JP2003511370A - Compounds for the treatment of vascular complications associated with diabetes and aging - Google Patents

Abstract

SUMMARY OF THE INVENTION The present invention is directed to the management of vascular complications associated with diabetes and aging, and in particular the complications of diabetes mellitus and other aging-related conditions, by degrading the AGEs already formed. For example, the following general formula I useful for the treatment of kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological conditions and tooth discoloration: Wherein R ¹ , R ² , and X are defined in the specification, or a pharmaceutically acceptable salt thereof. The present invention also discloses a process for the preparation of the analogous compounds and pharmaceutical compositions containing one or more compounds as defined above as active ingredients. The present invention further discloses a method of treating a diabetic patient by administering a compound as defined above alone or in combination with other diabetes therapeutics.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to pyridinium-based compounds and their use in the treatment of diabetes and its attendant disorders. More particularly, the present invention relates to syngeneic compounds, methods of making them, pharmaceutical compositions containing these compounds, and diabetes mellitus.
their use in the treatment of complications of S. The compounds of this system exhibit AGE breaking activity that is essential for the treatment of diabetes and aging-related complications including renal disease, nerve damage, atherosclerosis, retinopathy and dermatological symptoms. Show. The present invention also provides a pre-formed advanced cross-link that has already been formed.
ced glycosylation crosslinks) (re
non-enzymatic browning of the oral cavity including administration of an effective amount for verse
It also relates to a method of reversing the discoloration of the teeth due to attic browning.

BACKGROUND OF THE INVENTION 1912 Maillard was reducing.
It has been found that sugars such as glucose and ribose react with proteins to produce brown pigments. Further studies show that this is an irreversible non-enzymatic reaction,
It has been shown to occur in several natural systems, including stored food. The Maillard reaction occurs in two stages, an early process and an advanced process. Initially, the protein reacts with glucose to produce a stable Amadori product which subsequently crosslinks to produce advanced glycosylated end products.
generation of endion products (AGE). In most cases
AGE production is associated with protein browning and increased fluorescence.

In diabetes, glucose levels in blood are significantly higher than normal, and glucose and some proteins such as hemoglobin, lens crystallin.
, And reaction with collagen increase the production of AGE, which in turn causes complications associated with diabetes, such as nephropathy, microangiopathy, endothelial damage and dysfunction of other organs. In addition, the activity of some growth factors such as basic fibroblast growth factor is also impaired. AGE products have a low rate of turnover and recruitment, unlike normal proteins in tissues. AGE products are, in fact, RAGE (Receptor)
for Advanced Glycation End Products
A receptor for advanced glycosylation end products) and induces a complex immune response that involves activation of several unclear immunological processes. Diabetes mellitus is associated with microangiopathy and macroangiopathy (mac).
roangiopathy), as well as signs of oxidative stress whose mechanism has not yet been clearly elucidated.

In vitro AGE production can be studied in the laboratory by incubating bovine serum albumin with reducing sugars such as ribose or glucose. The production of AGE can be detected by an increase in fluorescence or an increase in cross-reactivity with anti-AGE antibody. Increased fluorescence appears to precede the production of AGE-specific antigenic epitopes. This increase in fluorescence has been used to monitor an increase in AGE production in vitro (Brownlee M et al., Science, 19).
1986; 232; 1629-1632.). In addition to the increase in fluorescence, one of the most important features of AGE production in vitro is AGE-specific but native (
native) The production of an antigenic epitope that is not specific to a protein. Therefore, it is possible to increase the antibody to the advanced glycosylation end product of one protein and use it to detect the AGE production of another protein. This is utilized as an important analytical tool in AGE research.

Due to the clinical importance of AGEs, many approaches have been used to diagnose, prevent, or revert the production of AGEs in the body. The production of AGE could be inhibited by the reaction of the initial glycosylation product resulting from the original reaction between the target protein and glucose. This inhibition may occur between the inhibitor and the initial glycosylation product, which would interfere with the subsequent reaction of the glycosylated protein with additional protein material to produce the cross-linked product of the latter step. Was believed to occur as a reaction to. Compounds such as aminoguanidine act to inhibit AGE production by such a mechanism.

Generation of AGEs for long-lived proteins also involves cross-linking of these proteins. AGE-derived protein crosslinks may be cleaved by compounds such as N-phenacyl thiazolium bromide (PTB) that react with AGE-derived protein crosslinks and cleave the covalent crosslinks. Shown (V
asan et al., Nature, 1996, 382: 275-278; U.S. Pat. No. 5,853,703, patent date: December 29, 1998). The mechanism by which AGE content in tissues is reduced is predicted to occur relatively quickly, in contrast to the slow acting aminoguanidine, due to the nature of the mechanism of action itself. The present description relates to compounds of the pyridinium group, which degrade AGEs already formed in a manner similar to and in some cases more effective than PTB.

SUMMARY OF THE INVENTION The main object of the present invention is to manage vascular complications associated with diabetes and aging, and especially diabetes mellitus and other aging related conditions such as kidney disease, nerve damage, atherosclerotic arteries. It is intended to provide a group of pyridinium compounds useful for treating complications such as sclerosis, retinopathy and dermatological symptoms. The present invention also relates to a method of reversing tooth discoloration due to nonenzymatic browning of the oral cavity comprising the administration of an amount effective to reverse advanced, already formed glycosylation crosslinks and the like. .

Another object of the present invention is to provide a pyridinium-based compound exhibiting AGE degrading activity.

Still another object of the present invention is to provide a method for producing a pyridinium-based compound exhibiting AGE decomposition activity.

Yet another object of the present invention is the novel pyridinium-based compounds according to the present invention and their pharmaceutically acceptable salts, and suitable carriers, solvents, excipients, diluents and pharmaceutical compositions. It is to provide a pharmaceutical composition in combination with other vehicles commonly used to manufacture things.

Yet another object of the present invention is to provide a compound of the present invention alone or in combination with a medicament for the treatment of diabetes, or a pharmaceutically acceptable salt thereof, in a required dose. It is intended to provide a method for treating diabetic patients by administering in admixture with an acceptable diluent, solvent, excipient, carrier or other vehicle suitable for this purpose.

[0012] Detailed Description of the Invention   The present invention has the following general formula I

[0013]

[Chemical 2]

Wherein R ¹ is —Y—R ³ , Y is selected from oxygen or NH, R ³ is selected from hydrogen, alkyl, aryl, R ² is alkyl, —Oalkyl, aryl, Selected from the group consisting of —O aryl, —NH alkyl and —NH aryl, X is a halide ion, an acetate ion, a perchlorate ion, a sulfonate ion,
Oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, hydrogen phosphate ion, phosphonate ion, phosphate ion, BF ₄ ⁻ , PF ₆ ^{− and the} like.

However, when (a) R ¹ is phenyl, R ² is also phenyl, and (b) R ² is phenyl and X is a halide ion, R ¹ is —OC.
The condition is that it is other than H ₃ . ) Provides a novel group of AGE decomposers.

“Alkyl” as used herein refers to an optionally substituted saturated hydrocarbon group having 1-4 carbon atoms joined together by a single carbon-carbon bond.
The saturated alkyl hydrocarbon group may be linear or branched. Substituent is -OH
Is.

As used herein, “aryl” refers to an optionally substituted aromatic group having at least one ring having a conjugated π-electron system, including at most two conjugated or fused ring systems. . Aryl includes carbocyclic aryl and heterocyclic aryl, all optionally halogen, sulfonamide, thio, amino, cyano, -Oalkyl, -NHalkyl, hydroxy, formyl, -Oaryl and -NH. It may be substituted with aryl.

Representative representative compounds of general formula I are listed in Table IA ([Table 1]). These compounds having the following chemical names are provided for illustration only and do not limit the invention in any way.

3-Carbonylamino-1- (2- (2,4-dichlorophenyl) -2-bromide
Oxoethyl)) pyridinium (Compound 1). 3- (Tetrahydrobenzothiazol-2-yl) aminocarbonyl-1-bromide
(2- (2,4-Dichlorophenyl) -2-oxoethyl) pyridinium (Compound 2). 1- (2-phenyl-2-oxoethyl) -3-((2-hydroxyethyl) aminocarbonyl) pyridinium bromide (Compound 3). 3-Carbonylamino-1- (2-thien-2′-yl-2-oxoethyl) pyridinium bromide (Compound 4) 1- (2-phenyl-2-oxoethyl) -3-((p-sulfonamide) Phenylene) aminocarbonyl) pyridinium (Compound 5).

1- (2-ethoxy-2-oxoethyl) -3-((2-hydroxyethyl) aminocarbonyl) pyridinium bromide (Compound 6). 1- (2-phenyl-2-oxoethyl) -3- (isopropyloxycarbonyl) pyridinium bromide (Compound 7). 1- (2-Methyl-2-oxoethyl) -3-((2-hydroxyethyl) aminocarbonyl) pyridinium chloride (Compound 8). 1- (2-thien-2'-yl-2-oxoethyl) -3-((2-hydroxyethyl) aminocarbonyl) pyridinium bromide (Compound 9). 1- (2- (2,4-dichlorophenyl-2-oxoethyl) -3- (isopropyloxycarbonyl) pyridinium bromide (Compound 10).

1- (2-phenyl-2-oxoethyl) -3-((4-methylthiazol-2-yl) aminocarbonyl) pyridinium bromide (Compound 11). 1- (2-phenylamino-2-oxoethyl) -3- (n-butyloxycarbonyl) pyridinium chloride (Compound 12). 1- (2-phenylamino-2-oxoethyl) -3- (n-butylaminocarbonyl) pyridinium chloride (Compound 13). 1- (2-phenylamino-2-oxoethyl) -3-((2-hydroxyethyl) aminocarbonyl) pyridinium chloride (Compound 14). 1- (2- (2,4-dichlorophenyl) -2-oxoethyl) -3- (bromide)
n-Butoxycarbonyl) pyridinium (Compound 15). 1- (2- (2,4-dichlorophenyl) -2-oxoethyl) -3- (bromide)
n-Butylamino-carbonyl) pyridinium (Compound 16).

Furthermore, some known pyridine derivatives have also been investigated for their AGE degrading activity, which activity has not been previously known for these molecules, and they have been reported in Table IB ([Table 2]). ) And their chemical names are listed below.

1- (2-phenyl-2-oxoethyl) -3- (1-phenyl-1-oxomethyl) pyridinium bromide (Compound 17: (Chemical Abstract: 91, P
47378Y, (1979)) 1- (2-phenyl-2-oxoethyl) -3- (methoxycarbonyl) bromide
Pyridinium (Compound 18: (Chemical Abstract: 91, P47378Y
, (1979))

[0024]

[Table 1]

[0025]

[Table 2]

According to one embodiment of the invention, the compound is present in a high concentration of A
It is used for the treatment of diabetes complications due to GE and aging-related complications such as kidney disease, nerve damage, atherosclerosis, retinopathy and dermatological conditions and tooth discoloration. The increase in preformed AGE concentration can be controlled by degrading the AGE product using the compounds described in this invention.

The present invention also provides a method for producing a pyridinium-based compound. The method for producing the compound 1 is as follows. A solution of 2,4-dichlorophenacyl bromide in toluene is added to nicotinamide dissolved in refluxing toluene, and the mixture is refluxed for 7 and a half hours, cooled,
The precipitated solid was collected by filtration, dissolved in methanol, treated with activated carbon, concentrated under reduced pressure, cooled in an ice-salt mixture, the precipitated solid was collected by filtration and washed with methanol to give the desired solid. Including obtaining the compound.

Similarly, other compounds of the general formula I are suitable substituted pyridine derivatives in alcoholic solvents such as methanol, ethanol, propanol and in high boiling solvents such as toluene or xylene. Prepared by obtaining the desired compound by quaternization by refluxing with the appropriate reagents for 6-48 hours.

In vitro AGE production studied in the laboratory by incubating the reducing sugar ribose with the protein bovine serum albumin resulted in browning of the solution and an increase in fluorescence. Fluorescence was used as a reference to monitor the increase in AGE production.

[0030]

EXAMPLES Example 1 AGE degrading agent activity was confirmed by the following screening method:

[0031] material:   Bovine serum albumin (fraction V) (BSA)   Ribose, analytical grade   Phosphate buffered saline (PBS)

Instrument: Microplate ELISA Reader-Speltramax Plus (Molecular Device, USA) Microplate Purifier (Bio-Tech Instruments, USA) pH Meter

Experimental Method 160 mg / ml protein, bovine serum albumin (BSA) and 1.6 M glucose sugar are dissolved in phosphate buffered saline (PBS). Sodium azide was added as a preservative at a concentration of 0.02%. The solution was aseptically filtered through a 0.22 μM filter and kept at 37 ° C. for 16 weeks for aging. After 16 weeks the solution was dialyzed against PBS, aliquoted and stored at -20 ° C.

To measure the AGE degrading activity, 10 μg / ml and 100 μg / ml of 1
After 6 weeks, AGE-BSA was incubated at different test compound concentrations for 24 hours at 37 ° C, and the AGE degrading activity of the test compounds was measured by ELISA.

The ELISA was performed as follows. 1. Different concentrations of AGE-BSA after 16 weeks were applied as standards on microtiter plates. Three coatings were similarly applied for each concentration. 2. Test sample on microtiter plate at 5ng-20 per well
Three pieces each were applied at a concentration of ng. 3. The plates were incubated at 37 ° C for 1 hour. 4. After the incubation, the plate was placed in PBST (0.05% Tween).
n) PBS containing 20) was used for washing.

Blocking was performed with 5% skim milk powder in PBS at 5.37 ° C. for 1 hour. 6. The plate was washed with PBST. 7. The first antibody against AGE-BSA was added and the plates were incubated at 37 ° C for 1 hour. 8. The plate was washed with PBST. 9. A second antibody, anti-rabbit HRPO (Horse-Radish Peroxidase) conjugate was added and the plates were incubated at 37 ° C for 1 hour.

10. The plate was washed with PBST. 11. Color development was performed using OPD (orthophenylenediamine dihydrochloride) and hydrogen peroxide. 12. Reading 450 nm after incubation for 15 minutes at 37 ° C-
The OD (optical density) at 620 nm was measured with a microplate ELISA reader.

[0038]   The degrading agent activity of a compound is determined by the following formula.

[0039]

[Equation 1] OD _450-620 control = absorption of 20 ng AGE-BSA after incubation at 37 ° C. for 24 hours without addition of test compound OD _450-620 test = addition of the required concentration of test compound for 24 hours at 37 ° C. Absorption of 20 ng of AGE-BSA after incubation

The% AGE degrading activity was calculated using the specific example compound and recorded in Table 2 ([Table 3]).

[0041]

[Table 3]

From the above, for example, Compound 12 has excellent AGE degrading activity, that is, PTB.
It has very good efficacy compared to.

The following examples show the process for the preparation of certain compounds of the invention given in Table 1 ([Table 1], [Table 2]). The following compounds are presented by way of illustration only and do not limit the invention in any way.

The preparation of Example 2 3--1- (2- (2,4-dichlorophenyl) -2-O Kisoechiru) pyridinium (Compound 1): nicotinamide (1.22 g, 0.01 mole ) Was dissolved in refluxing toluene (40 ml) to give 10 parts of 2,4-dichlorophenacyl bromide (3.0 g, 0.012 mol).
A solution of ml in toluene was added. The reaction mixture was refluxed for 7.5 hours and cooled. The precipitated solid was collected by filtration, dissolved in methanol, decolorized with activated carbon and concentrated under reduced pressure to a quarter volume. It was cooled in an ice-salt mixture, the precipitated solid was collected by filtration and washed with methanol (3 x 10 ml) to give a pure solid.

[0045]

[Chemical 3]

According to the above method, the corresponding pyridine derivative is refluxed with an appropriate reagent in an alcoholic solvent such as methanol, ethanol, propanol and the like or in a high boiling solvent such as toluene or xylene for 6 to 48 hours to give the desired compound. The following compounds were synthesized by obtaining

[0047] Example 3 3- (tetrahydropyran-benzothiazol-2-yl) aminocarbonyl) -1 - (2- (2,4-dichlorophenyl) -2-oxoethyl) pyridinium (of compound 2):

[0048]

[Chemical 4]

Example 4 1- (2-phenyl-2-oxoethyl) -3-((2-hydroxyethyl ) aminocarbonyl) pyridinium bromide (Compound 3):

[0050]

[Chemical 5]

Example 5 3-Carbonylamino-1- (2-thien-2'-yl-2-oxoethyl ) pyridinium bromide (Compound 4):

[0052]

[Chemical 6]

[0053] Example 6 of 1- (2-phenyl-2-oxoethyl) -3 - ((p-sulfonamide off Eniren) aminocarbonyl) pyridinium (Compound 5):

[0054]

[Chemical 7]

Example 7 1- (2-Ethoxy-2-oxoethyl) -3-((2-hydroxyethyl ) aminocarbonyl) pyridinium bromide (Compound 6):

[0056]

[Chemical 8]

[0057] Example 8 of 1- (2-phenyl-2-oxoethyl) -3- (isopropyloxy Cal Boniru) pyridinium (Compound 7):

[0058]

[Chemical 9]

Example 9 1- (2-Methyl-2-oxoethyl) -3-((2-hydroxyethyl) aminocarbonyl) pyridinium chloride (Compound 8):

[0060]

[Chemical 10]

[0061] Example 10 bromide 1- (2-thien-2'-yl-2-oxoethyl) -3 - ((2-hydro Kishiechiru) aminocarbonyl) pyridinium (Compound 9):

[0062]

[Chemical 11]

[0063] Example 11 bromide 1- (2- (2,4-dichlorophenyl) -2-oxoethyl) -3- (with isopropyl oxycarbonyl) pyridinium (Compound 10):

[0064]

[Chemical 12]

Example 12 1- (2-phenyl-2-oxoethyl) -3-((4-methylthiazol- 2-yl) aminocarbonyl) pyridinium bromide (Compound 11):

[0066]

[Chemical 13]

[0067] Example 13 chloride 1- (2-phenylamino-2-oxoethyl)-3-(n-Butokishikaru Boniru) pyridinium (Compound 12):

[0068]

[Chemical 14]

EXAMPLE 14 1- (2-Phenylamino-2-oxoethyl) -3- (n-butylaminocarbonyl ) pyridinium chloride (Compound 13):

[0070]

[Chemical 15]

Example 15 1- (2-phenylamino-2-oxoethyl) -3-((2- hydroxyethyl) aminocarbonyl) pyridinium chloride (Compound 14):

[0072]

[Chemical 16]

Example 16 1- (2- (2,4-dichlorophenyl) -2-oxoethyl) -3- (n -butoxycarbonyl) pyridinium bromide (Compound 15):

[0074]

[Chemical 17]

Example 17 1- (2- (2,4-dichlorophenyl) -2-oxoethyl) -3- (n -butylaminocarbonyl) pyridinium bromide (Compound 16):

[0076]

[Chemical 18]

Pharmaceutical Compositions Pharmaceutical compositions can be prepared by using pharmaceutically effective amounts of the compounds of general formula I, alone or in combination. The following pharmaceutical formulations (formulat
ion) are presented for illustrative purposes only and do not limit the manner in which they are used.

Oral Formulations Oral formulations can be administered in solid dosage forms such as, for example, pellets, powders, sachets or discrete units such as tablets and capsules. Other orally-administered pharmaceutical formulations include single-phase and two-phase liquid dosage forms in a ready-to-use form or in a form suitable for reconstitution such as a mixture, syrup, suspension or emulsion. included. The formulation may additionally contain diluents, dispersants, buffers, stabilizers, solubilizers, surfactants, preservatives, chelating agents and / or other pharmaceutical additives according to its usage. Good. Aqueous or non-aqueous excipients or combinations thereof may be used and may, if desired, contain suitable sweeteners, flavors or equivalents. In the case of suspensions or emulsions, suitable thickening agents, suspending agents, emulsifying agents may also be present. Alternatively, the compound has no other additives added,
It may be administered in its pure form, eg as a capsule or sachet. It can also be administered with excipients. The pharmaceutical formulation may provide slow, delayed or controlled release of the active ingredient as provided by the matrix or diffusion controlled system.

When the compound of the present invention, or a salt thereof or suitable complexeses, is provided as a stand-alone unit dosage form such as a tablet, it additionally has a medical property as used in the art. It may also contain an inactive excipient. Diluents such as starch, lactose, dicalcium phosphate, talc, magnesium stearate, polymerizable substances such as methylcellulose, fatty acids and derivatives, sodium starch glycolate (sod)
It is also possible to use ium start glycollate) or the like.

Example 18 Preparation of Oral Dosage Form: A typical tablet has the following composition: Active ingredient of formula I As described above Lactose 135 mg Starch 76 mg Polyvinylpyrrolidone (K-30) 2 mg Talc 1.5 mg Magnesium stearate 1.0 mg

Parenteral Formulations For parenteral administration, the compounds or their salts or suitable complexes thereof are
It can be in a sterile vehicle which can be aqueous or non-aqueous or a combination thereof. Examples of excipients are water, ethyl oleate, oils and derivatives of polyols, glycols and their derivatives. The injectable preparation may contain additives generally used, for example, stabilizers, solubilizers, pH adjusters, buffers, antioxidants, cosolvents, complexing agents, tonicity adjusters and the like.

Suitable additives include, for example, tartrate, citrate or similar buffers, alcohols, sodium chloride, dextrose and high molecular weight polymers.
Another option is reconstitution of sterile powder. The compound is in the form of more than once daily injections or intravenous infusion / infusion
Alternatively, it can be administered in the form of a suitable depot formulation.

Example 19 A formulation suitable for parenteral administration has the following composition: Active ingredient of formula I Polyethylene glycol (400) 0.75 ml sodium metabisulfite 0.01% isotonic saline as described above. / WFI sufficient amount

Other Dosage Forms The recommended dosage forms for dermatological applications and tooth discoloration are lotions, oral rinses and toothpastes, which contain a suitable amount of the compound of general formula I.

The above examples are presented for illustrative purposes only and do not limit the scope of the invention in any way.

[Procedure amendment]

[Submission date] June 5, 2001 (2001.6.5)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0029

[Correction method] Change

[Contents of correction]

In vitro AGE production studied in the laboratory by incubating the reducing sugar glucose with the protein bovine serum albumin resulted in browning of the solution and an increase in fluorescence. Fluorescence was used as a reference to monitor the increase in AGE production.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0031

[Correction method] Change

[Contents of correction]

Materials: Bovine serum albumin (Fraction V) (BSA) glucose , analytical grade phosphate buffered saline (PBS)

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0033

[Correction method] Change

[Contents of correction]

Experimental Method- ELISA (Enzyme-Linked Immunosorbent Assay) 160 mg / ml of protein, bovine serum albumin (BSA) and 1.6 M glucose sugar were added to phosphate buffered saline ( Dissolve in PBS). Sodium azide was added as a preservative at a concentration of 0.02%. The solution was aseptically filtered through a 0.22 μM filter and kept at 37 ° C. for 16 weeks for aging. After 16 weeks the solution was dialyzed against PBS, aliquoted and stored at -20 ° C.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0034

[Correction method] Change

[Contents of correction]

In order to measure the AGE degrading activity, 10 μg / ml of AGE after 16 weeks
-BSA was incubated at different test compound concentrations for 24 hours at 37 ° C, and the AGE degrading activity of the test compounds was measured by ELISA.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/12 A61K 47/12 47/26 47/26 47/32 47/32 47/34 47/34 47 / 36 47/36 A61P 1/02 A61P 1/02 3/10 3/10 9/00 9/00 9/10 9/10 13/12 13/12 17/00 17/00 25/00 25/00 27 / 02 27/02 43/00 111 43/00 111 C07D 213/803 C07D 213/803 213/82 213/82 417/12 417/12 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), A (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, C R, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, K Z, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI , SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW F term (reference) 4C055 AA10 BA01 CA02 CA57 CA58 CB02 CB08 CB11 DA01 GA01 4C063 AA01 BB09 CC62 DD12 EE01 4C076 AA12 BB11 CC11 CC21 DD27A DD41C DD67A EE13A EE23E EE38A FF01 FF15 4C083 AC691 AC692 AC861 AC862 CC41 DD27 EE31 EE35 4C086 AA01 AA02 AA03 BC17 BC84 GA13 GA14 MA01 MA03 MA04 MA05 MA17 MA34 MA55 MA66 NA14 ZA94 ZB07 ZB08 ZB21 ZB22 ZB26 ZC21

Claims (19)

[Claims] 1. The following general formula I, which is useful in the management of vascular complications associated with diabetes and aging-related disorders: (In the formula, R ¹ is —Y—R ³ , Y is selected from oxygen or NH, R ³ is selected from hydrogen, alkyl, and aryl, and R ² is alkyl, —Oalkyl, aryl, —Oaryl. , --NH alkyl and --NH aryl, X is a halide ion, an acetate ion, a perchlorate ion, a sulfonate ion,
Oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, hydrogen phosphate ion, phosphonate ion,
It is selected from the group consisting of phosphate ion, BF ₄ ⁻ and PF ₆ ⁻ . However, when (a) R ¹ is phenyl, R ² is also phenyl, and (b) R ² is phenyl and X is a halide ion, R ¹ is —OC.
The condition is that it is other than H ₃ . ] The pyridinium-type compound shown by these, and its pharmaceutically acceptable salt. 2. The compound according to claim 1, wherein X is a halide ion. 3. The following compounds: a) 1- (2-phenylamino-2-oxoethyl) -3- (n-butyloxycarbonyl) pyridinium chloride or a pharmaceutically acceptable salt thereof, b) 1 bromide. -(2-thien-2'-yl-2-oxoethyl) -3-((2-
Hydroxyethyl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, c) 1- (2-ethoxy-2-oxoethyl) -3-((2-hydroxyethyl) aminocarbonyl) pyridinium bromide or a pharmaceutical thereof Acceptable salt, d) 1- (2-phenylamino-2-oxoethyl) -3- (n-butylaminocarbonyl) pyridinium chloride or a pharmaceutically acceptable salt thereof, e) 1- (2-chloride) Phenylamino-2-oxoethyl) -3-((2-hydroxyethyl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, f) 1- (2-phenyl-2-oxoethyl) -3- (bromide) (2-hydroxyethyl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, g) 1- (2-methyl-2-oxy) bromide Ethyl) -3-((2-hydroxyethyl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, h) 1- (2-phenyl-2-oxoethyl) -3-((4-methylthiazole) bromide -2-yl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, i) 1- (2- (2,4-dichlorophenyl-2-oxoethyl) -3-
(Isopropyloxycarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, j) 3- (tetrahydrobenzothiazol-2-yl) aminocarbonyl) -1- (2- (2,4-dichlorophenyl) -2- Oxoethyl) pyridinium or a pharmaceutically acceptable salt thereof, k) 1- (2-phenyl-2-oxoethyl) -3-((p-sulfonamidophenylene) aminocarbonyl) pyridinium bromide or a pharmaceutically acceptable salt thereof 1) 3-carbonylamino-1- (2-thien-2'-yl-2-oxoethyl) pyridinium bromide or a pharmaceutically acceptable salt thereof, m) 1- (2- (2 , 4-Dichlorophenyl) -2-oxoethyl) -3
-(N-Butylaminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, n) 1- (2- (2,4-dichlorophenyl) -2-oxoethyl) -3 bromide
The compound according to claim 1, which is selected from the group consisting of-(n-butoxycarbonyl) pyridinium or a pharmaceutically acceptable salt thereof. 4. A method for producing a pyridinium-based compound according to claim 1, wherein
The process prepares a suitably substituted pyridine derivative according to the desired final product, followed by refluxing the substituted pyridine derivative with an appropriate reagent in an alcoholic solvent and / or a high boiling solvent for 6 to 48 hours. Quaternization
Ion) to obtain the desired compound. 5. Diabetes complications and aging, including kidney disease, nerve damage, retinal disorders, atherosclerosis, microvascular disorders, endothelial dysfunction, dermatological symptoms, tooth discoloration and disorders of other organs. Use of a compound of general formula I as defined in claim 1 in the manufacture of a medicament for the diseases associated with. 6. The compound is the following compound: a) 1- (2-phenylamino-2-oxoethyl) -3- (n-butyloxycarbonyl) pyridinium chloride or a pharmaceutically acceptable salt thereof, b). 1- (2-thien-2'-yl-2-oxoethyl) -3-((2-
Hydroxyethyl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, c) 1- (2-ethoxy-2-oxoethyl) -3-((2-hydroxyethyl) aminocarbonyl) pyridinium bromide or a pharmaceutical thereof Acceptable salt, d) 1- (2-phenylamino-2-oxoethyl) -3- (n-butylaminocarbonyl) pyridinium chloride or a pharmaceutically acceptable salt thereof, e) 1- (2-chloride) Phenylamino-2-oxoethyl) -3-((2-hydroxyethyl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, f) 1- (2-phenyl-2-oxoethyl) -3- (bromide) (2-hydroxyethyl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, g) 1- (2-methyl-2-oxy) bromide Ethyl) -3-((2-hydroxyethyl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, h) 1- (2-phenyl-2-oxoethyl) -3-((4-methylthiazole) bromide -2-yl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, i) 1- (2- (2,4-dichlorophenyl-2-oxoethyl) -3-
(Isopropyloxycarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, j) 3- (tetrahydrobenzothiazol-2-yl) aminocarbonyl) -1- (2- (2,4-dichlorophenyl) -2- Oxoethyl) pyridinium or a pharmaceutically acceptable salt thereof, k) 1- (2-phenyl-2-oxoethyl) -3-((p-sulfonamidophenylene) aminocarbonyl) pyridinium bromide or a pharmaceutically acceptable salt thereof A) 3-carbonylamino-1- (2-thien-2'-yl-2-oxoethyl) pyridinium bromide or a pharmaceutically acceptable salt thereof, m) 1- (2- (2 , 4-Dichlorophenyl) -2-oxoethyl) -3
-(N-Butylaminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, n) 1- (2- (2,4-dichlorophenyl) -2-oxoethyl) -3 bromide
Use according to claim 5, characterized in that it is selected from the group consisting of-(n-butoxycarbonyl) pyridinium or a pharmaceutically acceptable salt thereof. 7. Associated with diabetic complications and aging, including renal disease, nerve damage, retinal disorders, atherosclerosis, microvascular disorders, endothelial dysfunction, dermatological symptoms, discoloration of teeth and disorders of other organs. Use of 1- (2-phenyl-2-oxoethyl) -3- (1-phenyl-1-oxomethyl) pyridinium bromide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for a disease. 8. Diabetes complications and aging, including kidney disease, nerve damage, retinal disorders, atherosclerosis, microangiopathy, endothelial dysfunction, dermatological symptoms, discoloration of teeth and disorders of other organs. Bromide in the manufacture of a medicament for diseases associated with 1- (2
Use of -phenyl-2-oxoethyl) -3- (methoxycarbonyl) pyridinium or a pharmaceutically acceptable salt thereof. 9. A pharmaceutically acceptable amount of one or more of the compounds of general formula I as defined in claim 1 or a pharmaceutically acceptable salt (s) thereof. A pharmaceutical composition for treating diabetic complications and diseases associated with aging, which comprises a carrier, a diluent, a solvent or an excipient in admixture. 10. A pharmaceutical composition according to claim 9 in the form of an oral formulation. 11. The pharmaceutical composition according to claim 10, wherein the pharmaceutically acceptable carrier is selected from one or more compounds of starch, lactose, polyvinylpyrrolidone (K-30), talc and magnesium stearate. 12. A pharmaceutical composition according to claim 9 in the form of a parenteral formulation. 13. Dissolving the active ingredient of general formula I as defined in claim 1 in polyethylene glycol 400 and diluting the resulting solution with an isotonic solution or water to the desired concentration. The method for producing a parenteral formulation according to claim 12, which comprises: 14. A pharmaceutical composition according to claim 9 in the form of lotion, oral rinse, toothpaste. 15. Degrading AGEs already produced in a patient, comprising administering an effective amount of a compound of claim 1 alone or in combination with other drugs for the treatment of diabetes. To treat diabetic patients by doing. 16. An effective amount of 1- (2-phenyl-2-oxoethyl) -bromide.
Already formed in the patient, including administering 3- (1-phenyl-1-oxomethyl) pyridinium or a pharmaceutically acceptable salt thereof, alone or in combination with other drugs for the treatment of diabetes. For treating diabetic patients by degrading existing AGEs. 17. An effective amount of 1- (2-phenyl-2-oxoethyl) -bromide.
Administering 3- (methoxycarbonyl) pyridinium or a pharmaceutically acceptable salt thereof alone or in combination with other drugs for the treatment of diabetes,
A method for treating a diabetic patient by decomposing AGE that is already produced in the patient. 18. A method of preventing or treating a disease caused by diabetes and aging-related complications, wherein a patient in need of prophylaxis or treatment is treated with an effective amount of formula I according to claim 1. A method comprising administering the compound shown alone or in combination with a pharmaceutically acceptable carrier, diluent or excipient. 19. The method according to claim 18, wherein the disease to be prevented or treated is renal disorder, neuropathy, atherosclerosis, retinal disorder, dermatological disorder, oral non-enzymatic brown color. A method characterized by: browning, disorders of the endothelium or other organs and disorders of growth.