DE2738717A1 - Tri:hydroxy-piperidine derivs. - useful as glucosidase inhibitors for treating diabetes etc. and as animal feed additives - Google Patents

Abstract

Peperidine derivs. of formula (I) are new: (R1 = H, branched, linear or cyclic, opt. unsatd., aliphatic hydrocarbyl, aryl or heterocyclyl, all opt. substd.; R2 = H, OH, OR', SH, SR', NH2, NHR', NR'R", NH2CH2, R'NHCH2, R'R"NCH2, COOH, COOR', HOCH2, R'CONHCH2, R'CONR"CH2, R'SO2NHCH2, R'SO2NR"CH2, R'NHCONHCH2, R'NHCSNHCH2, R'OCONHCH2, SO3H, CN, CONH2, CONHR' or CONR'R"; R3 can be as R1 but is pref H, CH3, CH2OH, CH2NH2, CH2NHR', CH2NR'R", R'CONH.CH2, R'CONR"CH2, HalCH2, R'OCH2, R'COOCH2, R'SO2OCH2, R'SO2NHCH2, R'NH.CONHCH2, R'NHCSNH.CH2, R'OCONHCH2, CN, COOH, COOR', CONH2, CONHR', R'SO2NR"CH2, CONR'R"; R' and R" are as for R1; when (i) R3 = CH2OH; R2 = H or OH; (ii) R3 = CH2NH2 and R2 = OH; and also (iii) when R3=H, R2=H, OH, SO3H, CN or CH2NH2, R1 cannot be H). (I) inhibit alpha-glucosidases, esp. disaccharidases, so are useful in treating pre-diabetes, gastritis, obstipation, caries, gastro-intestinal infections, meterorism, flatulence, hypertension, atherosclerosis and esp. adiposity, diabetes and hyperlipoproteinaemia. They are also useful as animal feed additives to improve the meat-fat distribution.

Description

N-alkylated derivatives of 5-amino-5-deoxY-D-glucose, ver

proceed to their manufacture and their use The present invention relates to new N-alkylated derivatives of 5-amino-5-deoxy-D-glucose, several processes for their production as well as their use as pharmaceuticals, in particular as agents against diabetes, hyperlipemia and obesity, as well as in animal nutrition to influence it the meat / fat ratio in favor of the meat content.

It has now been found that the new N-alkylated derivatives of 5-amino-5-deoxy-D-slucose of the formula I, R1 is an optionally substituted, straight-chain, branched or cyclically saturated or unsaturated aliphatic hydrocarbon radical or an optionally substituted aromatic or heterocyclic radical and R2 is H, OH, alkoxy, amino, mono- and dialkylamino, -SO3H or -CN, strong inhibitors for -glucosidases are especially for saccharases. In addition, these compounds are intestinal glucose absorption inhibitors.

Among optionally substituted radicals R1 are preferred understood such hydrocarbon radicals or heterocyclic radical in which a or more hydrogen atoms through halogen, hydroxy, alkoxy, aryloxy or through optionally substituted amino groups or by optionally substituted Aryl or heterocyclic radicals are replaced.

R1 in the meaning of a saturated aliphatic hydrocarbon structure preferably represents straight-chain or branched alkyl having 1 to 30, in particular 1 to 18 carbon atoms. Examples include methyl, ethyl, n-propyl, n-butyl, t-butyl, n-hexyl, n-octyl, octyl- (2), dodecyl, lauryl, cetyl and stearyl.

These alkyl radicals can be one or more, preferably 1 to 5, identical or carry different substituents.

Examples of substituents include: hydroxyl alkoxy with preferably 1 to 4 carbon atoms, in particular methoxy and thoxy: amino 'monoalkylamino and dialkylamino preferably having 1 to 4 carbon atoms per alkyl radical, in particular monomethylamino, monoethylamino, dimethylamino and diethylenamino; Mercapto, alkylthio with usually 1 to 4 carbon atoms, especially ethnicthio and xthylthio; Halogen, preferably fluorine, chlorine and bromine; Alkylcarbonyl with preferably 1 to 4 carbon atoms in the alkyl radical; Carboxy, nitro, cyan, the aidehyde function and the Su.fonsäuregrurpe.

R1 stands for an unsaturated hydrocarbon radical preferably for straight-chain or branched alkenyl radicals with 2 to 6 carbon atoms, the other substituents such as hydroxy, alkoxy with 1 to 4 carbon atoms, mercapto, Alkylthio with 1 to 4 carbon atoms, halogen, nitro, etc. can carry.

R1 has the meaning of a cyclic hydrocarbon radical preferably for a carbocyclic radical with preferably 3 to 7 carbon atoms, which can be substituted, with the substituents in the open-chain hydrocarbon radicals mentioned groups and atoms come into consideration.

R1 in the meaning of an aromatic radical preferably stands for aromatic radicals with 6 or 10 carbon atoms in the aryl part, in particular phenyl, which can be substituted.

The aryl radicals can be one or more, preferably 1 to 3, identical or carry different substituents.

Examples of substituents are: alkyl with 1 to 10 Carbon atoms, in turn, again for example by chlorine, May be substituted with nitro or cyano; optionally substituted alkenyl radicals having 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; Mcrcapto, 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 having 1 to 4 carbon atoms per alkyl group, preferably methyl and dimethylaminosulfonyl; Nitro, cyan or the aldehyde group; Alkylcarbonylamino preferably having 1 to 4 carbon atoms; Alkylcarbonyl with 1 to 4 carbon atoms, benzoyl, benzylcarbonyl and phenylethylcarbonyl, the last-mentioned alkyl, phenyl, benzyl and phenylethyl radicals for their part can again be substituted, for example by chlorine, nitro or hydroxyl, as well as residues derived from sugars.

R1 The heterocyclic radicals child preferred by heteroparaffinic, heteroaromatic or heteroolefinic 5- or 6-g, lower rings with preferably 1 to 3 identical or different heteroatoms derived. Stand as feteroatoms Oxygen, sulfur or nitrogen. These ring systems can have further substituents such as, for example, hydroxyl, amino or C1-C4-alkyl groups carry or can be attached to them Benzene nuclei or further preferably 6-membered heterocyclic rings of the above Kind of fused.

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

When R2 has the meaning of alkoxy, monoalkyl- or dialkylamino each alkyl radical preferably has 1 to 4 carbon atoms.

In the compounds of the formula I, R2 is preferably H, OH, S03H and CN. Particularly preferred are those compounds of the formula I in which R2 = H or OH.

It has also been found that N-alkylated derivatives of 5-amino-5-deoxy-D-glucose of the formula I are obtained when compounds of the formula II, in which R1 has the meaning given above, the Isopropylider.schutzgruppe removed by careful acid hydrolysis, it may be useful to capture the compounds of formula I in the form of adducts of sulfurous acid or hydrocyanic acid (R2 = SO3H or CN) from the The compounds of the formula I with R2 = OH are set free by treatment with bases, preferably alkaline earth metal hydroxides such as Ca (OH) 2 or Sr (OH) 2, but in particular Ba (OH) 2, bisulfite addition products. By reaction with hydrogen donor reducing agents such as NaBH4, the compounds of the formula I with R2 = OH are obtained from the compounds of the formula I with R2 = ht.

It has also been found that compounds of the formula I with R2 = H are obtained if. 1-deoxynojirimycin of the formula III with carbonyl compounds of the formula IV in which R3 and Rr have either H or the meaning given for R1 or are members of an alicyclic or heterocyclic ring, is reacted in the presence of a hydrogen donor reducing agent.

Compounds of the formula I with R2 = are also obtained when amides of the formula V are used in which R5 is either H or has the meaning given for Rs, or carbamates of the formula VI - if appropriate, derivatives of these compounds provided with hydroxyl protective groups - reduced to amines with an amide reducing agent.

Another method of making compounds of the formula I with Ra = H consists in l-deoxinojirimycin of the formula III with reactive Alkylating agents of the formula VII Z - R1 VII converts, where R1 has the meaning given above and Z is one customary in alkylating agents easily leaving group such as halide or eO-SO3H.

Due to their strong inhibitory effect on -glucosidases represent the new derivatives of 5-amine-5-deoxy-D-glucose valuable agents for influencing represent a multitude of metabolic processes and thus enrich the treasure trove of medicines.

The individual procedures for preparing the active ingredients according to the invention are illustrated below: If a compound of the formula II with R1 = ethyl is used as the starting material, the course of the reaction can be reproduced as follows: With 1-deoxynojirimycin of the formula III and formaldehyde as starting materials, the following equation results: With benzaldehyde as the carbonyl component, the reductive alkylation is carried out as follows: Assuming acid amides of the formula V, the reaction can be described as follows: Urethanes of the formula IV - optionally as derivatives provided with hydroxyl protective groups - can be reduced to N-methyl-l-deoxyncjirimycin with LiAlH4: For the reaction of 1-deoxynojirimycin with alkylating agents, the reaction with allyl bromide is given as an example: The compounds of the formula II used as starting materials are new. However, they can be prepared by processes known per se from compounds known from the literature. For example, the compound of the formula VIII known from the literature go out and react these with carbonyl compounds of the formula IV in the presence of a hydrogen donor reducing agent to give compounds of the formula II.

The compound VIII can also be used with reactive acid derivatives to convert acid amides or urethanes and these with an amide reducing agent reduce to amines.

This is illustrated by an example: The compound of the formula VIII can also be reacted with reactive alkylating agents of the formula VII Z-R1 VII to give compounds of the formula II.

Furthermore, in the abovementioned reactions, known partially blocked derivatives of the formula IX can be used instead of compound VIII.

and then remove the tritl and benzyl protective groups in a known manner, for example with sodium in liquid ammonia. To prepare compounds of the formula II, the compound of the formula X, which is also known from the literature, can also be used with amines of the formula XI R1-NH2 XI in the presence of a hydrogen donor reagent, for example in the presence of NaBHsCN.

This reaction usually results in a mixture of diastereomers. The undesired diastereomer is optionally at this stage or on a later stage the usual chromatographic methods or separated by fractional crystallization. Finally, the trityl and benzyl protecting group in known ways, for example with sodium, in liquid Split off ammonia.

The splitting off of the isopropylidene protective group from the compounds of formula II takes place in a moderately strongly acidic to weakly acidic solution, preferably in a pH range between 1 and 4, in aqueous solution or in one with water miscible, water-based organic solvents. As acids can be diluted Minor acids such as sulfuric acid or organic acids such as Acetic acid can be used. The reaction is preferred at atmospheric pressure and a temperature between room temperature and the boiling point of the solvent carried out.

To work up the reaction mixture, the acid is neutralized and separated off as a salt or with the aid of a basic ion exchanger. The isolation of the compounds of the formula I where R2 = OH is then carried out, if appropriate, by a gentle process Removal of the solvent, for example by lyophilization.

A preferred embodiment of the splitting off of the isopropylidene protective group of compounds of the formula II consists in that one of the aqueous or hydrous alcoholic Lcs'ng of the compounds of formula II with SC2 saturates and several days stored at temperatures between 200 and 500C. The compounds of formula I. then fall as bisulfite adducts (R2 = -SO3H) which crystallize well, from which the compounds of formula I can be obtained with the aid of e.g.

Allow aqueous Ba (OH) 2 to release.

The reduction of compounds of the formula I with R2 = OH to veso bonds Formyl I with R2 = H is made using alkali metal borohydrides, alkali metal cyanoborohydrides or also of dialkylaninobo ~ anes. The use of sodium borohydride is preferred in aqueous solution or in a water-miscible organic water-containing solution Solvent, such as dioxane, at room temperature or optionally increased ten? erature.

The starting product of the formula III is known and is either by catalytic hydrogenation from the najirimycin Zs.S.inoye obtainable by fermentation et al., Tetrahedron 23, 2125-2144 (1968) 70der by extraction from mulberry bark (see DT-OS 2 656 602) or obtained fully synthetically. After a new advantageous Process 1-Deoxynojirimycin can also be produced by using organisms of the family Bacillaceae in usual nutrient solutions at temperatures of about 15 to about 80 ° C. for about 1 to about 8 days with aeration in conventional fermentation vessels cultivated, the cells hurled off and the deoxy compounds from the culture broth or the cell extracts isolated by conventional purification processes. German patent application P 26 58 563.7 - (Le A 17 58717.

The carbonyl compounds of the formula IV are either known or can be manufactured using standard processes.

Typical examples are: 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-Hexana 1,2-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, Cyclopentane carbaldehyde, cyclopentane acetaldehyde, cyclohexane carbaldehyde; Benzaldehyde, o-, m- and p-toluene carbaldehydes and phenylacetaldehyde; substituted by hydroxy straight and branched chain alkyl aldehydes such as 5-hydroxypentanal, 2-hydroxy-3-methylbutanal, 2-hydroxy-2-methylpropanal, 4-hydroxybutanal, 2-hydroxypropanal and 8-hydroxyoctanal; straight 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 by amino and hydroxy disubstituted straight and branched-chain alkyl aldehydes such as 2-hydroxy-5-aminopentanal, 3-hydroxy-3-methyl-4-aminobutanal, 2-hydroxy-4-aminobutanal, 2-hydroxy-3-aminopropanal, 2-hydroxy-2-methyl-3-aminopropanal, 2-amino-3-hydroxyoctanal and mono-N-alkyl derivatives thereof.

Furthermore: methoxy-acetaldehyde, ethoxy-acetaldehyde, n-propoxy-acetaldehyde, 1-propoxy-acetaldehyde, n-butoxy-acetaldehyde, 1-butoxy-acetaldehyde, tert-butoxy-acetaldehyde, Cyclopropylmethyloxy-acetaldehyde, cyclopropoxyacetaldehyde, 2-methoxy-ethoxy-acetaldehyde, 2-ethoxy-ethoxy-acetaldehyde, 2-methoxy (1-methyl-ethoxy) -acetaldehyde, 2-ethoxy (1-methyl-ethoxy) -acetaldehyde. Phenyloxyacetaldehyde, 2-methoxy-2-methyl-acetaldehyde, 2-ethoxy-2-methylacetaldehyde, 2-n-propoxy-2-methyl-acetaldehyde, 2- (1-propoxy-) 2-methyl-acetaldehyde, 2- (n-butoxy) -2-methyl-acetaldehyde, 2- (1-butoxy) -2-methyl-acetaldehyde, 2- (tert-butoxy.) - 2-methylacetaldehyde, 2-cyclopropylmethyloxy-2-methyl-acetaldehyde, 2-Cyclopropyloxy-2-methyl-acetaldehyde, 2-methoxy-ethoxy-α-methyl-acetaldehyde, 2-ethoxy-ethoxy-α-methyl-acetaldehyde, 2-methoxy- (1-methyl-ethoxy) α-methyl-acetaldehyde, 2-methoxy-2,2-dimethyl-acetaldehyde, 2-ethoxy-2,2-dimethylacetaldehyde, 2-cyclopropylmethyloxy-acetaldehyde, 2 - # - butoxy-2,2-dimethyl-acetaldehyde, methylthio-acetaldehyde, ethylthio-acetaldehyde, n-propylthioacetaldehyde, 1-propylthio-acetaldehyde, cyclopropylmethylthio-acetaldehyde, 3-methoxy-propanal, 3-ethoxypropanal, 3-n- and 3-l-propcxy-propanal, 3-n-, 3-i- and 3-tert-butoxy-propanal, 3-cyclopropyloxy-propanal, 3-cyclopropylmethyloxy-propanal 3-methoxy-3- = ethyl-propanal, 3-ethoxy-3-methyl-propanal, 3-n- and 3-i-propoxy-3- = ethylpropanal, 3-n-, 3-i- and 3-tert-butoxy-3-ethyl-propanal, 2,3 and 4-methoxy-butanal, 2,3 and 4-ethoxy-butanal, 2-methylthio-propanal, 2-ethylthio-propanal, 3-methylthiopropanal, 3-ethylthio-propanal, 2-methylthio-butanal, 3-methylthio-butanal, 4-methylthio-butanal, Furfural, tetrahydrofurfural, thiophene, 5-bromothiophene, 5-methylfurfural, pyranocarbaldehyde.

Also mentioned as ketones are, 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-methoxyacetophenone, m-nitroacetophenone.

An example of a hydrogen donor reducing agent that can be used is formic acid use (Leuckart-Wallach reaction).

The formic acid is used in large excess.

With formaldehyde as the carbonyl component, the reaction can take place in aqueous Solution, with ketones and less reactive aldehydes in anhydrous formic acid. The reaction temperatures are between 100 and 2000C, if necessary, the reaction must be carried out in an autoclave.

The hydrogen donor reducing agent can also be catalytically excited Use hydrogen. The main catalyst used is Raney nickel, it however, noble metal catalysts can also be used. The response is in the generally at pressures between 80 and 150 atmospheres H2 pressure and temperatures performed between 70 and 1500C. Protic, polar solvents are used as solvents alcohols are particularly preferred.

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

The reaction is generally carried out at room temperature. It can, however, also be beneficial to briefly heat to reflux temperature.

The process is usually carried out in an inert solution medium. Although anhydrous aprotic solvents can be used (e.g. tetrahydrofuran, if the reducing agent is morpholinoborane) it usually becomes protic after all Solvent used.

A lower alkanol, for example, is suitable as such, or preferably Water or an aqueous lower alkanol (e.g. aqueous methanol or ethanol) or other aqueous solvent systems such as aqueous dimethylformamide, aqueous Hexamethylphosphoric triamide, aqueous tetrahydrofuran or aqueous ethylene glycol dimethyl ether.

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

The acid amides of the formula V and urethanes of the formula VI are in part known or can by known processes from compound III and reactive acid derivatives, which can also be formed in situ from the free acids can be obtained.

The reaction can be carried out in such a way that only the amino group of the compound III 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 initially formed, which are then formed by reaction with alcoholic ammonia or by Alkali alcoholate-catalyzed transesterification can be converted into the N-acylated compounds. The latter procedure is explained using an example: The reduction of the acid amides of the formula II to aminesLdevr formula I (R = H) can take place with complex metal hydrides or with hydrogen boride compounds. The use of NaBH4 in pyridine or also of sodium acyloxyborohydrides, especially that of sodium trifluoroacetoxyborohydride, is preferred. The reducing agents are usually used in excess. Sodium trifluoroacetoxyborohydride is generated in situ from sodium borohydride and trifluoroacetic acid. In addition to pyridine, polar aprotic solvents such as dioxane, tetraydrofuran or ELElyme can be used as solvents. The reaction is preferably carried out at the boiling point of the solvent. If necessary, LiAlH4 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 VII are known or known can be produced using common methods. Implementation with the connection III takes place in inert organic solvents at room to boiling temperature with or without the addition of an acid-binding agent.

The following new active ingredients may be mentioned in detail: N-methyl-1-nojirimcyn N-ethyl-1- "N-n-butyl-1-N-stearyl-1-N-i-propyl-1-N-benzyl-1-N-allyl-1-N- (β-methoxyethyl) -1-nojirimycin N- (β-Dimethylaminoethyl) -1-nojirimycin N- (o-Hydroxybenzyl) -1-nojirimiycin N-methyl-1-deoxynojirimycin N-Ethyl-1-N-n-Butyl-1- "N-Stearyl-1-N-i-Propyl-1-N-Benzyl-1-" N-Allyl-1- "N- (ß-methoxyethyl) -1-deoxynojirimycin N- (ß-dimethylaminoethyl) -1- "N- (o-hydroxybenzyl) -1- "N-methyl-1-deoxynojirimycin-1-sulfonic acid N-ethyl-1-" "N-n-butyl-1-" "N-stearyl-1- nn Ni-propyl-1- n N-benzyl-1- "" N-allyl-1- "" N- (ß-methoxyethyl) -1- "" N- (ß-dimethylaminoethyl) -1-deoxynojirimycin-1- sulfonic acid N- (o-hydroxybenzyl) -1- n N-methyl-1-cyano-deoxynojirimycin N-ethyl-1- n N-n-butyl-1- 1. n N-stearyl-1- n n N-i-propyl-1- "n 1 N-benzyl-1- 1 n N-allyl-1-" "N- (β-methoxyethyl-1-cyano-deoxynojirimycin N- (B-dimethylaminoethyl) -1-cyano-deoxynojirimycin N- (o-hydroxybenzyl-1-cyano-deoxynojirimycin.

The inhibitors according to the invention are suitable as therapeutics for the following indications: prediabetes, gastritis, constipation, tooth decay, atheroskelerosis and especially obesity, diabetes and hyperlipoprotemia.

To broaden the spectrum of activity, it may be advisable to use inhibitors for glycoside hydrolases, which complement each other in their effect, to combine, 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 it has already been mentioned. For example, it can be useful to use saccherase inhibitors according to the invention to combine with already known anylase inhibitors.

In some cases, combinations of the invention are also advantageous Inhibitors with known oral antidiabetics (ß-cytotropic sulfonylurea derivatives and / or blood sugar-active biguanides) as well as with blood lipid-reducing agents such as B. clofibrate, nicotinic acid, chelestyramine and others.

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

Pharmaceutical preparations can be a larger or smaller amount of the inhibitor, e.g. B. 0.1% to 99.5 5 ', in combination with a pharmaceutical Compatible non-toxic, inert carrier, the carrier being one or more distilled, semi-solid or liquid diluents, Fillers and / or non-toxic, inert and pharmaceutically acceptable formulation aid may contain. Such pharmaceutical preparations are preferably in the form of dosage units, a. H. physically-discrete, a certain amount of the Units containing inhibitors which are a fraction or a large amount of the dose which correspond to the induction of the desired inhibitory effect. the Dosage units can be 1, 2, 3, 4 or more single dozen or 1/2, 1/3 and 1/4 contained in a single dose. A single dose preferably contains a sufficient amount close active ingredient to when administered according to a predetermined dosage regimen egg or more dosage units to achieve the nested inhibitory effect, with a whole, a half, or a third or a quarter of the daily dose usually is given with all main and side meals during the day.

Other therapeutic agents also have a special who gene. Although the dosage and dosage regimen should be carefully considered in each case, using thorough professional judgment and taking age into account, the weight and condition of the patient, the type and severity of the disease, the dosage will usually range between about 1 to about 1 x 104 SIE / kg of body weight per day. In some cases you become a achieve sufficient therapeutic effect while cit a lower dose in other cases a larger dose will be required.

Crale application can be made using solid and liquid dosage units be carried out, such as. B. Powders, tablets, coated tablets, capsules, granules, suspensions, Solutions and the like.

Powder is made by crushing the substance into an appropriate size and mixing with a likewise 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, Is it desirable to have a non-metabolizable carbohydrate, such as

to use a cellulose derivative.

Sweeteners, flavor additives, preservatives, dispersants and coloring agents can also be included.

The capsules can be prepared by preparing the powder mixture described above and by filling already formed gelatine casings. The powder mix can be used before the filling process with lubricants, such. 3. silica gel, talc, magnesium stearate, Add calcium stearate or solid polyethylene glycol. The mixture can also be used with a disintegrator or solubilizer, such as. B.

Add agar-agar, calcium carbonate or sodium carbonate, if ingested the capsule to improve the accessibility of the inhibitor.

The tablets are made, for example, by manufacturing a powder mixture, coarse or fine-grained, and adding a lubricant and Disintegrators. This mixture is used to form tablets. Prepare a powder mix one before by mixing the substance, which has been comminuted in a suitable manner and supplements a diluent or other carrier as described above. If necessary, a binder is added: e.g. B. Carboxymethylcellulose, Alinate, Gelatin or polyvinylpyrrolidone, a solution retarder such as B. paraffin, an absorption accelerator, such as. B. a quaternary salt and / or a Adsorbents, such as B. bentonite, kaolin or calcium phosphate. The powder mixture can be granulated are together with a binder, such as. B. syrup, starch paste, fi zienschleim, or solutions made from cellulosic or polymeric materials. Then you pret the product through a coarse sieve. As an alternative to this, you can mix the powder through run a tablet machine and the resulting irregularly shaped Chop pieces down to grain size. So that the resulting grains do not get into the tablet-forming nozzles are stuck, you can add a conductive agent to them, such as 3. Stearic acid, stearate salt, talc or iron, mineral oil. This made slippery Mixture is then compressed into tablet form. The active ingredients can also be used with free-flying inert carriers are combined and brought directly into tablet form omitting the granulating or dismantling steps. You can get the product provided with a clear or opaque protective cover, e.g. B. a shellac cover, a coating of sugar or polymer substances and a polished shell of wax. Coloring agents can be added to these coatings so as to be between the different ones Dosage units can be differentiated.

The preparation forms to be administered orally, such as. B. Solutions, Syrup and nlixire can be prepared in dosage units so that a certain close preparation contains a certain amount of active ingredient. Syrup can be made like this be that the active ingredient in an aqueous solution, which suitable flavorings contains, is dissolved; Elixirs are made using non-toxic, alcoholic Carriers received. Suspensions can be obtained by dispersing the compound in represent 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 indicated on the capsule.

In addition, the dosage can be assured that the active ingredient is released with a delay, e.g. B. by adhering to 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, fruit juice, beer, chocolate and other key products, and canned goods, such as B. jam, with these products being therapeutically effective Amount A best given mode of one of the inhibitors according to the invention.

The inhibitors according to the invention also have the property on, in animals the ratio of the proportion of unwanted fat to the proportion of Desired low-fat meat (lean meat) in favor of lean meat to a great extent to influence. This is of particular importance for rearing and keeping of farm animals, e.g.

B. in pig fattening, but also of considerable importance for the Raising and keeping other farm animals and ornamental animals. Using the Inhibitors can continue to significantly streamline the feeding process Animals lead, in terms of time, quantity and quality. Since she is a Causing some delay in digestion will reduce the retention time of the nutrients prolonged in the digestive tract, thereby reducing the need for ad libitum feeding is made possible. Furthermore, when using the inventive In many cases, inhibitors result in considerable savings in valuable protein feed.

The active ingredients can thus be used in practically all areas of animal nutrition as a means of reducing fat deposits as well as saving on feed protein used earth.

The effectiveness of the active ingredients is largely independent of the species and sex of the animals. The ingredients have proven to be particularly valuable in animal species that generally lead to increased fat storage in certain periods of life tend.

As animals in which the inhibitors help reduce fat accumulation and / or can be used to save feed protein, be for example the following useful and d ornamental animals are called: Warm-blooded animals such as cattle, pigs, horses, sheep, Goats, cats, dogs, rabbits, fur animals, e.g. B.

Candles, chinchilles, other ornamental animals, e.g. B. guinea pigs and H2msttr, 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 the animals use to achieve the desired Effect is administered, can because of the beneficial properties of the active ingredients can be varied widely. It is preferably about 0.5 mg to 2.5 g, in particular 10 to 100 mg / kg feed per day. The duration of administration can range from a few hours or days up to several years. The right active ingredient as well the appropriate duration of administration are closely related to the feeding goal. They depend in particular on the type, age, gender and state of health and how the animals are kept and can easily be determined by any specialist.

The active compounds according to the invention are administered to animals in the customary manner Methods administered. The type of administration depends, in particular, on the type used Behavior and general condition of the animals. , So the administration can be once or several times a day, at regular or irregular intervals, orally. Oral administration is preferred in most cases for convenience in the rhythm of the food and / or drink intake of the animals, to be preferred.

The active ingredients can be administered as pure substances or in formulated form the formulated form both as a premix, i.e. in a mixture with non-toxic inert carriers of any kind, as well as part of a total ration in the form a supplementary feed or as a component part of a sole mixed feed understand is. The application of suitable preparations is also included about the drinking water.

If appropriate, the active ingredients can also be used together in formulated form with other nutrients and active ingredients, e.g. B. mineral salts, trace elements, vitamins, Proteins, energy sources (e.g. starch, sugar, fats), colorants and / or Flavors or other feed additives, such as. B.

Growth promoters, are administered in a suitable form. The active substances can be given to the animals before, during or after feeding.

Oral administration together with 2 = 3 with the food is recommended and / or drinking water, the active ingredients of the total amount or only, depending on requirements Parts of the feed and / or Trir.k.assers can be added.

The active ingredients can simply table by customary methods as pure substances, preferably finely divided Form or in formulated form as a mixture with measurable, non-toxic carriers, if appropriate also in the form of a premix or a feed concentrate, the feed and / or the Drinking water can be added.

The feed and / or drinking water can for example be according to the invention Active ingredients in a concentration of about 0.001 to 5.0%, in particular 0.02 to 2.0 Vo (weight) included. The optimal level of concentration of the active ingredient in the Feed and / or drinking water is ir.sbescrdere depending on the amount of feed and / or the drinking water consumption of the animals and can easily be determined by any expert will.

The type of feed and its composition are irrelevant here. All common, commercially available or special feed compositions can be used should be used, preferably the usual, necessary for a balanced diet Balance of energy and protein, including vitamins and minerals contain. The feed can, for example, consist of vegetable substances, B. oilcake meal, grain meal, grain by-product th, but also from hay, Fermentation fodder, beets and other fodder crops, made from animal materials, e.g. B. meat and fish products, bone meal, fats, vitamins, e.g. B. A, D, E, K and 3 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 can preferably be about 0.1 to 50%, in particular 0.5 to 5.0% (weight) e.g. N-methyl-1-deoxynojirimycin in addition to any edible carriers and / or mineral salts, e.g. carbonate feed lime and are used according to the common mixing methods.

Compound feeds preferably contain 0.001 to 5.0%, in particular 0.02 up to 2.0% (weight), for example, of N-methyl-1-deoxynojirimycin in addition to the usual Raw material components of a compound feed, e.g. B. Corn ears or by-products, Oil cake meal, animal protein, minerals, trace elements and vitamins. she can be prepared according to the usual mixing methods.

The active ingredients can preferably be used in premixes and compound feed optionally also by their surface covering suitable means, eg. B. with non-toxic waxes or gelatine protected from air, light and / or moisture will.

Example of the composition of a finished compound feed, for Poultry containing an active ingredient according to the invention: 200 g wheat, 340 g corn, 360.3 g soy meal, 60 g beef tallow, 15 g dicalcium phosphate, 10 g calcium carbonate, 4 g coded table salt, 7.5 g vitamin-mineral mixture and 3.2 g active ingredient premix result in 1 kg of feed after careful mixing.

The vitamin-mineral mixture consists of: 6000 I.U. vitamin A, 1000 I.U. vitamin D3, 10 mg vitamin E, 1 mg vitamin K3, 3 mg riboflavin, 2 mg pyridoxine, 20 mg vitamin B12, 5 mg calcium pantothenate, 30 mg nicotinic acid, 200 mg choline chloride, 200 mg Mn SO4 x H20, 140 mg Zn 504 x 7H2O, 100 mg Fe SO4 x 7H2O and 20 mg Cu SO4 x 5H2O.

The active ingredient premix contains z. B. 1-deoxynojirimycin in the desired amount, e.g. B. 1600 mg and an additional 1 g DL-methionine as well as so much soybean meal, that 3.2 g premix arise.

Example of the composition of a mixed pig feed that has a Active ingredient of formula I contains: 630 g of meal meal (made up of 200 g corn, ~ 50 g barley, 150 g oat and 130 g wheat meal), 80 g fish meal, 60 g soy meal, 58.8 g tapioca flour, 3a g brewer's yeast, 50% vitamin-mineral mixture for pigs (composition, e.g. as for chick feed) 30 g flax cake flour, 30 g corn gluten feed, 10 g soybean oil, 10 g sugar cane molasses and 2 g active ingredient remix (Composition e.g. for chick feed) result in 1 kg after careful mixing Lining.

The specified feed mixtures are preferably for rearing and b: twinned by chicks or pigs, but they can be the same or similar Composition can also be used for rearing and fattening other animals.

The inhibitors can be used individually or in any mixtures can be used with each other.

Saccharase inhibition test in vitro The saccharase inhibition test in vitro enables the enzyme-inhibiting activity of a substance to be determined by comparing the activity of the solubilized intestinal disacchartdase complex in the presence or in the absence (so-called 100% value) of the inhibitor. As a substrate, which determines the specificity of the inhibition test, serves included a practically glucose-frete sucrose (glucose <100 ppm); the determination of enzyme activity is based on the spectrophotometric determination of released glucose by means of Glucose dehydrogenae and Ni cotinamide adenine dinucleotide as a cofactor.

One sucrose inhibitor unit (SIE) is defined as that inhibitory activity, which in a defined test approach a predetermined saccharolytic activity reduced by one unit (saccharase unit = SE); the saccharase unit is defined as the enzyme activity which Under given conditions, a µxol sucrose per min splits and thus for Release of one µmol each of glucose, which will pass the test, and fructose, which is not recorded in the test leads.

The intestinal disaccharidase complex is derived from pig small intestine mucosa by tryptic digestion, precipitation from 66% ethanol at -200C, taking up the precipitate in 100 mM phosphate buffer, pH 7.0 and subsequent dialysis against the same buffer won.

10 µl of a sample solution, which is prepared in such a way that the extinction of the test batch at least 1056, but not more than 25% below that of the 100% value are, with 100 rl of a dilution of the intestinal disaccharidase complex in 0.1 M maleate buffer, pH 6.25, and preincubated for 10 min at 370C. The dilution of the disaccharidase complex is to an activity of 0.1 SE / ml to adjust.

The saccharolytic reaction is then stopped by adding 100 pl a 0.4 M solder of sucrose ("SERvA 35579") in 0.1 M maleate buffer, pH 6.25 started and after an incubation period of 20 min at 37 ° C by the Add 1 ml of glucose dehydrogenase reagent (1 vial of glucose dehydrogenase-mutarotase mixture lyophilized ("MERCK 14053") and 331.7 mg ß-nicotinamide adenine dinucleotide (free Acid, "BOEHRINGER" grade I) dissolved in 250 ml of 0.5 M Tris buffer, pH 7.6 ) stopped. To detect the glucose, it is incubated for 30 min at 370C and finally photomotorized at 340 nm against a reagent blank (with enzyme, but without sucrose).

The calculation of the inhibitory activity of inhibitors is made more difficult because that even minor changes in the test system, for example a minor 100% value varying from determination to determination, from one that can no longer be neglected Influence on the test result. You get around these difficulties by working with each provision runs a standard with; a saccharase inhibitor is used as the standard of the formula C25H43O18N, which has a specific inhibitory activity of 77 700 SIE / g and when used in amounts of 10 to 20 ng in the test to an inhibition specified above Order of magnitude leads. Knowing the difference in absorbance at 340 nm from 100% value and the approach inhibited by the standard can be derived from the extinction difference of 100% value and the approach inhibited by the sample solution, taking into account the used Calculate the amount of inhibitor in a known way, its specific inhibitory activity, expressed in sucrose inhibitor units per gram (SIE / g).

Specific saccharase inhibitory activity in vitro 1-deoxynojirinycin 465,000 SIE / g N-methyl-1-deoxynojirimycin 2,330,000 SIE / g Manufacturing example 3.2 g of 1-deoxynojirimycin are added to 4 ml of 98% formic acid while cooling with ice and 2 ml of 30% aqueous formaldehyde. It is then refluxed for 8 hours heated. After cooling, the reaction mixture is diluted with acetone. It's falling a resinous precipitate. The acetone solution is decanted off and washed the resin several times with acetone. The residue is then distilled in Dissolved water and the solution by adding basic ion exchanger in the # OH-Form (Amberlite JRA 410) freed from formic acid. The ion exchanger will filtered off and the aqueous solution brought to dryness under reduced pressure. 3.0 g of resinous N-methyl-1-deoxynojirimycin remain. The connection can can be further purified by chromatography on cellulose. As a superplasticizer hydrous butanol is used.

For characterization, the compound is used with acetic anhydride / pyridine 1: 1 at room temperature into the peracetylated compound, N-methyl-2,3,4,6-tetra-O-acetyl-1-deoxynojirirnycin, convicted. A proton resonance spectrum in CDCl3 measured: Between Ü = 2.0 and 2.1 ppm there are 4 singlets for together 12 protons corresponding to the methyl groups of the O-acetyl groups (CH3-O-C-). the methyl group bonded to N (CH3-N () is found as a singlet at O = 2.45 ppm.

Between C = 2.1 and 2.5 ppm absorb as poorly resolved multiplets two protons on a carbon atom bonded to nitrogen (-C-N '). Another one of those Proton appears as a doublet of a doublet (J1 = 11 Hz; J2 = 4 Hz) at # = 3.18 ppm. At Ö = 4.16 and # = 4.22 ppm a methylene group absorbs (-CH2-O-C-CH3) as an AB system. The remaining three protons (-C-O-C-CH3) are found as a multiplet HO between # -4.9 and 5.2 ppm.

Claims (12)

Claims 1. Compounds of the formula I in which R1 is an optionally substituted straight-chain, branched, cyclic, saturated or unsaturated aliphatic hydrocarbon radical or an optionally substituted aromatic or heterocyclic radical and R2 is H, OH, alkoxy, amino, mono- and dialkylamino, -SO3H or -CN. 2. Compounds according to claim 1, in which R1 is an optionally substituted alkyl radical with 1 to 30, preferably 1 to 18 carbon atoms, one optionally substituted alkenyl radical with 2 to 6 carbon atoms, one optionally substituted carbocyclic radical with 3 to 7 carbon atoms, an optionally substituted phenyl, Naphthyl or benzyl radical or an optionally substituted 5- or 6-membered one heterocyclic radical with preferably 1 to 3 identical or different Heteroatoms and R2 denotes H, OH, alkoxy with 1 to 4 carbon atoms, mono- and dialkylamino with 1 denotes up to 4 carbon atoms per alkyl radical, -S03H or -CN. 3. Compounds according to claims 1 and 2, in which R2 is H, -OH or -S03H. 4. N-methyl-1-deoxynojirimycin. 5. Process for the preparation of compounds of the formula I. in which R1 and R2 have the meaning given above, characterized in that compounds of the formula II in which R1 has the meaning given above, is subjected to acid hydrolysis to remove the isopropylidene protective group and the compounds of the formula II with R3 = -OH as such or optionally after reaction with sulfurous acid, hydrocyanic acid, alcohols, mono- or dialkylamines or reaction with hydrogen Donor reducing agents isolated in the form of their derivatives. 6. A process for the preparation of compounds of the formula I in which R1 has the meaning given above and R2 is hydrogen, characterized in that 1-deoxynojirimycin of the formula III a) with carbonyl compounds of the formula IV in which R3, R4 are either H or have the meaning given above for Ra or are members of an alicyclic or heterocyclic ring, are reacted in the presence of a hydrogen donor reducing agent or b) with reactive alkylating agents of the formula VII Z-R1 VII in R1 has the meaning given above and Z represents a readily leaving group customary in alkylating agents, converts it and works up the batches in the customary manner. 7. Medicinal product characterized by a content of a compound according to claims 1 to 3 and optionally pharmaceutically suitable additives. 8. A method for producing a medicament according to claim 7, characterized in that a compound according to claim 1 is optionally formulated using pharmaceutically acceptable additives. 9. Method for influencing the carbohydrate metabolism, thereby characterized in that a compound according to claims 1 to 3 people or Applied to animals. 10. Use of a compound according to claims 1 to 3 in the treatment of obesity, diabetes and / or hyperlipemia. 11. Animal feed, characterized by a content of a compound according to claims 1 to 3. 12. Use of a compound according to claims 1 to 3 in the Animal nutrition.