CN1534028A - New azadicyclo salt kind compound and its use in treating protein aging disease - Google Patents
New azadicyclo salt kind compound and its use in treating protein aging disease Download PDFInfo
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- CN1534028A CN1534028A CNA031086527A CN03108652A CN1534028A CN 1534028 A CN1534028 A CN 1534028A CN A031086527 A CNA031086527 A CN A031086527A CN 03108652 A CN03108652 A CN 03108652A CN 1534028 A CN1534028 A CN 1534028A
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Abstract
An azaheterocyclic compound and/or its pharmacological salt and hydrate, their medicinal composition and their application in preparing medicines for increasing skin elasticity and treating diabetes, renal injury, vascular injury, hypertension etc and in preparing the antistaling agent of protein are disclosed.
Description
Technical field
The present invention relates to substituted nitrogen heterocyclic dicyclo salt compounds, its preparation method, the pharmaceutical composition and the purposes of described compound in prevention or treatment and AGE (advancedglycosylation endproducts AGE) diseases associated or symptom that contain them, increase skin elasticity or reduce wrinkle of skin as (i), (ii) treat diabetes, the (iii) treatment or the sequela of diabetes-alleviating, (iv) treat or the alleviation kidney injury, (v) treatment or alleviating vascular damage, (vi) treat or alleviation hypertension, (vii) treat or the relieving retina pathology, (viii) treatment or the damage of alleviation crystallin, (ix) treatment or alleviation cataract, (x) treatment or alleviation peripheral neuropathy, (xi) treatment or relief from osteoarthritis.
Background technology
There is reaction between known sugars and the albumen, as far back as 1912, Maillard finds glucose and other reducing sugar and amino acid reaction, formed stable brown pigment through a series of dehydrogenation rearrangement, discover that further storage and heat food also can produce this pigment that is formed by sugar and polypeptide, the formation of this pigment has reduced proteic biological activity, and relevant application patent can be with reference to US.08/588249.The reducing sugar of this non-enzymatic catalysis and the reaction of free amino acid can form a kind of stable diketo by product, promptly known Amadori product.Particularly the β side chain residue of protoheme surface amino groups acid and glucose response generate protoheme Alc.Such reaction also can take place in other albumen in the body, such as lens, collagen protein and neuroprotein (Advanced Glycosylation; Chemistry, Bilolgy andImplications for Diabetes and Aging, Advances inPharmacology, Vol.23, pp.1-34 Academic Press 1992).
Above-mentioned being reflected at can quicken under the situation that the diabetes glucose level increases to take place, and also above-mentioned reaction can take place under the euglycemia state.The formation of aging course and lipofuscin simultaneously is closely related, and same collagen protein wears out and can simulate with sugar and collagen protein external.The collagen product of glucose induction has been caused the crosslinking reaction between the albumen like this by other albumen capture reaction.This glucose induction crosslinking reaction produced is advanced glycation end products (advancedglycosylation endproducts AGE), known AGE is relevant with the concurrent effect of diabetes, normal aging course also causes the increase of AGE, thereby intravital AGE is not only because its unusual pathological chemistry structure but also can be caused the pathological change that complicated diabetes are relevant with aging by some specific acceptors identification.
The methods of treatment that some accumulation aspects by stoping AGE have been arranged at present.One of them method can be referring to US.4758583, its guide's thing aminoguanidine and analogue thereof can stop the formation of AGE, thereby, also stoped AGE simultaneously and organized further crosslinked by having stoped glycation product further to transform into AGE with early stage glycation product reaction.The validity of this method is estimated on the animal model of diabetes and aging rat, also comprises other indexs as great vessels, kidney and europathology aspect simultaneously.People such as Vlassara sum up these data.(Vlassara et al, 1994 Biology of Diseases, " Pathogenic effects of advanced glycosylation:biochemical, biologic and clinical implications fordiabetes and aging " Laboratory Investigation 70:138-151; Brownlee, 1995, " The pathological implications of proteinglycation " Clin.Invest.Med., 18:275-281; And Brownlee, 1995, " Advanced protein glycosylation in diabetes and aging ", Ann.Rev.Med.46:223-34.)
The another kind of method of controlling AGE in the tissue has particularly formed in tissue and the method for cumulative AGE cross-linking products (these cross-linking products cause clinical or subclinical pathological change) is the AGE cross-linking products that reverse or cracking have formed.People such as Vassan prove that the method for this cracking AGE is effective (vassan et al Nature.1996, Vol.382 (18) 275-278).The AGE crosslinking structure that compound, preparation and the method for announcing in United States Patent (USP) U.S.5656261 and US08/588249 and US08/848776 can be have in vivo formed with external cracking.Studies show that the cardiovascular disorder that this compounds causes for aging has good effect (Wolffenbuttel etal., 1998, " Breakers of Advanced Glycation End ProductsRestores Large Artery Properites in ExperimentalDiabetes ", Proc.Nat.Acad.Sci.U.S.A.95:4630-4634).In these researchs, given reversing in diabetes rat AGE cracking agent 1-3 week of 9 weeks because the Aorta sclerosis that diabetes cause.The parameter of improving has cardiac output, Peripheral resistance, body arterial compliance, aorta input resistance and carotid artery conformability (US.6319934).
Summary of the invention
The objective of the invention is to seek and developmental function in the small molecules cracking agent of AGE, thereby being used for the AGE that cracking formed stops protein-crosslinking, crosslinked albumen is carried out cracking, thereby promote proteic metabolism, further improve owing to AGE in vivo increase the various pathological changes that cause, comprise and increase skin elasticity or reduce wrinkle of skin, sequela, kidney injury, blood vessel injury, hypertension, retinopathy, crystallin damage, cataract, peripheral neuropathy or the osteoarthritis of treatment diabetes or treatment or diabetes-alleviating.The glycosylated protein that this protein-crosslinking structure cracking agent of while is acted on is not limited to human body protein, also comprises vegetable-protein or animal proteinum in the farm crop, thereby can expand the fresh-keeping purposes that is used for farm crop vegetable-protein and animal proteinum.
The present invention has been found that the compound of general formula I can be used for the treatment of and/or prevent the multiple disease that is caused by protein glycosylation.
The inventor finds unexpectedly, R in general formula I
1The position is to have than better AGE lytic activity of the preferred compound ALT-711 that discloses among the US5656267 and lower toxicity on one five yuan to eight yuan the raceme of new compound of alicyclic structure and the multiple in vitro and in vivo model of optically active isomer.
Therefore first aspect of the present invention relates to the compound of general formula I, its raceme or optically active isomer or its pharmacologically acceptable salt or hydrate.
Wherein:
X is O or S,
Y is O or S,
R
1Be a C
5～C
8Alicyclic ring,
R
2Be hydrogen, C
1～C
8Straight chain or branched-chain alkyl or C
2～C
8Straight chain or branched-chain alkenyl, C
3～C
8Cycloalkyl, C
5～C
8Cycloalkenyl group, hydroxyl, C
1～C
4Alkoxyl group, C
1～C
4Alkylamino, sulfydryl, various sulfonic groups, halogen, itrile group, trifluoromethyl, trifluoromethoxy can not have replacement on alkyl wherein or the alkenylene chain, can be selected from one or more following group yet and replace: C
3～C
8Cycloalkyl, C
5～C
7Cycloalkenyl group or Ar
2,
Ar
1And Ar
2Independently be selected from aromatic carbocyclic or heterocycle, ring wherein can be monocycle, dicyclo or three rings; Each ring is elementary composition by 5～6, comprises 1～6 in the heterocycle and is selected from following heteroatoms: O, S, N; Can not have replacement on the ring, can be selected from following substituting group yet and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C by 1-3
1～C
6The straight or branched alkyl, C
2～C
6The straight or branched thiazolinyl, C
1～C
4Alkoxyl group, C
2～C
4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl or amino,
Z
-It is acceptable acid group pharmaceutically.
The present invention relates to pharmaceutical composition on the other hand, and it comprises at least a compound of Formula I or its pharmaceutical salts or its hydrate and pharmaceutical carrier or vehicle.
The present invention relates to the method for preparing compound of Formula I or its pharmaceutical salts or its hydrate on the other hand, and it comprises:
A) with following formula thiocarbamide or urea and have the cyclic ketones of formula II
R wherein
1Definition cotype I described in,
React under halogen catalysis according to document (J.Amer.Chem.Soc., 1949,71,4007) and to obtain the formula III compound,
R wherein
1Described in X definition cotype I,
B) formula III compound and Isopentyl nitrite reaction are obtained formula IV compound
R wherein
1Described in X definition cotype I,
C) with formula IV compound and the reaction of formula V compound
R wherein
2, Y and Ar
1Definition the same, formula V compound can be according to document (Tetrahedron Letters No.38, pp 3653-3656,1979) preparation obtains the compound of Formula I that Z is Br, and randomly, adopt suitable salt to change resulting compound into another kind of salt, obtain compound of Formula I
R wherein
1, R
2, X, Ar
1And described in the definition cotype I of Z.
Another aspect of the present invention relates to the purposes that at least a formula I compound or its pharmaceutical salts or its hydrate are used to prepare the medicine that prevents and/or treats the various diseases that protein glycosylation causes.
The invention still further relates to the method that prevents and/or treats the aging various diseases that is caused of protein glycosylation, it comprises needs the above-mentioned patient who prevents and/or treats with preventing and/or treating at least a formula I compound of significant quantity or its pharmaceutical salts or its hydrate.
The glycosylated protein that The compounds of this invention can act on is not limited to human body protein, also comprises plant or animal organ's albumen in the farm crop, thereby The compounds of this invention or composition can be used for the fresh-keeping purposes of farm crop vegetable-protein and animal proteinum.
More particularly, the present invention relates to formula I compound, its raceme or optically active isomer or its pharmaceutical salts or its hydrate
Wherein:
X is O or S,
Y is O or S,
R
1Be a C
5～C
8Alicyclic ring,
R
2Be hydrogen, C
1～C
8Straight chain or branched-chain alkyl or C
2～C
8Straight chain or branched-chain alkenyl, C
3～C
8Cycloalkyl, C
5～C
8Cycloalkenyl group, hydroxyl, C
1～C
4Alkoxyl group, C
1～C
4Alkylamino, sulfydryl, various sulfonic groups, halogen, itrile group, trifluoromethyl, trifluoromethoxy can not have replacement on alkyl wherein or the alkenylene chain, can be selected from one or more following group yet and replace: C
3～C
8Cycloalkyl, C
5～C
7Cycloalkenyl group or Ar
2,
Ar
1And Ar
2Independently be selected from aromatic carbocyclic or heterocycle, ring wherein can be monocycle, dicyclo or three rings; Each ring is elementary composition by 5～6, comprises 1～6 in the heterocycle and is selected from following heteroatoms: O, S, N; Can not have replacement on the ring, can be selected from following substituting group yet and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C by 1-3
1～C
6The straight or branched alkyl, C
2～C
6The straight or branched thiazolinyl, C
1～C
4Alkoxyl group, C
2～C
4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl or amino,
Z
-It is acceptable acid group pharmaceutically.
The raceme that a preferred embodiment of the present invention is a formula I compounds represented or optically active isomer or its pharmacologically acceptable salt or hydrate,
Wherein:
X is S,
Y is O,
R
1, R
2And Ar
1Definition same as above,
Z
-Be halogen acid group F
-, Cl
-, Br
-, I
-, perhaps methanesulfonate is to the methylsulphonic acid root.Wherein most preferably Hydrogen bromide root and methanesulfonate.
According to the present invention, the compound below the raceme of formula I compound or optically active isomer or its pharmaceutical salts or hydrate are preferred:
Wherein more preferably
(±) 3-[2-(4-bromo-phenyl)-1-methyl-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
(±) 3-(1-methyl-2-oxygen-2-phenyl-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
The raceme of The compounds of this invention or the pharmacologically acceptable salt of optically active isomer comprise its inorganic salt or organic salt, and it includes but not limited to: hydrochloride, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, oxalate, pivalate, adipate, alginate, lactic acid salt, Citrate trianion, tartrate, succinate, maleate, fumarate, picrate, aspartate, gluconate, benzoate, mesylate, esilate, benzene sulfonate, tosilate and embonate.
Formula I compound of the present invention can prepare by following reaction scheme:
Reaction scheme I:
It comprises formula IV compound:
X is O, S,
R
1Be C
5～C
8Alicyclic ring,
React with formula V compound,
Y is O or S,
R
2Be hydrogen or C
1～C
8Straight chain or branched-chain alkyl or C
2～C
8Straight chain or branched-chain alkenyl, C
3～C
8Cycloalkyl, C
5～C
8Cycloalkenyl group, hydroxyl, C
1～C
4Alkoxyl group, C
1～C
4Alkylamino, sulfydryl, various sulfonic groups, halogen, itrile group, trifluoromethyl, trifluoromethoxy can not have replacement on alkyl wherein or the alkenylene chain, can be selected from one or more following group yet and replace: C
3～C
8Cycloalkyl, C
5～C
7Cycloalkenyl group or Ar
2,
Ar
1And Ar
2Independently be selected from aromatic carbocyclic or heterocycle, ring wherein can be monocycle, dicyclo or three rings; Wherein each ring is elementary composition by 5～6, comprises 1～6 in the heterocycle and is selected from following heteroatoms: O, S, N; Can not have replacement on the ring, can be selected from following substituting group yet and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C by 1-3
1～C
6The straight or branched alkyl, C
2～C
6The straight or branched thiazolinyl, C
1～C
4Alkoxyl group, C
2～C
4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl or amino,
Obtaining Z is the formula I compound of Br, and randomly, adopts suitable salt to change resulting compound into another kind of salt, obtains compound of Formula I,
X wherein, Y, R
1, R
2And Ar
1Definition the same,
Z
-It is acceptable acid group pharmaceutically.
On the superincumbent reaction scheme, the reaction of formula IV compound and formula V compound is a kind ofly not under the situation of solubilizing agent, in 80 ℃～100 ℃, to carry out in the nitrogen 5～96 hours when the liquid in the presence of solvent such as ethanol or acetonitrile or the butanone or when two kinds of raw materials have.
The product that reaction obtains can leave standstill crystallization, and recrystallization or use silica gel column chromatography are handled and purified again.Here employed silica gel is conventional silica gel for chromatography, granularity 10～40 μ m, and eluent is formulated by single or multiple solvent, is preferably pressed the mixed solvent of different ratios preparation by methylene dichloride and methyl alcohol.Obtain formula I compound of the present invention behind the purifying.
Can adopt employed formula IV compound, for example route II in the synthetic above-mentioned reaction scheme of several different methods.
Reaction scheme II:
R wherein
1, the definition cotype I formula compound of X,
The cyclic ketones of employing formula II obtains the formula III compound with thiocarbamide or urea reaction under the effect of iodine, handle deaminize with Isopentyl nitrite then in anhydrous tetrahydro furan, obtains formula IV compound.Can adopt the method purifying of molecular distillation or silica gel column chromatography, here employed silica gel is conventional silica gel for chromatography, granularity 10～40 μ m, eluent is formulated by single or multiple solvent, is preferably pressed the mixed solvent of different ratios preparation by ethyl acetate and hexanaphthene.
Employed formula V compound can prepare (Tetrahedron Letters No.38, pp3653-3656,1979) according to the method for document record in reaction scheme I:
R wherein
2, Y and Ar
1Definition cotype I compound,
The α position of employing formula VI is CH
2Compound, and the bromo that adopts cupric bromide or bromine or NBS to carry out the α position obtains formula V compound.The purifying mode that can adopt is the method for molecular distillation or chromatography, here employed silica gel is conventional silica gel for chromatography, granularity 10～40 μ m, eluent is formulated by single or multiple solvent, is preferably pressed the mixed solvent of different ratios preparation by ethyl acetate and hexanaphthene.Formula V compound must be removed a spot of α position two bromo-derivatives by purifying.
Another aspect of the present invention relates to pharmaceutical composition, and it contains raceme or the optically active isomer and at least a pharmaceutically acceptable carrier of The compounds of this invention.Described pharmaceutical composition can be prepared into various forms according to different way of administration.The mentioned compound of the present invention also can be prepared to various pharmacologically acceptable salts.
The present invention can adopt asymmetric synthesis to obtain single optically active isomer.But the fractionation to racemic modification is the main means that obtain optical pure compound.Method for splitting mainly contains following four kinds: crystallization process, chromatography, KINETIC METHOD and enzyme process.Fractionation for the compound raceme that the present invention relates to, preferably have the crystallization process of practical value: in the solution of the mixed solvent that water, organic solvent or the water of raceme and organic solvent form, add a kind of chiral acid (resolving agent), form diastereomer, utilize diastereomer in solvent different solubility and one of them is preferentially separated out.Preferred chiral acid can be a tartrate, mandelic acid, and camphorsulfonic acid etc., and chromatography mainly uses the HPLC chiral column to separate the compound that obtains single optical purity.
Pharmaceutical composition of the present invention comprises formula I compound or pharmaceutically acceptable salt thereof of the present invention or hydrate and one or more suitable pharmaceutically acceptable carrier of effective dose.The pharmaceutical carrier here includes but not limited to: ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum albumin, buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, lanolin.
The compounds of this invention is the potent crosslinking protein cracking agent of a class.Compare with ALT-711, The compounds of this invention has the aging proteic ability of better cracking glycosylation, therefore can be used for pre-fire prevention treatment and AGE diseases associated, it increases skin elasticity or reduces wrinkle of skin including, but not limited to (i), (ii) treat diabetes, the (iii) treatment or the sequela of diabetes-alleviating, (iv) treat or the alleviation kidney injury, (v) treatment or alleviating vascular damage, (vi) treatment or alleviation hypertension (are vii) treated or the relieving retina pathology, (viii) treatment or the damage of alleviation crystallin, (ix) treatment or alleviation cataract, (x) treatment or alleviation peripheral neuropathy, (xi) treatment or relief from osteoarthritis.
The present invention also can expanded application in stoping or reversing because the tooth staining that the non-enzymatic glycosylation in the oral cavity causes.The therapeutic regimen that contains compound of the present invention can change according to related purposes.
The non-enzymatic reaction that occurs in the oral cavity can cause tooth staining.At present employed anti-moth erosion agent can be quickened this carbonylation reaction and further cause the painted of tooth.The cationic germicide that has a class to have anti-moth erosion function recently is used for conventional oral cavity and cleans.These cationic antibacterial agent have the A Laixi fourth, cetyl pyridinium oxymuriate or the like.And these preparations can quicken a step Maillard reaction crucial in the glycosylation, and then painted (Nordbo, J.Dent.Res., the 58:1429 (1979)) of acceleration tooth.And be reported in that observation in vitro has arrived Tubulicid and benzalkonium chloride can catalysis glycosylation (brownization reaction).Because the Maillard reaction, Tubulicid adds the formation of having quickened pigment in sugar and the amino acid whose mixture.
For these reasons, compound involved in the present invention and pharmaceutical composition thereof can be used for the oral cavity.Additive in oral cavity scavenging solution and the toothpaste.
In the such use of relevant The compounds of this invention, can adopt the appropriate form of nontoxic and pharmaceutically acceptable carrier to be applied in Jiekouye gargle and the toothpaste.
The pharmaceutical composition of The compounds of this invention can be used with following any-mode: oral, spraying sucks, rectal application, nasal cavity applied medicine, cheek medication, local application, non-enterally administer, as subcutaneous, vein, intramuscular, intraperitoneal is in the sheath, in the ventricle, breastbone interior and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenous administration mode.
When medicine for oral use, The compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet uses generally comprises lactose and W-Gum, also can add lubricant such as Magnesium Stearate in addition.The thinner that capsule preparations uses generally comprises lactose and dried corn starch.Aqueous suspension preparation then normally mixes use with activeconstituents with examples of suitable emulsifiers and suspension agent.If desired, also can add some sweeting agents, perfume compound or tinting material in the above oral preparations form.
When local medication, particularly treat local external application easy to reach and suffer from face or organ, during as eyes, skin or lower intestinal tract nervous system disease, can The compounds of this invention be made different local application's dosage forms, specify as follows according to different trouble faces or organ:
When the eye topical application, The compounds of this invention can be mixed with the dosage form of a kind of micronization suspension or solution, and the carrier that uses is the Sterile Saline of isoosmotic certain pH, wherein can add also not adding preservative agent such as zephiran chloride alkoxide.For eye usefulness, also compound can be made paste form such as vaseline paste.
When topical application, The compounds of this invention can be made into suitable ointment, lotion or creme dosage form, wherein activeconstituents is suspended or is dissolved in one or more carriers.The spendable carrier of ointment formulation includes but not limited to: mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The all right aseptic injection preparation form medication of The compounds of this invention comprises aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilization also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.
It may be noted that in addition, the using dosage of The compounds of this invention and using method will depend on all multifactor, comprise activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of patient's age, body weight, sex, natural health situation, nutritional status, compound.Preferred using dosage is between 0.01～100mg/kg body weight/day, and wherein optimal dosage is in the 20mg/kg-30mg/kg body weight/day.
Embodiment
Embodiment
Following enforcement illustrative preferred embodiment on the contrary of the present invention does not constitute any limitation the present invention.
Melting point compound is measured by SRY-1 type fusing point instrument, and temperature is not calibrated.
1H-NMR spectrum is measured by Bruker ARX 400 or US Varian Unity Inova 600 type nuclear magnetic resonance spectrometers, and the FAB mass spectrum is measured by the Zabspect high-resolution mass spectrometer.
Preparation 1:4,5,6,7-tetrahydrochysene-benzothiazole-2-amine
With 39 gram (0.4mol) pimelinketone, 61 gram (0.8mol) thiocarbamides and 102 gram (0.8mol) iodine are poured in the 2000ml hot water then 100 ℃ of heating 9 hours, remove by filter insolubles,, divide three extractions with the 600ml chloroform with the ammoniacal liquor alkalization, the organic phase anhydrous sodium sulfate drying filters, and reclaims solvent, add the 100ml ethyl acetate, crystallization obtains 20 gram products 4,5,6,7-tetrahydrochysene-benzothiazole-2-amine, 83～88 ℃ of fusing points.
Prepare 24,5,6, the 7-tetrahydrochysene-benzothiazole
With 11.5 gram (0.075mol) 4,5,6,7-tetrahydrochysene-benzothiazole-2-amine is dissolved in the 100ml anhydrous tetrahydro furan, is added drop-wise under 45 ℃ in the Isopentyl nitrite solution (150ml) of 1.5M, is added dropwise to complete the back and stirs 1 hour, reclaim solvent then, ethyl acetate: hexanaphthene=20: 1 column chromatographies obtains 3.5 gram products, productive rate 33%.
Embodiment 1:3-(2-xenyl-4-base-2-oxygen-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
With 1.08 gram (0.0077mol) 4,5,6, the 7-tetrahydrochysene-benzothiazole is dissolved in the 5ml dehydrated alcohol, adds 2.7 gram (0.01mol) 1-xenyl-4-base-2-bromo-ethyl ketones, and reflux 1.5 hours leaves standstill crystallization, filters to obtain crude product.Crude product process silica gel column chromatography column purification (methylene dichloride: methyl alcohol=8: 1), obtain the white solid title compound, (1.5g, 50%m.p.237-241 ℃), MS[M]
+=334.1m/e;
1H-NMR (600MHz, DMSO) δ 1.824 (m 4H); (2.674 m 2H); (2.942 m 2H); 6.369 (s2H); (7.475 m 1H); (7.556 t J=7.8Hz 2H); (7.811 ddJ=1.2,8.4Hz 2H); (7.977 dd J=1.8,7.2Hz 2H); (8.147 ddJ=1.8,7.2 2H); (9.995 s 1H).
Embodiment 2:3-[2-(3-nitro-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(3-nitro-phenyl)-ethyl ketone, obtains title compound (0.3g, 25%, m.p.215-219 ℃).
MS[M]
+＝303.0m/e；
1H-NMR(600MHz，DMSO)δ1.823(m?4H)；2.689(m?2H)；2.941(m?2H)；6.425(s?2H)；7.965(t?J＝8.4Hz1H)；8.460(d?J＝7.8Hz?2H)；8.612(d?J＝9.6Hz?2H)；8.775(tJ＝2.4Hz?2H)；9.962(s1H)。
Embodiment 3:3-[2-(4-methylsulfonyl-phenyl-2-oxygen-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(4-methylsulfonyl phenyl)-ethyl ketone, obtains title compound (1.25g, 96%, m.p.190-195 ℃).
MS[M]
+＝336.0m/e；
1H-NMR(600MHz，DMSO)δ1.821(m?4H)；2.675(m?2H)；2.937(m?2H)；3.33(s?3H)；6.365(s?2H)；8.222(dd?J＝1.8，6.6Hz?1H)；8.281(dd?J＝1.8，6.6Hz?2H)；9.966(s?1H)。
Embodiment 4:3-[2-(3, the 4-dichlorophenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(3, the 4-dichlorophenyl)-ethyl ketone, obtains title compound (1.05g, 81%, m.p.206-210 ℃).
MS[M]
+＝326.0m/e；1H-NMR(600MHz，DMSO)(1.814(m?4H)；2.658(m?2H)；2.929(m?2H)；6.314(s?2H)；7.992(m?2H)；8.300(d?J＝1.8Hz?2H)；9.943(s1H)。
Embodiment 5:3-(1-methyl-2-oxygen-2-phenyl-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-phenyl-propyl group-1-ketone, obtains title compound (0.53g, 42%, m.p.237-241 ℃).
MS[M]+＝273.3m/e；1H-NMR(600MHz，DMSO)(1.788(m?4H)；1.919(d?J＝7.2?3H)；2.42(d?J＝16.0Hz?1H)；2.929(m?2H)；3.091(d?J＝16.0Hz?1H)；6.890(m?1H)；7.662(m?2H)；7.805(m1H)；8.191(m?2H)；10.306(s?1H)。
Embodiment 6:3-[2-(4-bromo-phenyl)-1-methyl-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(4-bromo-phenyl)-propyl group-1-ketone, obtains title compound (0.6g, 26%, m.p.146-154 ℃).
MS[M]
+＝354.3m/e；
1H-NMR(600MHz，DMSO)δ1.786(m?4H)；1.902(dJ＝7.2Hz?3H)；2.498(m?1H)；2.923(m?2H)；3.055(m?1H)；6.8857(dd?J＝7.2，14.4Hz?1H)；7.889(m?2H)；8.143(m?2H)；10.32(s?1H)。
Embodiment 7:3-(2-naphthalene-2-base-2-oxygen-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(2-naphthalene-2-yl)-ethyl-1-ketone, obtains title compound (3g, 90%, m.p.190-193 ℃).
MS[M]
+＝308.1m/e；
1H-NMR(600MHz，DMSO)δ1.830(m?4H)；2.700(m2H)；2.953(m?2H)；6.471(s?2H)；7.709(m?2H)；8.073(m?4H)；8.825(m?1H)；10.034(s?1H)。
Embodiment 8:3-[2-(2-nitro-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(2-nitro-phenyl)-ethyl ketone, obtains title compound (1.1g, 83%, m.p.217-219 ℃).
MS[M]
+＝303.3m/e；
1H?NMR(600MHz，CD
3OD)δ2.029(m?4H)；2.910(m2H)；3.00(m?2H)；7.923(m?3H)；8.287(m?1H)。
Embodiment 9:3-[2-(3-methoxyl group-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(3-methoxyl group-phenyl)-ethyl ketone, obtains title compound (1.2g, 76%, m.p.196-200 ℃).
MS[M]
+＝288.0m/e；
1H-NMR(600MHz，DMSO)δ1.810(m?4H)；2.656(m?2H)；2.936(m?2H)；3.865(s?3H)；6.389(s?2H)；7.381(m?1H)；7.559(m?2H)；7.677(m?1H)；10.022(s?1H)。
Embodiment 10:3-[2-(2,5-dimethoxy-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(2,5-dimethoxy-phenyl)-ethyl ketone, obtains title compound (1.2g, 82%, m.p.210-215 ℃).
MS[M]
+＝318.1m/e；
1H-NMR(600MHz，DMSO)δ1.799(m?4H)；2.618(m?2H)；2.924(m?2H)；3.756(s?3H)；3.978(s?3H)；6.059(s?2H)；7.326(m?3H)；10.002(s?1H)。
Embodiment 11:3-(2-oxygen-2-right-tolyl-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(4-methyl-phenyl)-ethyl ketone, obtains title compound (0.3g, 22%, m.p.187-189 ℃).
MS[M]
+＝272.0m/e；
1H-NMR(600MHz，DMSO)δ1.810(m?4H)；2.504(m?3H)；2.642(m?2H)；2.931(m?2H)；6.325(s?2H)；7.465(d?J＝5.2Hz?2H)；7.966(d?J＝5.6Hz?2H)；10.002(s?1H)。
Embodiment 12:3-[2-(4-nitro-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(4-nitro-phenyl)-ethyl ketone, obtains title compound (0.5g, 32%, oily matter).
MS[M]
+＝303.1m/e；
1H-NMR(600MHz，DMSO)δ1.961(m?4H)；2.744(m?2H)；2.999(m?2H)；6.343(s?2H)；8.330(d?J＝9.0Hz2H)；8.439(d?J＝9.2Hz?2H)；9.934(d?J＝2Hz?1H)。
Embodiment 13:3-[2-(4-fluoro-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(4-fluoro-phenyl)-ethyl ketone, obtains title compound (3g, 88%, m.p.187-194 ℃).
MS[M]
+＝276.1m/e；
1H-NMR(600MHz，DMSO)δ1.948(m?4H)；2.706(m?2H)；2.986(m?2H)；6.246(s?2H)；7.354(m?2H)；8.191(m?2H)；9.909(s?1H)。
Embodiment 14:3-[2-(4-methoxyl group-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(4-methoxyl group-phenyl)-ethyl ketone, obtains title compound (0.9g, 50%, m.p.200-205 ℃).
MS[M]
+＝288.1m/e；
1H-NMR(600MHz，CD
3ODδ1.942(m?4H)；2.698(m?2H)；2.983(m?2H)；3.917(s?3H)；7.108(m?2H)；8.088(m?2H)。
Embodiment 15:3-[2-(4-chloro-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(4-chloro-phenyl)-ethyl ketone, obtains title compound (0.6g, 33%, m.p.196-202 ℃).
MS[M]
+＝292.1m/e；
1H-NMR(600MHz，DMSOδ1.949(m?4H)；2.703(m?2H)；2.987(m?2H)；6.232(s?2H)；7.640(m?2H)；8.097(m2H)；9.892(s?1H)。
Embodiment 16:3-[2-(4-bromo-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-(4-bromo-phenyl)-ethyl ketone, obtains title compound (0.4g, 23%, m.p.207-213 ℃).
MS[M]
+＝338.1m/e；
1H-NMR(600MHz，DMSOδ1.949(m?4H)；2.696(m?2H)；2.987(m?2H)；6.213(s?2H)；7.805(m?2H)；7.998(m2H)；9.878(s?1H)。
Embodiment 17:3-(2-xenyl-4-base-2-oxygen-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-mesylate
Compound (the 0.5g that will prepare by embodiment 1 method, 0.0012mol) and 0.26g (0.0012mol) methylsulfonic acid silver stirring reaction 10min in 15ml methyl alcohol, cross filter solid then, concentrate, it is an amount of to add ether, obtain crystalloid title compound (0.37g, 95%, m.p.229-232 ℃).
MS[M]
+＝334.1m/e；
1H-NMR(600MHz，DMSOδ1.823(m?4H)；2.298(S?3H)；2.677(m?2H)；2.944(m?2H)；6.388(s?2H)；7.480(m?1H)；7.548(m?2H)；7.805(m?2H)；7.815(d?J＝7.2Hz?2H)；7.978(d?J＝8.3Hz?2H)；8.150(d?J＝8.3Hz?2H)；10.017(s?1H)。
Embodiment 18:3-(2-oxygen-2-phenyl-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, bromo ketone wherein is 2-bromo-1-phenyl-ethyl ketone, obtains title compound (0.27g, 16%, m.p.204-210 ℃).
MS[M]
+＝259.1m/e；
1H-NMR(600MHz，DMSOδ1.950(m?4H)；2.712(m?2H)；2.991(m?2H)；6.288(t?J＝3.6Hz?2H)；7.608(m?2H)；7.732(m?1H)；8.104(m?2H)；9.938(d?J＝4.2Hz1H)。
The ELISA shaker test of embodiment 19 cracking AGE-BSA-collagen cross-linking structures
With AGE-BSA be coated on crosslinked, the external preparation of rat tail glue protein AGE crosslinking structure on the 96 hole enzyme plates, employing ELISA method assessing compound is to the crosslinked splitting action of AGE.
The 96 hole enzyme plate preparations of tail glue primordial covering:
(body weight 200 ± 20g), tail is got in acute execution to normal Wister rat, carries out with lower tail collagen protein preparation process under 4 ℃.At first, extract tail tendon collagen silk, with the physiological saline washing and remove non-collagen silk tissue, wash 3 times through distilled water again, shred, be soaked in 1 week in 0.1% Glacial acetic acid under 4 ℃, during jolt often.With the centrifugal 30min of 8000g, collect centrifugal supernatant collagen solution at last, protein content is measured in the dilution back.By 96 hole enzyme plates (Costar), 4 ℃, 24h discard coating buffer with the full hole of every hole 70 μ g collagen proteins bag, air-dry under the aseptic condition, preservative film bag quilt, and 4 ℃ of storages are standby.
The AGE-BSA preparation:
(Roch) 50mg/ml and 0.5M glucose are in 0.2M PBS (PH7.4) for bovine serum albumin BSA (V), and under 37 ℃ of aseptic conditions, lucifuge was hatched 3-4 month, and making it form glycosylation BSA is BSA-AGE.Simultaneously, the BSA with no glucose prepares sugar based BSA.Dialyse in 0.01M PBS (pH7.4) dialyzate then, remove unreacted glucose, fluorescent scanning (Exi/Em (395/460nm)) and SDS-PAGE identify that BSA-AGE forms, and adopts the Lowery method to carry out protein quantification simultaneously.
The analysis determining method flow process:
Tail glue primordial covering 96 orifice plates are expired in the hole and acid collagen 1h with pH7.4 PBS; 37 ℃ of SuperBlock (PIERCE), sealing 1h; PBST (PBS-Tween) washes plate 3 times, vibrates 1 minute at every turn; Dilute AGE-BSA with PBS, add in the capable hole of A, B, C, the D of 96 orifice plates with the AGE-BSA 100 μ l that obtain maximum degree of crosslinking concentration, the BSA of same concentrations adds in the capable hole of E, F, G, H, and 1 is listed as in preceding 3 holes PBS as system and reagent blank, under 37 ℃, make it and collagen cross-linking 4h; PBST washes plate 4 times, and 1min at interval vibrates; Test-compound adopts pH7.4 PBS dilution, gets 100 μ l/ holes and is added on crosslinked and each 4 hole, BSA hole of AGE-BSA respectively, and the same manner adds PBS 100 μ l/ holes and contrasts as non-cracking, hatches 16h for 37 ℃; PBST washes plate 4 times, and 1min at interval vibrates; Add 37 ℃ of the 80 μ l/ hole anti-BSA antibody of rabbit (1: 500), 50min; PBST washes plate 4 times, and 1min at interval vibrates; Add 37 ℃ of 80 μ l/ hole horseradish peroxidase-labeled goat anti-rabbit iggs (1: 1000), 50min; PBST washes plate 3 times, and 1min at interval vibrates; Add substrate solution TMB (3,3 ', 5,5 '-tetramethyl benzidine) 100 μ l/ pore chamber temperature, black out 20min; Use 2mol/L H
2SO
4Termination reaction; In the 10min, under BOBRAD Mode1550 plate reading machine 450nm, the OD value is read in the zeroing of plate blank well.
Data analysis:
Average OD value adopts 4 hole mean values.
Proofread and correct the OD mean value in the OD mean value-BSA hole in OD=AGE-BSA hole
Cleavage rate is represented with the percentage that the OD value reduces:
[the OD mean value in (the OD mean value in PBS hole-be subjected to reagent thing hole OD mean value)/PBS hole] * %
Cleavage rate the results are shown in Table 1 (result is the mean value of The selection result more than 3 times) 0.1, under 1mmol/L or the low concentration according to the above-mentioned steps test-compound:
Table 1:ELISA measures the cleavage rate of compound to the AGE-BSA-collagen cross-linking
| The compound sequence number | The different concentration range (mmol/L) of cleavage rate (OD reduction value %) | ||||||
| ????1 | ????0.1 | ????0.3 | ????0.03 | ????0.01 | ????0.003 | ????0.001 | |
| ????ALT-711 | ????15.2 | ????13.4 | |||||
| ????1 | ????9.3 | ????2.65 | |||||
| ????2 | ????7.1 | ????7.9 | |||||
| ????3 | ????13.4 | ????14.1 | |||||
| ????4 | ????10.6 | ????12.9 | |||||
| ????5 | ????47.2 | ????5.9 | ????27.3 | ||||
| ????6 | ????22.1 | ????20.4 | |||||
| ????7 | ????8.9 | ????10.3 | |||||
| ????8 | ????5.8 | ????10.4 | |||||
| ????9 | ????7.1 | ????7.9 | |||||
| ????10 | ????5.1 | ????12.2 | |||||
| ????11 | ????5.2 | ????12.3 | |||||
| ????12 | ????9.3 | ????2.6 | |||||
| ????13 | ????14.1 | ????13.4 | |||||
| ????14 | ????13.4 | ????5.1 | |||||
| ????15 | ????17.2 | ||||||
| ????16 | ????8.7 | ????8.9 | |||||
| ????17 | ????7.6 | ????10.5 | |||||
| ????18 | ????16.5 | ||||||
Reverse the effect of AGE crosslinking structure in embodiment 20 bodies
For further confirming to reverse the crosslinked effect of AGE in the above-mentioned test-compound body, we have estimated 6 pairs of crosslinked unkehr effects of aged diabetes rat RBC surfaces A GE-IgG of compound.
Duplicating of aging diabetes rat model:
The Wister rat, male, body weight 180-200g, the peritoneal injection streptozotocin, 65mg/Kg, 1 time, glucose level is higher than the 16mmol/L rat, the conventional raising for 32 weeks.
Animal grouping and test-compound give mode:
32 all diabetes rats are divided into 5 groups, and every group 8-10, difference peritoneal injection physiological saline, ALT-711 (1mg/Kg), #16 compound, 1mg/Kg, #16 compound, 3mg/Kg, #16 compound, 10mg/Kg, every day 1 time, continuous 3 weeks.
RBC preparation and RBC-IgG analyze:
Rat gives compound after 3 weeks, gets blood, and anticoagulant heparin, PH7.4 PBS are given a baby a bath on the third day after its birth inferior, dilution in 1: 250.
RBC-IgG analyzes at Multscreen-IP, 0.45 μ m, and (Millipore MAIPS4510) with 37 ℃ of sealings of 300 μ l Superblock (PIERCE) 1h, washes plate 1 time with the full hole of PBST to 96 orifice plates, washes plate 2 times with PBS again; To add in the hand-hole with the RBC 50 μ l of PBS dilution and mixing, every rat RBC sample adds 4 repeating holes, stays 4 holes to add PBS as the antibody control hole simultaneously.PBS washes RBC 1 time, adds 50 μ l
The mouse IgG of the horseradish peroxidase-labeled rabbit Chinese People's Anti-Japanese Military and Political College (1: 2000), room temperature, 2h; PBS washes 4 times, adds substrate solution OPD (O-Phenylene Diamine) 100 μ l/ holes, room temperature, lucifuge 30min; Use 2mmol/L H
2SO
450 μ l/ hole termination reactions; Change every hole liquid 120 μ l over to coventional type 96 hole enzyme plates fast, under BOBRAD Model 550 plate reading machine 490nm, the OD value is read in the blank zeroing of plate.
Data analysis:
RBC-IgG content represents that with sample OD value correction value the average OD value of each sample is the mean value in 4 holes, and every group of sample average RBC-IgG content is the mean value of 8 animals.
Proofread and correct the OD mean value of every rat RBC of OD=sample OD mean value-monoclonal antibody body opening
Cleavage rate is represented with the percentage that RBC-IgG content reduces:
[(control animals RBC-IgG-is subjected to reagent thing treatment group RBC-IgG)/control animals RBC-IgG] * %
The results are shown in Table 2 according to above-mentioned experimental technique step test-compound cleavage rate:
Table 2
Compound and dosage cleavage rate (%)
ALT-711???????????41.5
(1mg/kg)
6(1mg/kg)?????????38.6
6(3mg/kg)?????????55.8
6(10mg/kg)????????57.1
Claims (10)
1. formula I compound, its raceme or optically active isomer or its pharmaceutically useful salt or hydrate
Wherein:
X is O or S,
Y is O or S,
R
1Be C
5～C
8Alicyclic ring,
R
2Be hydrogen or C
1～C
8Straight chain or branched-chain alkyl or C
2～C
8Straight chain or branched-chain alkenyl, C
3～C
8Cycloalkyl, C
5～C
8Cycloalkenyl group, hydroxyl, C
1～C
4Alkoxyl group, C
1～C
4Alkylamino, sulfydryl, various sulfonic groups, halogen, itrile group, trifluoromethyl, trifluoromethoxy can not have replacement on alkyl wherein or the alkenylene chain, can be selected from one or more following group yet and replace: C
3～C
8Cycloalkyl, C
5～C
7Cycloalkenyl group or Ar
2,
Ar
1And Ar
2Independently be selected from aromatic carbocyclic or heterocycle, ring wherein can be monocycle, dicyclo or three rings; Each ring is elementary composition by 5～6, comprises 1～6 in the heterocycle and is selected from following heteroatoms: O, S, N; Can not have replacement on the ring, can be selected from following substituting group yet and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C by 1-3
1～C
6The straight or branched alkyl, C
2～C
6The straight or branched thiazolinyl, C
1～C
4Alkoxyl group, C
2～C
4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl or amino,
Z
-It is acceptable acid group pharmaceutically.
2. the compound of claim 1 or its pharmaceutically useful salt or hydrate, wherein:
X is S,
Y is O,
R
1And R
2And Ar
1Substituting group defines with claim 1,
Z
-Be halogen acid group F
-, Cl
-, Br
-, I
-, perhaps methanesulfonate is to the methylsulphonic acid root.
3. claim 1 or 2 each described compounds, it is selected from:
3-(2-xenyl-4-base-2-oxygen-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-[2-(3-nitro-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene--benzothiazole-3-hydrobromate
3-[2-(4-methylsulfonyl-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-[2-(3, the 4-dichlorophenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
(±) 3-(1-methyl-2-oxygen-2-phenyl-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
(±) 3-[2-(4-bromo-phenyl)-1-methyl-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-(2-naphthalene-2-base-2-oxygen-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-[2-(2-nitro-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-[2-(3-methoxyl group-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-[2-(2,5-dimethoxy-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-(2-oxygen-2-right-tolyl-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-[2-(4-nitro-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-[2-(4-fluoro-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-[2-(4-methoxyl group-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-[2-(4-chloro-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-[2-(4-bromo-phenyl)-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
3-(2-xenyl-4-base-2-oxygen-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-mesylate
3-(2-oxygen-2-phenyl-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
4. the compound in the claim 3, it is
(±) 3-[2-(4-bromo-phenyl)-1-methyl-2-oxygen-ethyl]-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
(±) 3-(1-methyl-2-oxygen-2-phenyl-ethyl)-4,5,6,7-tetrahydrochysene-benzothiazole-3-hydrobromate
5. pharmaceutical composition comprises each described compound of claim 1～4 and at least a pharmaceutically acceptable carrier.
6. prepare the method for claim 1-4 compound described in each, it comprises makes formula IV compound
R wherein
1With the definition of X with claim 1,
React with the compound of formula V,
R wherein
2, Y, Ar
1Definition with claim 1, obtaining Z is the formula I compound of Br, and randomly, adopts suitable salt to change resulting compound into another kind of salt, obtains compound of Formula I,
R wherein
1, R
2, X, Y, Ar
1With the definition of Z with claim 1.
7. each described compound of claim 1～4 is used to prepare the purposes of the medicine of cracking advanced glycation end products.
8. each described compound of claim 1～4 is used for preparation (i) increase skin elasticity or minimizing wrinkle of skin in animal body, (ii) treat diabetes, the (iii) treatment or the sequela of diabetes-alleviating, (iv) treat or the alleviation kidney injury, (v) treatment or alleviating vascular damage, (vi) treat or alleviation hypertension, (vii) treat or the relieving retina pathology, (viii) treatment or the damage of alleviation crystallin, (ix) treatment or alleviate cataract, (x) treatment or alleviate peripheral neuropathy or (xi) purposes of the medicine of treatment or relief from osteoarthritis.
9. each described compound of claim 1～4 purposes of being used to prepare the painted reversal agent of animal body inner teeth gear or being used to prevent and reverse other oral preparations of tooth staining.
10. each described compound of claim 1～4 is used to prepare the purposes of vegetable-protein, animal proteinum preservation agent.
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|---|---|---|---|---|
| WO2006034605A1 (en) * | 2004-09-28 | 2006-04-06 | Beijing Molecule Science And Technology Co., Ltd. | Novel azabicyclic ring ammoniums and their use for treating protein aging disease |
| WO2007085203A1 (en) * | 2006-01-27 | 2007-08-02 | Beijing Molecule Science And Technology Co., Ltd | New substituted pentabasic azaheterocyclic compounds and its use of treating protein aging disease |
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| EP1327887A3 (en) * | 1995-01-18 | 2008-12-10 | Synvista Therapeutics, Inc. | Use of thiazolium compounds for preventing and reversing the formation of advanced glycosylation end products |
| US6121300A (en) * | 1998-11-10 | 2000-09-19 | Wagle; Dilip R. | Reversing advanced glycosylation cross-links using heterocyclic-substituted thiazolium salts |
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2003
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006034605A1 (en) * | 2004-09-28 | 2006-04-06 | Beijing Molecule Science And Technology Co., Ltd. | Novel azabicyclic ring ammoniums and their use for treating protein aging disease |
| WO2007085203A1 (en) * | 2006-01-27 | 2007-08-02 | Beijing Molecule Science And Technology Co., Ltd | New substituted pentabasic azaheterocyclic compounds and its use of treating protein aging disease |
| US7799813B2 (en) | 2006-01-27 | 2010-09-21 | Beijing Molecule Science And Technology Co., Ltd. | Salts of substituted 5-membered azacycle and use thereof in the treatment of diseases related to protein aging |
| RU2444517C2 (en) * | 2006-01-27 | 2012-03-10 | Бейджинг Моликьюл Сайенс Энд Текнолоджи Ко., Лтд | Novel salts of substituted 5-member azacycle and use thereof in treating protein ageing related diseases |
| CN101007789B (en) * | 2006-01-27 | 2014-08-20 | 北京摩力克科技有限公司 | Substituted quinary aza heterocyclic salt compound and its uses in therapeutic protein aging-related disease |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1324019C (en) | 2007-07-04 |
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