mass spectrometry: 1268 (C ₃₇ H ₇₆ N ₂ O ₃₀ ). 4-dimethylaminosulfonyl-phenyl-O
-{C}-(1→4)-O-α-D-Glcp-
(1→4)-β-D-glucopyranoside 18 Molecular weight _of the acetylated compound determined by mass spectrometry: 1332 ( _{C57H76N2O32S ) .} 4-benzoyl-phenyl-O-{C}-(1
→4) -O-α-D-Glcp-(1→4)-β-
D-glucopyranoside 19 Molecular weight of the acetylated compound measured by mass spectrometry: 1329 (C ₆₂ H ₇₅ NO ₃₁ ). Example 2 Phenyl-O-{C}-(1→4)-O-α-
D-Glcp-(1→4)-β-D-glucopyranoside 2 8.8 g (7.3 g) from Example 9 in 22 ml acetone
mmol) of compound 26 in 14 ml at room temperature.
3.2 g (34 mmol) of phenol in H ₂ O and
Add to a solution of 1.08 g (19.3 mmol) KOH.
The mixture is stirred overnight and then diluted with 50 ml of benzene. The organic phase is separated and concentrated in a rotary evaporator. The residue is taken up in 200 ml of benzene and the benzene solution is extracted by shaking three times, first with 20 ml of water, then with 40 ml of 2N NaOH and finally with 80 ml of water. The benzene phase is dried, filtered and concentrated. Residue: 6.4g. The residue is stirred in a solution of 50 mg Na in 50 ml MeOH overnight. The mixture is then diluted with water and neutralized using Amberlite IRC50 (H ⁺ form). After evaporation, the solution is evaporated to dryness in a rotary. Residue: 3.2g. A column (length 50 cm, diameter 2.4 cm) filled with cellulose (Merck: “Avicel”) was filled with this distillate.
pour it on top. Butanol saturated with water is used as eluent. The flow rate is 15 drops/min: fractions of 400 drops are collected each. Fractions 36-57 are
This gives 1.5 g of amorphous compound 2. Similarly, prepare the following compound: Phenyl-O-{C}-(1→4)-β-D-
Glucopyranoside 13 The product was characterized by nuclear magnetic resonance spectroscopy at 220 MHz, ¹³ C-NMR spectroscopy and mass spectrometry of the acetylated compound. Example 3 Methyl-O-{C}-(1→4)-O-α-D
-Glcp-(1→4)-β-D-glucopyranoside 14 1.3 g of yellow mercury oxide (), 0.1 g of mercury bromide () and 2.0 g of dry erite in 20 ml
of anhydrous methanol and 20 ml of pure chloroform at room temperature for 1.5 hours. Then 3.0 g of compound 26 from Example 9 are added and the mixture is stirred overnight. The undissolved residue is separated off and the liquid is evaporated to dryness in a rotary evaporator. The residue is taken up in chloroform and the solution is clarified by one more filtration and then concentrated again. The residue is stirred overnight at room temperature with 75 ml of a 0.1 strength solution of sodium methanolate in methanol. The mixture is then diluted to 400 ml with water and then neutralized using a weakly acidic ion exchanger (H ⁺ form). The solvent was removed in a rotary evaporator and the residue was dissolved in cellulose (“Avicel”,
Column (length 70 cm: diameter 2.4
Flow over cm. The column is eluted with butanol/ethanol/water 3:1:1. Fractions of approximately 8 ml are collected and individual fractions are examined by thin layer chromatography. Fractions 60-92 are
Contains 500g of compound 14. After acetylation using acetic anhydride/pyridine,
Measure the mass spectrum of the compound. Molecular weight measured by mass spectrometry: 1163
_{( C5OH69NO3O )} . Similarly, the following compound is prepared: Ethyl-O-{C}-(1→4)-β-D-glucopyranoside 15 Molecular weight of acetylated compound measured by mass spectrometry: 889 (C ₃₉ H ₅₅ NO ₂₂ ) Example 4 n-Butyl-O-{C}-(1→4)-O-α
-D-Glcp-(1→4)-β-D-glucopyranoside 16 From a mixture of 40 ml of nitromethane and 40 ml of benzene, 20 ml of liquid are distilled off with exclusion of moisture. After cooling, 1 ml n-butanol and 1 g
of dry elite is added and the mixture is stirred for 30 minutes at 40°C. Then, after adding 0.5 g of mercuric cyanide () and 2.4 g of compound 26 from Example 9, the mixture is heated at 40-50 DEG C. for a further 24 hours. The reaction mixture is then diluted with benzene and the benzene solution is washed first with water, then with sodium bicarbonate solution and finally with water again. After drying, evaporate to dryness on a rotary evaporator. The residue is 50 ml of a 0.1% solution of sodium methanolate in methanol.
Deacetylate overnight at room temperature.
This mixture is diluted with water and then neutralized using a weakly acidic ion exchanger. The solution is concentrated in a rotary evaporator and the residue is passed onto a column packed with cellulose. The column is eluted with butanol saturated with water. Individual fractions are examined by thin layer chromatography. Obtain 500 mg of amorphous compound 16. _Molecular weight of the acetylated compound determined by mass _spectrometry : 1205 ( _C53H75NO30 ). The following compound was produced in the same manner: n-octyl-O-{C}-(1→4)-O-
α-D-Glcp-(1→4)-β-D-glucopyranoside 17 n-hexadecyl-O-{C}-(1→4)-
O-α-D-Glcp-(1→4)-β-D-glucopyranoside 18 Benzyl-O-{C}-(1→4)-O-α-
D-Glcp-(1→4)-β-D-glucopyranoside 19 _Molecular weight _of the acetylated compound determined by mass spectrometry: 1239 ( _C56H73NO30 ). Benzyl-O-{C}-(1→4)-β-D-
glucopyranoside 20 _Molecular weight of the acetylated compound determined by mass spectrometry: 951 ( _C44H57NO22 ) _. Example 5 Methyl-O-{C}-(1→4)-α-D-
Glucopyranoside 21 1g of -C-{C}-(1→4)-α-D-
Glcp-(1→4)-D-glucopyranose,
In 100 ml of anhydrous methanol and 2 ml of concentrated sulfuric acid,
Heat under reflux for 10 hours. After cooling, the mixture is 100%
ml of water and neutralize the solution with _NaCO3 . The mixture is filtered and the liquid is concentrated in a rotary evaporator. Dissolve the residue in a small amount of water and soak in a strongly acidic ion exchanger (Dowex).
50WX4, H ⁺ form).
The column is eluted first with water and then with 0.025NHCl. Individual fractions are examined by thin layer chromatography. Fractions 44-60 are 360 mg of 21
give. _Molecular weight of the acetylated compound determined by mass spectrometry: 875 ( _C38H53NO22 ) _. The α-structure of the glucoside is confirmed by nuclear magnetic resonance spectroscopy at 100MHz. Example 6 Methyl-O-{C}-(1→4)-α-D-glucopyranoside 21 1 g of -O-{C}-(1→4)-D-glucopyranose was dissolved in 1% methanolic hydrochloric acid 100
ml and warmed to 60°C for 24 hours. The solution is then evaporated to dryness in a rotary evaporator. The residue is dissolved in water and the solution is neutralized with a basic ion exchanger (OH ^- form). The aqueous solution was mixed with a strongly acidic ion exchanger (Dowex).
50WX4, H ⁺ form).
The subsequent procedure is similar to that described in Example 5.
Yield: 500mg 21. Example 7 D-Sorbitol-4-[-O-{C}-(1
→4)-α-D-glucopyranoside〕 22 1g of -O-{C}-(1→4)-O-α-D
-Glcp-(1→4)-D-glucopyranose
Dissolve in 50ml of distilled water. This solution has a concentration of 1
% sodium hydroxide solution to adjust the pH to 10. Then 100 mg of NaBH ₄ are added and the mixture is stirred at room temperature for 48 hours. After neutralizing this with a weakly acidic ion exchanger, the aqueous solution is run onto a column packed with a strongly acidic ion exchanger (Dowex WX4, H ⁺ form). The column is eluted first with water and then with 0.05N hydrochloric acid.
Get 370mg of 22. α _D =96.8° (H ₂ O; c=1%) Molecular weight of the acetylated compound determined by mass spectrometry: 1235 (C ₅₃ H ₇₃ NO ₃₂ ). Example 8 Trideca-O-acetyl-O-{C}-(1→
4) -O-β-D-Glcp-(1→4)-D-glucopyranose 23 3.8g of O-{C}-(1→4)-O-α-D
-Glcp-(1→4)-D-glucopyranose,
Stir in 50 ml acetic anhydride and 50 ml pyridine at room temperature for 48 hours. The mixture was then concentrated in a rotary evaporator, the residue was dissolved in chloroform and extracted by shaking the chloroform solution three times with water, followed by Na ₂ SO ₄
Dry using. After removal of the solvent, 6.2 g of amorphous 23 are obtained. The molecular weight of this compound determined by mass spectrometry is 1191 (C ₅₁ H ₆₉ NO ₃₁ ). The following compounds can be prepared in the same way: deca-O-acetyl-O-{C}-(1→4)
-D-Glucopyranose 24 Hexadeca-O-acetyl-O-{4,6-dideoxy-4-[1S(1,4,6/5)-4,
5,6-trihydroxy-3-hydroxymethyl-4-O-α-D-glucopyranosyl-(1→
4)-cyclohex-2-en-1-ylamino]-α-D-glucopyranosyl}-(1→4)
-O-α-D-Glcp-(1→4)-D-glucopyranose 25 Example 9 Dodeca-O-acetyl-{C}-(1→4)-
O-α-D-Glcp-(1→4)-α-D-glucopyranosyl bromide 26 Dissolve 5 g of 23 in 15 ml of glacial acetic acid. 10 ml of a saturated solution of hydrogen bromide in glacial acetic acid are added to the ice-cold solution. The mixture is then stirred for 1 hour while cooling in a water bath. It is then diluted with chloroform and the chloroform solution is extracted by shaking with water until the wash water is neutral. Dry the chloroform solution with Na ₂ SO ₄
Evaporate after evaporation. Yield: 4.6g of 26. This amorphous crude product is used for the production of glucosides without further purification. In the same way, the following compound is prepared: Inar-O-acetyl-O-{C}-(1→4)
-α-D-glucopyranosyl bromide 27 Pentadeca-O-acetyl-O-4,6-dideoxy-4-[1S-(1,4,6/5)-4,
5,6-trihydroxy-3-hydroxymethyl-4-O-α-D-glucopyranosyl-(1→
4)-Cyclohex-2-en-1-ylamino]-α-D-glucopyranosyl-(1→4)-
O-α-D-Glcp-(1→4)-α-D-glucopyranosyl bromide 28 Example 10 Phenyl-O-{C}-(1→4)-O-α-
D-Glcp-(1→4)-β-D-thioglucopyranoside 32 2.24 g of compound 26 from Example 9 are added to an ice-cold solution of 0.264 g (2 mmol) of sodium thiophenolate in 10 ml of anhydrous dimethylformamide, and the mixture is heated under exclusion of moisture. , stir at room temperature for 24 hours. This is concentrated to dryness under vacuum. The evaporation residue is taken up in chloroform/water, the phases are separated, the chloroform phase is washed twice with water, dried and then evaporated under vacuum. The resulting residue is stirred for 1 hour in an ice bath with a solution of 100 mg of sodium in 25 ml of absolute methanol, the resulting suspension is neutralized with glacial acetic acid and then concentrated in a rotary evaporator. The residue is taken up in a small amount of dimethylformamide/water/butanol and loaded onto a column (length 65 cm, diameter 3 cm) packed with cellulose (Avicel, Merck). The column is eluted with butanol saturated with water and the individual fractions are examined by thin layer chromatography. 670 mg of amorphous compound 32 with an optical rotation value α _D =106.7° (H ₂ O; c=1%) are obtained. Molecular weight of the acetylated compound, determined by mass spectrometry: 1241 (C ₅₅ H ₇₁ NO ₂₉ S) The following compound is produced in the same way: 2-aminophenyl-O-{C}-(1→4)
-O-α-D-Glcp-(1→4)-β-D-thioglucopyranoside 33 Molecular weight of the acetylated compound determined by mass spectrometry: 1298 (C ₅₇ H ₇₄ N ₂ O ₃₀ S) 2-Benzothiazolyl-O-{C}-(1→
4) -O-α-D-Glcp-(1→4)-β-D
-Thioglucopyranoside 34 Mass spectra of acetylated compounds were measured. Benzyl-O-{C}-(1→4)-O-α-
D-Glcp-(1→4)-β-D-thioglucopyranoside 35 Molecular weight _of the acetylated compound determined by mass spectrometry: 1255 ( _C56H73NO20S ) _. 36 4-Phenoxy-phenyl-O-{C}-
(1→4)-O-α-D-Glcp-(1→4)-
β-D-thioglucopyranoside Molecular weight of the acetylated compound determined by mass spectrometry: 1333 (C ₆₁ H ₇₅ NO ₃₀ S) α _D = 107.5° (c = 1%, H ₂ O). 37 4-Aminophenyl-O-{C}-(1→
4) -O-α-D-Glcp-(1→4)-β-
D-thioglucopyranoside 38 Indolyl-3-O-{C}-(1→4)-
O-α-D-Glcp-(1→4)-β-D-glucopyranoside 4-Carboxymethyl-phenyl-O-{C}
-(1→4)-O-α-D-Glcp-(1→4)
-β-D-thioglycopyranoside 39 Molecular weight of the acetylated compound measured by mass spectrometry: 1299 (C ₅₇ H ₇₃ NO ₃₁ S), α _D = 101.3° (H ₂ O; c = 1%) Pyridine-4-O-{C}- (1 → 4) -O-
α-D-Glcp-(1→4)-D-glucopyranoside 40 Example 11 N-p-tolyl-O-{C}-(1→4)-O
-α-D-Glcp-(1→4)-D-glucopyranosylamine 36 A solution of 1 g of p-toluidine in 4.8 ml of absolute ethanol is added to a solution of 1 g of the compound (m=0, n=2) in 2 ml of 0.001N sulfuric acid. The mixture is stirred for 3 days at room temperature, 400 mg of barium carbonate are added, the mixture is filtered and the liquid is concentrated in a rotary evaporator. The evaporation residue is dried in a desiccator, triturated with ether, filtered and washed with ether. The crude product obtained (1.1 g) is dissolved in a small amount of methanol and applied to a column (length 70 cm, diameter 2.6 cm) packed with cellulose (Avicel, Merck).
The column is eluted with a 4:1 methanol/ethanol mixture and the individual fractions are examined by thin layer chromatography. 380 mg of an amorphous compound containing an optical rotation value α _D =109.1° (H ₂ O; 1%) are obtained. Molecular weight _of the acetylated _compound determined by mass spectrometry: 1238 ( _{C56H74N2O29 )} . The following compound is produced in the same way: N-phenyl-O-{C}-(1→4)-O-
α-D-Glcp-(1→4)-D-glucopyranosylamine 37 α _D =97.6° (H ₂ O; c = 1%). Molecular weight of the acetylated compound measured by mass spectrometry: 1224 (C ₅₅ H ₇₂ N ₂ O ₂₉ ) O-{C}-(1→4)-O-α-D-Glcp
-(1→4)-D-glucopyranosylmorpholine 38 Molecular weight _{of the} acetylated compound determined by mass spectrometry: 1218 ( _C53H74N2O30 ) _. 39 O-{C}-(1→4)-O-α-D-
Glcp-(1→4)-D-glucopyranosyl-
N′-phenylpiperazine Molecular weight _of the acetylated compound determined by mass spectrometry _: 1298 ( _{C59H79N3O29 )} . α _D =127.1 (H ₂ O; c = 1%). 40 N-(p-methoxy-phenyl)-O-
{C}-(1→4)-α-D-Glcp-(1→
4)-D-glucopyranosylamine Molecular weight of the acetylated compound determined by mass spectrometry: 1254 (C ₅₆ H ₇₄ N ₂ O ₃₀ ) α _D =133.5 (H ₂ O; c=1%). 41 N-benzyl-O-{C}-(1→4)-O
-α-D-Glcp-(1→4)-D-glucopyranosylamine Molecular weight of the acetylated compound measured by mass spectrometry: 1280 (C ₅₈ H ₇₆ N ₂ O ₃₆ ) α _D = 144.1 (H ₂ O; c = 1%) 42 N-(p-acetylaminophenyl) -O-
α-D-Glcp-(1→4)-D-glucopyranosylamine Molecular weight _of the acetylated compound determined by mass _spectrometry : 1281 ( _C57H75N3O30 ) _. α _D = 122.2 (H ₂ O; c = 1%) Example 12 O-{C}-(1→4)-O-α-D-Glcp
-(1→4)-1-thio-D-glucopyranose 39 A 22.24 g (20 mmol) of compound 26 from Example 9 were added to a suspension of 1.56 g (20 mmol) of thiourea in 20 ml of acetone and the mixture was dissolved under exclusion of moisture. Stir for 15 minutes under reflux. Concentrate this to dryness in vacuo.
The crude product is used in the next reaction. B 25.76 g (20 mmol) of dodeca-OC-
(1→4)-β-D-glucopyranosyl-isothiuronium bromide and 30 ml of carbon tetrachloride,
A solution of 3.41 g (17.9 mmol) of sodium pyrosulfite in 20 ml of water, heated to 85°C, is added and the mixture is stirred at 85°C for 10 minutes. After cooling, it is diluted with chloroform, the phases are separated, the chloroform phase is washed twice with ice water, dried and concentrated under vacuum. The residue was taken up in a small amount of chloroform and silica gel 60
Flow onto a column (length 90 cm: diameter 4 cm) packed with (Merck). This column was mixed with chloroform/
Elute with ethyl acetate 2:1 and examine the individual fractions by thin layer chromatography. 10.6 g of amorphous compound are obtained. Empirical formula: C ₄₉ H ₆₇ NO ₂₉ S Mass spectrum: m/e = 1131 (equivalent to M-H ₂ S) Thin layer chromatography: Finished silica gel
60F254 plate (Merck) Eluent: Chloroform/ethyl acetate 1:2 Rf _rel = 0.354 (for the compound from Example 9,
Rf = 1.0) For deacetylation, add 250 ml of this compound to
Stir in an ice bath for 2 hours with a solution of 1 g of sodium in absolute ethanol, and the resulting suspension
Add 100ml of water and mix the mixture with a weakly acidic ion exchanger, namely Amberlite IRC50 (Celva),
After neutralizing with water, filter and evaporate the liquid under vacuum. The residue is dissolved in a small amount of water and the solution is lyophilized. 6 g of an amorphous compound with optical rotation α _D =+125.0° (H ₂ O; c=1%) are obtained.

Claims (1)

[Claims] 1 formula In the formula, n and m each independently represent a number from 0 to 8, and the sum n+m is a number from 0 to 8, and X is a group -OR, -SH, -SR, _-NH2 , -
NHR or -NRR ₁ , where R is optionally substituted alkyl,
represents an alkenyl, cycloalkyl, aralkyl, aryl or heterocyclic group, R ₁ represents an optionally substituted alkyl, cycloalkyl, aralkyl or aryl group, or R and R ₁ taken together with a nitrogen atom 1. A treatment for diabetes, steatosis or hyperlipidemia, characterized in that it contains as an active ingredient an amino-sugar derivative, which may form a heterocyclic ring. 2.200 as a mixture with solid or liquefied gaseous diluents and except in the presence of surfactants.
Claim 1 containing an amino-sugar derivative of formula () as an active ingredient in a mixture with a liquid diluent other than a solvent having a molecular weight smaller than
The treatment agent described in section. 3. The therapeutic agent according to claim 1, which contains the amino-sugar derivative of formula () as an active ingredient in the form of a sterile or isotonic aqueous solution. 4. The therapeutic agent according to claim 2 or 3, containing 0.5 to 95% by weight of the active ingredient. 5. A therapeutic agent according to claim 1 in a dosage unit form comprising an amino-sugar derivative of formula (). 6. The therapeutic agent according to claim 1 in the form of a tablet, pill, capsule, ampoule or suppository containing an amino-sugar derivative of formula (). 7 In formula (), X is -OR, -SH, -
SR, -NH ₂ , -NHR or -NRR ₁ group, where R is 1 to 5 hydroxyl groups or C ₁ to
represents an alkyl group having 1 to 18 carbon atoms optionally substituted by a C ₄ alkoxy group, or optionally 1 to 3 C ₁ -C ₄ alkyl,
OH, _C1 - _C4 alkoxy, amino, C1- _C4 alkylamino, di- _C1 - _C4 alkylamino, carboxyl, _{methoxycarbonyl} , nitro, glucopyranyl, benzoyl, p-hydroxyphenylethylcarbonyl, _C1 ~ _C4 alkylaminosulfonyl or _C1 - _C4 dialkylaminosulfonyl group; represents phenyl which may be substituted by, or represents a benzyl group or a 2-benzothiazolyl group; R ₁ represents C ₁ -C ₄ alkyl;
The therapeutic agent according to claim 1, which may form a morpholine or piperidine ring together with R.