Indian Patents. 250728:A COMPOUND OF PYRIDINIUM SERIES

Title of Invention	A COMPOUND OF PYRIDINIUM SERIES
Abstract	The invention discloses novel compounds of the pyridinium series useful for the management of diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth, by breaking preformed AGE, of the general formula I, or pharmaceutically acceptable salts thereof,

Full Text	The present invention relates to a new class of compounds of pyridiuium series and to their use in treatment of diabetes and related illnesses. More particularly the invention relates to compounds of this series, methods for their preparation, pharmaceutical composition containing these compounds and their use in the treatment of complications of diabetes mellitus. The compounds of this series exhibit AGE breaking activity, which is essential for the treatment of diabetic and aging-related complications including kidney disease, nerve damage, atherosclerosis, retinopathy and dermatological conditions. The invention also extends to the method of reversing the discoloration of teeth resulting from nonenzymatic browning in the oral cavity which comprises administration of an amount effective to reverse pre-formed advanced glycosylation crosslinks. Maillard in 1912 found that reducing sugars, such as glucose and ribose react with proteins to form brown pigments. Further studies have shown that this is an irreversible non-enzymatic reaction, which occurs in several natural systems including stored foodstuff. Maillard reaction occurs in two stages, early and advanced. Initially, proteins react with glucose to form stable Amadori products, which subsequently cross-links to form advanced glycation end products (AGE), In most cases, the formation of AGE also accompanies browning of the proteins and increase in the fluorescence. In diabetes, where blood glucose level is significantly higher than normal, the reaction of glucose with several proteins such as haemoglobin, lens crystallin and collagen, gives rise to the formation of AGE, which in turn, is responsible for the complications associated with diabetes, such as nephropathy, microangiopathy, endothelial dysfunction and other organ dysfunctions. In addition, the activity of several growth factors, such as basic fibroblast growth factor, is also impaired. AGE products, unlike normal proteins in tissue, have a slower rate of turnover and replenishment. It has been reported that AGE products may in fact elicit a complex. immunological reaction involving RAGE (Receptor for Advanced Glycation End Products) receptors and activation of several incompletely defined immunological processes. It has been documented that diabetes with evidence of microangiopathy and macroangiopathy also show evidence of oxidative stress, the mechanism of which has not been elucidated. In vitro AGE formation can be studied in the laboratory by incubating reducing sugars, such as ribose or glucose with bovine serum albumin. AGE formation can be detected by increase in the fluorescence or increased cross reactivity with anti-AGE antibodies. The increase in fluorescence seems to precede formation of AGE specific antigenic epitopes. This increase in fluorescence is used to monitor the increased AGE formation in vitro (Brownlee M et al, Science 1986; 232:1629-1632). In addition to the increase in the fluorescence, one of the most important features of in vitro AGE formation is the formation of antigenic epitopes that are specific to AGE and not to the native proteins. Therefore, it is possible to raise antibodies against advanced glycation end products of one protein and use them to detect AGE formation in other proteins. This has served as an important analytical tool in AGE research. Due to the clinical significance of AGE formation, many approaches are being used to diagnose, prevent, or revert AGE formation in the body. The formation of AGE could be inhibited by reacting with an early glycosylation product that results from the original reaction between the target protein and glucose. The inhibition was believed to take place as the reaction between the inhibitor and the early glycosylation product appeared to interrupt the subsequent reaction of the glycosylated protein with additional protein material to form the cross linked late stage product. Compounds like aminoguanidine act to inhibit AGE formation by such mechanism. The formation of AGE on long-lived proteins is also associated with cross- linking of these proteins. The AGE derived protein cross-links have been shown to be cleaved by compounds like N- phenacyl thiazolium bromide (PTB), which reacts with and cleaves covalent, AGE derived protein cross links (Vasan et al. Nature 1996; 382: 275-278 ; US 5,853,703, Date of Patent : Dec. 29, 1998). The mechanism of reducing the AGE content in tissues is expected to take place relatively rapidly, in contrast to aminoguanidine, which acts slowly by its very nature of mechanism of action. This current specification is related to compounds of pyridinium class, which break pre-formed AGE, like PTB, and in some cases even more effectively by than PTB. The main objective of the present invention is to provide a new class of compounds of the pyridinium series which are useful for the management of diabetes and aging related vascular complications and particularly in the treatment of complications of diabetes mellitus and other aging related conditions including kidney disease, nerve damage, atherosclerosis, retinopathy and dermatological conditions. The invention also extends the method to reverse the discoloration of teeth resulting from nonenzymatic browning in the oral cavity which comprises administration of an amount effective to reverse the pre-formed advanced glycosylation crosslinks, etc. Another object of the present invention is to provide compounds of the pyridinium series, which exhibit AGE breaking activities. Yet another object of the present invention is to provide a method of preparation of compounds of the pyridinium series which exhibit AGE breaking activities. 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 suitable carriers, solvents, excepients, diluents and other media normally employed in preparing such compositions. Still another object of the invention is to provide a method of treatment of a diabetic patient by administration of the compounds of the invention, either singly or in combination with drugs for anti-diabetic therapy, or pharmaceutically acceptable salts thereof in required dosage in admixture with pharmaceutically acceptable diluent, solvent, excepients, carriers or other media as may be appropriate for the purpose. The present invention provides for a new class of AGE breakers, of general formula I, 6 wherein R1 is -R4-R5 or -N(R7) N (R7) R9; R4 is selected from the group consisting of -N(R7)R6O, -N(R7)R6N(R7)-, OR6O, and -OR6N(R7)-, where R6 is alkyl; R5 15 selected from the group consisting of alkyl, alyl including heteroaryl, -COR7, SO2R7, -C(S) NHR7, -C(NH)NHR7, -COR10, where R7 is selected from the group consisting of H, alkyl and aryl including heteroaryl provided R7 might be different for R1 and R3 in the same compound; R2 is selected from the group consisting of F, Cl, Br, I, OR7, NO2, alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR7R10, C(O)OR7, NR7RI0, N=C(R7)(R10), SR7, SO2NH2) SO2 alkyl and SO2aryl, and m is 0, 1 or 2; R3 is selected from the group consisting of R7, OR7, N(R7) (R10), N=C(R7) (R10), N(R7) N(R7) (R10), N(R7) N=C(R7) (R10) and CH(R7)C(0)R8 where R8 is selected from the group consisting of R7, OR7 and NR7R10; R9 is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl, C(O)R10, -SO2R10, -C(S)NHR,0, -C(NH) NH (R10) and -C(O) NHR,0, R10 is selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case optionally different from substituent R10, provided R10 might be different for R1 and R3 in the same compound; X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF4" and PF6; with proviso that, (i) when two alkyl groups are present on the same carbon or nitrogen, they are optionally linked together to form a cyclic structure and (ii) the nitrogen of heteroaryl ring of R10, when present, is optionally quaternized with compound such as X-CH2C(O)-R;, As used herein, "alkyl" refers to an optionally substituted hydrocarbon group joined by single carbon-carbon bonds and having 1 to 8 carbon atoms joined together. The alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. The substituents are selected from F, Cl, Br, 1, N, S, O and aryl. Preferably, no more than three substituents are present. As used herein "aryl" refers to an optionally substituted aromatic group with atleast one ring having a conjugated pi- electron system, containing upto two conjugated or fused ring systems. Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. The substituents are selected from F, Cl, Br, I, N, S, O and straight chain or branched C1-C6 hydrocarbon. The novel compounds of the invention of general formula I having m as 0 and - COR1 at position 3 are listed in Table 1A and the novel compounds of the invention of general formula 1 having m as 0 and - COR1 at position 4 are listed in Table IB. The following compounds suggested are by way of example alone of the representative compounds of the general formula I as defined above and in no way restrict the invention: N,N'-Bis[3 -carbonyl-1 -(2-phenyl-2 -oxoethyl)-pyridiniurn] hydrazine dibromide (compound 1); N,N'-Bis[3-carbonyl-l-(2-ethoxy -2- oxoethyl)pyridinium]hydrazine dibromide (compound 2); N,N'-Bis[3 -carbonyl-1 -(2-(2,4-dichloropheny l)-2-oxoethyl)p\ridinium]hydrazine dibromide (compound 3); 1- (2- Ethoxy -2- oxoethyl) -3- (2- (2- p>Tidyl) hydrazinocarbonyl) pyridinium bromide (compound 4); 1- (2- Thien -2'- yl -2- oxoethyl) -3- (methanesulfonyl hydrazinocarbonyl) pyridinium bromide (compound 5); N,N'-Bis[3-carbonyl-l- (2- thien -2'- yl -2- oxoethyl)pyridinium]hydrazine dibromide (compound 6); 1- (2- Ethoxy -2- oxoethyl) -3- (2- (benzoyjoxy) ethylarninocarbonyl) pyridinium bromide (compound 7); 1- (2.- (2,4- Dichlorophenyl) -2- oxoethyl) -3- (2-(behzoyloxy)ethylamiiio-carbonyi) pyridinium bromide (compound 8); '1- (2- Thien -2'- yl -2- oxoethyl) -3- (2- (2- pyridyl) hydrazinocarbony]) pyridinium bromide (compound 9); 1- (2- Phenyl -2- oxoethyl) -3- (2- (2- pyridyl)hydrazinocarbonyl) pyridinium bromide (compound 10); l-(2-Phenyl-2-oxoethyl)-3-(hydrazinocarbon}l)pyridinium bromide (compound 11); l-(2- Phenyl -2- oxoethyl) -3- (methanesulfonyl hydrazinocarbonyl) pyridinium bromide (compound 12); 1- (2- Ethoxy -2- oxoethyl) -3- (methanesulfonyl hydrazinocarbonyl) pyridinium bromide (compound 13); l-(2-Phenyl-2-oxoethyl) -3- (phenylsulfonylhydrazino carbonyl) pyridinium bromide (compound 14); l-(2-Phenyl-2-oxoethyl) -2-chloro-3- (phenylsulfonylhydraziiio carbonyl) pyridinium bromide (compound 15); l-(2- Phenyl -2- oxoethyl) -3- (2- (acetoxy)ethyloxy carbonyl) pyridinium bromide (compound 16); l-(2-Ethoxy -2- oxoethyl) -3- (2- (benzoyloxv) ethyloxy carbonyl) pyridmiuin bromide (compound 17); l-(2- Thien -2'- yl -2- oxoethyl)-4-(2-(benzoyloxy)ethylaminocarbonyl) pyridinium bromide (compound 18); l-(2-Ethoxy -2- oxoethyl) -4-(phenylsulfonyl hydrazino carbonyl) pyridinium bromide (compound 19); l-(2-Phenylamino-2-oxoethyl)-4- (phenylsulfonyl hydrazino carbonyl) pyridinium chloride (compound 20); ' l-(2-Ethoxy -2- oxoethyl) -3-(phenylsulfonyl hydrazino carbonyl) pyridinium bromide (compound 21); l-(2-(2,4-Dichlorophenyl)-2-oxoethyl)-3-(2(methoxy)ethyloxycarbonyl) pyridinium bromide (Compound 22); l-(2-Phenylamino-2-oxoethyl)-3-((benzoyloxy)ethylaminocarbonyl) pyridinium chloride (compound 23); l-(2-Thien-2'-yl-2-oxoethyl)-3-(phenylaminocarbonyl hydrazinocarbonyl) pyridinium bromide (compound 24); l-(2-Phenyl-2-oxoethyl)-3-(2-(acetoxy)ethylaminocarbonyl) pyridinium bromide (compound 25); 1 -(2-Phenylamino-2-oxoethyl)-3-(phenyl sulfonyl hydrazino carbonyl) pyridinium chloride (compound 26); 1 -(2-Phenylamino-2-oxoethyl)-3-((4-methylphenyl) sulfonyl hydrazino carbonyl) pyridinium chloride (compound 27); l-(2-Phenyl-2-oxoethyl)-3-(2-(benzoyloxy)ethyloxy carbonyl) pyridinium bromide (compound 28); l-(2-Thien-2'-yl-oxoethyl)-3-(phenylcarbonyl hydrazino carbonyl) pyridinium bromide (compound 29); 1 -(2-Ethoxy-2-oxoethyl)-3-((phenylmethyl)sulfonyl hydrazino carbonyl) pyridinium bromide (compound 30); 1 -(2-Phenyl-2-oxoethyl)-3-((phenylmethyl)sulfonyl hydrazino carbonyl) pyridinium bromide (compound 31); N, N' - Bis [3-carbonyl-l-(2-furan-2'-yl-2-oxoethyl) pyridinium ]hydrazme dibromide. (Compound No: 32); N,N'-Bis [3-carbonyl-1- (2-thien-2'-yl-2-oxoethyl) pyridinium] hydrazine dichloride.(Compound No: 33); l-(2-Thien-2'-yl-2-oxoethyl)-3-((2-(l-oxo-3-cyclohexyl)-propyl)-hydrazino carbonyl)-pyridinium bromide.( Compound No: 34); l-(2-Phenylamino-2-oxo ethyI)-3-({2-(l-oxo-3-cyclohexyl)-propyl} -hydrazino- carbonyl}-pyridiniura bromide.(Compound No: 35); l-(2-Thien-2'-yl-2-oxoethyl)-3-[2-(benzoyloxyethylamino carbonyl]-pyridiniuim romide (Compound No: 36); l-(4-Ethoxy-2, 4-dioxobutyl)-3-(2-(benzoxyloxy)ethylamino carbonyl)-pyridinium chloride. (Compound No: 37); l-(2',4'-Dichloro-phenyl-2-oxoethyI)-3-(2-methoxyethylaminocarbonyl)-pyridinium bromide. (Compound No: 38); N,N'-Bis-[3-carbonyl-1 -(2-cycIopropylamino-2-oxoethyl) pyridinium] hydrazine dichloride. (Compound No: 39); l-(2-Cyclopropyamino-2-oxoethyl)-3-(2-methoxyethylaminocarbonyl)-pridinuam chloride. (Compound No: 40); N-N'-Bis [3-carbonyl-l-(2-isopropylamino-2-oxoethyl) pyridinium] hydrazine dichloride. (Compound No: 41); 1 -(2-Thien-2'yl-2-oxoethyl)-3-(2-(2-chloro-3 -pyridoylhydrazinocarbonyl )- pyridinium chloride. (Compound No: 42); l-(2-Isopropylamino-2-oxoethyl)-3-(2-methylsulfonylhydrazinocarbonyl)- pyridinium chloride. (Compound No: 43); l-(2-(l-Pyrrolidinyl)-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl) pyridinium chloride.(Compound No: 44); l-(2-Thien-2'-yl-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl) pyridinium chloride. (Compound No: 45); N,N-Bis[3-carbonyl- l-(2-hydroxy-2-oxoethyl)pyridinium]hydrazine dichloride (Compound No: 46); l-(2-Thien-2'-yl-2-oxoethyl)-3-((2-methoxy ethyl) amino carbonyl)-5-bromo pyridinium chloride (Compound No: 47); The invention also provides a process for the preparation of novel compounds of the pyridinium series. The said process for the preparation of compound 1, comprises, adding a solution of phenacyl bromide in isopropanol to N,N'-bis-(nicotinyl)hydrazine dissolved in methanol, refluxing for six hours, cooling, filtering the precipitated solid, washing the solid with hot ethyl acetate and finally purifying the solid with 20 ml of methanol : ethyl acetate (3 : 1) to yield the desired compound. Similarly, the other novel compounds of general formula I, are prepared from properly substituted pyridine derivatives followed by quarteraization with appropriate reagent by refluxing in alcoholic solvents like, methanol, ethanol, propanol, etc and high boiling solvents like toluene or xylene etc, for 6-48 hrs. to give the desired compounds. The in vitro AGE formation, studied in the laboratory, by incubating reducing sugar glucose, with protein bovine serum albumin, resulted in browning of solution and increase in the fluorescence. Fluorescence was used as the criteria to monitor the increased AGE formation. Example 1 AGE breaker activity has been confirmed by the screening procedure as mentioned below: Materials: Bovine serum albumin (fraction V) (BSA) Glucose, analytical grade Phosphate buffered saline (PBS) Equipment: Microplate ELISA Reader - Spectramax Plus (Molecular Devices, USA) Microplate washer, (Bio -Tec Instruments, USA) pH meter Methods of experiment: Elisa (Enzyme Linked Immunosorbent Assay) 160 mg/ml of protein, bovine serum albumin, BSA and 1.6M glucose sugar were dissolved in phosphate buffered saline, PBS. Sodium azide was added at 0.02% concentration as a preservative. The solution was filtered asceptically through a 0.22 uM filter and kept for aging at 37°C for 16 weeks. After 16 weeks the solution was dialyzed against PBS, aliquoted and stored at - 20°C. To determine the AGE breaking activity, 10µg/ml of the 16 weeks AGE- BSA was incubated with different concentrations of the test compounds at 37°C for 24 hours and AGE breaking activity of the test compounds by ELISA was determined. ELISA was performed as follows: 1. Different concentrations of 16 weeks AGE-BSA were coated on a microtitre plate as standard. Each concentration is coated in triplicates. 2. The test samples were coated on microtitre plate at a concentration of 5 ng. to 20 ng per well in triplicates. 3. The plate was incubated at 37°C for one hour. 4. After incubation the plate was washed with PBST (PBS with 0.05% Tween 20). 5. Blocking with 5% skimmed milk in PBS at 37°C for one hour was done. 6. The plate was washed with PBST. 7. Primary antibody against AGE-BSA was added and the plate is incubated at 37°C for one hour. 8. The plate was washed with PBST 9. Secondary antibody anti rabbit HRPO (Horse-Radish Per Oxidase) conjugate was added and the plate is incubated at 37°C for one hour. 10. The plate was washed with PBST. 11. Colour development with OPD (orthophenylenediamine dihydrochloride) and hydrogen peroxide was done. 12. OD (optical density) at (450nm reading - 620nm reading) was measured after incubation at 37°C for 15 minutes with Microplate ELISA Reader. The breaker activity of the compounds were determined by the following formula: OD450-620Control= Absorbance of 20ng AGE-BSA after incubation at 37°C for 24 hours without test compound OD450-620Test= Absorbance of 20ng AGE-BSA after incubation at 37°C for 24 hours with required concentration of test compound Using specific examples, the % AGE breaking activity was calculated and recorded in Table 2. Hence compound 6 has significant AGE breaking activity i.e. a comparatively much supeR10r potency vis-a-vis PTB. The following examples give method of preparation of the specific novel compounds of the invention as given in Table 1. The following compounds suggested are by way of example alone and in no way restrict the invention. Example 2 Preparation of N,N'-bis [3-carbonyl-1- (2-phenyl-2-oxoethyl) pyridinium] hydrazine dibromide (compound 1): To a boiling solution of N, 2,-bis-(nicotihyl)hydrazine (1.21 g., 0.005 mol.) in methanol (20 ml.), a solution of phenacyl bromide (1.99 g., 0.01 mol.) in isopropanol (10 ml.) was added and the reaction mixture was refluxed for 6 hrs. The reaction mixture was concentrated under vacuum (~10 ml.) and filtered. The obtained residue was washed with hot ethylacetate and then the isolated solid was powdered. It was recrystallised from a mixture of methanol and ethylacetate (3:1, 20 ml) to afford a pale yellow solid. Yield : 60% m.p. : 260 - 262°C (decomp.) IR(KBr, cm-1) : 1696 and 1680 1H NMR (DMSOd6, 400MHz) δ: 11.65(2H,s), 9.56(2H,s), 9.21-9.16(4H,m), 8.49- 8.45 (2H,m), 8.08-8.05 (4H,d), 7.81-7.77(2H,m), 7.68-7.64 (4H,m), 6.58 (4H,s) Mass (m/z): 479, 480 According to the above mentioned procedure the following compounds are synthesized by reacting the corresponding pyridine derivatives with appropriate reagents by refluxing in methanol, ethanol, propanol, toluene or xylene for 6-48 hrs. to get the desired compounds: Example 3 N,N'-Bis[3-carbonyl-l- (2- ethoxy -2-oxoethyl) pyridiniuml hydrazine dibromide (compound 2): Yield: 47% m.p. : 180-182°C (decomp.) IR(KBr, cm"1) : 1744, 1664 1H NMR (DMSOd6, 400MHz) δ: 11.65 (2H,s), 9.62 (2H,s), 9.28-9.26 (2H,d), 9.17-9.15 (2H,d), 8.47-8.44 (2H,m), 5.77 (4H,s), 4.26 (4H,q), 1.27 (6H,t) Mass (m/z) : 415, 416 Example 4 N,N'-Bis[3-carbonyl-l- (2- (2,4- dichlorophenyl) -2- oxoethyl) pyridinium] hydrazine dibromide (compound 3): Yield : 24% m.p. : 225 - 227°C (decomp.) IR(KBr, cm'1): 1702,1666 1H NMR (DMSOd6, 400 MHz) δ: 11.69 (2H,s), 9.58 (2H,bs), 9.20-9.18 (4H,m); 8.49-8.47 (2H,m), 8.17-8.15 (2H,d), 7.92 (2H,bs), 7.78-7.76 (2H,d), 6.50 (4H,s) Mass (m/z): 615, 617, 618, 620. Example 5 1- (2- Ethoxy -2- oxoethyl) -3- (2- (2- pvridyl) hydrazinocarbonyl) pyridinium bromide (compound 4): Yield: 16% m.p. : 210-212°C IR (KBr, cm-1): 3140, 3005, 1732 and 1690 1H NMR (DMSO6, 400MHz) δ: 9.63 (lH,s), 9.27 (2H,d), 8.49-8.45 (lH,m) 8.13- 8.07 (2H,m), 7.32-7.30 (lH,m), 7.12-7.1 l(lH,m), 5.77 (2H,s), 4.23 (2H,q), 1.25 (3H,t) Mass (m/z): 301, 302 Example 6 1- (2- Thien -2'- yl -2- oxoethyl) -3- (methanesulfonyl hydrazinocarbonyl) pyridinium bromide (compound 5): Yield : 30 % m.p : 199-200 °C IR (KBr, cm"1): 1714, 1673 1HNMR (DMSOd6, 400 MHz) δ: 11.38 (lH,s), 9.97 (lH,s) 9.51 (lH,s), 9.16 (lH,d), 9.06 - 9.04 (lH,m), 8.43 - 8.39 (lH,m), 8.25 - 8.21 (2H,m), 7.43 - 7.41 (lH,t), 6.45 (2H,s), 3.08 (3H,s). Mass (m/z) : 340, 341, 342 Example 7 N,N'-Bis[3-earbonyl-l- (2- thien -2'- yl -2- oxoethyl)pyridiniumlhydrazine dibromide (compound 6): Yield: 33% m.p.: 259 - 261°C (decomp.) IR (KBr, cm"1): 3330, 1702, 1674, 1655 and 1626 1H NMR (DMSOd6 400 MHz) δ: 11.59 (2H,s), 9.50'(2H,s), 9.15-9.08 (4H,m), 8.40-8.36 (2H,m), 8.17-8.14 (4H,m), 7.33(2H,t), 6.42 (4H,s) Mass (m/z): 491, 492. Example 8 1- (2- Ethoxy -2- oxoethyl) -3- (2- (benzoyloxv) ethylaminocarbonyl) pyridinium bromide (compound 7); Yield: 85% m.p. : 132-134oC IR (KBr, cm-1): 3210, 3067, 1726, 1687, 1656 1H NMR (DMSOd6, 400 MHz) δ: 9.46 (lH,s), 9.37 (lH,t), 9.11(lH,t), 8.97 (lH,d), 8.33-8.29 (lH,m) 7.95-7.93 (2H,m), 7.63-7.59 (lH,m), 7.49-7.45 (2H,m), 5.65 (2H,s), 4.39 (2H,t), 4.19 (2H,q), 3.70-3.69 (2H,m), 1.20 (3H,t) Mass (m/z) : 357, 358, 359 Example 9 1- (2- (2,4- Dichlorophenvl) -2- oxoethyl) -3- (2-( benzoyloxykthyl aminocarbonyl) pyridinium bromide (compound 8): Yield: 75% m.p. : 102-104oC IR(KBr, cm"1): 1703, 1685, 1675 1H NMR (DMSOd6, 400 MHz) δ: 9.41-9.37 (2H,m), 9.03-8.98 (2H,m)8.34-8.30 (lH,m), 8.04 (lH,d), 7.91-7.89 (2H,m), 7.82 (lH,d),7.68-7.65 (lH,m), 7.58-7.55 (lH,m), 7.43 (2H,t), 6.35 (2H,s). 4.36 (2H,t), 3.68-3.64 (2H,m) Mass (m/z): 457, 458, 459, 460, 461,462 Example 10 1- (2- Thien -2'- yl -2- oxoethyl) -3- (2- (2- pyridyl) hydrazinocarbonyl) pyridinium bromide (compound 9): Yield: 10% m.p. : 212-214°C (decomp) IR(KBr, cm"1): 1685, 1649 1H NMR (DMSOd6, 400 MHz) δ: 11.21 (lH,bs), 9.59 (lH,s), 9.19 (2H,d), 8-44 (lH,t), 8.27-8.24 (2H,m), 8.08 (lH,bs), 7.62 (lH.bs), 7.44 (lH,t), 6.85-6.79 (2H,m), 6.50 (2H,s) Mass (m/z): 339, 340, 341 Example 11 1- (2- Phenyl -2- oxoethyl) -3- (2- (2- pyridyl) hydrazinocarbonyl) pyridinium bromide (compound 10): Yield : 4% m.p. : 190°C (decomp) IRCKBr.cm1): 1683, 1670, 1648 1H NMR (DMSOd6, 400 MHz) δ: 11.14 (lH,bs), 9.53 (lH,s), 9.18-9.13 (2H,m), 8.45-8.42 (lH,t), 8.08-8.06 (3H,m), 7.80 (lH,t), 7.67 (2H,t), 7.62-7.55 (lH,m), 6.83-6.76 (2H,m), 6.54 (2H,s) Mass (m/z) : 333, 334, 335 Example 12 l-(2-PhenyI-2-oxoethyl) -3- (hvdrazinocarbonyl) pyridinium bromide (compound 11). Yield: 15% m.p. :215-216°C IR(KBr, cm"'): 1695, 1680 1HNMR (DMSOd6, 400 MHz) δ: 10.25 (lH,s) 9.65 (lH,s), 9.35 - 9.32 (2H,m), 8.90 - 8.88 (lH,ra) 8.50 - 8.46 (2H,d), 8.21 - 8.17 (lH,m), 8.05 - 8.07 (2H,m), 6.50 (2H,s), 4.45 (2H,s). Mass(m/z) : 256, 257. Example 13 1- (2- Phenyl -2- oxoethyl) -3- (methanesulfonyl hvdrazinocarbonyl) pyridinium bromide (compound 12): Yield: 35% m.p.: 227- 228 °C IR(KBr, cm-1): 1710, 1702 lHNMR (DMSOd6, 400 MHz) δ: 11.30, (lH,s), 9.88 (lH,s), 9.41 (lH,s), 9.06 - 9.05 (lH,d) 8.98 - 8.96 (lH,d), 8.34 - 8.31 (lH,m), 7.97 (2H,d), 7.72 .- 7.69 (lH,t), 7.59 - 7.56 (2H,t), 6.44 (2H,s), 2.99 (3H,s) Mass (m/z): 334, 335 Example 14 l-(2- Ethoxy -2- oxoethyl) -3- (methanesulfonyl hydrazinocarbonyl) pyridinium bromide (compound 13): Yield: 38% m.p: 75- 76 °C IR(KBr, cm-1): 1739, 1697 1HNMR (DMSOd6, 400 MHz) δ : 11.39 (lH,s), 9.96 (lH,s), 9.56 (lH,s), 9.23 (lH,d), 9.06 (lH,d), 8.40 (lH,t), 5.75 (2H,s), 4.27-4.22 (2H,q), 3.08 (3H,s), 1.26 (3H,t) Mass (m/z): 301, 302, 303 Example 15 l-(2-Phenyl-2-oxoethyl)-3-(phenylsulforiyIhydrazino carbonyl) pyridinium bromide (compound 14): Yield: 28% m.p: 187-188°C(dec.) IR(KBr, cm-1): 1700, 1633 1HNMR (DMSOd6, 400 MHz) δ : 11.38 (lH,s), 10.45 (lH,s), 9.33(1 H,s), 9.13 - 9.12 (lH,d), 8.95 (1H, d), 8.38 (lH,t), 8.05 (2H,d), 7.89 (2H,d), 7.80 (lH,t), 7.66 (3H,t), 7.57 (2H,t), 6.50 (2H,s). Mass(m/z) : 396, 397, 398 Example 16 1- (2-Phenyl-2-oxoethvl)-2-chloro-3-(phenyIsuIfonylhydrazino carbonyl) pyridinium bromide (compound 15): Yield: 23% m.p. : 247 - 250°C (decomp) IR(KBr, cm-1): 1685, 1679, 1HNMR (DMSOd6, 400 MHz) δ : 11.12 (lH,s), 9.49 (lH,s), 9.07 - 9.03(lH,m), 8.44 (1H, t), 8.07 (2H,d), 7.80 (lH,t), 7.67 (2H,t), 7.18 (2H,t), 6.87 (2H,d), 6.77 (lH,t), 6.50 (2H,s). Mass(m/z) : 430, 431, 432 Example 17 l-(2- Phenyl -2- oxoethyl) -3- (2- (acetoxy) ethyloxy carbonyl) pyridinium bromide (compound 16); Yield : 40% m.p. : 152-153°C IR(KBr, cm-1) :1737, 1691, 1635 1HNMR (DMSOds, 400 MHz) δ :9.63(lH,s), 9.24(lH,d), 9.12(lH,d), 8.43(lH,t), 8.07(2H,d), 7.80(lH,t), 7.67(2H,t), 6.59(2H,s), 4.62-4.60 (2H,m), 4.39 - 4.37(2Hm), 2.03 (3H,s) Mass(m/z) :328, 329 Example 18 1- (2- Ethoxy -2- oxoethyl) -3- (2- (benzoyloxy) ethyloxycarbonyl) pyridinium bromide (compound 17): Yield : 35% m.p. : 142-143oC IRCKBr,cm-1) : 1736,1718,1636 1HNMR (DMSOd6, 400 MHz) δ : 9.60(1 H,s), 9.20-9.18(lH,d), 9.04- 9.02(lH,d), 8.33-8.29(lH,m), 7.90-7.88(2H,d), 7.58-7.57(lH,m), 7.46-7.42(2H,m), 5.67(2H,s), 4.71-4.68(2H,m), 4.58-4.56(2H,m), 4.15(2H,q), 1.16(3H,t) Mass(m/z) : 358,359,360 Example 19 1- (2- Thien -2'- yl -2- oxoethvl)-4-(2-(benzoyloxy)etfavlaminocarbonyl) pyridinium bromide (compound 18): m.p. : 210-211°C IR(KBr cm-1) : 1723,1680,1668 1HNMR (DMSOd6, 400 MHz) δ : 9.52 (lH,t), 9.14 (2H,d), 8.50 (2H,d), 8.25 - 8.21 (2H,m), 8.01 - 7.99 (2H,d), 7.67 (lH,t), 7.55 - 7.51 (2H,m), 7.42 - 7.40 (lH,m), 6.42 (lH,s) 4.47 - 4.45 (2H,t), 3.77 - 3.73 (2H, m). Mass(m/z) : 395, 396 Example 20 l-(2-Ethoxy-2-oxoethyl)-4-(phenvlsutfonyl hydrazino carbonyl) pvridinium bromide (Compound 19): Yield: 60% m.p. : 171 - 173°C. IR(KBr, cm-1): 1745, 1685, 1645. 1HNMR (DMSOd6, 400 MHz) δ : 11.41 (1H, s), 10.39 (1H, s), 9.10 (2H, d), 8.27 (2H, d), 7.82 - 7.80 (2H, d), 7.60 - 7.57 (1H, t), 7.50 - 7.46 (2H, t), 5.63 (2H, s), 4.18-4.12 (2H,q), 1.19-1.15 (3H,t). Mass (m/z) : 364,365, 366 Example 21 1-(2-Phenvlamino-2-oxoethyl)-4-(phenyIsulfonyl hydrazino carbonyl) pyridinium chloride (Compound 20): Yield: 10% m.p. : 225 - 227°C. IR(KBr, cm-1) : 1693, 1642, 1592 1HNMR(DMSOd6, 400 MHz) δ : 11.55 (1H, s), 10.99 (1H, s), 10.49 (1H, s), 9.20 (2H, d), 8.34 (2H, d), 7.89 (2H,d), 7.73 - 7.64 (1H, t), 7.61 - 7.56 .(4H, m), 7.37 - 7.33 (2H, t), 7.12 - 7.09 (1H, t), 5.73 (2H, s). Mass (m/z) : 411,412, 413,414 Example 22 l-(2-Ethoxy-2-oxoethvl)-3-(phenylsulfonvlhvdrazino carbonyl) pvridinium bromide (Compound 21): Yield: 75% m.p. : 145 - 147 °C. IRCKBrcm-1) : 1744, 1713, 1633 1HNMR (DMSOds, 400MHz) δ : 11.27(lH,s),10.36 (1H, s), 9.28(lH,s), 9.09(lH,d), 8.83(lH,d),8.27 - 8.24 (lH,m), 7.82 - 7.79 (2H,m), 7.58 (lH,t), 7.48 (2H,t), 5.59 (2H, s), 4.17 -4.12 (2H, q), 1.16(3H,t). Mass (m/z) : 364, 365, 366 Example 23 l-(2-(2,4-Dichlorophenyl)-2-oxoethvI)-3- (2(methoxy) ethyloxvcarbonyl) pyridinium bromide (Compound 22): Yield : 25% m.p.: 156-158°C. IR(KBr, cm"1): 1731, 1706, 1640 1HNMR (DMSO dg, 400 MHz) δ : 9.61 (1H, s), 9.20 (1H, d), 9.13 (1H, d), 8.45 - 8.41 (1H, m), 8.15 (1H, d), 7.92(1H, d), 7.78 - 7.76 (1H, m), 6.49 (2H, s), 4.56 - 4,54 (2H, m), 3.72 - 3.69 (2H, q), 3.31 (3H, s). Mass (m/z) : 368,369, 370, 371 Example 24 l-(2-PhenvIamino-2-oxoethvD-3-(2-(benzovloxyl) ethylaminocarbonvl) pyridinium chloride (Compound 23): Yield: 70% m.p. :171-172°C IR (KBr, cm'1): 1720, 1692, 1668 "HNMR : (DMSOd^ 400 MHz) δ : 11.06 (1HS s), 9.67 (1H, t), 9.59 (1H, s), 9.20 (lH,d), 9.11 (1H, d), 8.36 - 8.32(1 H, m), 8.00 (2H, d), 7.66 - 7.61 (3H, m), 7.51 (2H,1), 7.34 (2H, t), 7.10 (1H, t), 5.77 (2H,s), 4.45 (2H, t), 3.76 - 3.72 (2H,q). Mass (m/z): 404, 405, 406, 407 Example 25 l-(2-Thien-2-vI-2-oxoethvlV3-(phenvlaminocarbonylhvdrazinocarbonvl) pyridinium bromide (Compound 24): Yield : 30% m.p.: 202 - 204°C. ER. (KBr, cm'1): 1718, 1673 1HNMR : (DMSOds, 400 MHz) δ : 11.03 (IK s), 9.55 (1H, s), 9.18 (1H, d), 9.10 (1H, d), 9.00 (1H, s);8.57 (lH,s), 8.46 - 8.42 (1H, t), 8.25 - 8.22 (2H, m), 7.47 - 7.45 (2H, d), 7.43 - 7.41 (1H, t), 7.29 - 7.25 (2H, t), 7.0 - 6.96 (1H, t), 6.46 (2H, s). Mass (m/z): 381, 382, 383 Example 26 i-(2-Phenyl-2-oxoethyl)-3-(2-(acetoxv) ethylaminocarbonyl) pyridinium bromide (Compound 25): Yield: 55% m.p. : 186-188 IR(KBr, cm"1) : 1734, 1697, 1679 ]HNMR (DMSOdk, 400 MHz) δ : 9.47(lH,s), 9.36 (lH,t), 9.13-9.05 (2H, m), 8.42 - 8.38 (1H, m), 8.06 (2H, d), 7.80 (1H, t), 7.67 (2H, t), 6.54 (2H, s), 4.18 (2H,t), 3.61 - 3.57 (2H,q), 2.02 (3H,s). Mass (m/z): 327, 328,329. Example 27 l-(2-Phenviamino-2-oxoethyl)-3-(phenyl sulfonyl hydrazino carbonyl) pyridinium chloride (Compound 26): Yield: 38% m.p. :232-234°C. IR (KBr, cm"1): 1689,1636, 1596 1HNMR (DMSOds, 400 MHz) δ : 11.30 (1H, s), 10.80 (1H, s), 10.37 (1H, s), 9.29 (1H, s), 9.09 (1H, d), 8.81 (1H, d), 8.25 - 8.21 (1H, t), 7.82 - 7.80 (2H, d), 7.59 - 7.46 (5H, m), 7.28 - 7.24 (2H, t), 7.04 - 7.00 (1H, t), 5.62 (2H,s). Mass (m/z): 411, 412, 413, 414 Example 28 l-(2-PhenvIamino-2-oxoethvl)-3-((4-niethvlphenyl)suIfonyl hvdrazino carbonyl) pvridinium chloride (Compound 27): Yield : 48% m.p. : 205 - 206°C IR(KBr, cm"1): 1712, 1681, 1632 1HNMR (DMSOde, 400 MHz) δ : 11.35 (1H, s), 10.86 (1H, s), 10.36 (1H, s), 9.38 (1H, s), 9.17 (1H, d), 8.90 (lH,d), 8.34 - 8.30 (1H, in), 7.78 - (2H,d), 7.59 (2H, d), 7.37 - 7.33 (4H,m), 7.11 (lH,t), 5.70 (2H,s), 2.36 (3H, s). Mass (m/z): 425, 426, 427, 428 Example 29 l-(2-Phenyl-2-oxoethvU-3-(2-(benzoyloxy)ethyIoxy carbonyl) pyridinium bromide (Compound 28): Yield: 35% m.p.: 132-134°C. IR (KBr, cm"1): 1730, 1705, 1690 1HNMR (DMSO4, 400 MHz) δ : 9.80 (1H, s), 9.36 (1H, d), 9.30 (1H, d), 8.58 (1H, t), 8.21 (2H, d), 8.12 (2H, d), 7.95 (1H, t), 7.85 - 7.80 (3 H, m), 7.68 (2H, t), 6.71 (2H, s), 4.95 - 4.93 (2H, m), 4.82 - 4.80 (2H, m). Mass (m/z): 390, 391, 392. Example 30 t -f2-Thien-2'-vl-2-oxoethvI)-3-(Dhenylca rbonvl hyd razino carbonyl) pvridinium bromide (Compound 29): Yield: 45% m.p. : 80-81 °C IRCKBrCm1): 1700, 1663, 1631 !HNMR (DMSOdg, 400MHz) δ : 11.49 (1H, s), 10.95 (1H, s), 9.67 (1H, s), 9.34 (1H, d), 9.27 (1H, d), 8.52 ~ 8.48 (1H, m), 8.29 - 8.28 (2H, m), 8.00 (2H, d), 7.68 (1H, t), 7.59 (2H, t), 7.46 (1H, t), 6.63 (2H,s) Mass (m/z): 366,367, 368,369 Example 31 l-(2-Ethoxy-2-oxoethvl)-3-((phenylmethvl)sulfonvlhydrazino carbonyl) pyridinium bromide (Compound 30): Yield: 50% m.p. : 147-148°C ffi. (KBr, cm"1) : 1749, 1698, 1640 1HNMR (DMSOds, 400 MHz) δ : 11.57 (1H, s), 10.21 (lH,s), 9.75 (lH,s), 9.38 (1H, d), 9.24 (1H, d), 8.59 - 8.56(1H, m), 7.67 - 7.65 (2H, m), 7.58 - 7.52 (3H, m), 5.90 (2H, s), 4.68 (2H, s), 4.45 - 4.39 (2H, q), 1.43 (3H, t). Mass (m/z): 377, 378, 379 Example 32 l-(2-Phenyl-2-oxoethyl)-3-((phenyImethyl)sulfonylhvdrazino carbonyQpyridinium bromide (Compound 31): Yield : 80% m.p. : 205-207° C ffi. (KBr, Cm"1) : 1687,1637 IHNMR (DMSOds, 400 MHz) δ : 11.59 (lH,s), 10.20 (lH,s), 9.71 (lH,s), 9.33 (1H, d), 9.27 (1H, d), 8.62 - 8.59(1H, m), 8.25 - 8.23 (2H, d), 7.99 -7.95 (1H, t), 7.86 - 7.82 (2H, t), 7.67 - 7.65 (2H, m), 7.57 - 7.52 (3H, m),6.72 (2H, s), 4.69 (2H, s). Mass (m/z): 410,411, 412, 413 Example 33 N, N' - Bis r3-carbonyl-l-(2-furan-2'-vI-2-oxoethvn pyridinium lhvdrazine dibromide. (Compound No: 32) Yield :23% Yield 15% m.p. 217 219 °C(dec) IR (KBr, cm"1) :3190, 1708, 1667 and 1404 1H NMR (DMSO d6, 400 MHz) 8: 11.07 (lH.s), 10.22 (lH,s), 9.51 (IH.s), 9.16 - 9.15 (IH.d), 9.06 - 9.04 (IH.d), X 42 - 8.40 (lH,m). 8.25 - 8.21 (2H,m), 7.43 - 7.40 (lH.m), 6 44 (7ll,s), 2.25 -2.22 (2H.t), 1.72- 1,60 (5H,m), 1.49- 1.43(2H,q). 1.24 - 1 10 (IHjn), 0.9-0 85 (211.ml Mass (in /) 40-J. 101,402 and 403 Example 36 l-(2-Phenvlamino-2-oxo cthvl)-3-( \|2-(l-oxo-3-cvclohexyl)-nroi)vli -hvdni/ino- carbonvll-pvridinium bromide.K ortuMiund No: 35): Yield : 25% m.p : 234-236 °C (dec) IR (KBr, cm!) : 1689, 1652 and 1625 '11 NMR (DMSO 4,400 MHz) δ: 11.11 (lH,s), 10.95 (IH,s), 10.23 (lH,s), 9.56 (IH.s), 9.23 - 9.21 (IH.d), 9.06 - 9.04 (IH,d), 8.38-8.35 (IH,m). 7.62 - 7.60 (2H,d), 7.37 - 7.33 (2H,t), 7.12 - 7.C9 (lH,t), 5.75 (2H,s), 2.25 - 2.22 (2H,t), 1.72 - I.60(5H,n) 1.49- 1.43 (2H,m), 1.25- 1.10 (4H,m), 0.91 - 0.83 (2H,m) Mass(m//) :409, 410, 411 and 412 Example 37 l-(2-Thien-2'-vI-2-oxoethyl)-3-[2-(benzovloxy)ethvlaminocarbonyl1- pyridinium bromide (Compound No:36); Yield : 40% m.p. : 125-127°C IR(KBr, cm-1) :1710 and 1675 1H NMR (DMSO6, 400 MHz) δ: 9.48 (1 H,s), 9.43 - 9.41 (1 H,t), 9.12 - 9.11 (lH,d), 9.05 - 9.02 (lH,d), 8.40 - 8.36 (1 H,m), 8.25 - 8.20 (2H,m), 8.00 - 7.98 (2H,m), 7.68 - 7.64 (lH,m), 7.54-750 (2H,m), 7.42 - 7.40 (lH,m), 6.43 (2H,s), 4.46-4.43 (2H,t), 3.77-3.73 (2H,q) Mass (m/z) :395, 396, 397 and 398 Example 38 l-(4-Ethoxv-2, 4-dioxobutyl)-3-(2-(benzoxvloxv)ethvIamino carbonvl)- pyridinium chloride. (Compound No: 37); Yield : 35% m.p. : 147-149°C IR (KBr, cm4) :1743, 1720, 1680 and 1627 1H NMR (DMSOd6, 400 MHz) δ: 9.62 - 9.59 (lH,t), 9.32 - 9.29 (lH,s), 9.05 - 9.03 (lH,d), 8.93 - 8.90 (lH,d), 8.27 - 8.24 (lH,m), 7.92 - 7.89 (2H,d), 7.59 - 7.55 (lH,m), 7.45 - 7.41 (2H,m), 5.82 (2H,s), 4.37-4.34 (2H,t), 4.08-4.03 (2H,q), 3.80 (2H,s), 3.67-3.63 (2H,q), 1.15-1.11 (3H,t), Mass (m/z) :399, 400 and 401 Example 39 l-(2'4'-DichIoro-phenyl-2-oxoethyl)-3-(2-methoxyethyl aminocarbonyl)- pyridinium bromide. (Compound No: 38); Yield : 70% m.p. : 93-95 °C BR. (KBr, cm"1) :1704, 1664 and 1636 1H NMR (DMSO d6, 400 MHz) δ: 9.48 (lH,s), 9.29 (lH,bs), 9.11 - 9.08 (2H,m), 8.41 - 8.38 (lH,m), 8.15 - 8.13 (lH,d), 7.92 - 7.91 (lH,t), 7.78 - 7.75 (lH,m), 6.44 (2Hs,) 3.52 (2H,bs), 3.51 (2H,bs); 3.28 (3H,s) Mass (m/z) :367,368,369 and 370 Example 40 N,N'-Bis-[3-carbonyl-l-(2-cvclopropylamino-2-oxoethvl) pyridiniuml hydrazine dichloride. (Compound No: 39); Yield : 40% m.p. : 228-230 °C IR (KBr cm"1) :1675,1636 and 1298 1H NMR (DMSO 4, 400 MHz) S: 11.85 (2H,s), 9.59 (2H,s), 9.25 - 9.19 (4H,m), . 9.00 - 8.99 (2H,d), 8.39 - 8.36 (2H,m), 5.53 (4H,s), 2.73 - 2.66 (2H,m), 0.78 - 0.62 (4H,m), 0.53 - 0.49 (4H,m) Mass (m/z) 437,438 and 439 Example 41 l-(2-CvcIopropvlamino-2-oxoethyl)-3-(2-methoxvethvIaminocarbonyl)- pyridinium chloride. (Compound No: 40); Yield : 10% m.p. : 122-124 °C IR(KBr, cm-1) :1661, 1633, 1549 and 1121 1H NMR (DMSO d6, 400 MHz) δ: 9.40 (lH,s), 9.08 - 9.02 (2H,m), 8.28 - 8.25 (lH,m), 5.53 (2H,s), 3.66 - 3.61 (4H,m), 3.39 (3H,s), 2.78 - 2.74 (lH,m), 0.80 - 0.75 (2H,m), 0.64 - 0.61 (2H,m) Mass (m/z) :278, 279 and 280 Example 42 N-N'-Bis [3-carbonyl-l-(2-isopropvlamino-2-oxoethvl) pvridiniuml hydrazine dichloride. (Compound No: 41): Yield : 35% m.p. : 114-116 °C (dec) IR (KBr, cm-1) :1707, 1668 and 1637 1H NMR (OMSO d6: 400 MHz) δ: 11.84 (2H,s), 9.59 (2II,s), 9.21-9.18 (4H,m), 8.74-8.72 (2H,d), 8.39 - 8.35 (2H,m), 5.53 (4H,s), 3.92 - 3.84 (2H,m), 1.14-1.02 (12H,d) Mass(m/z) : 441, 442 and 443 Example 43 l-(2-Thien-2 yl-2-oxoethyl-3-(2-(2-chloro-3-pyridovlhydrazinocarbonyl)- pyridinium chloride. (Compound No: 42); Yield : 56% m.p. : 233-235 °C IR (KBr, cm -1) : 1680, 1637, 1404 and 1293 1H NMR (DMSO d6, 400 MHz) δ: 11.62 (lH,s), 11.05 (lH,s), 9.62 (lH,s), 9.24 - 9.23 (1 H,d), 9.18-9.16(1 H,d), 8.58 - 8.56 (1 H,m), 8.46 - 8.43 (1 H,m), 8.26 - 8.24 (2H,m), 8.02 - 8.00 (lH.tn), 7.61-7.58 (lH,m), 7.43 - 7.41 (lH,m), 6.51 (2H,s) Mass (m/z) :401, 402, 403, 404 and 405 Example 44 l-(2-Isopropvlamino-2-oxoetbyI)-3-(2-methylsulfonylhydrazinocarbonyl)- pyridinium chloride. (Compound No: 43); Yield : 10% m.p. : 227 - 229 °C IR(KBr, cm-1) :1691, 1670, 1566 and 1330 1HNMR (DMSO d6, 400 MHz) δ: 11.55 (lH,s), 9.94 (lH,s), 9.52 (lH,s), 9.16 - 9.14 (lH,m), 9.09 - 9.07 (lH,m), 8.72 - 8.70 (lH,m), 8.34 - 8.30 (lH,m)> 5.50 (2H,s), 3.89 - 3.84 (lH,m), 3.11 (3H.s), 1.13 - 1.12 (6H,d) Mass(m/z) :315,316 and 317 Example 45 l-(2-(l-Pyrrolidinvl)-2-oxoethvl)-3-(methanesulfonvI hydrazino carbonyl) pyridinium chloride (Compound No; 44); Yield :21.00% m.p. :205-207°C IR (KBr, cm-1) : 1699, 1646 and 1589 1HNMR :(DMSO d6, 400 MHz) 5 : 11.50 (1H, s), 9.94 (1H, s), 9.46 (1H, s), 9.11 - 9.06 (2H, m), 8.36 - 8.33 (1H, t), 5.75 (2H, s), 3.55 - 3.48 (3H, m), 3.10 (3H, s), 2.00 - 1.95 (2H, m), 1.87-1.81 (2H, m) Mass (m/z) :327, 328, 329 and 330 Example 46 l-(2-Thien-2'-vl-2-oxoethvI)-3-(methanesulfonyl hvdrazino carbonvl) pyridinium chloride (Compound No: 45); Yield :31.00% m.p. :215-217°C ' 1R (KBr, cm-1) :1685, 1666 and 1635 1HNMR :(DMSO d, 400 MHZ) 8: 11.49, (1H, s), 9.96 (1H, s), 9.55 (1H, s), 9.18 (1H, d), 9.10 (1H, d), 8.43 - 8.39 (1H, t), 8.25 - 8.22 (2H, m), 7.42 (1H, t) 6.47 (2H, s), 3.09 (3H, s). Mass (m/z) :340, 341, 342 and 343 Example 47 N,N'-Bis[3-carboDvl-l-(2-hvdroxv-2-oxoethynpyridinium1hydrazine dichloride (Compound No: 46); Yield : 43.00% m.p. :235 - 240°C (d) IR (KBr, cm"1) : 1743, 1700 and 1672 1HNMR (DMSO d, 400 MHz) δ: 11.89 (2H, s), 9.69 (2H, s), 9.31 - 9.29 (2 H, d), 9.25 - 9.23 (2H, d), 8.43 - 8.39 (2H, t) 5.70 (4H, s) Mass(m/z) :360,361,362 Example 48 l-(2-Thien-2'-vl-2-oxoethyI)-3-((2-methoxy ethyl) amino carbonvD-S-bromo pyridinium chloride (Compound No: 47); Yield :31.00% m.p. :180-182°C IR (KBr, cm"1) : 1661 and 1620 1HNMR (DMSO dg, 400 MH2) δ : 9.58 - 9.54 (2H, d), 9.43 - 9.39 (2H, d), 8.25 - 8.21 (2H, m), 7.41 (1H, t), 6.43 (2H, s), 3.51 (4H, m), 3.29 (3H, s). Mass(m/z) : 384, 385, 386, 387 and 388 Example 49 l-(2-Thien-2'-vl-2-oxoethyl)-3-fl-oxo-l-(2-methoxvcarbonvl)pyridvn hydrazino pyridinium chloride (Compound No: 48); Yield :30.00% m.p. :222 - 225°C IR (KBr, cm"1) : 1726, 1708 and 1662 1HNMRCDMSOd^OOMH^S: 11.47 (lH,s), 11.23 (1H, s), 9.58 (1H, s), 9.22 - 9.15 (3H, m), 8.56 - 8.53 (1H, d), 8.46 - 8.43 (1H, t) 8.25 - 8.21 (3H, m), 7.42 (1H, t), 6.49 (2H, s), 3.95 (3H, s) Mass (m/z) :425, 426 and 427 Pharmaceutical compositions may be prepared with a pharmaceutically effective quantity of compounds of general formula 1, individually or in combination. The following pharmaceutical formulations suggested are by way of example alone and in no way restrict the forms in which they can be used. Oral formulations may be administered as solid dosage forms for example pellets, powders, sachets or discreet units such as tablets or capsules and like. Other orally administered pharmaceutical preparations include monophasic and biphasic liquid dosage forms either in ready to use form or forms suitable for reconstirution such as mixtures, s)Tups, suspensions or emulsions. The preparations in addition may contain diluents, dispersing agents, buffers, stabilizers, solubilizers, surfactants, preservatives, chelating agents and/ or other pharmaceutical additives as are used. Aqueous or non aqueous vehicle or their combination may be used and if desired may contain suitable sweetener, flavoring agent or similar substances. In case of suspension or emulsion a suitable thickening agent or suspending agent or emulsifying agent may be present in addition. Alternatively, the compounds may be administered as such in their pure form unassociated with other additives for example as capsules or sachets. It may also be administered with a vehicle. Pharmaceutical preparations can have a slow, delayed or controlled release of active ingredients as is provided by a matrix or diffusion controlled system. When the present invention or its salts or suitable complexes is presented as a discreet unit dosage form like tablet, it may contain in addition medically inert excipients as are used in the art. Diluents such as starch, lactose, dicalcfum phosphate, talc, magnesium stearate, polymeric substances like methyl cellulose, fatty acids and derivatives, sodium starch glycollate, etc. may also be used. Example 50 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 pyrolidone (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 may be present in a sterile vehicle which may be an aqueous or non aqueous vehicle or a combination thereof. The examples of vehicles are water, ethyl oleate, oils and derivatives of polyols, glycols and their derivatives. It may contain additives common in injectable preparations like stabilizers, solubilizers, pH modifiers, buffers, antioxidants, cosolvents, complexing agents, tonicity modifiers, etc. Some suitable additives are for example tartrate, citrate or similar buffers, alcohol, sodium chloride, dextrose and high molecular weight polymers. Another alternative is sterile powder reconstirution. The compound may be administered in the form of injection for more than once daily administration, or intravenous infusion/ drip or suitable depot preparation. Example 51 Preparation suitable for parenteral administration has the following composition: Active ingredient of formula I as given above Polyethylene glycol (400) 0.75 ml Sodium metabisulphite 0.01 % Isotonic saline/ WFI q.s. For the derraatological application and for the discoloration of teeth, the recommended formulations are lotions, oral rinse and. toothpaste containing appropriate amount of the compounds of the general formula I. The above examples are presented by way of illustration alone and in no way limit the scope of the invention. t. WE CLAIM : 1. A compound selected from the group consisting of the following compounds (a) l -(2-phcnylammo-2-oxoethyl)- 1-(phenylsulfonyI hydrazino carbonyl) pyridinium chloride and pharmaceutically acceptable salts thereof, (b) l-(2-(2,4-dichlorophcnyl)-2-oxocthyl)-3- (2(mcthoxy) ethyloxycarbonyl) pyridirdium bromide and pharmaceutically acceptable salts thereof, (c) l-(2-phenylamino-2-oxoethyl)-3-((benzoyloxy) ethylaminocubonyl) pyridinium chloride and pharmaceutically acceptable salts thereof, (J) l-(2-:!:icn-2'-yl-2-cxoetliyl)-3-(phcnyhniinocarbonyI hydrazinocarbonyl) pyndmiun bromide and phannaceuUcally acceptable sails thereof, (L») l-(2-phenyl-2-oxocthyl}-3-(2-(accto\'y) cthylaminocarbonyl) nyridiniuin bromide and phanr.accutically acceptable salts thereof, (S) l-(2-pliccyIanuuo-2-oxocthyl>3-(phcr.yl sulfonyl hydrazino carbonyl) pyridiniu.71 chloride and plwrmaccuticaUy acceptable salts thereof, (3) l-(2-plicnylauiiiiu-2-oxoc,Jiyl)-3-{(4-iiictliylphcnyl)suJfoiiyl hydrazino carbonyl) pyridinium chloride and pharmacculicaJIy acceptable salts thereof, (h) l-(2-phenyl-2-oxocthyl)-3-(2-(bcnzoyloxy)cthyloxy carbonyl) pyridinium bromide and pharmaceutically acceptable salts thereof, (1) l-(2-thien-2,-yl-2-oxoethyl)-3-(phcnylcarbonyl hydrazino carbonyl) pyndinium bromide and pharmaceutically acceptable salts thereof, (j) l-(2-c:hoxy-2-cxocthyl)-3-((pharmaceutically)suIfonyl liydra/ino carbonyl) pyridinium bromide and pharmaceutically acceptable sails thereof, (lyl-(.2-phenyl-2-(exocthyl)-3-((phenylmcthyl)sulfonyl hydrazino carbony)) pyridiomm bromide and pharmaceutically acceptable salts thereof. (c ) N, N' - bis [3-carbonyl-l-(2-furan-2'-yl-2-oxoethyl) pyridinium ]hydrazine dibromide, (m) N,N'- bis [3-carbonyl -1- (2-thien-2'-yl-2-oxoethyI) pyridinium] hydrazine dichloride. (n ) N,N'-bis-[3-carbonyl-l-(2-cyc]opropylaraino-2-oxoethyl)pyridininum] hydrazine dichloride, ( o ) l-(2',4'-dichioro-phenyl-2-oxoethyl)-3-(2-methoxyethyl aminocarbonyl)- pyridinium bromide, ( P ) l-(2-thien-2'-yl-2-oxoethyl)-3-((2-methoxy ethyl) amino carbonyl)-5-bromo pyridinium chloride, (q,) 1 -(2-thien-2'-yl-2-oxoethyI)-3-(methanesulfonyl hydrazino carbonyl) pyridinium chloride, ( r) l-(2-thien-2yl-2-oxoethyl)-3-)2-(2-chloro-3-pyridoymydrazinocarbonyl)- pyridinium chloride, (' s ) 1 -(2-cyclopropylammo-2-oxoethyl)-3-(2-memoxyemyIaminocarbonyl)- pyridinium chloride, (t) l-(2-isopropyIarnino-2-oxoethyl)-3-(2-mediylsulfonymydtazinocarbonyl)- pyridinium chloride, (u) l-(2-phen)lamino-2-oxo ethyl)-3-({2-(l-oxo-3-cyclohexyl)-propyl} - hydrazino-carbonyl} -pyridinium bromide, ( Y). l-(2-uhien-2'-yl-2-oxoemyl)-3-[2-(benzoyIoxy)emylamino carbonyl]- pyridinium bromide, (w) l-(4-ethoxy-2,4-dioxobu(yl)-3-(2-(benzoxyloxy)ethylamino carbonyl)- pyridinium chloride and (x ) l-(2-tluen-2,-yl-2-oxoethyl)-3-[l-oxo-l-(2-methoxy carboiryl)pyridyl] hydrazino pyridiniuin chloride. 2. A process for the preparation of the compound as claimed in claim 1, which comprises preparing a substituted pyridine, according to the desired end product followed by quaternizing of the substituted pyridine, with an appropriate reagent by refluxing in an alcoholic and/or high boiling solvent for 6-48 hrs. to give the desired compound. 3. A pharmaceutical composition for treatment of diabetic complications and aging related diseases which comprises a pharmaceutically effective amount of one or more compounds, as defined in claim 1, or pharmaceutically acceptable salt(s) thereof in admixture with a pharmaceutically acceptable carrier, diluent, solvent or excepient. 4. The pharmaceutical composition as claimed in-claim 3, in the form of an oral formulation. 5. The pharmaceutical composition as claimed in claim 4, wherein said pharmaceutically acceptable carrier is selected from group consisting of starch, lactose, polyvinyl pyrolidone (K-30), talc and magnesium stearate. 6. The pharmaceutical composition as claimed in claim 3, in the form of a parenteral formulation. 7. A method for fee preparation of a parenteral formulation as claimed in claim 6, which comprises dissolving one or more compounds represented by general formula (I), as defined in claim 1, in polyethylene glycol 400 and diluting the solution so obtained, with an isotonic solution or water to a desired concentration. 8.Pharmaceutical composition as claimed in claim 5., in the form of a lotion, oral rinse and toothpaste. The invention discloses novel compounds of the pyridinium series useful for the management of diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth, by breaking preformed AGE, of the general formula I, or pharmaceutically acceptable salts thereof,

Full Text

The present invention relates to a new class of compounds of pyridiuium
series and to their use in treatment of diabetes and related illnesses. More
particularly the invention relates to compounds of this series, methods for their
preparation, pharmaceutical composition containing these compounds and their use
in the treatment of complications of diabetes mellitus. The compounds of this series
exhibit AGE breaking activity, which is essential for the treatment of diabetic and
aging-related complications including kidney disease, nerve damage,
atherosclerosis, retinopathy and dermatological conditions. The invention also
extends to the method of reversing the discoloration of teeth resulting from
nonenzymatic browning in the oral cavity which comprises administration of an
amount effective to reverse pre-formed advanced glycosylation crosslinks.
Maillard in 1912 found that reducing sugars, such as glucose and ribose react
with proteins to form brown pigments. Further studies have shown that this is an
irreversible non-enzymatic reaction, which occurs in several natural systems
including stored foodstuff. Maillard reaction occurs in two stages, early and
advanced. Initially, proteins react with glucose to form stable Amadori products,
which subsequently cross-links to form advanced glycation end products (AGE), In
most cases, the formation of AGE also accompanies browning of the proteins and
increase in the fluorescence.

In diabetes, where blood glucose level is significantly higher than normal, the
reaction of glucose with several proteins such as haemoglobin, lens crystallin and
collagen, gives rise to the formation of AGE, which in turn, is responsible for the
complications associated with diabetes, such as nephropathy, microangiopathy,
endothelial dysfunction and other organ dysfunctions. In addition, the activity of
several growth factors, such as basic fibroblast growth factor, is also impaired.
AGE products, unlike normal proteins in tissue, have a slower rate of turnover and
replenishment. It has been reported that AGE products may in fact elicit a complex.
immunological reaction involving RAGE (Receptor for Advanced Glycation End
Products) receptors and activation of several incompletely defined immunological
processes. It has been documented that diabetes with evidence of microangiopathy
and macroangiopathy also show evidence of oxidative stress, the mechanism of
which has not been elucidated.
In vitro AGE formation can be studied in the laboratory by incubating
reducing sugars, such as ribose or glucose with bovine serum albumin. AGE
formation can be detected by increase in the fluorescence or increased cross
reactivity with anti-AGE antibodies. The increase in fluorescence seems to precede
formation of AGE specific antigenic epitopes. This increase in fluorescence is used
to monitor the increased AGE formation in vitro (Brownlee M et al, Science 1986;
232:1629-1632). In addition to the increase in the fluorescence, one of the most

important features of in vitro AGE formation is the formation of antigenic epitopes
that are specific to AGE and not to the native proteins. Therefore, it is possible to
raise antibodies against advanced glycation end products of one protein and use
them to detect AGE formation in other proteins. This has served as an important
analytical tool in AGE research.
Due to the clinical significance of AGE formation, many approaches are
being used to diagnose, prevent, or revert AGE formation in the body. The
formation of AGE could be inhibited by reacting with an early glycosylation
product that results from the original reaction between the target protein and
glucose. The inhibition was believed to take place as the reaction between the
inhibitor and the early glycosylation product appeared to interrupt the subsequent
reaction of the glycosylated protein with additional protein material to form the
cross linked late stage product. Compounds like aminoguanidine act to inhibit AGE
formation by such mechanism.
The formation of AGE on long-lived proteins is also associated with cross-
linking of these proteins. The AGE derived protein cross-links have been shown to
be cleaved by compounds like N- phenacyl thiazolium bromide (PTB), which reacts
with and cleaves covalent, AGE derived protein cross links (Vasan et al. Nature
1996; 382: 275-278 ; US 5,853,703, Date of Patent : Dec. 29, 1998). The
mechanism of reducing the AGE content in tissues is expected to take place

relatively rapidly, in contrast to aminoguanidine, which acts slowly by its very
nature of mechanism of action. This current specification is related to compounds
of pyridinium class, which break pre-formed AGE, like PTB, and in some cases
even more effectively by than PTB.
The main objective of the present invention is to provide a new class of
compounds of the pyridinium series which are useful for the management of
diabetes and aging related vascular complications and particularly in the treatment
of complications of diabetes mellitus and other aging related conditions including
kidney disease, nerve damage, atherosclerosis, retinopathy and dermatological
conditions. The invention also extends the method to reverse the discoloration of
teeth resulting from nonenzymatic browning in the oral cavity which comprises
administration of an amount effective to reverse the pre-formed advanced
glycosylation crosslinks, etc.
Another object of the present invention is to provide compounds of the
pyridinium series, which exhibit AGE breaking activities.
Yet another object of the present invention is to provide a method of
preparation of compounds of the pyridinium series which exhibit AGE breaking
activities.

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
suitable carriers, solvents, excepients, diluents and other media normally employed
in preparing such compositions.
Still another object of the invention is to provide a method of treatment of a
diabetic patient by administration of the compounds of the invention, either singly
or in combination with drugs for anti-diabetic therapy, or pharmaceutically
acceptable salts thereof in required dosage in admixture with pharmaceutically
acceptable diluent, solvent, excepients, carriers or other media as may be
appropriate for the purpose.
The present invention provides for a new class of AGE breakers, of general formula
I,
6

wherein
R1 is -R4-R5 or -N(R7) N (R7) R9;
R4 is selected from the group consisting of -N(R7)R6O, -N(R7)R6N(R7)-, OR6O,
and -OR6N(R7)-,
where R6 is alkyl;
R5 15 selected from the group consisting of alkyl, alyl including heteroaryl,
-COR7, SO2R7, -C(S) NHR7, -C(NH)NHR7, -COR10,

where R7 is selected from the group consisting of H, alkyl and aryl including
heteroaryl provided R7 might be different for R1 and R3 in the same compound;
R2 is selected from the group consisting of F, Cl, Br, I, OR7, NO2, alkyl, aryl
including heteroaryl, formyl, acyl, C(O)NR7R10, C(O)OR7, NR7RI0, N=C(R7)(R10),
SR7, SO2NH2) SO2 alkyl and SO2aryl,
and m is 0, 1 or 2;
R3 is selected from the group consisting of R7, OR7, N(R7) (R10), N=C(R7) (R10),
N(R7) N(R7) (R10), N(R7) N=C(R7) (R10) and CH(R7)C(0)R8

where R8 is selected from the group consisting of R7, OR7 and NR7R10;
R9 is selected from the group consisting of hydrogen, alkyl, aryl including
heteroaryl, C(O)R10, -SO2R10, -C(S)NHR,0, -C(NH) NH (R10) and -C(O) NHR,0,
R10 is selected for the group consisting of H, alkyl or aryl including heteroaryl and
in each case optionally different from substituent R10, provided R10 might be
different for R1 and R3 in the same compound;
X is selected from group consisting of a halide ion, acetate ion, perchlorate ion,
sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion,
carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate
ion, BF4" and PF6;
with proviso that,
(i) when two alkyl groups are present on the same carbon or nitrogen, they are
optionally linked together to form a cyclic structure and
(ii) the nitrogen of heteroaryl ring of R10, when present, is optionally quaternized
with compound such as X-CH2C(O)-R;,
As used herein, "alkyl" refers to an optionally substituted hydrocarbon group
joined by single carbon-carbon bonds and having 1 to 8 carbon atoms joined
together. The alkyl hydrocarbon group may be linear, branched or cyclic, saturated
or unsaturated. The substituents are selected from F, Cl, Br, 1, N, S, O and aryl.
Preferably, no more than three substituents are present.

As used herein "aryl" refers to an optionally substituted aromatic group with
atleast one ring having a conjugated pi- electron system, containing upto two
conjugated or fused ring systems. Aryl includes carbocyclic aryl, heterocyclic aryl
and biaryl groups, all of which may be optionally substituted. The substituents are
selected from F, Cl, Br, I, N, S, O and straight chain or branched C1-C6
hydrocarbon.
The novel compounds of the invention of general formula I having m as 0
and - COR1 at position 3 are listed in Table 1A and the novel compounds of the
invention of general formula 1 having m as 0 and - COR1 at position 4 are listed in
Table IB. The following compounds suggested are by way of example alone of the
representative compounds of the general formula I as defined above and in no way
restrict the invention:
N,N'-Bis[3 -carbonyl-1 -(2-phenyl-2 -oxoethyl)-pyridiniurn] hydrazine dibromide
(compound 1);
N,N'-Bis[3-carbonyl-l-(2-ethoxy -2- oxoethyl)pyridinium]hydrazine dibromide
(compound 2);
N,N'-Bis[3 -carbonyl-1 -(2-(2,4-dichloropheny l)-2-oxoethyl)p\ridinium]hydrazine
dibromide (compound 3);

1- (2- Ethoxy -2- oxoethyl) -3- (2- (2- p>Tidyl) hydrazinocarbonyl) pyridinium
bromide (compound 4);
1- (2- Thien -2'- yl -2- oxoethyl) -3- (methanesulfonyl hydrazinocarbonyl)
pyridinium bromide (compound 5);
N,N'-Bis[3-carbonyl-l- (2- thien -2'- yl -2- oxoethyl)pyridinium]hydrazine
dibromide (compound 6);
1- (2- Ethoxy -2- oxoethyl) -3- (2- (benzoyjoxy) ethylarninocarbonyl) pyridinium
bromide (compound 7);
1- (2.- (2,4- Dichlorophenyl) -2- oxoethyl) -3- (2-(behzoyloxy)ethylamiiio-carbonyi)
pyridinium bromide (compound 8);
'1- (2- Thien -2'- yl -2- oxoethyl) -3- (2- (2- pyridyl) hydrazinocarbony]) pyridinium
bromide (compound 9);
1- (2- Phenyl -2- oxoethyl) -3- (2- (2- pyridyl)hydrazinocarbonyl) pyridinium
bromide (compound 10);
l-(2-Phenyl-2-oxoethyl)-3-(hydrazinocarbon}l)pyridinium bromide (compound 11);
l-(2- Phenyl -2- oxoethyl) -3- (methanesulfonyl hydrazinocarbonyl) pyridinium
bromide (compound 12);
1- (2- Ethoxy -2- oxoethyl) -3- (methanesulfonyl hydrazinocarbonyl) pyridinium
bromide (compound 13);

l-(2-Phenyl-2-oxoethyl) -3- (phenylsulfonylhydrazino carbonyl) pyridinium
bromide (compound 14);
l-(2-Phenyl-2-oxoethyl) -2-chloro-3- (phenylsulfonylhydraziiio carbonyl)
pyridinium bromide (compound 15);
l-(2- Phenyl -2- oxoethyl) -3- (2- (acetoxy)ethyloxy carbonyl) pyridinium bromide
(compound 16);
l-(2-Ethoxy -2- oxoethyl) -3- (2- (benzoyloxv) ethyloxy carbonyl) pyridmiuin
bromide (compound 17);
l-(2- Thien -2'- yl -2- oxoethyl)-4-(2-(benzoyloxy)ethylaminocarbonyl) pyridinium
bromide (compound 18);
l-(2-Ethoxy -2- oxoethyl) -4-(phenylsulfonyl hydrazino carbonyl)
pyridinium bromide (compound 19);
l-(2-Phenylamino-2-oxoethyl)-4- (phenylsulfonyl hydrazino carbonyl) pyridinium
chloride (compound 20);
' l-(2-Ethoxy -2- oxoethyl) -3-(phenylsulfonyl hydrazino carbonyl)
pyridinium bromide (compound 21);
l-(2-(2,4-Dichlorophenyl)-2-oxoethyl)-3-(2(methoxy)ethyloxycarbonyl) pyridinium
bromide (Compound 22);
l-(2-Phenylamino-2-oxoethyl)-3-((benzoyloxy)ethylaminocarbonyl)
pyridinium chloride (compound 23);

l-(2-Thien-2'-yl-2-oxoethyl)-3-(phenylaminocarbonyl hydrazinocarbonyl)
pyridinium bromide (compound 24);
l-(2-Phenyl-2-oxoethyl)-3-(2-(acetoxy)ethylaminocarbonyl)
pyridinium bromide (compound 25);
1 -(2-Phenylamino-2-oxoethyl)-3-(phenyl sulfonyl hydrazino carbonyl)
pyridinium chloride (compound 26);
1 -(2-Phenylamino-2-oxoethyl)-3-((4-methylphenyl) sulfonyl hydrazino carbonyl)
pyridinium chloride (compound 27);
l-(2-Phenyl-2-oxoethyl)-3-(2-(benzoyloxy)ethyloxy carbonyl)
pyridinium bromide (compound 28);
l-(2-Thien-2'-yl-oxoethyl)-3-(phenylcarbonyl hydrazino carbonyl)
pyridinium bromide (compound 29);
1 -(2-Ethoxy-2-oxoethyl)-3-((phenylmethyl)sulfonyl hydrazino carbonyl)
pyridinium bromide (compound 30);
1 -(2-Phenyl-2-oxoethyl)-3-((phenylmethyl)sulfonyl hydrazino carbonyl)
pyridinium bromide (compound 31);
N, N' - Bis [3-carbonyl-l-(2-furan-2'-yl-2-oxoethyl) pyridinium ]hydrazme
dibromide. (Compound No: 32);
N,N'-Bis [3-carbonyl-1- (2-thien-2'-yl-2-oxoethyl) pyridinium] hydrazine
dichloride.(Compound No: 33);
l-(2-Thien-2'-yl-2-oxoethyl)-3-((2-(l-oxo-3-cyclohexyl)-propyl)-hydrazino
carbonyl)-pyridinium bromide.( Compound No: 34);

l-(2-Phenylamino-2-oxo ethyI)-3-({2-(l-oxo-3-cyclohexyl)-propyl} -hydrazino-
carbonyl}-pyridiniura bromide.(Compound No: 35);
l-(2-Thien-2'-yl-2-oxoethyl)-3-[2-(benzoyloxyethylamino carbonyl]-pyridiniuim
romide (Compound No: 36);
l-(4-Ethoxy-2, 4-dioxobutyl)-3-(2-(benzoxyloxy)ethylamino carbonyl)-pyridinium
chloride. (Compound No: 37);
l-(2',4'-Dichloro-phenyl-2-oxoethyI)-3-(2-methoxyethylaminocarbonyl)-pyridinium
bromide. (Compound No: 38);
N,N'-Bis-[3-carbonyl-1 -(2-cycIopropylamino-2-oxoethyl) pyridinium] hydrazine
dichloride. (Compound No: 39);
l-(2-Cyclopropyamino-2-oxoethyl)-3-(2-methoxyethylaminocarbonyl)-pridinuam
chloride. (Compound No: 40);
N-N'-Bis [3-carbonyl-l-(2-isopropylamino-2-oxoethyl) pyridinium] hydrazine
dichloride. (Compound No: 41);
1 -(2-Thien-2'yl-2-oxoethyl)-3-(2-(2-chloro-3 -pyridoylhydrazinocarbonyl )-
pyridinium chloride. (Compound No: 42);
l-(2-Isopropylamino-2-oxoethyl)-3-(2-methylsulfonylhydrazinocarbonyl)-
pyridinium chloride. (Compound No: 43);
l-(2-(l-Pyrrolidinyl)-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl)
pyridinium chloride.(Compound No: 44);
l-(2-Thien-2'-yl-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl) pyridinium
chloride. (Compound No: 45);
N,N-Bis[3-carbonyl- l-(2-hydroxy-2-oxoethyl)pyridinium]hydrazine dichloride
(Compound No: 46);
l-(2-Thien-2'-yl-2-oxoethyl)-3-((2-methoxy ethyl) amino carbonyl)-5-bromo
pyridinium chloride (Compound No: 47);

The invention also provides a process for the preparation of novel
compounds of the pyridinium series.
The said process for the preparation of compound 1, comprises, adding a
solution of phenacyl bromide in isopropanol to N,N'-bis-(nicotinyl)hydrazine
dissolved in methanol, refluxing for six hours, cooling, filtering the precipitated
solid, washing the solid with hot ethyl acetate and finally purifying the solid with 20
ml of methanol : ethyl acetate (3 : 1) to yield the desired compound.
Similarly, the other novel compounds of general formula I, are prepared from
properly substituted pyridine derivatives followed by quarteraization with
appropriate reagent by refluxing in alcoholic solvents like, methanol, ethanol,
propanol, etc and high boiling solvents like toluene or xylene etc, for 6-48 hrs. to
give the desired compounds.
The in vitro AGE formation, studied in the laboratory, by incubating
reducing sugar glucose, with protein bovine serum albumin, resulted in browning of
solution and increase in the fluorescence. Fluorescence was used as the criteria to
monitor the increased AGE formation.
Example 1
AGE breaker activity has been confirmed by the screening procedure as
mentioned below:
Materials:

Bovine serum albumin (fraction V) (BSA)
Glucose, analytical grade
Phosphate buffered saline (PBS)
Equipment:
Microplate ELISA Reader - Spectramax Plus (Molecular Devices, USA)
Microplate washer, (Bio -Tec Instruments, USA)
pH meter
Methods of experiment: Elisa (Enzyme Linked Immunosorbent Assay)
160 mg/ml of protein, bovine serum albumin, BSA and 1.6M glucose sugar
were dissolved in phosphate buffered saline, PBS. Sodium azide was added at
0.02% concentration as a preservative. The solution was filtered asceptically
through a 0.22 uM filter and kept for aging at 37°C for 16 weeks. After 16 weeks
the solution was dialyzed against PBS, aliquoted and stored at - 20°C.
To determine the AGE breaking activity, 10µg/ml of the 16 weeks AGE-
BSA was incubated with different concentrations of the test compounds at 37°C for
24 hours and AGE breaking activity of the test compounds by ELISA was
determined.
ELISA was performed as follows:
1. Different concentrations of 16 weeks AGE-BSA were coated on a microtitre
plate as standard. Each concentration is coated in triplicates.

2. The test samples were coated on microtitre plate at a concentration of 5 ng. to 20
ng per well in triplicates.
3. The plate was incubated at 37°C for one hour.

4. After incubation the plate was washed with PBST (PBS with 0.05% Tween 20).
5. Blocking with 5% skimmed milk in PBS at 37°C for one hour was done.
6. The plate was washed with PBST.
7. Primary antibody against AGE-BSA was added and the plate is incubated at
37°C for one hour.
8. The plate was washed with PBST
9. Secondary antibody anti rabbit HRPO (Horse-Radish Per Oxidase) conjugate
was added and the plate is incubated at 37°C for one hour.
10. The plate was washed with PBST.
11. Colour development with OPD (orthophenylenediamine dihydrochloride) and
hydrogen peroxide was done.
12. OD (optical density) at (450nm reading - 620nm reading) was measured after
incubation at 37°C for 15 minutes with Microplate ELISA Reader.
The breaker activity of the compounds were determined by the following
formula:

OD450-620Control= Absorbance of 20ng AGE-BSA after incubation at 37°C for 24
hours without test compound
OD450-620Test= Absorbance of 20ng AGE-BSA after incubation at 37°C for 24
hours with required concentration of test compound
Using specific examples, the % AGE breaking activity was calculated and recorded
in Table 2.

Hence compound 6 has significant AGE breaking activity i.e. a comparatively much
supeR10r potency vis-a-vis PTB.
The following examples give method of preparation of the specific novel
compounds of the invention as given in Table 1. The following compounds
suggested are by way of example alone and in no way restrict the invention.
Example 2
Preparation of N,N'-bis [3-carbonyl-1- (2-phenyl-2-oxoethyl) pyridinium]
hydrazine dibromide (compound 1):
To a boiling solution of N, 2,-bis-(nicotihyl)hydrazine (1.21 g., 0.005 mol.) in
methanol (20 ml.), a solution of phenacyl bromide (1.99 g., 0.01 mol.) in
isopropanol (10 ml.) was added and the reaction mixture was refluxed for 6 hrs.
The reaction mixture was concentrated under vacuum (~10 ml.) and filtered. The
obtained residue was washed with hot ethylacetate and then the isolated solid was
powdered. It was recrystallised from a mixture of methanol and ethylacetate (3:1,
20 ml) to afford a pale yellow solid.
Yield : 60%

m.p. : 260 - 262°C (decomp.)
IR(KBr, cm-1) : 1696 and 1680
1H NMR (DMSOd6, 400MHz) δ: 11.65(2H,s), 9.56(2H,s), 9.21-9.16(4H,m), 8.49-
8.45 (2H,m), 8.08-8.05 (4H,d), 7.81-7.77(2H,m), 7.68-7.64 (4H,m), 6.58 (4H,s)
Mass (m/z): 479, 480
According to the above mentioned procedure the following compounds are
synthesized by reacting the corresponding pyridine derivatives with appropriate
reagents by refluxing in methanol, ethanol, propanol, toluene or xylene for 6-48
hrs. to get the desired compounds:
Example 3
N,N'-Bis[3-carbonyl-l- (2- ethoxy -2-oxoethyl) pyridiniuml hydrazine
dibromide (compound 2):
Yield: 47%
m.p. : 180-182°C (decomp.)
IR(KBr, cm"1) : 1744, 1664
1H NMR (DMSOd6, 400MHz) δ: 11.65 (2H,s), 9.62 (2H,s), 9.28-9.26 (2H,d),
9.17-9.15 (2H,d), 8.47-8.44 (2H,m), 5.77 (4H,s), 4.26 (4H,q), 1.27 (6H,t)
Mass (m/z) : 415, 416

Example 4
N,N'-Bis[3-carbonyl-l- (2- (2,4- dichlorophenyl) -2- oxoethyl) pyridinium]
hydrazine dibromide (compound 3):
Yield : 24%
m.p. : 225 - 227°C (decomp.)
IR(KBr, cm'1): 1702,1666
1H NMR (DMSOd6, 400 MHz) δ: 11.69 (2H,s), 9.58 (2H,bs), 9.20-9.18 (4H,m);
8.49-8.47 (2H,m), 8.17-8.15 (2H,d), 7.92 (2H,bs), 7.78-7.76 (2H,d), 6.50 (4H,s)
Mass (m/z): 615, 617, 618, 620.
Example 5
1- (2- Ethoxy -2- oxoethyl) -3- (2- (2- pvridyl) hydrazinocarbonyl) pyridinium
bromide (compound 4):
Yield: 16%
m.p. : 210-212°C
IR (KBr, cm-1): 3140, 3005, 1732 and 1690
1H NMR (DMSO6, 400MHz) δ: 9.63 (lH,s), 9.27 (2H,d), 8.49-8.45 (lH,m) 8.13-
8.07 (2H,m), 7.32-7.30 (lH,m), 7.12-7.1 l(lH,m), 5.77 (2H,s), 4.23 (2H,q), 1.25
(3H,t)
Mass (m/z): 301, 302

Example 6
1- (2- Thien -2'- yl -2- oxoethyl) -3- (methanesulfonyl hydrazinocarbonyl)
pyridinium bromide (compound 5):
Yield : 30 %
m.p : 199-200 °C
IR (KBr, cm"1): 1714, 1673
1HNMR (DMSOd6, 400 MHz) δ: 11.38 (lH,s), 9.97 (lH,s) 9.51 (lH,s), 9.16
(lH,d), 9.06 - 9.04 (lH,m), 8.43 - 8.39 (lH,m), 8.25 - 8.21 (2H,m), 7.43 - 7.41
(lH,t), 6.45 (2H,s), 3.08 (3H,s).
Mass (m/z) : 340, 341, 342
Example 7
N,N'-Bis[3-earbonyl-l- (2- thien -2'- yl -2- oxoethyl)pyridiniumlhydrazine
dibromide (compound 6):
Yield: 33%
m.p.: 259 - 261°C (decomp.)
IR (KBr, cm"1): 3330, 1702, 1674, 1655 and 1626
1H NMR (DMSOd6 400 MHz) δ: 11.59 (2H,s), 9.50'(2H,s), 9.15-9.08 (4H,m),
8.40-8.36 (2H,m), 8.17-8.14 (4H,m), 7.33(2H,t), 6.42 (4H,s)
Mass (m/z): 491, 492.

Example 8
1- (2- Ethoxy -2- oxoethyl) -3- (2- (benzoyloxv) ethylaminocarbonyl)
pyridinium bromide (compound 7);
Yield: 85%
m.p. : 132-134oC
IR (KBr, cm-1): 3210, 3067, 1726, 1687, 1656
1H NMR (DMSOd6, 400 MHz) δ: 9.46 (lH,s), 9.37 (lH,t), 9.11(lH,t), 8.97
(lH,d), 8.33-8.29 (lH,m) 7.95-7.93 (2H,m), 7.63-7.59 (lH,m), 7.49-7.45 (2H,m),
5.65 (2H,s), 4.39 (2H,t), 4.19 (2H,q), 3.70-3.69 (2H,m), 1.20 (3H,t)
Mass (m/z) : 357, 358, 359
Example 9
1- (2- (2,4- Dichlorophenvl) -2- oxoethyl) -3- (2-( benzoyloxykthyl
aminocarbonyl) pyridinium bromide (compound 8):
Yield: 75%
m.p. : 102-104oC
IR(KBr, cm"1): 1703, 1685, 1675
1H NMR (DMSOd6, 400 MHz) δ: 9.41-9.37 (2H,m), 9.03-8.98 (2H,m)8.34-8.30
(lH,m), 8.04 (lH,d), 7.91-7.89 (2H,m), 7.82 (lH,d),7.68-7.65 (lH,m), 7.58-7.55
(lH,m), 7.43 (2H,t), 6.35 (2H,s). 4.36 (2H,t), 3.68-3.64 (2H,m)
Mass (m/z): 457, 458, 459, 460, 461,462

Example 10
1- (2- Thien -2'- yl -2- oxoethyl) -3- (2- (2- pyridyl) hydrazinocarbonyl)
pyridinium bromide (compound 9):
Yield: 10%
m.p. : 212-214°C (decomp)
IR(KBr, cm"1): 1685, 1649
1H NMR (DMSOd6, 400 MHz) δ: 11.21 (lH,bs), 9.59 (lH,s), 9.19 (2H,d), 8-44
(lH,t), 8.27-8.24 (2H,m), 8.08 (lH,bs), 7.62 (lH.bs), 7.44 (lH,t), 6.85-6.79
(2H,m), 6.50 (2H,s)
Mass (m/z): 339, 340, 341
Example 11
1- (2- Phenyl -2- oxoethyl) -3- (2- (2- pyridyl) hydrazinocarbonyl) pyridinium
bromide (compound 10):
Yield : 4%
m.p. : 190°C (decomp)
IRCKBr.cm1): 1683, 1670, 1648
1H NMR (DMSOd6, 400 MHz) δ: 11.14 (lH,bs), 9.53 (lH,s), 9.18-9.13 (2H,m),
8.45-8.42 (lH,t), 8.08-8.06 (3H,m), 7.80 (lH,t), 7.67 (2H,t), 7.62-7.55 (lH,m),
6.83-6.76 (2H,m), 6.54 (2H,s)
Mass (m/z) : 333, 334, 335

Example 12
l-(2-PhenyI-2-oxoethyl) -3- (hvdrazinocarbonyl) pyridinium bromide
(compound 11).
Yield: 15%
m.p. :215-216°C
IR(KBr, cm"'): 1695, 1680
1HNMR (DMSOd6, 400 MHz) δ: 10.25 (lH,s) 9.65 (lH,s), 9.35 - 9.32 (2H,m),
8.90 - 8.88 (lH,ra) 8.50 - 8.46 (2H,d), 8.21 - 8.17 (lH,m), 8.05 - 8.07 (2H,m),
6.50 (2H,s), 4.45 (2H,s).
Mass(m/z) : 256, 257.
Example 13
1- (2- Phenyl -2- oxoethyl) -3- (methanesulfonyl hvdrazinocarbonyl)
pyridinium bromide (compound 12):
Yield: 35%
m.p.: 227- 228 °C
IR(KBr, cm-1): 1710, 1702
lHNMR (DMSOd6, 400 MHz) δ: 11.30, (lH,s), 9.88 (lH,s), 9.41 (lH,s), 9.06 -
9.05 (lH,d) 8.98 - 8.96 (lH,d), 8.34 - 8.31 (lH,m), 7.97 (2H,d), 7.72 .- 7.69
(lH,t), 7.59 - 7.56 (2H,t), 6.44 (2H,s), 2.99 (3H,s)

Mass (m/z): 334, 335
Example 14
l-(2- Ethoxy -2- oxoethyl) -3- (methanesulfonyl hydrazinocarbonyl) pyridinium
bromide (compound 13):
Yield: 38%
m.p: 75- 76 °C
IR(KBr, cm-1): 1739, 1697
1HNMR (DMSOd6, 400 MHz) δ : 11.39 (lH,s), 9.96 (lH,s), 9.56 (lH,s), 9.23
(lH,d), 9.06 (lH,d), 8.40 (lH,t), 5.75 (2H,s), 4.27-4.22 (2H,q), 3.08 (3H,s), 1.26
(3H,t)
Mass (m/z): 301, 302, 303
Example 15
l-(2-Phenyl-2-oxoethyl)-3-(phenylsulforiyIhydrazino carbonyl) pyridinium
bromide (compound 14):
Yield: 28%
m.p: 187-188°C(dec.)
IR(KBr, cm-1): 1700, 1633
1HNMR (DMSOd6, 400 MHz) δ : 11.38 (lH,s), 10.45 (lH,s), 9.33(1 H,s),
9.13 - 9.12 (lH,d), 8.95 (1H, d), 8.38 (lH,t), 8.05 (2H,d), 7.89 (2H,d),
7.80 (lH,t), 7.66 (3H,t), 7.57 (2H,t), 6.50 (2H,s).

Mass(m/z) : 396, 397, 398
Example 16
1- (2-Phenyl-2-oxoethvl)-2-chloro-3-(phenyIsuIfonylhydrazino carbonyl)
pyridinium bromide (compound 15):
Yield: 23%
m.p. : 247 - 250°C (decomp)
IR(KBr, cm-1): 1685, 1679,
1HNMR (DMSOd6, 400 MHz) δ : 11.12 (lH,s), 9.49 (lH,s), 9.07 - 9.03(lH,m),
8.44 (1H, t), 8.07 (2H,d), 7.80 (lH,t), 7.67 (2H,t), 7.18 (2H,t), 6.87 (2H,d), 6.77
(lH,t), 6.50 (2H,s).
Mass(m/z) : 430, 431, 432
Example 17
l-(2- Phenyl -2- oxoethyl) -3- (2- (acetoxy) ethyloxy carbonyl) pyridinium
bromide (compound 16);
Yield : 40%
m.p. : 152-153°C
IR(KBr, cm-1) :1737, 1691, 1635
1HNMR (DMSOds, 400 MHz) δ :9.63(lH,s), 9.24(lH,d), 9.12(lH,d),
8.43(lH,t), 8.07(2H,d), 7.80(lH,t), 7.67(2H,t), 6.59(2H,s), 4.62-4.60
(2H,m), 4.39 - 4.37(2Hm), 2.03 (3H,s)

Mass(m/z) :328, 329
Example 18
1- (2- Ethoxy -2- oxoethyl) -3- (2- (benzoyloxy) ethyloxycarbonyl) pyridinium
bromide (compound 17):
Yield : 35%
m.p. : 142-143oC
IRCKBr,cm-1) : 1736,1718,1636
1HNMR (DMSOd6, 400 MHz) δ : 9.60(1 H,s), 9.20-9.18(lH,d), 9.04-
9.02(lH,d), 8.33-8.29(lH,m), 7.90-7.88(2H,d), 7.58-7.57(lH,m), 7.46-7.42(2H,m),
5.67(2H,s), 4.71-4.68(2H,m), 4.58-4.56(2H,m), 4.15(2H,q), 1.16(3H,t)
Mass(m/z) : 358,359,360
Example 19
1- (2- Thien -2'- yl -2- oxoethvl)-4-(2-(benzoyloxy)etfavlaminocarbonyl)
pyridinium bromide (compound 18):
m.p. : 210-211°C
IR(KBr cm-1) : 1723,1680,1668
1HNMR (DMSOd6, 400 MHz) δ : 9.52 (lH,t), 9.14 (2H,d), 8.50 (2H,d), 8.25 -
8.21 (2H,m), 8.01 - 7.99 (2H,d), 7.67 (lH,t), 7.55 - 7.51 (2H,m), 7.42 - 7.40
(lH,m), 6.42 (lH,s) 4.47 - 4.45 (2H,t), 3.77 - 3.73 (2H, m).
Mass(m/z) : 395, 396

Example 20
l-(2-Ethoxy-2-oxoethyl)-4-(phenvlsutfonyl hydrazino carbonyl) pvridinium
bromide (Compound 19):
Yield: 60%
m.p. : 171 - 173°C.
IR(KBr, cm-1): 1745, 1685, 1645.
1HNMR (DMSOd6, 400 MHz) δ : 11.41 (1H, s), 10.39 (1H, s), 9.10 (2H, d),
8.27 (2H, d), 7.82 - 7.80 (2H, d), 7.60 - 7.57 (1H, t), 7.50 - 7.46 (2H, t), 5.63 (2H,
s), 4.18-4.12 (2H,q), 1.19-1.15 (3H,t).
Mass (m/z) : 364,365, 366
Example 21
1-(2-Phenvlamino-2-oxoethyl)-4-(phenyIsulfonyl hydrazino carbonyl)
pyridinium chloride (Compound 20):
Yield: 10%
m.p. : 225 - 227°C.
IR(KBr, cm-1) : 1693, 1642, 1592
1HNMR(DMSOd6, 400 MHz) δ : 11.55 (1H, s), 10.99 (1H, s), 10.49 (1H, s), 9.20
(2H, d), 8.34 (2H, d), 7.89 (2H,d), 7.73 - 7.64 (1H, t), 7.61 - 7.56 .(4H, m), 7.37 -
7.33 (2H, t), 7.12 - 7.09 (1H, t), 5.73 (2H, s).
Mass (m/z) : 411,412, 413,414

Example 22
l-(2-Ethoxy-2-oxoethvl)-3-(phenylsulfonvlhvdrazino carbonyl) pvridinium
bromide (Compound 21):
Yield: 75%
m.p. : 145 - 147 °C.
IRCKBrcm-1) : 1744, 1713, 1633
1HNMR (DMSOds, 400MHz) δ : 11.27(lH,s),10.36 (1H, s), 9.28(lH,s),
9.09(lH,d), 8.83(lH,d),8.27 - 8.24 (lH,m), 7.82 - 7.79 (2H,m), 7.58 (lH,t),
7.48 (2H,t), 5.59 (2H, s), 4.17 -4.12 (2H, q), 1.16(3H,t).
Mass (m/z) : 364, 365, 366
Example 23
l-(2-(2,4-Dichlorophenyl)-2-oxoethvI)-3- (2(methoxy) ethyloxvcarbonyl)
pyridinium bromide (Compound 22):
Yield : 25%
m.p.: 156-158°C.
IR(KBr, cm"1): 1731, 1706, 1640
1HNMR (DMSO dg, 400 MHz) δ : 9.61 (1H, s), 9.20 (1H, d), 9.13 (1H, d),
8.45 - 8.41 (1H, m), 8.15 (1H, d), 7.92(1H, d), 7.78 - 7.76 (1H, m), 6.49
(2H, s), 4.56 - 4,54 (2H, m), 3.72 - 3.69 (2H, q), 3.31 (3H, s).
Mass (m/z) : 368,369, 370, 371

Example 24
l-(2-PhenvIamino-2-oxoethvD-3-(2-(benzovloxyl) ethylaminocarbonvl)
pyridinium chloride (Compound 23):
Yield: 70%
m.p. :171-172°C
IR (KBr, cm'1): 1720, 1692, 1668
"HNMR : (DMSOd^ 400 MHz) δ : 11.06 (1HS s), 9.67 (1H, t), 9.59 (1H, s), 9.20
(lH,d), 9.11 (1H, d), 8.36 - 8.32(1 H, m), 8.00 (2H, d), 7.66 - 7.61
(3H, m), 7.51 (2H,1), 7.34 (2H, t), 7.10 (1H, t), 5.77 (2H,s), 4.45 (2H, t),
3.76 - 3.72 (2H,q).
Mass (m/z): 404, 405, 406, 407
Example 25
l-(2-Thien-2-vI-2-oxoethvlV3-(phenvlaminocarbonylhvdrazinocarbonvl)
pyridinium bromide (Compound 24):
Yield : 30%
m.p.: 202 - 204°C.
ER. (KBr, cm'1): 1718, 1673
1HNMR : (DMSOds, 400 MHz) δ : 11.03 (IK s), 9.55 (1H, s), 9.18 (1H, d), 9.10
(1H, d), 9.00 (1H, s);8.57 (lH,s), 8.46 - 8.42 (1H, t), 8.25 - 8.22 (2H, m), 7.47 -

7.45 (2H, d), 7.43 - 7.41 (1H, t), 7.29 - 7.25 (2H, t), 7.0 - 6.96 (1H, t), 6.46 (2H,
s).
Mass (m/z): 381, 382, 383
Example 26
i-(2-Phenyl-2-oxoethyl)-3-(2-(acetoxv) ethylaminocarbonyl) pyridinium
bromide (Compound 25):
Yield: 55%
m.p. : 186-188
IR(KBr, cm"1) : 1734, 1697, 1679
]HNMR (DMSOdk, 400 MHz) δ : 9.47(lH,s), 9.36 (lH,t), 9.13-9.05 (2H, m),
8.42 - 8.38 (1H, m), 8.06 (2H, d), 7.80 (1H, t), 7.67 (2H, t), 6.54 (2H, s), 4.18
(2H,t), 3.61 - 3.57 (2H,q), 2.02 (3H,s).
Mass (m/z): 327, 328,329.
Example 27
l-(2-Phenviamino-2-oxoethyl)-3-(phenyl sulfonyl hydrazino carbonyl)
pyridinium chloride (Compound 26):
Yield: 38%
m.p. :232-234°C.
IR (KBr, cm"1): 1689,1636, 1596

1HNMR (DMSOds, 400 MHz) δ : 11.30 (1H, s), 10.80 (1H, s), 10.37 (1H, s), 9.29
(1H, s), 9.09 (1H, d), 8.81 (1H, d), 8.25 - 8.21 (1H, t), 7.82 - 7.80 (2H, d), 7.59 -
7.46 (5H, m), 7.28 - 7.24 (2H, t), 7.04 - 7.00 (1H, t), 5.62 (2H,s).
Mass (m/z): 411, 412, 413, 414
Example 28
l-(2-PhenvIamino-2-oxoethvl)-3-((4-niethvlphenyl)suIfonyl hvdrazino
carbonyl) pvridinium chloride (Compound 27):
Yield : 48%
m.p. : 205 - 206°C
IR(KBr, cm"1): 1712, 1681, 1632
1HNMR (DMSOde, 400 MHz) δ : 11.35 (1H, s), 10.86 (1H, s), 10.36 (1H, s), 9.38
(1H, s), 9.17 (1H, d), 8.90 (lH,d), 8.34 - 8.30 (1H, in), 7.78 - (2H,d), 7.59 (2H,
d), 7.37 - 7.33 (4H,m), 7.11 (lH,t), 5.70 (2H,s), 2.36 (3H, s).
Mass (m/z): 425, 426, 427, 428
Example 29
l-(2-Phenyl-2-oxoethvU-3-(2-(benzoyloxy)ethyIoxy carbonyl) pyridinium
bromide (Compound 28):
Yield: 35%
m.p.: 132-134°C.
IR (KBr, cm"1): 1730, 1705, 1690

1HNMR (DMSO4, 400 MHz) δ : 9.80 (1H, s), 9.36 (1H, d), 9.30 (1H, d),
8.58 (1H, t), 8.21 (2H, d), 8.12 (2H, d), 7.95 (1H, t), 7.85 - 7.80 (3 H, m),
7.68 (2H, t), 6.71 (2H, s), 4.95 - 4.93 (2H, m), 4.82 - 4.80 (2H, m).
Mass (m/z): 390, 391, 392.
Example 30
t -f2-Thien-2'-vl-2-oxoethvI)-3-(Dhenylca rbonvl hyd razino carbonyl)
pvridinium bromide (Compound 29):
Yield: 45%
m.p. : 80-81 °C
IRCKBrCm1): 1700, 1663, 1631
!HNMR (DMSOdg, 400MHz) δ : 11.49 (1H, s), 10.95 (1H, s), 9.67 (1H, s),
9.34 (1H, d), 9.27 (1H, d), 8.52 ~ 8.48 (1H, m), 8.29 - 8.28 (2H, m), 8.00
(2H, d), 7.68 (1H, t), 7.59 (2H, t), 7.46 (1H, t), 6.63 (2H,s)
Mass (m/z): 366,367, 368,369
Example 31
l-(2-Ethoxy-2-oxoethvl)-3-((phenylmethvl)sulfonvlhydrazino carbonyl)
pyridinium bromide (Compound 30):
Yield: 50%
m.p. : 147-148°C
ffi. (KBr, cm"1) : 1749, 1698, 1640

1HNMR (DMSOds, 400 MHz) δ : 11.57 (1H, s), 10.21 (lH,s), 9.75 (lH,s),
9.38 (1H, d), 9.24 (1H, d), 8.59 - 8.56(1H, m), 7.67 - 7.65 (2H, m), 7.58 -
7.52 (3H, m), 5.90 (2H, s), 4.68 (2H, s), 4.45 - 4.39 (2H, q), 1.43 (3H, t).
Mass (m/z): 377, 378, 379
Example 32
l-(2-Phenyl-2-oxoethyl)-3-((phenyImethyl)sulfonylhvdrazino
carbonyQpyridinium bromide (Compound 31):
Yield : 80%
m.p. : 205-207° C
ffi. (KBr, Cm"1) : 1687,1637
IHNMR (DMSOds, 400 MHz) δ : 11.59 (lH,s), 10.20 (lH,s), 9.71 (lH,s),
9.33 (1H, d), 9.27 (1H, d), 8.62 - 8.59(1H, m), 8.25 - 8.23 (2H, d),
7.99 -7.95 (1H, t), 7.86 - 7.82 (2H, t), 7.67 - 7.65 (2H, m), 7.57 - 7.52
(3H, m),6.72 (2H, s), 4.69 (2H, s).
Mass (m/z): 410,411, 412, 413
Example 33
N, N' - Bis r3-carbonyl-l-(2-furan-2'-vI-2-oxoethvn pyridinium lhvdrazine
dibromide. (Compound No: 32)
Yield :23%

Yield 15%
m.p. 217 219 °C(dec)
IR (KBr, cm"1) :3190, 1708, 1667 and 1404
1H NMR (DMSO d6, 400 MHz) 8: 11.07 (lH.s), 10.22 (lH,s), 9.51 (IH.s), 9.16 -
9.15 (IH.d), 9.06 - 9.04 (IH.d), X 42 - 8.40 (lH,m). 8.25 - 8.21 (2H,m), 7.43 - 7.40
(lH.m), 6 44 (7ll,s), 2.25 -2.22 (2H.t), 1.72- 1,60 (5H,m), 1.49- 1.43(2H,q).
1.24 - 1 10 (IHjn), 0.9-0 85 (211.ml
Mass (in /) 40-J. 101,402 and 403
Example 36
l-(2-Phenvlamino-2-oxo cthvl)-3-( |2-(l-oxo-3-cvclohexyl)-nroi)vli -hvdni/ino-
carbonvll-pvridinium bromide.K ortuMiund No: 35):
Yield : 25%
m.p : 234-236 °C (dec)
IR (KBr, cm!) : 1689, 1652 and 1625
'11 NMR (DMSO 4,400 MHz) δ: 11.11 (lH,s), 10.95 (IH,s), 10.23 (lH,s), 9.56
(IH.s), 9.23 - 9.21 (IH.d), 9.06 - 9.04 (IH,d), 8.38-8.35 (IH,m). 7.62 - 7.60
(2H,d), 7.37 - 7.33 (2H,t), 7.12 - 7.C9 (lH,t), 5.75 (2H,s), 2.25 - 2.22 (2H,t), 1.72 -
I.60(5H,n) 1.49- 1.43 (2H,m), 1.25- 1.10 (4H,m), 0.91 - 0.83 (2H,m)
Mass(m//) :409, 410, 411 and 412

Example 37
l-(2-Thien-2'-vI-2-oxoethyl)-3-[2-(benzovloxy)ethvlaminocarbonyl1-
pyridinium bromide (Compound No:36);
Yield : 40%
m.p. : 125-127°C
IR(KBr, cm-1) :1710 and 1675
1H NMR (DMSO6, 400 MHz) δ: 9.48 (1 H,s), 9.43 - 9.41 (1 H,t), 9.12 - 9.11
(lH,d), 9.05 - 9.02 (lH,d), 8.40 - 8.36 (1 H,m), 8.25 - 8.20 (2H,m), 8.00 - 7.98
(2H,m), 7.68 - 7.64 (lH,m), 7.54-750 (2H,m), 7.42 - 7.40 (lH,m), 6.43 (2H,s),
4.46-4.43 (2H,t), 3.77-3.73 (2H,q)
Mass (m/z) :395, 396, 397 and 398
Example 38
l-(4-Ethoxv-2, 4-dioxobutyl)-3-(2-(benzoxvloxv)ethvIamino carbonvl)-
pyridinium chloride. (Compound No: 37);
Yield : 35%
m.p. : 147-149°C
IR (KBr, cm4) :1743, 1720, 1680 and 1627
1H NMR (DMSOd6, 400 MHz) δ: 9.62 - 9.59 (lH,t), 9.32 - 9.29 (lH,s), 9.05 -
9.03 (lH,d), 8.93 - 8.90 (lH,d), 8.27 - 8.24 (lH,m), 7.92 - 7.89 (2H,d), 7.59 - 7.55

(lH,m), 7.45 - 7.41 (2H,m), 5.82 (2H,s), 4.37-4.34 (2H,t), 4.08-4.03 (2H,q), 3.80
(2H,s), 3.67-3.63 (2H,q), 1.15-1.11 (3H,t),
Mass (m/z) :399, 400 and 401
Example 39
l-(2'4'-DichIoro-phenyl-2-oxoethyl)-3-(2-methoxyethyl aminocarbonyl)-
pyridinium bromide. (Compound No: 38);
Yield : 70%
m.p. : 93-95 °C
BR. (KBr, cm"1) :1704, 1664 and 1636
1H NMR (DMSO d6, 400 MHz) δ: 9.48 (lH,s), 9.29 (lH,bs), 9.11 - 9.08 (2H,m),
8.41 - 8.38 (lH,m), 8.15 - 8.13 (lH,d), 7.92 - 7.91 (lH,t), 7.78 - 7.75 (lH,m), 6.44
(2Hs,) 3.52 (2H,bs), 3.51 (2H,bs); 3.28 (3H,s)
Mass (m/z) :367,368,369 and 370
Example 40
N,N'-Bis-[3-carbonyl-l-(2-cvclopropylamino-2-oxoethvl) pyridiniuml
hydrazine dichloride. (Compound No: 39);
Yield : 40%
m.p. : 228-230 °C

IR (KBr cm"1) :1675,1636 and 1298
1H NMR (DMSO 4, 400 MHz) S: 11.85 (2H,s), 9.59 (2H,s), 9.25 - 9.19 (4H,m),
. 9.00 - 8.99 (2H,d), 8.39 - 8.36 (2H,m), 5.53 (4H,s), 2.73 - 2.66 (2H,m), 0.78 - 0.62
(4H,m), 0.53 - 0.49 (4H,m)
Mass (m/z) 437,438 and 439
Example 41
l-(2-CvcIopropvlamino-2-oxoethyl)-3-(2-methoxvethvIaminocarbonyl)-
pyridinium chloride. (Compound No: 40);
Yield : 10%
m.p. : 122-124 °C
IR(KBr, cm-1) :1661, 1633, 1549 and 1121
1H NMR (DMSO d6, 400 MHz) δ: 9.40 (lH,s), 9.08 - 9.02 (2H,m), 8.28 - 8.25
(lH,m), 5.53 (2H,s), 3.66 - 3.61 (4H,m), 3.39 (3H,s), 2.78 - 2.74 (lH,m), 0.80 -
0.75 (2H,m), 0.64 - 0.61 (2H,m)
Mass (m/z) :278, 279 and 280
Example 42
N-N'-Bis [3-carbonyl-l-(2-isopropvlamino-2-oxoethvl) pvridiniuml hydrazine
dichloride. (Compound No: 41):

Yield : 35%
m.p. : 114-116 °C (dec)
IR (KBr, cm-1) :1707, 1668 and 1637
1H NMR (OMSO d6: 400 MHz) δ: 11.84 (2H,s), 9.59 (2II,s), 9.21-9.18 (4H,m),
8.74-8.72 (2H,d), 8.39 - 8.35 (2H,m), 5.53 (4H,s), 3.92 - 3.84 (2H,m), 1.14-1.02
(12H,d)
Mass(m/z) : 441, 442 and 443
Example 43
l-(2-Thien-2 yl-2-oxoethyl-3-(2-(2-chloro-3-pyridovlhydrazinocarbonyl)-
pyridinium chloride. (Compound No: 42);
Yield : 56%
m.p. : 233-235 °C
IR (KBr, cm -1) : 1680, 1637, 1404 and 1293
1H NMR (DMSO d6, 400 MHz) δ: 11.62 (lH,s), 11.05 (lH,s), 9.62 (lH,s), 9.24 -
9.23 (1 H,d), 9.18-9.16(1 H,d), 8.58 - 8.56 (1 H,m), 8.46 - 8.43 (1 H,m), 8.26 - 8.24
(2H,m), 8.02 - 8.00 (lH.tn), 7.61-7.58 (lH,m), 7.43 - 7.41 (lH,m), 6.51 (2H,s)
Mass (m/z) :401, 402, 403, 404 and 405

Example 44
l-(2-Isopropvlamino-2-oxoetbyI)-3-(2-methylsulfonylhydrazinocarbonyl)-
pyridinium chloride. (Compound No: 43);
Yield : 10%
m.p. : 227 - 229 °C
IR(KBr, cm-1) :1691, 1670, 1566 and 1330
1HNMR (DMSO d6, 400 MHz) δ: 11.55 (lH,s), 9.94 (lH,s), 9.52 (lH,s), 9.16 -
9.14 (lH,m), 9.09 - 9.07 (lH,m), 8.72 - 8.70 (lH,m), 8.34 - 8.30 (lH,m)> 5.50
(2H,s), 3.89 - 3.84 (lH,m), 3.11 (3H.s), 1.13 - 1.12 (6H,d)
Mass(m/z) :315,316 and 317
Example 45
l-(2-(l-Pyrrolidinvl)-2-oxoethvl)-3-(methanesulfonvI hydrazino carbonyl)
pyridinium chloride (Compound No; 44);
Yield :21.00%
m.p. :205-207°C
IR (KBr, cm-1) : 1699, 1646 and 1589

1HNMR :(DMSO d6, 400 MHz) 5 : 11.50 (1H, s), 9.94 (1H, s), 9.46 (1H, s), 9.11
- 9.06 (2H, m), 8.36 - 8.33 (1H, t), 5.75 (2H, s), 3.55 - 3.48 (3H, m), 3.10 (3H, s),
2.00 - 1.95 (2H, m), 1.87-1.81 (2H, m)
Mass (m/z) :327, 328, 329 and 330
Example 46
l-(2-Thien-2'-vl-2-oxoethvI)-3-(methanesulfonyl hvdrazino carbonvl)
pyridinium chloride (Compound No: 45);
Yield :31.00%
m.p. :215-217°C
' 1R (KBr, cm-1) :1685, 1666 and 1635
1HNMR :(DMSO d*, 400 MHZ) 8: 11.49, (1H, s), 9.96 (1H, s), 9.55 (1H, s), 9.18
(1H, d), 9.10 (1H, d), 8.43 - 8.39 (1H, t), 8.25 - 8.22 (2H, m), 7.42 (1H, t) 6.47
(2H, s), 3.09 (3H, s).
Mass (m/z) :340, 341, 342 and 343
Example 47
N,N'-Bis[3-carboDvl-l-(2-hvdroxv-2-oxoethynpyridinium1hydrazine dichloride
(Compound No: 46);
Yield : 43.00%

m.p. :235 - 240°C (d)
IR (KBr, cm"1) : 1743, 1700 and 1672
1HNMR (DMSO d*, 400 MHz) δ: 11.89 (2H, s), 9.69 (2H, s), 9.31 - 9.29 (2 H,
d), 9.25 - 9.23 (2H, d), 8.43 - 8.39 (2H, t) 5.70 (4H, s)
Mass(m/z) :360,361,362
Example 48
l-(2-Thien-2'-vl-2-oxoethyI)-3-((2-methoxy ethyl) amino carbonvD-S-bromo
pyridinium chloride (Compound No: 47);
Yield :31.00%
m.p. :180-182°C
IR (KBr, cm"1) : 1661 and 1620
1HNMR (DMSO dg, 400 MH2) δ : 9.58 - 9.54 (2H, d), 9.43 - 9.39 (2H, d), 8.25 -
8.21 (2H, m), 7.41 (1H, t), 6.43 (2H, s), 3.51 (4H, m), 3.29 (3H, s).
Mass(m/z) : 384, 385, 386, 387 and 388
Example 49
l-(2-Thien-2'-vl-2-oxoethyl)-3-fl-oxo-l-(2-methoxvcarbonvl)pyridvn
hydrazino pyridinium chloride (Compound No: 48);
Yield :30.00%
m.p. :222 - 225°C

IR (KBr, cm"1) : 1726, 1708 and 1662
1HNMRCDMSOd^OOMH^S: 11.47 (lH,s), 11.23 (1H, s), 9.58 (1H, s), 9.22
- 9.15 (3H, m), 8.56 - 8.53 (1H, d), 8.46 - 8.43 (1H, t) 8.25 - 8.21 (3H, m), 7.42
(1H, t), 6.49 (2H, s), 3.95 (3H, s)
Mass (m/z) :425, 426 and 427
Pharmaceutical compositions may be prepared with a pharmaceutically
effective quantity of compounds of general formula 1, individually or in
combination. The following pharmaceutical formulations suggested are by way of
example alone and in no way restrict the forms in which they can be used.
Oral formulations may be administered as solid dosage forms for example
pellets, powders, sachets or discreet units such as tablets or capsules and like.
Other orally administered pharmaceutical preparations include monophasic and
biphasic liquid dosage forms either in ready to use form or forms suitable for
reconstirution such as mixtures, s)Tups, suspensions or emulsions. The preparations
in addition may contain diluents, dispersing agents, buffers, stabilizers, solubilizers,
surfactants, preservatives, chelating agents and/ or other pharmaceutical additives
as are used. Aqueous or non aqueous vehicle or their combination may be used and

if desired may contain suitable sweetener, flavoring agent or similar substances. In
case of suspension or emulsion a suitable thickening agent or suspending agent or
emulsifying agent may be present in addition. Alternatively, the compounds may be
administered as such in their pure form unassociated with other additives for
example as capsules or sachets. It may also be administered with a vehicle.
Pharmaceutical preparations can have a slow, delayed or controlled release of
active ingredients as is provided by a matrix or diffusion controlled system.
When the present invention or its salts or suitable complexes is presented as
a discreet unit dosage form like tablet, it may contain in addition medically inert
excipients as are used in the art. Diluents such as starch, lactose, dicalcfum
phosphate, talc, magnesium stearate, polymeric substances like methyl cellulose,
fatty acids and derivatives, sodium starch glycollate, etc. may also be used.
Example 50
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 pyrolidone (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 may be present in a sterile vehicle which may be an aqueous or
non aqueous vehicle or a combination thereof. The examples of vehicles are water,
ethyl oleate, oils and derivatives of polyols, glycols and their derivatives. It may
contain additives common in injectable preparations like stabilizers, solubilizers,
pH modifiers, buffers, antioxidants, cosolvents, complexing agents, tonicity
modifiers, etc.
Some suitable additives are for example tartrate, citrate or similar buffers,
alcohol, sodium chloride, dextrose and high molecular weight polymers. Another
alternative is sterile powder reconstirution. The compound may be administered in
the form of injection for more than once daily administration, or intravenous
infusion/ drip or suitable depot preparation.
Example 51
Preparation suitable for parenteral administration has the following
composition:
Active ingredient of formula I as given above
Polyethylene glycol (400) 0.75 ml

Sodium metabisulphite 0.01 %
Isotonic saline/ WFI q.s.
For the derraatological application and for the discoloration of teeth, the
recommended formulations are lotions, oral rinse and. toothpaste containing
appropriate amount of the compounds of the general formula I.
The above examples are presented by way of illustration alone and in no way
limit the scope of the invention. t.

WE CLAIM :
1. A compound selected from the group consisting of the following
compounds
(a) l -(2-phcnylammo-2-oxoethyl)- 1-(phenylsulfonyI hydrazino carbonyl)
pyridinium chloride and pharmaceutically acceptable salts thereof,
(b) l-(2-(2,4-dichlorophcnyl)-2-oxocthyl)-3- (2(mcthoxy) ethyloxycarbonyl)
pyridirdium bromide and pharmaceutically acceptable salts thereof,
(c) l-(2-phenylamino-2-oxoethyl)-3-((benzoyloxy) ethylaminocubonyl)
pyridinium chloride and pharmaceutically acceptable salts thereof,
(J) l-(2-:!:icn-2'-yl-2-cxoetliyl)-3-(phcnyhniinocarbonyI hydrazinocarbonyl)
pyndmiun bromide and phannaceuUcally acceptable sails thereof,
(L») l-(2-phenyl-2-oxocthyl}-3-(2-(accto\'y) cthylaminocarbonyl) nyridiniuin
bromide and phanr.accutically acceptable salts thereof,
(S) l-(2-pliccyIanuuo-2-oxocthyl>3-(phcr.yl sulfonyl hydrazino carbonyl)
pyridiniu.71 chloride and plwrmaccuticaUy acceptable salts thereof,
(3) l-(2-plicnylauiiiiu-2-oxoc,Jiyl)-3-{(4-iiictliylphcnyl)suJfoiiyl hydrazino
carbonyl) pyridinium chloride and pharmacculicaJIy acceptable salts thereof,
(h) l-(2-phenyl-2-oxocthyl)-3-(2-(bcnzoyloxy)cthyloxy carbonyl) pyridinium
bromide and pharmaceutically acceptable salts thereof,
(1) l-(2-thien-2,-yl-2-oxoethyl)-3-(phcnylcarbonyl hydrazino carbonyl)
pyndinium bromide and pharmaceutically acceptable salts thereof,
(j) l-(2-c:hoxy-2-cxocthyl)-3-((pharmaceutically)suIfonyl liydra/ino carbonyl)
pyridinium bromide and pharmaceutically acceptable sails thereof,
(lyl-(.2-phenyl-2-(exocthyl)-3-((phenylmcthyl)sulfonyl hydrazino carbony))

pyridiomm bromide and pharmaceutically acceptable salts thereof.
(c ) N, N' - bis [3-carbonyl-l-(2-furan-2'-yl-2-oxoethyl) pyridinium ]hydrazine
dibromide,
(m) N,N'- bis [3-carbonyl -1- (2-thien-2'-yl-2-oxoethyI) pyridinium] hydrazine
dichloride.
(n ) N,N'-bis-[3-carbonyl-l-(2-cyc]opropylaraino-2-oxoethyl)pyridininum]
hydrazine dichloride,
( o ) l-(2',4'-dichioro-phenyl-2-oxoethyl)-3-(2-methoxyethyl aminocarbonyl)-
pyridinium bromide,
( P ) l-(2-thien-2'-yl-2-oxoethyl)-3-((2-methoxy ethyl) amino carbonyl)-5-bromo
pyridinium chloride,
(q,) 1 -(2-thien-2'-yl-2-oxoethyI)-3-(methanesulfonyl hydrazino carbonyl) pyridinium
chloride,
( r) l-(2-thien-2yl-2-oxoethyl)-3-)2-(2-chloro-3-pyridoymydrazinocarbonyl)-
pyridinium chloride,
(' s ) 1 -(2-cyclopropylammo-2-oxoethyl)-3-(2-memoxyemyIaminocarbonyl)-
pyridinium chloride,
(t) l-(2-isopropyIarnino-2-oxoethyl)-3-(2-mediylsulfonymydtazinocarbonyl)-
pyridinium chloride,
(u) l-(2-phen)lamino-2-oxo ethyl)-3-({2-(l-oxo-3-cyclohexyl)-propyl} -
hydrazino-carbonyl} -pyridinium bromide,
( Y). l-(2-uhien-2'-yl-2-oxoemyl)-3-[2-(benzoyIoxy)emylamino carbonyl]-
pyridinium bromide,
(w) l-(4-ethoxy-2,4-dioxobu(yl)-3-(2-(benzoxyloxy)ethylamino carbonyl)-
pyridinium chloride and
(x ) l-(2-tluen-2,-yl-2-oxoethyl)-3-[l-oxo-l-(2-methoxy carboiryl)pyridyl]
hydrazino pyridiniuin chloride.
2. A process for the preparation of the compound as claimed in claim 1, which
comprises preparing a substituted pyridine, according to the desired end
product followed by quaternizing of the substituted pyridine, with an
appropriate reagent by refluxing in an alcoholic and/or high boiling solvent for
6-48 hrs. to give the desired compound.

3. A pharmaceutical composition for treatment of diabetic complications and aging
related diseases which comprises a pharmaceutically effective amount of one or
more compounds, as defined in claim 1, or pharmaceutically acceptable salt(s)
thereof in admixture with a pharmaceutically acceptable carrier, diluent,
solvent or excepient.
4. The pharmaceutical composition as claimed in-claim 3, in the form of an oral
formulation.
5. The pharmaceutical composition as claimed in claim 4, wherein said
pharmaceutically acceptable carrier is selected from group consisting of starch,
lactose, polyvinyl pyrolidone (K-30), talc and magnesium stearate.
6. The pharmaceutical composition as claimed in claim 3, in the form of a
parenteral formulation.
7. A method for fee preparation of a parenteral formulation as claimed in claim 6,
which comprises dissolving one or more compounds represented by general
formula (I), as defined in claim 1, in polyethylene glycol 400 and diluting the
solution so obtained, with an isotonic solution or water to a desired concentration.
8.Pharmaceutical composition as claimed in claim 5., in the form of a lotion, oral
rinse and toothpaste.

The invention discloses novel compounds of the pyridinium series useful for the
management of diabetes and aging-related vascular complications, including
kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological
disorders and discoloration of teeth, by breaking preformed AGE, of the general
formula I, or pharmaceutically acceptable salts thereof,

Documents:

828-CAL-1999-ABSTRACT .11.pdf

828-CAL-1999-ABSTRACT.pdf

828-CAL-1999-AMANDED CLAIMS.pdf

828-CAL-1999-ASSIGNMENT 1.1.pdf

828-CAL-1999-ASSIGNMENT.1.3.pdf

828-CAL-1999-ASSIGNMENT.pdf

828-CAL-1999-CLAIMS.pdf

828-CAL-1999-CORRESPONDENCE.1.3.pdf

828-CAL-1999-CORRESPONDENCE.pdf

828-CAL-1999-DESCRIPTION (COMPLETE) 1.1.pdf

828-CAL-1999-DESCRIPTION (COMPLETE).pdf

828-CAL-1999-EXAMINATION REPORT REPLY RECIEVED.pdf

828-CAL-1999-EXAMINATION REPORT.1.3.pdf

828-CAL-1999-EXAMINATION REPORT.pdf

828-CAL-1999-FORM 1 2.1.pdf

828-CAL-1999-FORM 1.pdf

828-CAL-1999-FORM 13.1.3.pdf

828-CAL-1999-FORM 13.pdf

828-CAL-1999-FORM 18.1.3.pdf

828-CAL-1999-FORM 18.pdf

828-CAL-1999-FORM 2 1.1.pdf

828-CAL-1999-FORM 2.pdf

828-CAL-1999-FORM 3 1.1.pdf

828-CAL-1999-FORM 3.1.3.pdf

828-CAL-1999-FORM 3.pdf

828-CAL-1999-FORM 4.1.3.pdf

828-CAL-1999-FORM 4.pdf

828-CAL-1999-FORM 5.1.3.pdf

828-CAL-1999-FORM 5.pdf

828-CAL-1999-FORM-27.pdf

828-CAL-1999-GPA.1.3.pdf

828-CAL-1999-GPA.pdf

828-CAL-1999-GRANTED-ABSTRACT.pdf

828-CAL-1999-GRANTED-CLAIMS.pdf

828-CAL-1999-GRANTED-DESCRIPTION (COMPLETE).pdf.pdf

828-CAL-1999-GRANTED-FORM 1.pdf

828-CAL-1999-GRANTED-FORM 2.pdf

828-CAL-1999-GRANTED-SPECIFICATION.pdf .pdf

828-CAL-1999-OTHERS DOCUMENTS.pdf

828-CAL-1999-OTHERS.1.3.pdf

828-CAL-1999-OTHERS.pdf

828-CAL-1999-PA.pdf

828-CAL-1999-REPLY TO EXAMINATION REPORT.1.3.pdf

828-CAL-1999-REPLY TO EXAMINATION REPORT.pdf

828-CAL-1999-SPECIFICATION.pdf

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Patent Number

250728

Indian Patent Application Number

828/CAL/1999

PG Journal Number

04/2012

Publication Date

27-Jan-2012

Grant Date

23-Jan-2012

Date of Filing

06-Oct-1999

Name of Patentee

TORRENT PHARMACEUTICALS LTD.

Applicant Address

CENTRAL PLAZA, 1ST FLOOR, ROOM # - 106, 2/6, SARAT BOSE ROAD CALCUTTA - 700 020, WEST BENGAL, INDIA, AND ALSO AT TORRENT HOUSE, NEAR DINESH HALL, OFF. ASHRAM ROAD, AHMEDABAD - 380 009, GUJRAT, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	SANKARANARAYANAN ALANGUDI	B-7, SWASTIK PARK, PREMSCHANDNAGAR ROAD, BODAKDEV, AHMEDABAD - 380054

PCT International Classification Number

C07D 213/80

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA