CN100349881C - New substituted penta azacyclo salt kind compound and its use in treating protein ageing related disease - Google Patents
New substituted penta azacyclo salt kind compound and its use in treating protein ageing related disease Download PDFInfo
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- CN100349881C CN100349881C CNB031215971A CN03121597A CN100349881C CN 100349881 C CN100349881 C CN 100349881C CN B031215971 A CNB031215971 A CN B031215971A CN 03121597 A CN03121597 A CN 03121597A CN 100349881 C CN100349881 C CN 100349881C
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Abstract
The present invention relates to a five membered nitrogen heterocyclic compound disclosed in the general formula I and/or medicinal salt thereof and medicinal hydrate thereof. Each group in the formula is defined in the right claiming document. The compound and a medical composition containing the compound are used for preparing medicines for enhancing skin elasticity or decreasing skin wrinkles, treating diabetes and treating or relieving diabetic sequelae, renal injuries, blood vessel injuries, hypertension, retinopathy, crystallin injuries, cataract, peripheral neuropathy and osteoarthritis, or the compound is used for preparing an oral preparation for preventing or reversing the colorization of teeth or a preservative for vegetable protein of various farm crops and animal protein.
Description
Technical field
The present invention relates to the substituted penta azacyclo 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 A1c.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.1-34A cademic 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 AGEs), known AGE is relevant with the complication of diabetes, normal aging course also causes the increase of AGEs, thereby intravital AGEs 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 U.S.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 AGEs 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 for diabetesand aging " Laboratory Investigation 70:138-151; Brownlee, 1995, " The pathological implica tions 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 AGEs in the tissue has particularly formed in tissue and the method for cumulative AGEs cross-linking products (these cross-linking products cause clinical or subclinical pathological change) is the AGEs cross-linking products that reverse or cracking have formed.People such as Vassan prove that the method for this cracking AGEs 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 U.S. Pat .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 et al., 1998, " Breakersof Advanced Glycation End Products Restores Large ArteryProperites in Experimental Diabetes ", Proc.Nat.Acad.Sci.U.S.A.95:4630-4634).In these researchs, given reversing in diabetes rat AGEs 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 (U.S.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, thereby further improve since AGE in vivo increase the various pathological changes that cause, comprise and increase skin elasticity or reduce wrinkle of skin, the sequela of treatment diabetes or treatment or diabetes-alleviating, kidney injury, blood vessel injury, hypertension, retinopathy, the crystallin damage, cataract, peripheral neuropathy or osteoarthritis.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
3Introduce on the raceme of the new compound behind the non-hydrogen substituting group and the multiple in vitro and in vivo model of optically active isomer the position has than better AGE lytic activity of the preferred compound ALT-711 that discloses among the US5656267 and lower toxicity.
Therefore, first aspect 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
1And R
2Can identical or different and independently be selected from hydrogen, C
1～C
4Alkyl or C
2～C
4Thiazolinyl; Perhaps R
1And R
2Link to each other and form aromatic nucleus Ar
2,
R
3Be C
1～C
8The straight or branched alkyl, C
2～C
8The straight or branched thiazolinyl, 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,
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) be CH with following formula thiocarbamide or urea and α position
2Formula II ketone
R wherein
1R
2Definition cotype I compound,
Reaction obtains the formula III compound under halogen catalysis, or reacts under halogen catalysis according to the method (J.Amer.Chem.Soc., 1949,71,4007) of document record and to obtain the formula III compound,
R wherein
1, R
2It is the same with the definition of X,
B) formula III compound and Isopentyl nitrite reaction are obtained formula IV compound
R wherein
1, R
2It is the same with the definition of X,
C) with formula IV compound and the reaction of formula V compound
R wherein
3, Y and Ar
1Definition the same, formula V compound can be according to method preparation (Tetrahedron Letters No.38, the pp 3653-3656 of document record, 1979), obtain the compound of Formula I that Z is Br, and randomly, adopt suitable salt to change resulting compound into another kind of salt
R wherein
1, R
2, R
3, X, Y, Ar
1The same with the definition 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 compound disclosed in this invention can act on is not limited to human body protein, also comprises vegetable-protein or animal organ's albumen in the farm crop, thereby compound disclosed by the invention or composition can be used for fresh-keeping purposes.
More specifically, 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
1And R
2Can identical or different and independently be selected from hydrogen, C
1～C
4Alkyl or C
2～C
4Thiazolinyl; Perhaps R
1And R
2Link to each other and form aromatic nucleus Ar
2,
R
3Be C
1～C
8The straight or branched alkyl, C
2～C
8The straight or branched thiazolinyl, 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,
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
-Be acceptable acid group pharmaceutically.
A preferred embodiment of the present invention is suc as formula the raceme of 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 R
3And Ar
1Definition same as above,
Z
-Be halogen acid group F
-, Cl
-, Br
-, I
-, perhaps methanesulfonate, to the methylsulphonic acid root, wherein most preferably Hydrogen bromide root and methanesulfonate.
According to the present invention, the compound below formula I compound or pharmaceutically acceptable salt thereof of the present invention or hydrate are preferred:
Wherein more preferably
3-(1-benzoyl-propyl group)-4,5-dimethyl-thiazole-3-hydrobromate.
According to the present invention, 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.
The compounds of this invention can prepare by following reaction scheme:
Reaction scheme I:
It comprises makes formula IV compound:
Wherein, X is O or S,
R
1And R
2Can identical or different and independently be selected from hydrogen, C
1～C
4Alkyl or C
2～C
4Thiazolinyl; Perhaps R
1And R
2Link to each other and form aromatic nucleus Ar
2,
Ar
2Be 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,
React with formula V compound
Wherein
Y is O or S,
R
3Be C
1～C
8The straight or branched alkyl, C
2～C
8The straight or branched thiazolinyl, 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,
Ar
1Be 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,
Obtain 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,
X wherein, Y, R
1, R
2, R
3And Ar
1Definition the same,
Z
-It is acceptable acid group pharmaceutically.
In the superincumbent reaction scheme, the reaction of formula IV compound and formula V compound is to have a kind of when the liquid not under the situation of solubilizing agent in the presence of solvent such as ethanol or acetonitrile or the butanone or when two kinds of raw materials, in 80 ℃～100 ℃, in nitrogen, carried out 5～96 hours.
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 10～40um, 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 in the synthetic above-mentioned reaction scheme of several different methods for example route II of employed formula IV compound.
Reaction scheme II:
R wherein
1, R
2With the definition cotype I compound of X,
The α position of employing formula II is CH
2Ketone under the effect of iodine, obtain the formula III compound with the reaction of thiocarbamide or urea, or according to the method (J.Amer.Chem.Soc. of document record, 1949,71,4007) reaction obtains the formula III compound under halogen catalysis, in anhydrous tetrahydro furan, handle deaminize then, obtain formula IV compound with Isopentyl nitrite.Can adopt the method purifying of molecular distillation or silica gel column chromatography, here employed silica gel is conventional silica gel for chromatography, granularity 10～40um, 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, pp 3653-3656,1979) according to the method for document record in reaction scheme I:
Adopting the α position is CH
2, the formula VII compound that replaces for fragrance of opposite side and adopt cupric bromide or bromo that bromine or NBS 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 10～40um, 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.
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.
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.
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 prevention and 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) treat or alleviation hypertension, (vii) treat or the relieving retina pathology, (viii) treatment or alleviation crystallin damage, (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 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
The following examples are illustrative preferred embodiments of the present invention, and the present invention is not constituted any limitation.
Melting point compound is measured by SRY-1 type fusing point instrument, and temperature is not calibrated.
1H-NMR spectrum is measured by BrukerARX400 or USVarianUnityInova600 type nuclear magnetic resonance spectrometer, and the FAB mass spectrum is measured by the Zabspect high-resolution mass spectrometer.
Embodiment 1:4,5-dimethyl-3-(1-methyl-2-oxygen-2-phenyl-ethyl)-thiazole-3-hydrobromate
With 4, (1.08 grams 0.0095mol) are dissolved in the 5ml dehydrated alcohol 5-dimethylthiazole, and (2.7 grams, 0.012mol), reflux 1.5 hours leaves standstill crystallization, filters to obtain crude product to add 2-bromo-1-phenyl-propyl group-1-ketone.Crude product is through silica gel column chromatography column purification (methylene dichloride: methyl alcohol=8: 1), obtain white solid (0.2g, 18%, m.p.169-170 ℃).MS[M]
+＝247.3m/e；
1H-NMR(600MHz，DMSO)δ1.926(d J＝7.16Hz 3H)；2.396(s 3H)；2.549(s 3H)；6.974(dd J＝7.16，14.4Hz 1H)；7.665(m 2H)；7.806(m 1H)；8.213(m 2H)；10.276(s 1H)。
Embodiment 2:3-[2-(4-bromo-phenyl)-1-methyl-2-oxygen-ethyl]-4,5-dimethyl-thiazole-3-hydrobromate
Press the preparation of embodiment 1 method, just bromo ketone wherein is 2-bromo-1-(4-bromo-phenyl)-propyl group-1-ketone, and thiazole derivative is 4, and the 5-dimethylthiazole obtains title compound (1g, 38%, m.p.201-206 ℃).MS[M]
+＝326.3m/e；
1H-NMR(600MHz，DMSO)δ1.909(d J＝7.2Hz 3H)；2.391(s 3H)；2.506(s 3H)；6.869(dd J＝1.8，7.1Hz 1H)；7.892(d J＝8.52Hz 2H)；8.130(d J＝8.6Hz 2H)；10.23(s 1H)。
Embodiment 3:5-(2-hydroxyl-ethyl)-4-methyl-3-(1-methyl-2-oxygen-2-phenyl-ethyl)-thiazole-3-hydrobromate
Press embodiment 1 method preparation, just bromo ketone wherein is 2-bromo-1-phenyl-propyl group-1-ketone, and thiazole derivative is that (4-methyl-thiazole-5-yl)-ethanol obtains title compound (0.23g, 12%, m.p.209-219 ℃) to 2-.MS[M]
+＝277.3m/e；
1H-NMR(600MHz，CD
3ODδ2.009(d J＝7.1Hz 3H)；2.452(s 3H)；3.138(td＝5.6Hz 3H)3.830(td＝5.5Hz 3H)；6.790(dd J＝7.2，14.4Hz 1H)；7.643(m 2H)；7.775(m 1H)；8.191(dd J＝1.28.4Hz 2H)；10.148(s 1H)。
Embodiment 4:3-(2-phenyl-4-base-2-oxygen-ethyl)-5,5-dioxy-5,6-dihydro-4H-thiophene [3,4-d] and thiazole-3-hydrobromate
Preparation 1:6-oxygen-3-sulphur-dicyclo [3.1.0] hexane 3, the 3-dioxide
Dripping H below 50 ℃
2O
2(0.378mol) in 25ml 2,5-dihydro-thiophene-1 in the formic acid solution of 1-dioxide (0.075mol), stirred 48 hours down in 40 ℃, had or not oxidisability with the starch potassium iodide paper test soln, if having then make the oxidisability disappearance with S-WAT.The acetone solution that adds 500ml then filters, and removes concentrated solution behind the inorganic salt, and recrystallization gets product 7.3 grams, and productive rate is 43.7%.
Preparation 2:4-bromo-1,1-dioxy-tetrahydrochysene-thiophene-3-alcohol
With 6.0g 6-oxygen-3-sulphur-dicyclo [3.1.0] hexane 3, the 3-dioxide is suspended in the Hydrogen bromide of 50ml 10% and refluxes, material dissolution is in 10% Hydrogen bromide after 2 hours, refluxed 8 hours, put cooling solid body and separate out filtration, obtain the 8.84g title product, white solid productive rate 91.8%, fusing point 190-193 ℃.
Preparation 3:4-bromo-1,1-dioxy-tetrahydrochysene-thiophene-3-ketone
With 1g 4-bromo-1,1-dioxy-tetrahydrochysene-thiophene-3-alcohol is dissolved in the acetone of 80ml through the potassium permanganate processing, splashes into Jone ' s reagent and filter under 25 ℃, concentrate, ethyl acetate: hexanaphthene=1: 1 silica gel column chromatography obtains the 0.37g white solid, productive rate 36%m.p.167-169 ℃.
Preparation 4:4,6-dihydro-thiophene [3,4-d] thiazole 5,5-dioxide
With 0.5g 4-bromo-1,1-dioxy-tetrahydrochysene-thiophene-3-ketone is dissolved in the 25ml dioxane, adds the 2.58g thioformamide, and heating refluxed 6 hours, reclaims solvent, column chromatography for separation.Obtain the 0.57g target compound, productive rate 26%.
Press the preparation of embodiment 1 method, just bromo ketone wherein is 2-bromo-1-(2-phenyl-4-yl)-ethyl-1-ketone, and thiazole derivative is 4,6-dihydro-thiophene [3,4-d] and thiazole 5,5-dioxide (0.15g, 12%, m.p.167-169 ℃).MS[M]
+＝295.3m/e；
1H-NMR(600MHz，DMSO)δ4.814(s 2H)；4.897(s 2H)；6.381(dJ＝5.4Hz 2H)；7.476(m 1H)；7.562(m 2H)；7.827(m 2H)；7.987(m 2H)；8.116(m 2H)；10.252(d J＝5.2Hz 1H)。
Embodiment 5:3-(1-methyl-2-oxygen-2-phenyl-ethyl)-benzothiazole-3-hydrobromate
Prepare this compound by embodiment 1 method, just bromo ketone wherein is 2-bromo-1-phenyl-propyl group-1-ketone, obtains title compound (0.4g, 25%, oily matter).
MS[M]
+＝269.1m/e；
1H NMR(600MHz，CD
3ODδ2.156(d J＝7.8Hz 3H)；7.307(dd J＝7.2，14.5Hz 1H)；7.668(m 2H)；7.797(m 1H)；7.912(m 2H)；8.255(m 3H)；8.458(m 1H)；10.783(s 1H)。
Embodiment 6:3-(1-benzoyl-propyl group)-4,5-dimethyl-thiazole-3-hydrobromate
Press the preparation of embodiment 1 method, just bromo ketone wherein is 2-bromo-1-phenyl-butyl-1-ketone, and thiazole derivative is 4, and the 5-dimethylthiazole obtains title compound (1.3g, 51%, m.p.212-214 ℃).MS[M]
+＝261.3m/e；
1H-NMR(600MHz，DMSO)δ0.956(d J＝7.2Hz 3H)；1.767(m 4H)；2.302(m 2H)；2.601(d J＝16.51H)；2.929(s 1H)；3.105(d J＝16.5Hz 1H)；3.359(m 3H)；6.724(t J＝5.9Hz 1H)；7.665(m 2H)；7.806(m 1H)；8.235(m 2H)；10.393(s 1H)。
Embodiment 7:3-[2-(4-bromo-phenyl)-1-methyl-2-oxygen-ethyl]-benzothiazole-3-hydrobromate
Press the preparation of embodiment 1 method, just bromo ketone wherein is 2-bromo-1-(4-bromo-phenyl)-propyl group-1-ketone, obtains title compound (0.3g, 17%, m.p.235-241 ℃).MS[M]
+＝348.1m/e；
1H NMR(600MHz，CD
3ODδ2.149(d J＝7.2Hz 3H)；7.286(dd J＝7.1，14.5Hz 1H)；7.885(m 4H)；8.176(m 2H)；8.290(d J＝8.7Hz 2H)；8.459(d J＝7.51H)。
Embodiment 8:3-[2-(4-bromo-phenyl)-1-methyl-2-oxygen-ethyl]-5-(2-hydroxyl-ethyl)-4-methyl-thiazole-3-hydrobromate
Press embodiment 1 method preparation, just bromo ketone wherein is 2-bromo-1-(4-bromo-phenyl)-propyl group-1-ketone, and thiazole derivative is that (4-methyl-thiazole-5-yl)-ethanol obtains title compound (0.47g, 26%, oily matter) to 2-.MS[M]
+＝356.0m/e；
1H NMR(600MHz，CD
3ODδ1.990(s 3H)；2.459(d J＝8.1Hz 3H)；3.096(td＝5.6Hz 2H)；3.827(td＝5.7Hz 2H)；7.825(m 2H)；8.097(m 2H)。
Embodiment 9: the ELISA shaker test of cracking AGE-BSA-collagen cross-linking structure
With AGE-BSA be coated on crosslinked, the external preparation of rat tail glue protein AGEs crosslinking structure on the 96 hole enzyme plates, employing ELISA method assessing compound is to the crosslinked splitting action of AGEs.
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 4 ℃ 0.1% Glacial acetic acid, 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 0.2MPBS (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-AGEs.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-AGEs 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 pH7.4PBS; 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-BSA100 μ l that obtains 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 the pH7.4PBS 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 PBS100 μ l/ hole 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 Model550 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] * %
According to above-mentioned steps, cleavage rate the results are shown in Table 1 (result is the mean value of The selection result more than 3 times) to test-compound 0.1,0.3, under 1mmol/L or the low concentration:
Table 1:ELISA measures the cleavage rate of compound to the AGE-BSA-collagen cross-linking
| Compound | Cleavage rate (OD reduction value %) | ||
| 1(mmol/L) | 0.1(mmol/L) | 0.3(mmol/L) | |
| ALT-711 1 2 3 4 5 6 7 8 | 15.2 14.5 7.2 9.5 | 13.4 3.4 10.4 15.3 8.5 10.3 10.3 | 8.1 21.1 * 69.3 |
* concentration is 0.01 (mmol/L)
Claims (9)
1. compound of Formula I, or its pharmacologically acceptable salt:
Wherein:
X is O or S,
Y is O or S,
R
1And R
2Can identical or different and independently be selected from hydrogen, C
1～C
4Alkyl or C
2～C
4Thiazolinyl; Perhaps R
1And R
2Link to each other and form aromatic nucleus Ar
2,
R
3Be C
1～C
8The straight or branched alkyl, C
2～C
8The straight or branched thiazolinyl, C
3～C
8Cycloalkyl, C
5～C
8Cycloalkenyl group, hydroxyl, C
1～C
4Alkoxyl group, C
1～C
4Alkylamino, sulfydryl, sulfonic group, 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,
Ar
1And Ar
2Independently be selected from aromatic carbocyclic or heterocycle, ring wherein is a monocycle; Described 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, also the substituting group that can be selected from below 1-3 replaces: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C
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,
Wherein:
X is S,
Y is 0,
R
1, R
2And R
3And 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 compound, it is selected from:
4,5-dimethyl-3-(1-methyl-2-oxygen-2-phenyl-ethyl)-thiazole-3-hydrobromate,
3-[2-(4-bromo-phenyl)-1-methyl-2-oxygen-ethyl]-4,5-dimethyl-thiazole-3-hydrobromate,
3-(1-benzoyl-propyl group)-4,5-dimethyl-thiazole-3-hydrobromate,
3-(2-phenyl-4-base-2-oxygen-ethyl)-5,5-dioxy-5,6-dihydro-4H-thieno-[3,4-d] thiazole-3-hydrobromate,
3-(1-methyl-2-oxygen-2-phenyl-ethyl)-benzothiazole-3-hydrobromate,
5-(2-hydroxyl-ethyl)-4-methyl-3-(1-methyl-2-oxygen-2-phenyl-ethyl)-thiazole-3-hydrobromate,
3-[2-(4-bromo-phenyl)-1-methyl-2-oxygen-ethyl]-benzothiazole-3-hydrobromate and
3-[2-(4-bromo-phenyl)-1-methyl-2-oxygen-ethyl]-5-(2-hydroxyl-ethyl)-4-methyl-thiazole-3-hydrobromate.
4. pharmaceutical composition, it comprises each described compound or pharmaceutically acceptable salt thereof of claim 1～3 and at least a pharmaceutically acceptable carrier.
5. the method for preparing each described compound of claim 1-3, it comprises makes formula IV compound
R wherein
1, R
2With the definition of X with claim 1,
React with formula V compound
Wherein
R
3, Y and Ar
1Definition with claim 1, obtain 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, R
3, X, Y, Ar
1With the definition of Z with claim 1.
6. each described compound of claim 1～3 is used to prepare the purposes of the medicine of cracking advanced glycation end products.
7. each described compound is used for preparation (i) increase elasticity or reduces wrinkle of skin in the claim 1～3, (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) purposes of treatment or relief from osteoarthritis medicine.
8. each described compound of claim 1～3 is used to prepare the reversal agent of tooth staining in animal body or other is used to prevent and reverse the purposes of the oral preparations of tooth staining.
9. each described compound of claim 1～3 is used for preparing the purposes of farm crop vegetable-protein, animal proteinum preservation agent.
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| CN104277011A (en) * | 2013-07-09 | 2015-01-14 | 中国人民解放军军事医学科学院毒物药物研究所 | Thiazolium inner salt compound and its use in treatment on protein aging-related diseases |
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| WO2002053158A1 (en) * | 2000-12-29 | 2002-07-11 | Alteon, Inc. | Method for treating glaucoma ib |
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| WO2002053158A1 (en) * | 2000-12-29 | 2002-07-11 | Alteon, Inc. | Method for treating glaucoma ib |
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