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EP0000947B1 - Nouveaux dérivés de 3,4,5-trihydroxy piperidine, procédé pour leur préparation et médicaments et aliments les contenant - Google Patents

Nouveaux dérivés de 3,4,5-trihydroxy piperidine, procédé pour leur préparation et médicaments et aliments les contenant Download PDF

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Publication number
EP0000947B1
EP0000947B1 EP78100750A EP78100750A EP0000947B1 EP 0000947 B1 EP0000947 B1 EP 0000947B1 EP 78100750 A EP78100750 A EP 78100750A EP 78100750 A EP78100750 A EP 78100750A EP 0000947 B1 EP0000947 B1 EP 0000947B1
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EP
European Patent Office
Prior art keywords
formula
compounds
deoxynojirimycin
denotes
methyl
Prior art date
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EP78100750A
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German (de)
English (en)
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EP0000947B2 (fr
EP0000947A1 (fr
Inventor
Bodo Dr. Junge
Hans Peter Dr. Krause
Lutz Dr. Müller
Walter Dr. Puls
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Bayer AG
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Bayer AG
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Priority claimed from DE19772738717 external-priority patent/DE2738717A1/de
Priority claimed from DE19772758025 external-priority patent/DE2758025A1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/132—Heterocyclic compounds containing only one nitrogen as hetero atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/30—Feeding-stuffs specially adapted for particular animals for swines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings

Definitions

  • 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.
  • 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.
  • pharmaceutically acceptable salts of the compounds of the formula I such as chlorides, sulfates, acetates, carbonates, oxalates, etc.
  • 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.
  • 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, dimethyl
  • heterocyclic substituents of the alkyl radicals are: phthalimido, pyridyl, thienyl, furyl, isoxazolyl, thiazolyl, glucopyranosyl, ribofuranosyl, oxiranyl and the like.
  • 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.
  • aromatic radicals such as naphthyl and in particular phenyl which have one or more, preferably 1 to 3 identical or
  • 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 ".
  • 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
  • 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.
  • heterocyclic radicals are derived, for example, from furan, pyran, pyrrolidine, piperidine, pyrazole, imidazole, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyridine, benzimidazole, quinoline, isoquinoline or purine.
  • 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).
  • R 3 very particularly preferably represents ⁇ CH 2 OH.
  • the new compounds of the formula I are potent inhibitors for ⁇ -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.
  • R 1 is an aliphatic or aromatic radical substituted by an acylamino, sulfonylamino, alkoxycarbonylamino, ureido or a thiourido group
  • 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.
  • Urethanes of the formula VIII - optionally as derivatives provided with hydroxyl protecting groups - can be reduced to n-methyl-1-deoxynojirimycin with LiAIH 4 :
  • 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:
  • the compound of formula X can also be used with reactive alkylating agents of formula IX convert to compounds of formula II.
  • 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.
  • 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.
  • the acid is neutralized and separated as a salt or with the aid of a basic ion exchanger.
  • 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.
  • 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 .
  • 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.
  • a polar solvent for example an alcohol, dimethyl sulfozide or in excess amine.
  • 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.
  • formic acid can be used as the hydrogen donor reducing agent (Leuckart-Wallach reaction).
  • the formic acid is used in large excess.
  • 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.
  • 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.
  • 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:
  • 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.
  • 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.
  • inhibitors according to the invention are suitable as therapeutics for the following indications:
  • Prediabetes Prediabetes, gastritis, constipation, caries, infections of the gastrointestinal tract, meteorism, flatulence, hypertension, atheroskelerosis and especially obesity, diabetes and hyperlipoprotemia.
  • 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.
  • combinations of the inhibitors according to the invention with known oral antidiabetics ⁇ -cytotropic sulfonylurea derivatives and / or blood sugar-effective biguanides
  • 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.
  • compositions 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.
  • 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.
  • 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.
  • 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.
  • a suitable carbohydrate such as. B. starch, lactose, sucrose or glucose
  • a non-metabolizable carbohydrate such as. B. to use a cellulose derivative.
  • Sweeteners 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.
  • 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
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • mice, monkeys, etc. 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.
  • 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.
  • suitable preparations via drinking water is also included.
  • 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.
  • B. mineral salts e.g. 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ -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 spiez er magnitude.
  • the extinction difference of 100% value and the test solution inhibited approach can take into account its specific inhibitory activity in a known manner calculate, expressed in saccharase inhibitor units per gram (SIE / g).
  • 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.
  • 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.
  • a strongly basic ion exchanger in the OH ⁇ form (Amberlite IRA 400 or Dowex 1 x 2) is filled.
  • molecular sieve 3A was added to the reaction mixture to bind the water of reaction.
  • the substance is a mixture of two diastereomeric compounds.
  • Mass spectrum The mass spectrum was measured from the compound peracetylated in pyridine / acetic anhydride.
  • 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.
  • the substance is a mixture of two diastereomeric compounds.
  • the compound was obtained from the above phthalimido compound by hydrazinolysis in methanol.
  • the compound was not purified by chromatography on a basic exchanger, but by recrystallization from methanol / water.
  • Rf value 0.7 (plates and eluent as specified for the above compound).
  • the compound was chromatographed on basic chromatography as indicated above, but finally eluting with 1% acetic acid.
  • Rf value 0.7 (plates and eluent as indicated above). Again, the compound was eluted from the basic exchanger with 1% acetic acid.
  • nojirimycin bisulfite adduct 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.
  • the compound was prepared from 1-acetamidomethyl-1-deoxynojirimycin in analogy to Example 6.
  • the compound was prepared from 1-aminomethyl-1-deoxynojirimycin and benzoyl chloride according to the procedure of Example 14.
  • the compound was prepared from 1-benzoylaminomethyl-1-deoxynojirimycin in analogy to Example 6.
  • the compound was prepared from 1-tosylamidomethyl-1-deoxynojirimycin according to the procedure of Example 6.
  • 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.
  • the compound was obtained from 1-acetamidomethyl-1-deoxynojirimycin by reductive alkylation with nonylaldehyde and NaCNBHg in methanol in analogy to Example 3.
  • 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.
  • 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.
  • 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 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.

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Claims (10)

1. Des composés de formule:
Figure imgb0180
dans laquelle:
Ri désigne H ou un reste d'hydrocarbure aliphatique saturé ou insaturé à chaîne droite, ramifié ou cyclique éventuellement substitué,
R2 représente:
Figure imgb0181
Figure imgb0182
Figure imgb0183
R3 représente H ou un reste d'hydrocarbure aliphatique saturé ou insaturé à chaîne droite, ramifié ou cyclique éventuellement substitué,
R' et R" représentent de l'hydrogène, un reste d'hydrocarbure aliphatique saturé ou insaturé à chaîne droite, ramifié ou cyclique éventuellement substituée ou un reste aromatique ou hétérocyclique éventuellement substitué, et R1 n'est pas un atome d'hydrogène lorsque
a) R2 est de l'hydrogène ou un groupe OH et R3 est un groupe CH2OH,
b) R2 est de l'hydrogène, un groupe OH, SO3H, CN ou CH2NH2 et R3 est de l'hydrogène, et
c) R2 est un groupe OH et R3 est un groupe CH2NH2,

et leurs sels et bioprécurseurs acceptables du point de vue pharmacetique.
2. Composés suivant la revendication 1, de formule:
Figure imgb0184
dans laquelle:
R1 est H ou un reste d'hydrocarbure aliphatique saturé ou insaturé à chaîne droite, ramifié ou cyclique éventuellement substitué, et
R2 désigne:
Figure imgb0185
Figure imgb0186
Figure imgb0187
R' et R" étant de l'hydrogène, un reste d'hydrocarbure aliphatique saturé ou insaturé à chaîne droite, ramifié ou cyclique éventuellement substitué ou un reste aromatique ou hétérocyclique éventuellement substitué et R, ne représente pas de l'hydrogène lorsque R2 est de l'hydrogène ou un groupe hydroxy.
3. Composés suivant la revendication 1, dans lesquels R2 représente
Figure imgb0188
Figure imgb0189
Figure imgb0190
4. La N-(n-heptyl)-1-déoxynojirimycine.
5. La N-méthyle-1-déoxynojirimycine.
6. Procédé de production de composés suivant la revendication 1, caractérisé en ce qu'on soumet les composés de formule II ou lla dans laquelle R1 et R3 ont la définition donnée ci-dessus:
Figure imgb0191
à l'hydrolyse acide pour éliminer les groupes protecteurs et on isole tels quels les composés de formule I dans laquelle R1 est un groupe -OH ou on les transforme, les cas échéant, en d'autres composés de formule I.
7. Procédé de production de composés suivant la revendication 1, caractérisé en ce qu'on fait réagir des composés de formule V:
Figure imgb0192
a) avec des composés carbonyliques de formule VI:
Figure imgb0193
dans laquelle:
Re, R7 ou bien désignent de l'hydrogène, ou bien ont la définition donnée ci-dessus pour R, ou bien sont des chaînons d'un noyau alicyclique ou hétérocyclique, en présence d'un agent réducteur donneur d'hydrogène, ou
b) avec des agents alkylants réactifs de formule IX:
Figure imgb0194
dans laquelle R1 a la définition donnée ci-dessus pour le terme alkyle et Z représente un groupe aisément partant classique pour des agents alkylants, et on traite les produits d'une manière classique.
8. Médicament, caractérisé en ce qu'il contient un composé suivant les revendications 1 à 5 et 'le cas échéant, des additifs acceptables du point de vue pharmaceutique.
9. Composés suivant les revendications 1 à 5, destinés à être utilisés dans le traitement de l'adiposité, du diabète et/ou de l'hyperlipidémie.
10. Aliment pour le bétail, caractérisé en ce qu'il contient un composé suivant les revendications 1 à 5.
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NL960027I2 (nl) 1997-07-01
IL55423A (en) 1982-09-30
NL960027I1 (nl) 1997-01-06
HU182449B (en) 1984-01-30
IE47070B1 (en) 1983-12-14
EP0000947B2 (fr) 1984-10-10
AU3930478A (en) 1980-03-06
EP0000947A1 (fr) 1979-03-07
IT7827067A0 (it) 1978-08-25
NO154918B (no) 1986-10-06
JPS6231703B2 (fr) 1987-07-09
IT1111197B (it) 1986-01-13
US4639436A (en) 1987-01-27
US4260622A (en) 1981-04-07
PT68474A (de) 1978-09-01
DK377678A (da) 1979-02-28
ES472838A1 (es) 1979-03-16
AT373239B (de) 1983-12-27
DE2860330D1 (en) 1981-03-12
LU90211I2 (fr) 1998-04-08
FI782607A7 (fi) 1979-02-28
NO782713L (no) 1979-02-28
NO154918C (no) 1987-01-14
FI72715C (fi) 1987-07-10
AU520686B2 (en) 1982-02-18
GR73065B (fr) 1984-01-30
DK152753B (da) 1988-05-09
FI72715B (fi) 1987-03-31
IL55423A0 (en) 1978-10-31
ATA621778A (de) 1983-05-15
IE781716L (en) 1979-02-27
CA1123437A (fr) 1982-05-11
JPS5446786A (en) 1979-04-12
AU3921478A (en) 1980-02-28
DK152753C (da) 1988-10-31

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