EP0000947A1 - 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 PDFInfo
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- EP0000947A1 EP0000947A1 EP78100750A EP78100750A EP0000947A1 EP 0000947 A1 EP0000947 A1 EP 0000947A1 EP 78100750 A EP78100750 A EP 78100750A EP 78100750 A EP78100750 A EP 78100750A EP 0000947 A1 EP0000947 A1 EP 0000947A1
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- Prior art keywords
- formula
- compounds
- deoxynojirimycin
- optionally substituted
- methyl
- Prior art date
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- 0 CC(C(*)C1OC(C)(C)CI)OC1O Chemical compound CC(C(*)C1OC(C)(C)CI)OC1O 0.000 description 7
- CWTYZGJUXMEDCJ-UHFFFAOYSA-N CC(C(C(C1O)O)O)NC1C#N Chemical compound CC(C(C(C1O)O)O)NC1C#N CWTYZGJUXMEDCJ-UHFFFAOYSA-N 0.000 description 1
- KCKFLUZFXYWZHS-NSCUHMNNSA-N CC(C(C1O)O)N(C/C=C/Cc(cc2)ccc2Cl)CC1O Chemical compound CC(C(C1O)O)N(C/C=C/Cc(cc2)ccc2Cl)CC1O KCKFLUZFXYWZHS-NSCUHMNNSA-N 0.000 description 1
- KLRDKDXWWCBMCJ-UHFFFAOYSA-N CC(C(C1O)O)NC(C)C1O Chemical compound CC(C(C1O)O)NC(C)C1O KLRDKDXWWCBMCJ-UHFFFAOYSA-N 0.000 description 1
- ARIAWFPKUVJPLU-MXFXWPKCSA-N CC(C([C@@H]1O)O)N(C)CC1O Chemical compound CC(C([C@@H]1O)O)N(C)CC1O ARIAWFPKUVJPLU-MXFXWPKCSA-N 0.000 description 1
- CWUFOXGNEQIIGX-UHFFFAOYSA-N CC(C=C1)=CCC1=C Chemical compound CC(C=C1)=CCC1=C CWUFOXGNEQIIGX-UHFFFAOYSA-N 0.000 description 1
Classifications
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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 new derivatives of 3,4,5-trihydroxypiperidine, several processes for their preparation and their use as medicaments, in particular as agents against diabetes, hyperlipemia and obesity, and in animal nutrition to influence the meat / fat ratio in favor of the meat content.
- the invention additionally also relates to pharmaceutically annehr l - bare salts of the compounds of formulas (Ia) and (Ib) such as chlorides, sulfates, acetates, carbonates, oxalates, etc., and organic precursor, said organic precursor compounds are understood which Structure differs from the active compound, which, however, is 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 radical with 2 to 18, in particular 3 to 10, carbon atoms, a mono-, bi- or tricyclic radical 3 to 10 carbon atoms, which can 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, the 1, 2, 3 or 4 heteroatoms, in particular can contain N, 0, S and to which a benzene ring or a further 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 C 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 may be substituted, heterocyclic carboxylic acids which are derived from 5- or 6-membered heterocycles which contain 1 to 3 heteroatoms (N, O, S) and in the heterocyclic ring by C 1 -C 4 alkyl, chlorine, bromine, amino may be substituted; Amino, monoalkylamino and dialkylamino with preferably 1 to 4 carbon atoms per alkyl radical, in particular monomethylamino, mono
- -Alkyl, C 1 -C 4 -alkoxy, nitro and / or amino may be substituted, heterocyclic Carboxylic acids derived from 5- or 6-membered heterocycles which contain 1 to 3 heteroatoms (N, O, S) and which can be substituted in the heterocyclic ring by C 1 -C 4 alkyl, chlorine, bromine, amino is;
- alkylthio with preferably 1 to 4 carbon atoms, especially methylthio 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.
- 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 especially phenyl which have one or more, preferably 1 to 3 identical or different substituents from the series -OH, -NH s , C 1 -C 4 alkyl-NH -, C 1 -C 4 -dialkyl-N-, C 1 -C 4 -alkoxy, NO 2 , -CN, -COOH, -COO-alkyl (C 1 -C 4 ), C 1 -C 6 -alkyl, Halogen, especially fluorine, chlorine or bromine, C 1 -C 4 alkylthio, -SH, C 1 -C 4 alkylsulfonyl, -SO 3 H, -SO 2 -NH 2 , -SOp-NH-alkyl (C 1 - C 4 ) can wear.
- aromatic radicals such as naphthyl and especially phenyl which have one or more, preferably 1 to 3 identical or different substituents from
- 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 aryl radicals can carry one or more, preferably 1 to 3 identical or different substituents.
- the heterocyclic radicals R 1 are preferably derived from heteroparaffinic, heteroaromatic or heteroolefinic 5- or 6-membered rings with preferably 1 to 3 identical or different heteroatoms.
- the heteroatoms are oxygen, sulfur or nitrogen.
- These ring systems can carry further substituents such as, for example, hydroxyl, amino or C 1 -C 4 alkyl groups, or benzene nuclei or further preferably 6-membered heterocyclic rings of the type mentioned can be fused to them.
- 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 , -CH 2 NH- (C 1 -C 14 alkyl), -CH 2 -NH-SO 2 - (C 1 to C 14 ) alkyl
- R 2 very particularly preferably represents -H, -S0 3 H, -CN
- R is preferably 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 a-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 by 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.
- 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.
- 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 converts in a manner known per se [S.INOUYE et.al., Tetrahedron 23, 2125-2144j via the ketone and the oxime into the amine, with a mixture of gluco- and ido compound generally forming from which the desired gluco compound XVIII can be isolated by the usual chromatographic methods.
- 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 off 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, and storing at temperatures between 20 ° and 50 ° C. for several days.
- the compounds of formula XXI are obtained by comparison compounds of the formula r wherein Rg 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, e.g. B. an alcohol, dimethyl sulfocide or in excess amine.
- a polar solvent e.g. B. an alcohol, dimethyl sulfocide or in excess amine.
- 1-deoxynojirimycin can also be prepared by cultivating organisms of the Bacillaceae family in conventional nutrient solutions at temperatures of about 15 to about 80 ° C. for about 1 to about 8 days with aeration in conventional fermentation vessels, spinning off the cells and the Dcsoxyharm isolated from the culture broth or the cell extracts by conventional purification methods [German Patent Application P 26 58 563.7 - (Le A 17 58717.
- 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.
- 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.
- water or an aqueous lower alkanol e.g. aqueous methanol or ethanol
- other aqueous solvent systems such as e.g. 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 are converted into the N-acylated compounds by alkali metal alkoxide-catalyzed transesterification.
- 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.
- LiAlH can also be used for the reduction, preferably if 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.
- 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, for example, B. clofibrate, nicotinic acid, cholestyramine and others.
- the compounds can be used without dilution, e.g. B. 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, e.g. B. 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 diluent can contain agents, fillers and / or non-toxic, inert and pharmaceutically acceptable formulation auxiliaries.
- 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 produce the desired inhibitory effect.
- the dosage units can be 1, 2, Contain 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 in any case be carefully weighed, using thorough professional judgment and taking into account the age, weight and condition of the patient, the nature and severity of the disease, the dosage will usually range between about 1 to about 1 x 10 4 SIE / kg of body weight per day. In some cases a sufficient therapeutic effect will be achieved 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, such as. B. powders, tablets, dragees, capsules, granules, suspensions, solutions and the like.
- Powder is produced by comminuting the substance into a suitable size and mixing it with a comminuted pharmaceutical carrier.
- a comminuted pharmaceutical carrier 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 festea 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. B. carobxymethyl cellulose, alginates, gelatin or polyvinylpyrrolidone, a solution retarder, such as. B. paraffin, a resorption accelerator, such as. B. a quaternary salt and / or Adsorbents, such as. B.
- a binder e.g. B. carobxymethyl cellulose, alginates, gelatin or polyvinylpyrrolidone
- a solution retarder such as. B. paraffin
- a resorption accelerator such as. B. a quaternary salt
- Adsorbents such as. B
- the powder mixture can be granulated together with a binder, such as. B. syrup, starch paste, acacia mucus, or solutions made of cellulose or polymer materials. Then you press the product through a coarse sieve. As an alternative to this, the powder mixture can be run through a tablet machine and the resulting irregularly shaped pieces crushed down to grain size. So that the resulting grains do not get stuck in the tray-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. B. syrup, starch paste, acacia mucus, or solutions made of cellulose or polymer materials. Then you press the product through a coarse sieve.
- the powder mixture can be run through a tablet machine and the resulting irregularly shaped pieces crushed down to grain size. So that the resulting grains do not get stuck in the tray-forming nozzles,
- the active compounds can also be combined with free-flowing inert carriers and brought directly into tablet form, with the omission of 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, fruit juice, beer, chocolate and other confectionery, and canned goods such as. B. jam, a therapeutically effective amount of at least one of the inhibitors according to the invention was added to these products.
- the foods 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 metabolic disorder-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 use 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 cause a certain "delay in digestion, the dwelling time of the nutrients in the digestive tract is lengthened, which enables ad libitum feeding with less effort. Furthermore, in many cases the use of the inhibitors according to the invention results in a considerable saving of valuable protein feed .
- 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.
- Warm-blooded animals such as cattle, pigs, horses, sheep, goats, cats, dogs, rabbits, fur animals , e.g. B. mink, chinchi
- 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 administration can range from a few hours or days 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 method 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 expediency, oral administration is preferred in most cases, particularly in the rhythm of the animals' food and / or drink intake.
- the active substances can be administered as pure substances or in formulated form, the formulated form being understood both as a Prexix, i.e. in a mixture with non-toxic inert carriers of any kind, and as part of an overall ration in the form of a supplementary feed or as a component of the mixture of a sole compound feed is.
- a Prexix i.e. in a mixture with non-toxic inert carriers of any kind
- suitable preparations via drinking water is also included.
- the active ingredients can optionally in formulated form together with other nutrients and active ingredients, 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.
- 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 ingredients can be mixed by pure methods, preferably in finely divided form, by conventional methods Form or in formulated orculated form in a mixture with ePbaren, non-toxic carriers, optionally also in the form of a premix or a feed concentrate, the feed and / or the drinking water are added.
- the feed and / or drinking water can, for example, contain the active substances according to the invention in a concentration of approximately 0.001 to 5.0%, in particular 0.02 to 2.0% (weight).
- the optimum level of the 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 easily be determined by any person skilled in the art.
- 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. B. oilcake meal, grain meal, grain by-products, but also from hay, fermented feed, beets and other fodder plants, from animal substances, eg. 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 can preferably be about 0.1 to 50 t, in particular 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.
- Compound feed 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 compound 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 compound 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, protected from air, light and / or moisture with non-toxic waxes or gelatin.
- 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 saccherase 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 (aog. 100% value) of the inhibitor.
- the substrate which determines the specificity of the inhibition test, is used a practically glucose-free sucrose (glucose ⁇ 100 ppm); the enzyme activity determination is based on the spectrophotometric determination of released glucose using glucose dehydrogenaea and nicotinamide adenine dinucleotide as cofactor.
- the inteatinal disaccharidase complex is obtained from pig intestinal mucosa by tryptic digestion, precipitation from 66% ethanol at -20 ° C., taking up the precipitatea in 100 mM phosphate buffer, pH 7.0 and final dialysis against the same buffer.
- 10 ul of a sample solution which is prepared so that the absorbance of the test batch is at least 10%, but not more than 25% below that of the 100% value, is diluted with 100 ul of the intestinal disaccharidase complex in 0.1 M Maleinate buffer, pH 6.25, added and pre-incubated for 10 at 37 ° C.
- the dilution of the disaccheridase 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 Add 1 ml glucose dehydrogenase reagent (1 vial of glucose dehydrogenase mutarotase mixture lyophilized (“MERCK 14053”) and 331.7 mg ⁇ -nicotinamide adenine dinucleoitide (free acid, "BOEHRTNGER” Reinhettsgrad I)) in 250 ml 0.5 M Tris buffer, pH 7.6 dissolved). To detect 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 used is a baccharase inhibitor of the formula C 25 H 43 O 18 N, which has a specific inhibitory activity of 77 700 SIU / g and, when used in quantities of 10 to 20 ng, leads to a test of the magnitude specified above in the test.
- the specificity of the inhibitory activity can be calculated from the extinction difference of 100% value and the approach inhibited by the sample solution, taking into account the amount of inhibitor used, expressed in saccharase inhibitor units per gram (SIE / g). Manufacturing examples
- 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 strongly basic ion exchanger in the OH ⁇ form (Amberlite IRA 400 or Dowex 1 x 2) is filled.
- strongly basic ion exchanger in the OH ⁇ form Amberlite IRA 400 or Dowex 1 x 2
- molecular sieve 3A was added to the reaction mixture to bind the water of reaction.
- the substance is a mixture of two diastereomeric compounds.
- the aldehyde required for the reaction was obtained from 0-acetylated 1-thioglucose and chloroacetaldehyde.
- the acetyl groups were split off in the end product by transesterification with catalytic amounts of NaOCH 5 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. FP: 187-188 ° C.
- Rf value 0.85 (on ready-made DC plates from Merck Kieselgel 60; eluent: ethyl acetate / methanol / H 2 O / 25% ammonia 100: 60: 40: 2).
- Rf value of 1-deoxynojirimycin 0.3.
- Rf value 0.7 (plates and eluent as specified for the above compound).
- the compound was chromatographed on basic chromatography as above, but finally eluting 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) 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; FP: 152-153 ° C. After recrystallization from methanol and a little water, the substance melts at 155-156 ° C.
- the compound was obtained in analogy to Example 3 by reductive methylation of 1-cyano-1-deoxynojirimycin with 35% aqueous formaldehyde solution and NaCNBH, in methanol.
- the residue was recrystallized first from a little water and then from water / methanol.
- 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.
- FP 216 ° C (from methanol).
- the compound was prepared from 1-benzoylaminomethyl-1-deoxynojirimycin in analogy to Example 6.
- FP 135-136 ° C (from butanol).
- the compound was prepared from 1-tosylamidomethyl-1-deoxynojirimycin according to the procedure of Example 6. FP: 218-219 ° C (from H 2 O).
- N- (1-deoxynojirimycin-yl) acetic acid 5 g were refluxed in 50 ml of dimethylformamide for 1/2 hour. The solvent was removed in a high vacuum on a rotary evaporator and the oil which remained was crystallized from 25 ml of ethanol. Yield of N- (1-deoxynojirimycin-yl) -acetic acid-6-lactone: 3.5 g of melting point 157-159 ° C.
- the methanolic solution was again concentrated and the residue was applied with water to a column filled with a strongly acidic exchanger in the H ⁇ form. It was eluted first with water and then with 0.25% ammonia. The fractions containing 1-hydroxymethyl-1-deoxy-nojirimycin 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 NaCNBH, in methanol in analogy to Example 3.
- This crude product is dissolved in 165 ml 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 is taken up in water / chloroform and Cut. The aqueous phase is concentrated.
- 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.
- reaction product was then eluted from the column with 0.3N NH 3 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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Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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DE2738717 | 1977-08-27 | ||
DE19772738717 DE2738717A1 (de) | 1977-08-27 | 1977-08-27 | N-alkylierte derivate der 5-amino- 5-deoxy-d-glucose, verfahren zu ihrer herstellung und ihre verwendung |
DE19772758025 DE2758025A1 (de) | 1977-12-24 | 1977-12-24 | Neue derivate von 3,4,5-trihydroxypiperidin, verfahren zu ihrer herstellung und ihre verwendung |
DE2758025 | 1977-12-24 |
Publications (3)
Publication Number | Publication Date |
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EP0000947A1 true EP0000947A1 (fr) | 1979-03-07 |
EP0000947B1 EP0000947B1 (fr) | 1981-01-14 |
EP0000947B2 EP0000947B2 (fr) | 1984-10-10 |
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Application Number | Title | Priority Date | Filing Date |
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EP78100750A Expired EP0000947B2 (fr) | 1977-08-27 | 1978-08-25 | Nouveaux dérivés de 3,4,5-trihydroxy piperidine, procédé pour leur préparation et médicaments et aliments les contenant |
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US (2) | US4639436A (fr) |
EP (1) | EP0000947B2 (fr) |
JP (1) | JPS5446786A (fr) |
AT (1) | AT373239B (fr) |
AU (2) | AU3921478A (fr) |
CA (1) | CA1123437A (fr) |
DE (1) | DE2860330D1 (fr) |
DK (1) | DK152753C (fr) |
ES (1) | ES472838A1 (fr) |
FI (1) | FI72715C (fr) |
GR (1) | GR73065B (fr) |
HU (1) | HU182449B (fr) |
IE (1) | IE47070B1 (fr) |
IL (1) | IL55423A (fr) |
IT (1) | IT1111197B (fr) |
LU (1) | LU90211I2 (fr) |
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- 1978-08-09 NO NO782713A patent/NO154918C/no unknown
- 1978-08-23 US US05/936,280 patent/US4639436A/en not_active Expired - Lifetime
- 1978-08-24 PT PT68474A patent/PT68474A/pt unknown
- 1978-08-24 IL IL55423A patent/IL55423A/xx active IP Right Grant
- 1978-08-24 AU AU39214/78A patent/AU3921478A/en active Pending
- 1978-08-24 GR GR57073A patent/GR73065B/el unknown
- 1978-08-25 IT IT27067/78A patent/IT1111197B/it active
- 1978-08-25 FI FI782607A patent/FI72715C/fi not_active IP Right Cessation
- 1978-08-25 CA CA310,084A patent/CA1123437A/fr not_active Expired
- 1978-08-25 IE IE1716/78A patent/IE47070B1/en not_active IP Right Cessation
- 1978-08-25 ES ES472838A patent/ES472838A1/es not_active Expired
- 1978-08-25 AT AT0621778A patent/AT373239B/de not_active IP Right Cessation
- 1978-08-25 DK DK377678A patent/DK152753C/da not_active IP Right Cessation
- 1978-08-25 HU HU78BA3696A patent/HU182449B/hu unknown
- 1978-08-25 JP JP10297478A patent/JPS5446786A/ja active Granted
- 1978-08-25 DE DE7878100750T patent/DE2860330D1/de not_active Expired
- 1978-08-25 EP EP78100750A patent/EP0000947B2/fr not_active Expired
- 1978-08-28 AU AU39304/78A patent/AU520686B2/en not_active Expired
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1979
- 1979-09-20 US US06/077,507 patent/US4260622A/en not_active Expired - Lifetime
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Cited By (49)
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FR2424258A1 (fr) * | 1978-04-28 | 1979-11-23 | Nippon Shinyaku Co Ltd | Derives de n-alkenylmoranoline et leur utilisation comme produits inhibant l'augmentation de sucre dans le sang |
EP0009633A1 (fr) * | 1978-09-09 | 1980-04-16 | Bayer Ag | Dérivés de la 3,4,5-trihydroxypipéridine, procédé pour leur préparation ainsi que médicaments et nourritures pour animaux les contenant |
EP0010745A1 (fr) * | 1978-11-06 | 1980-05-14 | Bayer Ag | Dérivés de la 2-hydroxy-méthyl-3,4,5-trihydroxy-pipéridine, leur préparation et médicaments les contenant |
EP0019899A1 (fr) * | 1979-06-05 | 1980-12-10 | Bayer Ag | Dérivés de la 3,4,5-trihydroxypipéridine, méthodes pour leur préparation et leur application comme produits pharmaceutiques et dans la nourriture du bétail |
EP0022192A1 (fr) * | 1979-06-27 | 1981-01-14 | Bayer Ag | 1-Alcadien-2,4-yl-2-hydroxyméthyl-3,4,5-trihydroxypipéridines, procédés pour leur préparation et leur utilisation comme médicaments |
EP0025140A1 (fr) * | 1979-09-07 | 1981-03-18 | Bayer Ag | Procédé de préparation de dérivés de 6-amino-6-désoxy-2,3-0-isopropylidène-alpha-L-sorbofuranose et produits intermédiaires de ce procédé |
US4348402A (en) * | 1979-10-19 | 1982-09-07 | Bayer Aktiengesellschaft | 2-Hydroxyalkyl-3,4,5-trihydroxy-piperidine compounds, their production and their medicinal use |
EP0027908A2 (fr) * | 1979-10-19 | 1981-05-06 | Bayer Ag | 2-Hydroxyalkyl-3,4,5-trihydroxy-pipéridines, procédés pour leur préparation et leur utilisation comme médicaments |
EP0027908A3 (en) * | 1979-10-19 | 1981-08-05 | Bayer Ag | 2-hydroxyalkyl-3,4,5,trihydroxy piperidines, processes for their preparation and their use as medicaments |
FR2474498A1 (fr) * | 1980-01-28 | 1981-07-31 | Nippon Shinyaku Co Ltd | Derives de bis-moranoline et leur utilisation pour inhiber l'augmentation de sucre dans le sang |
FR2478094A1 (fr) * | 1980-01-28 | 1981-09-18 | Nippon Shinyaku Co Ltd | Derives de cinnamylmoranoline a substitution ammonio, a activite d'inhibition de l'augmentation de niveau de sucre dans le sang |
EP0049858A3 (en) * | 1980-10-15 | 1982-10-13 | Bayer Ag | Process for the preparation of n-substituted derivatives of 1-desoxynojirimycin |
EP0049858A2 (fr) * | 1980-10-15 | 1982-04-21 | Bayer Ag | Procédé pour la préparation de dérivés de la désoxy-1 nojirimycine N-substitués |
EP0193770A2 (fr) * | 1985-02-28 | 1986-09-10 | Bayer Ag | Dérivés de 3,4,5-trihydroxypipéridine, procédé de préparation et leur utilisation |
EP0193770A3 (fr) * | 1985-02-28 | 1987-05-13 | Bayer Ag | Dérivés de 3,4,5-trihydroxypipéridine, procédé de préparation et leur utilisation |
US5434266A (en) * | 1985-11-19 | 1995-07-18 | Cornell Research Foundation, Inc. | Monosaccharide analog-based glycosidase inhibitors |
EP0230581A2 (fr) * | 1985-12-20 | 1987-08-05 | Bayer Ag | 3-Amino-4,5-dihydroxypipéridines, procédé pour leur préparation et leur utilisation |
EP0230581A3 (en) * | 1985-12-20 | 1987-08-19 | Bayer Ag | 3-amino-4,5-dihydroxypiperidines, process for their preparation and their use |
US4871747A (en) * | 1985-12-20 | 1989-10-03 | Bayer Aktiengesellschaft | 3-Amino-4,5-dihydroxypiperidines, process for their preparation and their use |
EP0240868A2 (fr) * | 1986-04-09 | 1987-10-14 | Bayer Ag | Procédé de préparation de la 1-désoxynojirimycine et de ses N-dérivés |
EP0240868A3 (en) * | 1986-04-09 | 1988-09-21 | Bayer Ag | Process for the preparation of 1-desoxynojirimycine and of its n-derivatives |
EP0322643A1 (fr) * | 1987-12-23 | 1989-07-05 | Bayer Ag | Médicaments contenant en mélange l'interferon et des 1-desoxy-piperidinoses, procédé pour leur préparation et leur application |
EP0345104A2 (fr) * | 1988-06-02 | 1989-12-06 | Merrell Dow Pharmaceuticals Inc. | Inhibiteurs d'alpha-glucosidase |
EP0345104A3 (fr) * | 1988-06-02 | 1991-04-10 | Merrell Dow Pharmaceuticals Inc. | Inhibiteurs d'alpha-glucosidase |
EP0350012A3 (fr) * | 1988-07-08 | 1990-09-05 | Meiji Seika Kaisha Ltd. | Composition antivirale |
EP0350012A2 (fr) * | 1988-07-08 | 1990-01-10 | Meiji Seika Kaisha Ltd. | Composition antivirale |
EP0367748A2 (fr) * | 1988-11-03 | 1990-05-09 | G.D. SEARLE & COMPANY | Composés antiviraux |
EP0367748A3 (fr) * | 1988-11-03 | 1991-05-08 | G.D. SEARLE & COMPANY | Composés antiviraux |
EP0389723A1 (fr) * | 1989-03-29 | 1990-10-03 | Merrell Dow Pharmaceuticals Inc. | Inhibiteurs d'alpha-glucosidases |
EP0406211A2 (fr) * | 1989-06-27 | 1991-01-02 | Monsanto Company | Inhibiteurs de fucosidase |
EP0406211B1 (fr) * | 1989-06-27 | 1994-03-30 | Monsanto Company | Inhibiteurs de fucosidase |
EP0422975A1 (fr) * | 1989-10-10 | 1991-04-17 | Merrell Dow Pharmaceuticals Inc. | Inhibiteurs de l'alpha-glucosidase |
EP0422307A1 (fr) * | 1989-10-10 | 1991-04-17 | Merrell Dow Pharmaceuticals Inc. | Inhibiteurs de alpha-glucosidase |
EP0425929A1 (fr) * | 1989-11-01 | 1991-05-08 | Bayer Ag | Procédé pour la préparation de N-(2-hydroxyéthyl)-2-hydroxyméthyl-3,4,5-trihydroxy-pipéridine et d'intermédiaires |
US5071990A (en) * | 1989-11-01 | 1991-12-10 | Bayer Aktiengesellschaft | Preparation of intermediates and the synthesis of n-(2-hydroxyethyl)-2-hydroxymethyl-3,4,5-trihydroxypiperidines |
EP0449026A2 (fr) * | 1990-03-24 | 1991-10-02 | Bayer Ag | Dérivés de désoxynojirimycine, procédé pour leur préparation et leur utilisation comme médicaments |
EP0449026A3 (en) * | 1990-03-24 | 1992-05-06 | Bayer Ag | Desoxynojirimycin derivatives, process for their preparation and their use in drugs |
EP0536402A1 (fr) * | 1990-06-29 | 1993-04-14 | Nippon Shinyaku Company, Limited | Derive de piperidine |
EP0536402A4 (en) * | 1990-06-29 | 1993-05-12 | Nippon Shinyaku Company, Limited | Piperidine derivative |
EP0481950A3 (en) * | 1990-10-18 | 1992-09-02 | Monsanto Company | 1,4-dideoxy-4-fluoronojirimycin |
EP0481950A2 (fr) * | 1990-10-18 | 1992-04-22 | Monsanto Company | 1,4-Dideoxy-4-fluoronojirimycine |
WO1995024391A1 (fr) * | 1994-03-09 | 1995-09-14 | Novo Nordisk A/S | Piperidines et pyrrolidines |
US5863903A (en) * | 1994-03-09 | 1999-01-26 | Novo Nordisk A/S | Use of hydroxy alkyl piperidine and pyrrolidine compounds to treat diabetes |
US9089515B2 (en) | 1999-08-10 | 2015-07-28 | Thomas Jefferson University | Long chain N-alkyl compounds and oxa-derivatives thereof |
WO2006136714A1 (fr) | 2005-06-23 | 2006-12-28 | Centre National De La Recherche Scientifique | Nouveaux composes de la famille des iminosucres, leurs utilisations pour le traitement de maladies lysosomales, ainsi que leur procede de preparation |
US8975280B2 (en) | 2006-05-24 | 2015-03-10 | The Chancellor, Masters And Scholars Of The University Of Oxford | Deoxynojirimycin and D-arabinitol analogs and methods of using |
ITUB20150176A1 (it) * | 2015-04-17 | 2016-10-17 | Dipharma Francis Srl | Sintesi di un azazucchero e i suoi intermedi |
EP3081555A1 (fr) * | 2015-04-17 | 2016-10-19 | Dipharma Francis S.r.l. | Synthèse d'un azasucre et ses intermédiaires |
US9708263B2 (en) | 2015-04-17 | 2017-07-18 | Dipharma Francis S.R.L. | Synthesis of an azasugar and the intermediates thereof |
Also Published As
Publication number | Publication date |
---|---|
IE47070B1 (en) | 1983-12-14 |
JPS5446786A (en) | 1979-04-12 |
FI782607A (fi) | 1979-02-28 |
DK152753C (da) | 1988-10-31 |
EP0000947B1 (fr) | 1981-01-14 |
JPS6231703B2 (fr) | 1987-07-09 |
GR73065B (fr) | 1984-01-30 |
ATA621778A (de) | 1983-05-15 |
CA1123437A (fr) | 1982-05-11 |
DE2860330D1 (en) | 1981-03-12 |
PT68474A (de) | 1978-09-01 |
EP0000947B2 (fr) | 1984-10-10 |
AU520686B2 (en) | 1982-02-18 |
IT7827067A0 (it) | 1978-08-25 |
AU3930478A (en) | 1980-03-06 |
AT373239B (de) | 1983-12-27 |
LU90211I2 (fr) | 1998-04-08 |
NO782713L (no) | 1979-02-28 |
US4260622A (en) | 1981-04-07 |
US4639436A (en) | 1987-01-27 |
IL55423A (en) | 1982-09-30 |
ES472838A1 (es) | 1979-03-16 |
IT1111197B (it) | 1986-01-13 |
FI72715C (fi) | 1987-07-10 |
NO154918B (no) | 1986-10-06 |
IL55423A0 (en) | 1978-10-31 |
DK152753B (da) | 1988-05-09 |
FI72715B (fi) | 1987-03-31 |
AU3921478A (en) | 1980-02-28 |
HU182449B (en) | 1984-01-30 |
NL960027I2 (nl) | 1997-07-01 |
IE781716L (en) | 1979-02-27 |
DK377678A (da) | 1979-02-28 |
NO154918C (no) | 1987-01-14 |
NL960027I1 (nl) | 1997-01-06 |
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