AU766824B2 - Novel compounds for the management of aging-related and diabetic vascular complications, process for their preparation and therapeutic uses - Google Patents

Description

1

AUSTRALIA

Patents Act 1990 Torrent Pharmaceuticals Ltd

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT r Invention Title: Novel compounds for the management of aging-related and diabetic vascular complications, process for their preparation and therapeutic uses The following statement is a full description of this invention including the best method of performing it known to us:-

I

BACKGROUND OF THE INVENTION The present invention relates to a new class of compounds of pyridinium 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 10 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 Seffective to reverse pre-formed advanced glycosylation crosslinks.

S"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 Snon-enzymatic reaction, which occurs in several natural systems including stored foodstuff.

$oo.

o 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.

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 S- 10 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 eoi 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 than PTB.

SUMMARY OF THE INVENTION 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- 10 formed advanced glycosylation crosslinks, etc.

i'"'"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.

°i 15 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 20 diabetic patient by administration of the compounds of the invention, either singly or in S•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.

A further object of the invention is to provide a method of breaking preformed AGE products which method comprises contacting the preformed AGE products with a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides for a new class of AGE breakers, of general formula I,

R

3

(I)

wherein RI is -R 4

-R

5 or -N(R 7 N (R 7 R9;

R

4 is selected from the group consisting of -N(R 7 )R0-,

-N(R

7

)R

6

N(R

7 OR0, and -OR 6

N(R

7 where R is alkyl;

R

5 is selected from the group consisting of alkyl, aryl including heteroaryl,

-COR

7 SO2R7, NHR 7

-C(NH)NHR

7 -CORlo,

-C(O)NHR

7 and -N(R 7

N=C

where R7 is selected from the group consisting of H, alkyl and aryl including heteroaryl provided R7 might be different for RI and R3 in the same compound; R2 is selected from the group consisting of F, Cl, Br, I, OR 7

NO

2 alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR 7 Rio, C(O)OR 7

NR

7 Rio, N=C(R 7

SR

7

SO

2

NH

2

SO

2 alkyl and SO 2 aryl, and m is 0, 1 or 2; R3 is selected from the group consisting of R7, OR7, N(R 7 (Rio), N=C(R 7 (Rio), N(R 7

N(R

7 (Rio), N(R 7

N=C(R

7 (Rio) and CH(R 7 )C(O)Rs where R is selected from the group consisting of R7, OR 7 and NR 7 Rio; R9 is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl, C(O)Rlo, -SO2Rio, -C(S)NHRio, -C(NH) NH (Rio) and NHRio, 10 Rio is selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case optionally different from substituent Rio, provided Rio might be different for Ri and S...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, BF 4 and PF 6 with proviso that, 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 Rio, when present, is optionally quaternized with compound such as X-CH 2

C(O)-R

3 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, I, 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 at least one ring having a conjugated pi- electron system, containing up to 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 Ci-C 6 hydrocarbon.

I

6 In a preferred aspect of the invention, the present invention provides novel compounds of formula I wherein COR 1 is at the 3 position and R 1 is a moiety of formula II 0

H

/N

H

N

Z-

(II)

0 wherein in formula II, at least one of positions 2, 4, 5 and 6 of the pyridino moiety and/or at least one of positions 3, 4 and 5 of the thienyl/furyl moiety are substituted; and wherein Y is S or O;

R

2 is independently selected from the group consisting of F, Cl, Br, I, OR 7

NO

2 alkyl, aryl including heteroacyl, formyl, acyl, C(O)NR 7 Rio, C(O)OR 7

NR

7 Rio, N=C(R 7 )(Rio),

SR

7 S02NH 2

SO

2 alkyl and SO 2 aryl and m is 0 or 1;

*R

7 is selected from the group consisting of H, alkyl and aryl including heteroaryl; RI is selected from the group consisting of H, alkyl and aryl including optionally substituted heteroaryl;

R

3 is a substituted thienyl moiety; X and Z are independently selected from the group consisting of 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,

BF

4 and PF 6 S"with the proviso that 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 a heteroaryl ring of Rio, when present, is optionally quaternized preferably with a compound such as Z-CH 2

C(O)-R

3 (iii) optionally, the thienyl/furyl moiety from R 3 and formula II are independently replaced by NHcyclopropyl.

Preferably at least one of positions 2, 4, 5 and 6 of the pyridino moiety and/or at least one of positions 3, 4 and 5 of the thienyl/furyl moiety of formula II are substituted with a moiety independently selected from the group consisting of F, Cl, Br, I, NO 2 alkyl and -C(O)NHRio. Rio is preferably lower alkyl, such as methyl, ethyl or propyl.

R

2 is preferably H m=0) or lower alkyl, such as methyl, ethyl or propyl.

X and Z are preferably independently selected from the group consisting of chloride, bromide, fluoride and iodide ions, more preferably chloride and bromide ions.

Y is preferably S.

In another preferred aspect of the invention, the present invention provides novel compounds of formula I as shown above wherein CORI is at the 3 position and

R

1 is -NHNHSO 2 Ri -NHNHCONHR 1 or -NHNHCORii; wherein Rn 1 is substituted or unsubstituted cyclic or acyclic alkyl, or aryl;

R

2 and X are as defined above; and R 3 is a substituted thienyl moiety; with the proviso that 1-(2-thien-2'-yl-2-oxoethyl)-3-(methanesulfonyl hydrazinocarobonyl) pyridinium bromide is specifically excluded.

It is preferred that compounds of the invention as defined above have at least or 50% AGE breaking activity at a concentration of 10 nM where %AGE breaking activity is as determined by the method described below in Example 1. More preferably, compounds have at least 60 or 70% AGE breaking activity at a concentration of 10 nM.

25 Specific novel compounds of the invention of general formula I having m as 0 or 1 and COR 1 at position 3 are listed in Table 1A and specific novel compounds of .the invention of general formula I having m as 0 and -CORI at position 4 are listed in Table lB. These compounds can be further defined by their following chemical names: 1 -(2-ethoxy oxoethyl) -4-(phenylsulfonyl hydrazino carbonyl) pyridinium bromide (compound 1); 1 -(2-phenylamino-2-oxoethyl)-4- (phenylsulfonyl hydrazino carbonyl) pyridinium chloride (compound 2); 1 -(2-ethoxy oxoethyl) -3 -(phenylsulfonyl hydrazino carbonyl) pyridinium bromide (compound 3 ,4 1 -dichlorophenyl)-2-oxoethyl)-3-(2(methoxy)ethyloxycarbonyl) pyridinium bromide (Compound 4); 1 -(2-phenylamino-2-oxoethyl)-3 -((benzoyloxy)ethylaminocarbonyl) pyridinium chloride (compound 1 -(2-thien-2'-yI- 2-oxoethyl)-3-(phenylarminocarbonyl hydrazinocarbonyl)pyridinium bromide (compound 6); 1-( 2 -phenyl-2-oxoethyl)-3-(2-(acetoxy)ethylaminocarbonyl) 20 pyridinium bromide (compound 7); 1 -(2-phenylamino-2-oxoethyl)-3 -(phenyl sulfonyl hydrazino carbonyl) pyridinium chloride (compound 8); 25 1 -(2-phenylanmino-2-oxoethyl)-3-((4-methylphenyl) sulfonyl hydrazino carbonyl)pyridinium chloride (compound 9); 1 -(2-phenyl-2-oxoethyl)-3 -(2-(benzoyloxy)ethyloxy carbonyl) pyridinium bromide (compound 1 -(2-thien-2'-yl-2-oxoethyl)-3 -(phenylcarbonyl hydrazino carbonyl) pyridinium bromide (compound 11); 1 -(2-ethoxy-2-oxoethyl)-3 -((phenylmethyl)sulfonyl hydrazino carbonyl)pyridinium bromide .(compound 12); 1 -(2-phenyl-2-oxoethyl)-3 -((phenylmethyl)sulfonyl hydrazino, carbonyl) pyridinium bromide (compound 13); N, N' bis [3-carbonyl-1-(2-furan-2'-yl-2-oxoethyl) pyridinium] hydrazine dibromide.

(Compound No: 14); N,N'-bis [3-carbonyl- 1- (2-thien-2'-yl-2-oxoethyl) pyridinium] hydrazine dichloride. (Compound No: 1 -(2-thien-2'-yl-2-oxoethyl)-3 1-oxo-3 -cyclohexyl)-propyl)-hydrazino carbonyl)pyridinium bromide.( Compound No: 16);- 1 -(2-phenylamino-2-oxo ethyl)-3 1-oxo-3 -cyclohexyl)-propyl} -hydrazino-carbonyl)}pyridinium bromide. (Compound No: 17); 1 -(2-thien-2'-yl-2-oxoethyl)-3 -[2-(benzoyloxy)ethylamino carbonyl]-pyridinium bromide (Compound No: 18); 1 -(4-ethoxy-2, 4-dioxobutyl)-3 -(2-(benzoyloxy)ethylamtino carbonyl)-pyridinium chloride.

(Compound No: 19); 1 -(2',4'-dichloro-phenyl-2-oxoethyl)-3 -(2-methoxyethyl amninocarbonyl)-pyridinium bromide. (Compound No: N,N'-bis-[3 -carbonyl-l1-(2-cyclopropylamino-2-oxoethyl) pyridinium] hydrazine dichioride.

(Compound No: 21); 1 2 -cyclopropylamino-2-oxoethyl)-3-(2-methoxyethylaminocarbonyl)-pyridinium chloride.

(Compound No: 22); N-N'-bis [3 -carbonyl-l1-(2-isopropylamino-2-oxoethyl) pyridinium] hydrazine dichloride.

20 (Compound No: 23); 1 -(2-thien-2'yl-2-oxoethyl)-3 -(2-(2-chloro-3 -pyridoylhydrazinocarbonyl) -pyridinium chloride. (Compound No: 24); 25 1 -(2-isopropylamino-2-oxoethyl)-3 -(2-methylsulfonyihydrazinocarbonyl) -pyridinium chloride. (Compound No: 1 1-pyrrolidinyl)-2-oxoethyl)-3-(methanesulfony hydrazino carbonyl) pyridinium chloride. (Compound No: 26); l-(2-thien-2'-yl-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl) pyridinium chloride.

(Compound No: 27); N,N'-bis[3 -carbonyl-l1-(2-hydroxy-2-oxoethyl)pyridinium]hydrazine dichloride (Compound No: 28); 1 -(2-thien-2'-yl-2-oxoethyl)-3-((2-methoxy ethyl) amino carbonyl)-5-bromo pyridinium chloride (Compound No: 29); 1 1 -thien-2'-yl-2-oxoethyl)-3 -oxo- 1-(2-methoxy carbonyl)pyridyl] hydrazino pyridinium chloride. (Compound No: 1 1-(2-thien-2' -yl-2-oxoethyl)-6-methyl-3 -carbonyl pyridinium]-2-[ 1-(2-Thien-2 I 'l2 oxoethyl -carbonyl pyridinium hydrazine dichloride(compound no: 3 1).

1 -(2-thien-2 I -yl-2-oxoethyl)-3 -(isopropylsulfonyl hydrazino carbonyl) pyridinium bromide(compound no: 32).

1 -(2-(4-benzyl piperidin- 1-yl)-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl) pyridinium chloride(compound no: 33).

1 -(2-(2-ethoxy carbonyl pyrrolidin- 1-yl)-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl) pyridinium chloride. (compound no: 34).

1-(2-thien-2 I -yl-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl )-5-bromo pyridinium bromide. (compound no: 1-(2-thien-2' -yl-2-oxoethyl)-3-(ethoxycarbonyl hydrazino carbonyl pyridinium bromide.

(compound no: 36).

1 -chloro-thien-2-yl)-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl pyridinium bromide (compound no: 37).

N,N' -bis[3-carbonyl-1-(2-(4-nitro-thien-2-yl)-2-oxoethyl)pyridinium] hydrazine dichioride. (compound no: 38).

1-(2-thien-2 I -yl-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl) OVOO: 20 -6-methyl pyridinium bromide. (compound no: 39).

N,N I -bis[3 -carbonyl- 1 -(2-(5-methyl-thien-2-yl)-2-oxoethyl) pyridinium] hydrazine dichloride. (compound no: ,*00.0 25 N,N -bis[3 -carbonyl-1I-(2-(2-ethoxycarbonyl pyrrolidin-1I-yl)-2-oxoethyl) pyridinium] hydrazine dichloride. (compound no: 41).

1-[l -(2-thien-2 I -yl-2-oxoethyl)-5-ami nocarbonyl-3-carbony pyridinium]-2-[1 -(2-Thien- 2'-yl-2-oxoethyl )-3-carbonyl pyridinium] hydrazine dichloride (compound no: 42).

1 -(2-(4-carbethoxy-thiazolidin-3 -yl)-2oxoethyl) -3 -(methanesulfonyl hydrazino carbonyl) ***pyridinium chloride (compound no: 43).

N,N' -bis[3 -carbonyl-l1-(2-(5-chloro-thien-2-yl)-2-oxoethyl) pyridinium] hydrazine, dichloride. (compound no: 44).

1 -methyl-thien-2-yl)-2-oxoethyl)-3 -(methanesulfonyl hydrazino, carbonyl pyridinium chloride (compound no: 1 -(2-(4-nitro-thien-2-yl)-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl pyridinium bromide. (compound no: 46).

1 -(2-phenylamnino-2-oxoethyl)-3 -(phenyl hydrazino carbonyl) pyridinium chloride (compound no: 47).

1 -(2-phenylamino-2-oxoethyl)-4 2-(benzoyloxy) ethylamino carbonyl pyridinium chloride (compound no: 48).

1 -2-(5-nitro-thien-2-yl)-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl pyridinium chloride (compound no: 49).

1-(2-thien-2 I -yl-2-oxoethyl)-3-(trifluoromethanesulfonyl hydrazino carbonyl) pyridiniumn bromide. (compound no. 1 -(2-thien-2 I -yl-2-oxoethyl)-3 -(phenyl hydrazino carbonyl) pyridinium bromide (compound no. 5 1).

1-(2-thien-2 I -yl-2-oxoethyl)-3 -(p-methoxy phenyl sulfonyl hydrazino carbonyl) pyridinium bromide (compound no. 52).

1-(2-ethoxy-2-oxoethyl)-3-(phenyl aminocarbonyl hydrazino carbonyl pyridiniumn bromide (compound no. 53).

1-(2-ethoxy-2-oxoethyl)-3-(p-toluene sulfonyl hydrazino carbonyl pyridinium bromide (compound no. 54).

1-(2-phenyl-2-oxoethyl)-3-(phenylamino carbonyl hydrazino carbonyl pyridinium bromide S 20 (compound no. 1 -(2-phenylamino-2-oxoethyl)-3 -(benzyl sulfonyl hydrazino carbonyl) pyridiniumchloride. (compound no. 56).

25 1 -(2-phenyl-2-oxoethyl)-4-(methanesulfony hydrazino, carbonyl pyridiniumn bromide (compound no. 57).

1-(2-phenyl-2-oxoethyl)-3-(phenyl hydrazino carbonyl pyridinium bromide. (compound no. 5 8).

1-(2-ethoxy-2-oxoethyl)-4-[2-(benzoyloxy) ethyl amino carbonyl pyridinium bromide *.:(compound no. 59).

1-(2-ethoxy-2-oxoethyl)-3-(phenyl hydrazino carbonyl pyridinium bromide. (compound no. 1 -(2-phenyl-2-oxoethyl)-3 -(p-methoxyphenyl sulfonyl hydrazino carbonyl pyridinium bromide. (compound no. 61).

1-(2-phenyl-2-oxoethyl)- 4-[2-(benzoyloxy) ethyl amino carbonyl pyridiniumn bromide.

(compound no. 62).

1 -(2-ethoxy-2-oxoethyl)- 4-(p-methanesulfonyl hydrazino carbonyl pyridinium bromide. (compound no. 63).

a. aaa* we a.

a q* a.

a *aaf o *9 Ce a a Ca..

an.

F*

a.

a. a.

Table 1A Representative Pyridinium derivatives (having m as 0 or 1 and -CORI at position 3) Compound R, -R 2

-R

3 -x No.

3 -NHNH-SO 2 Ph OEt Br 4 -OCH 2

CH

2

OCH

3 2,4-dichiorophenyl Br

-NHCH

2

CH

2 OCOPh NH phenyl CI 6 -NHINHCON]HPh 2-thienyl Br 7 NHCH 2

CH

2

OCOCH

3 phenyl Br 8 NHNHSO 2 Ph NH phenyl CI 9 NHNI\HS0 2 Ph(4-CH 3 NH phenyl CI 10 OCH 2

CH

2 OCOPh phenyl Br I1I -NIHNHCOPh 2-thienyl Br 12 NHfNHSO 2

CH

2 Ph GEt Br 13 NIHNHSO 2

CH

2 Ph phenyl Br 14 Structure 2-furyl Br Structure-(b) 2-thienyl C1 16 NHNI{COCH 2

CH

2 2-thienyl Br cyclohexyl 17 NI-NIICOCH 2

CH

2 NH-phenyl C1 cyclohexyl 18 NI{CH 2

CH

2 OCO-phenyl 2-thienyl Br 19 NIICH 2

CH

2 OCO-phenyl CH 2

CO

2 -ethyl C1

-NHCH

2

CH

2

OCH

3 -2,4-dichiorophenyl Br 21 Structure-(c) NH- cyclopropyl Cl 22 -NHCH 2

CH

2

OCH

3 NH-cyclopropyl C1 23 Structure-(d) NH-isopropyl C1 24 Structure-(e) 2-thienyl Cl

NHNI{SO

2

CH

3 NH-isopropyl Cl 26 NHNHSO 2

CH

3 1 -pyrrolidinyl Cl 27 NIINHSO 2

CH

3 2-thienyl Cl 28 Structure-(f) -OH 'Cl 29 NHCH 2

CH

2

OCH

3 2-thienyl Cl Structure-(g) 2-thienyl Cl 31 Structure 2-thienyl Cl 32 -NHNHlSO 2 isopropyl 2-thienyl Br 33 -NHNI{50 2

CH

3 Structure Cl 34 -NHNHSO 2

CH

3 Structure ()Cl

-NHNIHSO

2

CH

3 5- 2-thienyl Br Bro mo 36 -NHNHCOC 2

H

5 2-thienyl Br 37 -NHNIISO 2

CH

3 5-chloro-2-thienyl Br 38 Structure 4-nitro-2-thienyl Cl 39 -NHNHSO 2

CH

3 6- 2-thienyl Br meth yl Structure 5-methyl-2-thienyl Cl 41 Structure (in) Structure ()Cl 42 Structure 2-thienyl Cl 43 -NHNHSO 2

CH

3 Structure Cl 44 Structure 5-chloro-2-thienyl Cl -NHNI-10 2

CH

3 5-methyl-2-thienyl Cl 46 NHNHSO 2

CH

3 4-nitro-2-thienyl Br 47 -NHNHPh -NHPh Cl 49 -NIHNHSO 2

CH

3 5-nitro-2-thienyl Cl

-NHNIHSO

2

CF

3 2-thienyl Br 51 -NHNHPh 2-thienyl Br 52 -NHNHSO 2 -4-methoxy- 2-thienyl Br Phenyl 53 -NHNHCONHPh -GEt Br 54 -NHN HSO 2 -4-methyl- -GEt Br Phenyl -NHNTICONITPh Ph Br 56 -N}INHSO 2

CH

2 Ph -NH-Ph Cl 58 -NHNEiPh Ph Br -NINE[Ph -OEt Br 61 -NHNHSO 2 -4-methoxy- Ph Br Phenyl 0 0 0 0 0 0 oooo*: 00 :00.0.

0 0 0000 0 0 0000 0 00 0 0 0

-N-

H

-N-

H

(a) (b)

H

C'

HH

(f)

H:

3 CO 0 Structure (g9) -N C-Ph lDH 2 Structure (i) Structure (h) EtOOC Structure(j 0* 4* Structure (k) Structure (L)

H

2

N'

H

N

H

SN CI

YS

0 Structure (n) Structure (in) -N O 000C

H

Structure (a)Q C l

SC

0 Structure (P) Table 1B Representative Pyridinium derivatives (having m as 0 and -CORI at position 4) Compound -RI -R2 -R3 -X 1 NHNHSO 2 Ph OEt Br 2 NHNHSO 2 Ph NH phenyl CI 48 -NHCH 2

CH

2 0COPh -NHPh Cl 57 -NHNHS02CH 3 -Ph Br 59 -NHCH 2 CH20COPh -OEt Br 62 -NHCH 2

CH

2 0COPh -Ph Br 63 -NHNHS0 2

CH

3 -OEt Br a

S

a .a a C S a.

According to the embodiment of the present invention, the present compounds are used for the treatment of diabetic complications, and aging related complications including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological conditions and colouration of teeth occurring due to the higher levels of preformed AGE. The increased levels of preformed AGE can be brought under control by breaking the AGE products using compounds mentioned in the invention.

The invention also provides a process for the preparation of novel compounds of the pyridinium series.

The said process for the preparation of compound 15, comprises, adding a solution of 2-chloro acetylthiophene in isopropanol to N,N'-bis-(nicotinyl)hydrazine dissolved in methanol, refluxing for six hours, cooling, filtering the precipitated solid, washing the solid 18 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 are prepared from properly substituted pyridine derivatives followed by quartemnization with appropriate reagent by refluxing in alcoholic solvents like, methanol, ethanol, propanol, etc and/or high boiling solvents like toluene or xylene etc, for 6 48 hrs. to give the desired compounds.

The examples of substituted pyridine derivatives which can be used for preparation of specific compounds of the invention are given below: 1 N,N'-bis(nicotinyl)hydrazine 2. 3 -[(2-pyridyl)hydrazinocarbonyl]pyridine 3. 3-[(2-methanesulfonyl)hydrazinocarbonyl]pyridine 4. 3 -[(2-benzoyloxy)ethylaminocarbonyl]pyridine 3 -phyenyl sulfonyl)hydrazinocarbonyl]pyridine 6. 3-[(2-acetoxy)ethyloxycarbonyl]pyridine 7. 3 -[(2-benzoyloxy)ethyloxycarbonyl]pyridine 8. 3 -[(2-methoxy)ethyloxycarbonyl]pyridine 9. 3 -[(2-phyenylaminocarbonyl)hydrazinocarbonyl]pyridine 3 .{(2-acetoxy)ethylamninocarbonyl]pyridine 2011. 3 -[(2-(4-methylphenyl sulfonyl)hydrazinocarbonyl)]pyridine 12. 3-[(2-benzoyl)- hydrazino carbonyl]pyridine 13. 3-[(2-phenylmethane sulfonyl) hydrazino carbonyl]pyridine 14. 3 cyclohexylpropanoyl) hydrazino carbonyl]pyridine 3 -[(2-methoxy)ethylaminocarbonyl]pyridine 16. 3 -oxo-l1-(2-methoxycarbonyl)pyridyl]hydrazino pyridine The examples of quatemnizing agents which may be used in the reaction are given below: 1. 2-bromoacetyl thiophene 2-chloroacetyl thiopene phenacylbromide 4. phenacylchloride 2,4-dichloropheanacylbromide 6. N- phenyl chloroacetamide 7. N- cyclopropyl chloroacetamide 8. ethylbromoacetate 9. bromo acetylfuran 10. N- isopropylchloroacetamide 11. N- chloroacetyl-2-pyrrolidinone 12. chloroacetic acid In-vitro screening for AGE-breaking Activity 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.

l Example 1 AGE breaker activity has been confirmed by the screening procedure as mentioned below: Materials: S 20 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 pM filter and kept for aging at 37 0 C for 16 weeks. After 16 weeks the solution was dialyzed against PBS, aliquoted and stored at 20 0

C.

To determine the AGE breaking activity, 10g/ml of the 16 weeks AGE-BSA was incubated with different concentrations of the test compounds at 37 0 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 5. Blocking with 5% skimmed milk in PBS at 37 0 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 0 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 0 C for one hour.

10. The plate was washed with PBST.

11. Colour development with OPD (orthophenylenediamine dihydrochloride) and hydrogen 20 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: Breaker activity OD 45 o- 62 oControl OD 45 0- 62 0Test x 100

OD

45 0- 62 0Control

OD

450 620 Control= Absorbance of 20ng AGE-BSA after incubation at 37 0 C for 24 hours without test compound

OD

4 50- 62 oTest= Absorbance of 20ng AGE-BSA after incubation at 37 0 C for 24 hours with required concentration of test compound Using specific examples, the AGE breaking activity was calculated and recorded in Table 2.

Table 2 Sample Concentration (mM) Breakage PTB 10 27 47 Compound 4 10 13 41 Compound 5 10 37 Compound 14 10 14 Compound 15 5 Compound 20 5 17.66 Compound 21 5 22.8 Compound 22 10 12.38 Compound 24 10 12.51 Compound 25 10 10.85 Compound 27 10 17.53 Compound 29 10 32.38 Compound 31 2.5 85.67 Compound 32 10 31.45 Compound 33 10 20.94 Compound 34 10 25.34 Compound 35 2.5 29.36 Compound 36 10 33.43 Compound 37 10 40.85 Compound 38 10 75.92 Compound 39 1.0 77.69 Compound 40 10 81.95 Compound 41 10 20.31 Compound 42 1 95.36 Compound 43 10 25.06 Compound 44 10 78.41 Compound 45 10 25.17 Compound 46 10 60.94 Compound 47 2.5 68.35 Compound 48 10 19.07 Compound 49 1 42.01 Compound 50 10 92.64 6 6 CS a Hence compounds 5, 29,31,32, 35, 36-40, 42, 44, 46,47, 49 and 50 have superior AGE breaking activity compared to PTB, of which the potency of compounds 31, 38-40, 42, 44, 46, 47, 49 and 50 are significantly much higher.

In-vivo screening for AGE-breaking Activity The test compounds were studied for their beneficial effects on diabetic neuropathy and nephropathy in a rat model of diabetes. The rats were divided into three groups. The first group consisted of age matched untreated non-diabetic animals. The second group consisted of diabetic controls and the third group was the diabetic group treated with the test compound. Each treatment group had its own corresponding control and diabetic groups. The second and third groups were treated with Streptozotocin (STZ) at for the induction of diabetes. After completion of 12 weeks of diabetes the rats were treated with the test compound daily (doses shown in table) for a period of 8 weeks. At the end of the treatment the creatinine clearances and nerve conduction velocities (NCV) of the animals were estimated.

Creatinine clearances of the rats were estimated as follows Creatinine clearance Concentration of creatinine in the urine x ml urine oassed/minute Concentration of creatinine in the blood.

I.

The creatinine clearance in untreated diabetic group was compared with the treated group and the percentage improvements are shown in the Table 3.

The nerve conduction velocity was measured using a modified method of Biro et al 1998. Briefly under ether anesthesia the sciatic and tibial nerves were electrically stimulated at the sciatic notch or ankle, respectively. Electromyograms (EMG's) recorded from the plantar muscles consisted of two components: the short latency direct motor response and the monosynaptically elicited long-latency sensory response (H, Hoffmann reflex). Latency and the duration of the M responses were measured and the motor nerve conduction velocity (MNCV) was calculated as follows: MNCV Distance between the sciatic and tibial stimulation points.

Differences of the latency for Mseiatic and Mtibial t The percentage improvement in the nerve conduction velocities in the group treated with the test compounds was calculated as follows: Improvement in the NCV's NCV of the treated group NCV of the diabetic group NCV of the control group NCV of the diabetic group.

Table 3 Effect of compound Nos 14 and 21 on the creatinine clearance and nerve conduction velocities: Parameters Compound No.15 Compound No.21 mg/kg, (6.0 mg/kg, b.i.d.) Increase in creatinine 103.0 clearance Increase in the NCV 60.0 58.4 The results show that compounds of this class have beneficial effects on creatinine clearance and nerve conduction velocities.

Discussion of the test results: All the test compounds mentioned in the current application have shown an invitro AGE-breaker effect. Under conditions of chronic hyperglycemia in rats there is a spontaneous non-enzymatic reaction between glucose, lipids and proteins that leads to the formation of advanced glycosylation end products. In this animal model decreased creatinine clearance and decreased nerve conduction velocity have been demonstrated.

These changes are related to damage to renal and neuronal tissues. During chronic NIDDM patients, there is a decrease in the creatinine clearances as a manifestation of the diabetes induced renal damage. One of the major factors contributing to renal damage is the glycation of the long-lived proteins in the kidney. It is well recognized that there is a decrease in the nerve conduction velocities in chronic diabetic subjects, which is a manifestation of neuropathy. Breaking of cross-linked proteins in the neuronal tissues and associated vasculature could lead to an improvement in the neuronal function.

The compounds of the present invention have shown a functional improvement both in terms of the improvement in the creatinine clearance and an improvement in the nerve conduction velocities. The evidences stated above clearly demonstrate that these *0000* compounds could play a major role in the prevention and treatment of various diabetic and aging related complications like nephropathy and neuropathy.

99 9 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 1-(2-Ethoxv-2-oxoethyl)-4-(phenvlsulfonvl hydrazino carbonyl) pyridinium bromide (Compound 1): To a boiling solution of N-(benzene sulfonyl)-isonicotinic hydrazide (1.0g.,0.036 mol.) in isopropanol (25 ml), a solution of ethyl bromo acetate 0.036 mol.) in isopropanol was added and the reaction mixture was refluxed for 24 hrs. The reaction mixture was concentrated under vacuum (-10ml.) and was recrystalized from a mixture of methanol-ethyl acetate 1 SmI.) to afford the solid. The solid was fuirther washed with (10m1.) ethyl acetate yielding 1.05 g of required product.

Yield M. P. :171 173'C.

JR (KBr, cm') :1745, 1685, 1645.

'HNM~R (DMSOd 6 400 MVIHz) 5 11.41 (1H, 10.39 (1H, 9.10 (2H, d), 8.27 (2H, 7.82 7.80 (2H, 7.60 7.57 (1H, 7.50 7.46 (2H, 5.63 (2H, s), 4.18 -4.12 (2H, 1. 19 -1.15 (3H, t).

Mass (mlz) 364, 365, 366 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 of xylene for 6 48 hrs. to get the desired compounds.

Example 3 **1-(2-Phenviamino-2-oxoethyI)-4-(phenyisulfonyI hydrazino carbonyl) pyridinium chloride (Compound 2): Yield M. P. :225 227'C.

IR (KBr, cm-f') :1693, 1642, 1592 'HNMIR(DMSOd 6 400 MHz) 6 :11.55 (1H, 10.99 (1H, 10.49 (1H, 9.20 (2H, 8.34 (2H, 7.89 7.73 7.64 (1H, 7.61 7.56 (4H, in), 7.37 7.33 (2H, 7.12 7.09 (1H, 5.73 (2H, s).

Mass (mlz) :411, 412, 413, 414 Example 4 1-(2-Ethoxv-2-oxoethvI)-3-(phenvisulfonvlhydrazino carbonil) pyridinium bromide (Compound 3): Yield m.p. :145 147 'C.

JR(KBr :1744, 1713, 1633 'HNMR (DMSOd 6 400MHz)6 11.27(1I,s),10.36 (1H, 9.28(LH,s), 9.09(1H,d), 8.83(1H,d),8.27 8.24 7.82 7.79 7.58 (1H,t), 7.48 (2H, 5.59 (2H, 4.17 4. 12 (2H, 1.16(3H,t).

Mass (mlz) 364, 365, 366 Example '-Dichlorophenvl)-2-oxoethl)-3- (2(methoxv)ethloxvcarbonv) Dyridinium bromide (Compound 4): Yield m.p. :156- 158'C.

IR (KBr, cm') :1731, 1706, 1640 'HNMR (DMSO d 6 ,400 Mlz)5 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, 6.49 (2H, 4.56 4.54 (2H, 3.72 3.69 (2H, 3.31 (3H, s).

Mass 368, 369, 370, 371 goo* Example 6 1-(2-Phenlamino-2-oxoethl)-3-(2-(benzovloxvl) ethylaminocarbonvi) pyridinium chloride (Compound Yield i.p. 171 172T IR (KBr, cnf') :1720, 1692, 1668 'HNMR: (DMSOd 6 400 MIz) 6 :11.06 (1H, 9.67 (1H, 9.59 (1H, 9.20 9.11 (1H, 8.36 8.32(1H, 8.00 (2H, 7.66 7.61 (3H, m),7.51 (2H, t),7.34 (2H, 7. 10 (1H, 5.77 4.45 (2H,t), 3.76 3.72 (2H, q).

Mass (mlz) 404, 405, 406, 407 ExamDie 7 1-(2-Thien-2'-vl-2-oxoethvl)-3-(phenvlaminocarbonvI hydrazinocarbonvi) pyridinium bromide (Compound 6): Yield m.p. :202 204'C.

IR (KBr, :1718, 1673 'HNMR: (DMSOd 6 400 MHz) 5 :11.03 (1H, 9.55 (1H, 9.18 (1H, 9.10 (1H, 9.00 (1H, s),8.57 8.46 8.42 (1H, 8.25 8.22 (2H, 7.47 7.45 (2H, d), 7.43 7.41 (1H, 7.29 7.25 (2H, 7.0 6.96 (1H, 6.46 (2H, s).

*'Mass (mlz) 381, 382, 383 Example 8 1-(2-Phenvl-2-oxoethvl)-3-(2-(acetoxv) ethylaminocarbonvl) pyridinium bromide (Compound 7): Yield m.p. :186 188 JR (KBr, cm) :1734, 1697, 1679 'HNMR (DMSOd 6 400 MHz)6 9.47(1H,s), 9.36 9.13 9.05 (2H, 8.42 8.38 (1H, 8.06 (2H, 7.80 (1H, 7.67 (2H, 6.54 (2H, 4.18 3.61 3.57 2.02 (3H,s).

Mass 327, 328, 329.

Example 9 1-(2-Phenvlamino-2-oxoethvl)-3-(Phenv sulfonyl hydrazino carbonv) pyridinium chloride (Compound 8): Yield :38% m.p. 232 234C.

JR (KBr, cnm') :1689, 1636, 1596 'HNMR (DMSOd 6 400 MHz) 6 11.30 (1H, 10.80 (1H, 10.37 (1H, 9.29 (1H, 9.09 (1H, 8.81 (1H, 8.25 8.21 (1H, 7.82 7.80 (2H, 7.59 7.46 7.28 7.24 (2H, 7.04 7.00 (IH, 5.62 (2H,s).

Mass (mlz) :411, 412,413, 414 Example 1-(2-Phenvlamino-2-oxoethvI)-3-((4-methvphenvl)sulfonvI hydrazino carbonyl) pyridinium chloride (Compound 9): Yield 48% m.p. :205 206'C IR(KBr, 1712, 1681, 1632 'HNMR (DMSOd 6 400 MIHz) 6 :11.35 (1H, 10.86 (1H, 10.36 (1H, 9.38 (1H, 9.17 (1H, 8.90 8.34 8.30 (1H, 7.78 7.59 (2H, 7.37 7.33 7.11 5.70 2.36 (3H, s).

Mass (mlz) 425, 426, 427, 428 Example 11 -(2-Phenl-2-oxoethvl-3-(2-(benzovloxy)ethvloxy carbonyl) pyridinium bromide (Compound Yield m.p. 132-134 0

C.

IR (KBr, :1730, 1705, 1690 'HNMR (DMSOd 6 400 MHz) 5 9.80 (1H, 9.36 (1H, 9.30 (1H, d), 8.58 (IH, 8.21 (2H, 8.12 (2H, 7.95 (1H, 7.85 7.80 (3 H, m), 7.68 (2H, 6.71 (2H, 4.95 4.93 (2H, 4.82 4.80 (2H, m).

Mass (mlz) :390, 391, 392.

Example 12 1-(2-Thien-2'-vl-2-oxoethvl)-3-(phenvlcarbonyI hydrazino carbonvl) pyridinium bromide (Compound 11): Yield m.p. 80 81 0

C

IRKBr 1700, 1663, 1631 1 HNvR (DMSOd 6 4001Vz) 6 :11.49 (iR, 10.95 (1H, 9.67 (1H, s), 9.34 (1H, 9.27 (1H, 8.52 8.48 (1H, 8.29 8.28 (2H, 8.00 (2H, 7.68 (1H, 7.59 (2H, 7.46 (1H, 6.63 (2H,s) Mass :366, 367, 368, 369 Example 13 1-(2-Ethox-2-oxoethIl-3-((phenvimethvl)sulfonvI hvdrazino carbonyl) Dyridinium bromide (Compound 12): Yield m.p. 147 148C IR (KBr, :1749,1698, 1640 'HNMR (DMSOd 6 400 MHz) 6 :11.57 (IH, 10.21 9.75 (1H,s), 9.38 (1H, 9.24 (1H, 8.59 8.56(1H, 7.67 7.65 (2H, 7.58 7.52 (3H, 5.90(2H, s),4.68 (2H, 4.45 4.39(2H, q),1.43 (3H, t).

Mass (mlz) 377, 378, 379 ExamDie 14 1-(2-Phenl-2-oxoethl)-3-((phenlmethvl)sulfonvI hvdrazino carbonvlhwridinium bromide (Compound 13): Yield M.p. 205 207' C R (KBr, 1687, 1637 'HNMR (DMSOd 6 400 MHz) 6 :11.59 10.20 9.71 (1H,s), 9.33 (1H, 9.27 (1H, 8.62 8.59(1H, 8.25 8.23 (2H, d), 7.99 -7.95 (1H, 7.86 7.82 (2H, 7.67 7.65 (2H, 7.57 7.52 (3H, m),6.72 (2H, 4.69 (2H, s).

Mass :410,411,412,413 Example N, N' Bis [3-carbonvl-1-(2-furan-2'-vl-2-oxoethvl) pyridiniumi hydrazine dibromide. (Compound No: 14) Yield 23% M.P. 267-269 TC (dec) IR (KBr, cm') :1687, 1660 'HNMR(DMSOd 6 400MiHz)6: 11.65 9.56 9.21 -9.15 8.48- 8.44 8.23 7.74 7.73 6.91 6.90 (2H,d) 6.34 (4H,s) Mass (mlz) 459, 460, 461 Examplel16 NN'-Bis [3-carbonvi (2-thien-2'-vI-2-oxoethvI) pyridiniumi hydrazine 0 0dichloride.(Compound No: %..Yield M.P. :275-277 TC W. (KBr, :3374, 1665,1632, 1410 NMIR (DMSO d 6 400 MHz) 8: 11.88 9.66 9.29 9.24 8.48 8.44 8.25 8.23 7.43 7.41 6.53 (4H,s).

Mass 491, 492, 493, 494 Example 17 1-(2-Thien-2'-vI1-2-oxoethvl)-3-((2-(l-oxo-3-cvclohexvl)-nropvl)-hydrazilo carbonvi)pyridinium bromide( Compound No: 16); Yield m.P. :'217 -219 TC( dec) IR (KBr, cm") :3190, 1708, 1667 and 1404 'H NMR (DMSO d 6 400 MHz) 6 11.07 10.22 9.51 9.16 9.15 9.06-9.04 8.42- 8.40 8.25 -8.21 7.43 -7.40 6.44 2.25 -2.22 1.72 1,60 1.49- 1.43 1.24- 1.10 0.9-0.85 (2H,m) Mass :400,401,402 and 403 Example 18 1-(2-Phenvlamino-2-oxo ethvl)-3-(f2-(1-oxo-3-cvclohexl)-propvI -hydrazinocarbonyll-nyridinium bromide.(Compound No: 17); Yield m.p 234-236 C (dec) IR (KBr, cm') :1689, 1652 and 1625 'H NMR (DMSO d 6 400 MIHz) 6:11.11 10.95 (1Hs), 10.23 (1Hs), 9.56 (1H,s), 9.23 9.21 9.06 9.04 8.38-8.35 7.62 7.60 7.37 7.33 7.12-7.09 5.75 2.25-2.22 1.72- 1.60 (5H,m) 1.49- 1.43 000*00 1.25 1.10 0.91 -0.83 (2H,m) Mass (mlz) :409, 410, 411 and 412 Example 19 1-(2-Thien-2'-vI-2-oxoethvl)-3- [2-(benzovioxv~ethvyamino carbonvil-pyridinium bromide (Comnound No:18); Yield m.p. 125-127 0

C

IR (KBr, :1710 and 1675 'H NMR (DMSO d 6 400 MHz) 6: 9.48 9.43 9.41 9.12 9.11 (1H,d), 9.05 9.02 8.40 8.36 8.25 8.20 8.00 7.98 7.68 7.64 7.54-750 7.42 7.40 6.43 4.46-4.43 3.77- 3.73 (2H,q) Mass (mlz) :395, 396, 397 and 398 Example 1-(4-Ethoxv-2. 4-dioxobutvl)-3-(2-(benzoxvloxvjethvlamino carbonvl)-pvridinium chloride. (Compound No: 19); Yield m.p. 147-149C IR (KBr, :1743, 1720, 1680 and 1627 'H NMR (DMSO d 6 400 MHz) 6 9.62 9.59 9.32 9.29 9.05 9.03 8.93 8.90 8.27 8.24 7.92 7.89 7.59 7.55 (1H,m), lo 7.45 7.41 5.82 4.37-4.34 4.08-4.03 3.80 3.67- 3.63 1.15-1.11 (3H,t), Mass :399, 400 and 401 Example 21 1-(2',4'-Dichloro-phenvl-2-oxoethvl)-3-(2-methoxvethyI aminocarbonyl)-pyridinium too**: bromide. (Compound No: Yield m.p. :93-95 C IR (KBr, cm') :1704, 1664 and 1636 'H NMR (DMSO d 6 400 MHz) 6: 9.48 9.29 (1H,bs), 9.11 9.08 8.41 8.38 8.15 8.13 7.92- 7.91 7.78 7.75 6.44 (2Hs,) 3.52 (2H,bs), 3.51 (2H,bs), 3.28 (3H,s) Mass (mlz) :367,368,369 and 370 Example 22 N,N'-Bis- 13-carbonl- 1-(2-cvcloprovlamino-2-oxoethl) pyridiniuml hydrazine dichloride. (Compound No: 21); Yield m.p. 228-230 0

C

IR (KBr cm') :1675, 1636 and 1298 'H NMvR (DMSO d 6 400 MI~z) 5: 11. 85 9.59 9.25 9.19 9.00 8.99 8.39 8.36 5.53 2.73 2.66 0.78 0.62 0.53 0.49 (4H,m) Mass (mlz) 437, 438 and 439 Example 23 1-(2-Cvclopropvlamino-2-oxoethvl)-3-(2-methoxvethylaminocarbonvl)-pvridinium chloride. (Compound No: 22); Yield M.P. :122-124 T IR (KBr, cm) :1661, 163 3, 1549 and 1121 H NMvR (DMSO d 6 400 6: 9.40 9.08 9.02 8.28 8.25 (1H,m), 0 5.53 3.66 3.61 3.39 2.78 2.74 0.80 0.75 (2H,m), 0.64 0.61 (2H,m) 00*:Mass (mlz) :278, 279 and 280 0 Example 24 o oN-N'-Bis I3-carbonvl-1-(2-isopropylamino-2-oxoethvl) pyridinium] hydrazine dichloride. (Compound No: 23); Yield M.P. 114-116 TC (dec) IR (KBr, cm-1) :1707, 1668 and 1637 1H NMIR(DMSO d 6 ,400 MHz)6: 11.84 9.59 9.21 9.18 8.74- 8.72 8.39 8.3 5 5.53 3.92 3.84 1. 14 1.02 (12H,d) Mass (mlz) :441, 442 and 443 Example 1-(2-Thien-2'vl-2-oxoethvl)-3-(2-(2-chloro-3-pvridovlhvdrazinocarbonv)-pyridilium chloride, (Compound No: 24); Yield :56% mp. :233-235 C IR (KBr, cm- 1 1680, 1637, 1404 and 1293 'H NMR (DMSO d 6 400 MHz) 6 11.62 11.05 9.62 9.24 9.23 9.18 9.16 8.58 8.56 8.46 8.43 8.26- 8.24 (2H,m), 8.02 8.00 7.61-7.58 7.43 7.41 6.51 (2H,s) Mass (mlz) :401, 402, 403, 404 and 405 Examvle 26 1-(2-IsoDropvyamino-2-oxoethvl)-3-(2-methylsulfonylhvdrazinocarbonvl)-Dvridinium chloride. (Comound No: Yield m.p. :227-229 C JR (KBr, :1691, 1670, 1566 and 1330 'H NMR (DMSO d 6 400 MHz) 6:11.55 9.94 9.52 9.16 9.14 9.09 9.07 8.72 8.70 8.34 8.30 5.50 3.89 3.84 3.11 1.13- 1.12 (6H,d) Mass (mlz) :315, 316 and 317 Example 27 -PrrolidinvIl-2-oxoethv)-3-(methanesulfonyI hydrazino carbonvl) pyridinium chloride (Compound No: 26); Yield :21.00% m.p. :205-207 0

C

JR (KBr, cm-i) 1699, 1646 and 1589 1 HNMR :(DMSO d 6 400 MHz)5 11.50 (1H, 9.94 (1H, 9.46 (1H, 9.11 9.06 (2H, 8.36 8.33 (1H, 5.75 (2H, 3.55 3.48 (3H, 3.10 (3H, 2.00 1.95 (2H, 1.87- 1.81 (2H, m) Mass (mlz) :327, 328, 329 and 330 Examnle 28 1-(2-Thien-2'-vl-2-oxoethl)-3-(methanesulfonyl hydrazino carbonvl) pyridinium chloride (Compound No: 27); Yield :31.00% m.p. :215- 217C JR (KBr, :1685, 1666 and 1635 'HNMR :(DMSO d 6 400 MH,) 6: 11.49, (1H, 9.96 (1H, 9.55 (1H, 9.18 (1H, d), 9. 10 (1H, 8.43 8.39 (1H, 8.25 8.22 (2H, 7.42 (1H, t) 6.47 (2H, 3.09 (3H, s).

Mass (mz) :340, 341, 342 and 343 Example 29 N,N'-Bis 13-carbonvl- l-(2-hydroxv-2-oxoethvl) pyridiniumi hydrazine dichloride (Compound No: 28): Yield :43.00% m.p. :235 240C (d) JR (KBr, cm') :1743, 1700 and 1672 1 HNMR (DMSO d 6 400 MHz) 6: 11.89 (2H, 9.69 (2H, 9.31 9.29 (2 H, 9.25 o 9.23 (2H, 8.43 8.39 (2H, t) 5.70 (4H, s) 0*0.

.0 Mass :360,361,362 Example 1-(2-Thien-2-vl-2-oxoethvl)-3-((2-methoxy ethyl) amino pyridinium chloride (Compound No: 29); Yield :31.00% m.p. .180 182 0

C

JR (KBr, 1661 and 1620 'HNMR (DMSO d 6 400 MH,) 6 9.58 9.54 (2H, 9.43 9.39 (2H, 8.25 8.21 (2H, 7.41 (1H, 6.43 (2H, 3.51 (4H, 3.29 (3H, s).

Mass (mlz) :384, 385, 386, 387 and 388 Example 31 1-(2-Thien-2'-vl-2-oxoethvl)-3-[I1-oxo- 1-(2-methoxvcarbonvl) pyridyll hydrazino pyridinium chloride (Compound No: Yield :30.00% M.P. :222 225 0

C

IF. (KBr, cm-) :1726, 1708 and 1662 'H NMIR (DMSO d 6 400 MH) 86 11.47 (1H, 11.23 (1H, 9.58 (1H, 9.22 9.15 (3H, in), 8.56 8.53 (1H, 8.46 8.43 (1H, t) 8.25 8.21 (3H, in), 7.42 (1H, 6.49 (2H, 3.95 (3H, s) Mass :425, 426 and 427 Example 32 1- I1-(2-Thien-2' -vl-2-oxoethyl)-6methyl-3-carbonvl pyvridiniuml-2- I1-(2-Thien-2' -vl- 2-oxoethyl )-3--carbonyl pyridinium 1 hydrazine dichloride(compound no: 31), ::*Yield M.P. 76-80 0 c (dec) IF. KBr, cm 1 1637,1513 'HINMR (DMSO d 6 400MNHz) 5 11.69(2H,s), 9.59-9.53(2H,d), 9.19(2H,in), 9.05(1H,d), 8.46-8.43(1H,t) ,8.34(1H,d), 8.27-8.23(4H,in), 7.45-7.41(2H,n) ,6.56(2H,s) ,648(2H,s) ,2.81(3H,s).

Mass(iz) 505,506,507.

Example 33 1-(2-Thien-2' -vl-2-oxoethyl)-3-(isop~ropvlsulfonvl hydrazino carbonyl) pyridinium bromide(compound no: 32), Yield M.P 90-95%c (dec) 1R KBr,cm- 1 1638,1589 'HNMR (DMSO d 6 400 MI~z) 8 11 .27(1H,s) ,9.91(1H,s), 9.60(1H,s) 19- 9. 15(2H,m), 8.42-8.36(1H,m) ,8.25-8.21(2H,m) ,7.43-7.41(1H,t) ,45(2H,s), 1.35- 1 .34(6H,d).

Mass(mlz) 368,369,370 Example 34 1-(2-(4-Benzvl iperidin- 1-vi)-2-oxoethvI)-3-(methanesulfonvI hydrazino carbonyl) pyridinium chloride(compound no: 33), Yield 17% MYP 76-780c JR (KBr,cmn 1 1684,1650,1556,1540.

.*.*'HNMvR (DMSO d 6 400 Mifz) 6 11. 46(1 H, s) ,9.5 5(1 H,s) ,9.46(1H, s) ,9.09- 9.03(2H,m), 8.36-8.32(1H,t), 7.33-7.29(2H,m), 7.23-7.19(3H,m), 5.88-5.79(2H,m) ,4.30- 4.27(1H,d) ,3.76-3.73(IH,d), 3.10(4H,m) ,2.64(1H,t) ,2.57-2.55(2H,d), 1.85(1H,bs) ,1.72-1.63(2H,t) ,1.36-1.28(1H,q) ,1.13-1.03(1H,m) **.Mass(mlz) 431,432,433 Example .1-(2-(2-Ethoxl carbonyl pvyrrolidin-1-ylj-2-oxoethvl)-3-(methanesulfonvl hydrazino carbonyl) pyridinium chloride. (compound no: 34), Yield 14% M.P 88-91 0 c JR KBr, cm') 1735,1665,1539 'HNMR (DMSO d 6 400 MHz) 5 11.48(1H,s) ,9.96(1H,s) ,9.46(1H,s) ,9.09- 9.05(2H,m) ,8.38-8.34(1H,t), 5.94-5.80(211,q) ,4.37-4.36(1H,d), 4.08-4.06(2H,d), 3.68- 3.65(2H,m), 3 .09(4H,m) ,2.23-2. 18(2H,m), 2.04 -1 .93(3H,m) J1.18-1 .09(3H,t) Mass(mlz) 399,400,401 Example 36 1-(2-Thien-2' -vI-2-oxoethvl)-3-(methanesulfonvI hydrazino carbonyl pyridinium bromide. (compound no: Yield 54% M.P Above 190-195 0 c(dec) IR (KB 1682, 15 57, 1540, 1520 'HNMIR (DMSO d 6 400 M4Hz) 5 1 1.35(1H,s) ,1O.O1(1H,s) ,9.57-9.54(2H,d), 9.32(1H,s), 8.26-8.22(2H,m), 7.42(1H,s), 6.39(2H,s), 3.08(3H,s) Mass (mlz) 418,419,420 Example 37 1-(2-Thien-2'-vl-2-oxoethyl)-3-(ethoxvcarbonvl hydrazino carbonyl pyridinium bromide. (compound no: 36), Yield

MYP

JR KBr,cnf') 'H-NIVR(DMSOd 6 400 MHz) 5 9.18(1H,s), 9.05-9.04(1H,d), 8.42(1H,s), 4.12-4.1 1(2H,s), 1 .23(3H,s) Mass (mlz) 69% .155-1570c 1731,1665,1637 11.04(1H,s), 9.59(LH,s), 9.53(1H,s), 8.25-8.23(2H,m), 7.43(1H,s), 6.46(2H,s), 334,335,336 Example 38 1-(2-(5-chloro-thien-2-vi)-2-oxoethvI)-3-(methanesufonvl hydrazino carbonyl-) pyridinium bromide (compound no: 37), Yield

M.P

IR KBr,cm'1) 87% 228-230 0 c 1708, 1664, 163 1,15 'HNMvIR (DMSO d 6 400 M~lHz) 5 11.40(1H,s), 9.98(1H,s), 9.50(JH,s), 9.15(1H,d), 9.061H,d), 8.43-8.39(1H,t), 8.16-8.15(1H,d), 7.5 1-7.50(1H,d), 6.41(2H,s), 3.09 (3H,s) Mass (mlz) 374,375,376,377 Examplie 39 N-N'-BisI3-carbonvl- 1-(2-(4-nitro-thien-2-yi)-2-oxoethvl~hwridiniumI hydrazine dichloride. (compound no: 38), Yield 27% MY 204-207 0 c *ILB KBr,cm) 1681,1539,1514 'HNN'IR (DMSO d 6 400 MHz) 6 11. 90(2H, s) 9.63 (2H, s) ,9.3 1-9.3 0(4H, m) 9.24 -9.22(2H,m), 8.87(2H,s), 8.49-8.46(2H,t), 6.56 (4H,s) Mass (mlz) 581,582,583 Example *1-(2-Thien-2'-vl-2-oxoethyl)-3-(methanesulfonyI hydrazino carbon3L) -6-methyl pyridinium bromide, (compound no: 39), Yield 14% M.P 90-95 0 c(dec) LR (KB r, cm) 1677,1575 1 IHNfMll (DMSO d 6 400 MHz) 6 1 1.32(1H,s) 9.97(1H,s) 9.52(1H,s), 8.94- 8.92(1H,d) ,8.32-8.24(3H,m), 7.44(1H,t), 6.54(2H,s), 3.08(3H,s), 2.79(3H,s) Mass (mlz) 354,355,356 Example 41 N-N'-Bis 13-carbonvl- 1-(2-(5-methyl-thien-2-yi)-2-oxoethvl) pyridiniumi hydrazine dichloride, (compound no: Yield 37% M.P Above 166-168 0 c(dec) IR (KBr, cm') 1666,1500 'HNMR (DMSO d 6 400 MHz) 5 11.73(2H,s), 9.59(2H,s), 9.19-9.15(4H,d) 8.45-8.42(2H,t), 8. .06-8.05(2H,d) 15-7. 14(2H,d), 6.43 2.59(6H,s) Mass(ml/z) 519,520,521,522 Example 42 N-N'-Bis 13-carbonyl- 1-(2-(2-ethoxycarbonyI pyrrolidin- 1-vIO-2-oxoethvl) Pyridiniu ml hydrazine dichloride. (comound no: 41), Yield 28% M.P 118-1200c IR KBr, cm') 1660,1510 :'HNMVR (DMSO d 6 400 Mvllz) 5 11.75(2H,s), 9.51(2H,s), 9.20-9.10(4H,m) 8.43-8.40(2H,t), 5.97-5.83(4H,m) ,4.39-4.36(2H,m), 4.27-4.22(1H,q), 4. 12-4.05(4H,m), 3.71-3.63(4H,m), 3.48-3.40(1H,m), 2.26-2. 19(2H,m), 2.05-1 .91(5H,m), 1.30-1 .27(1H,t), 1. 19-1. 15 Mass(mlz) 609,610,611 Example 43 [1(2-Thien2'vl2oxoethy-5aminocarbonvi-3carbonvl pyridiniuml-2-I1-2- Thien-2%0v-2-oxoethyl )-3-carbonvl pyridinium I hydrazine dichloride (compound no: 42), Yield 54% M.P Above 127-129 0 c(dec) IR (KBr,cm-1) 1678, 1513 'BNMVR (DMSO d 6 400 M]Hz) 6 1 1.86(2H,s), 9.83-9.64(4H,t), 9.24 9.23(2H,s) 8.82(1H,s), 8.48-8.45(1H,t), 8.34(1H,s) 8.26-8.24(4H,m), 7.44 -7.42(2H,d), 6.52-6.46(4H,d) Mass (mlz) 534,535,536 Example 44 1-(2-(4-carbethoxv-thiazolidin-3vl1)-2--oxoethyl)-3-(methanesulfonvI hydrazino carbonyl) pyridinium chloride (compound no: 43), Yield 29% MPY 190-192 0 c 1k KBr,cm- 1 1673,1541 'HNMvIR (DMSO d 6 400 MIHz) 5 11.50(1H,s) 9.55(1H,s), 9.48(1H,s) 19.12-9.08(2H,m), 8.39-8.34(1H,t), 6.04 5.99(2H,m) 4.94 -4.91(1H,m), 4.87- 4.84(1H,d), 4.73-4.71(1H,d), 4.28-4.23(1H,q), 4.14 -4.09(1H,q), 3.43-3.38(1H,m),3.27- 3.22(1H,m), 3. 10(3H,s) ,1.30-1.27(1H,t), 1.20-1. 17(2H,m) Mass(m/z) 439,440,441 N-N'-Bis 13-carbonvl- 1-(2-(5-chloro-thien-2-vi)-2-oxoethvl) pyridinium] hydrazine 0 dichloride. (compound no: 44), Yield *0 M.P Above 200-205 0 c (dec) 20 IR (KBr, cm') 1674,1590,1500 'HNVR (DMSO d 6 400 Ilz) 5 1 1.90(2H,s), 9.64 -9.61(2H,d), 9.29- 9.20(4H,m), 8.47-8.44(2H,t), 8.18-8.1 7(2H,d),7.5 1-7.50(2H,d), 6.49-6.48(4H,s) Mass(ml/z) 559,560,561,562,563,564 Example 46 1-(2-(5-MethvI-thien-2-vl)-2-oxoethvI)-3-(methanesulfonv1 hydrazino carbonvi) ipyridinium chloride (compound no: Yield 22% MYP 196-198 0 c IR KBr,cm-1) 1689,1657 'NR(DMSO d 6 400 MVHz) 5 1 1.47(1H,s) ,9.98(1H,s) ,9.53(1H,s) ,9.17- 9.16(1H,d), 9.09-9.07(1H,d), 8.42-8.38(1H,t), 8.06-8.05(1H,d), 7.15-7.14(1H,d), 6.4 1(2H,s), 3.09(3H,s), 2.59(3H,s) Mass(mlz) 354,355,356,357 Example 47 1-(2-(4-Nitro-thien-2-vi)-2-oxoethvl)-3-(methanesulfonvI hydrazino carbonyi) pyridinium bromide. (comoound no: 46), Yield 52% M.P Above 200-205'c(dec) R KBr,cm- 1 1688,1631,1541 se.:'HNMR (DMSO d 6 400 Iz) 6 1 1.41(1H,s), 9.50(1H,s) 9.309-9.306(1H,d), 9.17-9.15(1H,d) ,9.09-9.07(lH,d) ,8.866-8.862(1H,d) ,8.45-8.41(1H,t), 6.50(2H,s), 3.09(3H,s) Mass(m/z) 385,386,387 Example 48 *.1-(2-Phenvlamino-2-oxoethyl)-3-(phenyl hydrazino carbonyl) pyridinium chloride (compound no: 47).

Yield M.P 165-1670c IR KBr,cm') 1679,1626,1600,1497 'HNMIR(DMSO d 6 400 M~llz) 5 11.18(1H,s), 11.10(1H,s), 9.62(1H,s), 9.24-9.22(1H,d), 9.17-9.15(1H,d), 8.40-8.36(1H,t), 8.19(1H,s), 7.63-7.61(2H,d) 7.37- 7.33(2H,t), 7.20-7.16(2H,t), 7.12-7.09(1H,t), 6.88-6.86(2H,d), 6.78-6.74(1H,t), 78(2H,s) Mass(mlz) 347,348,349 Example 49 1-(2-Phenylamino-2-oxoethvl)-4 -f 2-(benzoyloxv) ethylamino carbonyl 1 pyridinium chloride (compound no: 48), Yield M.P 178-180 0 c IR KB r, cm) 1700,1666,1559 1 HNMI( (DMSO d 6 400 Miz) 65 11. 13 (1 H,s) 9.74 -9.7 1(1 H,t) 9.23 9.22(2H,d), 8.52-8.50(2H,d), 8.01-7.99(2H,d) 7.68-7.60(3H,m), 7.54-7.51(2H,t) 7.36-7.32(2H,t) 7.12-7.08 5.75 (2H,s) 4.47-4.45(2H,t) 3.77-3.72(2H,q).

Mass (ml/z) 404,405,406 Example 1-2-(5-Nitro-thien-2-vl)-2-oxoethvl)-3-(methanesulfonyI hydrazino carbonvil pyridinium chloride (compound no: 49), Yield M.P Above 105-110 0 c(dec) 0.IR KBr,cm'1) 1680,1620 20 'HN'MIR (DMSO d 6 400 MIHz) 6 11 .48(1H,s), 9.98(1H,s), 9.52(1H,s), 9.16- 0* 0* 9.10(2H,m) ,8.45-8.41(1H,t) ,8.35-8.34(1H,d) ,8.25-8.24(IH,d), 6.50(2H,s), 3.09(3H,s).

Mass (mlz) 385,386,387 Example 51 1-(2-Thien-2'-vl-2-oxoethvlD3-(Trifluromethanesulfonvl hydrazino carbonvi)pyridinium bromide (compound no: Yield 22% M.P 77-79c IR KBr,cm- 1 2960, 1690, 1673, 1591 1 JPP4J (DMSO d 6 400 MHz) 8 1 1.76(1H,s), 1 1.27(1H,s), 9.61(1H,s), 9.20-9.19(1H,d) ,9.07-9.05(1H,d), 8.44-8.41(1H,t) ,8.25-8.22(2H,m), 7.34 7.41 6.46 (2H,s).

Mass (mlz) 394, 395, 396 Example 52 1-(2-Thien-2'-vI-2-oxoethvl)-3-(phenyl hydrazino carbonyl) pyridinium bromide (compound no. 51), Yield MYP 192-1940c 0IR KBr,cnf') 1669,1663,1603, *.oo 'HNMIR(DMSO d 6 400 MI~z) 6 10.99(1H,s), 9.54(1H,s), 9.17-9.14(2H,t), 0 0 06.79-6.75(1H,t), 6.46(2H,s) Mass(mlz) 338,339,340 *00.0*Example 53 0 0 20 1-(2-Thien-2'-vI-2-oxoethvl)-3-(p)-methoxp Phenyl sulfonyl hydrazino carbonvi) pyridinium bromide (compound no. 52), Yield 28% MYP 126-128 0 c IR KBr, cm') 1672,1653,1596 'HNMR (DMSO d 6 400 MI~z) 5 11.34 -1 1.33(1H,d), 10.27-10.26(1H,d), 9.34(1H,s), 9.13-9. 12(1H,d), 8.94-8.92(1H,d), 8.38-8.34(1H,t) ,8.24-8. 19(2H,m),7.82- 7.75(2H,m) ,7.42-7.40(1H,t), 7.07-7.04(2H,d) ,6.40(2H,s), 3.8 1(3H,s).

Mass(mlz) 432,433,434 Example 54 1-(2-Ethoxv-2-oxoethyl)-3-(phenvl aminocarbonyl hydrazino carbonyl) pyrid in jum bromide. (comnound no. 53), Yield MPY 183-185 0 c IR KBr,cm') 1746,1717,1682 'HNMIR (DMSO d 6 400 ME~z) 5 11 .02(1H,s), 9.57(1H,s), 9.22-9.21(1H,d), 9.1 1-9.09(1H,d), 9.00(1H,s), 8.57(1H,s) ,8.44-8.41(1H,m),7.47-7.45(2H,d) ,7.29- 7.25(2H,t) 7.00-6.96(1H,t), 5.74(2H,s), 4.28-4.23(2H,q), 1.28-1 .25(3H,t).

Mass(mlz) 343,344,345,346 Example *1-(2-Ethoxv-2-oxoethvl)-3-(p)-toluene sulfonyl hydrazino carbonvi) pyridinium bromide. (compound no. 54), Yield 54% M.PY 174-176 0 c iR (KBr,cm). 1746,1712,1634 20 'HNTVMR (DMSO d 6 400 MIHz) 5 1 1.33(1H,s), 1O.36(1H,s) 9.37(1H,s), 9.18-9.16(1H,d), 8.93-8.91(1H,d), 8.37-8.33(1H,t), 7.78-7.76(2H,d), 7.37-7.35(2H,d), 5.68 (2H,s) 4.26-4.20(2H,q) ,2.37(3H,s), 1,27-1 .23(3H,t).

Mass (mlz) 378,379,380,381 Example 56 1-(2-Phenvl-2-oxoethvl)-3-(p~henvlamino carbonvi1 hydrazino carbonyl pyridinium bromide. (compound no. Yield M.P 206-208 0 c IR KBr, cm') 1713,1684,1634 'HNMR (DMSO d 6 400 MHz) 5 11.05(1H,s), 9.55(1H,s), 9.18-9.13(2H,m), 9.02(1H,s), 8.59(1H,s), 8.49-8.45(1H,m) ,8.09-8.07(2H,d), 7.84-7.80(1H,t), 7.71- 7.67(2H,t), 7.49-7.47(2H,d), 7.30-7.26(2H,t), 7.01-6.97 (1H,t) ,6.56(2H,s).

Mass (mlz) 375,376,377 Example 57 1-(2-Phenvlamino-2-oxoethvI)-3-(benzvI sulfonyl hydrazino carbonyl) Dvridiniumchloride. (compound no. 56), Yield 48% M.PY 208-2 10 0 c IR (KBr, cm") 1712,1681,1632 'HNMR (DMSO d 6 400 MIHz) 6 1 1.46(1H,s) ,10.80(1H,s), 9.59(1H,s), 9.22- 9.20(1H,d) ,9.08-9.06(1H,d), 8.38-8.36(1H,t),7.60-7.58(2H,d) ,7.49(2H,m), 7.39- :*.Mass(mlz) 425,426,427,428 Examnle 58 1-(2-Phenvl-2-oxoethvD)-4-(methanesulfonvl hydrazino carbonvil~ pyridinium 20 bromide (compound no. 57), Yield M.P 190-192 0 c IR (KBr,cm-1) 1679,1630,1650 1 HNM\1R (DMSO d 6 400 IVLHz) 6 1 1.54(1H,s), 1.03(1H,s), 9.20-9.18(2H,d), 8.59-8.57(2H,d), 8. 10-8.08(2H,d), 7.84 -7.80(1H,t), 7.71-7.67(2H,t), 6.56(2H,s), 3 .08(3H,s).

Mass(mlz) 334,335,336 Example 59 1-(2-Phenyl-2-oxoethvl)-3-(phenvl hydrazino carbonyl pyridinium bromide (compound no. 58), Yield

M.P

1k KBr,cm'1) 'HNUIR (DMSO d 6 400MNIHz) 5 8.46-8.42(1H,t), 8.09-8.07(2H,d) 6.88-6.86(2H,d), 6.79-6.75( 1H,t), Mass(ml/z) 36% 204-206Oc 1686,1653,1630 I1.01(1H,s) ,9.53(lH,s) 17-9. 16(2H,m), 7.82-7.78(1H,t), 7.69-7.65(2H,t), 7.20-7.16(2H,t), 6.56(2H,s) 332,333 goes :6.00, Example 1-(2-Ethoxv-2-oxoethyl)-4- I2-(benzoyloxy) ethyl amino carbonyl 1 pyridiniu m bromide (compound no. 59), Yield

M.P

IR KBr, cm' 82% 154-1560c 1742,1719,1707,1675 a C a a *a a

C.

a. a

C.

'IiMJJ (DMSO d 6 400 MIHz) 6 9.57-9.54(1H,t), 9.22-9.20(2H,d), 8.51- 8.49(2H,d), 8.0O-7.98(2H,d), 7.68-7.64(1H,t), 7.54 -7.5 1(2H,t), 5.72(2H,s) 4.47- 4.44(2H,t), 4.27-4.21(2H,q), 3.76-3.72(2H,q), 1.27-1.24. (3H,t) 20 Mass(mlz) 357,358,359.

Example 61 1-(2-Ethoxy-2-oxoethvl)-3-(phenyI hydrazino carbonyl pyridinium bromide.(compound no. Yield 37% M.PY 185-187 0 c IR (KBr,cm- 1 1740,1690,1630.

'HNMR (DMSO d 6 400 MI~z) 5 1 1.01(1H,s), 9.58(1H,s), 9.23-9.14(2H,m), 8.42-8.39(1H,t), 8.19(1H,s), 7.20-7.16(2H,t) 6.87-6.85(2H,d), 6.78-6.75(1H,t), 5.75(2H,s), 4.28-4.22(2H,q), 1.28-1 .24(3H,t) Mass(mlz) 300,301,302.

Example 62 1-(2-Phenvl-2-oxoethvl)-3-(p)-methoxvphenvI sulfonyl hyd razino carbonyl) iyridinium bromide (comound no. 61'), Yield 59% MPY 188-190 0 c JR KBr,cm'1) 1671,1634,1580.

'HNMvIR (DMSO d 6 400 MIHz) 6 11.26-1 1.25(1H,d), 10. 17- 1.16(1H,d), 9.24(1H,s), 9.03-9.O1(1H,d), 8.87-8.85(1H,d), 8.3 1-8.27(1H,t), 7.97-7.96(2H,d), 7.74 7.69(3H,m), 7.60-7.56(2H,t), 6.99-6.97(2H,d), 6.40(2H,s), 3.73(3H,s).

Mass(mlz) 426,427,428,429 Example 63 1-(2-Phenvl-2-oxoethvl)- 4- I2-(benzovloxv') ethyl amino carbonyl I Pyridinium 15 bromide (Compound no. 62), :O*Yield 92% MY 202-204'c TR (KBr,cm') 1715,1692,1650 000 20 'HNVR (DMSO d 6 400 MiHz) 6 9.55(1H,s), 9.14 13(2H,d), 8.52- 0.8.5 1(2H,d), 8.07-7.99(4H,m), 7.80-7.51(6H,m), 6.52(2H,s), 4.46(2H,s), 3.76- 0 3.75(2H,s).

Mass(mlz) 3.89,390,391,392 Example 64 1-(2-Ethoxy-2-oxoethvl)- 4-(ip-methanesulfonyl hydrazino carbonvl Byrid inium bromide. (compound no. 63), Yield M.PY 94-96 0 c IR (KBr,cm- 1 1726,1681,1643 'HNMR (DMSO d 6 400 MHz) 5 11.49(1H,s) ,9.98(1H,s) ,9.23-9.21(2H,d), 8.54-8.52(2H,d), 5.73(2H,s), 4.28-4.22(2H,q), 3.09(3H,s), 1.28-1.25(3H,t).

Mass(m/z) 302,303,304,305.

Pharmaceutical Compositions Pharmaceutical compositions may be prepared with a pharmaceutically effective quantity of compounds of general formula I, 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 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 15 forms either in ready to use form or forms suitable for reconstitution such as mixtures, syrups, 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, dicalcium phosphate, talc, magnesium stearate, polymeric substances like methyl cellulose, fatty acids and derivatives, sodium starch glycollate, etc. may also be used.

Example Preparation of oral dosage form: A typical tablet has the following composition: Active ingredient of formula I Lactose Starch Polyvinyl pyrolidone (K-30) Talc Magnesium Stearate as given above 135 mg 76 mg 2 mg 1.5 mg 1.0 mg 0 0 0 0 0004 00 0 :00% 00 1.

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 15 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 reconstitution. 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 66 Preparation suitable for parenteral administration has the following composition: Active ingredient of formula I Polyethylene glycol (400) Sodium metabisulphite Isotonic saline/ WFI as given above 0.75 ml 0.01% q.s.

Other Formulations.

For the dermatological 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.

.o* *oo *o o **go o *oo

Claims (17)

1. A pyridinium derivative of formula I (Rz)m COR 1 +N X- R3z 0 (I) wherein CORI is at the 3 position and R 1 is a moiety of formula II r r r wherein in formula II at least one of positions 2, 4, 5 and 6 of the pyridino moiety and/or at least one of positions 3, 4 and 5 of the thienyl/furyl moiety are substituted; and wherein Y is S or O; R 2 is independently selected from the group consisting ofF, Cl, Br, I, OR 7 NO 2 alkyl, aryl including heteroacyl, formyl, acyl, C(O)NR 7 Rio, C(O)OR 7 NR 7 RIo, N=C(R 7 )(Rio), SR 7 SO 2 NH 2 SO 2 alkyl and SO 2 aryl and m is 0 or 1; R 7 is selected from the group consisting of H, alkyl and aryl including heteroaryl; Rio is selected from the group consisting of H, alkyl and aryl including optionally substituted heteroaryl; R 3 is a substituted thienyl moiety; X and Z are independently selected from the group consisting of 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, BF 4 and PF6"; with the proviso that, 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 a heteroaryl ring of Rio, when present, is optionally quaternized; (iii) optionally, the thienyl/furyl moiety from R 3 and formula II are independently 0* S* replaced by NHcyclopropyl.

2. A compound according to claim 1 wherein at least one of positions 2, 4, 5 and 6 of the pyridino moiety and/or at least one of positions 3, 4 and 5 of the thienyl/furyl moiety of formula II are substituted with a moiety independently selected from the group consisting ofF, Cl, Br, I, NO 2 alkyl and -C(O)NHRio.

3. A compound of formula I S. (R2) X [COR 1 +N X- R3 I (I) wherein COR 1 is at the 3 position and R 1 is -NHNHSO 2 RI 1 -NHNHCONHRII; or -NHNHCOR 11 R 11 is substituted or unsubstituted cyclic, acyclic alkyl or aryl; and R 2 R 3 and X are as defined in claim 1, with the proviso that 1-(2-thien-2'-yl-2-oxoethyl)-3-(methanesulfonyl hydrazinocarobonyl) pyridinium bromide is specifically excluded.

4. A pyridinium derivative which is selected from the group consisting of the following compounds: N,N'bis [3-carbonyl (2-thien-2'-yl-2-oxoethyl) pyridinium] hydrazine dichloride, N,N'-bis-[3-carbonyl-l-(2-cyclopropylamino-2-oxoethyl) pyridinium] hydrazine dichloride, 1-(2-phenylamino-2-oxoethyl)-4-(phenylsulfonyl hydrazino carbonyl)pyridinium chloride and pharmaceutically acceptable salts thereof, -dichlorophenyl)-2-oxoethyl)-3- (2(methoxy) ethyloxycarbonyl) pyridinium bromide and pharmaceutically acceptable salts thereof, 1-(2-phenylamino-2-oxoethyl)-3-((benzoyloxy) ethylaminocarbonyl) pyridinium chloride and pharmaceutically acceptable salts thereof, 1-(2-thien-2'-yl-2-oxoethyl)-3-(phenylaminocarbonyl hydrazinocarbonyl) pyridinium bromide and pharmaceutically acceptable salts thereof, 1-(2-phenyl-2-oxoethyl)-3-(2-(acetoxy) ethylaminocarbonyl) pyridinium bromide and pharmaceutically acceptable salts thereof, 1-(2-phenylamino-2-oxoethyl)-3-(phenyl sulfonyl hydrazino carbonyl) pyridinium chloride and pharmaceutically acceptable salts thereof, 1-(2-phenylamino-2-oxoethyl)-3-((4-methylphenyl)sulfonyl hydrazinocarbonyl) pyridinium chloride and pharmaceutically acceptable salts thereof, 1-(2-phenyl-2-oxoethyl)-3-(2-(benzoyloxy)ethyloxy carbonyl) pyridinium bromide and pharmaceutically acceptable salts thereof, 1-(2-thien-2'-yl-2-oxoethyl)-3-(phenylcarbonyl hydrazino carbonyl) pyridinium bromide and pharmaceutically acceptable salts thereof, 1 -(2-ethoxy-2-oxoethyl)-3 -((phenylmethyl)sulfonyl hydrazino carbonyl pyridinium bromide and pharmaceutically acceptable salts thereof, (in)l1-(2-phenyl-2-oxoethyl)-3 -((phenylmethyl)sulfonyl hydrazino carbonyl)pyridinium bromide and pharmaceutically acceptable salts thereof, N, N' bis [3 -carbonyl-1I-(2-fbran-2'-yl-2-oxoethyl) pyridinium] hydrazine dibromide, 1 -(2',4'-dichloro-phenyl-2-oxoethyl)-3 -(2-methoxyethyl aminocarbonyl)-pyridinium bromide, 1 -(2-thien-2'-yl-2-oxoethyl)-3 -((2-methoxy ethyl) amino pyridinium chloride, 1 -(2-thien-2'-yl-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl) pyridiniumn chloride, 1 -(2-thien-2'-yl-2-oxoethyl)-3 -(2-(2-chloro-3 -pyridoylhydrazinocarbonyl)-pyridinium chloride, *:oo 20 1 -(2-cyclopropylami no-2-oxoethyl)-3 -(2-methoxyethylaminocarbonyl)-pyridinium chloride, 1 -(2-isopropylamino-2-oxoethyl)-3 -(2-methylsulfonylhydrazinocarbonyl)-pyridinium chloride, 1 -(2-phenylamino-2-oxo ethyl)-3 1-oxo-3 -cyclohexyl)-propyl -hydrazino- carbonyl)-pyridinium bromide, 1 -(2-thien-2'-yl-2-oxoethyl)-3-12-(benzoyloxy)ethylamino carbonyl]-pyridinium bromide, 30 1 -(4-ethoxy-2, 4-dioxobutyl)-3 -(2-(benzoxyloxy)ethylamino carbonyl)-pyridinium chloride, (x)l1-(2-thien-2'-yl-2-oxoethyl)-3 -oxo-lI-(2-methoxy carbonyl) pyridyl] hydrazino pyridinium chloride, (y)l -(2-thien-2' -yl-2-oxoethyl)-5-aminocarbonyl-3 -carbonyl pyridinium]-2-[ 1-(2-thien- 2'-yl-2-oxoethyl )-3-carbonyl pyridinium] hydrazine dichloride, 1-(2-thien-2 I -yl-2-oxoethyl)-3 -(trifluoromethanesulfonyl hydrazino carbonyl) pyridinium bromide, (aa) 1-El-(2-thien-2 I-yl-2-oxoethyl)-6-methyl-3 -carbonyl pyridinium]-2- [1-(2-thien-2'-yl-2-oxoethyI )-3-carbonyl pyridinium hydrazine dichloride, (ab) N, I-bisI[3-carbonyl-1 -(2-(5-methyl-thien-2-yl)-2-oxoethyl) pyridinium] hydrazine dichloride, (ac) N,N I -bis[3-carbonyl-1I-(2-(5-chloro-thien-2-yl)-2-oxoethyl) pyridinium] hydrazine dichloride, (ad) 1 -(2-thien-2' -yl-2-oxoethyl)-3 -(methanesulfo'nyl hydrazino carbonyl )-6-methyl pyridinium bromide, (ae) N,N -bis[3 -carbonyl- 1 -(2-(4-nitro-thien-2-yl)-2-oxoethyl)pyridinium] hydrazine dichloride, (af) 1-(2-phenylamino-2-oxoethyl)-3-(phenyl hydrazino carbonyl) pyridinium chloride, (ag) 1 -(2-(4-nitro-thien-2-yl)-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl pyridinium bromide, (ah) 1 -(2-(5-nitro-thien-2-yl)-2-oxoethyl)-3-(methanesulfonyl hydrazino, carbonyl pyridinium chloride, (ai) 1-(2-(5-chloro-thien-2-yl)-2-oxoethyl)-3-(methanesulfony hydrazino carbonyl) (aj) 1-(2-thien-2' -yl-2-oxoethyl)-3-(ethoxycarbonyl hydrazino carbonyl) pyridinium bromide, (ak) 1 -(2-thien-2 I -yl-2-oxoethyl)-3 -(isopropylsulfonyl hydrazino carbonyl) pyridinium bromide, S (al) 1 -(2-thien-2 I -yl-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl) pyridinium bromide, (am) 1 -(2-(2-ethoxy carbonyl pyrrolidin- 1-yl)-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl) pyridinium chloride, (an) 1-(2-(5-methyl-thien-2-yl)-2-oxoethyl)-3-(methanesulfony hydrazino carbonyl) pyridinium chloride, (ao) 1 -(2-(4-carbethoxy-thiazolidin-3 -yl)-2-oxoethyl) -3 -(methanesulfonyl hydrazino carbonyl pyridinium chloride, (ap) 1 -(2-(4-benzyl piperidin- 1-yl)-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl) pyridinium chloride, (aq) N,N -bis[3 -carbonyl-l1-(2-(2-ethoxycarbonyl pyrrolidin- 1-yl)-2-oxoethyl) pyridinium] hydrazine dichloride, (ar) 1-(2-phenylamnino-2-oxoethyl)-4 2-(benzoyloxy) ethylamino carbonyl pyridinium chloride, (as) 1-(2-thien-2 I -yl-2-oxoethyl)-3-(phenyl hydrazino carbonyl) pyridinium bromide, (at) 1-(2-thien-2 -yl-2-oxoethyl)-3-(p-methoxy phenyl sulfonyl hydrazino carbonyl) pyridinium bromide, (au) 1-(2-ethoxy-2-oxoethyl)-3-(phenyl aminocarbonyl hydrazino carbonyl) pyridinium bromide, (av) 1-(2-ethoxy-2-oxoethyl)-3-(p-toluene sulfonyl hydrazino carbonyl) pyridinium bromide, (aw) 1-(2-phenyl-2-oxoethyl)-3-(phenylamino carbonyl hydrazino carbonyl) pyridinium bromide, (ax) 1-(2-phenylamino-2-oxoethyl)-3-(benzyl sulfonyl hydrazino carbonyl) pyridiniumchloride, (ay) 1-(2-phenyl-2-oxoethyl)-4-(methanesulfonyl hydrazino carbonyl) pyridinium bromide, (az) 1-(2-phenyl-2-oxoethyl)-3-(phenyl hydrazino carbonyl) pyridinium bromide, (ba) 1 -(2-ethoxy-2-oxoethyl)-4-[2-(benzoyloxy) ethyl amino carbonyl] pyridinium bromide, (bb) 1-(2-ethoxy-2-oxoethyl)-3-(phenyl hydrazino carbonyl pyridinium bromide, (bc) 1-(2-phenyl-2-oxoethyl)-3-(p-methoxyphenyl sulfonyl hydrazino carbonyl) pyridinium bromide, *.00 (bd) 1-(2-phenyl-2-oxoethyl)- 4-[2-(benzoyloxy) ethyl amino carbonyl] pyridinium bromide and (be) 1-(2-ethoxy-2-oxoethyl)- 4-(p-methanesulfonyl hydrazino carbonyl) pyridinium bromide.

A process for the preparation of the compound as claimed in any one of claims 1 to 4, 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.

6. The use of compound as claimed in any one of claims 1 to 4, in the manufacture of a medicament for diabetic complications and aging-related diseases, including kidney disease, nerve damage, retinopathy, atherosclerosis, microangiopathy, endothelial dysfunctions, dermatological conditions, discoloration of teeth and other organ dysfunctions.

7. A pharmaceutical composition for treatment of diabetic complications and aging related diseases which comprises a pharmaceutically effective amount of one or more compounds as claimed in any one of claims 1 to 4, or pharmaceutically acceptable salt(s) thereof in admixture with a pharmaceutically acceptable carrier, diluent, solvent or excipient.

8. The pharmaceutical composition as claimed in claim 7, in the form of an oral formulation.

9. The pharmaceutical composition as claimed in claim 8, wherein said o:.ooi pharmaceutically acceptable carrier is selected from group consisting of starch, lactose, polyvinyl pyrolidone talc and magnesium stearate. ooooo

10. The pharmaceutical composition as claimed in claim 7 in the form of a parenteral formulation. .o*

11. A method for the preparation of a parenteral formulation as claimed in claim which comprises dissolving one or more compounds 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.

12. The pharmaceutical composition as claimed in claim 6, in the form of a lotion, oral rinse and toothpaste.

13. A method for treating a diabetic patient by breaking a preformed AGE, within said patient, which comprises, administering an effective amount of a compound as claimed in any one of claims 1 to 4, either singly, or in combination with other drugs for antidiabetic therapy.

14. A method of preventing or treating diseases caused by diabetes and aging related complications, which comprises, administering to a patient in need thereof, an effective amount of a compound as claimed in any one of claims 1 to 4, either singly or in combination with a pharmaceutically acceptable carrier, diluent or excipient.

The method as claimed in claim 14, wherein the disease prevented or treated is a nephrological disorder, neurological disorder, atherosclerosis, retinal disorder, dermatological disorder, non-enzymatic browning of oral cavity, endothelial or other organ dysfunction and growth impairment.

16. The method as claimed in claim 15, wherein said compound is selected from the group consisting of: N,N'bis [3-carbonyl (2-thien-2'-yl-2-oxoethyl) pyridinium] hydrazine dichloride, S 15 N,N'-bis-[3-carbonyl- 1 -(2-cyclopropylamino-2-oxoethyl) pyridinium] hydrazine dichloride, 0 1-(2-phenylamino-2-oxoethyl)-4-(phenylsulfonyl hydrazino carbonyl)pyridinium chloride and pharmaceutically acceptable salts thereof, -dichlorophenyl)-2-oxoethyl)-3- (2(methoxy) ethyloxycarbonyl) pyridinium bromide and pharmaceutically acceptable salts thereof, 1-(2-phenylamino-2-oxoethyl)-3-((benzoyloxy) ethylaminocarbonyl) S' 25 pyridinium chloride and pharmaceutically acceptable salts thereof, 1-(2-thien-2'-yl-2-oxoethyl)-3-(phenylaminocarbonyl hydrazinocarbonyl) pyridinium bromide and pharmaceutically acceptable salts thereof, 1-(2-phenyl-2-oxoethyl)-3-(2-(acetoxy) ethylaminocarbonyl) pyridinium bromide and pharmaceutically acceptable salts thereof, 1-(2-phenylamino-2-oxoethyl)-3-(phenyl sulfonyl hydrazino carbonyl) pyridinium chloride and pharmaceutically acceptable salts thereof, 1-(2-phenylamino-2-oxoethyl)-3-((4-methylphenyl)sulfonyl hydrazinocarbonyl) pyridinium chloride and pharmaceutically acceptable salts thereof, 1-(2-phenyl-2-oxoethyl)-3-(2-(benzoyloxy)ethyloxy carbonyl) pyridinium bromide and pharmaceutically acceptable salts thereof, 1 -(2-thien-2'-yl-2-oxoethyl)-3 -(phenylcarbonyl hydrazino carbonyl) pyridinium bromide and pharmaceutically acceptable salts thereof, 1 -(2-ethoxy-2-oxoethyl)-3 -((phenylmethyl)sulfonyl hydrazino carbonyl)pyridimium bromide and pharmaceutically acceptable salts thereof, (in)l1-(2-phenyl-2-oxoethyl)-3 -((phenylmethyl)sulfonyl hydrazino carbonyl)pyridinium bromide and pharmaceutically acceptable salts thereof, N, N' bis [3-carbonyl-1-(2-furan-2'-yl-2-oxoethyl) pyridinium] hydrazine dibrom-ide, 1 -(2',4'-dichloro-phenyl-2-oxoethyl)-3 -(2-methoxyethyl aminocarbonyl)-pyridinium bromide, 1 -(2-thien-2'-yl-2-oxoethyl)-3 -((2-methoxy ethyl) amino carbonyl)-5 -bromo pyridinium chloride, (q)i1-(2-thien-2'-yl-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl) pyridinium 20 1 -(2-thien-2'-yl-2-oxoethyl)-3 -(2-(2-chloro-3 -pyridoylhydrazinocarbonyl)-pyridinium chloride, 1 -(2-cyclopropylarmino-2-oxoethyl)-3 -(2-methoxyethylaminocarbonyl)-pyridinium chloride, 1 -(2-isopropylanino-2-oxoethyl)-3 methylsulfonylhydrazinocarbonyl)-pyridinium chloride, 1 -(2-phenylamino-2-oxo ethyl)-3 1-oxo-3 -cyclohexyl)-propyl -hydrazino- ****carbonyl)-pyridinium bromide, 1 -(2-thien-2'-yl-2-oxoethyl)-3-II2-(benzoyloxy)ethylamino carbonyl]-pyridinium bromide, 1 -(4-ethoxy-2, 4-dioxobutyl)-3 -(2-(benzoxyloxy)ethylamino carbonyl)-pyridinium chloride, (x)l1-(2-thien-2'-yl-2-oxoethyl)-3 -oxo-l1-(2-methoxy carbonyl) pyridyl] hydrazino pyridinium chloride, 1-[l -(2-thien-2' -yl-2-oxoethyl)-5-aminocarbonyl-3 -carbonyl pyridinium] 1-(2-thien- 2' -yl-2-oxoethyl -carbonyl pyridinium] hydrazine dichloride, (z)l1-(2-thien-2' -yl-2-oxoethyl)-3 -(trifluoromethanesulfonyl hydrazino carbonyl) pyridinium bromide, (aa) 1 1 (-hi2 -yl-2-oxoethyl)-6-methyl-3 -carbonyl pyridinium]-2- [1 -(2-thien-2 -yl-2-oxoethyl -carbonyl pyridinium hydrazine dichloride, (ab) N,N I -bis[3 -carbonyl- 1 -(2-(5-methyl-thien-2-yl)-2-oxoethyl) pyridinium] hydrazine dichloride, 0 0 (ac) N, -bis[3 -carbonyl- 1 -chloro-thien-2-yl)-2-oxoethyl) pyridinium] hydrazine dichloride, (ad) 1-(2-thien-2' -yl-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl )-6-methyl pyridinium bromide, (ae) N,N'I -bis[3 -carbonyl- 1 -(2-(4-nitro-thien-2-yl)-2-oxoethyl)pyridinium] hydrazine dichloride, (af) 1 -(2-phenylamino-2-oxoethyl)-3 -(phenyl hydrazino carbonyl) pyridinium chloride, (ag) 1 -(2-(4-nitro-thien-2-yl)-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl pyridinium bromide, (ah) 1-(2-(5-nitro-thien-2-yl)-2-oxoethyl)-3-(methanesulfony hydrazino carbonyl pyridinium chloride, (ai) 1 -chloro-thien-2-yl)-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl) pyridinium bromide, (aj) 1-(2-thien-2' -yl-2-oxoethyl)-3-(ethoxycarbonyl hydrazino carbonyl) pyridinium bromide, (ak) 1 -(2-thien-2 I -yl-2-oxoethyl)-3 -(isopropylsulfonyl hydrazino carbonyl) pyridinium (at) 1 -(2-thien-2' -yl-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl) *~.-5-bromo pyridinium bromide, (am) 1 -(2-(2-ethoxy carbonyl pyrrolidin- 1 -yl)-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl) pyridinium chloride, (an) 1-(2-(5-methyl-thien-2-yl)-2-oxoethyl)-3-(methanesulfony hydrazino carbonyl) pyridinium chloride, (ao) 1 -(2-(4-carbethoxy-thiazolidin-3 -yl)-2-oxoethyl) -3 -(methanesulfonyl hydrazino carbonyl pyridinium chloride, (ap) 1 -(2-(4-benzyl piperidin- 1-yl)-2-oxoethyl)-3 -(methanesulfonyl hydrazino carbonyl) pyridinium chloride, (aq) N,N' -bis[3 -carbonyl- 1 -(2-(2-ethoxycarbonyl pyrrolidin- 1 -yl)-2-oxoethyl) pyridinium] hydrazine dichloride, (ar) 1-(2-phenylamino-2-oxoethyl)-4 2-(benzoyloxy) ethylamnino carbonyl pyridinium chloride, (as) 1-(2-thien-2 I -yl-2-oxoethyl)-3-(phenyl hydrazino carbonyl) pyridinium bromide, (at) 1-(2-thien-2' -yl-2-oxoethyl)-' -(p-methoxy phenyl sulfonyl hydrazino carbonyl) pyridinium bromide, (au) 1-(2-ethoxy-2-oxoethyl)-3-(phenyl aminocarbonyl hydrazino carbonyl pyridinium bromide, (av) 1-(2-ethoxy-2-oxoethyl)-3-(p-toluene sulfonyl hydrazino carbonyl) pyridinium bromide, (aw) 1 -(2-phenyl-2-oxoethyl)-3 -(phenylamino carbonyl hydrazino carbonyl pyridiniumn bromide, (ax) 1 -(2-phenylamino-2-oxoethyl)-3-(benzyl sulfonyl hydrazino carbonyl) pyridiniumchloride, (ay) I -(2-phenyl-2-oxoethyl)-4-(methanesulfony hydrazino carbonyl pyridinium bromide, (az) 1 -(2-phenyl-2-oxoethyl)-3-(phenyI hydrazino carbonyl pyridinium bromide, S 20 (ba) 1 -(2-ethoxy-2-oxoethyl)-4-[2-(benzoyloxy) ethyl amino carbonyl pyridiniumn 6 bromide, (bb) 1-(2-ethoxy-2-oxoethyl)-3-(phenyl hydrazino carbonyl pyridinium bromide, 25 (bc) 1-(2-phenyl-2-oxoethyl)-3-(p-methoxyphenyl sulfonyl hydrazino carbonyl) pyridinium bromide, (bd) I-(2-phenyl-2-oxoethyl)- 4-[2-(benzoyloxy) ethyl amino carbonyl] pyridinium.bromide and (be) 1 -(2-ethoxy-2-oxoethyl)- 4-(p-methanesulfonyl hydrazino carbonyl pyridiniumn :bromide.

17. A method of breaking preformed AGE products which method comprises contacting the preformed AGE products with a compound as claimed in any one of claims I to 4. Dated this 28th day of March 2001 TORRENT PHARMACEUTICLAS LTD Patent Attorneys for the Applicant:- F BRICE &CO