WO2007032016A1

WO2007032016A1 - An antimalarial baylis-hillman adducts and a process for the preparation thereof

Info

Publication number: WO2007032016A1
Application number: PCT/IN2005/000397
Authority: WO
Inventors: Narendra Puli; Gangadasu Banda; Srinivas Uppalanchi; Ravinder Mettu; Sriramoju Bharat Kumar; Ramesh Chilukuri; Vaidya Jayathirtha Rao; Janaswamy Madhusudhan Rao
Original assignee: Council Of Scientific And Industrial Research
Priority date: 2005-09-12
Filing date: 2005-12-02
Publication date: 2007-03-22
Also published as: PL1924558T3; JP2009507824A; EP1924558B1; US20070117822A1; EP1924558A1; US7666883B2

Abstract

The present invention is directed towards the synthesis of novel and new chloropyridine skeleton based compounds and these are Bayllis Hillman adducts having a remarkable in vitro anti-malarial activity. These compounds have been found to possess anti-malarial activity against chloroquine sensitive and chloroquine resistant Plasmodium falciparum. The anti-malarial compounds of the present invention inhibit the mature schizonts in vitro.

Description

AN ANTIMALARIAL BAYLIS-HILLMAN ADDUCTS AND A PROCESS FOR THE PREPARATION THEREOF

FIELD OF THE INVENTION The present invention relate to a novel Bayllis Hillman adduct which are having a remarkable in vitro anti-malarial activity against chloroquine sensitive and chloroquine resistance Plasmodium falciparum and a process for the preparation thereof. MCKGROUND OF THE INVENTION Malaria is one of the world's leading killer infectious diseases. Although almost a third of the Earth's population is considered to be at risk from this disease, about 90% of infections and deaths occur in Africa (Trigg, P.I., and Wernsdorfer, W.H., Parasitologia: (1999) 41, 329-332), contributing significantly to underdevelopment and poverty on this continent (Gallup, J.L., and Sachs, J.D., AmJ. Trop.Med. Hyg: (2001) 64s, 85-96). The estimated 300 million cases that occur per year result in considerable morbidity (e. g. fever, malaise, anorexia, anemia) and mortality of over 2 million children under age group of five (World malaria situation in 1994 part I. WkIy Epidemiol rec: (1997) 72, 269-274. The intracellular protozoal parasite Plasmodium falciparum, accounts for greater than 95% of the malarial deaths. An important contributor to the increase in incidence of malaria over the past 30 years has been the development of resistance of the malarial parasite to quinoline containing antimalarials such as chloroquine and quinine (Barat, L.M., and Boland, P.B., Drug resistance among malaria and other parasites. Met Dis Clin North Am: (1997) 11 (4), 969-987). In addition, it has been recognized that a number of complications, such as anemia, failure to gain weight and immunosuppression associated with malaria infection continue to occur for weeks and over months after the parasites are cleared from the body (Ho, M., Webster, H.K., and Looareesuwan, S. Antigen-specific immunosuppression in human malaria due to plasmodium falciparum. J. Infect Dis: (1986) 153, 763-771; McGregor, A., and Barr, M. Antibody response to tetanus toxoid inoculation in malarious and non-malarious Gambian children. Trans R Soc Trop Med hyg: (1962) 56, 364-367; Bradley-Moore, A.M., Greenwood, B.M. and Bradley, A.K. Malaria chemoprophylaxis with chloroquine in young Nigerian children. II. Effect on immune response to vaccination. Ann Trop Med Parasitol: (1985) 79, 563-573). For the majority of their life-cycle in humans, malaria parasites live in red blood cells. Within the erythrocytes, the parasites feed on hemoglobin, digesting the protein and releasing the heme. The heme which is released as the byproduct of hemoglobin is toxic compound to the parasite. The malarial parasite having a unique heme detoxication mechanism that the heme is converted to non-toxic heme polymer hemozoin (malaria pigment) within the food vacuole (Rudzinska, M.A., Trager, W. and Bray, R.S. Pinocytic uptake and the digestion of hemoglobin in malaria parasites. J. Protozool: (1965) 12(4), 563-576). Trager, W; Jensen, J. B. Science, (1976), 193, 674) that serves to protect the parasite from potentially toxic free heme, as well as to induce pathology in the infected host. Overtime, the intraerythrocytic parasite exhausts this energy and protein supply and then begins next stage of life cycle. Through a series of DNA and membrane divisions, trophozoites converted to mature schizonts. Schizonts-containing erythrocytes rupture, each releasing 6 to 24 merozoites and one large 'garbage bag' containing polymerized hemozoin. It is this process that produces febrile clinical attack. The released merozoites invade more erythrocytes to continue the cycle, which proceeds until death of the host or modulation by drugs or acquired immunity. The 2-chloropyridine based Baylis Hillman adducts and 4-quinolino-methanols are reported to be antimalarial agents. These classes of compounds are particularly acting on erythrocytic stage of the parasite.

The following references are examples for the synthesis of and biological evaluation of some of the antimalarial agents. These prior arts contain useful information and discussion on the preparation and properties of antimalarial agents. U.S.Pat.No.6,627,641(2003) reported the synthesis and use of naphthylisoquinoline alkaloids and their pharmaceutical formulation as efficient antmalarial agents.

U.S.Pat.No.6,479,660 (2000) reported the synthesis and use of quinoline compounds as antimalarial drugs. Sujatha, V.B. et.al. Bioorg & Med. Chem. Lett, 9, 731-736 (1999) reported the antimalarial activity of 3 -hydroxy alkyl-2-methylene-propionic acid derivatives.

U.S.PatNo. 6,689,777 (2004) reported the synthesis of novel substituted naphthothiozolium, aromatic guanylhydrazones and other compounds and compositions having antimalarial activity. Donald J.Krogstad. et al., Science, 238, 1283-1285 (1987) reported the mechanism of chloroquine resistance in Plasmodium. U.S.PatNo. 6,693,217 (2004) reported the synthesis of N, Nl- substituted asymmetrical imidodicarbonimidic diamides as antimalarial agents. Arnulf Dora et al., Nature ?>1A, 269-371 (1995) reported the process of heme polymerization and mechanism of action of chloroquine.

U.S.Pat.No. 180913 (2004) reported the synthesis of 2,4-diaminopyrimidine derivatives and their use as antimalarial agents by inhibiting dihydrofolate reductase (DHFR-Inhibitors) Christian Segheraert. et al. J.Med.Chem. 46,542-547(2003) reported the synthesis and antimalarial activity of N¹-(7-chloro-4quinolyl)-l,4 bis(3-aminopropyl) piperazine derivatives.

OBJECTS OF THE INVENTION

The main object of the present invention is to provide novel Baylis Hillman adducts based on the chloropyridine skeleton as anti malarial agents. Another object of the present invention is to provide pharmaceutical composition comprising novel Baylis Hillman adducts as antimalarial agents.

Still another object of the present invention is to provide a process for the preparation of novel

Baylis Hillman adduct based on the chloropyridine skeleton, as anti malarial agent.

SUMMARY OF THE INVENTION The present invention is directed towards the synthesis of novel chloropyridine skeleton based compounds and these are Bayllis Hillman adducts having a remarkable in vitro anti-malarial activity. These compounds have been found to possess anti-malarial activity against chloroquine sensitive and chloroquine resistance Plasmodium falciparum. The anti-malarial compounds of the present invention inhibit the mature schizonts in vitro. This invention meets the need for more efficient compounds against malaria, in particularly chloroquine resistance Plasmodium falciparum. Accordingly present invention provides novel compounds based on chloropyridine skeleton of general structural formula 1. These are the

Baylis Hillman reaction adducts having the general structure of formula I & II indicates total thirty seven (37) compounds which is represented below.

Formula 1 Ia: Rl=H, R2= CH3, X=acrylonitrile; Ha: Rl=H, R2=CH3, X=2- cyclopenten- 1 -one

Ib: Rl=H, R2= C2H5, X=acrylonitrile lib: Rl=H₅ R2=C2H5, X=2- cyclopenten- 1 -one

Ic: Rl=H, R2= Ph, X= acrylonitrile Hc: Rl=H, R2=Ph, X=2- cyclopenten- 1 -one

Id: Rl=COOMe, R2=H, X=acrylonitrile Hd: Rl= Ph, R2=CH3,

X=2-cyclopenten- 1 -one

Ie: Rl=H, R2=CH3, X=methyl acrylate He: Rl= COOMe,R2=H,

X=2-cyclopenten- 1 -one

If: Rl=H, R2=Ph, X=methyl acrylate Hf: Rl= Ph, R2=C00Et,

X=2-cyclopenten- 1 -one

Ig: Rl=H, R2=n-C5H11, X=acrylonitrile Hg: Rl=H, R2=4-OMe-Ph,

X-2-cyclopenten- 1 -one

Ih:Rl=Ph, R2=CH3, X=acrylonitrile Hh: Rl=H, R2=CH3,

X=2-cyclohexen- 1 -one

Ii: Rl=Ph, R2=C00Et, X=acrylonitrile IH: Rl=H, R2=C2H5,

X=2-cyclohexen- 1 -one

Ij: Rl=H, R2=4-OMe-Ph, X=acrylonitrile Hj: Rl=H, R2=Ph,

X=2-cyclohexen- 1 -one

Ik:Rl=H, R2=C2H5, X=methylacrylate Ilk: Rl=Ph, R2=CH3,

X=2-cyclohexen- 1 -one

II: Rl=H, R2=n-C5H11, X=methylacrylate III: Rl=COOMe, R2=H,

X=2-cyclohexen- 1 -one

Im: Rl=Ph, R2=CH3, X=methylacrylate Urn: Rl=Ph, R2=C00Et,

X=2-cyclohexen- 1 -one

In: Rl=COOMe,R2=H, X=methylacrylate Hn: Rl=H, R2=4-OMe-Ph,

X=cyclohexen- 1 -one

Io: Rl=Ph, R2=C00Et, X=methylacrylate

Ip: Rl=H, R2=4-OMe-Ph, X=methylacrylate

Iq: Rl=H, R2=CH3, X=ethylacrylate Ir: Rl=H₅ R2=C2H5, X=ethylacrylate Is: Rl=H, R2=Ph, X=ethylacrylate It: Rl=Ph, R2=CH3-, X=ethylacrylate Iu: Rl=COOMe,R2=H, X=ethylacrylate Iv: Rl=Ph, R2=COOEt, X=ethylacrylate

Iw: Rl=H, R2=4-OMe-Ph, X=ethylacrylate

DETAILED DESCRIPTION OF THE INVENTION

Accordingly the present invention provides a novel chloro pyridine skelton based Baylis-Hillman adduct having the general formula

^■wherein X=

Rl is selected from the group consisting of hydrogen, phenyl and carbomethoxy; R2 is selected from the group consisting of hydrogen, alkyl, CH₃, C₂H₅, phenyl, n-CsHn, carboethoxy and p- OMe-Ph; EWG is an electron withdrawing group selected from the group consisting of CN, COOMe and COOEt.

In an embodiment of the present invention the novel chloro pyridine skelton based Baylis- Hillman adduct used comprising the compounds of general formula I &II

I II

Rl is selected from the group consisting of hydrogen, phenyl and carbomethoxy; R2 is selected from the group consisting of hydrogen, alkyl, CH₃, C₂H₅, phenyl, n-C₅H_ll5 carboethoxy and p- OMe-Ph; EWG is an electron withdrawing group selected from the group consisting of CN, COOMe and COOEt. In yet another embodiment the novel chloro pyridine skelton based Baylis-Hillman adduct obtained is in the form of derivatives, analogues or salt thereof.

In yet another embodiment the novel chloro pyridine skelton based Baylis-Hillman adduct obtained is selected from the group consisting of 2-[(2-Chloro-5-methyl pyridine-3-yI)(hydroxy) methyl] acrylonitrile (Ia), 2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ib), 2-[(2-Chloro-5-phenylpyridine-3-yl) (hydroxy) methyl] acrylonitrile (Ic), methyl 6-chloro- 5-(2-cyano-l -hydroxy allyl) 2-pyridine carboxylate (Id), Methyl 2-[(2-chloro-5-methylpyridine- 3-)(hydroxy) methyl] acrylate (Ie), Methyl 2-[(2-chloro-5-phenylpyridine-3-yl)(hydroxy) methyl] acrylate (If), 2-[(2-chloro-5-n-pentylpyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ig), 2-[(2-Chloro-5-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] acrylonitrle (Ih), Ethyl 6- chloro-5-(2-cyano-l -hydroxy allyl)-2-phenyl-nicotinate (Ii), 2-[(2-Chloro-5-(4- methoxyphenyl)pyridine-3-yl) (hydroxy)methyl] acrylonitrile (Ij), Methyl 2-[(2-chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylate (Ik), Methyl 2-[(2-chloro-5-n-pentyl pyridine-3- yl)(hydroxy) methyl] acrylate (I 1), Methyl 2-[(2-chloro-5-methyl-6-phenyl pyridine-3- yl)(hydroxy) methyl] acrylate (Im), Methyl 6-chloro-5- [l-hydroxy-2- (methoxycarbonyl) allyl] pyridine-2-carboxylate (I n), Ethyl 6-chloro-5- (l-hydroxy-2- (methoxycarbonyl) allyl)-2- ohenyl-nicotinate (Io), Methyl 2-[(2-chloro-5- (4-methoxyphenyl) pyridine-3-yl)(hydroxy) methyl] acrylate (Ip), Ethyl 2-[(2-chloro-5-methyl pyridine-3-)(hydroxy) methyl] acrylate (Iq), Ethyl 2-[(2-chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylate (Ir), Ethyl 2-[(2-chloro-5- phenyl pyridine-3-yl)(hydroxy) methyl] acrylate (Is), Ethyl 2-[(2-chloro-5-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] acrylate (It), Methy-6-chloro-5-[l-hydroxy-2- (ethoxycarbonyl)allyl] pyridine-2-carboxylate (Iu), Ethyl 6-chloro-5-(l-hydroxy-2- (ethoxycarbonyl)allyl)-2-phenyl-nicotinate (Iv), Ethyl 2-[(2-chloro-5- (4-meth oxyphenyl) pyridine-3-yl)(hydroxy) methyl] acrylate (Iw), 2-[(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one (Ha), 2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one (lib), 2-[(2-Chloro-5-phenyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2- en-l-one (lie), 2-[(2-Chloro-5-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en- 1- one (Hd), Methyl-6-chloro-5-[hydroxy(5-oxo-l-cyclopentenyl)methyl]-2-pyridine carboxyl ate(IIe), Ethyl 6-chloro-5-[hydroxy(5-oxo-l-cyclopentenyl)methyl]-2-phenyl nicotinate (II f), 2- [(2-Chloro-5- (4-methoxyphenyl)pyridine-3-yl)(hydroxy) methyl]cyclopent-2-en-l-one(IIg), 2- [(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] 2-cyclohexenel-one (II h), 2-[(2-Chloro-5- ethyl pyridine-3-yl)(hydroxy) methyl] cyclohex-2-ene-l-one(IIi), 2-[(2-Chloro-5-phenyl pyridine-3-yl)(hydroxy) methyl] cyclohex-2-ene-l-one (Hj), Methyl 2-[(2-chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] "acrylate (Ik), Methyl 6-chloro-5-[hydroxy (5-oxo-l- cyclohexenyl)methyl]-2-pyridine carboxylate (II 1), Ethyl 6-chloro-5-[hydroxy(5-oxo-l- cyclohexenyl)methyl]-2-phenyl nicotinate (II m) and 2-[(2-Chloro-5-(4- methoxyphenyl)pyridine-3-yl)(hydroxy) methyl] cyclohex-2-en-l-one (H n). In yet another embodiment the novel chloro pyridine skelton based Baylis-Hillman adduct is active against chloroquine sensitive and chloroquine resistant Plasmodium falciparum strains. In yet another embodiment novel chloro pyridine skelton based Baylis-Hillman adduct exhibits an anti malarial activity against the erythrocytic stage of the malarial parasite.

The present invention further provides a pharmaceutical composition comprising novel anti malarial chloro pyridine skelton based Baylis-Hillman adduct, its derivatives, analogues or salt thereof optionally with pharmaceutically acceptable carriers, adjuvant and additives. The present invention further provides a method for the treatment of malaria in a subject wherein a dose of 1-45 μg/ml and 1-115 μg/ml drug is administered for IC50 against chloroquine sensitive (CQS) P. falciparum strain to such subject for schizont maturation inhibition (SMI) and total parasite growth inhibition (PGI), for at least 24 and 48 hrs, respectively . In yet another embodiment a dose of 25-125 μg/ml and 85-350 μg/ml drug is administered for IC90 against chloroquine sensitive (CQS) P.falciparum strain to such subject for schizont maturation inhibition (SMI) and total parasite growth inhibition (PGI), for at least 24 and 48 hrs, respectively.

In yet another embodiment a dose of 0.2-30 μg/ml and 5-15 μg/ml drug is administered for IC50 against chloroquine resistant Plasmodium falciparum strain to such subject for schizont maturation inhibition (SMI) and total parasite growth inhibition (PGI), for at least 24 and 48 hrs, respectively.

In yet another embodiment a dose of 1-125 μg/ml and 25-300 μg/ml drug is administered for IC90 against chloroquine resistant Plasmodium falciparum strain to such subject for schizont maturation inhibition (SMI) and total parasite growth inhibition (PGI), for at least 24 and 48 hrs, respectively. The present invention further provides a process for the preparation of chloro pyridine skelton Based Baylis-Hillman adduct having the general formula wherein

Rl is selected from the group consisting of hydrogen, phenyl and carbomethoxy; R2 is selected from the group consisting of hydrogen, alkyl, CH₃, C₂H₅, phenyl, H-C₅H₁1, carboethoxy and p- OMe-Ph; EWG is an electron withdrawing group selected from the group consisting of CN, COOMe and COOEt, which comprises reacting 2-chloro-5 and / or 6-substituted 3-pyridine carboxyaldehyde with an activated alkene or cyclic enone, optiomally in the presence of aqueous or non aqueous organic solvent, in the presence of a catalyst, at a temperature in the range of 20- 30 ⁰C, washing the organic layer of the above said reaction mixture with water or brine solution, followed by drying and purification by known method to obtain the desired product.

In yet another embodiment the 2-chloro-5 and / or 6-substituted 3-pyridine carboxyaldehyde used is selected from the group consisting of 2-Chloro-5-methylpyridinecarboxaldehyde, 2- Chloro-5-ethylnicotinaldehyde, 2-Chloro-5-phenyl nicotinaldehyde, methyl6-chloro-5-formyl-2- pyridincarboxylate ,2-chloro-5-methyl nicotinaldehyde, 2-Chloro-5-phenylnicotinaldehyde, 2- chloro-5-pentylnicotinaldehyde, 2-Chloro-5-methyl-6-phenylnicotinaldehyde, 2-Chloro-5- ethoxyacetate)-6-phenylnicotin aldehyde,2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde, 2- Chloro-5-ethylnicotin aldehyde, 2-Chloro-5-pentylnicotinaldehyde, 2-Chloro-5-methyl-6- phenylnicotin aldehyde, Methyl6-chloro-5-formyl-2-pyridin carboxylate, 2-Chloro-5- έthoxyacetate)-6-phenylnicotin aldehyde, 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde, 2- Chloro-5-methyl nicotinaldehyde, 2-Chloro-5-ethylnicotinaldehyde, 2-Chloro-5-phenylnicotin aldehyde, 2-Chloro-5-methyl-6-phenylnicotinaldehyde, Methyl 6-cnloro-5-formyl-2- pyridincarboxylate, 2-Chloro-5-ethoxyacetate)-6-phenylnicotin aldehyde,2-Chloro-5-(4- methoxyphenyl)-nicotinaldehyde, 2-Chloro-5-methyl nicotinaldehyde, 2-Chloro-5-ethylnicotin aldehyde, 2-Chloro-5-phenylnicotinaldehyde, 2-Chloro-5-methyl-6-phenylnicotin aldehyde, Methyl 6-chloro-5-formyl-2-pyridincarboxylate, 2-Chloro-5-ethoxyacetate)-6-phenyl nicotinaldehyde, 2-Chloro-5-(4-methoxyphenyl)-nicotin aldehyde, 2-Chloro-5- methylnicotinaldehyde, 2-Chloro-5-ethylnicotinaldehyde, 2-Chloro-5-phenylnicotinaldehyde, 2- chloro-substituted-S-pyridinecarboxy aldehyde, methyl 6-chloro-5-formyl-2-pyridincarboxylate,

2-Chloro-5-ethoxyacetate)-6-phenyl nicotinaldehyde and 2-Chloro-5-(4-methoxyphenyl)- nicotinaldehyde. •

In yet another embodiment the activated alkene used is selected from the group consisting of acrylonitrile, methyl acrylate and ethyl acrylate.

In yet another embodiment the cyclic enone used is selected from 2-cyclopenten-l-one and 2- cyclohexen- 1 -one.

In yet another embodiment the catalyst used is selected from di azabicylooctane (DABCO) and imidazole. In yet another embodiment the organic solvent used is selected from the group consisting of methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylsulphoxide (DMSO) and dimethylformamide(DMF) 1,4-dioxane, chloroform and sulpholane.

In yet another embodiment the molar ratio of 2-chloro-5 and / or 6-substituted 3 -pyridine carboxyaldehyde to activated alkene or cyclic enone used is in the range of 1:1 to 1:8. In yet another embodiment the molar ratio of 2-chloro-5 and / or 6-substituted 3-pyridine carboxyaldehyde to activated alkene in the reaction mixture used is in the range of 1 :5 to 1 :8.

In yet another embodiment the molar ratio of 2-chloro-5 and / or 6-substituted 3-pyridine carboxyaldehyde to cyclic enone used is preferably in the range of 1 : 1 to 1 :2.

In yet another embodiment the molar ratio of 2-chloro-5 and / or 6-substituted 3-pyridine carboxyaldehyde to catalyst used is in the range of 1 : 1 to 1 :2.

In yet another embodiment the molar ratio of activated alkene to catalyst used is in the range ofl:l to l:2.

In yet another embodiment the reaction mixture of aldehyde and alkene used is diluted with diethyl ether and is followed by washing with water and drying the resultant organic layer over sodium sulphate before subjected to purification by column chromatography.

In yet another embodiment the reaction mixture of aldehyde and cyclic-enone is taken into chloroform and the organic layer is washed with brine solution before drying and purification by known method to obtain the desired product.

In yet another embodiment the reaction time between aldehyde and cyclic-enone used is in the range of 20-40 minutes. In yet another embodiment the yield of the product chloro pyridine skelton based Baylis-Hillman adduct is in the range of 85-98% without forming side products.

A process as claimed in claim 9, wherein the product chloro pyridine skelton based Baylis- Hillman adduct obtained is selected from the group consisting of 2-[(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ia), 2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ib), 2-[(2-Chloro-5-phenylpyridine-3-yl) (hydroxy) methyl] acrylonitrile (Ic), methyl 6-chloro-5-(2-cyano-l -hydroxy allyl) 2-pyridine carboxylate (Id), Methyl 2-[(2- chloro-5-methylpyridine-3-)(hydroxy) methyl] acrylate (Ie), Methyl 2-[(2-chloro-5- phenylpyridine-3-yl)(hydroxy) methyl] acrylate (If), 2-[(2-chloro-5-n-pentylpyridine-3- yl)(hydroxy) methyl] acrylonitrile (Ig), 2-[(2-Chloro-5-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] acrylonitrle (Ih), Ethyl 6-chloro-5-(2-cyano-l -hydroxy aIlyI)-2-phenyl-nicotinate (Ii), 2- [(2-Chloro-5-(4-methoxyphenyl)pyridine-3-yl) (hydroxy)methyl] acrylonitrile (Ij), Methyl 2-[(2- chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylate (Ik), Methyl 2-[(2-chloro-5-n-pentyl pyridine-3-yl)(hydroxy) methyl] acrylate (1 1), Methyl 2-[(2-chloro-5-methyl-6-phenyl pyridine- 3-yl)(hydroxy) methyl] acrylate (Im), Methyl 6-chloro-5- [l-hydroxy-2- (methoxycarbonyl) allyl] pyridine-2-carboxylate (I n), Ethyl 6-chloro-5- (l-hydroxy-2- (methoxycarbonyl) allyl)-2- phenyl-nicotinate (Io), Methyl 2-[(2-chloro-5- (4-methoxyphenyl) pyridine-3-yl)(hydroxy) methyl] acrylate (Ip), Ethyl 2-[(2-chloro-5-methyl pyridine-3-)(hydroxy) methyl] acrylate (Iq), Ethyl 2-[(2-chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylate (Ir), Ethyl 2-[(2-chloro-5- phenyl pyridine-3-yl)(hydroxy) methyl] acrylate (Is), Ethyl 2-[(2-chloro-5-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] acrylate (It), Methy-6-chloro-5-[l-hydroxy-2- (ethoxycarbonyl)allyl] pyridine-2-carboxylate (Iu), Ethyl 6-chloro-5-(l-hydroxy-2- (ethoxycarbonyl)allyl)-2-phenyl-nicotinate (Iv), Ethyl 2-[(2-chloro-5- (4-meth oxyphenyl) pyridine-3-yl)(hydroxy) methyl] acrylate (Iw), 2-[(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one (Ha), 2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one (lib), 2-[(2-Chloro-5-phenyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2- en-l-one (lie), 2-[(2-Chloro-5-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en- l-one(IId), Methyl-6-chloro-5-[hydroxy(5-oxo-l-cyclopentenyl) methyl]-2-pyridine carboxyl ate(IIe), Ethyl 6-chloro-5- [hydroxy (5 -oxo-l-cyclopentenyl)methyl]-2-phenyl nicotinate (II f), 2- i(2-Chloro-5- (4-methoxyphenyl)pyridine-3-yl)(hydroxy) methyl]cyclopent-2-en-l-one(IIg), 2- [(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] 2-cyclohexenel-one (II h), 2-[(2-Chloro-5- ffthyl pyridine-3-yl)(hydroxy) methyl]cyclohex-2-ene-l-one(IIi), 2-[(2-Chloro-5-phenyl pyridine-3-yl)(hydroxy) methyl] cyclohex-2-ene-l-one (Hj), Methyl 2~[(2-chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] "acrylate (Ik), Methyl 6-chloro-5- [hydroxy (5-oxo-l- cyclohexenyl)methyl]-2-pyridine carboxylate (II 1), Ethyl 6-chloro-5-[hydroxy(5-oxo-l- cyclohexenyl)methyl]-2-phenyl nicotinate (II m) and 2-[(2-Chloro-5-(4- methoxyphenyl)pyridine-3-yl)(hydroxy) methyl] cyclohex-2-en-l-one (II n). In yet another embodiment the chloro pyridine skelton based Baylis-Hillman adduct obtained is active against chloroquine sensitive and chloroquine resistant plasmodium falciparum strains. In yet another embodiment the chloro pyridine skelton based Baylis-Hillman adduct obtained exhibits an anti malarial activity against the erythrocytic stage of the malarial parasite.

In yet another embodiment the Hillman adduct obtained is used in a pharmaceutical composition comprising novel anti malarial chloro pyridine skelton based Baylis-Hillman adduct, its derivatives, analogues or salt thereof optionally with pharmaceutically acceptable carriers, adjuvant and additives. The present invention is predicted on the discovery that certain Baylis Hillman adducts, preferably in substantially pure form has invitro antimalarial activity and therefore is useful for malaria treatment. The following preferred embodiments are given by way of illustration of the present invention and therefore should not be constructed to limit the scope of the present invention. Synthetic procedures for representative Baylis Hillman adducts Ia-If are disclosed in the present invention are described below.

GRNERAL SCHEME FOR FORMULAE I:

tertiary amine

2-chloro-3-pyιϊdinecarbox activated Baylis-Hillman ( Ia-Iw) aldehyde derivatives alkene adduct

Scheme-1

IfEWG = CN, the activated alkene is called as acrylonitrile IfEWG = COOMe, the activated alkene is called as methylacrylate If EWG = COOEt, the activated alkene is called as ethylacrylate GENERAL SCHEME FOR FORMULA II

.xx

n = 1,2

2-chloro-3-pyridine cyclic-eπone Baylis-Hillman carboxaldθhydβ adducts derivatives ( Ha-Un)

Scheme-2

If n = 1 , then the cyclic-enone is called as 2-cycIopenten-l-one

If n = 2, then the cyclic-enone is called as 2-cyclohexen-l-one The following examples are given by the way of illustration and therefore should not be construed to limit the scope of the invention

Experimental procedure for the synthesis of 2-[(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ia):

To a mixture of 2-Chloro-5-methylpyridinecarboxaldehyde (10 mmol, 1.55 g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (-4-5 min.) was diluted with diethyl ether (300 mL) and washed with water 3 x 50 mL. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.05 g).

Experimental procedure for the synthesis of 2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ib):

To a mixture of 2-Chloro-5-ethylnicotinaldehyde (10 mmol, 1.69 g) and DABCO (10 mmol.

1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~4-5min.) was diluted with diethyl ether (300 ml.) and washed with water 3 x

50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.20 g.). Experimental procedure for the synthesis of 2-[(2-Chloro-5-phenylpyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ic): To a mixture of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and DABCO (10 mmol.

1.12g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the^' reaction progress was monitored by TLC. Upon completion of the reaction mixture (~4-5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.68g.).

Experimental procedure for the synthesis of Methyl 6-chIoro-5-(2-cyano-l-hydroxy allyl) 2- pyridine carboxylate (Id): To a mixture of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 mmol, 1.99 g) and DABCO

(10 mmol. 1.12g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~4-5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.5Og.).

Experimental procedure for the synthesis of Methyl 2-[(2-chloro-5-methylpyridine-3-

)(hydroxy) methyl] aery late (Ie):

To a mixture of 2-Chloro-5-methylnicotinaldehyde (10 mmol, 1.55g) and DABCO (10 mmol. 1.12 g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.4Og.).

Experimental procedure for the synthesis of Methyl 2-[(2-chloro-5-phenyI pyridine-3-yl)

(hydroxy) methyl] acrylate (If):

To a mixture of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and DABCO (10 mmol.

1.12 g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300 ml.) and washed with water 3 x 50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (3.01 g.).

Experimental procedure for the synthesis of 2-[(2-chloro-5-n-pentyIpyridine-3-yI)(hydroxy) methyl] acrylonitrile (Ig):

To a mixture of 2-Chloro-5-pentylnicotinaldehyde (10 rnmol, 2.11 g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~4-5min.) was diluted with diethyl ether (300ml.) and washed with water 3 x 50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.62g.).

Experimental procedure for the synthesis of 2-[(2-Chloro-5-methyl-6-phenyl pyridine-3- yl)(hydroxy) methyl] acrylonitrle (Ih) : To a mixture of 2-Chloro-5-methyl-6-ρhenylnicotinaldehyde (10 mmol, 2.31 g) and DABCO (10 mmol. 1.12g) was added an acrylonitrile (60 mmol) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~4-5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.83g.). Experimental procedure for the synthesis of Ethyl 6-chloro-5-(2-cyano-l-hydroxy allyl)-2- phenyl-nicotinate (Ii): To a mixture of 2-Chloro-5-ethoxyacetate)-6-phenylnicotinaldehyde (10 mmol, 2.89g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~4-5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (3.41g.). Experimental procedure for the synthesis of 2-[(2-Chloro-5-(4-methoxyphenyl) pyridine-3- yl) (hydroxy)methyl] acrylonitrile (Ij):

To a mixture of 2-Chloro-5-(4-riiethoxyphenyl)-nicotinaldehyde (10 mmol, 2.45g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~4-5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.99g.). Experimental procedure for the synthesis of Methyl 2-[(2-chloro-5-ethyl pyridine-3-yl) (hydroxy) methyl] aery late (Ik):

To a mixture of 2-Chloro-5-ethylnicotinaldehyde (10 mmol, 1.69 g) and DABCO (10 mmol. 1.12g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.54g.). Experimental procedure for the synthesis of Methyl 2-[(2-chloro-5-n-pentyl pyridine-3-yl) (hydroxy) methyl] acrylate (11):

To a mixture of 2-Chloro-5-pentylnicotinaldehyde (10 mmol, 2.1 Ig) and DABCO (10 mmol. Ll 2g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.96g.).

Experimental procedure for the synthesis of Methyl 2-[(2-chloro-5-methyl-6-phenyl pyridine-3-yl) (hydroxy) methyl] acrylate (Im): To a mixture of 2-Chloro-5-methyl-6-phenylnicotinaldehyde (10 mmol, 2.3Ig) and DABCO (10 mmol. 1.12 g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (3.16 g.).

Experimental procedure for the synthesis of Methyl 6-chloro-5- [l-hydroxy-2- (methoxycarbonyl) allyl] pyridine-2-carboxylate (I n):

To a mixture of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 rnmol, 1.99 g) and DABCO (10 mmol. 1.12 g) was added an methyl/ethyl acrylate (60 rnmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.84g.).

'A Experimental procedure for the synthesis of Ethyl 6-chloro-5- (l-hydroxy-2- (methoxycarbonyl) aHyl)-2-phenyl-nicotinate (Io):

To a mixture of 2-Chloro-5-ethoxyacetate)-6-phenylnicotinaldehyde (10 mmol, 2.89g) and DABCO (10 mmol. 1.12 g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (3.74g.). Experimental procedure for the synthesis of Methyl 2-[(2-chloro-5- (4-methoxy phenyl) pyridine-3-yl) (hydroxy) methyl] acrylate (Ip):

To a mixture of 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde (10 mmol, 2.45 g) and DABCO (10 mmol. 1.12g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane

(2:8,v/v) to give the desired product in almost quantitative (3.32g.).

Experimental procedure for the synthesis of Ethyl 2-[(2-chloro-5-methyl pyridine-3-)

(hydroxy) methyl] acrylate (Iq): To a mixture of 2-Chloro-5-methylnicotinaldehyde (10 mmol, 1.55 g) and DABCO (10 mmol.

1.12 g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane

(2:8,v/v) to give the desired product in almost quantitative (2.54g.).

Experimental procedure for the synthesis of Ethyl 2-[(2-chloro-5-ethyl pyridine-3-yl)

(hydroxy) methyl] acrylate (Ir):

To a mixture of 2-Chloro-5-ethylnicotinaldehyde (10 mmol, 1.69 g) and DABCO (10 mmol. 1.12 g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.68g.).

Experimental procedure for the synthesis of Ethyl 2-[(2-chloro-5-phenyl pyridine-3- yl)(hydroxy) methyl] acrylate (Is):

(2:8,v/v) to give the desired product in almost quantitative (316.5g.). Experimental procedure for the synthesis of Ethyl 2-[(2-chloro-5-methyl-6-phenyI pyridine-

3-yl)(hydroxy) methyl] acrylate (It): To a mixture of 2-Chloro-5-methyl-6-phenylnicotinaldehyde (10 mmol, 2.31 g) and DABCO (10 mmol. 1.12 g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (3.3Og.).

Experimental procedure for the synthesis of Methy-6-chloro-5-[l-hydroxy-2- (ethoxycarbonyl)allyl] pyridine-2-carboxyIate (Iu): To a mixture of Methyl ό-chloro-S-formyl^-pyridincarboxylate (10 mmol, 1.99 g) and DABCO (10 mmol. 1.12g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (2.98g.).

Experimental procedure for the synthesis of Ethyl 6-chloro-5-(l-hydroxy-2- (ethoxycarbonyl)allyl)-2-pheny 1-nicotinate (Iv) : To a mixture of 2-Chloro-5-ethoxyacetate)-6-phenylnicotinaldehyde (10 mmol, 2.89g) and DABCO (10 mmol. 1.12g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions ^solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (3.88 g).

Experimental procedure for the synthesis of Ethyl 2-[(2-chloro-5- (4-methoxyphenyl) pyridine-3-yl)(hydroxy) methyl] acrylate (Iw):

To a mixture of 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde (10 mmol, 2.45 g) and DABCO (10 mmol. 1.12g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (~5min.) was diluted with diethyl ether (300ml.) and washed with water 3x50ml. The organic layer was dried over Na₂SO₄ and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8,v/v) to give the desired product in almost quantitative (346 g). Experimental procedure for the synthesis of 2-[(2-Chloro-5-methyl pyridine-3-yI)(hydroxy) methyl] cyclopent-2-en-l-one (Ila):

The clear solution of 2-Chloro-5-methylnicotinaldehyde (10 mmol, 1.55 g) and imidazole (10 mmol, 0.68 g) in 50ml.of MeOH was slowly charged with 50ml.of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-l-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl₃ thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30%EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 98% yield (2.32 g) Experimental procedure for the synthesis of 2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one (lib):

The clear solution of 2-Chloro-5-ethylnicotinaldehyde (10 mmol, 1.69) and imidazole (10 mmol, 0.68 g) in 50ml.of MeOH was slowly charged with 50ml.of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-l-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl₃ thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30%EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 97% yield (2.47g). Experimental procedure for the synthesis of 2-[(2-Chloro-5-phenyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one (lie):

The clear solution of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and imidazole (10 mmol) in 50ml.of MeOH was slowly charged with 50ml.of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-l-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl₃ thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30%EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 95% yield (2.84g). Experimental procedure for the synthesis of 2-[(2-Chloro-5-methyl-6-phenyl pyridine-3- yl)(hydroxy) methyl] cycIopent-2-en-l- one (Hd): The clear solution of 2-Ctøoro-5-memyl-6-phenylnicotinaldehyde (10 rnmol, 2.31 g) and imidazole (10 mmol) in 50ml.of MeOH was slowly charged with 50ml.of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-l-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCI₃ thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30%EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 93% yield (2.84 g). Experimental procedure for the synthesis of Methyl 6-chloro-5-[hydroxy(5-oxo-l- cyclopentenyl)methyl]-2-pyridine carboxylate (He): The clear solution of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 mmol, 1.99 g) and imidazole (10 mmol) in 50ml.of MeOH was slowly charged with 50ml.of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-l-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction excess MeOH was removed under reduced pressure, washed with water and extracted with CHCI₃ thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30%EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 90% yield (2.53 g). Experimental procedure for the synthesis of Ethyl 6-chloro-5- [hydroxy (5-oxo-l- cycIopentenyI)methyl]-2-phenyl nicotinate (II f): The clear solution of 2-Chloro-5-ethoxyacetate)-6-phenylnicotinaldehyde (10 mmol, 2.89 g) and imidazole (10 mmol) in 50ml.of MeOH was slowly charged with 50ml.of deionized water. To 3 stirred homogeneous reaction mixture was added 2-cyclopenten-l-one (10.2 mmol. 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCI3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 88% yield (3.26 g). Experimental procedure for the synthesis of 2-[(2-Chloro-5- (4-methoxyphenyl) pyridine-3- yl)(hydroxy) methyl] cyclopent-2- en-l-one (Ilg): The clear solution of 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde (10 mmol, 2.45 g) and imidazole (10 mmol) in 50ml.of MeOH was slowly charged with 50 ml.of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-l-one (10.2 mmol.0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl₃ thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 90% yield (2.97 g). Experimental procedure for the synthesis of 2-[(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] 2-cyclohexenel-one (II h): The clear solution of 2-Chloro-5-methylnicotinaldehyde (10 mmol, 1.55 g) and imidazole (10 mmol) in 50 ml.of MeOH was slowly charged with 50 ml.of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-l-one (10.2 mmol., 1 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl₃ thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 92% yield (2.22 g). Experimental procedure for the synthesis of 2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] cyclohex-2-ene-l-one (II i): The clear solution of 2-Chloro-5-ethylnicotinaldehyde (10 mmol, 1.69 g) and imidazole (10 mmol) in 50 ml.of MeOH was slowly charged with 50 ml.of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-l-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl₃ thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 95% yield (2.43 g). Experimental procedure for the synthesis of 2-[(2-Chloro~5-phenyl pyridine-3-yl)(hydroxy) methyl] cyclohex-2-ene-l-one (IIj): The clear solution of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and imidazole (10 mmol) in 50 ml.of MeOH was slowly charged with 50 ml.of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-l-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl₃ thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 95% yield (2.25 g). Experimental procedure for the synthesis of 2-[(2-Chloro-5-methyl-6-phenyl pyridine-3-yI) (hydroxy) methyl] cyclohex-2-ene-l-one (II k) The clear solution of 2-chloro-substituted-3-pyridinecarboxyaldehyde (10 mmol 2.31g ) and imidazole (10 mmol) in 50 ml.of MeOH was slowly charged with 50ml.of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-l-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCI₃ thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 90% yield (2.93 g). Experimental procedure for the synthesis of Methyl 6-chloro-5- [hydroxy (5- oxo-1- cyclohexenyl)methyl]-2-pyridine carboxylate (II 1): The clear solution of Methyl 6-chloro-5-foraiyl-2-pyridincarboxylate (10 mmol, 1.99 g) and imidazole (10 mmol, 0.68 g) in 50 ml.of MeOH was slowly charged with 50 ml.of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-l-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl₃ thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 87% yield (2.56 g).

Experimental procedure for ^* the synthesis of Ethyl 6-chloro-5-lhydroxy(5-oxo-l- cyclohexenyl)methyI]-2-phenyl nicotinate (II m): The clear solution of 2-Chloro-5-ethoxyacetate)-6-phenylnicotinaldehyde (10 mmol, 2.89 g) and imidazole (10 mmol) in 50 ml.of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-l-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCI₃ thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 92% yield (3.5 g). Experimental procedure for the synthesis of 2-[(2-Chloro-5- (4-methoxyphenyl) pyridine-3- yl)(hydroxy) methyl] cyclohex-2-en-l-one (II n): The clear solution of 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde (10 mmol, 2.45 g) and imidazole (10 mmol) in 50 ml.of MeOH was slowly charged with 50 ml.of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-l-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCI3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAc in hexane as eluent, gave pure Baylis-Hillman adduct in 91% yield (3.13 g). 2-[(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] acrylonitrile(Ia)

2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ib)

2-[(2-Chloro-5-phenylpyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ic)

Methyl 6-chloro-5-(2-cyano-l -hydroxy allyl) 2-pyridine carboxylate(Id)

Methyl 2-[(2-chloro-5-methylpyridine-3-)(hydroxy) methyl] acrylate(Ie)

Methyl 2-[(2-chloro-5-phenylpyridine-3-yl)(hydroxy) methyl] acrylate(If)

2-[(2-chloro-5-n-pentylpyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ig)

2-[(2-Chloro-5-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] acrylonitrile(Ih) yl)(hydroxy) methyl] acrylonitrile

Ethyl 6-chloro-5-(2-cyano-l-hydroxy allyl)-2-phenyl-nicotinate (Ii)

2-[(2-Chloro-5-(4-methoxyphenyl) pyridine-3-yl)(hydroxy)methyl] acrylonitrile (Ij)

Methyl 2-[(2-chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylate (Ik)

Methyl 2-[(2-chloro-5-n-pentyl pyridine-3-yl)(hydroxy) methyl] acrylate (11)

Methyl 2-[(2-chloro-5-methyI-6-phenyl pyridine-3-yl)(hydroxy) methyl] acrylate(Im)

Methyl 6-chloro-5- [l-hydroxy-2- (methoxycarbonyl) allyl] pyridine-2-carboxyIate(In)

Ethyl 6-chloro-5- (l-hydroxy-2- (methoxycarbonyl) allyl)-2-phenyl-nicotinate (Io)

Methyl 2-[(2-chloro-5- (4-methoxy phenyl) pyridine-3-yl)(hydroxy) methyl] acrylate(Ip)

Ethyl 2-[(2-chloro-5-methyl pyridine-3-)(hydroxy) methyl] acrylate(Iq)

Ethyl 2-[(2-chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylate (Ir)

Ethyl 2-[(2-chloro-5-phenyI pyridine-3-yI)(hydroxy) methyl] acrylate (Is)

Ethyl 2-[(2-chloro-5-methyl-6-phenyl pyridine-3-yI)(hydroxy) methyl] acrylate(lt)

Methyl ό-chloro-S-ll-hydroxy^^ethoxycarbony^allylJpyridine^-carboxylate^u)

Ethyl 6-chloro-5-(l-hydroxy-2-(ethoxycarbonyϊ)alIyl)-2-phenyl-nicotinate (Tv)

Ethyl 2-[(2-chloro-5- (4-methoxyphenyI) pyridine-3-yl)(hydroxy) methyl] acrylate(Iw)

2-[(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one(IIa)

2-[(2-Chloro-5-ethyI pyridine-3-yI)(hydroxy) methyl] cyclopent-2-en-l-one (lib)

2-[(2-Chloro-5-phenyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one(IIc)

2-[(2-Chloro-S-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-eii-l- one(IId)

Methyl 6-chloro-5-[hydroxy(5-oxo-l-cyclopentenyl)methyI]-2-pyridine carboxylate (lie)

Ethyl 6-chloro-5-[hydroxy(5-oxo-l-cycIopentenyI)methyI]-2-phenyl nicotinate (Ilf)

2-[(2-ChIoro-5- (4-methoxyphenyl) pyridine-3-yl)(hydroxy) methyl] cyclopent-2- en-1- one(IIg)

2-[(2-Chloro-5-methyl pyridine-3-yI)(hydroxy) methyl] 2-cyclohexen-l-one (Ilh)

2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] cyclohex-2-ene-l-one (Ili)

2-[(2-Chloro-5-phenyl pyridine-3-yl)(hydroxy) methyl] cyclohex-2-ene-l-one(IIj)

2-[(2-Chloro-5-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] cyclohex-2-ene-l-one(IIk)

Methyl 6-chIoro-5-[hydroxy(5-oxo-l-cyclohexenyl)methyI]-2-pyridine carboxyIate(III)

Ethyl 6-chloro-5-[hydroxy(5-oxo-l-cyclohexenyI)methyl]-2-phenyl nicotinate(IIm)

2-[(2-Chloro-5- (4-methoxyphenyl) pyridine-3-yl)(hydroxy) methyl] cyclohex-2-en-l- one(IIn)

The present invention may be better understood by reference to the following non-limiting Examples, which are provided as exemplary of the invention. The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. Synthetic procedures for representative Baylis Hillman adducts Ia-Iw and Ha-IIn were described below. Typical experimental procedure for Ia to Iw using EtOH solvent system: To a stirred solution of substrate aldehyde (substituted 2-chloro-pyridine-3-carboxyaldehyde) (lmmol) and DABCO (1,4-diaza bicyclo [2.2.2] ocatane; 100 mol%) in 5 mL of ethanol was added an activated alkene (1.2 mmol) at room temparature and the reaction progress was monitored by TLC. After completion (10 min) of the reaction, the excess solvent was removed under reduced pressure. The obtained residue was diluted with diethyl ether (150 ml.) and brine (50 ml.). After partition, the aqueous layer was extracted with chloroform (2 x 50 ml.). The combined organic layer was concentrated and the residue was subjected to column chromatography over silicagel, eluting with ethyl acetate and hexane to give the desired product. Typical experimental procedure for Ia to Iw using Acetonitrile solvent system: To a stirred solution of substrate aldehyde (substituted 2-chloro-pyridine-3-carboxyaldehyde) (1 mmol) and DABCO [1,4-diaza bicyclo (2.2.2) ocatane](100 mol%) in 5 mL of acetonitrile was added an activated alkene (1.2 mmol) at room temparature and the reaction progress was Sionitored by TLC. After completion (25 min) of the reaction, the excess solvent was removed under reduced pressure. The obtained residue was diluted with diethyl ether (150 ml.) and brine (50 ml.). After partition, the aqueous layer was extracted with chloroform (2 x 50 ml.). The combined organic layer was concentrated and the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane to give the desired product in almost quantitative yield. Typical experimental procedure for Ia to Iw using 1,4-dioxane solvent system:

To a stirred solution of substrate aldehyde (substituted 2-chloro-pyridine-3-carboxyaldehyde) (lmmol) and DABCO [1,4-diaza bicyclo (2.2.2) ocatane](100 mol%) in 5 mL of 1,4-dioxane was added an activated alkene (1.2 mmol) at room temparature and the reaction progress was monitored by TLC. After completion (12 min) of the reaction, the excess solvent was removed under reduced pressure. The obtained residue was diluted with diethyl ether (150 ml.) and brine (50 ml.). After partition, the aqueous layer was extracted with chloroform (2 x 50 ml.). The combined organic layer was concentrated and the residue was subjected to column chromatography over silicagel, eluting with ethyl acetate and hexane to give the desired product in almost quantitative yield. Typical experimental procedure for Ia to Iw using Tetrahydro furan (THF) solvent system: To a stirred solution of substrate aldehyde (substituted 2-chloro-pyridine-3-carboxyaldehyde) (1 mmol) and DABCO [1,4-diaza bicyclo (2.2.2) ocatane](100 mol%) in 5 mL of THF solvent was added an activated alkene (1.2 mmol) at room temparature and the reaction progress was monitored by TLC. Ater completion (20 min), of the reaction, the excess solvent was removed under reduced pressure. The obtained residue was diluted with diethyl ether (150 ml.) and brine (50 ml.). After partition, the aqueous layer was extracted with chloroform (2 x 50 ml.). The combined organic layer was concentrated and the residue was subjected to column chromatography over silicagel, eluting with ethyl acetate and hexane to give the desired product in almost quantitative yield. Typical experimental procedure for Ia to Iw using Dimethylformamide (DMF) solvent system:

To a stirred solution of substrate aldehyde (substituted 2-chloro-pyridine-3-carboxyaldehyde) (lmmol) and DABCO [1,4-diaza bicyclo (2.2.2) ocatane] (100 mol%) in 5 mL of DMF solvent was added an activated alkene (1.2 mmol) at room temparature and the reaction progress was monitored by TLC. After completion of the reaction, the excess solvent was removed under reduced pressure. The obtained residue was diluted with diethyl ether (150 ml.) and brine (50 ml.). After partition (12 min), the aqueous layer was extracted with chloroform (2 x 50 ml.). The combined organic layer was concentrated and the residue was subjected to column chromatography over silicagel, fluting with ethyl acetate and hexane to give the desired product in almost quantitative yield. Typical experimental procedure for Ia to Iw using Chloroform solvent system:

To a stirred solution of substrate aldehyde (substituted 2-chloro-pyridine-3-carboxyaldehyde) (lmmol) and DABCO [1,4-diaza bicyclo (2.2.2) ocatane] (100mol%) in 5 mL of chloroform was added an activated alkene (1.2 mmol) at room temparature and the reaction progress was monitored by TLC. Ater completion (25 min) of the reaction, the excess solvent was removed under reduced pressure. The obtained residue was diluted with diethyl ether (150 ml.) and brine (50 ml.). After partition, the aqueous layer was extracted with chloroform (2 x 50 ml.). The combined organic layer was concentrated and the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane to give the desired product in almost quantitative yield. Typical experimental procedure for II a-II n using aqueous methanol solvent system:

The clear solution of aldehyde (1 mmol) and imidazole (100 mol%) in 5 ml.of MeOH was slowly charged with 5 ml.of deionized water. To a stirred homogeneous reaction mixture was added cyclic-enone (1,2 mmol.) at room temperature and reaction progress was monitored by TLC for every 5 mins. After completion of the reaction (within 28-30 min), the excess solvent was removed under reduced pressure. The obtained residue was subjected to column chromatography over silica gel using ethylacetate, hexane (30:70, v/v) as eluting solvent system. The desired product was obtained in 82-98% yield.

Typical experimental procedure for II a-II n using methanol solvent system: To a stirred and clear homogeneous solution of aldehyde (lmmol) and imidazole (100 mol%) in 5 ml.of MeOH was added with cyclic-enone (1.2mmol.) at room temperature and reaction progress was monitored by TLC for every 5 mins. After completion of the reaction (within 90- 120 min), the excess solvent was removed under reduced pressure. The obtained residue was subjected to column chromatography over silica gel using ethylacetate, hexane (30:70, v/v) as eluting solvent system. The desired product was obtained in 82-98% yield. Typical experimental procedure for II a-II n using aqueous tetrahydro furan (aq. THF) solvent system:

The clear solution of aldehyde (1 mmol) and imidazole (100 mol%) in 5 ml.of THF was slowly charged with 5 ml.of deionized water. To a stirred homogeneous reaction mixture was added cyclic-enone (1.2 mmol.) at room temperature and reaction progress was monitored by TLC for every 5 mins. After completion of the reaction (within 40-60 min), the excess solvent was removed under reduced pressure. The obtained residue was subjected to column chromatography over silica gel using ethylacetate, hexane (30:70, v/v) as eluting solvent system. The desired product was obtained in 82-98% yield. Typical experimental procedure for II a-II n using aqueous dimethylformamide(aq. DMF) solvent system:

The clear solution of aldehyde (1 mmol) and imidazole (100 mol%) in 5 ml.of DMF was slowly charged with 5 ml.of deionized water. To a stirred homogeneous reaction mixture was added cyclic-enone (1.2 mmol.) at room temperature and reaction progress was monitored by TLC for every 5 mins. After completion of the reaction (within 45-60 min), the excess solvent was removed under reduced pressure. The obtained residue was subjected to column chromatography over silica gel using ethylacetate, hexane (30:70, v/v) as eluting solvent system. The desired product was obtained in 82-98% yield. Spectral data: EXAMPLE Ia

2-[( l-Chloro-S-methylpyridine-S-yl) (hydroxy) methyljacrylonitrile: ¹H-NMR (CDCl₃, 200MHz): δ 8.2 (d, IH), 7.78 (d, IH), 6.08 (s, IH), 6.09 (s, IH), 5.64 (s, IH ), 2.40 ( s,lH );¹³C-NMR: (CDCl₃, 50MHz): 148.36, 145.29, 136.96, 132.98, 132.19, 130.29, 124.12, 115.85, 68.60, 16.80; MS (m/z, %): 208, 156, 120, 93, 65, 39. Anal.calcd.for C₁₀H₉ClN₂O: C, 57.57%; H, 4.34%; N, 13.43%. Found: C, 57.85%; H, 4.68%; N, 13.52%. EXAMPLE Ib

2-[(2-Chloro-5-ethylpyridine-3-yl)(hydroxy) methyl] acrylonitrile:

¹H-NMR (CDCl₃, 200MHz): δ 8.18 (d, IH), 7.82 (d, IH), 6.1 (s, IH), 6.08 (s, IH), 5.66 (s, IH), 2.72 (q, 2H), 1.3 (t, 3H); ¹³C-NMR: (CDCl₃, 50MHz): δ 148.67, 146.36, 139.52, 136.92, 133.34, 131.59, 124.47, 116.22, 70.06, 25.34, 14.80; MS (EI) m/z: 222 (M⁺), 170, 134, 106, 77, 51. Anai.calcd.for C₁₁H₁₁ClN₂O: C, 59.31%; H, 5.02%; N, 12.58%. Found: C, 59.70%; H₅ 5.33%;

N, 12.75%.

EXAMPLE Ic

2-[(2-Chloro-5-phenyIpyridine-3-yl)(hydroxy) methyl] acrylonitrile: ^fH-NMR (CDCl₃, 200MHz): δ 8.58 (d, IH), 8.2 (d, IH)₅ 7.4-7.6 (m, 5H)₅ 6.14 (s, IH), 6.1 (s, IH)₅ 5.66 (s, IH). ¹³C-NMR: (CDCl₃, 50MHz): δ 70.37, 116.18, 124.13, 127.18, 128.78, 129.27, 132.05, 133.33, 135.57, 135.94, 136.82, 147.68; MS (EI) m/z: 270(M+), 245, 218, 182, 154, 141, 77.; Anal.calcd.for C₁₅H₁₁ClN₂O: C, 66.53%; H₅ 4.13%; N, 10.34%. Found: C, 66.67%; H, 4.38%; N, 10.70%. EXAMPLE Id

Methyl 6-chIoro-5- (2-cyano-l-hydroxyprop-2-en-l-yI) pyridine-2-carboxyIate: ¹H-NMR (CDCl₃, 200MHz): δ 8.15 (d, IH), 8.22 (d, IH)₅ 6.1 (d, 2H)₅ 5.73 (d, IH)₅ 3.98 (s, 3H); ¹³C-NMR: (CDCl₃, 50MHz): δ 164.05, 149.01, 147.33, 138.36, 137.96, 132.63, 124.42, 123.52, 115.98, 69.99, 53.19; MS (EI) m/z: 252 (M+), 222, 200, 194, 164, 112, 76, 59. Anal.calcd.for C_{1 !}H₉ClN₂O₃: C, 52.29%; H, 3.59%; N, 11.09%; Found: C, 52.56%; H, 3.68%; N₅ 11.34%.; EXAMPLE Ie

Methyl 2-[(2-chloro-5-methyIpyridine-3-yl)(hydroxy) methyl] acrylate: ¹H-NMR (CDCl₃, 200MHz): δ 8.11 (d, IH), 7.71 (d, IH), 6.32 (s,lH), 5.8 (s, IH ), 5.56 (s,lH ), 3.8 (s, 3H), 2.35 (s,3H ); ¹³C-NMR (CDCl₃, 50MHz): δ 166.06, 148.17, 146.52, 140.25, 137.85, 134.85, 132.44, 126.73, 67.89, 51.70, 17.34; MS (m/z, %): 241, 206, 156, 120, 92, 65. Anal.calcd.for C₁₁Hi₂ClNO₃: C, 54.68%; H, 4.99%; N, 5.80%. Found: C, 54.86%; H, 5.10%; N, 5.98%.

EXAMPLE If: Methyl 2-[(2-chloro-5-phenyIpyridine-3-yl)(hydroxy) methyl] acrylate: JH-NMR (CDCl₃, 200MHz): δ 8.48 (d, IH)₅ 8.12 (d, IH), 7.34-7.58 (m, 5H)₅ 6.34 (s, IH), 5.88 (s IH), 5.62 (s, IH), 4.18 (b, IH), 3.77 (s, 3H); ¹³C-NMR: (CDCl₃, 50MHz): δ 166.60, 148.39, 146.67, 139.91, 136.23, 136.06, 135.70, 135.13, 129.08, 128.44, 127.49, 127.00, 68.98, 52.13; MS (EI) m/z: 303 (M+), 268, 236, 218, 182, 153, 127, 115, 77, 55. Anal.calcd.for C₁₆H₁₄ClNO₃: C, 63.24%; H, 4.68%; N, 4.61%. Found: C, 63.42%; H, 4.88%; N, 4.86%. Ig:

2-[(2-Chloro-5-n-pentylpyridine-3-yl)(hydroxy) methyl] acrylonitrile: ¹H-NMR (CDCl₃, 200MHz): δ 8.18 (s, IH), 7.8 (s, IH), 6.45 (s, IH), 6.5 (s, IH), 5.62 (s, IH), 2.62 (t, 2H), 1.23-1.65 (m, 6H), 0.95 (t, 3H); MS EI (m/z): 264 (M+), 212,176,41; Anal.calcd.for Ci₄H_nClN₂O: C, 63.51%; H, 6.47%; N, 10.58%; Found: C, 63.96%; H, 6.88%; N, 10.92%.

2-[(2-Chloro-5-methyl-6-phenylpyridine-3-yl)(hydroxy) methyl] acrylonitrile: IH-NMR (CDCl₃, 200MHz): δ 7.82 (s, IH)₅ 7.35-7.55 (m, 5H), 6.07 (s, IH), 6.1 (s, IH), 5.62 (s, IH), 2.4 (s, 3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 158.71, 145.64, 139.69, 138.23, 131.72, 130.98, 128.81, 128.64, 128.25, 124.19, 116.36, 69.67, 19.27; MS (EI) m/z :284 (M+), 232, 196, 168, 119, 77, 52, 39. Anal.calcd.for C₁₆Hi₃ClN₂O: C, 67.48%; H, 4.60%; N, 9.84%. Found: C, 67.69%; H, 4.82%; N, 10.01%. Ii:

Ethyl 6-chIoro-5- (2-cyaαo-l-hydroxy alIyl)-2-phenyl-nicotinate:

¹H-NMR (CDCl₃, 200MHz): δ 8.82 (s, IH), 7.6 (m, 2H), 7.42 (m, 3H), 6.04 (s, 2H), 5.63 (s, IH), 5.4 (b, IH), 4.21 (q, 2H), 1.25 (t, 3H); MS (EI) m/z: 342(M+), 307, 262,254, 179,77; Anal.calcd.for C₁₈Hi₅ClN₂O₃ : C, 63.07%; H, 4.41%; N, 8.17%; Found: C, 62.88%; H, 4.65%; N, 8.47%.;

Ij: 2-{[2-Chloro-5-(4-methoxyphenyl)-pyridine-3-yl](hydroxy)methyl}acrylonitrile: ¹H-NMR (CDCl₃, 200MHz): δ 8.5 (s, IH), 8.12 (s, IH), 7.5 (m, 2H), 6.95 (m, 2H), 6.11 (d, 2H), 5.71 (s, IH), 3.84 (s, 3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 160.23, 147.08, 136.39, 135.00,133.34, 131.96, 128.26, 124.15, 116.26, 114.72, 70.23, 55.38; MS (EI) m/z: 300(M+), 248, 212, 185, 107, 65; Anal.calcd.for Ci₆H₁₃ClN₂O₂ : C₅ 63.90%; H, 4.36%; N, 9.31%; Found: C 64.01%; H, 4.54%; N, 9.46%.; Ik: Methyl 2-[(2-chloro-5-ethylpyridine-3-yl)(hydroxy) methyl] acrylate: ¹H-NMR (CDCl₃, 200MHz): δ 8.15 (d, IH), 7.77 (d, IH), 6.32 (s, IH), 5.81 (s, IH), 5.51 (s, IH), 3.81 (s, 3H), 2.7(q, 3H), 1.3 (t, 3H); ¹³C-NMR: (CDCl₃, 50MHz): δ 167.39, 149.27, 146.78, 140.28, 139.62, 137.77, 129.62, 126.34, 69.79, 51.60, 25.76, 14.72; MS (EI) m/z: 222 (M+), 187, 173, 102, 65; Anal.calcd.for Ci₂H₁₄ClNO₃: C, 56.37%, H, 5.52%, N, 5.19%, Found: C, 56.78%, H.5.89%, N, 5.62%.; II:

Methyl 2-[(2-chloro-5-n-pentylpyridine-3-yl)(hydroxy) methyl] acrylate: tø-NMR (CDCl₃, 200MHz): δ 8.1 (s, IH)₅ 7.68 (s, IH), 6.22 (s, IH), 5.78 (s, IH), 5.23 (s, IH), 3.78 (s, 3H), 2.58 (t, 2H), 1.2-1.65 (m, 6H), 0.9 (t, 3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 166.59, 148.29, 146.86, 140.06, 137.50;i34.62, 127.19, 68.80, 52.02, 32.11, 31.12, 30.46, 22.24, 13.93, 13.80; MS (EI) m/z: 297 (M+), 282, 224, 189, 155, 71; Anal.calcd.for.C ^H₂₀CINO₃: C, 60.50%; H, 6.77%; N, 4.70%; Found: C, 60.56%; H, 6.89%; N, 4.85%; Im:

Methyl 2-[(2-chloro-5-methyl-6-phenylpyridine-3-yl)(hydroxy) methyl] acrylate: ¹H-NMR (CDCl₃, 200MHz): δ 7.78 (s, IH), 7.35-7.55 (m, 5H), 6.37 (s, IH), 5.82 (s, IH), 5.65 (s, IH), 3.82 (b, IH), 2.4 (s, 3H); ¹³C-NMR: (CDCl₃, 50MHz): δl66.69, 157.90, 146.34, 139.94, 139.77, 138.68, 133.03, 130.22, 128.94, 128.35, 128.12, 127.34, 68.91, 52.11, 19.33; MS (EI) m/z: 317 (M+), 302, 2282, 250, 230, 196, 167, 141, 117; Anal.calcd.for C₁₇H₁₆ClNO₃ : C, 64.26%; H, 5.07%; N, 4.41%; Found: C, 64.77%; H, 5.24%; N, 4.52%; In: Methyl 6-chloro-5 [l-hydroxy-2-(methoxycarbonyl)prop-2-en-l-yl]pyridine-2-carboxylate: ¹H-NMR (CDCl₃, 200MHz): δ 8.12 (m, 2H), 6.32 (s, IH), 5.82 (s, IH), 5.52 (s, IH), 3.98 (s, 3H), 3.78 (s, 3H); ¹³C-NMR: (CDCl₃, 50MHz): δ 166.44, 164.30, 149.60, 147.02, 139.43, 138.26, 127.81, 124.00, 69.09, 52.99, 52.21; MS (EI) m/z: 285 (M+), 250, 217, 197, 164, 140, 115, 83, 59; Anal.calcd.for Ci₂H₁₂ClNO₅: C, 50.45%; H, 4.23%; N, 4.41%; Found: C, 50.89%; H, 4.44%; N, 4.67%; Io:

Ethyl 6-chloro-5-(l-hydroxy-2-(methoxycarbonyl) allyl)-2-phenyl-nicotinate: ^fH-NMR (CDCl₃, 200MHz): δ 8.8 (s, IH), 7.62 (m, 2H), 7.4 (m, 3H), 6.41 (s, IH), 5.98 (s, IH), 5.78 (s, IH), 4.2 (q, 2H), 3.68 (s, 3H), 1.25 (t, 3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 166.28, 165.57, 156.43, 149.39, 140.64, 139.61, 137.86, 133.07, 129.35, 128.99, 128.38, 128.28, 127.65, 67.95, 62.17, 52.14, 29.58, 13.55; MS (EI) m/z: 375 (M+), 330, 313, 299, 257, 165, 77; Anal.calcd.for: C₁₉H₁₈ClNO₅: C, 60.73%; H, 4.83%; N, 3.72%; Found: C, 60.89%; H, 4.99%; N, 3.87%.; Ip: Methyl 2-{[2-chloro-5-(4-methoxyphenyl)-pyridine-3-yl](hydroxy)methyl}acryIate: ¹H-NMR (CDCl₃, 200 MHz): δ 8.49 (s, IH), 8.1 (s, IH), 7.5 (m, 2H), 6.98 (m, 2H), 6.38 (s, IH), 5.9 (s, IH), 5.65 (s, IH), 3.85 (s, 3H), 3.8 (s, 3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 166.61, 160.00, 147.58, 146.17, 139.88, 135.70, 135.19, 135.00, 128.12, 127.48, 114.80, 114.57, 68.96,

60.33, 55.30, 52.14, 24.58; MS (EI) m/z: 333 (M+), 299, 273, 248, 212, 170, 141, 99, 43;

Anal.calcd.for Ci₇Hi₆ClNO₄: C, 61.18%; H, 4.83%; N, 4.20%; Found: C, 61.45%; H, 4.99%; N,

4.67%.; Iq:

Ethyl2-[(2-chloro-5-methylpyridine-3-yl)(hydroxy)methyl]acrylate:

¹H-NMR (CDCl₃, 200 MHz):8.06 (d,lH ), 7.66 (d,lH ), 6.28 (s,lH ), 5.76 (s,lH ), 5.55 (s,lH ),

4.16 (q,2H ), 2.30 (s,3H), 1.25 (t,3H ); ¹³C-NMR: (CDCl₃, 50 MHz): δ 166.30, 148.83, 146.89,

140.15, 137.98, 134.49, 132.70, 127.37, 127.08, 69.08, 61.23, 17.70, 14.06; MS EI (m/z): 255 (M⁺), 220, 192, 154, 146, 120, 92, 65. Anal.calcd.for C₁₂H₁₄ClNO₃: C, 56.35%; H, 5.55%; N,

5.48%. Found: C, 56.66%; H, 5.74%; N, 5.62%.

Ir:

Ethyl 2-[(2-chloro-5-ethylpyridine-3-yl)(hydroxy) methyl] acrylate:

¹H-NMR (CDCl₃, 200MHz): δ 8.13 (d, IH), 7.66 (d, IH), 6.28 (s,lH), 5.75 (s,lH), 5.28 (s,lH), 4.25 (q, 2H), 2.64 (q, 2H), 1.2o (t, 3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 167.65, 151.26, 147.68,

140.32, 139.62, 136.73, 128.75, 125.36, 70.78, 60.92, 25.96, 17.12, 14.12; MS EI (m/z): 269

(M⁺), 234, 204, 166, 132, 104, 79; Anal.calcd.for C₁₃H₁₆ClNO₃: C, 57.89%; H, 5.98%; N, 4.2%; found: C, 58.12%; H, 6.22%; N, 4.36%.;

Is: Ethyl 2-[(2-chloro-5-phenylpyridine-3-yl)(hydroxy) methyl] acrylate:

¹H-NMR (CDCl₃, 200 MHz): δ 8.5 (d, IH), 8.12 (s, IH), 7.35-7.6 (m, 5H), 6.34 (s, IH)₅ 5.88 (s,

IH), 5.62 (s, IH), 4.3 (q, 2H), 3.88 (b, IH), 1.3 (t, 3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 166.65,

148.89, 147.12, 140.62, 136.74, 136.54, 136.18, 135.65, 129.55, 128.90, 127.61, 127.47, 69.61,

61.68, 14.43; MS (EI) m/z: 317 (M+), 302, 282, 268, 254, 216, 182, 153, 127, 115, 77, 55. Anal.calcd.for Ci₇H₁₆ClNO₃: C, 64.26%; H, 5.07%; N, 4.40%. Found: C, 64.53%; H, 5.25; N,

4.62%.

It:

Ethyl 2-[(2-chloro-5-methyl-6-phenylpyridine-3-yl)(hydroxy) methyl] acrylate:

¹H-NMR (CDCl₃, 200 MHz): 7.78 (s, IH), 7.35-7.55 (m, 5H), 6.38 (s, IH), 5.82 (s, IH), 5.62 (s, IH), 4.25 (q, 2H), 2.4 (s, 3H), 1.33 (t, 3H); δ ¹³C-NMR: (CDCl₃, 50MHz): δ 167.65, 156.35,

145.87, 140.87, 138.67, 137.67, 135.42, 129.87, 127.93, 127.56, 124.42, 70.91, 54.64, 20.12, 14.56; MS (EI) m/z: 331 (M+), 302, 231, 165, 77; Anal.calcd.for C₁₈H₁₈ClNO₃: C, 65.16%; H,

5.47%; N, 4.22%; Found: C, 65.45%; H, 4.56%; N, 4.44%.;

Iu:

Methyl 6-chloro-5[l-hydroxy-2-(ethoxycarbonyl)prop-2-en-l-yl]pyridine-2-carboxylate: ¹H-NMR (CDCl₃, 200MHz): δ 8.12 (sharp q, 2H), 6.32, (s, IH), 5.85 (s, IH)₅ 5.52 (s, IH)₅ 4.25

(q, 2H), 3.98 (s, IH), 3.70 (b, IH), 1.32 (t, 3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 165.79, 164.20, 149.58, 146.75, 139.81, 139.75, 138.20, 127.32, 123.89, 68.77,

61.16, 52.89, 13.85;

MS (EI) m/z: 299 (M+), 264, 219, 178, 129; Anal.calcd.for C₁₃H₁₄ClNO₅ : C, 52.10%; H, 4.71%; N, 4.67%; Found: C, 52.43%; H, 4.97%; N, 4.86%.;

I v:

Ethyl 6-chloro-5- (l-hydroxy-2- (ethoxycarbonyl) allyl)-2-phenyl-nicotinate:

¹H-NMR (CDCl₃, 200 MHz): δ 8.8 (s, IH), 7.61 (m, 2H), 7.4 (m, 3H), 6.40 (s, IH), 5.99 (s, IH),

5.77 (s, IH), 4.25 (q, 2H), 4.2 (q, 2H), 1.32 (t, 3H), 1.25 (t, 3H); MS (EI) m/z: 389 (M+), 354, 306, 209, 165, 77; Anal.calcd.for C₂₀H₂₀ClNO₅ : C, 61.61%; H, 5.17%; N, 3.59%; Found: C,

61.89%; H, 5.64%; N, 3.82%.;

I w:

Ethyl 2-{[2-chloro-5- (4-methoxyphenyl)-pyridine-3-yl](hydroxy) methyl} acrylate:

¹H-NMR (CDCl₃, 200 MHz): δ 8.48 (s, IH), 8.12 (s, IH), 7.5 (m, 2H), 6.98 (m, 2H), 6.39 (s, IH), 5.91 (s, IH), 5.66 (s, IH), 4.25 (q, 2H), 1.32 (t, 3H); MS (EI) m/z: 347(M+), 312, 213, 239,

181, 176, 107, 65; Anal. calcd. for C₁₈H₁₈ClNO₄: C, 62.16%; H, 5.22%; N, 4.03%; Found: C,

62.28%; H, 5.56%; N, 4.23%.; H a:

2-[(2-Chloro-5-methylpyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one: ¹H-NMR (CDCl₃, 200 MHz): δ 8.16 (d, IH), 7.82 (d, IH), 7.14 (sharp t, IH), 5.78 (s, IH), 4.18

(d, IH), 2.65 (m, 2H), 2.52 (m, 2H), 2.4 (s, 3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 209.59, 160.53,

148.72, 146.06, 144.98, 137.62, 134.93, 132.85, 65.65, 35.07, 26.69, 17.73; MS EI (m/z): 237

^M⁺), 202, 156, 117, 92, 39. Anal.calcd.for C₁₂H₁₂ClNO₂: C, 60.61%; H, 5.13%; N, 5.89%.

Found: C, 60.80%; H, 5.23%; N, 5.98%. II b:

2-[(2-ChIoro-5-ethylpyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one: ¹H-NMR (CDCl₃, 200 MHz): δ 8.18 (d, IH)₅ 7.78 (d, IH), 7.21 (t, IH), 5.58 (s, IH), 4.25 (b, IH), 2.66 (q, 2H), 2.4 (m, 2H), 2.54 (m, 2H), 1.29 (t, 3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 207.82, 150.62, 149.74, 148.54, 139.76, 138.28, 133.21, 128.66, 65.42, 38.92, 25.88, 23.25, 14.95; MS EI (m/z): 251 (M⁺), 216, 170, 131, 104, 53; Anal.calcd.for C₁₃H₁₄ClNO₂: C, 62.03%; H, 5.61%; N, 5.56%; found: C, 62.44%, H, 5.98%; N, 14.56%.; H c:

2-[(2-Chloro-5-phenylpyridine-3-yl)(hydroxy) methyl] cycIopent-2-en-l-one: ¹H-NMR (CDCl₃, 200 MHz): δ 8.53 (s, IH), 8.21 (s, IH), 7.36-7.55 (m, 5H), 7.19 (sharp t, IH), 5.85 (s, IH), 2.46-2.72 (m, 4H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 205.82, 152.12, 149.75, 138.92, f38.48, 136.18, 130.14, 125.51, 124.91, 59.77, 45.08, 23.55; MS (EI) m/z: 299(M+), 264, 236, 153, 77; Anal.calcd.for Ci₇H₁₄ClNO₂: C, 68.18%; H, 4.70%; N, 4.67%. Found: C₅ 68.24%; H, 4.83%; N, 4.87%. H d: 2- [(2-Chloro-5-methyl-6-pheny lpy ridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one: ¹H-NMR (CDCl₃, 200 MHz): δ 7.85 (s, IH ), 7.35-7.55 (m, 5H ), 7.25 (sharp t, IH ), 5.82 (s, IH ), 4.09 (d,lH), 2.62-2.68 (m,2H), 2.48-2.55 (m,2H), 2.4 (s,3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 210.02, 160.43, 157.93, 145.54, 144.70, 139.45, 138.81, 133.34, 130.44, 128.97, 128.39, 128.19, 66.19, 35.11, 26.72, 19.39; MS (EI) m/z: 313 (M+), 278, 50, 235, 193, 115, 77; Anal.calcd.for C₁₈Hi₆ClNO₂ : C, 68.90%; H, 5.14%; N, 4.46%; Found: C, 69.12%; H, 5.43%; N, 4.76%.; H e:

Methyl- 6-chloro-5- [hydroxy (S-oxo-cyclopent-l-en-l-ytymethylJpyridine-^-carboxylate: ¹H-NMR (CDCl₃, 200 MHz): δ 8.13 (d, IH), 8.25 (d, IH), 7.22 (sharp t, IH), 5.88 (s, IH), 3.98 (s, 3H), 2.65 (m, 2H), 2.5 (m, 2H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 199.93, 164.33, 149.16, 148.69, 146.77, 139.95, 138.26, 123.94, 68.52, 52.93, 38.23, 25.74, 22.25; MS (EI) m/z: 281 (M+), 246, 218, 202, 188, 122, 69; Anal.calcd.for C₁₃H₁₂ClNO₄ : C, 55.43%; H, 4.29%; N, 4.97%; Found: C, 55.67%; H, 4.67%; N, 5.14%.; H f:

Ethyl 6-chIoro-5-[hydroxy(5-oxo-l-cycIopentenyl)methyl]-2-phenyl nicotinate: ¹H-NMR (CDCl₃, 200 MHz): δ 8.9 (s, IH), 7.6 (m, 2H), 7.42 (m, 3H), 7.22 (t, IH), 5.92 (s, IH), 4.2 (q, 2H), 2.65 (m, 2H), 2.5 (t, 2H), 1.1 (t, 3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 205.82, 167.64, 149.25, 149.18, 139.80, 139.22, 136.43, 134.40, 132.7, 129.11, 128.36, 123.26, 117.75, 60.49, 57.2, 45.02, 23.25, 14.35; MS (EI) m/z: 371 (M+), 336, 318, 275, 263, 178, 77; Anal.calcd.for

C₂₀Hi₈ClNO₄: C, 64.61%; H, 4.88%; N, 3.77%; Found: C, 64.92%; H₅ 5.09%; N, 3.78%.;

\l g: 2-[(2-ChIoro-5- (4-methoxyphenyl) pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l- one:

¹H-NMR (CDCl₃, 200 MHz): δ 8.43 (d, IH), 8.13 (d, IH), 7.49 (m, 2H), 7.18 (t, IH), 6.92 (m, 3H), 5.8 (s, IH), 3.82 (s, 3H), 2.53 (m, 2H), 2.45 (m, 2H); MS (EI) m/z: 329 (M+), 294, 276, 251, 107, 65; Anal.calcd.for Ci₈Hi₆ClNO₃: C, 65.56%; H, 4.89%; N, 4.25%; Found: C, 65.87%; H, 5.12%; N, 4.45%.; H h:

2-[(2-ChIoro-5-methylpyridine-3-yl)(hydroxy) methyl] cyclohex-2-en-l-one:

¹H-NMR (CDCl₃, 200 MHz): δ 8.1 (d, IH), 7.78 (d, IH), 6.46 (t, IH), 5.72 (s, IH), 2.5 (m, 2H), 2.36 (s, 3H), 2.38 (m, 2H), 2.03 (m, 2H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 200.24, 148.49, 148.22, 138.70, 137.95, 134.73, 132.55, 68.37, 38.34, 25.74, 22.35, 17.70; MS EI (m/z): 251 (M⁺), 216, 198, 116, 84, 65, 48. Anal.calcd.for C₁₃Hi₄ClNO₂: C, 62.01%; H, 5.64%; N, 5.56%. Found: C, 62.24%; H, 5.74%; N, 5.68%. H i:

2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] cyclohex-2-ene-l-one:

¹H-NMR (CDCl₃, 200 MHz): δ 8.14 (d, IH), 7.76 (d, IH), 6.5 (t, IH), 5.72 (s, IH), 4.22 (b, IH), 2.64 (q, 2H), 2.5 (m, 2H), 2.38 (m, 2H), 2.02 (m, 2H), 1.18 (t, 3H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 200.23, 149.42, 148.86, 139.06, 138.76, 135.32, 134.17, 128.13, 67.75, 38.03, 25.86, 25.78, 12.34, 14.95; MS (m/z,%): 265, 230, 212, 130, 98, 79, 62; Anal.calcd.for C₁₄HI₆CINO₂: C, 63.28%; H, 6.07%; N, 5.27%; Found: C, 63.54%, H, 6.42%; N, 5.44%.;

2-[(2-Chloro-5-phenylpyridine-3-yl)(hydroxy) methyl] cyclohex-2-en-l-one:

¹H-NMR (CDCl₃, 200 MHz): δ 8.5 (s, IH), 8.2 (s, IH), 7.34-7.64 (m, 5H), 6.5 (t, IH), 5.8 (s,

IH), 3.85(b, IH), 2.05 (m, 2H), 2.35-2.6 (m, 4H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 200.29, 148.46, 148.00, 146.42, 138.64, 136.41, 136.01, 135.79, 135.39, 129.07, 128.39, 127.06, 68.53, 38.33, 25.76, 22.34. MS (EI) m/z: 313 (M+), 278, 260, 217, 71, 57; Anal.calcd.for C₁₈Hi₆ClNO₂:

C, 68.90%; H, 5.14%; N, 4.46%. Found: C, 69.12%; H, 5.27%; N, 4.48%.

Il k:

2-[(2-Chloro-5-methyI-6-phenylpyridine-3-yl)(hydroxy) methyl] cyclohex-2-en-l-one:

¹H-NMR (CDCl₃, 200 MHz): δ 7.85 (s, IH), 7.35-7.55 (m, 5H)₅ 6.66 (t, IH), 5.75 (s, IH)₅ 3.86 (d, IH), 2.5 (m, 2H), 2.4 (m, 2H), 2.4 (s, 3H)₅ 2.0 (m, 2H); ¹³C-NMR: (CDCl₃₅ 50 MHz): δ 200.29, 148.46, 148.00, 146.42, 138.64, 136.41, 136.01, 135.79, 135.39, 129.07, 128.39, 127.06, 68.53, 38:33, 25.76, 22.34; MS (EI) m/z: 327 (M⁺), 311, 291, 273, 249, 218, 117; Anal.calcd.for C₁₉Hi₈ClNO₂: C, 69.62%; H, 5.53%; N, 4.27%; Found: C₅ 70.07%; H, 5.74%; N, 4.56%.; Il l:

Methyl-6-chloro-5-[hydroxy(6-oxo-cyclohex-l-en-l-yl)methyl]pyridine-2-carboxyIate:

¹H-NMR (CDCl₃, 200 MHz): δ 8.12 (d, 2H), 8.02 (d, IH), 6.52 (t, IH), 5.83 (s, IH), 3.98 (s, 3H)₅ 2.5 (m, 2H), 2.4 (m, 2H), 2.05 (m, 2H); ¹³C-NMR: (CDCl₃, 50 MHz): δ 199.93, 164.33, 149.16, 148.69, 146.77, 139.95, 138.26, 123.94, 68.53, 52.93, 38.23, 25.74, 22.25; MS (EI) m/z: 295(M+), 260, 232, 229, 201, 160, 112, 59; Anal.calcd.for Ci₄H₁₄ClNO₄: C, 56.86%; H, 4.77%; N, 4.74%; Found: C, 57.12%; H, 4.98%; N, 4.98%.; H m:

Ethyl 6-chloro-5-[hydroxy(5-oxo-l-cyclohexenyI)methyl]-2-phenyI nicotinate: ¹H-NMR (CDCl₃, 200 MHz): δ 8.92 (s, IH), 7.6 (m, 2H)₅ 7.4 (m, 3H)₅ 6.59 (t, IH)₅ 5.98 (s, IH), 4.2 (q, 2H), 2.38-2.57 (m, 4H), 2.02 (m, 2H), 1.1 (t, 3H); MS (EI) m/z: 385(M+), 350, 332, 321, 278, 165, 73; Anal.calcd.for C₂₁H₂₀ClNO₄: C, 65.37%; H, 5.22%; N, 3.63%; Found: C, 65.78%; H, 5.67%; N, 3.78%.; H n:

2-[(2-Chloro-5- (4-methoxyphenyl) pyridine-3-yl)(hydroxy) methyl] cyclohex-2-en-l-one: ¹H-NMR (CDCl₃, 200 MHz): δ 8.45 (s, IH), 8.13 (s, IH), 7.5 (d, 2H), 6.95 (d, 2H), 6.55 (t, IH), 5.78 (s, IH), 3.82 (s, 3H), 2.3-2.6 (m, 4H), 2.02 (m, 2H); MS (EI) m/z: 343(M+), 308, 290, 247, 107, 65; Anal.calcd.for C₁₉H₁₈ClNO₃: C, 66.38%; H, 5.28%; N, 4.07%; Found: C, 66.97%; H, 5.56%; N, 4.34%.; Antimalarial Activity:

Parasites were cultured in O (+) erythrocytes in RPMI- 1640 media supplemented with 25mM HEPES buffer and 10% AB (+) serum by candlejar technique.⁹ Initial culture was maintained in small vials (2.5 cm dia.) with 10% haematocrit, i.e. lOμl erythrocytes containing 1.5% ring stage parasite in lOOμl complete media. The culture volume per well for the assay was lOOμl. Parasitemia was determined for each set of culture, number of parasites for the assay were adjusted at 1 to 1.5% by diluting with fresh O(+) RBC. Assay was done in 96 well rnicrotitre flat-bottomed tissue culture plates. Parasite culture was synchronized at ring forms using density gradient method¹⁰ and cultured for 24h. in the presence of various doses of compounds and chloroquine for their effect in schizont maturation. Test was done in duplicate wells for each close of the drugs. Control culture was done with RPMI- 164 containing 10% AB (+) serum. Growth of the parasites from duplicate wells of each concentration was monitored in JSB stained¹¹ blood smears by counting number of schizont per 200 asexual parasites. Percent schizont maturation inhibition was calculated by the formula: (1-N_t/N_c) xlOO where, N₁ and N_c represent the number of schizont in the test and control well respectively. The effects on parasite growth by the compounds (Ia-If) of the present invention, together with data are shown in tables 1 and 2 respectively.

Table 1 : Antimalarial activities, IC₅₀ and IC₉₀ of compounds Ia-If against Chloroquine sensitive (CQS) P .falciparum strain

SMI: Schizont maturation inhibition determined after 24hr. PGI: Total parasite growth inhibition determined after 48hr. Table 2: Antimalarial activities, IC₅₀ and IC₉₀ of compounds Ia-If against Chloroquine resistant (CQR) P. falciparum strain

SMI: Schizont maturation inhibition determined after 24hr. PGI: Total parasite growth inhibition determined after 48hr.

Claims

We Claim

1. A novel chloro pyridine skelton based Baylis-Hillman adduct having the general formula

wherein

Rl is selected from the group consisting of hydrogen, phenyl and carbomethoxy; R2 is selected from the group consisting of hydrogen, alkyl, CH₃, C₂Hs, phenyl, n-C₅Hπ, carboethoxy and p- OMe-Ph; EWG is an electron withdrawing group selected from the group consisting of CN, COOMe and COOEt.

2. A novel chloro pyridine skelton based Baylis-Hillman adduct as claimed in claim 1, comprising the compound of general formula I or II

I II Rl is selected from the group consisting of hydrogen, phenyl and carbomethoxy; R2 is selected from the group consisting of hydrogen, alkyl, CH₃, C₂H₅, phenyl, n-C₅Hπ, carboethoxy and p- OMe-Ph; EWG is an electron withdrawing group selected from the group consisting of CN, COOMe and COOEt.

3. A novel Baylis-Hillman adduct obtained as claimed in claim 1 comprises chloro pyridine skelton based Baylis-Hillman adduct of general formula I and II, its derivatives, analogues or salt thereof.

4. A novel chloro pyridine skelton based Baylis-Hillman adduct obtained as claimed in claims 1&3 is selected from the group consisting of 2-[(2-Chloro-5-methyl pyridine-3- yl)(hydroxy) methyl] acrylonitrile (Ia), 2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ib), 2-[(2-Chloro-5-phenylpyridine-3-yl) (hydroxy) methyl] acrylonitrile (Ic), diethyl ό-chloro-S-^-cyano-l-hydroxy allyl) 2-pyridine carboxylate (Id), Methyl 2-[(2-chloro- 5-methylpyridine-3-)(hydroxy) methyl] acrylate (Ie), Methyl 2-[(2~chloro-5-phenylpyridine-3- yl)(hydroxy) methyl] acrylate (If), 2-[(2-chloro-5-n-pentylpyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ig), 2-[(2-Chloro-5-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] acrylonitrle (Ih), Ethyl 6-chloro-5-(2-cyano-l -hydroxy allyl)-2-phenyl-nicotinate (Ii), 2-[(2-Chloro-5-(4- methoxyphenyl)pyridine-3-yl) (hydroxy)methyl] acrylonitrile (Ij), Methyl 2-[(2-chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylate (Ik), Methyl 2-[(2-chloro-5-n-pentyl pyridine-3- yl)(hydroxy) methyl] acrylate (I 1), Methyl 2-[(2-chloro-5-methyl-6-phenyl pyridine-3- yl)(hydroxy) methyl] acrylate (Im), Methyl 6-chloro-5- [l-hydroxy-2- (methoxycarbonyl) allyl] pyridine-2-carboxylate (I n), Ethyl 6-chloro-5- (l-hydroxy-2- (methoxycarbonyl) allyl)-2- phenyl-nicotinate (Io), Methyl 2-[(2-chloro-5- (4-methoxyphenyl) pyridine-3-yl)(hydroxy) methyl] acrylate (Ip), Ethyl 2-[(2-chloro-5-methyl pyridine-3-)(hydroxy) methyl] acrylate (Iq), Ethyl 2-[(2-chloro-5-ethyl ρyridine-3-yl)(hydroxy) methyl] acrylate (Ir)₅ Ethyl 2-[(2-chlόro-5- phenyl pyridine-3-yl)(hydroxy) methyl] acrylate (Is), Ethyl 2-[(2-chloro-5-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] acrylate (It), Methy-6-chloro-5-[l-hydroxy-2- (ethoxycarbonyl)allyl] pyridine-2-carboxylate (Iu), Ethyl 6-chloro-5-(l-hydroxy-2- (ethoxycarbonyl)allyl)-2-phenyl-nicotinate (Iv), Ethyl 2-[(2-chloro-5- (4-meth oxyphenyl) pyridine-3-yl)(hydroxy) methyl] acrylate (Iw), 2-[(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one (Ha), 2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one (lib), 2-[(2-Chloro-5-phenyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2- en-l-one (lie), 2-[(2-Chloro-5-methyl-6-phenyl pyridϊne-3-yl)(hydroxy) methyl] cyclopent-2-en- I- one (lid), Methyl-6-chloro-5-[hydroxy(5-oxo-l-cyclopentenyl)methyl]-2-pyridine carboxyl ate(IIe), Ethyl 6-chloro-5-[hydroxy(5-oxo-l-cyclopentenyl)methyl]-2-phenyl nicotinate (II f), 2- [(2-Chloro-5- (4-methoxyphenyl)pyridine-3-yl)(hydroxy) methyl]cyclopent-2-en-l-one(IIg), 2- [(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] 2-cyclohexenel-one (II h), 2-[(2-Chloro-5- ethyl pyridine-3-yl)(hydroxy) methyl]cyclohex-2-ene-l-one(IIi), 2-[(2-Chloro-5-phenyl pyridine-3-yl)(hydroxy) methyl] cyclohex-2-ene-l-one (Hj), Methyl 2-[(2-chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylate (Ik), Methyl 6-chloro-5-[hydroxy (5-oxo-l- cyclohexenyl)methyl]-2-pyridine carboxylate (II 1), Ethyl 6-chloro-5-[hydroxy(5-oxo-l- cyclohexenyl)methyl]-2-phenyl nicotinate (II m) and 2-[(2-Chloro-5-(4- methoxyphenyl)pyridine-3-yl)(hydroxy) methyl] cyclohex-2-en-l-one (II n).

5. A novel chloro pyridine skelton based Baylis-Hillman adduct as claimed in claims 1-4 is active against chloroquine sensitive and chloroquine resistant plasmodiwn falciparum strains.

6. A novel chloro pyridine skelton based Baylis-Hillman adduct as claimed in claims 1-5 exhibits an anti malarial activity against the erythrocytic stage of the malarial parasite.

7. A pharmaceutical composition comprising novel anti malarial chloro pyridine skelton based Baylis-Hillman adduct, its derivatives, analogues, salts or mixture thereof optionally with pharmaceutically acceptable carriers, adjuvants and additives.

8. A pharmaceutical composition as claimed in claim 7, wherein the novel anti malarial chloro pyridine skelton based Baylis-Hillman adduct used is comprising the compound of general formula I or II

II

Rl is selected from the group consisting of hydrogen, phenyl and carbomethoxy; R2 is selected from the group consisting of hydrogen, alkyl, CH₃, C₂H₅, phenyl, n-C₅Hπ, carboethoxy and p- OMe-Ph; EWG is an electron withdrawing group selected from the group consisting of CN, COOMe and COOEt.

9. A method for the treatment of malaria in a subject wherein a dose of 1-45 μg/ml and 1- 115 μg/ml drug is administered for IC50 against chloroquine sensitive (CQS) P. falciparum strain to such subject for schizont maturation inhibition (SMI) and total parasite growth inhibition (PGI), for at least 24 and 48 hrs, respectively .

10. A method for the treatment of malaria in a subject wherein a dose of 25-125 μg/ml and 85- 350 μg/ml drug is administered for IC90 against chloroquine sensitive (CQS) P falciparum strain to such subject for schizont maturation inhibition (SMI) and total parasite growth inhibition (PGI), for at least 24 and 48 hrs, respectively.

11. A method for the treatment of malaria in a subject wherein a dose of 0.2-30 μg/ml and 5-15 μg/ml drug is administered for IC50 against chloroquine resistant Plasmodium falciparum strain to such subject for schizont maturation inhibition (SMI) and total parasite growth inhibition (PGI), for at least 24 and 48 hrs, respectively.

12. A method for the treatment of malaria in a subject wherein a dose of 1-125 μg/ml and 25- 300 μg/ml drug is administered for IC90 against chloroquine resistant plasmodium falciparum strain to such subject for schizont maturation inhibition (SMI) and total parasite growth inhibition (PGI), for at least 24 and 48 hrs, respectively.

13. A process for the preparation of chloro pyridine skelton based Baylis-Hillman adduct having the general formula

therein X=

Rl is selected from the group consisting of hydrogen, phenyl and carbomethoxy; R2 is selected from the group consisting of hydrogen, alkyl, CH₃, C₂H₅, phenyl, n-C₅H_{l l5} carboethoxy and p- OMe-Ph; EWG is an electron withdrawing group selected from the group consisting of CN, COOMe and COOEt, which comprises reacting 2-chloro-5 and / or 6-substituted 3 -pyridine carboxyaldehyde with an activated alkene or cyclic enone, optiomally in the presence of aqueous ύr non aqueous organic solvent, in the presence of a catalyst, at a temperature in the range of 20- 30 ⁰C, washing the organic layer of the above said reaction mixture with water or brine solution, followed by drying and purification by known method to obtain the desired product.

14. A process as claimed in claim 13, wherein the 2-chloro-5 and / or 6-substituted 3- pyridine carboxyaldehyde used is selected from the group consisting of 2-Chloro-5- methylpyridinecarboxaldehyde, 2-Chloro-5-ethylnicotinaldehyde, 2-Chloro-5- phenylnicotinaldehyde,methyl6-chloro-5-formyl-2-pyridincarboxylate ,2-chloro-5- methylnicotinaldehyde, 2-Chloro-5-phenylnicotinaldehyde, 2-chloro-5-pentylnicotinaldehyde, 2- Chloro-5-methyl-6-phenylnicotinaldehyde, 2-Chloro-5-ethoxyacetate)-6- phenylnicotinaldehyde,2-Chloro-5-(4-methoxy ph enyl)-nicotinaldehyde, 2-Chloro-5- εthylnicotinaldehyde, 2-Chloro-5-pentyl nicotinaldehyde, 2-Chloro-5-methyl-6- phenylnicotinaldehyde,Methyl6-chloro-5-formyl-2-pyridin carboxylate, 2-Chloro-5- ethoxyacetate)-6-phenylnicotin aldehyde, 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde, 2-

Chloro-5-methyl nicotinaldehyde, 2-Chloro-5-ethylnicotinaldehyde, 2-Chloro-5-phenylnicotin aldehyde, 2-Ctøoro-5-memyl-6-phenylnicotinaldehyde, Methyl 6-chloro-5-formyl-2- pyridincarboxylate, 2-Chloro-5-ethoxyacetate)-6-phenylnicotin aldehyde,2-Chloro-5-(4- methoxyphenyl)-nicotinaldehyde, 2-Chloro-5 -methyl nicotinaldehyde, 2-Chloro-5-ethylnicotin aldehyde, 2-Chloro-5-phenylnicotinaldehyde, 2-Chloro-5-methyl-6-phenylnicotin aldehyde, Methyl ό-chloro-S-formyl^-pyridincarboxylate, 2-Chloro-5-ethoxyacetate)-6-phenyl nicotinaldehyde, 2-Chloro-5-(4-methoxyphenyl)-nicotin aldehyde, 2-Chloro-5- methylnicotinaldehyde, 2-Chloro-5-ethylnicotinaldehyde, 2-Chloro-5-phenylnicotinaldehyde, 2- chloro-substituted-3-pyridinecarboxy aldehyde, methyl 6-chloro-5-formyl-2-pyridincarboxylate, 2-Chloro-5-ethoxyacetate)-6-phenyl nicotinaldehyde and 2-Chloro-5-(4-methoxyphenyl)- nicotinaldehyde.

15. A process as claimed in claim 13, wherein the activated alkene used is selected from the group consisting of acrylonitrile, methyl acrylate and ethyl acrylate.

16. A process as claimed in claim 13, wherein the cyclic enone used is selected from 2- cyclopenten-1-one and 2-cyclohexen-l-one.

17. A process as claimed in claim 13, wherein the catalyst used is selected from di azabicylooctane (DABCO) and imidazole.

18 A process as claimed in claim 13, wherein the organic solvent used is selected from the group consisting of methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylsulphoxide (DMSO) and dimethylformamide(DMF) 1,4-dioxane, chloroform and sulpholane.

19. A process as claimed in claim 13, wherein the molar ratio of 2-chloro-5 and / or 6- substituted 3 -pyridine carboxyaldehyde to activated alkene or cyclic enone used is in the range of !:1 to 1:8.

20. A process as claimed in claim 13, wherein the molar ratio of 2-chloro-5 and / or 6- substituted 3 -pyridine carboxyaldehyde to activated alkene in the reaction mixture used is in the range of 1 :5 to 1 :8.

21. A process as claimed in claim 13, wherein the molar ratio of 2-chloro-5 and / or 6- substituted 3 -pyridine carboxyaldehyde to cyclic enone used is preferably in the range of 1:1 to 1:2.

22. A process as claimed in claim 13, wherein the molar ratio of 2-chloro-5 and / or 6- substituted 3-pyridine carboxyaldehyde to catalyst used is in the range of 1 : 1 to 1 :2.

23. A process as claimed in claim 13, wherein the molar ratio of activated alkene to catalyst used is in the range ofl : 1 to 1 :2.

24. A process as claimed in claim 13, wherein the reaction mixture of aldehyde and alkene ysed is diluted with diethyl ether and is followed by washing with water and drying the resultant organic layer over sodium sulphate before subjected to purification by column chromatography.

25. A process as claimed in claim 13, wherein the reaction mixture of aldehyde and cyclic- enone used is taken into chloroform, the organic layer is washed with brine solution- before drying and purification by known method to obtain the desired product.

26. A process as claimed in claim 13, wherein the reaction time between aldehyde and cyclic-enone used is in the range of 20-40 minutes.

27. A process as claimed in claim 13, wherein the yield of the product chloro pyridine skelton based Baylis-Hillman adduct is in the range of 85-98% without forming side products.

28. A process as claimed in claim 13, wherein the product chloro pyridine skelton based Baylis- Hillman adduct obtained is selected from the group consisting of 2-[(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ia), 2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylonitrile (Ib), 2-[(2-Chloro-5-phenylpyridine-3-yl) (hydroxy) methyl] acrylonitrile (Ic), methyl 6-chloro-5-(2-cyano-l -hydroxy allyl) 2-pyridine carboxylate (Id), Methyl 2-[(2- chloro-5-methylpyridine-3-)(hydroxy) methyl] acrylate (Ie), Methyl 2-[(2-chloro-5- phenylpyridine-3-yl)(hydroxy) methyl] acrylate (If), 2-[(2-chloro-5-n-pentyrpyridine-3- yl)(hydroxy) methyl] acrylonitrile (Ig), 2-[(2-Chloro-5-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] acrylonitrle (Ih), Ethyl 6-chloro-5-(2-cyano-l -hydroxy allyl)-2-phenyl-nicotinate (Ii), 2- [(2-Chloro-5-(4-methoxyphenyl)pyridine-3-yl) (hydroxy)methyl] acrylonitrile (Ij), Methyl 2-[(2- chloro-5 -ethyl pyridine-3-yl)(hydroxy) methyl] acrylate (Ik), Methyl 2-[(2-chloro-5-n-pentyl pyridine-3-yl)(hydroxy) methyl] acrylate (1 1), Methyl 2-[(2-chloro-5-methyl-6-phenyl pyridine- 3-yl)(hydroxy) methyl] acrylate (Im), Methyl 6-chloro-5- [l-hydroxy-2- (methoxycarbonyl) allyl] pyridine-2-carboxylate (I n), Ethyl 6-chloro-5- (l-hydroxy-2- (methoxycarbonyl) allyl)-2- phenyl-nicotinate (Io), Methyl 2-[(2-chloro-5- (4-methoxyphenyl) ρyridine-3-yl)(hydroxy) methyl] acrylate (Ip), Ethyl 2-[(2-chloro-5-methyl pyridine-3-)(hydroxy) methyl] acrylate (Iq), Ethyl 2-[(2-chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] acrylate (Ir), Ethyl 2-[(2-chloro-5- phenyl pyridine-3-yl)(hydroxy) methyl] acrylate (Is), Ethyl 2-[(2-chloro-5-methyl-6-phenyl pyridine-3-yiχhydroxy) methyl] acrylate (It), Methy-6-chloro-5-[l-hydroxy-2- (ethoxycarbonyl)allyl] pyridine-2-carboxylate (Iu), Ethyl 6-chloro-5-(l-hydroxy-2- (ethoxycarbonyl)allyl)-2-phenyl-nicotinate (Iv), Ethyl 2-[(2-chloro-5- (4-meth oxyphenyl) pyridine-3-yl)(hydroxy) methyl] ""acrylate (Iw), 2-[(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one (Ha), 2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en-l-one (lib), 2-[(2-Chloro-5-phenyl pyridine-3-yiχhydroxy) methyl] cyclopent-2- en-l-one (lie), 2-[(2-Chloro-5-methyl-6-phenyl pyridine-3-yl)(hydroxy) methyl] cyclopent-2-en- l-one(IId), Methyl-6-chloro-5-[hydroxy(5-oxo-l-cyclopentenyl) methyl]-2-pyridine carboxyl ate(IIe), Ethyl 6-chloro-5-[hydroxy(5-oxo-l-cyclopentenyl)methyl]-2-phenyI mcotinate (II f), 2- [(2-Chloro-5- (4-methoxyphenyl)pyridine-3-yl)(hydroxy) methyl]cyclopent-2-en-l-one(IIg), 2- [(2-Chloro-5-methyl pyridine-3-yl)(hydroxy) methyl] 2-cyclohexenel-one (II h), 2-[(2-Chloro-5- ethyl pyridine-3-yl)(hydroxy) methyl]cyclohex-2-ene-l-one(IIi), 2-[(2-Chloro-5-phenyl pyridine-3-yl)(hydroxy) methyl] cyclohex-2-ene-l-one (Hj), Methyl 2-[(2-chloro-5-ethyl pyridine-3-yi)(hydroxy) methyl] acrylate (Ik), Methyl 6-chloro-5-[hydroxy (5-oxo-l- cyclohexenyl)methyl]-2-pyridine carboxylate (II 1), Ethyl 6-chloro-5-[hydroxy(5-oxo-l- cyclohexenyl)methyl]-2-phenyl nicotinate (II m) and 2-[(2-Chloro-5-(4- methoxyphenyl)pyridine-3-yl)(hydroxy) methyl] cyclohex-2-en-l-one (II n).

29. A process as claimed in claim 13, wherein chloro pyridine skelton based Baylis-Hillman adduct obtained is active against chloroquine sensitive and chloroquine resistant Plasmodium falciparum strains.

30. A process as claimed in claim 13, wherein chloro pyridine skelton based Baylis-Hillman adduct obtained exhibits an anti malarial activity against the erythrocytic stage of the malarial parasite.

31. A process as claimed in claim 13, wherein the Hillman adduct obtained is used in a pharmaceutical composition comprising novel anti malarial chloro pyridine skelton based Baylis- Hillman adduct, its derivatives, analogues or salt thereof optionally with pharmaceutically acceptable carriers, adjuvant and additives.