MXPA02003496A

MXPA02003496A - Pyridinium derivatives for the treatment of diabetic and agingrelated vascular complications.

Info

Publication number: MXPA02003496A
Application number: MXPA02003496A
Authority: MX
Inventors: Sankaranarayanan Alangudi
Original assignee: Torrent Pharmaceuticals Ltd
Priority date: 1999-10-06
Filing date: 1999-10-15
Publication date: 2005-06-20
Also published as: BR9915962A; WO2001025209A1; EP1220843A1; HK1044336A1; CA2351075A1; JP2003511370A; AU5994499A; CZ20011808A3; HUP0301687A2; PL348049A1; CN1329597A

Abstract

The invention discloses compounds of the pyridinium series useful for the management of diabetes and agingrelated vascular complications, and particularly in the treatment of complications of diabetes mellitus and other agingrelated conditions including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological conditions and discoloration of teeth by breaking preformed AGE, of general formula (I), or pharmaceutically acceptable salts thereof, wherein, R 1, R 2 and X are as defined in the specification. The invention also discloses method of preparation of the compounds of the series and pharmaceutical composition having one or more compounds as defined above as active ingredients. The invention further discloses a method of treatment of a diabetic patient by administering the compounds as defined above, either singly or in combination with other drugs for antidiabetic therapy.

Description

DERIVATIVES OF PYRIDINE FOR THE TREATMENT OF DIABETIC VASCULAR COMPLICATIONS AND AGE-RELATED COMPLICATIONS FIELD OF THE INVENTION The present invention relates to a class of compounds of the pyridinium series and to their use in the treatment of diabetes and related diseases. More particularly, the invention relates to compounds of this series to methods for their preparation. ! to a pharmaceutical composition containing these compounds and to their use in the treatment of diabetes mellitus complications. The compounds of this series exhibit an activity that decomposes the final glycation end products, which is essential for the treatment of diabetic complications related to diabetes. aging, including kidney disease, nerve damage, atherosclerosis, retinopathy, and dermatological conditions. The invention also extends to the method for reversing discoloration of the teeth resulting from the non-enzymatic brown coloration in the oral cavity which comprises the administration of an effective amount to reverse the previously formed advanced glycosylation crosslinks. BACKGROUND OF THE INVENTION Maillard discovered in 1? than the reducing sugars! such as glucose and ribosai react with proteins to form brown pigments- Additional studies have shown that this is an irreversible non-enzymatic reaction that occurs in several natural systems, including stored food materials. The Maillard reaction occurs in two stages! Early and advanced- Initially, proteins react with glucose to form stable Amadori products that subsequently cross-link to form advanced glycation end products (AGE). In most cases, AGE formation also accompanies brown hair coloring. proteins and the increase in fluorescence. In diabetes! where the blood glucose level is significantly higher than normal n the reaction of glucose with various i-proteins such as hemoglobin! The crystalline lens and collageni leads to the formation of AGEi which in turn is responsible for the complications associated with diabetes, such as nephropathy-? microangiopathy-i endothelial dysfunction and other organ dysfunction- In addition, the activity of several growth factors also deteriorates! such as the basic fibroblast growth factor- AGEi products, unlike normal proteins in the tissue, have a slower rate of change and filling-It has been reported that AGE products can actually provoke a complex immune reaction that involves RAGE receptors (Receiver for Advanced Glycation End Products) and the activation of several incompletely defined immunological processes- It has been documented that diabetes with evidence of microangiopathy and macroangiopathy also shows evidence of oxidative stress whose mechanism has not been elucidated. You can study the formation of AGE in vitro in the laboratory! by incubating reducing sugars! such as ribose or glucosei with bovine serum albumin- The formation of AGE can be detected by the increase in fluorescence or by the greater cross-reactivity with anti-AGE antibodies- The increase in fluorescence seems to precede the formation of epitopes AGE specific antigens- This increase in fluorescence is used to monitor the greater formation of AGE in vitro (Brounlee M- and collaborators Science nflbi? 3 ?: IbSI-ltB - In addition to the increase in fluorescence! one of the most characteristic important in AGE formation in vitro is the formation of antigenic epitopes that are specific for AGE and not for native proteins- Therefore, it is possible to raise the antibodies against the advanced glycation end products of a proteini and use them to detect the formation of AGE in other proteins- This has served as an important analytical tool in AGE research. Due to the clinical significance of the formation of AGEs, many approaches are being used to diagnose! prevent or reverse the formation of A GE in the body- The formation of AGE could be inhibited by reaction with an early glycosylation product that results from the original reaction between the target protein and glucose- It was believed that the inhibition took place as the reaction between the inhibitor and the tempranal glycosylation product that seemed to interrupt the subsequent reaction of the glycosylated protein with the additional protein material to form the late-cross-linked product. Compounds such as aminoguanidine act to inhibit the formation of AGE by this mechanism - The formation of AGEs in long-lived proteins is also associated with the cross-linking of these proteins. It has been shown that the cross-links of proteins derived from A GE are dissociated by compounds such as N-phenacylthiazolium bromide (PTB) n that reacts with iy dissociate the cross-links of A covalent GE-derived proteins (Vasan and colabor Adores! Nature? ¾¾ 3 ?? -?? 75 -? 7? Patent of the United States of America Number US 5? ß53 ?? 03? Patent Date: December of ?? d). It is expected that the mechanism to reduce the content of AGE in the tissues takes place relatively quickly in contrast to the aminoguanidine which acts slowly due to its nature as a mechanism of action. The present specification is related to compounds of the pyridinium class that decompose the previously formed AGE as PTBi and in some cases in an even more effective way than by ??? SUMMARY OF THE INVENTION The main objective of the present invention is to provide a class of compounds of the pyridinium series which are useful for the management of vascular complications related to diabetes and aging! and in particular in the treatment of diabetes mellitus complications and other conditions related to aging! including kidney disease, nerve damage-atherosclerosis, retinopathy, and dermatological conditions-The invention also extends to the method for reversing discoloration of the teeth resulting from non-enzymatic brown coloring in the oral cavity which comprises the administration of an amount effective to reverse advanced glycosylation crosslinks previously formed n etcetera. Another object of the present invention is to provide compounds of the pyridinium series that exhibit activities that break down the AGE. Yet another object of the present invention is to provide a method for the preparation of compounds of the pyridinium series that exhibit activities that decompose the AGE. - Still another object of the invention is to provide pharmaceutical compositions with a new class of compounds of the pyridinium series according to the invention and their pharmaceutically acceptable salts! in combination with vehicles without solvent excipients! diluents and other suitable means normally employed in the preparation of these compositions - Still another object of the invention is to provide a method for the treatment of a diabetic patient by administering the compounds of the invention-i either alone or in combination with drugs for antidiabetic therapy or pharmaceutically acceptable salts thereof in a requsrated dosage mixed with diluents, solvents, or excipients in vehicles or other pharmaceutically acceptable means which may be appropriate for the purpose; DETAILED DESCRIPTION OF THE INVENTION The present invention provides a new class of compounds that decompose the A G E i of the formula I: wherein: R1 is -Y-R3 Y is selected from oxygen or NHi R3 is selected from hydrogeni, alkyl-aryloyl R2 is selected from the group consisting of alkyl-0-alkyl-1-aryloyl-O-arylone - NH-alkylOi and -NH-aryloxy X is selected from the group consisting of a halide ion of ionic ion of perchlorate ion of sulfonate ion of oxalate ion of citraton ion of tosylate ion of maleaton ion of mesylate ion of carbonate ion sulfite phosphoric hydrogen ion-? phosphonated ion phosphate ion BF-Ti PFb'n and so on- with the proviso that when R2 is phenyl and X is a halide ion then R1 is different from -OCHa- As used in the present "alkyl" it refers to an optionally substituted saturated hydrocarbon group linked by individual carbon-carbon bonds-i and having 1 to 1 carbon atoms attached to each other. The saturated alkyl hydrocarbon group can be linear or branched. The substituent is -OH. As used herein "aryl" refers to an aromatic group optionally substituted with at least one ring having a conjugated pi electron system containing up to two conjugated or fused ring systems - aryl includes carbocyclic aryl and heterocyclic aryl all which may be optionally substituted with halogenon sulfonamidoi thioi aminoi cyanon-0-alkylo-NH-alkylOi hydroxyl formyl-0-arylon and -NH-aryl- Representative compounds of the general formula I which are novel are listed in Table IA- These compounds! with the following chemical names are suggested by way of example only and in no way restrict the invention- 3-carbonylamino-l- < E- (Bi4-dichlorophenyl) -E-oxoethyl)) pyridinium (compound 1) · Bromide of 3- (tetrahydrobenzothiazol-E-yl) amino-carbonyl-1 (E- (Ei4-dichlorophenyl) -E-oxoethyl) pyridinium (compound E) - L- (S-phenyl-E-oxoethyl) -3- ((E-hydroxy-ethy-Dinocarbonyl) pyridinium bromide (compound 3) · 3- (carbonylamino-l- (E-thien-E 'bromide -l-E-oxoethyl Jpyridinium (compound 4) L- (E-phenyl-E-oxoethyl) -3- ((p-sulfonamidophenylene-J-carinocarboni-D-pyridinium bromide (Compound S) - L- (E-ethoxy-S-oxoethyl) bromide ) -3- ((E-hydroxyethyl) dinocarbonyl Jpyridinium (compound b). L- (E-phenyl-B-oxoethyl) -3- (isopropyl xicarbonyl) pyridinium bromide (compound?) | L- (E-methyl) -bromide -E-oxoethyl) -3- ((E-hydroxyethyl) aminocarbonyl) pyridinium (compound fi). Bromide of l- (E-thien-E'-yl-E-oxoethyl) -3- ((E-hydroxyethyl) Jaminocarbonyl Jpiridinium (compound U- Bromide of l- (E- (Ei4-dichlorophenyl-E-oxoethyl J-3 (isopropyloxycarbonyl Jpyridinium (compound 10.) - Bromide of l- (E-phenyl-E-oxoethyl) -3- ( (4-methylthia zol-E-yl) aminocarbonyl) pyridinium (compound 11) - 1- (β-phenylamino-E-oxoethyl) -3- (n-butyloxycarbonyl) pyridinium chloride (compound 1EJ- l- (E-phenylamino- E-oxoethyl) -3- (n-butylam indocarbonyl) pyridinium (compound 13) - L- (2-phenylamino-S-oxoethyl) -3- ((? -hydroxyethyl) aminocarbonyl) pyridinium chloride (compound 14). Bromide of 1- (? - (? I4-dichlorophenyl) -E-oxoethyl) -3- (n-butoxycarboni 1) pyridinium (compound 15). Bromide of l- (E- (Ei4-dichlorophenyl) -E-oxoethyl) -3- (n-butylamino-carbonyl) pyridinium (compound Ib). In addition, some pyridine derivatives known for their decomposition activity of advanced glycation end products (AGEs) have also been studied and were not previously known for these molecules and are as listed in Table lBn with their chemical names as given followed: L- (E-phenyl-E-oxoethyl) -3- (l-phenyl-1-oxomethyl) pyridinium bromide (compound 17: (Reference: Chemical Abstracts: lli P4737flYn (l1.?*.))). Bromide of l- (B-phenyl-S-oxoeti 1) -3- (methoxycarbonyl) pyridinium (compound Ifl: (Reference: Chemical Abstracts: ¾i P4737flYn (1171))).

Table IA - Piridinium Derivatives (Innovative) Compound -R1 -R2 -X No. 1 NH2 2, -dichlorophenyl Br 2-tetrahydrobenzo-2,4-dichlorophenyl Br thiazol-2-yl-amino 3 NHCH 2 CH 2 OH phenyl Br 4 NH 2 2-thienyl Br 5 (p-sulfonamido- Phenyl Br phenylene) amino L, NHCHsCHaOH OEt Br 7 0CH (CH 3) s Phenyl Br fi NHCHsCHaOH CH3 Br NHCHaCHaOH? -thienyl Br ID 0CH (CH 3) 2 Ei 4 -dichlorophenyl Br 11 < 4-Methylthiazole-S-Phenyl Br il) amino 1? 0CHsCH2CH2CH3 NHPh Cl 13 NHCHaCHaCHaCH3 NHPh Cl 14 NHCHaCHsOH NHP Cl 1S OCHACHaCHACHa Si4-dichlorophenyl Br Ib NHCHachCHACHa 2i-Dichlorophenyl Br Table IB - Pyridinium Derivatives (known) according to one embodiment of the present invention! The present compounds are used for the treatment of diabetic complications and complications related to aging! including kidney disease, nerve damage! atherosclerosis! retinopathy dermatological conditions! and coloring of the teeth that occur due to the higher levels of preformed AGEs. The higher levels of preformed AGE can be put under control by decomposing the AGE products using the compounds mentioned in the invention. The invention also provides a process for the preparation of the novel compounds of the pyridinium series - This process for the preparation of compound 1, comprises adding a solution of 2,4-dichloro-phenacyl bromide in toluene to nicotinamide dissolved in refluxing toluene, refluxing for seven hours. and half an hour, cool, filter the precipitated solid, dissolve in methanol, treat with activated carbon, concentrate with cooling in an ice-salt mixture, filter the precipitated solid, and wash with methanol to obtain the desired compound. In a similar way! the other compounds of the general formula I are prepared from appropriately substituted pyridine derivatives! followed by quaternization with the appropriate reagent refluxing in alcoholic solvents such as methanoln ethanoln propanoli etcéteran and high boiling point solvents such as toluene or xylene and so on for 4fl hours to give the desired compounds- AGE formation in vitro-i studied in the laboratory by incubating ribosan reducing sugar with the bovine serum albumin protein resulted in the brown coloring of the solution and the increase in fluorescence- fluorescence was used as the criterion to monitor the formation of increased AGE - Example 1 The decomposition activity of AGE has been confirmed by the screening procedure mentioned below: Materials: Bovine serum albumin (fraction V) (BSA) Ribosan analytical grade Serum regulated with phosphate (PBS) Equipment: Microplate ELISA reader - Spectramax Plus (Molecular DevicGSi USA) Microplate washer (Bio-Tec Instrumentsi EUA) pH meter Experiment methods -ELISA (Enzyme-linked immunosorbent assay) - IbD milligrams / milliliter of pnoteínai bovinei BSAi sleep albumin and glucose sugar 1-bfli were dissolved in phosphate-buffered serum PBS- Sodium azide was added at a concentration of the percent DE as conservative- The solution was aseptically filtered through a Q- filter? p and was saved for aging at 37 ° C for Ib weeks- After Ib weeks the solution was dialyzed against phosphate-regulated serum was divided into aliquots! and it was stored at -2 ° C. To determine the decomposition activity of AGEi, micrograms / milliliter ID of the AGE-BSA of Ib weeks were incubated with different concentrations of the test compounds at 37 ° C for? 4 hoursi and the AGE decomposition activity of the test compounds by ELISA. The ELISA was performed as follows: 1- Different concentrations of AGE-BSA of Ib weeks were applied to a microtiter plate as standard- Each concentration is applied in triplicate- 2 · The test samples were applied on a microtiter plate to a concentration of S nanograms at? 0 nanograms per well in triplicate. 3- The plate was incubated at 37 ° C for 1 hour- 4- After incubation! the plate was washed with PBST (PBS with Tween 2D at? -? por percent). 5- Blocking was done with 5% skim milk in phosphate buffered serum at 37 ° C for 1 hour- b- The plate was washed with PBST. 7- The primary antibody against AGE-BSAi and the plate was incubated at 37 ° C for 1 hr-fl. The plate was washed with PBST · 1- The secondary antibody conjugate / HRPO (horseradish peroxidase) anti-rabbit i was added and the plate was incubated at 37 ° C for 1 hour. ID. The plate was washed with PBST. 11 · The development of color was made with OPD (orthophenylenediamine dihydrochloride) and hydrogen peroxide | 12- OS (optical density) was measured (reading of 450 nanometers - reading of -20 nanometers) after incubation at 37 ° C for 15 minutes with the ELISA Reader of Microplates - The decomposition activity of the compounds was determined by the following formula: % Decomposition activity = OD45o-62oControl - OD.eo.62o Test x 100 OD45o-62oControl OD45o-62oControl = Absorbance of 20 nanograms of AGE-BSA after incubation at 37 GC for 24 hours without test compound. Absorbance of 20 nanograms of AGE-BSA after incubation at 37 ° C for 24 hours with the required concentration of the test compound. Using specific examples, the percentage of AGE decomposition activity was calculated, and recorded in Table 2.

Table 2 Accordingly, for example, compound 12 has a significant AGE decomposition activity, i.e., a comparatively much higher power vis-a-vis PTB. The following examples give a method of preparing the specific compounds of the invention as given in Table 1. The following suggested compounds are by way of example only, and in no way restrict the invention.

EXAMPLE 2 Preparation of 3-carbonylamino-1- (2- (2,4-dichloro-phenyl) -2-oxoethyl) pyridinium bromide (compound 1) Nicotinamide (1.22 grams, 0.01 mol) was dissolved in refluxing toluene (40 mg). milliliters), and a solution of 2,4-dichlorophenacyl bromide (3.0 grams, 0.012 moles) in 10 milliliters of toluene was added. The reaction mixture was refluxed for 7.5 hours and cooled. The precipitated solid was filtered and dissolved in methanol, decolorized with activated charcoal, and concentrated in vacuo to a quarter of its volume. It was cooled in an ice-salt mixture, and the precipitated solid was filtered and washed with methanol (10 milliliters three times) to give a pure solid. Yield: 39 percent mp: 237-239 ° C IR (KBr, cm "1): 3331, 3133, 1706, 1678 ??? NMR (DMSOd6, 400 MHz) d: 9.54 (lH, s), 9.18-9.11 ( 2H, m), 8.67 (lH, s), 8.40 (lH, t), 8.42-8.38 (2H, m), 7.88 (lH, s), 7.75-7.72 (lH, m), 6.49 (2H, s) Mass (m / z): 309, 310, 311, 312, 187, 159. According to the aforementioned procedure, the following compounds are synthesized by reaction of the corresponding pyridine derivatives with the appropriate reagents, refluxing in alcoholic solvents such as methanol, ethanol, propanol, et cetera, and high-boiling solvents such as toluene or xylene, for 6 to 48 hours, to give the desired compounds: E emplo 3 3- (tetrahydrobenzothiazol-2-yl) bromide aminocarbonyl) -1- (2- (2,4-dichlorophenyl) -2-oxoethyl) pyridinium (compound 2): Yield: 48 percent Pf: 165-167 ° C (decomposed) IR (KBr, cnf1): 3333, 1714, 1684, 1635 XH NMR (CD3OD, 400 MHz) d: 9.45 (lH, s), 9.27-9.2 (1H, m), 8.92-8.91 (lH, m), 8.24 - 8.21 (1H, m), 8.01 - 7.99 (1H, m), 7.72-7.71 (lH, m), 7.57-7.54 (lH, m), 2.59-2.57 (4H, m), 1.85 (4H, m) . Mass (m / z): 446, 447, 448, 449, 416, 307 and 266 Example 4 1- (2-phenyl-2-oxoethyl) -3- < (2-hydroxyethyl) aminocarbonyl) pyridinium (compound 3): Yield: 98 percent. mp: 182-184 ° C (decomposition) IR (KBr, cm "1): 3289, 3241, 1690 and 1660 XH NMR (DMSOd6, 400 MHz) d: 9.47 (lH, s), 9.21 (lH, t), 9.09 (2H, t), 8.41-8.37 (lH, m), 8.08-8.04 (2H, m), 7.82-7.78 (lH, m), 7.69-7.65 (2H, m), 6.52 (2H, s), 4.86 (lH, t), 3.58-3.54 (2H, m), 3.42-3.38 (2H, m) Mass (m / z): 285, 242, 149, 119, 91 Example 5 Bromide of 3-carbonylamino-l - (2-thien-2'-yl-2-oxoethyl) pyridinium (compound 4) Yield: 35 percent mp: 212-215 ° C (decomposition) IR (KBr), cm "1): 3295, 3126, 1680, 1671, 1640? NMR (DMS0d6, 400 MHz) d: 9.49 (1H, s), 9.13-9.11 (lH, d), 9.07-9.05 (lH, d), 8.60 (lH, bs), 8.40-8.38 (1H, m), 8.25-8.19 (3H, m), 7.43-7.40 (lH, t), 644 (2H, s) Mass (m / z): 247, 248, 249, 193. EXAMPLE 6 1- (2-Phenyl-2-oxoethyl) -3- ((p-sulfonamidophenylene) -aminocarbonyl) pyridinium bromide (compound 5): yield: 44 percent mp: 188-190 ° C IR (KBr, cm "1): 3296, 1700, 1679. X H NMR (DMSOdg, 400 MHz) d: 11.25 (lH, s), 9.58 (lH, s), 9.25 (lH, d), 9.16 (1H , d), 8.45 (lH, t), 8.10 (2H, d), 7.94 (2H, d), 7.86 (2H, d), 7.82 (lH, t), 7.68 (2H, t), 7.36 (2H, s), 6.5 (2H, s). Mass (m / z): 396, 277 Example 7 1- (2-Ethoxy-2-oxoethyl) -3- ((2-hydroxyethyl) aminocar-bonyl) pyridinium bromide (compound 6): Yield: 87 percent mp : 138-140 ° C IR (KBr, cm "1): 1748, 1669 1 H NMR (CD30D, 400 MHz) d: 9.43 (lH, s), 9.09-9.02 (2H, m), 8.26 (??,? a), 5.64 (2H, s), 4.31 (2H, q), 3.73 (2H, t), 3.54 (2H, t), 1. 32 (3H, t). Mass (m / z): 251, 252, 165, 166. Example 8 1- (2-Phenyl-2-oxoethyl) -3- (isopropyloxycarbonyl) -pyridinium bromide (compound): Yield: 46 percent Mw: 172 -174 ° C IR (KBr, cm "1): 1726, 1692 X H NMR (DMSOd 6, 400 MHz) d: 9.55 (lH, s), 9.16 (lH, d), 9.08 (lH, d), 8.39-8.36 (lH, m), 8.04 (2H, d), 7.77 (lH, t), 7.64 (2H, t), 6.53 (2H, s), 5.25-5.19 (lH, m), 1.34 (6H, d). Mass (m / z): 284, 285, 242. EXAMPLE 9 1- (2-Methyl-2-oxoethyl) -3- ((2-hydroxyethyl) aminocarbonyl) pyridinium chloride (compound 8): Yield: 47 percent. p.f .: 178-180 ° C IR. { KBr, cm: 1): 1727, 1660 X H NMR (DMSOd6, 400 MHz) d: 9.33 (1H, t), 9.30 (lH, s), 9.06 (lH, d), 8.90 (lH, d), 8.25- 8.21 (??,? A), 5.75 (2H, s), 4.84 (lH, bs), 3.47 (2H, t), 3.30 (2H, t), 2.23 (3H, s) Mass (m / z): 223, 224, 225. EXAMPLE 10 1- (2-Thien-2'-yl-2-oxoethyl) -3- < (2-hydroxyethyl) ami-nocarbonyl) pyridinium (compound 9): Yield: 60 percent mp: 207-209 ° C IR (KBr, cm-1): 1673, 1656 XH NMR (DMSOd6, 400 MHz) d: 9.47 (lH, s), 9.18-9.05 (3H, m), 8.38-8.34 (lH, m), 8.23-8.19 (2H, m), 7.39 (lH, t), 6.44 (2H, s), 3.55-3.50 (2H, m), 3.40-3.37 (2H, m). Mass (m / z): 291, 292, 292. EXAMPLE 11 1- (2- (2,4-Dichlphenyl) -2-oxoethyl) -3- (isopropyloxycarbonyl) pyridinium bromide (compound 10): Yield: 26 percent. Mp: 160-162 ° C IR (KBr, cm "1): 1726, 1705 XH NMR (DMS0d6, 400 MHz) d: 9.55 (lH, s), 9.15 (lH, d), 9.08 (lH, d), 8.40-8.36 (lH, m), 8.11 (lH, d), 7.89 (lH, bs), 7.75-7.72 (lH, m), 6.44 (2H, s), 5.26-5.20 (lH, m), 1.34 ( 6H, d) Mass (m / z): 352, 353, 354, 310. Example 12 Bromide of 1- <2-phenyl-2-oxoethyl) -3- ((4-methylthiazol-2-yl) - aminocarbonyl) pyridinium (compound 11): Yield: 30 percent mp: 165-167 ° C IR (KBr, cm "1): 3409, 3319 and 1698: H RM (DMSOdg, 400 MHz) d: 9.58 (1H, S ), 9.22 (lH, d), 9.11 (lH, d), 8.42-8.38 (lH, m), 8.07 (2H, d), 7.81 (1H, t), 7.68 (2H, t), 6.86 (lH, t > s), 6.56 (2H, s), 2.30 [3H, s). Mass (m / z): 337, 338, 232, 105. EXAMPLE 13 1- (2-Phenylamino-2-oxoethyl) -3- (n-butoxycarbonyl) -pyridinium chloride (compound 12): Yield: 10 percent , mp: 150-152 ° C IR (KBr, cm "1): 3228, 1742, 1678 (bs) XH NMR (DMSOdg 400 MHz) d: 10.96 (lH, s), 9.65 (lH, s), 9.28 ( lH, t), 9.09 (lH, d), 8.37 - 8.34 (lH, m), 7.62-7.59 (2H, m), 7.37 - 7.33 (2H, m), 7.11 (lH, t), 5.79 (2H, s), 4.41 (2H, t), 1.76-1.72 (2H, m), 1.48-1.43 (2H, m), 0.94 (3H, t), Mass (m / z): 314, 315. Example 14 Chloride of 1- (2-phenylamino-2-oxoethyl) -3- (n-butylaminocarbo-nil) pyridinium (compound 13); Yield: 37 percent mp: 182-185 ° C IR (KBr, cm "1): 3245, 1742, 1679 X H NMR (DMSOd 6, 400 MHz) d: 10.97 (lH, s), 9.50 (lH, s), 9.24 (lH, t), 9.13 (lH, d), 9.02 (lH, d), 8.28- 8.25 (??, p?), 7.57 (2H, d), 7.30 (2H, t), 7.05 (lH, t), 5.70 (2H, s), 3.30-3.26 (2H, m), 1.52 - 1.48 ( 2H, m), 1.34-1.30 (2H, m), 0.86 (3H, t). Mass (m / z): 312, 313. EXAMPLE 15 1- (2-Phenylamino-2-oxoethyl) -3- ((2-hydroxyethyl) amy-nocarbonyl) pyridinium chloride (compound 14): Yield: 58 percent mp: 225-227 ° C IR (KBr, cm "1): 3448, 3271, 1702 and 1663 ??? NMR (DMSOd6, 400 MHz) d: 11.07 (lH, s), 9.58 (1H, S), 9.35 ( lH, t), 9.17 (lH, d), 9.11 (lH, d), 8.33-8.29 (1H, m), 7.60 (2H, d), 7.32 (2H, t), 7.08 (lH, t), 5.75 (2H, s), 4.90 (lH, t), 3.57-3.53 (2H, m), 3.40-3.36 (2H, m) Mass (m / z): 300, 301, 302. Example 16 Bromide 1- (2- (2,4-dichlorophenyl) -2-oxoethyl) -3- (n-butoxycarbonyl) pyridinium (compound 15): Yield: 38 percent Pf: 154-156 ° C IR (KBr, cm " 1): 3435, 3389, 1731 and 1704 ¾ NMR (D SOde, 400 MHz) d: 9.60 (lH, s), 9.21 (lH, d), 9. 14 (lH, d), 8.43 (lH, t), B.16 (lH, d), 7.92 (lH, s), 7.78- 7.76 (lH, m), 6.51 (2H, s), 4.42 (2H, t), 1.76-1.72 (2H, m), 1.48-1.42 (2H, m), 0.94 (3H, t). Mass (m / z): 366, 367, 368, 369, 370. EXAMPLE 17 1- (2- (2, -Dichlorophenyl) -2-oxoethyl) -3- (n-butyl-aminocarbonyl) pyridinium bromide (compound 16): Yield: 35 percent mp: 142-144 ° C IR (KBr, cm "1): 3382, 1698, 1672. *? NMR (DMSOde, 400 MHz) d 9.37 (lH, s), 9.07 (lH , t), 8.99 (2H, t), 8.31-8.28 (lH, m), 8.04 (lH # d), 7.82-7.81 (lH, d), 7.68-7.65 (lH, m), 6.34 (2H, s ), 3.27-3.24 (2H, m), 1.47-1.43 (2H, m), 1.29-1.24 (2H, m), 0.81 (3H, t), Mass (m / z): 365, 366, 367, 368 369 Pharmaceutical Compositions Pharmaceutical compositions can be prepared with a pharmaceutically effective amount of the compounds of the general formula I, individually or in combination. The following suggested pharmaceutical formulations are by way of example only, and in no way restrict the ways in which they may be used.

Oral formulations Oral formulations may be administered as solid dosage forms, for example, granules, powders, lozenges, or separate units such as tablets or capsules, and the like. Other orally administered pharmaceutical preparations include monophasic and biphasic liquid dosage forms, either in a ready-to-use form, or in forms suitable for reconstitution, such as mixtures, syrups, suspensions, or emulsions. The preparations may contain in addition diluents, dispersing agents, pH regulators, stabilizers, solubilizers, surfactants, preservatives, chelating agents, and / or other pharmaceutical additives that are used. Aqueous or non-aqueous vehicles or their combination can be used, and if desired, they can contain suitable sweetening or flavoring agents, or similar substances. In the case of the suspension or emulsion, there may be in addition a suitable thickening agent or suspending agent or emulsifying agent present. In an alternative way, the compounds can be administered as such in their pure form, not associated with other additives, for example as capsules or tablets. They can also be administered with a vehicle. The pharmaceutical preparations can have a slow, delayed, or controlled release of the active ingredients as disposed in a matrix or controlled diffusion system. When the present invention or its suitable salts or complexes are presented as a separate unit dosage form as a tablet, it may contain, in addition, medically inert excipients that are used in the art. Diluents, such as starch, lactose, calcium diphosphate, talc, magnesium stearate, polymeric substances such as methylcellulose, fatty acids and their derivatives, sodium starch glycolate, and the like may also be used.

Example 18 Preparation of oral dosage form: A typical tablet has the following composition: Active ingredient of formula I as given above Lactose 135 mg Starch 76 mg Polyvinyl pyrrolidone (-30) 2 mg Talc 1.5 mg Magnesium stearate 1.0 mg Parenteral Formulations For parenteral administration, the compounds or their appropriate salts or complexes thereof, may be present in a sterile vehicle, which may be an aqueous or non-aqueous vehicle, or a combination thereof. Examples of the vehicles are water, ethyl oleate, oils and derivatives of polyols, glycols and their derivatives. They may contain additives common in injectable preparations, such as stabilizers, solubilizers, pH modifiers, regulators, antioxidants, cosolvents, complexing agents, tonicity modifiers, and the like. Some suitable additives are, for example, tartrate, citrate, or similar regulators, alcohol, sodium chloride, dextrose, and high molecular weight polymers. Another alternative is the reconstitution of sterile powder. The compound can be administered in the form of injection for administration more than once a day, or in an intravenous infusion / drip, or in an adequate depot preparation. Example 19 The preparation suitable for parenteral administration has the following composition: Active ingredient of the formula I as given above Polyethylene glycol (400) 0.75 ml Sodium metabisulphite 0.01% Isotonic serum / water for injection q.s.

Other Formulations For the dermatological application and for the discoloration of the teeth, the recommended formulations are lotions, oral rinses, and toothpastes containing the appropriate amount of the compounds of the general formula I. The above examples are presented by way of illustration only , and in no way limit the scope of the invention.

Claims

1. A compound of the pyridinium series of the general formula I, and its pharmaceutically acceptable salts, useful for the management of vascular complications associated with diabetes and disorders related to aging: (I) wherein: R1 is -Y-R3 and is selected from oxygen or NHR3 is selected from hydrogen! aryl alkyl Rs is selected from the group consisting of alkyl-0-alkyl aryloyl-0-aryloi-NH-alkyloyl and -NH-aryloxy X is selected from the group consisting of a halide ion of acetate ion perchloraton ion of sulfonate ion of oxalate ion of citrate ion of tosylate ion of maleate ion of mesylate ion of carbonate ion of sulfiton ion of hydrogen phosphoric ion of phosphonate phosphate ion BFM_I PFt "and so on, with the proviso that when Ra is phenyl and X is a haluron ion, then R1 is different from -0CH3. The compound according to claim 1, characterized in that X is a halide ion 3. The compound according to the claim claimed in the claim li which is selected from the group consisting of the following compounds: a) L- (2-phenylamino-2-oxoethyl) -3- (n-butyloxycarbonyl) pyridinium chloride or a pharmaceutically acceptable salt thereof b) Bromide of l- (2-thien-2'-il-2) -oxoethyl) -3 - ((2-hydroxyethyl) aminocarbonyl) pyridiniumi or a pharmaceutically acceptable salt thereof c) L- (2-ethoxy-2-oxoethyl > -3- ((2-hydroxyethyl) aminocarbonyl) pyridiniumi or a pharmaceutically acceptable salt thereof d) L- (E-phenylamino-E-oxoethyl) -3- (n-butylaminocarbonyl) pyridiniumi chloride or a pharmaceutically acceptable salt thereof ie) L- (E-phenylamino-E-oxoethyl) -3- < (S-hydroxyethyl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof if) 1- (E-phenyl-E-oxoethyl) -3- ((S-hydroxyethyl) aminocarbonyl) pyridinium bromide or a pharmaceutically acceptable salt thereof g) 1- (5-Methyl-E-oxoethyl) -3- ((E-hydroxyethyl) aminocarbonyl) pyridiniumi bromide or a pharmaceutically acceptable salt thereof. h) L- (E-phenyl-E-oxoethyl) bromide - 3- ((4-Methylthiazol-E-yl) aminocarboni-1-Jpiridinium or a pharmaceutically acceptable salt thereof i) L- (2- (En 4 -dichlorophenyl-E-oxo-ethyl) -3- (isopropyloxycarbonyl) bromide) pyridinium or a pharmaceutically acceptable salt thereof. j) 3- (Tetrahydrobenzothiazol-E-yl) aminocarbonyl bromide (5- (in 4-dichlorophenyl) -E-oxoethyl) pyridi-nioi or a pharmaceutically acceptable salt thereof. Bromide of l- (E-phenyl-E-oxoethyl) -3- ((p-sulfonamidophenylene) aminocarbonyl)) pyridinium or a pharmaceutically acceptable salt of the same 1) 3-carboni lamino-1- (E-thien) bromide -E'-il-E-oxoet iDpyridinium to a pharmaceutically acceptable salt of the same im) Bromide of l- (E- (En 4 -dichlorophenyl) -E-oxo-ethyl) -3- (n-butylaminocarbonyl) pyridinion or a pharmaceutically acceptable salt thereof in. Bromide 4- (E- (Ei4-dichlorophenyl) -E-oxo-ethyl) -3- (n-butoxycarbonyl) pyridinium-i or a pharmaceutically acceptable salt thereof 4- A process for the preparation of compounds of the pyridinium series, according to claim 1, characterized in that this process comprises the preparation of the appropriately substituted pyridine derivatives, according to the desired end products, followed by the quaternization of the substituted pyridine derivatives, with a appropriate reagent, refluxing in alcoholic solvents and / or in high boiling point solvents for 6 to 48 hours, to obtain the desired compounds. 5. The use of a compound of the general formula I as defined in claim 1 -? in the manufacture of a drug for diabetic complications and diseases related to aging n including kidney disease i nerve damage i retinopathy atherosclerosis i microangiopathy i endothelial dysfunction-i dermatological conditions! discoloration of the teeth and other organ dysfunctions; 6. Use in accordance with the claims of claim 5, characterized in that this compound is selected from the group consisting of: a) l- (S-phenylamino-E-oxoethyl) -3- (n-butyloxycarbonyl) pyridinium chloride or a pharmaceutically acceptable salt thereof b) Bromide of l- (E-thien-E'-yl-E-oxoethyl) -3- ((S-hydroxyetiDaminocarbonyl) pyridiniumi or a pharmaceutically acceptable salt thereof ic) l- (E-ethoxy-E-oxoethyl) bromide -3- ((? -hydroxyethyl) aminocarbonyl) pyridiniumi or a pharmaceutically acceptable salt thereof d) L- (E-phenylamino-E-oxoethyl) -3- (n-butylaminocarbonyl) pyridiniumi chloride or a pharmaceutically acceptable salt thereof ie) l- (E-phenylamino-E-oxoethyl) -3 - (<; E-hydroxyethyl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof. F) L- (E-phenyl-E-oxoethyl) -3- < < E-hydroxyethyl) aminocarbonyl) pyridinium or a pharmaceutically acceptable salt thereof (g) L- (E-methyl-E-oxoethyl) -3 - ((E-hydroxyethyl) aminocarbonyl) pyridiniumi bromide or a pharmaceutically acceptable salt thereof. Broauro gives l- < 2-phenyl-2-oxoethyl) -3-C (4-methylthiazol-B-yl) aainocarbonyl) pyridinium or a araacifiu tically acceptable salt of the ai sao ii) Bromide of l- (2- (2i4-dichlorophenyl-2- oxo-ethyl) -3- (isopropyloxycarbonyl) pyridinium or an acceptable characer faraceu-ti salt of the aismoi j) 3- (tetrahydrobenzothiazol-2-yl) aainocarbonyl > -] ^ < 2- (214-dichlorophenyl) -2-oxoethyl) pyridinium-i or a pharmaceutically acceptable salt thereof i) l- (2-phenyl-B-oxoethyl) -3- < < p-sulfonaaidophenylene) aainocarbonyl)) pyridinium or a pharmaceutically acceptable salt of the ai sao; 1) 3-Carbonylamino-1- (2-thien-2-yl-2-oxoethyl) pyridinium-1-broaide or an acceptable pharmaceutically acceptable salt thereof m) L- (2- (2-i4-dichlorophenyl) bromide) -2-oxo-ethyl) -3- (n-butylaminocarbonyl) pyridinium or an acceptable faraacetic acid salt of the ai sao) l- (2- <2-i4-dichlorofenyl) -2-oxo-ethyl broauride ) -3- (n-butoxycarbonyl) pyridinium or an acceptable pharmaceutically acceptable salt thereof. 7 · The use of l- (2-phenyl-E-oxoethyl) -3- (l-phenyl-l-oxoaethyl) pyridinium-1 broaur or of an acceptable pharaonic-therapeutic salt of aisao-i in the manufacture of a medication for diabetic coapplications and diseases related to aging! including kidney disease, nerve damage, retinopathy, atherosclerosis, microangiopathy, endothelial dysfunction, and dermatological conditions! Discoloration of teeth and other organ dysfunctions. fl. The use of 1- (β-phenyl-5-oxoethyl) -3- (methoxycarbonyl) pyridinium bromide or a pharmaceutically acceptable salt of mismon in the manufacture of a medicament for diabetic complications and diseases related to aging! including kidney disease! damage to the nervesi retinopathy atherosclero-sisi microangiopathy, endothelial dysfunction, dermatological conditions-discoloration of the teeth, and other organ dysfunctions. A pharmaceutical composition for the treatment of diabetic complications and diseases related to aging! which comprises a pharmaceutically effective amount of one or more compounds of the general formula I n as defined by claim l or pharmaceutically acceptable salts thereof i in admixture with a carrier! dilute the solvent or excipient arcereutically acceptable- ID- The pharmaceutical composition in accordance with what is claimed in the indication T i in the form of an oral formulation- 11 · The pharmaceutical composition in accordance with that claimed in the IDi claim characterized in that the pharmaceutically acceptable carrier is selected from one or more of the starch compounds lactosai pol ivini lpirrol idone (K-30) and talc and magnesium stearate- B- The pharmaceutical composition in accordance with that claimed in claim in the form of a parenteral formulation. 13- A method for the preparation of a parenteral formulation according to the claim in claim IBi which comprises dissolving the active ingredient of the general formula li as defined in claim I in polyethylene glycol MQDi and diluting the solution thus obtained with a Isotonic solution or water to the desired concentration. 14- A pharmaceutical composition in accordance with that claimed in the claim Ti in the form of oral rinse and toothpaste lotions. 15. A method for the treatment of a diabetic patient, by the decomposition of the AGE previously formed inside the patient, which comprises administering an effective amount of a compound in accordance with that claimed in claim 1, either alone or in combination with other drugs for antidiabetic therapy. 16. A method for the treatment of a diabetic patient, by decomposing the advanced glycation end products previously formed within this patient, which comprises administering an effective amount of 1- (2-phenyl-2-oxoethyl) bromide -3- (1-phenyl-l-oxomethyl) pyridinium or a pharmaceutically acceptable salt thereof, either alone or in combination with other drugs for antidiabetic therapy. 17. A method for the treatment of a diabetic patient by decomposing the advanced glycation end products previously formed within this patient, which comprises administering an effective amount of 1- (2-phenyl-2-oxoethyl) bromide - 3- (me-toxicarbonyl) pyridinium or a pharmaceutically acceptable salt thereof, either alone or in combination with other drugs for antidiabetic therapy. 18. A method for preventing or treating diseases caused by diabetes and complications related to aging which comprises administering to a patient in need thereof an effective amount of a compound of the formula I in accordance with that claimed in the claim or only or in combination with a diluent carrier or pharmaceutically acceptable excipient-19. The method according to claim 18, characterized in that the disease that is prevented or treated is a nephrological disorder, a neurological disorder, atherosclerosis, a disorder retinal, a dermatological disorder, a nonenzymatic brown color of the oral cavity, an endothelial or other organ dysfunction, and impaired growth. (I) The invention discloses compounds of the pyridinium series useful for the management of vascular complications related to diabetes and aging, and in particular in the treatment of complications of diabetes mellitus and other conditions related to aging, including kidney disease. , damage to the nerves, atherosclerosis, retinopathy, dermatological conditions, and discoloration of the teeth, by the decomposition of the previously formed AGE, of the general formula (I), or pharmaceutically acceptable salts thereof, wherein R1, R2, and X are as defined in the specification. The invention also provides the method for the preparation of the compounds of the series, and a pharmaceutical composition having one or more compounds as defined above as active ingredients. The invention also discloses a method of treating a diabetic patient by administration of the compounds defined above, either alone or in combination with other drugs for antidiabetic therapy. * * * * *