EP0000947B2 - Neue Derivate von 3,4,5-Trihydroxypiperidin, Verfahren zu ihrer Herstellung und sie enthaltende Arznei- und Futtermittel - Google Patents

Neue Derivate von 3,4,5-Trihydroxypiperidin, Verfahren zu ihrer Herstellung und sie enthaltende Arznei- und Futtermittel Download PDF

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Publication number
EP0000947B2
EP0000947B2 EP78100750A EP78100750A EP0000947B2 EP 0000947 B2 EP0000947 B2 EP 0000947B2 EP 78100750 A EP78100750 A EP 78100750A EP 78100750 A EP78100750 A EP 78100750A EP 0000947 B2 EP0000947 B2 EP 0000947B2
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Prior art keywords
formula
compounds
deoxynojirimycin
alkyl
denotes
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German (de)
English (en)
French (fr)
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EP0000947A1 (de
EP0000947B1 (de
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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 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 however, be 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 such as chlorides, sulfates, acetates, carbonates, oxalates, etc.
  • organic precursors being understood to mean compounds whose structure differs from the active compound however, be converted into the active compound in the patient's body after administration to humans or animals.
  • 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, CI, Br, C, -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, monoethyl
  • C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 alkoxy, nitro and / or amino may be substituted, heterocyclic carbon Acids which are 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 4C 4 -alkyl, chlorine, bromine, amino is; Mercapto, 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 above-mentioned type, in particular also sugars, very particularly heterocyclic radicals derived from hexoses or pentoses, which can be connected directly to the alkyl radical via a
  • 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 2 , 1 C 1 ⁇ C 4 -alkyl- NH ⁇ , C 1 ⁇ C 4 -dialkyl-N ⁇ C l -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 1 ⁇ C 4 alkylthio, -SH, C 1 1C 4 alkylsulfonyl, -S0 3 H, ⁇ SO 2 ⁇ NH 2 ' ⁇ SO 2 ⁇ NH-alkyl) (C 1 ⁇ C 4 ).
  • 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 hydroxy, 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 come into consideration for the cyclic mono-, bi- or tricyclic radicals R ,, 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, -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 is preferably -H, -OH, -S0 3 H, -CN, ⁇ CH 2 NH 2 , ⁇ CH 2 NH ⁇ (C 1 ⁇ C 14 alkyl). ⁇ CH 2
  • R 2 very particularly preferably represents ⁇ H, -S0 3 H, -CN
  • R 3 preferably represents hydrogen, -CH 2 0H, -CH 3 , -CH 2 NH 2 , ⁇ CH 2 NH ⁇ (C 1 ⁇ C 6 -alkyl) or or ⁇ CH 2 ⁇ 0 ⁇ (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 connections are valuable. Means to influence 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.
  • Urethanes of the formula VIII - optionally as derivatives provided with hydroxyl protective groups - can be reduced with LiAIH 4 to n-methyl-1-deoxynojirimycin (by way of example, not claimed here):
  • 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 Ila 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 11 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 2 and storing for several days at temperatures between 20 ° and 50 ° C.
  • 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 eg H 2 / Raney nickel, H 2 / P + 0 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, such as an alcohol, dimethyl sulfozide or in excess amine.
  • a polar solvent such as 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 from 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 methods [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 (e.g. aqueous methanol) or other aqueous solvent systems such as e.g. B. 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 biguanides with an effect on blood sugar
  • blood lipid-lowering active substances 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 produce 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 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 ° 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 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 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 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 ingredients 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 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 proteins, including vitamins and minerals, which is necessary for a balanced diet.
  • the feed can be composed, for example, pflanzf f chen substances, for.
  • Premixes may preferably be about 0.1 to 50%, especially 0.5 to 5.0% (weight) e.g. N-methyt-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 N-methyl-1-deoxynojirimycin, for example, 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 (glucose ⁇ 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 porcine 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 ⁇ 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 ° C. 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 0 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 mun g 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).
  • aqueous phase is brought to dryness again, 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 e form (Amberlite IRA 400 or Dowex 1 x 2) is filled.
  • a strongly basic ion exchanger in the OH e 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.
  • Mass spectrum The mass spectrum was measured from the compound peracetylated in pyridine / acetic anhydride.
  • 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 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 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 H ⁇ 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 NaCNBH 3 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 mf absolute tetrahydrofuran and dripped at -70 ° C. into a mixture of 24.6 g sodium in 820 ml 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 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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EP78100750A 1977-08-27 1978-08-25 Neue Derivate von 3,4,5-Trihydroxypiperidin, Verfahren zu ihrer Herstellung und sie enthaltende Arznei- und Futtermittel Expired EP0000947B2 (de)

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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
DE2758025 1977-12-24
DE19772758025 DE2758025A1 (de) 1977-12-24 1977-12-24 Neue derivate von 3,4,5-trihydroxypiperidin, verfahren zu ihrer herstellung und ihre verwendung

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Families Citing this family (245)

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Publication number Priority date Publication date Assignee Title
JPS5943946B2 (ja) * 1978-04-28 1984-10-25 日本新薬株式会社 Ｎ−アルケニルモラノリン誘導体
DE2839309A1 (de) * 1978-09-09 1980-03-27 Bayer Ag 3,4,5-trihydroxypiperidin-derivate
DE2848117A1 (de) * 1978-11-06 1980-05-14 Bayer Ag Derivate des 2-hydroxymethyl-3,4,5- trihydroxy-piperidins, ihre herstellung und verwendung zur beeinflussung des kohlenhydrat- und fettstoffwechsels
DE2922760A1 (de) * 1979-06-05 1980-12-11 Bayer Ag Neue derivate von 3,4,5-trihydroxypiperidin, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel sowie in der tierernaehrung
DE2925943A1 (de) * 1979-06-27 1981-01-29 Bayer Ag 1-alkadien-2,4-yl-2-hydroxymethyl3,4,5-trihydroxypiperidine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE2936240A1 (de) 1979-09-07 1981-03-26 Bayer Ag, 51373 Leverkusen Verfahren zur herstellung bekannter und neuer 6-amino-6-desoxy-2,3-0-isopropyliden-(alpha)-l-sorbofuranose-derivate sowie neue zwischenprodukte des verfahrens
DE2942365A1 (de) * 1979-10-19 1981-05-14 Bayer Ag, 5090 Leverkusen 2-hydroxyalkyl-3,4,5-trihydroxy-(pi)-peridine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
JPS56108767A (en) * 1980-01-28 1981-08-28 Nippon Shinyaku Co Ltd Bismoranoline derivative
JPS56108768A (en) * 1980-01-28 1981-08-28 Nippon Shinyaku Co Ltd Cinnamylmoranoline derivative
DE3007078A1 (de) * 1980-02-26 1981-09-10 Bayer Ag, 5090 Leverkusen Neue derivate von 3,4,5-trihydroxypiperidin, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel sowie in der tierernaehrung
DE3038901A1 (de) * 1980-10-15 1982-05-06 Bayer Ag, 5090 Leverkusen Verfahren zur herstellung von n-substituierten derivaten des 1-desoxynojirimycins
US4634765A (en) * 1984-12-18 1987-01-06 Merrell Dow Pharmaceuticals Inc. Homodisaccharide hypoglycemic agents
DE3507019A1 (de) * 1985-02-28 1986-08-28 Bayer Ag, 5090 Leverkusen Neue derivate von 3,4,5-trihydroxypiperidin, verfahren zu ihrer herstellung und ihre verwendung
US5231185A (en) * 1985-11-19 1993-07-27 Cornell Research Foundation, Inc. Monosaccharide analog-based glycosidase inhibitors
DE3620645A1 (de) * 1985-12-20 1987-07-02 Bayer Ag 3-amino-4,5-dihydroxypiperidine, verfahren zu ihrer herstellung und ihre verwendung
DE3611841A1 (de) * 1986-04-09 1987-10-15 Bayer Ag Verfahren zur herstellung von 1-desoxynojirimycin und dessen n-derivaten
DE3737523A1 (de) * 1987-11-05 1989-05-18 Bayer Ag Verwendung von substituierten hydroxypiperidinen als antivirale mittel
US5192772A (en) * 1987-12-09 1993-03-09 Nippon Shinyaku Co. Ltd. Therapeutic agents
IL88740A (en) * 1987-12-21 1993-01-31 Monsanto Co Pharmaceutical compositions containing n-n-butyl deoxynojirimycin for treating aids
US4849430A (en) * 1988-03-09 1989-07-18 Monsanto Company Method of inhibiting virus
DE3743749A1 (de) * 1987-12-23 1989-07-13 Bayer Ag Arzneimittel enthaltend in kombination interferon und 1-desoxy-piperidinosen, verfahren zu deren herstellung und deren verwendung
US5250545A (en) * 1988-02-12 1993-10-05 Meiji Seika Kaisha, Ltd. Cancer cell metastasis inhibitor methods
EP0344383A1 (en) * 1988-06-02 1989-12-06 Merrell Dow Pharmaceuticals Inc. Novel alpha-Glucosidase inhibitors
EP0345104B1 (en) * 1988-06-02 1995-11-02 Merrell Dow Pharmaceuticals Inc. Novel Alpha-glucosidase inhibitors
US4880917A (en) * 1988-07-01 1989-11-14 Merrell Dow Pharmaceuticals Inc. Process for hydrolyzing 2,6-dideoxy-2,6-iminoheptononitrile derivatives using trifluoroacetic acid and dinitrogen tetroxide
EP0350012A3 (en) * 1988-07-08 1990-09-05 Meiji Seika Kaisha Ltd. Antiviral composition
US5043416A (en) * 1988-09-26 1991-08-27 Monsanto Company Method of inhibiting virus
US5221746A (en) * 1988-11-03 1993-06-22 G. D. Searle & Co. 1,5-dideoxy-1,5-imino-D-glucitol derivatives
US4973602A (en) * 1988-11-03 1990-11-27 G. D. Searle & Co. Antiviral compounds and a method of use thereas
US5310745A (en) * 1988-11-03 1994-05-10 G. D. Searle & Co. Antiviral compounds
US5003072A (en) * 1988-11-03 1991-03-26 G. D. Searle & Co. 1,5-dideoxy-1,5-imino-D-glucitol derivatives
US4937357A (en) * 1988-11-03 1990-06-26 G. D. Searle & Co. Intermediates for antiviral compounds
US4876268A (en) * 1988-11-03 1989-10-24 G. D. Searle & Co. Antiviral compounds and use thereof
US5144037A (en) * 1988-11-03 1992-09-01 G. D. Searle & Co. 1,5-dideoxy-1,5-imino-d-glucitol derivatives
US4957926A (en) * 1988-12-22 1990-09-18 Monsanto Company Method of treating herpesviruses
EP0389723A1 (en) * 1989-03-29 1990-10-03 Merrell Dow Pharmaceuticals Inc. Novel alpha-glucosidase inhibitors
US5100797A (en) * 1989-06-27 1992-03-31 Monsanto Company Fucosidase inhibitors
EP0422307A1 (en) * 1989-10-10 1991-04-17 Merrell Dow Pharmaceuticals Inc. Novel alpha-glucosidase inhibitors
DE3936295A1 (de) * 1989-11-01 1991-05-02 Bayer Ag Verfahren zur herstellung von zwischenprodukten und zur synthese von n-(2-hydroxyethyl)-2-hydroxymethyl-3,4,5-trihydroxypiperidine
US5030638A (en) * 1990-02-26 1991-07-09 G. D. Searle & Co. Method of antiviral enhancement
DE4009561A1 (de) * 1990-03-24 1991-09-26 Bayer Ag Neue desoxynojirimycinderivate, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln
US5252587A (en) * 1990-04-27 1993-10-12 Merrell Dow Pharmaceuticals, Inc. N-derivatives of 1-deoxy nojirimycin
US5536732A (en) * 1990-04-27 1996-07-16 Merrell Pharmaceuticals Inc. N-derivatives of 1-deoxy nojirimycin
US5151519A (en) * 1990-05-07 1992-09-29 G. D. Searle & Co. Process for the preparation of 1,5-(alkylimino)-1,5-dideoxy-d-glucitol and derivatives thereof
US5504078A (en) * 1990-06-08 1996-04-02 Merrell Dow Pharmaceuticals Inc. α-glucosidase inhibitors
WO1992000277A1 (en) * 1990-06-29 1992-01-09 Nippon Shinyaku Co., Ltd. Piperidine derivative
US5561134A (en) * 1990-09-25 1996-10-01 Rhone-Poulenc Rorer Pharmaceuticals Inc. Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties
US5128347A (en) * 1990-10-18 1992-07-07 Monsanto Company Glycosidase inhibiting 1,4-dideoxy-4-fluoronojirimycin
US5273981A (en) * 1990-10-18 1993-12-28 Monsanto Company Intramolecular carbamate derivative of 2,3-Di-O-blocked-1,4-dideoxy-4-fluoro-nojirimycins
US5216168A (en) * 1992-04-01 1993-06-01 G. D. Searle & Co. 2- and 3- amino and azido derivatives of 1,5-iminosugars
US5258518A (en) * 1992-04-01 1993-11-02 G. D. Searle & Co. 2-substituted tertiary carbinol derivatives of deoxynojirimycin
US5206251A (en) * 1992-04-01 1993-04-27 G. D. Searle & Co. 2- and 3- amino and azido derivatives of 1,5-iminosugars
US5331096A (en) * 1992-04-01 1994-07-19 G. D. Searle & Co. 2- and 3-sulfur derivatives of 1,5-iminosugars
US5342951A (en) * 1992-04-01 1994-08-30 G.D. Searle & Co. 2- and 3-sulfur derivatives of 1,5-iminosugars
US5268482A (en) * 1992-04-01 1993-12-07 G. D. Searle & Co. 2- and 3-sulfur derivatives of 1,5-iminosugars
US6291657B1 (en) * 1993-05-13 2001-09-18 Monsanto Company Deoxygalactonojirimycin derivatives
US5399567A (en) * 1993-05-13 1995-03-21 Monsanto Company Method of treating cholera
US5798366A (en) * 1993-05-13 1998-08-25 Monsanto Company Method for treatment of CNS-involved lysosomal storage diseases
US5863903A (en) * 1994-03-09 1999-01-26 Novo Nordisk A/S Use of hydroxy alkyl piperidine and pyrrolidine compounds to treat diabetes
ATE243196T1 (de) * 1994-03-09 2003-07-15 Novo Nordisk As Piperidine und pyrrolidine
US20030100532A1 (en) 1997-02-14 2003-05-29 Gary S. Jacob Use of n-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds in combination therapy for treating hepatitis virus infections
GEP20022788B (en) * 1997-04-15 2002-09-25 Csir Za Pharmaceutical Compositions Having Appetite Suppressant Activity
ATE258919T1 (de) 1997-11-10 2004-02-15 Searle & Co Verwendung von alkylierten iminozuckern zur behandlung von multipler medikamentenresistenz
CA2319713C (en) 1998-02-12 2012-06-26 G.D. Searle & Co. Use of n-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds for treating hepatitis virus infections
US6689759B1 (en) 1998-02-12 2004-02-10 G. D. Searle & Co. Methods of Treating hepatitis virus infections with N-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds in combination therapy
AP1224A (en) 1998-03-19 2003-11-14 Bristol Myers Squibb Co Biphasic controlled release delivery system for high solubility pharmaceuticals and method.
US6274597B1 (en) 1998-06-01 2001-08-14 Mount Sinai School Of Medicine Of New York University Method of enhancing lysosomal α-Galactosidase A
CZ2001964A3 (cs) 1998-09-17 2002-01-16 Bristol-Myers Squibb Company Lék a farmaceutická kombinace pro léčení diabetu, rezistence na inzulín, obezitu, hyperglykémie, hypeinzulínem nebo zvýąené hladiny mastných kyselin
AU3595500A (en) * 1999-02-12 2000-08-29 G.D. Searle & Co. Use of substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds for treating hepatitis virus infections
CA2362785A1 (en) 1999-02-12 2001-02-08 G.D. Searle & Co. Glucamine compounds for treating hepatitis virus infections
US6548529B1 (en) 1999-04-05 2003-04-15 Bristol-Myers Squibb Company Heterocyclic containing biphenyl aP2 inhibitors and method
GB0100889D0 (en) 2001-01-12 2001-02-21 Oxford Glycosciences Uk Ltd Compounds
US7816560B1 (en) 1999-08-10 2010-10-19 Thomas Jefferson University Long chain n-alkyl compounds and oxa-derivatives thereof
GB2355657B (en) * 1999-10-27 2004-07-28 Phytopharm Plc Inhibitors Of Gastric Acid Secretion
US6586438B2 (en) 1999-11-03 2003-07-01 Bristol-Myers Squibb Co. Antidiabetic formulation and method
CN1422156A (zh) * 2000-02-14 2003-06-04 法马西亚公司 N－取代的－1,5－二脱氧－1,5－亚氨基－d－葡萄糖醇化合物在治疗肝炎病毒感染中的用途
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
GB2363985B (en) * 2000-06-30 2004-09-29 Phytopharm Plc Extracts,compounds & pharmaceutical compositions having anti-diabetic activity and their use
WO2002011716A2 (en) * 2000-08-07 2002-02-14 Ranbaxy Signature Llc Liquid formulation of metformin
FR2816840B1 (fr) * 2000-11-17 2004-04-09 Flamel Tech Sa Medicament a base de microcapsules d'anti-hyperclycemiant a liberation prolongee et son procede de preparation
AU2002254940A1 (en) * 2001-03-12 2002-09-24 Novartis Pharma Gmbh Combination of nateglinide or repaglinide with at least one further antidiabetic compound
DE60209343T2 (de) 2001-04-11 2006-10-26 Bristol-Myers Squibb Co. Aminosäurekomplexe von c-arylglycosiden zur behandlung von diabetes und verfahren
FR2830447B1 (fr) * 2001-10-09 2004-04-16 Flamel Tech Sa Forme galenique orale microparticulaire pour la liberation retardee et controlee de principes actifs pharmaceutiques
US8101209B2 (en) * 2001-10-09 2012-01-24 Flamel Technologies Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles
US6806381B2 (en) * 2001-11-02 2004-10-19 Bristol-Myers Squibb Company Process for the preparation of aniline-derived thyroid receptor ligands
EP1443919A4 (en) * 2001-11-16 2006-03-22 Bristol Myers Squibb Co DOUBLE INHIBITORS OF THE FATTY ACID BINDING PROTEIN OF THE ADIPOCYTES AND THE FATTY ACID BINDING PROTEIN OF KERATINOCYTES
FR2833813B1 (fr) * 2001-12-26 2005-08-26 Phytosynthese Complement alimentaire destine a l'animal
ATE419840T1 (de) 2002-04-09 2009-01-15 Flamel Tech Sa Orale wässrige suspension, mikrokapseln enthaltend, zur kontrollierten freisetzung von wirkstoffen
JP4698950B2 (ja) * 2002-04-09 2011-06-08 フラメル・テクノロジー アモキシシリンの改変された放出のための、マイクロカプセルの水性懸濁液形態での経口医薬品製剤
AU2003248960B2 (en) * 2002-07-17 2009-06-25 Idorsia Pharmaceuticals Ltd Piperidinetriol derivatives as inhibitors of glycosylceramidsynthase
CA2492404C (en) * 2002-07-17 2012-02-07 Oxford Glycosciences (Uk) Ltd Piperidinetriol derivatives as inhibitors of glycosylceramide synthase
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
TW200504021A (en) * 2003-01-24 2005-02-01 Bristol Myers Squibb Co Substituted anilide ligands for the thyroid receptor
EP1587783A4 (en) * 2003-01-24 2006-11-08 Bristol Myers Squibb Co CYCLOALKYL-CONTAINING ANILID LIGANDS FOR THE THYROID RECEPTOR
RS20050890A (sr) * 2003-05-30 2007-12-31 Ranbaxy Laboratories Limited, Supstituisani pirol derivati
US7459474B2 (en) * 2003-06-11 2008-12-02 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor and method
GB0313678D0 (en) * 2003-06-13 2003-07-16 Oxford Glycosciences Uk Ltd Novel compounds
GB0313677D0 (en) * 2003-06-13 2003-07-16 Oxford Glycosciences Uk Ltd Novel compound
US7371759B2 (en) * 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
FR2861991B1 (fr) * 2003-11-07 2008-01-18 Centre Nat Rech Scient Utilisation d'inhibiteurs de glucosidase pour une therapie de la mucoviscidose
PT1689757E (pt) 2003-11-12 2014-12-09 Sino Med Internat Alliance Inc Compostos heterocíclicos de ácido borónico
US7420059B2 (en) * 2003-11-20 2008-09-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7501426B2 (en) * 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
US7262318B2 (en) * 2004-03-10 2007-08-28 Pfizer, Inc. Substituted heteroaryl- and phenylsulfamoyl compounds
US20050288340A1 (en) * 2004-06-29 2005-12-29 Pfizer Inc Substituted heteroaryl- and phenylsulfamoyl compounds
US7786163B2 (en) * 2004-07-12 2010-08-31 Forest Laboratories Holdings Limited (BM) Constrained cyano compounds
US7572805B2 (en) 2004-07-14 2009-08-11 Bristol-Myers Squibb Company Pyrrolo(oxo)isoquinolines as 5HT ligands
WO2006037069A1 (en) * 2004-09-28 2006-04-06 Allergan, Inc. Compositions comprising nb-dnj, ne-dnj or d-glucaro-delta-lactam and their uses for the treatment of pain and other neurological conditions
US7517991B2 (en) * 2004-10-12 2009-04-14 Bristol-Myers Squibb Company N-sulfonylpiperidine cannabinoid receptor 1 antagonists
DE102004054054A1 (de) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine
US8003617B2 (en) * 2004-11-10 2011-08-23 Genzyme Corporation Methods of treating diabetes mellitus
JP2008520642A (ja) * 2004-11-23 2008-06-19 ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー 脂血症を治療するためのＨＭＧ−ＣｏＡ還元酵素阻害剤としての７−（２Ｈ−ピラゾール−３−イル）−３，５−ジヒドロキシ−ヘプタン酸誘導体
WO2006076597A1 (en) * 2005-01-12 2006-07-20 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
US7314882B2 (en) * 2005-01-12 2008-01-01 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
US7361766B2 (en) 2005-01-12 2008-04-22 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
US7317024B2 (en) 2005-01-13 2008-01-08 Bristol-Myers Squibb Co. Heterocyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US20060160850A1 (en) * 2005-01-18 2006-07-20 Chongqing Sun Bicyclic heterocycles as cannabinoid receptor modulators
EP1846410B1 (en) * 2005-02-10 2009-01-21 Bristol-Myers Squibb Company Dihydroquinazolinones as 5ht modulators
UA91546C2 (uk) * 2005-05-03 2010-08-10 Бьорінгер Інгельхайм Інтернаціональ Гмбх КРИСТАЛІЧНА ФОРМА 1-ХЛОР-4-(β-D-ГЛЮКОПІРАНОЗ-1-ИЛ)-2-[4-((S)-ТЕТРАГІДРОФУРАН-3-ІЛОКСИ)-БЕНЗИЛ]-БЕНЗОЛУ, СПОСІБ ЇЇ ОДЕРЖАННЯ ТА ЇЇ ЗАСТОСУВАННЯ ПРИ ПРИГОТУВАННІ ЛІКАРСЬКИХ ЗАСОБІВ
US7772191B2 (en) 2005-05-10 2010-08-10 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
BRPI0612928A2 (pt) 2005-05-17 2010-12-07 Amicus Therapeutics Inc Método para aumentar a atividade de uma enzima de (alfa)-glucosidade em uma célula e método para tratar doença de pompe
WO2006133447A1 (en) * 2005-06-08 2006-12-14 Amicus Therapeutics, Inc. Crystalline sugar compositions and method of making
EP1888610A1 (en) * 2005-06-08 2008-02-20 Amicus Therapeutics, Inc. Stabilization of triflated compounds
US7973157B2 (en) * 2005-06-08 2011-07-05 Amicus Therapeutics, Inc. Imino and amino sugar purification
US7888381B2 (en) 2005-06-14 2011-02-15 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity, and use thereof
US7317012B2 (en) * 2005-06-17 2008-01-08 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoind-1 receptor modulators
US7632837B2 (en) * 2005-06-17 2009-12-15 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid-1 receptor modulators
US7629342B2 (en) * 2005-06-17 2009-12-08 Bristol-Myers Squibb Company Azabicyclic heterocycles as cannabinoid receptor modulators
US7452892B2 (en) * 2005-06-17 2008-11-18 Bristol-Myers Squibb Company Triazolopyrimidine cannabinoid receptor 1 antagonists
TW200726765A (en) * 2005-06-17 2007-07-16 Bristol Myers Squibb Co Triazolopyridine cannabinoid receptor 1 antagonists
US20060287342A1 (en) * 2005-06-17 2006-12-21 Mikkilineni Amarendra B Triazolopyrimidine heterocycles as cannabinoid receptor modulators
FR2887549B1 (fr) * 2005-06-23 2009-07-10 Centre Nat Rech Scient Nouveaux composes de la famille des iminosucres, leurs utilisations, notamment pour le traitement de maladies lysosomales, ainsi que leur procede de preparation
MX2008000811A (es) * 2005-07-28 2008-03-18 Squibb Bristol Myers Co Tetrahidro-1h-pitido[4,3-b]indoles substituidos como agonistas y antagonistas del receptor de serotonina.
DE102005035891A1 (de) 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
US7795436B2 (en) * 2005-08-24 2010-09-14 Bristol-Myers Squibb Company Substituted tricyclic heterocycles as serotonin receptor agonists and antagonists
US7741317B2 (en) 2005-10-21 2010-06-22 Bristol-Myers Squibb Company LXR modulators
US8618115B2 (en) 2005-10-26 2013-12-31 Bristol-Myers Squibb Company Substituted thieno[3,2-d]pyrimidinones as MCHR1 antagonists and methods for using them
JP2009514851A (ja) * 2005-11-08 2009-04-09 ランバクシー ラボラトリーズ リミテッド （３ｒ，５ｒ）−７−［２−（４−フルオロフェニル）−５−イソプロピル−３−フェニル−４−［（４−ヒドロキシメチルフェニルアミノ）カルボニル］−ピロール−１−イル］−３，５−ジヒドロキシ−ヘプタン酸ヘミカルシウム塩の製法
US7888376B2 (en) 2005-11-23 2011-02-15 Bristol-Myers Squibb Company Heterocyclic CETP inhibitors
US7592461B2 (en) 2005-12-21 2009-09-22 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7553836B2 (en) * 2006-02-06 2009-06-30 Bristol-Myers Squibb Company Melanin concentrating hormone receptor-1 antagonists
TW200744583A (en) * 2006-03-14 2007-12-16 Ranbaxy Lab Ltd Statin stabilizing dosage formulations
US20070238770A1 (en) * 2006-04-05 2007-10-11 Bristol-Myers Squibb Company Process for preparing novel crystalline forms of peliglitazar, novel stable forms produced therein and formulations
PE20080697A1 (es) * 2006-05-03 2008-08-05 Boehringer Ingelheim Int Derivados de benzonitrilo sustituidos con glucopiranosilo, composiciones farmaceuticas que contienen compuestos de este tipo, su uso y procedimiento para su fabricacion
MX2008014024A (es) 2006-05-04 2008-11-14 Boehringer Ingelheim Int Formas poliformas.
EP1852108A1 (en) 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
PE20080251A1 (es) * 2006-05-04 2008-04-25 Boehringer Ingelheim Int Usos de inhibidores de dpp iv
EP2032134B1 (en) * 2006-05-09 2015-06-24 Genzyme Corporation Methods of treating fatty liver disease comprising inhibiting glucosphingolipid synthesis
EP2023927B1 (en) * 2006-05-24 2015-02-25 United Therapeutics Corporation Deoxynojirimycin and d-arabinitol analogs and methods of using
TW200811101A (en) * 2006-07-14 2008-03-01 Ranbaxy Lab Ltd Polymorphic forms of an HMG-CoA reductase inhibitor and uses thereof
GB0614947D0 (en) * 2006-07-27 2006-09-06 Isis Innovation Epitope reduction therapy
EP2049126A2 (en) * 2006-08-02 2009-04-22 United Therapeutics Corporation Liposome treatment of viral infections
CA2666814A1 (en) * 2006-08-21 2008-05-29 United Therapeutics Corporation Combination therapy for treatment of viral infections
US7968577B2 (en) 2006-11-01 2011-06-28 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US8198311B2 (en) 2006-11-01 2012-06-12 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
WO2008070496A2 (en) 2006-12-01 2008-06-12 Bristol-Myers Squibb Company N- ( (3-benzyl) -2, 2- (bis-phenyl) -propan-1-amine derivatives as cetp inhibitors for the treatment of atherosclerosis and cardiovascular diseases
EP2368560A1 (en) 2007-03-12 2011-09-28 Zadec ApS An anti-diabetic extract of rooibos
US8097728B2 (en) * 2007-04-30 2012-01-17 Philadelphia Health & Education Corporation Iminosugar compounds with antiflavirus activity
US8304447B2 (en) 2007-05-31 2012-11-06 Genzyme Corporation 2-acylaminopropoanol-type glucosylceramide synthase inhibitors
EP2170930B3 (en) 2007-06-04 2013-10-02 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
US20090011994A1 (en) * 2007-07-06 2009-01-08 Bristol-Myers Squibb Company Non-basic melanin concentrating hormone receptor-1 antagonists and methods
PE20090938A1 (es) * 2007-08-16 2009-08-08 Boehringer Ingelheim Int Composicion farmaceutica que comprende un derivado de benceno sustituido con glucopiranosilo
EP2190434B1 (en) * 2007-08-17 2019-04-17 Boehringer Ingelheim International GmbH Purin derivatives for use in the treatment of fap-related diseases
WO2009045503A1 (en) 2007-10-05 2009-04-09 Genzyme Corporation Method of treating polycystic kidney diseases with ceramide derivatives
JP2011503081A (ja) 2007-11-01 2011-01-27 ブリストル−マイヤーズ スクイブ カンパニー グルココルチコイド受容体、ＡＰ−１および／またはＮＦ−κＢ活性の調節剤として有用な非ステロイド性化合物、並びにその使用
US20110015226A1 (en) 2008-02-18 2011-01-20 Summit Corporation Plc Treatment of Energy Utilization Disease
KR20100127842A (ko) * 2008-03-26 2010-12-06 유니버시티 오브 옥스퍼드 소포체 표적화 리포좀
PE20091730A1 (es) 2008-04-03 2009-12-10 Boehringer Ingelheim Int Formulaciones que comprenden un inhibidor de dpp4
PE20091928A1 (es) * 2008-05-29 2009-12-31 Bristol Myers Squibb Co Tienopirimidinas hidroxisustituidas como antagonistas de receptor-1 de hormona concentradora de melanina no basicos
PE20100156A1 (es) * 2008-06-03 2010-02-23 Boehringer Ingelheim Int Tratamiento de nafld
ES2627848T3 (es) 2008-06-04 2017-07-31 Synergy Pharmaceuticals Inc. Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros trastornos
EP2321341B1 (en) 2008-07-16 2017-02-22 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
CA2731685A1 (en) 2008-07-28 2010-02-04 Genzyme Corporation Glucosylceramide synthase inhibition for the treatment of collapsing glomerulopathy and other glomerular disease
BRPI0916997A2 (pt) 2008-08-06 2020-12-15 Boehringer Ingelheim International Gmbh Inibidor de dpp-4 e seu uso
UY32030A (es) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "tratamiento para diabetes en pacientes inapropiados para terapia con metformina"
KR101657960B1 (ko) * 2008-08-15 2016-09-20 베링거 인겔하임 인터내셔날 게엠베하 Ｆａｂ-관련 질환의 치료에 사용하기 위한 푸린 유도체
AU2009290911A1 (en) 2008-09-10 2010-03-18 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
US8309593B2 (en) 2008-10-03 2012-11-13 Genzyme Corporation 2-acylaminopropoanol-type glucosylceramide synthase inhibitors
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
ES2467108T3 (es) 2008-12-09 2014-06-11 Gilead Sciences, Inc. Moduladores de receptores tipo toll
MX2011006713A (es) 2008-12-23 2011-07-13 Boehringer Ingelheim Int Formas salinas de compuesto organico.
AR074990A1 (es) 2009-01-07 2011-03-02 Boehringer Ingelheim Int Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina
EP2395983B1 (en) 2009-02-13 2020-04-08 Boehringer Ingelheim International GmbH Pharmaceutical composition comprisng a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof
MX345494B (es) * 2009-02-13 2017-02-02 Boehringer Ingelheim Int Gmbh * Composición farmacéutica que comprende derivados de glucopiranosil difenilmetano, dosificación farmacéutica de la misma, procesos para su preparación y usos de la misma para el control glucemico mejorado en un paciente.
KR101755133B1 (ko) 2009-02-23 2017-07-06 유나이티드 세러퓨틱스 코오포레이션 이미노슈가 및 바이러스성 질환을 치료하는 방법
JP5951996B2 (ja) * 2009-02-24 2016-07-13 ユナイテッド セラピューティクス コーポレーション イミノ糖及びアレナウイルス感染症を治療する方法
EP2411005A1 (en) 2009-03-27 2012-02-01 Bristol-Myers Squibb Company Methods for preventing major adverse cardiovascular events with dpp-iv inhibitors
CN102427804A (zh) * 2009-03-27 2012-04-25 牛津大学之校长及学者 降低胆固醇水平的脂质体
CN102639133B (zh) 2009-06-12 2015-03-11 联合治疗公司 亚氨基糖和治疗布尼亚病毒性疾病以及披膜病毒性疾病的方法
JP5653438B2 (ja) * 2009-09-04 2015-01-14 ユナイテッド セラピューティクス コーポレイション オルトミクソウイルス感染の治療方法
CN105748476A (zh) * 2009-09-04 2016-07-13 联合治疗公司 亚氨基糖以及治疗丝状病毒性疾病的方法
KR101459530B1 (ko) * 2009-09-04 2014-11-07 유나이티드 세러퓨틱스 코오포레이션 폭스바이러스 감염의 치료 방법
JP5758900B2 (ja) * 2009-09-30 2015-08-05 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング グルコピラノシル置換ベンジルベンゼン誘導体の調製方法
JP5736377B2 (ja) * 2009-09-30 2015-06-17 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング １−クロロ−４−（β−Ｄ−グルコピラノス−１−イル）−２−［４−（（Ｓ）−テトラヒドロフラン−３−イルオキシ）ベンジル］ベンゼンの結晶形の調製方法
UY32919A (es) * 2009-10-02 2011-04-29 Boehringer Ingelheim Int Composición farmacéutica, forma de dosificación farmacéutica, procedimiento para su preparación, mé todos para su tratamiento y sus usos
EP2504002B1 (en) 2009-11-27 2019-10-09 Boehringer Ingelheim International GmbH Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
PH12012502162A1 (en) 2010-05-05 2013-02-04 Boehringer Ingelheim Int Combination therapy
US20130072519A1 (en) 2010-05-21 2013-03-21 Edward Lee Conn 2-phenyl benzoylamides
KR102018038B1 (ko) 2010-06-24 2019-09-05 베링거 인겔하임 인터내셔날 게엠베하 당뇨병 요법
US10940159B2 (en) 2010-07-09 2021-03-09 James Trinca Green Combination immediate/delayed release delivery system for short half-life pharmaceuticals including remogliflozin
JP5769710B2 (ja) * 2010-07-22 2015-08-26 ビオフェルミン製薬株式会社 脂質代謝改善剤、脂質代謝改善作用増強剤、抗肥満剤及び抗肥満作用増強剤
US20130156720A1 (en) 2010-08-27 2013-06-20 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
CA2828343A1 (en) 2011-03-04 2012-09-13 The Scripps Research Institute Edn3-like peptides and uses thereof
AR085689A1 (es) 2011-03-07 2013-10-23 Boehringer Ingelheim Int Composiciones farmaceuticas de metformina, linagliptina y un inhibidor de sglt-2
PL2731947T3 (pl) 2011-07-15 2019-07-31 Boehringer Ingelheim International Gmbh Podstawiona dimeryczna pochodna chinazoliny, sposób jej wytwarzania i jej zastosowanie w kompozycjach farmaceutycznych do leczenia cukrzycy typu I i II
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US20150050371A1 (en) 2012-03-09 2015-02-19 Biotropics Malaysia Berhad Extract Formulations of Rhodamnia Cinerea And Uses Thereof
US9192617B2 (en) 2012-03-20 2015-11-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
JP6224084B2 (ja) 2012-05-14 2017-11-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 糸球体上皮細胞関連障害及び／又はネフローゼ症候群の治療に用いるｄｐｐ−４阻害薬としてのキサンチン誘導体
WO2013171166A1 (en) 2012-05-14 2013-11-21 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp-4 inhibitor for use in the treatment of sirs and/or sepsis
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
US9499482B2 (en) 2012-09-05 2016-11-22 Bristol-Myers Squibb Company Pyrrolone or pyrrolidinone melanin concentrating hormone receptor-1 antagonists
US9586900B2 (en) 2012-09-05 2017-03-07 Bristol-Myers Squibb Company Pyrrolone or pyrrolidinone melanin concentrating hormone receptor-1 antagonists
US9486433B2 (en) 2012-10-12 2016-11-08 Mochida Pharmaceuticals Co. Ltd. Compositions and methods for treating non-alcoholic steatohepatitis
ITMI20122090A1 (it) 2012-12-06 2014-06-07 Dipharma Francis Srl Sintesi di un inibitore delle glicosiltransferasi
ITMI20130083A1 (it) 2013-01-22 2014-07-23 Dipharma Francis Srl Imminozucchero in forma cristallina
US9889108B2 (en) 2013-03-15 2018-02-13 Mochida Pharmaceutical Co., Ltd. Compositions and methods for treating non-alcoholic steatohepatitis
AU2014235215A1 (en) 2013-03-15 2015-10-01 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
US9486494B2 (en) 2013-03-15 2016-11-08 Synergy Pharmaceuticals, Inc. Compositions useful for the treatment of gastrointestinal disorders
US10441560B2 (en) 2013-03-15 2019-10-15 Mochida Pharmaceutical Co., Ltd. Compositions and methods for treating non-alcoholic steatohepatitis
CA2812519A1 (en) 2013-04-05 2014-10-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US20140303097A1 (en) 2013-04-05 2014-10-09 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
HK1215398A1 (zh) 2013-04-05 2016-08-26 勃林格殷格翰国际有限公司 依帕列净的治疗用途
JP2016516804A (ja) 2013-04-17 2016-06-09 ファイザー・インク 心血管疾患を治療するためのｎ−ピペリジン−３−イルベンズアミド誘導体
EP2986304B1 (en) 2013-04-18 2022-01-12 Boehringer Ingelheim International GmbH Pharmaceutical composition, methods for treating and uses thereof
CN105764916B (zh) 2013-06-05 2021-05-18 博士医疗爱尔兰有限公司 鸟苷酸环化酶c的超纯激动剂、制备和使用所述激动剂的方法
US9593113B2 (en) 2013-08-22 2017-03-14 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
US9526728B2 (en) 2014-02-28 2016-12-27 Boehringer Ingelheim International Gmbh Medical use of a DPP-4 inhibitor
MX2017000026A (es) 2014-07-11 2017-05-01 Gilead Sciences Inc Moduladores de receptores tipo toll para el tratamiento de virus de inmunodeficiencia humana (vih).
RU2021109549A (ru) 2014-08-29 2021-05-13 Тес Фарма С.Р.Л. ИНГИБИТОРЫ α-АМИНО-β-КАРБОКСИМУКОНАТ ε-СЕМИАЛЬДЕГИД-ДЕКАРБОКСИЛАЗЫ
BR102015023450A2 (pt) 2014-09-16 2016-04-12 Gilead Sciences Inc formas sólidas de um modulador do receptor semelhante a toll
WO2016055901A1 (en) 2014-10-08 2016-04-14 Pfizer Inc. Substituted amide compounds
US9718777B2 (en) 2014-12-11 2017-08-01 Navinta, Llc Process for the preparation of high purity miglustat
ITUB20150176A1 (it) 2015-04-17 2016-10-17 Dipharma Francis Srl Sintesi di un azazucchero e i suoi intermedi
BR112018072298A2 (pt) 2016-05-02 2019-02-12 Florida State University Research Foundation, Inc. tratamento de infecções pelo vírus da zika usando inibidores da alfa-glicosidase
BR112018072401A2 (pt) 2016-06-10 2019-02-19 Boehringer Ingelheim International Gmbh combinações de linagliptina e metformina
EP3526199B1 (en) 2016-10-14 2022-04-13 Tes Pharma S.r.l. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
CN109922813A (zh) 2016-11-10 2019-06-21 勃林格殷格翰国际有限公司 药物组合物、治疗方法及其用途
JP7638868B2 (ja) 2018-11-20 2025-03-04 ティエエッセ ファルマ ソチエタ レスポンサビリタ リミタータ α－アミノ－β－カルボキシムコン酸セミアルデヒドデカルボキシラーゼ阻害剤
PE20220138A1 (es) 2019-01-18 2022-01-27 Astrazeneca Ab Inhibidores de la pcsk9 y metodos de uso de los mismos
US11369592B2 (en) 2020-02-21 2022-06-28 Florida State University Research Foundation, Inc. Treatment of human coronavirus infections using alpha-glucosidase glycoprotein processing inhibitors

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1555654A (en) * 1977-06-25 1979-11-14 Exxon Research Engineering Co Agricultural burner apparatus
DE2660486C2 (de) * 1975-12-29 1984-03-08 Nippon Shinyaku Co., Ltd., Kyoto Verwendung von 2-Hydroxymethyl-3,4,5-trihydroxypiperidin als Arzneimittel
US4065562A (en) * 1975-12-29 1977-12-27 Nippon Shinyaku Co., Ltd. Method and composition for reducing blood glucose levels
GB2020278B (en) * 1978-05-03 1983-02-23 Nippon Shinyaku Co Ltd Moranoline dervitives
JPS5943948B2 (ja) * 1978-07-06 1984-10-25 日本新薬株式会社 置換モラノリン誘導体
DE2830469A1 (de) * 1978-07-11 1980-01-24 Bayer Ag Herstellung von l-desoxy-nojirimycin und n-substituierten derivaten
JPS5943948A (ja) * 1982-09-03 1984-03-12 Toyota Motor Corp 可変ベンチユリ型気化器

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NO154918B (no) 1986-10-06
FI72715C (fi) 1987-07-10
NO154918C (no) 1987-01-14
IL55423A (en) 1982-09-30
FI782607A7 (fi) 1979-02-28
NO782713L (no) 1979-02-28
AT373239B (de) 1983-12-27
AU3930478A (en) 1980-03-06
AU520686B2 (en) 1982-02-18
EP0000947A1 (de) 1979-03-07
IL55423A0 (en) 1978-10-31
FI72715B (fi) 1987-03-31
AU3921478A (en) 1980-02-28
LU90211I2 (fr) 1998-04-08
US4639436A (en) 1987-01-27
JPS5446786A (en) 1979-04-12
IE47070B1 (en) 1983-12-14
ES472838A1 (es) 1979-03-16
NL960027I2 (nl) 1997-07-01
IT1111197B (it) 1986-01-13
US4260622A (en) 1981-04-07
JPS6231703B2 (enExample) 1987-07-09
NL960027I1 (nl) 1997-01-06
DK152753C (da) 1988-10-31
DE2860330D1 (en) 1981-03-12
GR73065B (enExample) 1984-01-30
HU182449B (en) 1984-01-30
IT7827067A0 (it) 1978-08-25
IE781716L (en) 1979-02-27
DK152753B (da) 1988-05-09
DK377678A (da) 1979-02-28
CA1123437A (en) 1982-05-11
ATA621778A (de) 1983-05-15
EP0000947B1 (de) 1981-01-14
PT68474A (de) 1978-09-01

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