EP0000947B1 - 3,4,5-trihydroxypiperidine derivatives, process for their preparation and medicaments and fodder containing them - Google Patents

Description

The present invention relates to novel derivatives of 3,4,5-trihydroxypiperidine, several processes for their preparation, medicaments containing this compound, these compounds for use in the treatment of diabetes, hyperlipemia and obesity, as well as their use in animal nutrition to influence meat / Fat ratio in favor of the meat content.

in der

• R₁ H oder einen gegebenenfalls substituierten, geradkettigen, verzweigten oder cyclischen gesättigten oder ungesättigten aliphatischen Kohlenwasserstoffrest darstellt,
  
  
  ―SO₃H, -CN oder -CONR'R" bedeutet und
• R₃ die für R, gegebene Bedeutung annehmen kann, wobei
• R', R" Wasserstoff, einen gegebenenfalls substituierten geradkettigen, verzweigten oder cyclischen gesättigten oder ungesättigten aliphatischen Kohlenwasserstoffrest oder einen gegebenenfalls substituierten aromatischen oder heterocyclischen Rest bedeutet und wobei
• R, nicht Wasserstoff ist, wenn
  • a) R₂ Wasserstoff oder OH und R₃ CH₂0H
  • b) R₂ Wasserstoff, OH, SO₃H, CN oder CH₂NH₂ und R₃ Wasserstoff und
  • c) R₂ OH und R₃ CH₂NH₂ bedeuten.

The new derivatives can be represented by the formula

in the

• R _{1 represents} H or an optionally substituted, straight-chain, branched or cyclic saturated or unsaturated aliphatic hydrocarbon radical,
  
  
  ―SO ₃ H, -CN or -CONR'R "means and
• R ₃ can assume the meaning given for R, where
• R ', R "is hydrogen, an optionally substituted straight-chain, branched or cyclic saturated or unsaturated aliphatic hydrocarbon radical or an optionally substituted aromatic or heterocyclic radical and wherein
• R, is not hydrogen if
  • a) R _{2 is} hydrogen or OH and R ₃ CH ₂ 0H
  • b) R _{2 is} hydrogen, OH, SO ₃ H, CN or CH ₂ NH ₂ and R _{3 is} hydrogen and
  • c) R ₂ OH and R ₃ CH ₂ NH ₂ mean.

The invention also relates to pharmaceutically acceptable salts of the compounds of the formula I, such as chlorides, sulfates, acetates, carbonates, oxalates, etc., and organic precursors, organic precursors being understood to mean compounds whose structure differs from the active compound which, however, are converted into the active compound in the patient's body after administration to humans or animals.

R ₁ , R ', R "preferably mean an alkyl radical having 1 to 30, in particular 1 to 18, carbon atoms, an alkenyl radical or alkynyl or tricyclic radical with 3 to 10 carbon atoms, which may be saturated, mono- or di-unsaturated, an aryl radical with 6 or 10 carbon atoms, a heterocyclic radical with 3 to 8, in particular 3 to 6 ring members, which may contain 1, 2, 3 or 4 heteroatoms, in particular N, 0, S, and on which a benzene ring or another heterocycle of the type mentioned can be fused, wherein said radicals 1 to 5 can in particular carry 1, 2 or 3 substituents.

Examples of substituents for alkyl are: hydroxy, alkoxy with preferably 1 to 4 carbon atoms, in particular methoxy and ethoxy; Acyloxy, the acyl radical of aliphatic carboxylic acids having 1 to 7 carbon atoms, aromatic carboxylic acids, in particular phenylcarboxylic acids, which are in the phenyl radical by -OH; Halogen, in particular F, Cl, Br, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro and / or amino, heterocyclic carboxylic acids which are derived from 5- or 6-membered heterocycles, which contain 1 to 3 heteroatoms (N, O, S) and can be substituted in the heterocyclic ring by C, -C ₄ alkyl, chlorine, bromine, amino; Amino, monoalkylamino and dialkylamino with preferably 1 to 4 carbon atoms per alkyl radical, in particular monomethylamino, monoethylamino, dimethylamino and diethylamino, monoacylamino, the acyl radical of aliphatic carboxylic acids having 1 to 7 carbon atoms, aromatic carboxylic acids, in particular phenylcarboxylic acids, in the phenyl radical by -OH , -Halogen, in particular F, Cl, Br, C ₁ ―C ₄ alkyl, C ₁ ―C ₄ alkoxy, nitro and / or amino may be substituted, heterocyclic carboxylic acids which are derived from 5- or 6-membered heterocycles , which contain 1 to 3 heteroatoms (N, 0, S) and can be substituted in the heterocyclic ring by C, -C ₄ alkyl, chlorine, bromine, amino; Mercapto, alkylthio with preferably 1 to 4 carbon atoms, especially methyl thio and ethylthio; Halogen, preferably fluorine, chlorine and bromine; Alkylcarbonyl preferably having 1 to 4 carbon atoms in the alkyl radical; Carboxy, nitro, cyan, the aldehyde function, the sulfonic acid group; as well as heterocyclic radicals of the abovementioned type, in particular also heterocyclic radicals derived from sugars, very particularly from hexoses or pentoses, which can be connected directly to the alkyl radical via a ring atom or via a -0-, -S- or -NH-bridge.

Examples of heterocyclic substituents of the alkyl radicals are: phthalimido, pyridyl, thienyl, furyl, isoxazolyl, thiazolyl, glucopyranosyl, ribofuranosyl, oxiranyl and the like. The like are furthermore suitable as substituents of the alkyl radicals aromatic radicals such as naphthyl and in particular phenyl which have one or more, preferably 1 to 3 identical or different substituents from the series -OH, -NH ₂ , 1 _Ci - _C4- alkyl- _NH - , C _l -C ₄ dialkyl-N-, C, -C _4- alkoxy, N0 ₂ , -CN, -COOH, -COO-alkyl (C ₁ -C ₄ ), C ₁ ―C ₆ alkyl, halogen , especially fluorine, chlorine or bromine, C _l -C ₄ alkylthio, -SH, C _l -C ₄ alkylsulfonyl, ―SO ₃ H, ―SO ₂ ―NH ₂ , ―SO ₂ ―NH-alkyl (C ₁ - C ₄ ) can wear.

The alkyl radical can also carry a mono-, bi- or tricyclic substituent with preferably 3 to 10 carbon atoms, which in turn can be substituted by hydroxyl, amino, halogen, in particular fluorine, chlorine, bromine or -COOH.

The alkyl radical preferably carries substituents such as hydroxy, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio having 1 to 4 carbon atoms, halogen, nitro, amino, monoalkylamino having 1 to 4 carbon atoms and acylamino, the acyl radical of aliphatic carboxylic acids having 1 to 6 carbon atoms is derived.

The substituents mentioned for the alkyl radicals are suitable for the cyclic mono-, bi- or tricyclic radicals R ₁ , R 'and R ".

The aryl radicals R 'and R "can carry one or more, preferably 1 to 3 identical or different substituents. Examples of substituents are: alkyl having 1 to 10 C atoms, which in turn can be substituted, for example, by chlorine, nitro or cyano , optionally substituted alkenyl radicals with 1 to 10 carbon atoms; hydroxy, alkoxy with preferably 1 to 4 carbon atoms; amino, monoalkyl and dialkylamino with preferably 1 to 4 carbon atoms per alkyl radical; mercapto, alkylthio with preferably 1 to 4 carbon atoms; carboxy, carbalkoxy with preferably 1 to 4 carbon atoms, the sulfonic acid group, alkylsulfonyl with preferably 1 to 4 carbon atoms arylsulfonyl, preferably phenylsulfonyl; aminosulfonyl, alkylamino and dialkylaminosulfonyl with 1 to 4 carbon atoms per alkyl group, preferably methyl and dimethylaminosulfonyl; nitro, cyano or the aldehyde group; alkylcarbonylamyl preferably 1 to 4 carbons toffee atoms; Alkylcarbonyl with 1 to 4 carbon atoms, benzoyl, benzylcarbonyl and phenylethylcarbonyl, where the latter alkyl, phenyl, benzyl and phenylethyl radicals in turn can be substituted, for example, by chlorine, nitro or hydroxy.

The heterocyclic radicals R 'and R "are preferably derived from heteroparaffinic, heteroaromatic or heteroolefinic 5- or 6-membered rings with preferably 1 to 3 identical or different heteroatoms. Oxygen, sulfur or nitrogen are heteroatoms. These ring systems can include further substituents such as, for example Hydroxy, amino or C ₁ ―C ₄ alkyl groups carry or to them benzene nuclei or other preferably 6-membered heterocyclic rings of the type mentioned can be fused.

Particularly preferred heterocyclic radicals are derived, for example, from furan, pyran, pyrrolidine, piperidine, pyrazole, imidazole, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyridine, benzimidazole, quinoline, isoquinoline or purine.

Ganz besonders bevorzugt steht R₂ für ―H, ―SO₃H, -CN,

R₃ steht bevorzugt für Wasserstoff, ―CH₂OH, ―CH₃, ―CH₂NH₂, ―CH₂NH―(C₁―C₆-Alkyl) oder

oder ―CH₂―O―(C₁―C₆-Alkyl).
Ganz besonders bevorzugt jedoch steht R₃ für ―CH₂OH.In the compounds of the formula I, R ₂ preferably represents -H, -OH, ―SO ₃ H, -CN, -CH ₂ NH ₂ ,

R ₂ very particularly preferably represents ―H, ―SO ₃ H, -CN,

R ₃ preferably represents hydrogen, ―CH ₂ OH, ―CH ₃ , ―CH ₂ NH ₂ , ―CH ₂ NH― (C ₁ ―C ₆ alkyl) or

or ―CH ₂ ―O― (C ₁ ―C ₆ alkyl).
However, R ₃ very particularly preferably represents ―CH ₂ OH.

It has been found that the new compounds of the formula I are potent inhibitors for α-glucosidases, in particular for disaccharidases. Therefore, the new compounds are valuable means of influencing a variety of metabolic processes and thus enrich the pharmaceutical treasure. Compared to the 2-hydroxymethyl-3,4,5-trihydroxypiperidine known from DT-OS 2 656 602, the new compounds have advantageous therapeutic properties.

In particular, when feeding rats with cooked starch, it can be seen that the addition of a compound according to the invention inhibits the rise in blood glucose levels considerably more than that of the aforementioned prior art compound.

In the following, instead of the steric formula, a planar notation is chosen for reasons of writing technology, which, unless it is determined by the respective formula, is to be understood as meaning the steric arrangement according to formula I.

in der

• R₁ und R₃ die oben angegebene Bedeutung haben,

durch vorsichtige Säurehydrolyse die Isopropyliden- oder Cyclohexylidenschutzgruppe entfernt, wobei es gegebenenfalls zweckmäßig ist, die Verbindungen der Formel I in der Form von Addukten der schwefligen Säure oder der Blausäure abzufangen (R₂ = SO₃H oder CN). Aus dem Bisulfitadditionsprodukten werden die Verbindungen der Formel I mit R₂ = OH durch Behandlung mit Basen, vorzugsweise Erdalkalihydroxiden wie Ca(OH)₂, oder Sr(OH)₂, insbesondere aber Ba(OH)₂ in Freiheit gesetzt. Durch Umsetzung mit Wasserstoff-Donor-Reduktionsmitteln wie beispielsweise NaBH₄ werden aus den Verbindungen der Formel I mit R₂ = OH die Verbindungen der Formel I mit R₂ = H gewonnen.It has furthermore been found that compounds of the formula I are obtained if compounds of the formula II or IIa

in the

• R ₁ and R _{3 have} the meaning given above,

the isopropylidene or cyclohexylidene protective group is removed by careful acid hydrolysis, it possibly being expedient to trap the compounds of the formula I in the form of adducts of sulfurous acid or hydrocyanic acid (R ₂ = SO ₃ H or CN). The compounds of formula I with R ₂ = OH are liberated from the bisulfite addition products by treatment with bases, preferably alkaline earth metal hydroxides such as Ca (OH) ₂ , or Sr (OH) ₂ , but in particular Ba (OH) ₂ . By reaction with hydrogen donor reducing agents such as NaBH ₄ , the compounds of formula I with R ₂ = H are obtained from the compounds of formula I with R ₂ = OH.

It has furthermore been found that compounds of the formula I are obtained if the compounds of the formula I with R ₂ = OH are reacted in a manner known per se with hydrocyanic acid to give compounds of the formula with R ₂ = CN and, if appropriate, from these by catalytic hydrogenation of the nitrile group Compounds with R ₂ = ―CH ₂ NH ₂ and optionally the amino group in a manner known per se to give compounds in which R ₂ = R'CONCH ₂ -, R'CONR "CH ₂ -, NHR' ― CH ₂ -, NR 'R "―CH ₂ - or R'SO ₂ NHCH ₂ - is acylated, alkylated or sulfonylated.

The compounds of formula I in which R _{2 is} -OR ', -SH, -SR', -NH ₂ , -NHR 'or -NR'R "can be obtained by combining compounds of formula I with R ₂ = -OH in a manner known per se with alcohols (R'OH), H ₂ S, mercaptans (R'SH), ammonia or amines (H ₂ NR ', HNR'R ").

The compounds of formula I in which R _{2 is} -COOH are obtained by hydrolyzing compounds of formula 1 with R ₂ = -CN in a manner known per se.

From the carboxylic acids thus obtained, compounds of the formula I with R ₂ = ―COOR 'can be prepared in a manner known per se by reaction with alcohols (R'OH), compounds of the formula I with R ₂ = -CONHR' or -CONR'R " or -CONH ₂ obtained by aminolysis of the esters with NH ₃ , R'NH ₂ or R'R "N.

Compounds of the formula with R ₂ = ―OH can also be obtained if compounds of the formula II are reacted with trifluoroacetic anhydride to give compounds of the formula III in a reaction step A and then the isopropylidene protective group is split off in reaction step B by acid hydrolysis and then in step C in a neutral to alkaline reaction medium removed the trifluoroacetyl group of compound IV.

In den Formeln stehen

• R₄ für Trifluoracetyl und
• R_s für Trifluoracetyl oder Wasserstoff.

The reaction sequence given can be illustrated as follows:

Stand in the formulas

• R ₄ for trifluoroacetyl and
• R _s for trifluoroacetyl or hydrogen.

This reaction sequence can be transferred analogously to compounds of the formula IIa.

mit Carbonylverbindungen der Formel VI

in der R₆ und R₇ entweder H oder die für R₁ gegebene Bedeutung haben oder Glieder eines alicyclischen oder heterocyclischen Ringes sind, in Gegenwart eines Wasserstoff-Donor-Reduktionsmittels umsetzt.It has also been found that compounds of the formula where R ₂ = H are obtained when compounds of the formula V

with carbonyl compounds of formula VI

in which R ₆ and R _{7 have} either H or the meaning given for R ₁ or are members of an alicyclic or heterocyclic ring, in the presence of a hydrogen donor reducing agent.

in der R₈ entweder H ist oder die für R₁ gegebene Bedeutung hat, oder Carbamate der Formel VIII

- gegebenenfalls auch mit Hydroxyschutzgruppen versehene Derivate dieser Verbindungen - mit einem Amid-Reduktionsmittel zu Aminen reduziert.Furthermore, compounds of the formula with R ₂ = H are obtained if amides of the formula VII

in which R _{8 is} either H or has the meaning given for R ₁ , or carbamates of the formula VIII

- If appropriate, also derivatives of these compounds provided with hydroxyl protective groups - reduced to amines with an amide reducing agent.

umsetzt, wobei R₁ die oben für Alkyl angegebene Bedeutung hat und Z eine in Alkylierungsmitteln gebräuchliche leicht austretende Gruppe wie beispielsweise Halogenid oder ^⊖O―SO₃H ist.Another process for the preparation of compounds of formula I with R ₂ = H is that compounds of formula V with reactive alkylating agents of formula IX

is implemented, wherein R _{1 has} the meaning given above for alkyl and Z is a group which is customary in alkylating agents and is a readily exiting group such as, for example, halide or ^⊖ O ― SO ₃ H.

verwandelt und diese entweder reduktiv in die ―CH₃-Gruppe oder über eine ―CH₂―N₃-Gruppe reduktiv in eine Aminogruppe überführt. Verbindungen der Formel I erhält man auch, wenn man in Verbindungen der Formel 1 mit R₃ = ―CH₂NH₂ die Aminogruppe in an sich bekannter Weise mit Aldehyden oder Ketonen in Gegenwart eines Wasserstoffdonors, mit Alkylhalogeniden, Carbonsäure- oder Sulfonsäurechloriden, Chlorkohlensäureestern, Isocyanaten und Senfölen derivatisiert.Furthermore, compounds of the formula I are obtained if, for example in compounds of the formula I with R ₃ = ―CH ₂ OH, the -CH ₂ 0H group is selectively converted in a manner known per se

transformed and either reductively converted into the ―CH ₃ group or reductively into an amino group via a ―CH ₂ ―N ₃ group. Compounds of the formula I are also obtained if, in compounds of the formula 1 with R ₃ = ―CH ₂ NH _2, the amino group in a manner known per se with aldehydes or ketones in the presence of a hydrogen donor, with alkyl halides, carboxylic acid or sulfonic acid chlorides, chlorocarbonic acid esters, Isocyanates and mustard oils derivatized.

Compounds of the formula I in which R _{1 is} an aliphatic or aromatic radical substituted by an acylamino, sulfonylamino, alkoxycarbonylamino, ureido or a thiourido group are obtained starting from compounds of the formula I in which R ₁ is an amino group Substituted aliphatic or aromatic radical is, by reaction of this amino group with carboxylic acid or sulfonic acid chlorides, with chlorocarbonic acid esters, isocyanates or mustard oils in a manner known per se.

• Verwendet man als Ausgangsstoff eine Verbindung der Formel II mit R, = Aethyl, so läßt sich der Reaktionsablauf wie folgt wiedergeben:
  

The individual procedures for the preparation of the active compounds according to the invention are illustrated below:

• If a compound of formula II with R = ethyl is used as the starting material, the course of the reaction can be represented as follows:
  

With 1-deoxynojirimycin of formula V and formaldehyde as starting materials, the following formula scheme results:

With benzaldehyde as carbonyl component, the reductive alkylation is carried out as follows:

If one starts from acid amides of formula VII, the reaction can be described as follows:

Urethanes of the formula VIII - optionally as derivatives provided with hydroxyl protecting groups - can be reduced to n-methyl-1-deoxynojirimycin with LiAIH ₄ :

For the reaction of 1-deoxynojirimycin with alkylating agents, the reaction with allyl bromide is given as an example:

Some of the compounds of the formula II used as starting materials are known. This is the case when R ₃ = H, -CH ₂ 0H or ―CH ₂ NH ₂ and R ₁ = H. Other compounds of formula II or Ila are new; however, they can be prepared from known compounds from processes known per se.

ausgehen und diese mit Carbonylverbindungen der Formel VI in Gegenwart eines Wasserstoff-Donor-Reduktionsmittels zu Verbindungen der Formel II umsetzen.For example, the compound of formula X known from the literature

go out and implement them with carbonyl compounds of formula VI in the presence of a hydrogen donor reducing agent to compounds of formula II.

Furthermore, the compound X can be reacted with reactive acid derivatives to give acid amides or urethanes and these can be reduced to amines with an amide reducing agent. This is illustrated using an example:

zu Verbindungen der Formel II umsetzen.The compound of formula X can also be used with reactive alkylating agents of formula IX

convert to compounds of formula II.

und anschließend die Trityl- und Benzyl-Schutzgruppen auf bekanntem Wege, beispielsweise mit Natrium in flüssigem Ammoniak, entfernen. Zur Darstellung von Verbindungen der Formel II kann auch die ebenfalls literaturbekannte Verbindung der Formel XII

mit Aminen der Formel XIII

in Gegenwart eines Wasserstoff-Donor-Reduktionsmittels, beispielsweise in Gegenwart von NaBH₃CN, umgesetzt werden. Bei dieser Reaktion entsteht in der Regel ein Diastereomerengemisch. Das nicht erwünschte Diastereomere wird gegebenenfalls auf dieser Stufe oder auf einer späteren Stufe durch die üblichen chromatographischen Methoden oder durch fraktionierte Kristallisation abgetrennt. Schließlich werden die Trityl-und Benzylschutzgruppe auf bekanntem Wege, beispielsweise mit Natrium, in flüssigem Ammoniak abgespalten.Furthermore, it is also possible to use known partially protected derivatives of the formula XI in place of the compound X in the reactions mentioned above.

and then remove the trityl and benzyl protecting groups in a known manner, for example with sodium in liquid ammonia. The compound of the formula XII, which is also known from the literature, can also be used to prepare compounds of the formula II

with amines of formula XIII

in the presence of a hydrogen donor reducing agent, for example in the presence of NaBH ₃ CN. This reaction usually creates a mixture of diastereomers. The undesired diastereomer is optionally separated off at this stage or at a later stage by the customary chromatographic methods or by fractional crystallization. Finally, the trityl and benzyl protective groups are split off in a known manner, for example with sodium, in liquid ammonia.

mit Reagentien mit Carbanioncharakter wie beispielsweise Alkyl-Li oder Grignard-Verbindungen oder dem Li-Salz des 1,3-Dithians zur Reaktion bringt und die erhaltenen Verbindungen der Formel XVII

in an sich bekannter Weise [S. INOUYE et al., Tetrahedron 23, 2125-21441 über das Keton und das Oxim in das Amin umwandelt, wobei in der Regel ein Gemisch von gluco- und ido-Verbindung entsteht, aus dem sich die gewünschte gluco-Verbindung XVIII durch die üblichen chromatographischen Methoden isolieren läßt.

Furthermore, new compounds of the formula II or IIa can also be obtained by using the degradation products of the D-glucose of the formulas XIV to XVI known from the literature

with reagents with carbanion character such as alkyl-Li or Grignard compounds or the Li salt of 1,3-dithiane to react and the compounds of formula XVII

in a manner known per se [p. INOUYE et al., Tetrahedron 23, 2125-21441 converts via the ketone and the oxime into the amine, a mixture of gluco and ido compound usually being formed, from which the desired gluco compound XVIII can be obtained by the usual chromatographic Methods can be isolated.

Removal of the benzyl protective group by catalytic hydrogenation or with Na in liquid NH ₃ then gives the compounds of the formula II.

wobei auch hier in der Regel die gewünschte gluco-Verbindung von der ido-Verbindung durch übliche chromatographische Methoden abgetrennt werden muß. Die weitere Abwandlung der Nitrilgruppe durch Hydrierung oder Hydrolyse von oder nach der Entfernung der Benzylschutzgruppe führt zu weiteren Verbindungen der Formel II.Compounds of the formula XIX are obtained if the aldehydes of the formulas XIV to XVI are reacted in a manner known per se with amines and hydrocyanic acid to give aminonitriles, for example XVI to XIX

the desired gluco compound must also be separated from the ido compound by customary chromatographic methods. The further modification of the nitrile group by hydrogenation or hydrolysis from or after the removal of the benzyl protective group leads to further compounds of the formula II.

die durch Michael-Addition von Aminen nach chromatographischer Trennung von gluco- und ido-Isomeren Verbindungen der Formel Ila liefern.The reaction of XIV to XVI with CH-acidic compounds such as nitroalkanes, alkyl nitriles, CH-acidic esters or ketones can also lead to compounds of the formula 11. This gives unsaturated compounds, for example of the formula XX, either directly or by dehydrating the aldol addition products,

which by Michael addition of amines after chromatographic separation of gluco and ido isomers provide compounds of formula Ila.

The isopropylidene protecting group is split off from the compounds of the formula II in moderately strongly acidic to weakly acidic solution, preferably in a pH range between 1 and 4, in aqueous solution or in a water-miscible, water-containing organic solvent. Diluted mineral acids such as sulfuric acid or organic acids such as acetic acid can be used as acids. The reaction is preferably carried out at atmospheric pressure and a temperature between room temperature and the boiling point of the solvent.

To work up the reaction mixture, the acid is neutralized and separated as a salt or with the aid of a basic ion exchanger. The compounds of the formula I with R ₂ = OH are then isolated, if appropriate, by gentle removal of the solvent, for example by lyophilization.

A preferred embodiment of the cleavage of the isopropylidene protecting group from compounds of the formula II consists in saturating the aqueous or water-containing alcoholic solution of the compounds of the formula II with SC ₂ and storing at temperatures between 20 ° and 50 ° C. for several days. The compounds of the formula I are then obtained as bisulfite adducts which usually crystallize well (R ₂ = ―SO ₃ H), from which the compounds of the formula I can be released with the aid of, for example, aqueous Ba (OH) ₂ .

The reduction of compounds of the formula I with R ₂ = OH to compounds of the formula I with R ₂ = H is carried out by using alkali metal borohydrides, alkali metal cyanoborohydrides or also dialkylaminoboranes. It is preferred to use sodium borohydride in aqueous solution or in a water-miscible water-containing organic solvent, such as, for example, dioxane, at room temperature or, if appropriate, at elevated temperature. However, the reduction is very particularly preferably carried out catalytically using Pt or Pd as the catalyst or in the presence of Raney-Ni. It is preferred to work in aqueous solution at room temperature.

mit starker Mineralsäure vom pH _<1 bei -20 bis +20°C hydrolysiert und anschließend bei pH 4 bis 6 mit z.B. H₂/Raney-Nickel, H_Z/P + O₂ oder NaBH₄ hydriert.Compounds of formula I are further obtained by using compounds of formula

hydrolyzed with strong mineral acid of pH _< 1 at -20 to + 20 ° C and then hydrogenated at pH 4 to 6 with, for example, H ₂ / Raney nickel, H _{Z /} P + O ₂ or NaBH ₄ .

worin R₉ H oder CH₃CO und R₁₀ Mesyl oder Tosyl bedeuten mit Aminen der Formel

bei 20 bis 150°C in einem polaren Lösungsmittel, z.B. einem Alkohol, Dimethylsulfozid oder in überschüssigem Amin umsetzt.The compounds of formula XXI are obtained by using compounds of formula

wherein R _{9 is} H or CH ₃ CO and R _{10 is} mesyl or tosyl with amines of the formula

at 20 to 150 ° C in a polar solvent, for example an alcohol, dimethyl sulfozide or in excess amine.

The starting product of the formula V with R ₃ = ―CH ₂ OH is known and is obtained either by catalytic hydrogenation from the nojirimycin [s. S. INOUYE et al., Tetrahedron 23, 2125-2144 (1968)] or by extraction from mulberry bark (see DT-OS 2 656 602) or else fully synthetic. According to a new advantageous method, 1-deoxynojirimycin can also be prepared by using organisms of the Bacillaceae family in the usual way Nutrient solutions at temperatures of about 15 to about 80 ° C. are cultured for about 1 to about 8 days with aeration in conventional fermentation vessels, the cells are spun off and the deoxy compound is isolated from the culture broth or the cell extracts by customary cleaning processes [German Offenlegungsschrift 26 58 563.7].

The carbonyl compounds of formula VI are either known or can be prepared by standard methods.

• Gerad- oder verzweigtkettige Alkylaldehyde wie Formaldehyd, Acetaldehyd, n-Propanal, n-Butanal, 2-Methylpropanal, n-Pentanal, 2-Methylbutanal, 3-Methylbutanal, 2,2-Dimethylpropanal, n-Hexanal, 2-Athylbutanal, n-Heptanal und n-Octanal; Alkenylaldehyde wie Propenal, 2-Methylpropenal, 2-Butenal, 2-Methyl-2-butenal, 2-Äthyl-2-hexenal; Cyclische Aldehyds wie Cyclopropancarbaldehyd, Cyclopentancarbaldehyd, Cyclopentancetaldehyd, Cyclohexancarbaldehyd; Benzaldehyd, o-, m- und p-toluolcarbaldehyde und Phenylacetaldehyd; durch Hydroxy substituierte gerad- und verzweigtkettige Alkylaldehyde wie 5-Hydroxypentanal, 2-Hydroxy-3-methylbutanal, 2-Hydroxy-2-methylpropanal, 4-Hydroxybutanal, 2-Hydroxypropanal und 8-hydroxyoctanal; durch Amino substituierte gerad- und verzweigtkettige Alkylaldehyde wie 5-Aminopentanal, 2-Aminopropanal, 3-Aminopropanal, 4-Aminobutanal, 2-Amino-3-methylbutanal, 8-Aminooctanal and mono-N-Alkylderivate davon; und durch Amino und Hydroxy disubstituierte gerad- und verzweigtkettige Alkylaldehyde wie 2-Hydroxy-5-aminopentanal, 3-Hydroxy-3-methyl-4-aminobutanal, 2-Hydroxy-4-aminobutanai, 2-Hydroxy-3-aminopropanal, 2-Hydroxy-2-methyl-3-aminopropanal, 2-Amino-3-hydroxyoctanal und mono-N-Alkylderivate davon.

The following are typical examples:

• Straight or branched chain alkyl aldehydes such as formaldehyde, acetaldehyde, n-propanal, n-butanal, 2-methylpropanal, n-pentanal, 2-methylbutanal, 3-methylbutanal, 2,2-dimethylpropanal, n-hexanal, 2-ethylbutanal, n- Heptanal and n-octanal; Alkenyl aldehydes such as propenal, 2-methylpropenal, 2-butenal, 2-methyl-2-butenal, 2-ethyl-2-hexenal; Cyclic aldehydes such as cyclopropanecarbaldehyde, cyclopentanecarbaldehyde, cyclopentanecetaldehyde, cyclohexanecarbaldehyde; Benzaldehyde, o-, m- and p-toluenecarbaldehydes and phenylacetaldehyde; straight-chain and branched-chain alkyl aldehydes substituted by hydroxy, such as 5-hydroxypentanal, 2-hydroxy-3-methylbutanal, 2-hydroxy-2-methylpropanal, 4-hydroxybutanal, 2-hydroxypropanal and 8-hydroxyoctanal; straight-chain and branched-chain alkyl aldehydes substituted by amino, such as 5-aminopentanal, 2-aminopropanal, 3-aminopropanal, 4-aminobutanal, 2-amino-3-methylbutanal, 8-aminooctanal and mono-N-alkyl derivatives thereof; and straight and branched chain alkyl aldehydes disubstituted by amino and hydroxy, such as 2-hydroxy-5-aminopentanal, 3-hydroxy-3-methyl-4-aminobutanal, 2-hydroxy-4-aminobutanai, 2-hydroxy-3-aminopropanal, 2- Hydroxy-2-methyl-3-aminopropanal, 2-amino-3-hydroxyoctanal and mono-N-alkyl derivatives thereof.

• Methoxy-acetaldehyd, Aethoxy-acetaldehyd, n-Propoxy-acetaldehyd, i-Propoxy-acetaldehyd, n-Butoxy-acetaldehyd, i-Butoxy-acetaidehyd, tert.-Butoxy-acetaldehyd, Cyclopropylmethyloxyacetaldehyd, Cyclopropoxyacetaldehyd, 2-Methoxy-äthoxy-acetaldehyd, 2-Aethoxy-äthoxy-acetaldehyd, 2-Methoxy( 1-methyl-äthoxy)-acetaldehyd, 2-Aethoxy( 1-methyl-äthoxy)-acetaldehyd, Phenyloxy-acetaldehyd, 2-Methoxy-2-methyl-acetaldehyd, 2-Aethoxy-2-methyl-acetaldehyd, 2-n-Propoxy-2-methyl-acetaldehyd, 2-(i-Propoxy-) 2-methyl-acetaldehyd, 2-(n-Butoxy)-2-methyl-acetaldehyd, 2-(i-Butoxy)-2-methyl-acetaldehyd, 2-(tert.-Butoxy)-2-methyl-acetaldehyd, 2-Cyclopropylmethyloxy-2-mäthyl-acetaldehyd, 2-Cyclopropyloxy-2-methyl-acetaldehyd, 2-Methoxy-äthoxy-a-methyl-acetaldehyd, 2-Aethoxy-äthoxy-a-methyl-acetaldehyd, 2-Methoxy-( 1-methy)-äthoxy)α-methyl-acetaldehyd, 2-Methoxy-2,2-dimethyl-acetaldehyd, 2-Aethoxy-2,2-dimethyl-acetaldehyd, 2-Cyclopropylmethyloxy-acetaldehyd, 2-w-Butoxy-2,2-dimethyl-acetaldehyd, Methylthio-acetaldehyd, Aethylthio-acetaldehyd, n-Propylthio-acetaldehyd, i-Propylthio-acetaldehyd, Cyclopropylmethylthioacetaldehyd, 3-Methoxy-propanol, 3-Aethoxypropanal, 3-n- und 3-i-propoxy-propanal, 3-n-, 3-i- und 3-tert.-Butoxy-propanal, 3-Cyclopropyloxy-propanal, 3-Cyclopropylmethyloxy-propanal, 3-Methoxy-3-methyl-propanal, 3-Aethoxy-3-methyl-propanal, 3-n- und 3-i-propoxy-3-methyl-propanal, 3-n-, 3-i-und 3-tert.-Butoxy-3-methyl-propanal, 2,3 und 4-Methoxy-butanal, 2,3 und 4-Aethoxy-butanal, 2-Methylthio-propanal, 2-Aethylthio-propanal, 3-Methylthio-propanal, 3-Aethylthio-propanal, 2-Methylthio-butanal, 3-Methylthio-butanal, 4-Methylthio-butanal, Furfurol, Tetrahydrofurfurol, Thiophen, 5-Bromthiophen, 5-Methylfurfurol, Pyran-carbaldehyd.

Furthermore:

• Methoxy-acetaldehyde, ethoxy-acetaldehyde, n-propoxy-acetaldehyde, i-propoxy-acetaldehyde, n-butoxy-acetaldehyde, i-butoxy-acetaidehyde, tert-butoxy-acetaldehyde, cyclopropylmethyloxyacetaldehyde, cyclopropoxyacetaldehyde, 2-methoxy-ethoxy-acetaldehyde , 2-ethoxyethoxyacetaldehyde, 2-methoxy (1-methylethoxy) acetaldehyde, 2-ethoxy (1-methylethoxy) acetaldehyde, phenyloxyacetaldehyde, 2-methoxy-2-methylacetaldehyde, 2 -Ethoxy-2-methyl-acetaldehyde, 2-n-propoxy-2-methyl-acetaldehyde, 2- (i-propoxy-) 2-methyl-acetaldehyde, 2- (n-butoxy) -2-methyl-acetaldehyde, 2 - (i-Butoxy) -2-methyl-acetaldehyde, 2- (tert-butoxy) -2-methyl-acetaldehyde, 2-cyclopropylmethyloxy-2-methyl-acetaldehyde, 2-cyclopropyloxy-2-methyl-acetaldehyde, 2- Methoxy-ethoxy-a-methyl-acetaldehyde, 2-ethoxy-ethoxy-a-methyl-acetaldehyde, 2-methoxy- (1-methy) -ethoxy) α-methyl-acetaldehyde, 2-methoxy-2,2-dimethyl- acetaldehyde, 2-ethoxy-2,2-dimethyl-acetaldehyde, 2-cyclopropylmethyloxy-acetaldehyde, 2-w-butoxy-2,2-dimethyl-acetaldehyde, methylthio-acetaldehyde ehyd, ethylthio-acetaldehyde, n-propylthio-acetaldehyde, i-propylthio-acetaldehyde, cyclopropylmethylthioacetaldehyde, 3-methoxy-propanol, 3-ethoxypropanal, 3-n- and 3-i-propoxy-propanal, 3-n-, 3- i- and 3-tert-butoxy-propanal, 3-cyclopropyloxy-propanal, 3-cyclopropylmethyloxy-propanal, 3-methoxy-3-methyl-propanal, 3-ethoxy-3-methyl-propanal, 3-n- and 3 -i-propoxy-3-methyl-propanal, 3-n-, 3-i- and 3-tert-butoxy-3-methyl-propanal, 2,3 and 4-methoxy-butanal, 2,3 and 4- Aethoxy-butanal, 2-methylthio-propanal, 2-ethylthio-propanal, 3-methylthio-propanal, 3-ethylthio-propanal, 2-methylthio-butanal, 3-methylthio-butanal, 4-methylthio-butanal, furfural, tetrahydrofurfural, Thiophene, 5-bromothiophene, 5-methylfurfural, pyranecarbaldehyde.

• Aceton, Methyläthylketon, Methyl-n-propylketon, Diäthylketon, Methylbutylketon, Cyclopentanon, Di-n-propyl-keton, Cyclohexanon, 3-Methylcyclohexanon, 4-Methylcyclohexanon, Acetophenon, Propiophenon, Butyrophenon, Phenylaceton, p-Methoxyacetophenon, m-Nitroacetophenon.

The following may also be mentioned as ketones, for example:

• Acetone, methyl ethyl ketone, methyl n-propyl ketone, diethyl ketone, methyl butyl ketone, cyclopentanone, di-n-propyl ketone, cyclohexanone, 3-methylcyclohexanone, 4-methylcyclohexanone, acetophenone, propiophenone, butyrophenone, phenylacetone, p-methoxyachenophenone.

For example, formic acid can be used as the hydrogen donor reducing agent (Leuckart-Wallach reaction). The formic acid is used in large excess. With formaldehyde as the carbonyl component, the reaction can be carried out in aqueous solution, with ketones and less reactive aldehydes in anhydrous formic acid. The reaction temperatures are between 100 and 200 ° C, if necessary the reaction must be carried out in an autoclave.

Catalytically excited hydrogen can also be used as the hydrogen donor reducing agent. Raney nickel is the most suitable catalyst, but noble metal catalysts can also be used. The reaction is generally carried out at pressures between 80 and 150 atmospheres of H ₂ pressure and temperatures between 70 and 150 ° C. Protic, polar solvents, especially alcohols, are preferred as solvents.

Alkali metal cyanoborohydrides, dialkylaminoboranes and alkali metal borohydrides are also used as hydrogen donor reducing agents. The use of sodium cyanoborohydride is particularly preferred in this process variant.

The reaction is generally carried out at room temperature. However, it can also be advantageous to heat to the reflux temperature.

The process is usually carried out in an inert solvent. Although anhydrous aprotic solvents can be used (e.g. tetrahydrofuran if the reducing agent is morpholinoborane), a protic solvent is usually used. A lower alkanol is particularly suitable as such. But it can also be water or an aqueous lower alkanol (for example aqueous methanol or ethanol) or other aqueous solvent systems, such as for example aqueous dimethylformamide, aqueous hexamethylphosphoric triamide, aqueous tetrahydrofuran or aqueous ethylene glycol dimethyl ether can be used.

The process is usually carried out in a pH range from 1 to 11, a pH range between 4 and 7 is preferred.

Some of the acid amides of the formula VII and urethanes of the formula VIII are known or can be obtained by known processes from compound V and reactive acid derivatives which can also be formed in situ from the free acids.

The reaction can be carried out in such a way that only the amino group of compound V reacts with the acid derivative, for example by using excess acid anhydride in an aqueous or alcoholic solution or in such a way that the peracylated compounds are formed first, which are then reacted with alcoholic ammonia or Transesterification catalyzed by alkali alcoholate are converted into the N-acylated compounds. The latter method is explained using an example:

The reduction of the acid amides of the formula II to amines of the formula (R = H) can be carried out using complex metal hydrides or else using hydrogen boron compounds. Preference is given to using NaBH ₄ in pyridine or else sodium acyloxyborohydrides, especially sodium trifluoroacetoxyborohydride. The reducing agents are usually used in excess. Sodium trifluoroacetoxyborohydride is generated in situ from sodium borohydride and trifluoroacetic acid. In addition to pyridine, suitable solvents are polar aprotic solvents such as dioxane, tetrahydrofuran or diglyme. The reaction is preferably carried out at the boiling point of the solvent. Optionally, LiAIH ₄ can also be used for the reduction, preferably when the hydroxyl groups are previously protected in the usual way.

The reactive alkylating agents of the formula IX are known or can be prepared by customary processes. The reaction with the compound V takes place in inert organic solvents at room to boiling temperature with or without the addition of an acid-binding agent.

The following are listed as new active ingredients:

Compounds of the formula

Compounds of the formula

Compounds of the formula

Die nachstehend aufgeführten Beispiele umfassen bezüglich der Konfiguration am C-1-Atom sowohl a- als auch β-Form

The examples below include both a- and β-form with respect to the configuration at the C-1 atom

Compounds of the formula

The examples below include both α- and β-forms with regard to the configuration at the C-1 atom.

Compounds of the formula

Compounds of the formula

Compounds of the formula

The inhibitors according to the invention are suitable as therapeutics for the following indications:

Prediabetes, gastritis, constipation, caries, infections of the gastrointestinal tract, meteorism, flatulence, hypertension, atheroskelerosis and especially obesity, diabetes and hyperlipoprotemia.

In order to broaden the spectrum of action, it may be advisable to combine inhibitors for glycoside hydrolases which complement one another in their action, be it that they are combinations of the inhibitors according to the invention with one another or combinations of the inhibitors according to the invention with those already known. For example, it may be useful to combine saccharase inhibitors according to the invention with already known amylase inhibitors.

In some cases, combinations of the inhibitors according to the invention with known oral antidiabetics (β-cytotropic sulfonylurea derivatives and / or blood sugar-effective biguanides) and with blood lipid-lowering active ingredients, such as e.g. Clofibrate, nicotinic acid, cholestyramine and others.

The compounds can be used without dilution, e.g. can be applied as a powder or in a gelatin shell or in combination with a carrier in a pharmaceutical composition.

Pharmaceutical preparations can contain a greater or lesser amount of the inhibitor, for example 0.1% to 99.5%, in combination with a pharmaceutically acceptable, non-toxic, inert carrier, the carrier being one or more solid, semi-solid or liquid diluents, fillers and / or may contain non-toxic, inert and pharmaceutically acceptable formulation aid. Such pharmaceutical preparations are preferably in the form of dosage units, ie physically discrete units containing a certain amount of the inhibitor, which correspond to a fraction or a multiple of the dose required to achieve the desired inhibitory effect. The dosage units can contain 1, 2, 3, 4 or more single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains a sufficient amount of active ingredient to achieve the desired inhibitory effect when administered in accordance with a predetermined dosage regimen of one or more dosage units, with a whole, half, or a third or a quarter of the daily dose usually being all, main and Side meals are administered during the day. Other therapeutic agents can also be taken. Although the dosage and dosage regimen should be carefully considered in any case, do using thorough professional judgment and with due regard ^g of the age, weight and condition of the patient, the nature and severity of the disease, the dosage is usually in a Range between about 1 to about 1 x 10 ° SIE / kg of body weight per day. In some cases, one becomes an adequate therapeutic Achieve effect with a lower dose, while in other cases a larger dose will be required.

Oral application can be carried out using solid and liquid dosage units, e.g. Powders, tablets, dragees, capsules, granules, suspensions, solutions and the like.

Powder is produced by comminuting the substance to a suitable size and mixing it with a comminuted pharmaceutical carrier. Although an edible carbohydrate, such as. B. starch, lactose, sucrose or glucose is normally used for this purpose and can also be used here, it is desirable to have a non-metabolizable carbohydrate, such as. B. to use a cellulose derivative.

Sweeteners, flavor additives, preservatives, dispersants and colorants can also be used.

The capsules can be produced by preparing the powder mixture described above and by filling gelatin shells that have already been formed. The powder mixture can be filled with lubricants such as z. B. silica gel, talc, magnesium stearate, calcium stearate or solid polyethylene glycol. The mixture can also be used with a disintegrator or solubilizer, such as. B. agar agar, calcium carbonate or sodium carbonate to improve the accessibility of the inhibitor when taking the capsule.

The tablets are made, for example, by producing a powder mixture, coarse or fine-grained, and adding a lubricant and disintegrator. This mixture is used to form tablets. A powder mixture is prepared by mixing the substance, which has been comminuted in a suitable manner, and supplementing a diluent or another carrier as described above. If necessary, add a binder: e.g. Carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, a solution retarder, such as. B. paraffin, a resorption accelerator, such as. B. a quaternary salt and / or an adsorbent such. B. bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated together with a binder such as e.g. B. syrup, starch paste, acacia mucus, or solutions made of cellulose or polymer materials. Then you press the product through a coarse sieve. Alternatively, the powder mixture can be run through a tablet machine and the resulting unevenly shaped pieces crushed to grain size. So that the resulting grains do not get stuck in the tablet-forming nozzles, you can add a lubricant, such as. B. stearic acid, stearate salt, talc or mineral oil. This lubricated mixture is then pressed into tablet form. The active ingredients can also be combined with free-flowing inert carriers and brought directly into tablet form, omitting the granulate or fragmentation steps. The product can be provided with a clear or opaque protective cover, e.g. B. a coating of shellac, a coating of sugar or polymer substances and a polished shell made of wax. Dyes can be added to these coatings so that a distinction can be made between the different dosage units.

The oral forms of preparation, such as. B. solutions, syrup and elixirs can be prepared in dosage units so that a certain amount of preparation contains a certain amount of active ingredient. Syrup can be prepared in such a way that the active ingredient is dissolved in an aqueous solution which contains suitable flavorings; Elixirs are obtained using non-toxic, alcoholic carriers. Suspensions can be prepared by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers, such as. B. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters, preservatives, taste-improving additives such as. B. peppermint oil or saccharin and the like can also be added.

Dosage instructions can be given on the capsule. In addition, the dosage can be secured so that the active ingredient is released with a delay, e.g. B. by compliance with the active ingredient in polymer substances, waxes or the like.

In addition to the pharmaceutical compositions mentioned above, foods containing these active ingredients can also be produced; For example, sugar, bread, potato products, juice, beer, chocolate and other confectionery, and canned goods such as. As jam, a therapeutically effective amount of at least one of the inhibitors according to the invention was added to these products.

The foodstuffs produced using the active compounds according to the invention are suitable both for dieting in patients who suffer from metabolic disorders and for the nutrition of healthy people in the sense of a dietary preventive diet.

The inhibitors according to the invention furthermore have the property of influencing the ratio of the proportion of undesirable fat to the proportion of the desired low-fat meat (lean meat) to a large extent in favor of the lean meat. This is of particular importance for the rearing and keeping of farm animals, e.g. B. in pig fattening, but also of considerable importance for the rearing and keeping of other farm animals and ornamental animals. The wounding of the inhibitors can further lead to a considerable rationalization of the feeding of the animals, both in terms of time, quantity and quality. Since they have a certain delay in Cause digestion, the dwell time of the nutrients in the digestive tract is extended, which enables ad libitum feeding with less effort. Furthermore, the use of the inhibitors according to the invention results in considerable savings in valuable protein feed in many cases.

The active ingredients can thus be used in practically all areas of animal nutrition as a means of reducing the amount of fat and saving feed protein.

The effectiveness of the active ingredients is largely independent of the type and gender of the animals. The active ingredients are particularly valuable in animal species that tend to store more fat at all or in certain stages of life.

The following useful and ornamental animals may be mentioned as examples of animals in which the inhibitors can be used to reduce fat deposits and / or to save feed protein: warm-blooded animals such as cattle, pigs, horses, sheep, goats, cats, dogs, rabbits, fur animals , e.g. B. mink, chinchilla, other ornamental animals, e.g. B. guinea pigs and hamsters, laboratory and zoo animals, e.g. B. rats, mice, monkeys, etc. poultry, e.g. B. broilers, chickens, geese, ducks, turkeys, pigeons, parrots and canaries and cold-blooded animals, such as fish, e.g. B. carp and reptiles, e.g. B. snakes.

The amount of active ingredients that are administered to the animals to achieve the desired effect can be varied widely because of the favorable properties of the active ingredients. It is preferably about 0.5 mg to 2.5 g, in particular 10 to 100 mg / kg of feed per day. The duration of the process can be from a few hours or tabs to several years. The right amount of active ingredient and the right duration of administration are closely related to the feeding goal. They depend in particular on the type, age, gender, state of health and type of keeping of the animals and are easy to determine by any specialist.

The active compounds according to the invention are administered to the animals by the customary methods. The type of administration depends in particular on the type, behavior and general condition of the animals. Thus, the administration can take place orally once or several times a day, at regular or irregular intervals. For reasons of consistency, oral administration is preferred in most cases, particularly in the rhythm of the animals' food and / or drink intake.

The active ingredients can be administered as pure substances or in formulated form, the formulated form being understood both as a premix, i.e. in a mixture with non-toxic inert carriers of any type, and as part of an overall ration in the form of an additional feed or as a component of the mixture of a sole compound feed is. The application of suitable preparations via drinking water is also included.

If appropriate, the active compounds can also be formulated together with other nutrients and active compounds, eg. B. mineral salts, trace elements, vitamins, proteins, energy sources (z. B. starch, sugar, fats), colors and / or flavors or other feed additives, such as. B. growth promoters, administered in a suitable form. The active substances can be given to the animals before, during or after eating.

Oral administration together with the feed and / or drinking water is recommended, the active ingredients being added to the total amount or only parts of the feed and / or drinking water as required.

The active compounds can be added to the feed and / or the drinking water as usual by simple mixing as pure substances, preferably in finely divided form or in formulated form in a mixture with edible, non-toxic carriers, optionally also in the form of a premix or a feed concentrate.

The feed and / or drinking water can, for example, contain the active compounds according to the invention in a concentration of approximately 0.001 to 5.0%, in particular 0.02 to 2.0% (weight). The optimal concentration of the active ingredient in the feed and / or drinking water depends in particular on the amount of feed and / or drinking water intake by the animals and can be easily determined by any specialist.

The type of feed and its composition are irrelevant. All customary, commercially available or special feed compositions can be used, which preferably contain the usual balance of energy and protein substances, including vitamins and minerals, which is necessary for a balanced diet. The feed can be composed, for example, of vegetable substances, e.g. As oil cuck meal, grain meal, grain by-products, but also from hay, fermentation feed, beets and other fodder plants, from animal substances, e.g. B. meat and fish products, bone meal, fats, vitamins, e.g. B. A, D, E, K and B complex as well as special protein sources, e.g. B. yeasts and certain amino acids and minerals and trace elements, such as. B. phosphorus and iron, zinc, manganese, copper, cobalt, iodine etc.

Premixes may preferably be about 0.1 to 50%, especially 0.5 to 5.0% (weight) e.g. N-methyl-1-deoxynojirimycin along with any edible carriers and / or mineral salts, e.g. contain carbonated lime and are produced according to the usual mixing methods.

Mixed feeds preferably contain 0.001 to 5.0%, in particular 0.02 to 2.0% (weight) of, for example, N-methyl-1-deoxynojirimycin in addition to the usual raw material components of a mix feed, e.g. B. cereal meal or by-products, oil cake meal, animal protein, minerals, trace elements and vitamins. They can be produced using the usual mixing methods.

Preferably in premixes and compound feeds, the active ingredients can optionally also be covered by suitable agents covering their surface, e.g. B. with non-toxic waxes or gelatin from air, light and / or moisture.

• 200 g Weizen, 340 g Mais, 360,3 g Sojaschrot, 60 g Rindertalg, 15 g Dicalciumphosphat, 10 g Calciumcarbonat, 4 g jodiertes Kochsalz, 7,5 g Vitamin-Mineral-Mischung und 3,2 g Wirkstoff-Premix ergeben nach sorgfältigem Mischen 1 kg Futter.

Example of the composition of a finished compound feed, for poultry, which contains an active ingredient according to the invention:

• 200 g wheat, 340 g maize, 360.3 g soybean meal, 60 g beef tallow, 15 g dicalcium phosphate, 10 g calcium carbonate, 4 g iodized table salt, 7.5 g vitamin-mineral mixture and 3.2 g active ingredient premix carefully mixing 1 kg of feed.

• 6000 I.E. Vitamin A, 1000 I.E. Vitamin D₃, 10 mg Vitamin E, 1 mg Vitamin K₃, 3 mg Riboflavin, 2 mg Pyridoxin, 20 mcg Vitamin B₁₂, 5 mg Calciumpantothenat, 30 mg Nikotinsäure, 200 mg Cholinchlorid, 200 mg Mn S0₄ x H₂0, 140 mg Zn S0₄ x 7H₂0₁ 100 mg Fe S0₄ x 7H₂0 und 20 mg Cu SO₄ x 5H₂0. Der Wirkstoff-Premix enthält z. B. N-Methyl-1-desoxynojirimycin in der gewünschten Menge, z. B. 1600 mg und zusätzlich 1 g DL-Methionin sowie so viel Sojabohnenmehl, daß 3,2 g Premix entstehen.

The vitamin-mineral mixture consists of:

• 6000 IU vitamin A, 1000 IU vitamin D ₃ , 10 mg vitamin E, 1 mg vitamin K ₃ , 3 mg riboflavin, 2 mg pyridoxine, 20 mcg vitamin B ₁₂ , 5 mg calcium pantothenate, 30 mg nicotinic acid, 200 mg choline chloride, 200 mg Mn S0 ₄ x H ₂ 0, 140 mg Zn S0 ₄ x 7H ₂ 0 ₁ 100 mg Fe S0 ₄ x 7H ₂ 0 and 20 mg Cu SO ₄ x 5H ₂ 0. The active ingredient premix contains e.g. B. N-methyl-1-deoxynojirimycin in the desired amount, e.g. B. 1600 mg and an additional 1 g of DL-methionine and so much soybean meal that 3.2 g of premix are formed.

• 630 g Futtergetreideschrot (zusammengesetzt aus 200 g Mais-, 150 g Gerste-, 150 g Hafer- und ₁₃₀ g Weizenschrot), 80 g Fischmehl, 60 g Sojaschrot, 58,8 g Tapiokamehl, 8 g Bierhefe, 50 g Vitamin-Mineral-Mischung für Schweine (Zusammensetzung, z. B. wie beim Kükenfutter) 30 g Leinkuchenmehl, 30 g Maiskelberfutter, 10 g Sojaöl, 10 g Zuckerrohrmelasse und 2 g Wirkstoff-Premix (Zusammensetzung z. B. beim Kükenfutter) ergeben nach sorgiältigem Mischen 1 kg Futter.

Example of the composition of a pig feed containing an active ingredient of formula I:

• 630 g of feed grain meal (composed of 200 g maize meal, 150 g barley meal, 150 g oat meal and ₁₃₀ g wheat meal), 80 g fish meal, 60 g soy meal, 58.8 g tapioca meal, 8 g brewer's yeast, 50 g vitamin mineral Mix for pigs (composition, e.g. as with chick feed) 30 g linseed cake flour, 30 g corn flakes, 10 g soybean oil, 10 g sugarcane molasses and 2 g active ingredient premix (composition e.g. with chick feed) result in 1 kg after thorough mixing Lining.

The specified feed mixtures are preferably matched for rearing and fattening chicks or pigs, but they can also be used in the same or a similar composition for rearing and fattening other animals.

The inhibitors can be used individually or in any mixtures with one another.

Sucrose inhibition test in vitro

The saccharase inhibition test in vitro enables the enzyme-inhibitory activity of a substance to be determined by comparing the activity of the solubilized intestinal disaccharidase complex in the presence or absence (so-called 100% value) of the inhibitor. A practically glucose-free sucrose (Giucose <100 ppm) serves as the substrate, which determines the specificity of the inhibition test; the enzyme activity determination is based on the spectrophotometric determination of released glucose using glucose dehydrogenase and nicotinamide adenine dinucleotide as cofactor.

A saccharase inhibitor unit (SIE) is defined as that inhibitory activity which, in a defined test mixture, reduces a given saccharolytic activity by one unit (saccharase unit = SE); the saccharase unit is defined as that enzyme activity which cleaves one µmol of sucrose per min under given conditions and thus leads to the release of one µmol of glucose, which is determined in the test, and fructose, which is not recorded in the test.

The intestinal disaccharidase complex is obtained from swine small intestine mucosa by tryptic digestion, precipitation from 66% ethanol at -20 ° C, taking up the precipitate in 100 mM phosphate buffer, pH 7.0 and final dialysis against the same buffer.

10 ul of a sample solution that is prepared so that the absorbance of the test mixture is at least 10%, but not more than 25% below that of the 100% value, with 100 ul of a dilution of the intestinal disaccharidase complex in 0.1 M Maleinate buffer, pH 6.25, added and preincubated for 10 min at 37 ° C. The dilution of the disaccharidase complex should be set to an activity of 0.1 SE / ml.

The saccharolytic reaction is then started by adding 100 .mu.l of a 0.4 M solution of sucrose ("SERVA 35579") in 0.1 M maleinate buffer, pH 6.25 and after an incubation period of 20 min at 37.degree the addition of 1 ml of glucose dehydrogenase reagent (1 vial of glucose dehydrogenase mutarotase mixture lyophilized ("MERCK 14035") and 331.7 mg of β-nicotinamide adenine dinucleotide (free acid, "BOEHRINGER" purity grade I) in 250 ml 0.5 M Tris buffer, pH 7.6 dissolved). To detect the glucose, incubate for 30 min at 37 ° C. and finally photometry at 340 nm against a blank reagent (with enzyme, but without sucrose).

The calculation of the inhibitory activity of inhibitors is made more difficult by the fact that even minor changes in the test system, for example a 100% value which varies slightly from one determination to the next, are no longer negligible influence on the test result. These difficulties are avoided by running a standard with every determination; the standard is a saccharase inhibitor of the formula C ₂₅ H ₄₃ O ₁₈ N, which has a specific inhibitory activity having ty of 77 700 is / g and used amounts of 10 to 20 ng in the test to a HEM m _u ng leads from above spiezifizierter magnitude. If the difference in absorbance at 340 nm of 100% value and the standard inhibited approach is known, the extinction difference of 100% value and the test solution inhibited approach, taking into account the amount of inhibitor used, can take into account its specific inhibitory activity in a known manner calculate, expressed in saccharase inhibitor units per gram (SIE / g).

Specific in vitro saccharase inhibitory activity

Manufacturing examples example 1 N-methyl-1-deoxynojirimycin

3.2 g of 1-deoxynojirimycin and 2 ml of 30% aqueous formaldehyde are added to 4 ml of 98% formic acid while cooling with ice. The mixture is then heated under reflux for 8 hours. After cooling, the reaction mixture is diluted with acetone. Ex is a resinous precipitate. The acetone solution is decanted off and the resin is washed several times with acetone. The residue is then dissolved in distilled water and the solution was freed by addition of basic ion exchangers in the OH ^s form (Amberlite JRA 410) of formic acid. The ion exchanger is filtered off and the aqueous solution is brought to dryness under reduced pressure. This leaves 3.0 g of resinous N-methyl-1-deoxynojirimycin. The compound can be further purified by chromatography on cellulose. Water-containing butanol is used as the eluent.

Melting point: 153 ° C (ethanol).

Mass spectrum: The most important peak in the upper mass range is found at m / l = 146 (M-CH ₂ 0H).

For further characterization, the compound with acetic anhydride / pyridine is converted 1: 1 at room temperature into the peracetylated compound, N-methyl-2,3,4,6-tetra-0-acetyl-1-deoxynojirimycin. A proton resonance spectrum of this derivative was measured in CDCl _{3 at} 100 MHz: Between δ = 2.0 and 2.1 ppm there are 4 singlets for a total of 12 protens, which correspond to the methyl groups of the O-acetyl groups

findet man als Singlett bei 8 = 2,45 ppm. Zwischen 8 = 2,1 und 2,5 ppm absorbieren als schlecht aufgelöste Multipletts zwei Protonen an einem an Stickstoff gebundenen C-Atom

The methyl group attached to N.

can be found as a singlet at 8 = 2.45 ppm. Between 8 = 2.1 and 2.5 ppm, poorly resolved multiplets absorb two protons on a nitrogen atom bound by nitrogen

Another such proton appears as a doublet from a doublet (J, = 11 Hz; J ₂ = 4 Hz) at 8 = 3.18 ppm.

als AB-System. Die restlichen drei Protonen

At 8 = 4.16 and 8 = 4.22 ppm a methylene group absorbs

as an AB system. The remaining three protons

can be found as a multiplet between 8 = 4.9 and 5.2 ppm.

Example 2 N-n-butyl-1-deoxynojirimycin

To 3.2 g of 1-deoxynojirimycin (0.02 mol) in 40 ml of absolute methanol, 12.5 ml of n-butyraldehyde, 0.01 mol of methanolic HCl and 1.5 g of NaCNBH ₃ are added in succession with ice cooling and stirring. The reaction mixture is stirred for 12 hours at room temperature. Then the mixture is evaporated to dryness on a rotary evaporator. The residue is dissolved in 50 ml of water and extracted 3 times with 30 ml of CHCI ₃ . The aqueous phase is again brought to dryness, the residue is taken up in 30 ml of H ₂ O and applied to a 50 cm long and 2 cm wide column which is ^treated with a strongly basic ion exchanger in the OH ^⊖ form (Amberlite IRA 400 or Dowex 1 x 2) is filled.

It is eluted with water and the individual fractions are examined by thin layer chromatography. (Silica gel plates; mobile phase: ethyl acetate / methanol / water / 25% ammonia 100: 60: 40: 2; spray reagent: KMnO _Δ solution). The fractions containing Nn-butyl-1-deoxynojirimycin are combined and the aqueous solution is concentrated on a rotary evaporator. Acetone is added to the residue, crystallization occurring.

The crystals are suctioned off, washed briefly with acetone and dried. 3 g of N-n-butyl-1-deoxynojirimycin with a melting point of 126-127 ° C. are obtained.

Mass spectrum: The most important peaks in the upper mass range can be found at / e = 188 (MCH ₂ OH) and m / e = 176 (M ― CH ₄ ―CH ₂ ―CH ₃ ).

In the case of less reactive aldehydes, molecular sieve 3A was added to the reaction mixture to bind the water of reaction.

The following were produced analogously to this regulation:

N-ethyl-1-deoxynojirimycin

Massenspektrum: Intensiver Peak bei m/e = 160 (M―CH₂OH).

Mass spectrum: intense peak at m / e = 160 (M ― CH ₂ OH).

N-n-propyl-1-deoxyjojirimycin

Massenspektrum: Intensiver Peak bei m/e = 174 (M―CH₂OH). Außerdem Peaks bei m/e = 206 (M+H) und m/e=204 (M-H).

Mass spectrum: intense peak at m / e = 174 (M ― CH ₂ OH). Also peaks at m / e = 206 (M + H) and m / e = 204 (MH).

N-iso-butyl-1-deoxynojirimycin

Massenspektrum: Die wichtigsten Peaks im oberen Massenbereich findet man bei m/e = 188 (M―CH₂OH), m/e = 176

m/e=220 (M+H) und m/e=218 (M―H).

Mass spectrum: The most important peaks in the upper mass range can be found at m / e = 188 (M ― CH ₂ OH), m / e = 176

m / e = 220 (M + H) and m / e = 218 (M ― H).

N-n-heptyl-1-deoxynojirimycin

Schmelzpunkt: 111―113°C(Aceton).

Melting point: 111-113 ° C (acetone).

Mass spectrum: The most important peak in the upper mass range is m / e = 230 (M ― CH ₂ OH). There are also peaks at m / e = 262 (M + H) and 260 (MH).

N-benzyl-1-deoxynojirimycin

Massenspektrum: Den wichtigsten Peak im oberen Massenbereich findet man bei m/e = 222 (M-CH₂0H).

Mass spectrum: The most important peak in the upper mass range can be found at m / e = 222 (M-CH ₂ 0H).

Melting point: 183-184 ° C (methanol).

N- (2-pyridyl) methy-1-deoxynojirimycin

Massenspektrum: Die wichtigsten Peaks im oberen Massenbereich findet man bei m/e = 255 (M+H), m/e = 236 (M-H₂0) und m/e = 223 (M-CH₂0H).

Mass spectrum: The most important peaks in the upper mass range can be found at m / e = 255 (M + H), m / e = 236 (MH ₂ 0) and m / e = 223 (M-CH ₂ 0H).

Melting point: 174―175 ° C (ethanol)

N-2-hydroxyethyl-1-deoxyjojirimycin

Schmelzpunkt: 114°C (Äthanol)

Melting point: 114 ° C (ethanol)

Mass spectrum: The most important peak in the upper mass range is m / e = 176 (M-CH ₂ 0H).

N-2,3-dihydroxy-n-propyl-i-deoxynojirimycin

Massenspektrum: Die wichtigsten Peaks im oberen Massenbereich liegen bei m/e = 206 (M―CH₂OH) und m/e = 176. Die Substanz ist ein Gemisch zweier diastereomerer Verbindungen.

Mass spectrum: The most important peaks in the upper mass range are m / e = 206 (M ― CH ₂ OH) and m / e = 176. The substance is a mixture of two diastereomeric compounds.

N- (S-β-D-glucopyranosyl-2-mercaptoethyl) -1-deoxynojirimycin

Massenspektrum: Das Massenspektrum wurde von der in Pyridin/Acetanhydrid peracetylierten Verbindung gemessen.

Mass spectrum: The mass spectrum was measured from the compound peracetylated in pyridine / acetic anhydride.

m/e = 588 und m/e = 344.The most important peaks in the upper mass range can be found at m / e = 648

m / e = 588 and m / e = 344.

The aldehyde required for the reaction was obtained from O-acetylated 1-thioglucose and chloroacetaldehyde. The acetyl groups were split off in the end product by transesterification with catalytic amounts of NaOCH ₃ in MeOH.

N-oxiranyl-methyl-1-deoxynojirimycin

Massenspektrum: Die wichtigsten Peaks in oberen Massenbereich findet man bei m/e = 219 (M), m/e = 202, m/e = 188 (M-CH₂0H) und m/e = 176

Mass spectrum: The most important peaks in the upper mass range can be found at m / e = 219 (M), m / e = 202, m / e = 188 (M-CH ₂ 0H) and m / e = 176

The substance is a mixture of two diastereomeric compounds.

N- (3-N-phthalimido-n-propyl) -1-deoxynojirimycin

Massenspektrum: Die wichtigsten Peaks im oberen Massenbereich wurden bei m/e = 348, m/e = 319 (M-CH₂0H), m/e = 301, m/e = 200, m/e = 188, m/e = 174, m/e 160 und m/e = 147 gefunden.

Mass spectrum: The most important peaks in the upper mass range were at m / e = 348, m / e = 319 (M-CH ₂ 0H), m / e = 301, m / e = 200, m / e = 188, m / e = 174, m / e 160 and m / e = 147 found.

In this case, chromatography on basic ion exchangers was dispensed with and the compound was purified by boiling with acetone and recrystallization from ethanol.

F.P .: 208-210 ° C.

N- (3-amino-n-propyl) -1-deoxynojirimycin

Massenspektrum: Die wichtigsten Peaks im oberen Massenbereich liegen bei m/e = 189 (M-CH₂0H) und m/e = 146.

Mass spectrum: The most important peaks in the upper mass range are m / e = 189 (M-CH ₂ 0H) and m / e = 146.

The compound was obtained from the above phthalimido compound by hydrazinolysis in methanol.

N- (1-deoxynojirimycin-yl) acetic acid

Massenspektrum: Die wichtigsten Peaks im oberen Massenbereich findet man bei m/e = 203 (M-H₂0), m/e = 159, m/e = 145 und m/e = 100.

Mass spectrum: The most important peaks in the upper mass range can be found at m / e = 203 (MH ₂ 0), m / e = 159, m / e = 145 and m / e = 100.

The compound was not purified by chromatography on a basic exchanger, but by recrystallization from methanol / water.

F.P .: 187-188 ° C.

N-o-nitrobenzyl-1-deoxynojirimycin

Rf-Wert: 0,85 (auf DC-Fertigplatten der Firma Merck Kieselgel 60; Fließmittel:Essigester/Methanol/ H₂O/25%iger Ammoniak 100:60:40:2).

Rf value: 0.85 (on pre-fabricated DC plates from Merck Kieselgel 60; eluent: ethyl acetate / methanol / H ₂ O / 25% ammonia 100: 60: 40: 2).

For comparison: Rf value of 1-deoxynojirimycin: 0.3.

N-o-carboxybenzyl-1-deoxynojirimycin

Rf value: 0.7 (plates and eluent as specified for the above compound).

For purification, the compound was chromatographed on basic chromatography as indicated above, but finally eluting with 1% acetic acid.

N-p-carboxybenzyl-1-deoxynojirimycin

Rf-Wert: 0,7 (Platten und Fließmittel wie oben angegeben). Auch hier wurde die Verbindung mit 1 %iger Essigsäure vom basischen Austauscher eluiert.

Rf value: 0.7 (plates and eluent as indicated above). Again, the compound was eluted from the basic exchanger with 1% acetic acid.

Melting point: 280-281 ° C (methanol)

N-p-sulfobenzyl-1-deoxynojirimycin

4.8 g of benzaldehyde-4-sulfonic acid, 1.8 ml of glacial acetic acid and 0.8 g of NaCNBH _{3 were} added to 2 g of 1-deoxynojirimycin in 40 ml of methanol. The mixture was heated under reflux for 4 hours and stirred overnight at room temperature. The precipitated reaction product was filtered off and recrystallized from water. Yield: 1.2 g melting point: ~ 320 ° C (decomposition).

Example 3 N-β-phenylethyl-1-deoxynojirimycin

3 g of phenylacetaldehyde and 0.8 g of NaCNBH _{3 were added} to 2 g of 1-deoxynojirimycin and 1.8 ml of acetic acid in 40 ml of methanol. The mixture was then stirred at room temperature overnight. The reaction mixture was brought to dryness on a rotary evaporator. The residue was dissolved in ethanol / H ₂ 0 2: 1 and applied to a column filled with a strongly acidic ion exchanger in the H ^⊖ form (Amberlite IR 120). The column was washed with 2 L ethanol / H ₂ O 2: 1. The reaction product was then eluted from the column with ethanol / 2% aqueous NH ₃ 2: 1. The individual fractions were examined by thin layer chromatography and those which contained N-β-phenylethyl-1-deoxynojirimycin were pooled and brought to dryness. The residue was crystallized from approximately 100 ml of ethanol. Yield: 2.5 g of N-β-phenylethyl-1-deoxynojirimycin with a melting point of 179-181 ° C.

The following were produced in an analogous way:

N-n-pentyl-1-deoxynojirimycin

F.P.: 97°C (aus Aceton)

FP: 97 ° C (from acetone)

N-n-Hexyl-1-deoxynojirimycin

F.P.: 112―113°C (aus Ethanol/Aceton)

FP: 112―113 ° C (from ethanol / acetone)

N-n-octyl-1-deoxynojirimycin

F.P.: 115―117°C (aus Ethanol/Aceton)

FP: 115―117 ° C (from ethanol / acetone)

N-n-nonyl-1-deoxynojirimycin

F.P.: 105―107°C (aus Ethanol/Aceton)

FP: 105―107 ° C (from ethanol / acetone)

N-n-decyl-1-deoxynojirimycin

F.P.: 151 °C (sintert bei 91 °C, aus MeOH/Aceton)

FP: 151 ° C (sintered at 91 ° C, from MeOH / acetone)

N-n-undecyl-1-deoxynojirimycin

F.P.: 162°C (sintert bei 97°C, aus Ethanol/Aceton)

FP: 162 ° C (sinters at 97 ° C, from ethanol / acetone)

N-n-dodecyl-1-deoxynojirimycin

F.P.: 164°C (sintert bei 97°C, aus Ethanol/Aceton)

FP: 164 ° C (sinters at 97 ° C, from ethanol / acetone)

N-n-tetradecyl-1-deoxynojirimycin

F.P.: 105-107°C (aus Methanol)

FP: 105-107 ° C (from methanol)

N-n- (5'-hydroxypentyl) -1-deoxynojirimycin

F.P.: 86-87°C (aus Butanol)

FP: 86-87 ° C (from butanol)

N-cyclohexylmethyl-1-deoxynojirimycin

F.P.: 138-140°C (aus Aceton)

FP: 138-140 ° C (from acetone)

N- (3'-Cyclohexenylmethyl) -1-deoxynojirimycin

F.P.: 142-144°C (aus Aceton)

FP: 142-144 ° C (from acetone)

N- (2'-Norbornen-5'-yl-methyl) -1-deoxynojirimycin

F.P.: 160-162°C (aus Ethanol)

FP: 160-162 ° C (from ethanol)

N-p-chlorobenzyl-1-deoxynojirimycin

F.P.: 153-155°C (aus Aceton)

FP: 153-155 ° C (from acetone)

N-m-methylbenzyl-1-deoxynojirimycin

F.P.: 134-136°C (aus Methanol)

FP: 134-136 ° C (from methanol)

N- (p-biphenylmethyl) -1-deoxynojirimycin

F.P.: 240-245°C (aus Wasser/Ethanol)

FP: 240-245 ° C (from water / ethanol)

N- (n-3'-phenylpropyl) -1-deoxynojirimycin

F.P.: 125―127°C (aus Ethanol)

FP: 125―127 ° C (from ethanol)

Example 4 N-allyl-1-deoxynojirimycin

5 g 1-Desoxynojirimycin in 30 ml Dimethylformamid und 30 ml H₂O wurden mit 5 g Ag₂O und 5. g Allylbromid drei Stunden bei Raumtemperatur gerührt. Anschließend wurden die Silbersalze abfiltriert und das Filtrat wurde am Rotationsverdampfer zur Trockne gebracht. Der Rückstand wurde ans Ethanol umkristallisiert. Ausbeute: 4,5 g N-Allyl-1-desoxynojirimycin vom F.P. 131-132°C.

5 g of 1-deoxynojirimycin in 30 ml of dimethylformamide and 30 ml of H ₂ O were stirred with 5 g of Ag ₂ O and 5. g of allyl bromide for three hours at room temperature. The silver salts were then filtered off and the filtrate was brought to dryness on a rotary evaporator. The residue was recrystallized from ethanol. Yield: 4.5 g of N-allyl-1-deoxynojirimycin from FP 131-132 ° C.

The following connections were made in an analogous manner. The isolation and purification of the end products was also carried out, if necessary, by chromatography over a strongly acidic ion exchanger (H⊕ form).

N-propargyl-1-deoxyjirimycin

F.P.: 160°C (aus Aceton)

FP: 160 ° C (from acetone)

N- (3 ', 4'-dichlorobenzyl) -1-deoxynojirimycin

F.P.: 130-132°C

FP: 130-132 ° C

N- (p-nitrobenzyl) -1-deoxynojirimycin

F.P.: 144-146°C

FP: 144-146 ° C

N- (m-nitrobenzyl) -1-deoxynojirimycin

F.P.: 168-170°C

FP: 168-170 ° C

Example 5 1-cyano-1-deoxynojirimycin

17.5 g of nojirimycin bisulfite adduct are added to 200 ml of H ₂ O and 21.2 g of Ba (OH) ₂ x 8 H ₂ O. The mixture is stirred for one hour at room temperature and the solid is filtered off with suction. The filtrate is mixed with 12 ml of liquid hydrocyanic acid and allowed to stir for 1/2 hour. The solution is filtered again and concentrated to 20 ml on a rotary evaporator. 20 ml of MeOH are initially added, the desired product starting to crystallize out, and the crystallization is completed by adding 100 ml of ethanol. The precipitate was filtered off.

Yield: 12.0 g of 1-cyano-1-deoxynojirimycin; F.P .: 152-153 ° C. After recrystallization from methanol and a little water, the substance melts at 155-156 ° C.

Example 6 N-methyl-1-cyano-1-deoxynojirimycin

Die Verbindung wurde in Analogie zu Beispiel 3 durch reduktive Methylierung von 1-Cyano-1- desoxynojirimycin mit 35%-iger wäßriger Formaldehydlösung und NaCNBH₃ in Methanol erhalten. Massenspektrum: Die wichtigsten Peaks im oberen Massenbereich liegen bei m/e = 171 (M―CH₂OH), m/e = 157 und m/e = 144.

The compound was obtained in analogy to Example 3 by reductive methylation of 1-cyano-1-deoxynojirimycin with 35% aqueous formaldehyde solution and NaCNBH ₃ in methanol. Mass spectrum: The most important peaks in the upper mass range are m / e = 171 (M ― CH ₂ OH), m / e = 157 and m / e = 144.

Example 7 1-deoxynojirimycin-1-carboxylic acid

10 g 1-Cyano-l-desoxynojirimycin wurden mit 5 g NaOH in 100 ml H₂O eine Stunde unter Rückfluß erhitzt. Anschließend wurde mit konz. HCI schwach sauer gestellt (pH=4). Dann wurde am Rotationsverdampfer zur Trockne eingeengt. Der Rückstand wurde mit Methanol in der Hitze extrahiert, das NaCI wurde abgetrennt und die methanolische Lösung erneut zur Trockne gebracht. Der Rückstand wurde zuerst aus wenig Wasser und dann aus Wasser/Methanol umkristallisiert. Ausbeute: 10,5 g 1-Desoxynojirimycin-1-carbonsäure vom F.P.: 268-270°C.

10 g of 1-cyano-1-deoxynojirimycin were refluxed with 5 g of NaOH in 100 ml of H ₂ O for one hour. Subsequently, with conc. HCl slightly acidified (pH = 4). The mixture was then evaporated to dryness on a rotary evaporator. The residue was extracted with methanol while hot, the NaCl was separated off and the methanolic solution was brought to dryness again. The residue was recrystallized first from a little water and then from water / methanol. Yield: 10.5 g of 1-deoxynojirimycin-1-carboxylic acid from FP: 268-270 ° C.

Example 8 1-Deoxynojirimycin-1-carboxylic acid ethyl ester

7 g of 1-deoxynojirimycin-1-carboxylic acid were heated under reflux with 100 ml of ethanolic hydrochloric acid for 2 hours. The mixture was then evaporated to dryness on a rotary evaporator. The residue was mixed with ethanol and to release the base with ethanolic ammonia. It was filtered and the ethanolic solution was concentrated.

Yield of non-crystalline 1-deoxynojirimycin-1-carboxylic acid ethyl ester: 8 g.

NMR spectrum at 100 MHz in CD ₃ OD:

• Triplet at δ = 1.3 ppm (3H, ―COO ― CH5 ₂ ―CH ₃ );
• Multiplet at 8 = 2.4-2.6 ppm (1 H,
  
• Multiplet at 8 = 3.2-3.5 ppm (4H)
• Multiplet at 8 = 3.6―3.9 ppm (2H, ―CH ₂ OH)
• Quartet at 8 = 4.25 ppm (2H, ―COO ― CH ₂ ―CH ₃ )

Example 9 N-methyl-1-deoxynojirimycin-1-carboxylic acid ethyl ester

From 1-deoxynojirimycin-1-carboxylic acid ethyl ester in analogy to Example 6. Mass spectrum: The most important peaks in the upper mass range can be found at: m / e = 218 (M-CH _z OH), m / e = 200, m / e = 176 , m / e = 158 and m / e = 126.

Example 10 1-deoxynojirimycin-1-carboxamide

6 g 1-Desoxynojirimycin-1-carbonsäureethylester wurden in 90 ml 25%-igem wäßrigem Ammoniak eine Stunde unter Rückfluß erhitzt. Die abgekühlte Lösung wurde mit Ethanol versetzt und ein ausgefallener Niederschlag (1,2 g; Ammoniumsalz der 1-Desoxynojirimycin-1-carbonsäure) abgetrennt. Das Filtrat wurde eingeengt, in Wasser aufgenommen und auf eine mit stark basischem Austauscher in der OH^8-Form (Amberlite IRC 400) gefüllte Säule aufgetragen. Es wurde mit Wasser eluiert. Die Fraktionen, die das Carbonsäureamid enthielten, wurden zusammengefaßt und eingeengt. Der Rückstand wurde aus Ethanol umkristallisiert. Ausbeute: 3 g 1-Desoxynojirimycin-1-carbonsäureamid von Schmelzpunkt 175-176°C.

6 g of 1-deoxynojirimycin-1-carboxylic acid ethyl ester were refluxed in 90 ml of 25% aqueous ammonia for one hour. The cooled solution was mixed with ethanol and a precipitate (1.2 g; ammonium salt of 1-deoxynojirimycin-1-carboxylic acid) was separated off. The filtrate was concentrated, taken up in water and applied to a column filled with a strongly basic exchanger in the OH ⁸ form (Amberlite IRC 400). It was eluted with water. The fractions containing the carboxamide were pooled and concentrated. The residue was recrystallized from ethanol. Yield: 3 g of 1-deoxynojirimycin-1-carboxamide of melting point 175-176 ° C.

Example 11 1 1-deoxynojirimycin-1-carboxylic acid benzylamide

500 mg 1-Desoxynojirimycin-1-carbonsäureethylester wurden in 1 ml Benzylamin 5 Minuten zum Sieden erhitzt. Nach dem Abkühlen wurde mehrfach mit Ether verrührt und abdekantiert. Der Rückstand wurde aus Methanol umkristallisiert.

500 mg of ethyl 1-deoxynojirimycin-1-carboxylate were boiled in 1 ml of benzylamine for 5 minutes. After cooling, the mixture was stirred several times with ether and decanted off. The residue was recrystallized from methanol.

Yield: 400 mg of 1-deoxynojirimycin-1-carboxylic acid benzylamide from F.P. 221-222 ° C.

Example 12 N-methyl-1-deoxynojirimycin-1-carboxylic acid benzylamide

From 1-deoxynojirimycin-1-carboxylic acid benzylamide in analogy to Example 6. F.P .: 229-230 ° C (from methanol).

Example 13 1-aminomethyl-1-deoxynojirimycin

5 g 1-Cyano-1-desoxynojirimycin wurden in 100 ml Wasser mit 10 g Raney-Nickel als Katalysator eine Stunde bei 3,5 Athmosphären H_2-Druck in einer Schüttelbirne hydriert. Dann wurde vom Katalysator abgesaugt, die Lösung wurde am Rotationsverdampfer zur Trockne gebracht. Der Rückstand wurde in wenig siedendem Methanol aufgenommen, die Lösung wurde filtriert und erneut zur Trockne gebracht. Der Rückstand wurde aus ca. 15 ml Methanol umkristallisiert.

5 g of 1-cyano-1-deoxynojirimycin were hydrogenated in 100 ml of water with 10 g of Raney nickel as catalyst for one hour at 3.5 atmospheres of H ₂ pressure in a shaking pear. The catalyst was then filtered off with suction, and the solution was brought to dryness on a rotary evaporator. The residue was taken up in a little boiling methanol, the solution was filtered and brought to dryness again. The residue was recrystallized from about 15 ml of methanol.

Yield: 3.4 g of 1-aminomethyl-1-deoxynojirimycin with a melting point of 148-150 ° C. After recrystallization from methanol, the melting point rises to 154-155 ° C.

Example 14 1-acetamidomethyl-1-deoxynojirimycin

3,8 g 1-Aminomethyl-1-desoxynojirimycin in 40 ml Me0H/H₂0 1:1 wurden bei 0°C mit 3 ml Acetanhydrid versetzt. Es wurde 15 Minuten bei 0°C und 30 Minuten bei Raumtemperatur gerührt. Dann wurde am Rotationsverdampfer zur Trockne eingeengt. Der Rückstand wurde in ca. 60 ml Wasser aufgenommen, und es wurde mit basischem Austauscher (OH⊖-Form) neutralisiert. Nach Entfernen des Austauschers wurde erneut zur Trockne eingeengt und der Rückstand zweimal aus Ethanol umkristallisiert.

3.8 g of 1-aminomethyl-1-deoxynojirimycin in 40 ml of MeOH / H ₂ 0 1: 1 were mixed with 0 ml of acetic anhydride at 0 ° C. The mixture was stirred at 0 ° C. for 15 minutes and at room temperature for 30 minutes. The mixture was then evaporated to dryness on a rotary evaporator. The residue was taken up in about 60 ml of water, and it was neutralized with a basic exchanger (OH⊖ form). After removing the exchanger, the mixture was again concentrated to dryness and the residue was recrystallized twice from ethanol.

Yield of 1-acetamidomethyl-1-deoxynojirimycin: 3 g of mp: 169-171 ° C.

MS spectrum: The most important peaks in the upper mass range can be found at m / e = 216, m / e = 203, m / e = 162 (base peak) and m / e = 144.

Example 15 N-methyl-1-acetamidomethyl-1-deoxynojirimycin

The compound was prepared from 1-acetamidomethyl-1-deoxynojirimycin in analogy to Example 6.

MS spectrum: The most important peaks in the upper mass range can be found at m / e = 176 and m / e = 158. Less intense peaks at m / e = 230, m / e = 218 and 217.

Example 16 1-benzoylaminomethyl-1-deoxynojirimycin

Die Verbindung wurde aus 1-Aminomethyl-1-desoxynojirimycin und Benzoylchlorid nach der Vorschrift von Beispiel 14 hergestellt.

The compound was prepared from 1-aminomethyl-1-deoxynojirimycin and benzoyl chloride according to the procedure of Example 14.

F.P .: 216 ° (from methanol).

Mass spectrum: The most important peaks in the upper mass range are m / e = 278, m / e = 265, m / e = 175, m / e = 162 and m / e = 105.

Example 17 N-methyl-1-benzoylaminomethyl-1-deoxynojirimycin

The compound was prepared from 1-benzoylaminomethyl-1-deoxynojirimycin in analogy to Example 6.

FP: 135-136 ° C (from butanol).

Example 18 1-tosylamidomethyl-1-deoxynojirimycin

960 mg 1-Aminomethyl-1-desoxynojirimycin wurden mit 1 g Tosylchlorid in 10 ml MeOH/H₂O 1:1 drei Stunden unter Rückfluß erhitzt. Anschließend wurde das Lösungsmittel am Rotationsverdampfer abgezogen, und der Rückstand wurde mit Aceton verrührt. Die Festsubstanz wurde abgesaugt, in Wasser gelöst und mit basischem Ionenaustauscher neutralisiert. Nach Entfernen des lonenaustauschers wurde die Lösung am Rotationsverdampfer zur Trockne gebracht, und der Rückstand wurde aus Wasser umkristallisiert.

960 mg of 1-aminomethyl-1-deoxynojirimycin were refluxed with 1 g of tosyl chloride in 10 ml of MeOH / H ₂ O 1: 1 for three hours. The solvent was then removed on a rotary evaporator and the residue was stirred with acetone. The solid substance was suctioned off, dissolved in water and neutralized with a basic ion exchanger. After removing the ion exchanger, the solution was brought to dryness on a rotary evaporator and the residue was recrystallized from water.

Yield of 1-tosylamidomethyl-1-deoxynojirimycin: 600 mg of melting point: 173-175 ° C.

• Singlett bei δ = 2,36 ppm
  
• Multiplett bei δ = 2,4-2,7 ppm
  
• AA'BB'-System zwischen δ = 7,2 und 7,8 ppm (4H,
  

NMR spectrum:

• Singlet at δ = 2.36 ppm
  
• Multiplet at δ = 2.4-2.7 ppm
  
• AA'BB 'system between δ = 7.2 and 7.8 ppm (4H,
  

The remaining eight C-H protons cannot be assigned individually and absorb between 8 = 2.9 and δ = 3.9 ppm.

Example 19 N-methyl-1-tosylamidomethyl-1-deoxynojirimycin

The compound was prepared from 1-tosylamidomethyl-1-deoxynojirimycin according to the procedure of Example 6.

FP: 218-219 ° C (from H ₂ 0).

Example 20 1- (N'-phenylureidomethyl) -1-deoxynojirimycin

960 mg 1-Aminomethyl-1-desoxynojirimycin in 10 ml Methanol/Wasser 1:1 wurden bei -20°C mit 0,8 ml Phenylisocyanat 1/4 Stunde gerührt. Dann ließ man die Temperatur allmählich auf Raumtemperatur steigen. Nach Entfernen des Lösungsmittels wurde der Rückstand auf eine mit Cellulose gefüllte Säule aufgetragen. Es wurde mit Butanol, das 10% Wasser enthielt, eluiert. Die Fraktionen, die das Desoxynojirimycinderivat enthielten, wurden zusammengefaßt und eingeengt. Der Rückstand wurde aus Ethanol umkristallisiert.

960 mg of 1-aminomethyl-1-deoxynojirimycin in 10 ml of methanol / water 1: 1 were stirred at -20 ° C. with 0.8 ml of phenyl isocyanate for 1/4 hour. Then the temperature was allowed to gradually rise to room temperature. After removing the solvent, the residue was applied to a column filled with cellulose. It was eluted with butanol containing 10% water. The fractions containing the deoxynojirimycin derivative were pooled and concentrated. The residue was recrystallized from ethanol.

Yield: 400 mg of 1- (N'-phenylureidomethyl) -1-deoxynojirimycin with a melting point of 161-162 ° C. Mass spectrum: The most important peaks in the upper mass range can be found at m / e = 218, m / e = 200 and m / e = 187, another small peak at m / e = 293.

Example 21 N- (1-deoxynojirimycin-yl) acetic acid benzylamide

500 mg N-(1-Desoxynojirimycin-yl)-essigsäure-6-lacton wurden mit 1 ml Benzylamin in 20 ml DMF 6 Stunden unter Rückfluß erhitzt. Das Lösungsmittel wurde im Hochvakuum entfernt und der Rückstand aus Ethanol/Aceton 1:2 umkristallisiert.

500 mg of N- (1-deoxynojirimycin-yl) -acetic acid-6-lactone were refluxed with 1 ml of benzylamine in 20 ml of DMF for 6 hours. The solvent was removed under high vacuum and the residue was recrystallized from ethanol / acetone 1: 2.

Yield: 400 mg of N- (1-deoxynojirimycin-yl) acetic acid benzylamide with a melting point of 129 ° C. Mass spectrum: The most important peaks in the upper mass range can be found at m / e = 292, m / e = 279, m / e = 203 and m / e = 106.

The following was produced in an analogous way:

N- (1-Deoxynöjirimycin-yl) acetic acid-n-butylamide

Massenspektrum: Die wichtigsten Peaks im oberen Massenbereich finden sich bei m/e = 245, m/e = 203, m/e = 176, m/e = 159 und m/e = 145.

Mass spectrum: The most important peaks in the upper mass range can be found at m / e = 245, m / e = 203, m / e = 176, m / e = 159 and m / e = 145.

Example 22 1-hydroxymethyl-1-deoxynojirimycin

A suspension of 2.3 g of 1-deoxynojirimycin-1-carboxylic acid ethyl ester in 50 ml of absolute THF was added to 1.9 g of LiAIH ₄ in 50 ml of absolute THF. The mixture was stirred at room temperature for one hour and then refluxed for 5 hours. Subsequently, 20 ml of ethyl acetate, 2 ml of water and 4 ml of 15% KOH were added dropwise with stirring. The precipitate was filtered off and extracted with a methanol / water mixture. The methanol / water extract was brought to dryness on a rotary evaporator and the residue was extracted with methanol. The methanolic solution was again concentrated and the residue was applied with water to a column filled with a strongly acidic exchanger in the ^HO form. It was eluted first with water and then with 0.25% ammonia. The fractions containing 1-hydroxymethyl-1-deoxynojirimycin were pooled and concentrated. 500 mg of 1-hydroxymethyl-1-deoxynojirimycin were obtained.

Mass spectrum: The most important peak (base peak) in the upper mass range is m / e = 162. Smaller peaks can be found at m / e = 144 and m / e = 102.

Example 23 6-0-Benzoyl-1-deoxynojirimycin

3.5 g of powdered K ₂ CO ₃ and 2.0 g of benzoyl chloride were added to 2.1 g of 1-deoxynojirimycin in 40 ml of acetone and 15 ml of water at room temperature. The mixture was heated to 40 ° C. for 3 hours and then stirred at room temperature overnight. Then salts were filtered off and the solution was concentrated in vacuo. The residue was chromatographed on a silica gel column. It was eluted first with ethyl acetate / methanol 10: 4 and finally with ethyl acetate / methanol / water / ammonia 10: 4: 0.5: 0.02. Fractions of 10 ml each were collected. Fractions 51-57 contained 350 mg of 6-0-benzoyl-1-deoxynojirimycin from FP 160 ° C (from methanol).

Example 24 N- (β-methoxyethyl) -1-deoxynojirimycin

5,2 g β-Methoxyacetaldehyddimethylacetal in 15 ml H₂O und 5 ml Methanol wurden mit 0,6 ml konz. HCI 48 Stunden bei Raumtemperatur und 6 Stunden bei 60°C hydrolysiert. Dann wurden bei Raumtemperatur 1,6 g 1-Desoxynojirimycin und 0,7 g NaCNBH₃ hinzugegeben. Man ließ über Nacht bei Raumtemperatur und dann noch 12 Stdn. bei 50°C reagieren. Das Reaktionsgemisch wurde im Vakuum zur Trockne gebracht, der Rückstand in Wasser auf eine mit stark saurem lonenaustauscher in der H^⊕-Form (Amberlite IR 120) gefüllte Säule aufgetragen. Es wurde zunächst mit Wasser, dann mit 2%-igem Ammoniak elueirt. Die Fraktionen, die N-(ß-Methoxyethyl)-1-desoxy- nojirimycin enthielten, wurden zusammengefaßt und eingeengt. Der Rückstand wurde zur Trennung von wenig Ausgangsprodukt (1-Desoxynojirimycin) an einer Cellulosesäule chromatographiert. Als Fließmittel wurde Butanol/Wasser 9:1 verwendet.

5.2 g of β-methoxyacetaldehyde dimethyl acetal in 15 ml of H ₂ O and 5 ml of methanol were mixed with 0.6 ml of conc. HCI hydrolyzed for 48 hours at room temperature and 6 hours at 60 ° C. Then 1.6 g of 1-deoxynojirimycin and 0.7 g of NaCNBH _{3 were} added at room temperature. The mixture was left to react overnight at room temperature and then for a further 12 hours at 50 ° C. The reaction mixture was brought to dryness in vacuo, the residue in water was applied to a column filled with a strongly acidic ion exchanger in the H ^⊕ form (Amberlite IR 120). It was eluted first with water, then with 2% ammonia. The fractions containing N- (β-methoxyethyl) -1-deoxy-nojirimycin were pooled and concentrated. The residue was chromatographed on a cellulose column to separate little starting material (1-deoxynojirimycin). Butanol / water 9: 1 was used as flow agent.

Yield of N- (β-methoxyethyl) -1-deoxynojirimycin: 1.2 g.

Rf value 0.57 (thin layer chromatography on ready-to-use silica gel 60 plates from Merck, eluent: ethyl acetate / methanol / H ₂ O / 25% ammonia 100: 60: 40: 2).

For comparison, the Rf value for 1-deoxynojirimycin = 0.3.

The following were obtained in an analogous manner:

N- (β-methylmercaptoethyl) -1-deoxynojirimycin

Massenspektrum: Die wichtigsten Peaks im oberen Massenbereich liegen bei m/e = 220, m/e = 206 und m/e = 176 (base peak).

Mass spectrum: The most important peaks in the upper mass range are m / e = 220, m / e = 206 and m / e = 176 (base peak).

N- (β-ethylmercaptoethyl) -1-deoxynojirimycin

Massenspektrum: Die wichtigsten Peaks im oberen Massenbereich liegen bei m/e = 220 und m/e = 176 (base peak).

Mass spectrum: The most important peaks in the upper mass range are m / e = 220 and m / e = 176 (base peak).

N- [ß- (ß'-methoxy) ethoxyethyl] -1-deoxynojirimycin

Massenspektrum: Die wichtigsten Peaks im oberen Massenbereich liegen bei m/e = 234 und m/e = 176. Weitere Peaks findet man bei m/e = 218, m/e = 204, m/e = 158, m/e = 146 und m/e = 132.

Mass spectrum: The most important peaks in the upper mass range are m / e = 234 and m / e = 176. Further peaks can be found at m / e = 218, m / e = 204, m / e = 158, m / e = 146 and m / e = 132.

Example 25 N-n-nonyl-1-acetamidomethyl-1-deoxynojirimycin

The compound was obtained from 1-acetamidomethyl-1-deoxynojirimycin by reductive alkylation with nonylaldehyde and NaCNBHg in methanol in analogy to Example 3.

Mass spectrum: The most important peaks in the upper mass range are m / e = 329, m / e = 288 (base peak), m / e = 270 and m / e = 258.

Example 26 1-n-nonylaminomethyl-1-deoxynojirimycin

1.2 ml of acetic acid, 1.56 g of nonylaldehyde and 0.7 g of NaCNBHg were added to 1.9 g of 1-aminomethyl-1-deoxynojirimycin in 40 ml of methanol at 0 ° C. The mixture was stirred at 0 ° C. for one hour and then at room temperature overnight. The reaction mixture was then brought to dryness on a rotary evaporator. The residue was taken up in water and applied to a column filled with a strongly acidic ion exchanger in the H ^⊕ form (Amberlite IR 120). The column was eluted with 1: 1 ethanol / water, then with 0.3% aqueous ammonia and finally with a 1: 1 mixture of ethanol and 0.6% aqueous ammonia. The fractions which contained 1-n-nonylaminomethyl-1-deoxynojirimycin after checking by thin-layer chromatography were pooled and concentrated.

Yield: 1 g.

Rf value: 0.52; 1-deoxynojirimycin: 0.3. Plates and solvents as in Example 25.

Example 27 N-methyl-nojirimycin hydrochloride 1. Production of the starting products

In a solution of 294.0 g (0.5 mol) of 3-0-benzyl-6-0-triphenylmethyl-1,2-isopropylidene-5-amino-5-deoxy-aD-glucofuranose in 800 ml of absolute THF and 83.6 57 ml of ethyl chloroformate, dissolved in 360 ml of absolute THF, are added dropwise with ice cooling to ml of triethylamine. The mixture is stirred at 20 ° C for 2 hours, suctioned off from the precipitated salt and concentrated. It is taken up in ethyl acetate, shaken twice with water, dried and concentrated. 318.6 g (98.3% of theory) of crude 3-0-benzyl-6-0-triphenylmethyl-1.2-0-isopropylidene-5-ethoxycarbonylamino-5-deoxy-aD-glucofuranose are obtained as a slightly yellow oil .

174.7 g of this oil are dissolved in 340 ml of absolute ether and added dropwise at 10 ° C to 15 ° C in a suspension of 39 g of lithium aluminum hydride in 690 ml of absolute ether. It is then heated to reflux for 5 hours. The mixture is then decomposed with ice cooling by dropping 520 ml of ethyl acetate, 40 ml of water and finally 78.5 ml of 15% potassium hydroxide solution. It is suctioned off, washed with ether and i.V. evaporated. 144.2 g (91.3% of theory) of 3-0-benzyl-6-0-triphenylmethyl-1,2-isopropylidene-5-methylamino-5-deoxy-a-D-glucofuranose are obtained as colorless oil.

This crude product is dissolved in 165 mh of absolute tetrahydrofuran and dripped at -70 ° C. into a mixture of 24.6 g of sodium in 820 ml of liquid ammonia cooled with dry ice / acetone. A further 2.5 g of sodium are added in portions and the mixture is stirred for 2 hours. Then 91 g of ammonium chloride are added in portions at -70 ° C. and the mixture is left to smoke overnight without a cold bath. The suspension obtained is stirred with 500 ml of methanol. It is suctioned off and the filtrate is concentrated. The evaporation residue was taken up in water / chloroform and separated. The aqueous phase is concentrated. The crude product thus obtained is purified on a Dowex 50 WX 4 exchanger column. After recrystallization from ethyl acetate, 14.8 g (24.3% of theory) of 5-methylamino-5-deoxy-1.2.-0-isopropylidene-α-D-glucofuranose with a melting point of 124 ° C.-126 ° C. are obtained.

C ₁₀ H ₁₉ NO ₅ (239.2) Calc .: C = 51.5 H = 8.15 N = 6.0

2. N-methyl-nojirimycin (hydrochloride)

A solution of 470 mg of 5-methylamino-5-deoxy-1.2-0-isopropylidene-aD-glucofuranose in 2 ml of 6N HCl is left to stand in the refrigerator for 16 hours, then the mixture is concentrated in vacuo at 20 ° C., dissolved twice in water and again constricted. The non-crystalline N-methyl-nojirimycin hydrochloride obtained in this way showed in the sucrose inhibition test a three times stronger effect than 1-deoxy-nojirimycin.

Example 28 N-cyclohexyl-1-deoxy-nojirimycin Method A

2 g (12.25 mmol) of 1-deoxy-nojirimycin are dissolved in 40 ml of absolute methanol and 1.8 ml (30 mmol) of glacial acetic acid and successively with 5.2 ml (50 mmol) of cyclohexanone and 3.4 g (54 mmol) ) Sodium cyanoborohydride added. This mixture is heated to reflux for 96 hours (TLC control), cooled and concentrated in vacuo. The syrupless evaporation residue is taken up 1: 1 in methanol / water and cleaned on an exchange column with Dowex 50 WX 4 H ^O form. 1.9 g of pure product are obtained.

Rf: 0.58; Ethyl acetate / methanol / water / 25% ammonia water 120: 70: 10: 1, TLC plates silica gel 60 F 254 Merck Rf 1-deoxy-nojirimycin: 0.13

Method B

• N-Isopropyl-1-desoxy-nojirimycin
• Rf: 0,45
• N-(1-Methyl-decyl)-1-desoxy-nojirimycin, Diastereomerengemisch Rf: 0,79 und 0,86
• (Platten und Laufmittel wie in Beispiel 30 angegeben)

1 g of 6-cyclohexylamino-2.3-0-isopropylidene-6-deoxy-aL-sorbofuranose melting at 95 ° C (made from 1-0-acetyl-2.3-0-isopropylidene-6-0-p-toluenesulfonyl-aL-sorbofuranose by boiling with cyclohexylamine in butanol) is allowed to stand in a mixture of 6 ml of methanol / 6N hydrochloric acid 1: 1 at 0 ° C for 40 hours, diluted with 10 ml of water, mixed with 3.0 ml of triethylamine and 2 hours after adding platinum dioxide hydrogenated at 3.5 bar. It is filtered from the catalyst, concentrated in vacuo and purified by exchange chromatography on Dowex 50 WX 4. 610 mg of 1-cyclohexyl-1-deoxy-nojirimycin are obtained, which is identical to the product prepared by method A. The following were prepared in accordance with method A:

• N-isopropyl-1-deoxy-nojirimycin
• Rf: 0.45
• N- (1-methyl-decyl) -1-deoxy-nojirimycin, mixture of diastereomers Rf: 0.79 and 0.86
• (Plates and eluent as indicated in Example 30)

Example 29 1.6-deoxynojirimycin (a) 5-Azido-3-O-benzyl-5.6-dideoxy-1.2.-O-isopropylidene-α-D-glucofuranose

186 g (0,5 Mol) 3-O-Benzyl-6-desoxy-1.2-O-isopropyliden-5-O-methylsulfonyl-β-L-idofuranose (hergestellt nach: T.D. Inch, Carbohyd. Res. (1967), 45-52), 500 ml Dimethylsulfoxid und 65 g (1 Mol) NaN₃ wurden 5 Stdn. auf 120-125°C unter einem leichten Stickstoffstrom erhitzt. Nach dem Abkühlen wurde der Ansatz auf 500 ml Eiswasser gegeben, 3 x mit Petrolether extrahiert, die organische Phase mit Wasser gewaschen und über Na₂S0₄ getrocknet. Nach dem Einrotieren erhielt man 156 g (99%) der rohen 5-Azido-3-0-benzyl-5.6-didesoxy-1.2-0-isopropyliden-a-D-glucofuranose als Öl, die bei Bedarf durch Chromatographie an Kieselgel der Fa. Merck (70-230 mesh) mit Hexan/Ether 3:1 als Laufmittel rein dargestellt werden kann.

186 g (0.5 mol) of 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-5-O-methylsulfonyl-β-L-idofuranose (manufactured according to: TD Inch, Carbohyd. Res. (1967), 45-52), 500 ml of dimethyl sulfoxide and 65 g (1 mol) of NaN ₃ were heated at 120-125 ° C. for 5 hours under a gentle stream of nitrogen. After cooling, the mixture was added to 500 ml of ice water, extracted 3 times with petroleum ether, the organic phase washed with water and dried over Na ₂ S0 ₄ . After spinning in, 156 g (99%) of the crude 5-azido-3-0-benzyl-5.6-dideoxy-1.2-0-isopropylidene-aD-glucofuranose were obtained as an oil, which if necessary by chromatography on silica gel from Merck (70-230 mesh) with hexane / ether 3: 1 as eluent.

Characteristic bands in 'H-NMR (100 MHz, solvent C ₆ D ₆ ) are: 8 = 7.15 ppm (m, 5H), 5.72 ppm (d, J = 4Hz, 1 H), 1.32 ppm (s, 3H), 1.17 ppm (d, J = 6Hz, 3H), 1.06 ppm (s, 3H).

(b) 5-Amino-3-O-benzyl-5.6-dideoxy-1.2-O-isopropylidene-α-D-glucofuranose

6 g (0.156 mol) of LiAIH ₄ in 250 ml of anhydrous tetrahydrofuran were added and 100 g (0.313 mol) of unpurified 5-azido-3-0-benzyl-5.6-dideoxy 1.2-0-isopropylidene-aD-glucofuranose were added dropwise at room temperature Add 200 ml of anhydrous tetrahydrofuran. The approach was Stirred at room temperature overnight and refluxed for 1 hour. After cooling, 6 ml of water and then 18 ml of 15% KOH solution were added dropwise with ice-cooling, the mixture was stirred overnight, the precipitate was filtered off and the filtrate was rotated in. The residue was taken up in 500 ml of ether and extracted twice with 100 ml of 2 normal hydrochloric acid. The aqueous phase was made alkaline with 45% NaOH solution and extracted three times with 200 ml ether. After drying the organic phase over Na ₂ SO ₄ , the solvent was spun off. 62.5 g (68%) of 5-amino-3-0-benzyl-5.6-dideoxy-1.2-0-isopropylidene-aD-glucofuranose were obtained as an oil.

The ¹ H ― NMR (100 MHz, CDCl ₃ as solvent) shows the following characteristic bands: = 7.3 ppm (m, 5H), 5.8 ppm (d, J = 4Hz, 1 H), 5.70 ppm (d, J = 12Hz, 1 H), 5.58 ppm (d, J = 4Hz, 1 H), 5.42 ppm (d, J = 12Hz, 1 H), 3.98 ppm (d, J = 4Hz), 1.45 ppm (s, 3H), 1.30 ppm (s, 3H), 1.15 ppm (d, J = 6Hz, 3H).

(c) 5-Amino-5.6-dideoxy-1,2-isopropylidene-a-D-glucofuranose

50 g (0,17 Mol) 5-Amino-3-O-benzyl-5.6-didesoxy-1:2-O-isopropyliden-α-D-glucofuranose in 1 L Methanol wurden in Gegenwart von 10 g Palladium auf Kohle (5%-ig) bei 60°C unter einem Druck von 70 atm 5 Stdn. hydriert. Nach dem Abfiltrieren des Katalysators wurde das Lösungsmittel abrotiert. Ausbeute: 25,7 g (76%). Durch Umkristallisieren aus Essigester erhält man Kristalle.

50 g (0.17 mol) of 5-amino-3-O-benzyl-5.6-dideoxy-1: 2-O-isopropylidene-α-D-glucofuranose in 1 L of methanol were added to carbon in the presence of 10 g of palladium (5 %) hydrogenated at 60 ° C under a pressure of 70 atm for 5 hours. After filtering off the catalyst, the solvent was spun off. Yield: 25.7 g (76%). Crystallization is obtained by recrystallization from ethyl acetate.

The ¹ H ― NMR (100 MHz, substance dissolved in CDCl ₃ and shaken out with D ₂ 0): δ = 5.97 ppm (d, J = 4Hz, 1 H), 4.50 ppm (d, J = 4Hz, 1 H), 4.34 ppm (d, J = 4Hz, 1H), 1.49 ppm (s, 3H), 1.32 ppm (s, 3H), 1.28 ppm (d, J = 6Hz, 3H).

(d) 5-Amino-5.6-dideoxy-D-glucose-1-sulfonic acid

10 g (0,049 Mol) 5-Amino-5.6-didesoxy-1.2-0-isopropyliden-a-D-glucofurose wurden in 50 ml Wasser suspendiert und 15 Stdn.

10 g (0.049 mol) of 5-amino-5.6-dideoxy-1.2-0-isopropylidene-aD-glucofurose were suspended in 50 ml of water and 15 hours.

(e) 1.6-dideoxynojirimycin

10 g (0,041 Mol) 5-Amino-5.6-didesoxy-D-glucose-1-sulfonsäure, 120 ml Wasser, 13,3 g Ba(OH)₂ x 8 H₂0 (0,042 Mol) und 10 g Raney-Nickel wurden bei Raumtemperatur und Normaldruck bis zum Ende der Wasserstoffaufnahme (etwa 7 Stdn.) hydriert. Der Ansatz wurde filtriert und das Filtrat i.Vak. eingedampft. Es blieb ein Öl zurück, das nach kurzer Zeit durchkristallisierte und sich aus Methanol umkristallisieren ließ.

10 g (0.041 mol) of 5-amino-5.6-dideoxy-D-glucose-1-sulfonic acid, 120 ml of water, 13.3 g of Ba (OH) ₂ x 8 H ₂ O (0.042 mol) and 10 g of Raney nickel were hydrogenated at room temperature and normal pressure until the end of the hydrogen uptake (about 7 hours). The mixture was filtered and the filtrate i.Vak. evaporated. An oil remained, which crystallized after a short time and could be recrystallized from methanol.

Yield: 5.3 g (83%), mp 163-164 ° C.

• δ = 3.24 ppm, 1.12 ppm (d, J = 6Hz).

The following are the characteristic bands in ¹ H ― NMR (100 MHz, solvent D ₂ 0):

• δ = 3.24 ppm, 1.12 ppm (d, J = 6Hz).

Initiated sulfur dioxide. A clear solution resulted, whereupon the mixture was heated to 60.degree. The deposition of crystalline 5-amino-5.6-dideoxy-D-glucose-1-sulfonic acid began after about 4 hours. For working up, the batch was mixed with 100 ml of methanol, left to stand overnight and the precipitate of 5-amino-5.6-dideoxy-D-glucose-1-sulfonic acid was suctioned off.

Yield: 8.5 g (71%), mp. 180 ° C dec.

The ¹ H ― NMR (100 MHz, solvent DMSO-d _e shows as a characteristic band at δ = 1.13 ppm a doublet with J = 6Hz.

Example 30 N- (1-deoxyglucityl) -1-deoxynojirimycin

0.8 g (0.01 mol) deoxynojirimycin, 7.2 g (0.04 mol) glucose, 40 ml methanol, 10 ml water, 1.5 ml glacial acetic acid and 1.3 g NaBN ₃ CN were added overnight at room temperature stirred and then boiled under reflux for 6 hours. The approach was i.Vak. evaporated to dryness, mixed with 10 ml of 2N HCl, warmed to 40 ° C. until the evolution of hydrogen had ended, placed on a column (30 cm long, 2.5 cm in diameter) with an acidic ion exchanger (Lewatit TWS 40) and with 2 L of water washed. The reaction product was then eluted from the column with 0.3N NH _a solution, the eluate i.Vak. evaporated and the residue on 100 g of silica gel from Merck (70-230 mesh) with methanol / conc. Ammonia solution in the ratio 10: 5 purified by column chromatography. Yield: 1 g.

The reaction product can be characterized by the following fragments in the mass spectrum: m / e = 296 (20%), 278 (15%), 176 (100%), 158 (30%), 132 (30%).

Example 31 1-deoxy-6-0-methylnojirimycin a) 3-0-Benzyl-1.2-0-isopropylidene-6-0-methyl-ß-L-idofuranose

440 g of 5,6-anhydro-3-0-benzyl-1,2-0-isopropylidene-β-L-idofuranose 1.5 l of methanol and 92 g of sodium methylate were boiled under reflux for 1 hour. After cooling, the mixture was neutralized with glacial acetic acid, methanol was distilled off, the residue was added to 300 ml of water and extracted with chloroform. After drying over sodium sulfate and distilling off the solvent, 388 g of an oil remained.

b) 3-O-Benzyl-1,2-O-isopropylidene-6-O-methyl-5-O-methylsulfonyl-β-L-idofuranose

148 ml of methanesulfonic acid chloride were added dropwise to 384 g (1), 380 ml of pyridine and 760 ml of chloroform and the mixture was stirred at room temperature overnight. For working up, 200 ml of ice water were added, the mixture was stirred for 20 minutes and extracted three times with 200 ml of chloroform. The organic phase was washed twice with dilute hydrochloric acid, then with water and with 10% sodium hydrogen carbonate solution and dried over sodium sulfate. After the solvent had been distilled off in vacuo, the residue was recrystallized from ethyl acetate. 347 g were obtained.

After filtration over 200 g of silica gel, a further 26 g could be isolated from the mother liquor. Yield: 79%

Melting point: 133 ° C.

c) 5-Azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-6-O-methyl-α-D-glucofuranose

201 g (2) 500 ml of hexamethylphosphoric triamide and 65 g of sodium azide were heated overnight to 100-110 ° C. under a light nitrogen atom. After cooling, the mixture was poured onto ice water, extracted 4 times with ether, the combined ether extracts washed with dilute hydrochloric acid, water and NaHCO _a solution, dried over Na ₂ SO _{4 and} evaporated in vacuo. 159 g (91%) remained.

d) 5-Amino-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-6-O-methyl-α-D-glucofuranose

134.5 g (3) in 200 ml of anhydrous THF were added dropwise to 7.3 g of LiAIH ₄ in 500 ml of anhydrous tetrahydrofuran (THF) at room temperature, the mixture was stirred for 4 hours and the mixture was left overnight Stand at room temperature. Then 7.3 ml of H ₂ 0 were slowly added dropwise, 22 ml of 15% KOH solution were then added and the mixture was stirred at room temperature for 8 hours. The precipitate was filtered off, washed with THF and the filtrate evaporated in vacuo. The oil obtained was covered with 300 ml of ether and 150 ml of 5N hydrochloric acid were added with ice cooling at 0-10 ° C., the organic phase was separated off, washed once with dilute hydrochloric acid and the combined aqueous phases once with ether. Then the aqueous phase was mixed with 100 ml of 40% NaOH solution and extracted three times with 150 ml of ether each time. The combined ether extracts were dried over Na ₂ S0 ₄ and evaporated in vacuo. There remained 91 g as an oil.

e) 5-Amino-5-deoxy-1,2-O-isopropylidene-6-O-methyl-α-D-glucofuranose

A solution of 85 g (4) in 500 ml of anhydrous THF was added to 1.51 of liquid ammonia at -70 ° C. and then 30.5 g of sodium were added in small pieces. After 4 hours, the batch was carefully mixed in portions with a total of 106 g of NH ₄ Cl and then left overnight at room temperature, the ammonia evaporating. Methanol was added to the residue, the precipitate was filtered off with suction and the filtrate was evaporated in vacuo. The residue was taken up in ether and dilute hydrochloric acid at 0-10 ° C., the ether phase was extracted three times with a total of 300 ml of dilute hydrochloric acid, the combined hydrochloric acid phases were treated with 200 ml of concentrated sodium hydroxide solution and extracted three times with a total of 600 ml of chloroform. After drying the chloroform extract over Na ₂ SO ₄ , the solvent was evaporated in vacuo and the residue was recrystallized from ethyl acetate. 47 g (77%), melting point 95 ° -96 ° C., were obtained.

f) 5-amino-5-deoxy-6-O-methyl-D-glucose-1-sulfonic acid

10 g (5) were dissolved in 50 ml of water. Then it was passed into the solution for 2 hours at room temperature, then overnight at 60 ° C. SO ₂ . The crystal slurry was mixed with 100 ml of methanol, left to stand at room temperature for 1 day, the precipitate was suction filtered and dried over CaCl ₂ in vacuo. 11.8 g (99%) were obtained. Melting point 154 ° C (with decomposition)

g) 1-deoxy-6-0-methylnojirimycin

11 g (6) in 90 ml of water were mixed with 13.3 g of Ba (OH) ₂ .8 H ₂ O. The product was hydrogenated without isolation in the presence of 5 g of Raney nickel under normal pressure at room temperature for 10 hours. The undissolved matter was filtered off and the clear solution was evaporated in vacuo. The residue was taken up in 30 ml of 2N hydrochloric acid and placed on a column with an acidic ion exchanger. It was washed with 2 l of water and eluted with 0.3 N ammonia solution. After evaporation of the eluate in vacuo, crystalline 1-deoxy-6-0-methylnojirimycin remained, which after Recrystallization from ethanol melts at 145-146 ° C.

Yield: 5.5 g (78%).

Claims (10)

1. Compounds of the formula

in which

R₁ denotes H or an optionally substituted, straight-chain, branched or cyclic saturated or unsaturated aliphatic hydrocarbon radical

R₂ denotes

-S0₃H, -CN, or -CONR'R",

R₃ denotes H or an optionally substituted, straight-chain, branched or cyclic saturated or unsaturated aliphatic hydrocarbon radical,
wherein

R' and R" represent hydrogen, an optionally substituted, straight-chain, branched or cyclic saturated or unsaturated aliphatic hydrocarbon radical or an optionally substituted aromatic or heterocyclic radical and wherein R₁ does not denote hydrogen if

a) R₂ denotes hydrogen or OH and R₃ denotes CH₂0H,

b) R₂ denotes hydrogen, OH, SO₃H, CN or CH₂NH₂ and R₃ denotes hydrogen and

c) R₂ denotes OH and R₃ denotes CH₂NH₂

and their pharmaceutically acceptable salts and bioprecursors.

2. Compounds according to claim 1 of the formula

in which

R₁ denotes H or an optionally substituted, straight-chain, branched or cyclic saturated or unsaturated aliphatic hydrocarbon radical and

R₂ denotes

wherein

R' and R" represent hydrogen, an optionally substituted straight-chain, branched or cyclic saturated or unsaturated aliphatic hydrocarbon radical or an optionally substituted aromatic or heterocyclic radical, and wherein R, is not hydrogen if R₂ is hydrogen or hydroxy.

3. Compounds according to claim 1, in which R₂ represents

and R₃ represents

4. N-(n-Heptyl)-1-desoxynojirimycin.

5. N-Methyl-1-desoxynojirimycin.

6. Process for the production of compounds according to claim 1, characterised in that compounds of the formula II or Ila in which R, and R₃ have the above mentioned meaning

are subjected to acid hydroslysis to remove the protective groups and the compounds of formula I, in which R₂ = -OH, are isolated as such or are optionally reacted to give further compounds of the formula I.

7. Process for the production of compounds according to claim 1, characterised in that compounds of the formula V

are reacted a) with carbonyl compounds of the formula VI

in which

R₆ and R₇ either denote H or have the meaning indicated above for R₁ or they are members of an alicyclic or heterocyclic ring,

in the presence of a hydrogen donor reducing agent or b) with reactive alkylating agents of the formula

in which R, has the meaning indicated above for alkyl and Z represents an easily eliminated group which is customary in alkylating agents, and the mixtures are worked up in the customary manner.

8. Medicaments, characterised in that they contain a compound according to claims 1 to 5 and, if appropriate, pharmaceutically suitable additives.

9. Compounds according to claims 1 to 5 for use in the treatment of adiposity, diabetes and/or hyperlipaemia.

10. Animal feedstuffs, characterised in that they contain a compound according to claims 1 to 5.