WO2006034605A1

WO2006034605A1 - Novel azabicyclic ring ammoniums and their use for treating protein aging disease

Info

Publication number: WO2006034605A1
Application number: PCT/CN2004/001119
Authority: WO
Inventors: Song Li; Hao Cui; Lili Wang; Gang Cheng; Wu Zhong; Aihua Nie; Hongying Liu; Yuandong Hu; Junhai Xiao; Zhibing Zheng
Original assignee: Beijing Molecule Science And Technology Co., Ltd.
Priority date: 2004-09-28
Filing date: 2004-09-28
Publication date: 2006-04-06

Abstract

The present invention relates to azabicyclic ring ammoniums of general formula I in which the definition of each radical is described in the specification and/or their pharmaceutically acceptable salts and hydrates; pharmaceutical compositions comprising the same, also to the uses of those compositions for the preparation of medicaments for (i) improving the elasticity or reducing wrinkles of the skin, (ii) treating diabetes, (iii) treating or ameliorating adverse sequelae of diabetes, (iv) treating or ameliorating kidney damage, (v) treating or ameliorating blood vasculature, (vi) treating or ameliorating hypertension, (vii) treating or ameliorating retinopathy, (viii) treating or ameliorating damage to lens proteins, (ix) treating or ameliorating cataracts, (x) treading or ameliorating peripheral neuropathy, (xi) treating or ameliorating osteoarthritis, or use for the preparation of a buccal medicament for preventing or reversing the staining of teeth, or the use for the preparation of various freshness keeper for crops plant protein, animal protein.

Description

New azabicyclic salt compounds and

Use of aging protein aging diseases

The present invention relates to a substituted azabicyclic salt compound, a process for the preparation thereof, a pharmaceutical composition containing the same, and the use of the compound for preventing or treating a disease or symptom associated with AGE (advanced glycosylation endproducts AGE), such as (i) Increase skin elasticity or reduce skin wrinkles, ( ϋ ) treat diabetes, ( iii ) treat or alleviate the sequelae of diabetes, ( iv ) treat or relieve kidney damage, (V) treat or relieve vascular damage, (vi) treat or relieve Blood pressure, (vii) treatment or relief of retinopathy, (viii) treatment or relief of lens protein damage, (ix) treatment or relief of cataract, (X) treatment or relief of peripheral neuropathy, (xi) treatment or relief of osteoarthritis.

Background technique

It is known that there is a reaction between sugar and protein. As early as 1912, Maillard found that glucose and other reducing sugars reacted with amino acids, and after a series of dehydrogenation rearrangements, a stable brown pigment was formed. Further research found that storage and heating of food were also It is capable of producing such pigments formed from sugars and polypeptides, and the formation of such pigments reduces the biological activity of the proteins. For related application patents, reference is made to US Pat. No. 08/588,249. The reaction of this non-enzymatic reducing sugar with a free amino acid results in a stable diketone by-product, the known Amador i product. In particular, the β side chain residue of the amino acid on the surface of heme reacts with glucose to form heme Alc. Such reactions occur in other proteins in the body, such as the lens, collagen and neuroprotein (Advanced Glycosylation; Chemistry, Bilolgy and Implications for Diabetes and Aging, Advances in Pharmacology, Vol. 23, pp. 1-34 Academic Press 1992).

The above reaction will accelerate when the blood sugar level of diabetes increases, normal The above reaction also occurs under blood sugar conditions. At the same time, the aging process is closely related to the formation of lipofuscin. The same monthly primordial protein aging can be simulated with sugar and collagen in vitro. The glucose-induced gum product is captured by other proteins, which causes a cross-linking reaction between the proteins. This glucose-induced cross-linking reaction produces advanced glycosylation endproducts (AGE), which is known to be associated with the concurrent effects of diabetes. The normal aging process also causes an increase in AGE. Its abnormal pathochemical structure is also recognized by some specific receptors to cause complex diabetes and aging-related pathological changes.

Currently, there are already some treatments that prevent the accumulation of AGE. One of the methods can be found in US Pat. No. 4,758,583, the lead aminoguanidine and its analogs can prevent the formation of AGE, and prevent the glycosylation product from further exaggerating into AGE by reacting with early glycosylation products, while also preventing AGE. Further cross-linking with the organization. The effectiveness of this method was evaluated in animal models of diabetes and aging rats, as well as other indicators such as macrovascular, renal, and neuropathological aspects. These data are summarized by Vlassara et al. (Vlassara et al, 1994 Biology of Diseases, "Pathogenic effects of advanced glycosylation: biochemical, biologic and clinical implications for diabetes and aging" Laboratory Investigation 70: 138-151; Brownlee, 1995,

"The pathological implications of protein glycation" Clin. Invest. Med., 18: 275-281; and Brownlee, 1995,

"Advanced protein glycosylation in diabetes and aging" , Ana. Rev. Med.46: 223-34. )

Another method of controlling AGE in j tissue, particularly AGE cross-linked products that have formed and accumulated in tissues (these cross-linked products cause clinical or subclinical pathological changes) is to reverse or cleave the already formed AGE cross-linked product. . Vassan et al. demonstrated that this method of cleavage of AGE is effective (vassan et al Nature. 1996, Vol. 382 (18) 275-278). The compounds, formulations, and methods disclosed in U.S. Patent No. 5,656, 261 and U.S. Patent Application Serial No. 08/588, 249, and U.S. Studies have shown that such compounds have a good effect on cardiovascular disease caused by aging (Wolffenbut tel et al., 1998, " Breakers of Advanced Glycat ion End Products Res tores Large Artery Proper i tes in Exper imental Diabetes ,, , Proc. Nat Acad. Sci. USA 95: 4630-4634 ). In these studies, AGE lysing agents given to 9-week diabetic rats for 1-3 weeks reversed the arteriosclerosis caused by diabetes. Improved parameters have cardiac output, 夕卜Peripheral resistance, body compliance, aortic input resistance, and carotid compliance (US. 6319934).

Summary of the invention

The object of the present invention is to find and develop a small molecule cleavage agent for AGE, which is used to cleave an already formed AGE to prevent protein cross-linking, to cleave the already cross-linked protein, thereby promoting protein metabolism, and further improving AGE in Various pathological changes caused by increased body weight, including increased skin elasticity or reduced skin wrinkles, treatment of diabetes or treatment or relief of diabetes sequelae, kidney damage, vascular injury, hypertension, retinopathy, lens protein damage, cataract, peripheral neuropathy Or osteoarthritis. At the same time, the glycosylated protein which is acted upon by the protein cross-linking structure cleavage agent is not limited to human proteins, but also includes plant proteins or animal proteins in crops, thereby expanding the use of plant proteins and animal proteins in crops.

The present inventors have found that compounds of formula I are useful in the treatment and/or prevention of a variety of diseases caused by glycosylation of proteins.

The present inventors have unexpectedly discovered that the racemates and optical isomers of the derivative compounds of the alicyclic structure having a five- to eight-membered formula in the formula I have a higher ratio than the US5 in vitro and in vivo. The preferred compound ALT-711 disclosed in 656267 is better Ammonia

AGE base cleavage activity and lower toxicity.

Accordingly, a first aspect of the invention relates to a compound of formula I, a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt or hydrate thereof.

X is 0 or s,

Y is 0 or s,

^ is a C ₅ ~ C ₈ 0 ^ alicyclic ring,

R ₂ is hydrogen, (^~(: ₈ linear or branched alkyl or C ₂ -C ₈ straight or branched alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₈ cycloalkenyl, Hydroxy, d~C ₄ alkoxy, d~ c ₄ alkylamino, fluorenyl, various sulfonic acid groups, halogen, nitrile group, trifluoromethyl, trifluoromethoxy, alkyl or alkenyl chain It may be unsubstituted or substituted by one or more groups selected from the group consisting of c ₃ ~c ₈ cycloalkyl, c ₅ ~c ₇ cycloalkenyl or

Ar ₂ ,

Α _Γι and Ar _{2 are} independently derived from an aromatic carbocyclic ring or a heterocyclic ring, wherein the ring may be monocyclic, bicyclic or tricyclic; each ring consists of 5 to 6 elements, and the heterocyclic ring contains 1 to 6 selected from below. Heteroatoms: 0, S, Ν; the ring may be unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoro, trifluoromethoxy , C^Cs straight or branched alkyl, C ₂ ~C ₆ straight or branched, (^~ alkoxy, C ₂ ~C ₄ alkenoxy, phenoxy, benzyloxy, carboxy or

Z_ is a pharmaceutically acceptable acid radical. Another aspect of the invention relates to a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

Another aspect of the invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof, which comprises:

a) a thiourea or urea of the formula and a cyclic ketone of formula II

Where ^ is defined as in Equation I,

Reaction according to literature (J. Amer. Chem. Soc., 1949, 71, 4007) under halogen catalysis

Where and definition are as described in the same formula I,

b) reacting a compound of formula I II with isoamyl nitrite to give a compound of formula IV

Where ^ and the definition are as described in the same formula I,

c) reacting a compound of formula IV with a compound of formula V

Wherein R ₂ , Y and Ar _a have the same meanings as above, the compound of the formula V can be prepared according to the literature (Tetrahedron Letters No. 38, pp 3653-3656, 1979), to obtain a general formula I wherein ruthenium is Br, and optionally Converting the resulting compound to another salt using a suitable salt to provide a compound of formula I,

Wherein R ₂ , X, Α _Γι Ζ are as defined in the formula I.

Another aspect of the invention relates to the use of at least one compound of formula I or a pharmaceutically acceptable salt thereof or hydrate thereof for the manufacture of a medicament for the prevention and/or treatment of various diseases caused by glycosylation of a protein.

The present invention also relates to a method for preventing or treating various diseases caused by aging of protein glycosylation, which comprises administering a prophylactically and/or therapeutically effective amount of at least one compound of the formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof, in need thereof Patients who are prevented and/or treated.

The glycosylated protein to which the compound of the present invention acts is not limited to human proteins, but also includes plant or animal organ proteins in crops, and thus the compounds or compositions of the present invention can be used for the preservation of plant proteins and animal proteins in crops.

More specifically, the present invention relates to a compound of formula I, a racemate or an optical isomer thereof or a pharmaceutically acceptable salt thereof or a hydrate thereof

X is 0 or s,

Y is 0 or s,

Is a C ₅ ~ C ₈ alicyclic ring,

R ₂ is hydrogen, d~C _{8 is} straight-chain branched alkyl or C ₂ -C ₈ straight or branched alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₈ cycloalkenyl, hydroxy , d O) alkoxy, d-alkylamino, fluorenyl, various sulfonyl, halogen, nitrile, trifluoromethyl, trifluoromethoxy, wherein the alkyl or alkenyl chain may be unsubstituted, It may also be substituted by one or more groups selected from the group consisting of C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl or Ar ₂ ,

Α _Γι and Ar _{2 are} independently selected from an aromatic carbocyclic ring or a heterocyclic ring, wherein the ring may be monocyclic, bicyclic or tricyclic; each ring is composed of 5 to 6 elements, and the heterocyclic ring contains 1 to 6 selected from below. Heteroatoms: 0, S, N; The ring may be unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethyl Oxy, d~C ₆ straight or branched alkyl, C ₂ ~C ₆ straight or branched alkenyl, ~0 ₄ alkoxy, C ₂ ~ C ₄ alkenyloxy, phenoxy, benzyloxy Base, carboxyl or amino group,

Z is a pharmaceutically acceptable acid radical.

A preferred embodiment of the invention is a racemate or optical isomer represented by a compound of formula I or a pharmaceutically acceptable salt or 7J thereof,

among them:

X is S,

Y is 0, The definitions of R _{l 5} R ₂ and Α _Γι are the same as above.

The first one is the halogenate F-, Cl-, Br-, Γ, or methanesulfonate, p-toluenesulfonate. Among them, hydrogenate and methylate are most preferred.

According to the present invention, the racemate or optical isomer of the hydrazine compound or a pharmaceutically acceptable salt or hydrate thereof is preferably the following compound:

( ± ) 3- [2-(4-Bromo-phenyl)-1-methyl-2-oxo-ethyl]-4, 5, 6, 7-tetrahydro-benzothiazole-3-hydrobromide Salt

(±) 3-(1-Methyl-2-oxo-2-phenyl-ethyl)-4,5,6,7-tetrahydro-benzothiazolyl-3-hydrobromide

The pharmaceutically acceptable salt of the racemate or optical isomer of the compound of the present invention includes inorganic Salt or organic salt, including but not limited to: hydrochloride, hydrobromide, amiodate, nitrate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, acetate, propionate, Butyrate, oxalate, trimethylacetate, adipate, alginate, lactate, citrate, alcoholate, succinate, maleate, fumaric acid Salt, picrate, aspartate, gluconate, benzoate, methanesulfonate, ethanesulfonate, besylate, p-toluenesulfonate and pamoate.

The compounds of formula I according to the invention can be prepared by the following reaction scheme:

Reaction route I:

X is 0, S,

^ is ~ ( ₈ alicyclic,

Reacting with a compound of formula V,

Y is 0 or S,

R is hydrogen or d Cs straight or branched alkyl or C ₂ ~C ₈ straight or branched alkenyl, ₃ ~ ( ₈ cycloalkyl, (: ₅ ~ (: ₈ cycloalkenyl, hydroxy, CC ^oxy, d~

(alkylamino, fluorenyl, various sulfonic acid groups, halogen, nitrile group, trifluoromethyl, trifluoromethoxy, wherein the alkyl or alkenyl chain may be unsubstituted or may be selected from below Substituted by one or more groups: ( ₃ ~ 0 ₈ cycloalkyl, c ₅ ~ c ₇ ring or Ar ₂ ,

Ar _x and ^: Ar _{2 are} independently selected from an aromatic carbocyclic ring or a heterocyclic ring, and the ring of ^^ may be a monocyclic or bicyclic tricyclic ring; wherein each ring is composed of 5 to 6 elements, and the heterocyclic ring contains 1 to 6 selected From the following heteroatoms: 0, S, N; the ring may be unsubstituted or substituted by one to three substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, three Fluoromethoxy, straight or branched alkyl, C ₂ ~C ₆ straight or branched alkenyl, (^~( ₄ alkoxy, C ₂ ~C ₄ alkenyloxy, phenoxy, benzyloxy) Base, carboxyl or amino group,

A compound of formula I wherein Z is Br is obtained, and optionally, the resulting compound is converted to another salt using a suitable salt to provide a compound of formula I,

Where X, Y, Rx, R ₂ and Α _Γι are as defined above,

The first one is a pharmaceutically acceptable acid radical.

In the above reaction scheme, the reaction of the compound of the formula IV with the compound of the formula V is carried out in the presence of a solvent such as ethanol or acetonitrile or methyl ethyl ketone or in the case where the two materials have a solvent; in the case of a liquid without solvent, at 80 ° C ~100 ° C, 5 to 96 hours in nitrogen.

The product obtained by the reaction can be crystallized by standing, recrystallized or purified by silica gel column chromatography. The silica gel used here is silica gel for conventional chromatography, particle size. 10 ~ 40μπι, the eluent is prepared from a single or a plurality of solvents, preferably from a different ratio of dichloromethane to methanol (the prepared mixed solution is purified to obtain the compound of the formula I.

A variety of methods can be employed to form the compounds of formula IV used in the above schemes, such as Scheme II.

Reaction route II:

its

The cyclic ketone of formula II is reacted with urea or urea under the action of iodine to give a compound of formula III, which is then treated with isoamyl nitrite in anhydrous tetrahydrofuran to give the compound of formula IV. It can be purified by high vacuum distillation or silica gel chromatography. The silica gel used here is silica gel for conventional chromatography, the particle size is 10~40μιη, and the eluent is prepared from single or multiple solvents, preferably by ethyl acetate. A mixed solvent of cyclohexane in different proportions.

The compound of formula V used in Scheme I can be prepared according to methods described in the literature (Tetrahedron Letters No. 38, p 3653-3656, 1979):

Vi v Y=S , 0

Wherein R ₂ , Y and Α _Γι are as defined for the compound of formula I,

The compound of formula VI can be obtained by using the compound of formula VI as CH ₂ and using copper bromide or bromine or NBS. The purification method may be a high vacuum distillation or a chromatographic method. The silicon used herein is a silica gel for conventional chromatography, and the particle size is 10 to 40 μm. The eluent is prepared from a single solvent or a plurality of solvents, preferably acetic acid. A mixed solvent of ethyl ester and cyclohexane in different ratios. The compound of formula V must be purified to remove a small amount of "dibromo.

Another aspect of the invention relates to a pharmaceutical composition comprising a racemate or an optical isomer of a compound of the invention and at least one pharmaceutically acceptable carrier. The pharmaceutical composition can be prepared in a prepared form depending on the route of administration. The compounds mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts.

The present invention can employ asymmetric synthesis to give a single optical isomer. However, resolution of the racemate is the primary means of obtaining optically pure compounds. There are four main methods of resolution: crystallization, chromatography, kinetics and enzymatic methods. For the resolution of the racemate of the compound of the present invention, a crystallization method of practical value is preferred: a racemic body Water, an organic solvent or a solution of a mixed solvent of water and an organic solvent, a chiral acid (resolving agent) is added to form a diastereomer, and the solubility of the diastereomer in the solvent is different. ^ One of them is prioritized. Preferably, the chiral acid is tartar, mandelic acid, camphorsulfonic acid, etc., and the chromatographic method is mainly carried out by using a HPLC chiral column to obtain a single optical purity compound.

The pharmaceutical compositions of the present invention comprise an effective amount of a compound of formula I according to the invention, or a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutically acceptable carriers. Pharmaceutical carriers herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, Partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone , Cellulose, Polyethylene Glycol, Sodium Carboxymethyl Cellulose, Polyacrylate, Beeswax, Lanolin.

The compounds of the invention are a class of potent cross-linking protein cleavage agents. Compared with ALT-711, the compounds of the present invention have better ability to cleave glycosylated aging proteins, and thus can be used for preventing fire treatment of AGE-related rickets, including but not limited to

( i ) increase skin elasticity or reduce skin wrinkles, ( ϋ ) treatment of diabetes,

(iii) treating or alleviating the sequelae of diabetes, (iv) treating or relieving kidney damage, (V) treating or relieving vascular damage, (vi) treating or relieving hypertension, (vi i) treating or relieving retinopathy, (vi ii Treat or relieve lens damage,

(ix) treating or relieving cataracts, (X) treating or relieving peripheral neuropathy, (xi) treating or relieving osteoarthritis.

The invention may also be extended to prevent or reverse tooth coloration due to non-enzymatic glycosylation reactions in the oral cavity. The regimen containing the compound of the present invention can be varied depending on the use involved.

It occurs in the oral cavity of non-enzymatic reaction may result in tooth staining agent, an _anti-β decay currently-used carbon-based can accelerate this reaction leads to further tooth coloration. Recently, there has been a class of cationic bactericides having anti-corrosion function for conventional oral cleaning. These cations have antibacterial agents such as alexidine, cetylpyridinium chloride, etc. However, these preparations can be used in the one-step Mai l lard reaction of the fruit bond in the oral glycosylation reaction, and then the teeth are added. Coloring ( Nordbo, L Dent. Res., 58: 1429 (1979) ) and it has been reported that chlorhexidine and chlorhexidine can catalyze the glycosylation reaction (browning reaction) in vitro. Due to the Mai l lard reaction, washing Bethai added a mixture of sugar and amino acids to accelerate the formation of pigments.

For the above reasons, the compounds of the present invention and pharmaceutical compositions thereof can be used in the oral cavity. Especially used as an additive in oral cleaning solutions and toothpastes.

In the above-mentioned use of the compound of the present invention, it can be applied to a mouthwash and a toothpaste in a suitable form of a non-toxic and pharmaceutically acceptable carrier.

The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Inside, intraventricular, intrasternal and intracranial injection or input, or with an explant. Among them, oral, intraperitoneal or intravenous administration is preferred.

When administered orally, the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions. Among them, the carrier used for the tablet generally comprises lactose and corn starch, and a lubricant such as magnesium stearate may also be added. The diluent used in the capsule preparation generally comprises lactose and dried corn starch. Aqueous suspension formulations are usually prepared by admixing the active ingredient with suitable emulsifying and suspending agents. If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.

In the case of topical administration, especially in the treatment of facial surfaces or organs easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs. Form _{5 is} specifically illustrated as follows: When applied topically to the eye, the compound of the invention may be formulated into a micronized suspension In the form of a liquid or solution, the carrier used is an isotonic, sterile saline solution of a certain pH, with or without a preservative such as a benzyl chloride alkoxide. For ophthalmic use, it can also be formulated into a paste-shaped cream.

When applied topically to the skin, the compounds of the invention may be in the form of a suitable ointment, lotion or cream preparation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers for ointment preparations include, but are not limited to: mineral oil, liquid Vaseline white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams which may be used include, but are not limited to: mineral oils , sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. Alternatively, sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.

It should also be noted that the dosage and method of use of the compounds of the invention will depend on a number of factors including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition. And the subjective judgment of the doctor. The preferred dosage is from 0.01 to 100 mg/kg body weight per day, wherein the optimal dose is from 20 mg/kg to 30 mg/kg body weight per day.

detailed description

Example

The following examples are illustrative of preferred embodiments of the invention and are not to be construed as limiting.

The melting point of the compound was determined by a SRY-1 type melting point apparatus and the temperature was not corrected. The 'H-NMR spectrum was measured by a Bruker AX 400 or US Varian Uni Inova 600 type nuclear magnetic apparatus, and the FAB mass spectrum was measured by a Zabspect high resolution mass spectrometer. Preparation 1: 4, 5, 6, 7-tetrahydro-indolozole-2-amine

39 3⁄4 (0.4niol) cyclohexanone, 61g (0.8mol) thiourea and 102g (0.8mol) iodine were heated at 100 ° C for 9 hours, then poured into 2000 πι hot water, filtered to remove insoluble matter, with ammonia Alkaliization, extraction with three times of 600 ml of chloroform, drying of the organic phase with anhydrous sodium sulfate, filtration, recovery of solvent, addition of 100 ml of ethyl acetate, crystallization, yielding 20 g of product 4, 5, 6, 7-tetrahydro-benzene Thiazol-2-amine, melting point 83 ~ 88 °C.

Preparation of 2 4, 5, 6, 7-tetrahydro-benzothiazole

11.5 g (0.075 mol) of 4,5,6,7-tetrahydro-benzothiazole-2-amine was dissolved in 100 ml of anhydrous tetrahydrofuran, and added dropwise to a 1.5 M solution of isoamyl nitrite at 45 ° C. (150 ml), after completion of the dropwise addition, the mixture was stirred for 1 hour, and then the solvent was recovered, and ethyl acetate: hexane: 20:1 column chromatography to give 3.5 g of product. /. . Example 1: 3-(2-Phenyl-4-yl-2-oxo-ethyl)-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide

1.08 g (0.00 ⁷⁷ mol) of 4,5,6,7-tetrahydro-benzothiazole was dissolved in 5 ml of absolute ethanol, and 2.7 g (O. Olmol) of 1-biphenyl-4-yl-2- Bromo-ethanone was heated under reflux for 1.5 hours, allowed to stand for crystallisation, and filtered to give a crude material. The crude product was purified by column chromatography through silica gel (dichloromethane: methanol = 8: 1), to give the title compound as a white solid, (1.5g, 50% mp237-241 " C), MS [Μ] + = 334 l /. 'H-NMR (600MHz, DMSO) 51.824 (m 4H); 2.674 (m 2H); 2.942 (m 2H); 6.369 (s 2H) ; 7.475 (m 1H) ; 7.556 (t 7 = 7.8 Hz 2H) ; 7.811 (dd 7 = 1.2, 8.4 Hz 2H); .7.977 (dd 7 = 1.8, 7.2 Hz 2H); 8.147 (dd 7 = 1.8, 7.2 2H); 9.995 (s 1H). Example 2: 3- [ 2-(3-Nitro-phenyl)-2-oxo-ethyl]- 4, 5, 6, 7-four Hydrogen-benzothiazole-3-hydrobromide

Prepared according to the method of Example 1, wherein the bromo ketone is 2-bromo-1-(3-nitro-phenyl)-:ethyl ketone to obtain the standard compound (0.3g, 25%, mp215-2, 19 ° C). ■· : , ■: ·

MS [M] +-303. Qm/e; 'H-NMR (600MHz, DMSO) δ 1.823 (m 4H); 2.689 (m 2H); 2.941 (m 2H); 6.425 (s 2H); 7.965 (t 7 = 8.4 Hz 1H); 8.460 (d 7 = 7.8 Hz 2H); 8.612 (d 7 = 9.6 Hz 2H); 8.775 (t 7 = 2.4 Hz 2H); 9.962 (s 1H). Example 3: 3-[2-(4-sulfonyl-phenyl-2-oxo-ethyl)-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide

Prepared by the method of Example 1, wherein the bromo ketone was 2-bromo-1-(4-methylsulfonylphenyl)-ethanone to give the title compound (1, 25 g, 96%, mp 190-195 ° C) .

MS [M] ⁺ = 336. Om/e; ^J H-NMR (600MHz, DMSO) δ 1.821 (m 4H); 2.675 (m 2H); 2.937 (m 2H); 3.33 (s 3H); 6.365 (s 2H ); 8 _k 222 (dd 7 = 1.8, 6.6 Hz 1H); 8.281 (dd 1 = 1.8, 6.6 Hz 2H); 9.966 (s 1H). Example 4: 3-[2-(3,4-Dichlorophenyl)-2-hydroxy-ethyl]-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide

Prepared by the method of Example 1, wherein the bromo ketone was 2-bromo-1-(3,4-dichlorophenyl)-ethanone to give the title compound (.1.05 g, 81%, mp 206-210 ° C ). '

MS [M] ⁺ = 326. Om/e; 1H-MR (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=l.8Hz 2H); 9.943 (s 1H). Example 5: 3-(l-Methyl-2-oxo-2-phenyl-ethyl)-4,5,6,7-tetrahydro-benzothiazol-3- 1L bromate::

Prepared by the method of Example 1, wherein the bromo ketone was 2-bromo-1-phenyl-propyl-1-one, to the title compound (0.53 g, 42%, m. p. 237-241 ° C).

MS [M] +=273.3 m/e; 1H-NMR (600 MHz, DMSO) ( 1.788 (m 4H); 1.919 (d J = 7.2 3H).; 2.42 (d J = 16.0 Hz 1H); 2.929 (m 2H ); 3.091 (d J = 16.0 Hz 1H); 6.890 (m 1H); 7.662 (m 2H);

7.805 (m 1H); 8.191 (m 2H) ; 10· 306 (s 1H). Example 6: 3-[2-(4-Bromo-phenyl)-1-methyl-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzoxazole-3-hydrobromide Acid salt

Prepared according to the method of Example 1, wherein the bromo ketone was 2-bromo-1-(4-bromo-phenyl)-propyl-1-one to give the title compound (0.6 g, 26%, mp146-154 ° C ). MS[M] ⁺ =354.

DMSO) δ 1.786 ( m 4H); 1.902 (d 7 = 7.2 Hz 3H); 2.498 (ra 1H); 2.923 (m 2H); 3.055 Cm lH); 6.8857 (dd 7=7.2, 14.4 Hz 1H); 7.889 ( m 2H) ;

8.143 (m 2H); 10.32 (s 1H). Example 7: 3-(2-Naphthalene-2-yl-2-oxo-ethyl)- 4, 5, 6, 7-tetrahydro-benzoxazole-3-hydrobromide

Prepared according to the method of Example 1, wherein the bromo ketone was 2-bromo-1-(2-naphthalen-2-yl)-ethyl-1-one to give the title compound (3 g, 90%, mp 190-193 ° C ). MS[M] ⁺ = 308. e; ^X H-NMR (600MHz, DMSO) δ 1. 830 (m 4H); 2.700 (m 2H); 2.953 (m 2H); 6.471 (s 2H); 7.709 (m 2H); G.073 (m 4H) ; 8.825 (m 1H) ; 10.034 (s 1H). Example 8: 3-[2-(2-Nitro-phenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazepine-3-hydrobromide

</ RTI>_{</RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI>}<RTIgt_; MS[M] ⁺ = 303. 327/e; ^x H NMR (600MHz, CD ₃ 0D) δ 2.029 (m 4H); 2.910 (m 2H); 3.00 (m 2H); 7.923 (m 3H) ; 8.287 (m 1H) „ Implementation 4 9 : 3-[2-( 3 -Methoxy-phenyl)-2-ethoxy-ethyl] ― 4, 5, 6, 7-tetrahydro-benzothiazole-3-hydrobromide Acid salt

Prepared according to the method of Example 1, wherein the bromo ketone was 2-bromo-1-(3-methoxy-phenyl)-ethyl ketone to give the title compound (1.2 g, 76%, mp 196-200 ° C) .

MS [M] ⁺ = 288. </ RTI><RTIgt;2H); 7.381 (m 1H) ; 7.559 (m 2H) ; 7.677 (m 1H) ; 10.022 (s

1H). , Example 10: 3-[2-( 2,5-Dimethoxy-phenyl)-2-oxo-ethyl - 4, 5, 6, 7 -tetrahydro-benzothiazole-3 -hydrogen Bromate

Prepared according to the method of Example 1, wherein the bromo ketone was 2-bromo-1-(2,5-dimethoxy-phenyl)-ethyl ketone to give the title compound (1.2 g, 82%, mp 210- 215 ° C).

MS [M] ⁺ = 318. lm / e; 'H-NMR (600MHz, DMSO) δ 1.799 ( 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).

(2-oxo-2-p-tolyl-ethyl) -4, 5, 6, 7-tetrahydro Benzothiazole-3-hydrobromide k

Prepared according to the method of Example 1, wherein the bromo ketone is ² -bromo: 1-( ⁴ -methyl-phenyl)-ethyl steel, which gives the title compound (0, "3g, 22%, mp Ϊ87-189 ) ₀

MS [Μ] ⁺ = 272. O/zz/e; "H-R (600MHz, DMSO) δ 1.810 (m 4H); 2.504 (m 3H); 2.642 (m 2H); 2.931 (m 2H); 6.325 ( s 2H);

7.465 (d /=5.2Hz2H); 7.966 (d J=5.6Hz 2H) ; 10.002 (s 1H). Example 12: 3-[2-(4-Nitro-phenyl)-2-oxo-ethyl] -4, 5, 6, 7-tetrahydro-benzothiazole - bromic acid

The title compound (0.5 g, 32%, oil) was obtained.

MS [M] ⁺ = 303. \m/e\ 'H-NMR (600MHz, DMSO) δ 1.961 (m 4H); 2.744 (m 2H); 2.999 (m 2H); 6.343 (s 2H) ; 8.330 (d 7=9.0 Hz 2H); 8.439 (d 7-9.2 Hz 2H); 9.934 (d 7=2 Hz 1H). Example 13: 3-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazole-3-hydrochloride

Prepared by the method of Example 1 to give the title compound (3 g, 88%, m. p. 187-194 ° C).

MS [M] ⁺ = 276. ln / e; 'H-NMR (600MHz, DMSO) δ 1.948 (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). Example 14: 3-[2-(4-Methoxy-phenyl)-2-oxo-yl]

4, 5, 6, 7-tetrahydro-benzoxazole -3 -hydrobromide

Prepared according to the method of Example 1, wherein the bromo ketone is 2-bromo-1-(4-methoxy- Phenyl) - ethyl ketone to afford the title compound (0.9g, 50%, mp 200-205 ° C) 0 ...

"MS [M] ⁺ = 288. l/z//e; 'H-NMR (600 MHz, CD ₃ 0D δ 1.942 (m 4H); 2.698 (m 2H); 2.983 (m 2H); 3.917 (s 3H) 7.108 (m 2H); 8.088 (m 2H) „ Example 15: 3-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro- Benzothiazole-3-hydrobromide

Prepared by the method of Example 1, which is 2-bromo-bromoketone - l- (4-chloro - phenyl) - ethyl ketone, to give the title compound (0.6g, 33%, mp 196-202 ° C) o

MS [M] ⁺ = 292. lm / e; ^X H-NMR (600 MHz, DMSO δ 1.949 (m 4H); 2.703 (m 2H); 2.987 (m 2H); 6.232 (s 2H); 7.640 (m2H); 8.097 (m 2H); 9.892 (s 1H). Example 16: 3-[2-(4-Bromo-phenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzene Thiazol-3-hydrobromide

Prepared according to the method of the first embodiment, wherein the bromo ketone is 2-bromo-1-(4-bromo-phenyl)-ethyl ketone to give the title compound (0.4 g, 23%, m.p, 207-213°C) _o

MS [M] ⁺ = 338. lm/e; 'H-NNiR (600 MHz, DMSO δ 1.949 (m 4H); 2.696 (m 2H); 2.987 (m, 2H); 6.213 (s 2H); 7.805 (m2H) 7.998 (m 2H); 9.878 (s 1H). Example 17: 3-(2-diphenyl-4-yl-2-oxo-ethyl)-4,5,6,7-tetrahydro-benzene Thiazole-3-methanesulfonate

Compound (0.5g, 0.0012mol) prepared in Example 1 will be obtained and implemented 0. ² 6g (0.0012mol) Yue silver sulfonate lOmin the reaction was stirred in 15ml of methanol, then solid was filtered, concentrated, and an appropriate amount of diethyl ether was added to give crystals Title Compound (0.37g, 95%, mp 229-232°C) ₀

MS [M] ⁺ = 334. i /e; 'H-NM . (600MHz, DMSO δ 1.823 (m 4H); 2.298 (S 3H); 2.677 (m 2Ϊ); 2.944 (m 2H); 6.388 (s 2H 7.480 (m 1H) ; 7.5 8 (m2H) ; 7.805 (m2H) ; 7.815 (d 7 = 7.2 Hz 2H); 7.978 (d 7 = 8.3 Hz 2H); 8.150 (d 7 = 8.3 Hz 2H); (s 1H). Example 18: 3-(2-oxo-2-phenyl-ethyl)-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide

Prepared by the method of Example 1 to give the title compound (0.27 g, 16%, m. p. 204-210.

MS[ ] ⁺ =259. lz?/e; 'HN R (600MHz, DMSO δ 1.950 (m 4H); 2.712 (m 2H); 2.991 (m 2H); 6.288 (t 7=3.6Hz 2H) ; 7.608 ( m2H); 7.732 (m 1H); 8.104 (m 2H); 9.938 (d 1 = 4.2 Hz 1H) ₀ Example 19 ELISA screening test for cleavage of AGE-BSA-collagen cross-linking structure with AGE-BSA and coating at 96 The rat tail rubber protein was cross-linked on the well plate and the AGE cross-linked structure was prepared in vitro. The cleavage effect of the compound on AGE cross-linking was evaluated by ELISA method. - The tail collagen was coated with 96-well ELISA plate.

Normal Wister rats (body weight 200 ± 20 g), acutely sacrificed, tailed, and the following tail collagen preparation process was carried out at 4 °C. First, the cercaria collagen filaments were extracted, washed with physiological saline and the non-collagen silk tissue was removed, washed twice with double distilled water, cut, and immersed in 0.1% glacial acetic acid at 4 ° C for 1 week, during which shaking was often performed. Finally, the mixture was centrifuged at 8000 g for 30 min, and the collagen solution from the sputum and supernatant was collected, and the protein content was determined after being diluted. 96-well microtiter plate coated with 70μ8 I proprotein per well (Costar), 4 ° C, 24 h, discard the coating solution, air-dried, wrap-coated under windowless conditions, stored at 4 ° C for later use.

AGE-BSA preparation:

Bovine serum albumin BSA (V) ( Roch ) SOmg ml and 0.5M glucose were incubated in 0.2M PBS (pH 7.4) at 37 ° C under sterile conditions for 3-4 months in the dark to form a glycosyl group. BSA is BSA-AGE. At the same time, aglycosylated BSA was prepared with glucose-free BSA. Then, dialysis was carried out in 0. OIM PBS (pH 7, 4), and unreacted glucose was removed. Fluorescence scanning (Exi/Em (395/460 am)) and SDS-PAGE were used to identify BSA-AGE formation, and the Lowery method was used. Protein quantification.

Analytical measurement method flow:

The tail collagen was coated in a 96-well plate, and the acidic collagen was neutralized with pH 7.4 PBS; SuperBlock (PIERCE) 37. C, blocked lh; PBST (PBS-Tween) wash plate 3 times, shaking for 1 minute each time; dilute AGE-BSA with PBS to obtain maximum cross-linking concentration of AGE-BSA ΙΟΟμΙ into 96-well plates A, B, C In the wells of row D, the same concentration of BSA was added to the E, F, G, and H rows, and PBS was used as the system and reagent blank in the first 3 wells of the first column, and crosslinked with collagen for 4 hours at 37 ° C; PBST The plate was washed 4 times with an interval of 1 min; the test compound was diluted with H7.4 PBS, and ΙΟΟμΙ/well was added to each of the AGE-BSA cross-linking and BSA 4 wells, and PBS ΙΟΟμΙ/well was added as a non-lytic control in the same manner. . Incubate for 16 h; wash plate 4 times with PBST, shake at intervals for 1 min; add 80 μl /well rabbit anti-BSA antibody (1 : 500 ) at 37 ° C, 50 min; wash plate 4 times with PBST, shake at intervals for 1 min; add 80 μl / well horseradish Peroxidase-labeled goat anti-rabbit IgG ( 1 : 1O00 ) 37 °G, 50 min; wash plate 3 times with PBST, shaking for 1 min; add substrate TMB (3, 3, , 5, 5, - tetradecyl) Benzidine) ΙΟΟμΙ/well room temperature, closed light for 20 min; terminate the reaction with 2mol/L H ₂ S0 ₄ ; within 10 min, at the B0BRAD Model550 plate reader 450nm, the blank hole of the plate is zero-read to read the 0D value.

data analysis: The average OD value was a 4-well average.

Correction of 0D average of OD-AGE-BSA - 0D average of BSA wells The rate of cleavage is expressed as a percentage reduction of OD^;

[ ( 0D average of PBS well - average value of 0D of test drug well) / 0D average of PBS well] x%

According to the above steps, the results of the test compound at a concentration of 0.1, lmmol/L or lower are shown in Table 1 (the results are all 3 or more screening results ^ average):

Table 1: ELISA assay for compound cleavage rate of AGE-BSA-collagen cross-linking

Example 20 In vivo reversal AGE cross-linking structure

To confirm the effect of the above test compound in reversing AGE cross-linking in vivo, we evaluated the inverse of Compound 6 on the surface of EBC cross-linking of EBC in aged diabetic rats. Turn effect.

Replication of an aging rat model of diabetes:

Wi s ter rats, male, weighing 180-200 g, intraperitoneal injection of urinary sputum, 65 mg/Kg, once, blood glucose level was higher than 16 awake ol/L rats, often kept for 32 weeks.

Animal grouping and test compound administration methods:

32-week diabetic rats were divided into 5 groups, 8-10 each, intraperitoneally injected with physiological salt ice, ALT-711 (1mg/Kg), #16 compound, 1 mg/Kg, #16 compound, 3 mg/ Kg, #16 compound, 10 mg/Kg, once a day for 3 weeks.

RBC preparation and RBC-IgG analysis:

After 3 weeks of administration of the compound to the rats, blood was taken, heparin was anticoagulated, and washed with PH.7.4 PBS three times, 1:250 dilution.

RBC-IgG analysis was performed in Mul t screen-IP, 0. 45 μιη, 96 孑L plate (Mi ll ipore, MAIPS4510) with 300 μl Superblock ( PIERCE ) at 37 °C for 1 h, washed once with PBST full well, and then with PBS. Plates were washed twice; RBC 50 μl diluted and mixed with PBS was added to the wells, and '4 replicate wells were added to each rat RBC sample, while 4 wells were added to PBS as antibody control wells. PBS 3⁄4t RBC 1 time, force σ into 50μ1

Horseradish peroxidase-labeled rabbit anti-rat IgG (1:2000), room temperature, 2 h; wash 4 times with PBS, add substrate solution 0PD (o-phenylenediamine) Ι ΟΟμΙ/well, room temperature, protected from light for 30 min; The reaction was terminated with ₂ mmol/L H ₂ S0 ₄ 50 μl/well; 120 μl of each well was transferred to a common 96-well microtiter plate, and the plate blank was zeroed at a BOBRAD Model 550 plate reader at 490 nm, and the 0D value was read.

data analysis:

The RBC-IgG content is expressed as the corrected value of the sample 0D value, and the average 0D value of each sample is the average of 4 wells, and the average RBC-IgG content of each sample is 8 animals. average value.

Correction 0D = 0C average of each rat RBC sample 0D average of single antibody wells

The rate of cleavage is expressed as a percentage reduction in RBC-IgG content:

[(Control animal RBC-IgG - Test drug treatment group RBC-IgG) / Control group Animal RBC- IgG ] x%

The results of the test compound cleavage rate according to the above experimental method steps are shown in Table 2:

Table 2

Compound and dose cracking rate (%)

ALT-711 41. 5

( lmg/kg )

6 ( lmg/kg ) 38. 6

6 ( 3mg/kg ) 55. 8

6 ( 10mg/kg ) 57. 1

Claims

Rights request

1 · a compound of formula I, a racemate or an optical isomer or a pharmaceutically acceptable salt or hydrate thereof

among them:

X is 0 or S,

Is 0 or S,

1^ is ( ₅ ~ (^ alicyclic,

R ₂ is hydrogen or d ~ C ₈ straight or branched alkyl or C ₂ ~ C ₈ straight or branched alkenyl, 0 ₃ ~ (cycloalkyl, C ₅ ~ C ₈ cycloalkenyl, hydroxy, D~C ₄ alkoxy, d ~ C ₄ alkylamino, fluorenyl, various sulfonic acid groups, halogen, nitrile group, trifluoromethyl, trifluoroyl group, wherein the alkyl or alkenyl chain may be unsubstituted , may also be substituted by one or more groups selected from the group consisting of: c ₃ ~c ₈ cycloalkyl, c ₅ ~c ₇ cycloalkenyl or

Ar ₂ ,

Ar _{2 is} independently selected from an aromatic carbocyclic ring or a heterocyclic ring, wherein the ring may be a specific ring, a bicyclic ring or a tricyclic ring; each ring is composed of 5 to 6 elements, and the heterocyclic ring contains 1 to 6 hetero atoms selected from the following : 0, S, N; The ring may be unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, D~C _fi linear or branched alkyl, C ₂ ~C ₆ straight or branched alkenyl, (^~(: ₄ alkoxy, C ₂ ~C ₄ alkenoxy, phenoxy, benzyloxy) Base, carboxyl group, gas group,

z is a pharmaceutically acceptable acid radical.

2. A compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein:

Y is 0, '

^ and R ₂ and human ^ substituents are defined in accordance with claim 1,

Z is a halogenate F-, Cl-, Br-, hydrazine, or methanesulfonate, p-methylsulfonate.

3. A compound according to any one of claims 1 or 2 which is selected from the group consisting of:

3-(2-biphenyl-4-yl-2-oxo-ethyl)-4,5,6,7-tetrahydro-benzothiazole-

3-[2-(3-Nitro-phenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazol-3-hydrobromide

3-[2-(4-Methanesulfonyl-phenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide

3-[2-(3,4-Dichlorophenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazol-3-hydrobromide

(Earth) of 3- (1-methyl - ² - oxo - ² - phenyl - ethyl) - ^4, 5, 6, 7-tetrahydro - benzothiazole - 3- hydrobromide

(士) 3- [2-(4-Bromo-phenyl)-1-methyl-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide Salt

3-(2-naphthalene-2-yl-2-oxo-ethyl)-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide

3-[2-(2-Nitro-phenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide

3-[2-(3-Methoxy-phenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide 3-[2-(2,5-Dimethoxy-phenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide.

3-(2-Oxo-2-p-tolyl-ethyl)-4, 5, 6, 7-tetrahydro-benzothiazole-3-hydrobromide : :

3-[2-(4-Nitro,phenyl)-2-ethoxy-ethyl]-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide

3-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide

3-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazolyl-3-hydrobromide

3-[2-(4-Chloro-phenyl)-2-oxo-ethyl] -4, 5, 6, 7-tetrahydro-benzothiazole-3-hydrobromide

3-[2-(4-Bromo-phenyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazole-3 - hydrobromide

3-(2-biphenyl-4-yl-2-oxo-ethyl)-4,5,6,7-tetrahydro-benzothiazole-3-sulfonate

3-(2-Oxo-2-phenyl-ethyl)-4,5,6,7-tetrahydro-benzothiazole-3-hydrobromide

4. The compound of claim 3 which is

( ± ) 3 - [2-(4-Bromo-N-yl)-1-methyl-2-oxo-ethyl] -4, 5, 6, 7 -tetrahydro-benzothiazole-3-hydrobromide Salt

( ± ) 3- (1-methyl-2-oxo-2-phenyl-ethyl) - 4, 5, 6, ⁷ -tetraoxo-benzothiazole-3-hydrobromide

5. A pharmaceutical composition comprising the compound of any one of claims 1 to 4 and at least one pharmaceutically acceptable carrier.

6. A method of preparing a compound as claimed in any one of claims 1 to 4 which comprises Compound of formula IV

Definition of requirement 1:

Reacting with a compound of formula V,

Wherein R ₂ , Y, A is as defined in claim 1, obtaining a compound of formula I wherein Z is Br, and optionally converting the resulting compound to another salt using a suitable salt to provide a compound of formula I,

Where R ₂ , X, Y, ^ and ? The definition is the same as claim 1.

7. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for cleavage of advanced glycation end products.

8. The compound according to any one of claims 1 to 4 for use in the preparation of an animal (i) for increasing skin elasticity or reducing skin wrinkles, (ii) for treating diabetes,

(iii) treating or alleviating the sequelae of diabetes, (iv) treating or relieving kidney damage, (V) treating or relieving vascular damage, (vi) treating or relieving high blood Pressure, (vii) treatment or relief of retinopathy, (viii) treatment or relief of lens protein damage, (ix) treatment ^ relief of cataract, (X) treatment or relief of peripheral nerves or (xi) treatment or relief of osteoarthritis Use of the object.

9. Use of a compound according to any one of claims 1 to 4 for the preparation of an animal tooth color reversal agent or other oral preparation for preventing and reversing tooth coloration.

10. Use of a compound according to any one of claims 1 to 4 for the preparation of a plant protein or animal protein preservative.