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WO2006034605A1 - Nouveaux ammoniums a noyaux azabicycliques et leur utilisation pour le traitement des troubles lies au vieillissement des proteines - Google Patents

Nouveaux ammoniums a noyaux azabicycliques et leur utilisation pour le traitement des troubles lies au vieillissement des proteines Download PDF

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Publication number
WO2006034605A1
WO2006034605A1 PCT/CN2004/001119 CN2004001119W WO2006034605A1 WO 2006034605 A1 WO2006034605 A1 WO 2006034605A1 CN 2004001119 W CN2004001119 W CN 2004001119W WO 2006034605 A1 WO2006034605 A1 WO 2006034605A1
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WIPO (PCT)
Prior art keywords
ethyl
tetrahydro
oxo
hydrobromide
benzothiazole
Prior art date
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Ceased
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PCT/CN2004/001119
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English (en)
Chinese (zh)
Inventor
Song Li
Hao Cui
Lili Wang
Gang Cheng
Wu Zhong
Aihua Nie
Hongying Liu
Yuandong Hu
Junhai Xiao
Zhibing Zheng
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Beijing Molecule Science and Technology Co Ltd
Institute of Pharmacology and Toxicology of AMMS
Original Assignee
Beijing Molecule Science and Technology Co Ltd
Institute of Pharmacology and Toxicology of AMMS
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Application filed by Beijing Molecule Science and Technology Co Ltd, Institute of Pharmacology and Toxicology of AMMS filed Critical Beijing Molecule Science and Technology Co Ltd
Priority to PCT/CN2004/001119 priority Critical patent/WO2006034605A1/fr
Publication of WO2006034605A1 publication Critical patent/WO2006034605A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to a substituted azabicyclic salt compound, a process for the preparation thereof, a pharmaceutical composition containing the same, and the use of the compound for preventing or treating a disease or symptom associated with AGE (advanced glycosylation endproducts AGE), such as (i) Increase skin elasticity or reduce skin wrinkles, ( ⁇ ) treat diabetes, ( iii ) treat or alleviate the sequelae of diabetes, ( iv ) treat or relieve kidney damage, (V) treat or relieve vascular damage, (vi) treat or relieve Blood pressure, (vii) treatment or relief of retinopathy, (viii) treatment or relief of lens protein damage, (ix) treatment or relief of cataract, (X) treatment or relief of peripheral neuropathy, (xi) treatment or relief of osteoarthritis.
  • AGE advanced glycosylation endproducts AGE
  • ⁇ side chain residue of the amino acid on the surface of heme reacts with glucose to form heme Alc.
  • Such reactions occur in other proteins in the body, such as the lens, collagen and neuroprotein (Advanced Glycosylation; Chemistry, Bilolgy and Implications for Diabetes and Aging, Advances in Pharmacology, Vol. 23, pp. 1-34 Academic Press 1992).
  • the above reaction will accelerate when the blood sugar level of diabetes increases, normal
  • the above reaction also occurs under blood sugar conditions.
  • the aging process is closely related to the formation of lipofuscin.
  • the same monthly primordial protein aging can be simulated with sugar and collagen in vitro.
  • the glucose-induced gum product is captured by other proteins, which causes a cross-linking reaction between the proteins.
  • This glucose-induced cross-linking reaction produces advanced glycosylation endproducts (AGE), which is known to be associated with the concurrent effects of diabetes.
  • AGE advanced glycosylation endproducts
  • the normal aging process also causes an increase in AGE. Its abnormal pathochemical structure is also recognized by some specific receptors to cause complex diabetes and aging-related pathological changes.
  • the object of the present invention is to find and develop a small molecule cleavage agent for AGE, which is used to cleave an already formed AGE to prevent protein cross-linking, to cleave the already cross-linked protein, thereby promoting protein metabolism, and further improving AGE in Various pathological changes caused by increased body weight, including increased skin elasticity or reduced skin wrinkles, treatment of diabetes or treatment or relief of diabetes sequelae, kidney damage, vascular injury, hypertension, retinopathy, lens protein damage, cataract, peripheral neuropathy Or osteoarthritis.
  • the glycosylated protein which is acted upon by the protein cross-linking structure cleavage agent is not limited to human proteins, but also includes plant proteins or animal proteins in crops, thereby expanding the use of plant proteins and animal proteins in crops.
  • the present inventors have unexpectedly discovered that the racemates and optical isomers of the derivative compounds of the alicyclic structure having a five- to eight-membered formula in the formula I have a higher ratio than the US5 in vitro and in vivo.
  • the preferred compound ALT-711 disclosed in 656267 is better Ammonia
  • a first aspect of the invention relates to a compound of formula I, a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt or hydrate thereof.
  • X is 0 or s
  • Y is 0 or s
  • ⁇ is a C 5 ⁇ C 8 0 ⁇ alicyclic ring
  • R 2 is hydrogen, ( ⁇ (: 8 linear or branched alkyl or C 2 -C 8 straight or branched alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 8 cycloalkenyl, Hydroxy, d ⁇ C 4 alkoxy, d ⁇ c 4 alkylamino, fluorenyl, various sulfonic acid groups, halogen, nitrile group, trifluoromethyl, trifluoromethoxy, alkyl or alkenyl chain It may be unsubstituted or substituted by one or more groups selected from the group consisting of c 3 ⁇ c 8 cycloalkyl, c 5 ⁇ c 7 cycloalkenyl or
  • ⁇ ⁇ and Ar 2 are independently derived from an aromatic carbocyclic ring or a heterocyclic ring, wherein the ring may be monocyclic, bicyclic or tricyclic; each ring consists of 5 to 6 elements, and the heterocyclic ring contains 1 to 6 selected from below.
  • Heteroatoms 0, S, ⁇ ; the ring may be unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoro, trifluoromethoxy , C ⁇ Cs straight or branched alkyl, C 2 ⁇ C 6 straight or branched, ( ⁇ alkoxy, C 2 ⁇ C 4 alkenoxy, phenoxy, benzyloxy, carboxy or
  • Z_ is a pharmaceutically acceptable acid radical.
  • Another aspect of the invention relates to a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • Another aspect of the invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof, which comprises:
  • the compound of the formula V can be prepared according to the literature (Tetrahedron Letters No. 38, pp 3653-3656, 1979), to obtain a general formula I wherein ruthenium is Br, and optionally Converting the resulting compound to another salt using a suitable salt to provide a compound of formula I,
  • R 2 , X, ⁇ ⁇ ⁇ are as defined in the formula I.
  • Another aspect of the invention relates to the use of at least one compound of formula I or a pharmaceutically acceptable salt thereof or hydrate thereof for the manufacture of a medicament for the prevention and/or treatment of various diseases caused by glycosylation of a protein.
  • the present invention also relates to a method for preventing or treating various diseases caused by aging of protein glycosylation, which comprises administering a prophylactically and/or therapeutically effective amount of at least one compound of the formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof, in need thereof Patients who are prevented and/or treated.
  • glycosylated protein to which the compound of the present invention acts is not limited to human proteins, but also includes plant or animal organ proteins in crops, and thus the compounds or compositions of the present invention can be used for the preservation of plant proteins and animal proteins in crops.
  • the present invention relates to a compound of formula I, a racemate or an optical isomer thereof or a pharmaceutically acceptable salt thereof or a hydrate thereof
  • X is 0 or s
  • Y is 0 or s
  • R 2 is hydrogen, d ⁇ C 8 is straight-chain branched alkyl or C 2 -C 8 straight or branched alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 8 cycloalkenyl, hydroxy , d O) alkoxy, d-alkylamino, fluorenyl, various sulfonyl, halogen, nitrile, trifluoromethyl, trifluoromethoxy, wherein the alkyl or alkenyl chain may be unsubstituted, It may also be substituted by one or more groups selected from the group consisting of C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl or Ar 2 ,
  • ⁇ ⁇ and Ar 2 are independently selected from an aromatic carbocyclic ring or a heterocyclic ring, wherein the ring may be monocyclic, bicyclic or tricyclic; each ring is composed of 5 to 6 elements, and the heterocyclic ring contains 1 to 6 selected from below.
  • Heteroatoms 0, S, N;
  • the ring may be unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethyl Oxy, d ⁇ C 6 straight or branched alkyl, C 2 ⁇ C 6 straight or branched alkenyl, ⁇ 0 4 alkoxy, C 2 ⁇ C 4 alkenyloxy, phenoxy, benzyloxy Base, carboxyl or amino group,
  • Z is a pharmaceutically acceptable acid radical.
  • a preferred embodiment of the invention is a racemate or optical isomer represented by a compound of formula I or a pharmaceutically acceptable salt or 7J thereof,
  • the first one is the halogenate F-, Cl-, Br-, ⁇ , or methanesulfonate, p-toluenesulfonate. Among them, hydrogenate and methylate are most preferred.
  • the racemate or optical isomer of the hydrazine compound or a pharmaceutically acceptable salt or hydrate thereof is preferably the following compound:
  • the pharmaceutically acceptable salt of the racemate or optical isomer of the compound of the present invention includes inorganic Salt or organic salt, including but not limited to: hydrochloride, hydrobromide, amiodate, nitrate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, acetate, propionate, Butyrate, oxalate, trimethylacetate, adipate, alginate, lactate, citrate, alcoholate, succinate, maleate, fumaric acid Salt, picrate, aspartate, gluconate, benzoate, methanesulfonate, ethanesulfonate, besylate, p-toluenesulfonate and pamoate.
  • inorganic Salt or organic salt including but not limited to: hydrochloride, hydrobromide, amiodate, nitrate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, acetate, propionate
  • ⁇ is ⁇ ( 8 alicyclic
  • Y is 0 or S
  • R is hydrogen or d Cs straight or branched alkyl or C 2 ⁇ C 8 straight or branched alkenyl, 3 ⁇ ( 8 cycloalkyl, (: 5 ⁇ (: 8 cycloalkenyl, hydroxy, CC ⁇ oxy, d ⁇
  • Ar x and : Ar 2 are independently selected from an aromatic carbocyclic ring or a heterocyclic ring, and the ring of ⁇ may be a monocyclic or bicyclic tricyclic ring; wherein each ring is composed of 5 to 6 elements, and the heterocyclic ring contains 1 to 6 selected From the following heteroatoms: 0, S, N; the ring may be unsubstituted or substituted by one to three substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, three Fluoromethoxy, straight or branched alkyl, C 2 ⁇ C 6 straight or branched alkenyl, ( ⁇ ( 4 alkoxy, C 2 ⁇ C 4 alkenyloxy, phenoxy, benzyloxy) Base, carboxyl or amino group,
  • a compound of formula I wherein Z is Br is obtained, and optionally, the resulting compound is converted to another salt using a suitable salt to provide a compound of formula I,
  • the first one is a pharmaceutically acceptable acid radical.
  • reaction of the compound of the formula IV with the compound of the formula V is carried out in the presence of a solvent such as ethanol or acetonitrile or methyl ethyl ketone or in the case where the two materials have a solvent; in the case of a liquid without solvent, at 80 ° C ⁇ 100 ° C, 5 to 96 hours in nitrogen.
  • a solvent such as ethanol or acetonitrile or methyl ethyl ketone
  • the product obtained by the reaction can be crystallized by standing, recrystallized or purified by silica gel column chromatography.
  • the silica gel used here is silica gel for conventional chromatography, particle size. 10 ⁇ 40 ⁇ , the eluent is prepared from a single or a plurality of solvents, preferably from a different ratio of dichloromethane to methanol (the prepared mixed solution is purified to obtain the compound of the formula I.
  • the cyclic ketone of formula II is reacted with urea or urea under the action of iodine to give a compound of formula III, which is then treated with isoamyl nitrite in anhydrous tetrahydrofuran to give the compound of formula IV.
  • It can be purified by high vacuum distillation or silica gel chromatography.
  • the silica gel used here is silica gel for conventional chromatography, the particle size is 10 ⁇ 40 ⁇ , and the eluent is prepared from single or multiple solvents, preferably by ethyl acetate. A mixed solvent of cyclohexane in different proportions.
  • R 2 , Y and ⁇ ⁇ are as defined for the compound of formula I,
  • the compound of formula VI can be obtained by using the compound of formula VI as CH 2 and using copper bromide or bromine or NBS.
  • the purification method may be a high vacuum distillation or a chromatographic method.
  • the silicon used herein is a silica gel for conventional chromatography, and the particle size is 10 to 40 ⁇ m.
  • the eluent is prepared from a single solvent or a plurality of solvents, preferably acetic acid. A mixed solvent of ethyl ester and cyclohexane in different ratios.
  • the compound of formula V must be purified to remove a small amount of "dibromo.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a racemate or an optical isomer of a compound of the invention and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be prepared in a prepared form depending on the route of administration.
  • the compounds mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts.
  • the present invention can employ asymmetric synthesis to give a single optical isomer.
  • resolution of the racemate is the primary means of obtaining optically pure compounds.
  • a crystallization method of practical value is preferred: a racemic body Water, an organic solvent or a solution of a mixed solvent of water and an organic solvent, a chiral acid (resolving agent) is added to form a diastereomer, and the solubility of the diastereomer in the solvent is different.
  • a chiral acid is tartar, mandelic acid, camphorsulfonic acid, etc.
  • the chromatographic method is mainly carried out by using a HPLC chiral column to obtain a single optical purity compound.
  • compositions of the present invention comprise an effective amount of a compound of formula I according to the invention, or a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutically acceptable carriers.
  • Pharmaceutical carriers herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, Partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone , Cellulose, Polyethylene Glycol, Sodium Carboxymethyl Cellulose, Polyacrylate, Beeswax, Lanolin.
  • the compounds of the invention are a class of potent cross-linking protein cleavage agents. Compared with ALT-711, the compounds of the present invention have better ability to cleave glycosylated aging proteins, and thus can be used for preventing fire treatment of AGE-related rickets, including but not limited to
  • the invention may also be extended to prevent or reverse tooth coloration due to non-enzymatic glycosylation reactions in the oral cavity.
  • the regimen containing the compound of the present invention can be varied depending on the use involved.
  • the compounds of the present invention and pharmaceutical compositions thereof can be used in the oral cavity. Especially used as an additive in oral cleaning solutions and toothpastes.
  • the compound of the present invention can be applied to a mouthwash and a toothpaste in a suitable form of a non-toxic and pharmaceutically acceptable carrier.
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Inside, intraventricular, intrasternal and intracranial injection or input, or with an explant.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier used for the tablet generally comprises lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsule preparation generally comprises lactose and dried corn starch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with suitable emulsifying and suspending agents. If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.
  • the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs.
  • Form 5 is specifically illustrated as follows: When applied topically to the eye, the compound of the invention may be formulated into a micronized suspension
  • the carrier used is an isotonic, sterile saline solution of a certain pH, with or without a preservative such as a benzyl chloride alkoxide. For ophthalmic use, it can also be formulated into a paste-shaped cream.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be in the form of a suitable ointment, lotion or cream preparation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers for ointment preparations include, but are not limited to: mineral oil, liquid Vaseline white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams which may be used include, but are not limited to: mineral oils , sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions.
  • a sterile injectable preparation including sterile aqueous or oily suspension or sterile injection solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the dosage and method of use of the compounds of the invention will depend on a number of factors including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition. And the subjective judgment of the doctor.
  • the preferred dosage is from 0.01 to 100 mg/kg body weight per day, wherein the optimal dose is from 20 mg/kg to 30 mg/kg body weight per day.
  • Example 10 3-[2-( 2,5-Dimethoxy-phenyl)-2-oxo-ethyl - 4, 5, 6, 7 -tetrahydro-benzothiazole-3 -hydrogen Bromate
  • Example 12 3-[2-(4-Nitro-phenyl)-2-oxo-ethyl] -4, 5, 6, 7-tetrahydro-benzothiazole - bromic acid
  • Bovine serum albumin BSA (V) ( Roch ) SOmg ml and 0.5M glucose were incubated in 0.2M PBS (pH 7.4) at 37 ° C under sterile conditions for 3-4 months in the dark to form a glycosyl group.
  • BSA is BSA-AGE.
  • aglycosylated BSA was prepared with glucose-free BSA.
  • dialysis was carried out in 0. OIM PBS (pH 7, 4), and unreacted glucose was removed. Fluorescence scanning (Exi/Em (395/460 am)) and SDS-PAGE were used to identify BSA-AGE formation, and the Lowery method was used. Protein quantification.
  • the tail collagen was coated in a 96-well plate, and the acidic collagen was neutralized with pH 7.4 PBS; SuperBlock (PIERCE) 37. C, blocked lh; PBST (PBS-Tween) wash plate 3 times, shaking for 1 minute each time; dilute AGE-BSA with PBS to obtain maximum cross-linking concentration of AGE-BSA ⁇ into 96-well plates A, B, C In the wells of row D, the same concentration of BSA was added to the E, F, G, and H rows, and PBS was used as the system and reagent blank in the first 3 wells of the first column, and crosslinked with collagen for 4 hours at 37 ° C; PBST The plate was washed 4 times with an interval of 1 min; the test compound was diluted with H7.4 PBS, and ⁇ /well was added to each of the AGE-BSA cross-linking and BSA 4 wells, and PBS ⁇ /well was added as a non-lytic control in the same manner.
  • the average OD value was a 4-well average.
  • Table 1 ELISA assay for compound cleavage rate of AGE-BSA-collagen cross-linking
  • Wi s ter rats male, weighing 180-200 g, intraperitoneal injection of urinary sputum, 65 mg/Kg, once, blood glucose level was higher than 16 awake ol/L rats, often kept for 32 weeks.
  • 32-week diabetic rats were divided into 5 groups, 8-10 each, intraperitoneally injected with physiological salt ice, ALT-711 (1mg/Kg), #16 compound, 1 mg/Kg, #16 compound, 3 mg/ Kg, #16 compound, 10 mg/Kg, once a day for 3 weeks.
  • RBC-IgG analysis was performed in Mul t screen-IP, 0. 45 ⁇ , 96 ⁇ L plate (Mi ll ipore, MAIPS4510) with 300 ⁇ l Superblock ( PIERCE ) at 37 °C for 1 h, washed once with PBST full well, and then with PBS. Plates were washed twice; RBC 50 ⁇ l diluted and mixed with PBS was added to the wells, and '4 replicate wells were added to each rat RBC sample, while 4 wells were added to PBS as antibody control wells. PBS 3 ⁇ 4t RBC 1 time, force ⁇ into 50 ⁇ 1
  • Horseradish peroxidase-labeled rabbit anti-rat IgG (1:2000), room temperature, 2 h; wash 4 times with PBS, add substrate solution 0PD (o-phenylenediamine) ⁇ ⁇ /well, room temperature, protected from light for 30 min; The reaction was terminated with 2 mmol/L H 2 S0 4 50 ⁇ l/well; 120 ⁇ l of each well was transferred to a common 96-well microtiter plate, and the plate blank was zeroed at a BOBRAD Model 550 plate reader at 490 nm, and the 0D value was read.
  • substrate solution 0PD o-phenylenediamine
  • the RBC-IgG content is expressed as the corrected value of the sample 0D value, and the average 0D value of each sample is the average of 4 wells, and the average RBC-IgG content of each sample is 8 animals. average value.
  • the rate of cleavage is expressed as a percentage reduction in RBC-IgG content:

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Abstract

La présente invention concerne des ammoniums à noyaux azabicycliques de formule générale I, dans laquelle la définition de chaque radical est décrite dans la description, et/ou leurs sels et hydrates pharmaceutiquement acceptables ; les compositions pharmaceutiques comprenant ces mêmes éléments, également en vue de l’utilisation de ces compositions pour la préparation de médicaments destinés à (i) améliorer l’élasticité ou réduire les rides cutanées, (ii) traiter le diabète, (iii) traiter ou améliorer des effets indésirables liés au diabète, (iv) traiter ou améliorer des lésions rénales, (v) traiter ou améliorer le système vasculaire sanguin, (vi) traiter ou améliorer l’hypertension, (vii) traiter ou améliorer la rétinopathie, (viii) traiter ou améliorer les lésions des protéines lenticulaires, (ix) traiter ou améliorer les cataractes, (x) traiter ou améliorer la neuropathie périphérique, (xi) traiter ou améliorer l’arthrose, ou utilisation pour la préparation d’un médicament oral visant à prévenir ou à inverser la coloration des dents, ou utilisation pour la préparation de divers conservateurs de fraîcheur pour les protéines de plantes cultivées et les protéines animales.
PCT/CN2004/001119 2004-09-28 2004-09-28 Nouveaux ammoniums a noyaux azabicycliques et leur utilisation pour le traitement des troubles lies au vieillissement des proteines Ceased WO2006034605A1 (fr)

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WO1996022095A2 (fr) * 1995-01-18 1996-07-25 Alteon Inc. Utilisation de composes de thiazolium pour empecher et inverser la formation de produits finis de glycosylation avancee
WO2001052847A1 (fr) * 2000-01-19 2001-07-26 Alteon, Inc. Composes thiazole, imidazole et oxazole et traitements de troubles associes au vieillissement des proteines
WO2001062250A1 (fr) * 2000-02-23 2001-08-30 Alteon, Inc. Composes de thiazolium et traitements de troubles lies au vieillissement des proteines
JP2003183253A (ja) * 2001-12-20 2003-07-03 Nippon Soda Co Ltd Ｎ−オニウム塩化合物および酸発生剤およびそれらを含有する硬化性組成物
CN1534027A (zh) * 2003-04-02 2004-10-06 中国人民解放军军事医学科学院毒物药 新的取代五元氮杂环盐类化合物及其治疗蛋白老化相关疾病的用途
CN1534028A (zh) * 2003-04-02 2004-10-06 中国人民解放军军事医学科学院毒物药 新的氮杂双环盐类化合物及其治疗蛋白老化疾病的用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022095A2 (fr) * 1995-01-18 1996-07-25 Alteon Inc. Utilisation de composes de thiazolium pour empecher et inverser la formation de produits finis de glycosylation avancee
WO2001052847A1 (fr) * 2000-01-19 2001-07-26 Alteon, Inc. Composes thiazole, imidazole et oxazole et traitements de troubles associes au vieillissement des proteines
WO2001062250A1 (fr) * 2000-02-23 2001-08-30 Alteon, Inc. Composes de thiazolium et traitements de troubles lies au vieillissement des proteines
JP2003183253A (ja) * 2001-12-20 2003-07-03 Nippon Soda Co Ltd Ｎ−オニウム塩化合物および酸発生剤およびそれらを含有する硬化性組成物
CN1534027A (zh) * 2003-04-02 2004-10-06 中国人民解放军军事医学科学院毒物药 新的取代五元氮杂环盐类化合物及其治疗蛋白老化相关疾病的用途
CN1534028A (zh) * 2003-04-02 2004-10-06 中国人民解放军军事医学科学院毒物药 新的氮杂双环盐类化合物及其治疗蛋白老化疾病的用途

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