WO2011151701A1

WO2011151701A1 - 6 - methyl - 4 - phenyl - 5 - ( phenyl or cycloalkyl) carbamoyl - 1,2,3, 4 - tetrahydropyrimidin- 2 - one derivatives as antitubercular agents

Info

Publication number: WO2011151701A1
Application number: PCT/IB2011/001184
Authority: WO
Inventors: Dhiman Sarkar; Sampa Sarkar; Rohit Ramesh Joshi; Vijay Murlidhar Khedkar; Raghuvir Ramakant Pissurlenkar; Evans Cliffton Coutinho; Anamik Kantilal Shah
Original assignee: Council Of Scientific & Industrial Research
Priority date: 2010-05-31
Filing date: 2011-05-31
Publication date: 2011-12-08
Also published as: CN102971301B; RU2012154338A; RU2590163C2; CN102971301A; BR112012030633A2; ZA201209026B

Abstract

The present invention discloses antitubercular compounds selected from tetrahydropyrimidones/ tetrahydrothiopyrimidone derivatives of Formula (1) and its pharmaceutically acceptable salts for the treatment of Mycobacterium in the dormant phase. Formula (1) wherein, R is H, halogen, dihalogen, O-alkyl, di- O-alkyl, R₁ is phenyl, chlorophenyl, nitrophenyl, diclorophenyl, cycloalkyl, preferably cyclohexyl, X is O or S.

Description

6 -METHYL - 4 - PHENYL - 5 - ( PHENYL OR

CYCLOALKYL) CARBAMOYL - 1 ,2,3, 4 - ETRAHYDROPYRIMIDIN- 2 - ONE DERIVATIVES AS ANTITUBERCULAR AGENTS

Technical field of invention

The present invention relates to compounds of formula 1 exhibiting and tubercular activity. Particularly, this invention relates to compounds that exhibit anti tubercular activity in dormant stage of mycobacterium and to the process for the preparation thereof.

Formula 1 wherein, R is H, halogen, dihalogen, O-alkyl, di- O-alkyl , R| is phenyl, chlorophenyl, nitrophenyl, diclorophenyl, cycloalkyl preferably cyclohexyl , X is O or S.

Background and prior art

Tuberculosis is known to afflict about 8 million people annually, with 2 million deaths occurring due to it annually. India is known to have the largest incidence of the disease in its population with up to 1.8 million affected. The rise in HIV infections and the neglect of TB control programs have provoked a resurgence of tuberculosis. The emergence of drug-resistant strains has also contributed to this new epidemic with, from 2000 to 2004, 20% of TB cases being resistant to standard treatments and 2% resistant to second-line drugs. In the background of this grim scenario, there is a need for continuous research to be done to come up with newer and newer drugs that can effectively combat the disease.

Most available anti tubercular drugs and several new molecules that have been proposed for activity against the bacilli act against the bacteria in their growing phase. V. Virsodia et al in an article titled "Synthesis, screening for antitubercular activity and 3D-QSAR studies of substituted N-phenyl-6-methyl-2-oxo-4-phenyl-l ,2,3,4- tetrahydropyrimidine-5-carboxamide" in the European Journal of Medicinal Chemistry, 43 2103-21 15 (2008) reports the synthesis and evaluation of substituted N-phenyl-6- methyl-2-oxo-4-phenyl-l ,2,3,4-tetrahydropyrimidine-5-carboxamides as anti tubercular agents. But these agents have been found to be active against the tested Mycobacterium strain in its active or growing phase.

An article titled "One-pot synthesis of 5-carboxamlide-dmydropyrimidinones using etidronic Acid" by Akshay M. Pansuriya et.al; published in General Papers ARKIVOC 2009 (vii) 79-85 having ISSN 1551-7012; describes synthesis of 5-carboxanilide-4- substituted d ydropyrimidinones using a cyclocondensation reaction of a 1 ,3-diketone, an aldehyde, and urea. The said 5-carboxanilide-4-substiruted dihydropyrimidinones derivatives exhibit broad range of biological effects including antiviral, antitumor, antibacterial, anti-inflammatory activities. However, the antitubercular activity against Mycobacterium strain in its active or growing phase or in dormant phase is not known. There is a need in the art to have molecules that can act against the bacilli in their dormant phase to effectively reduce the incidence of tuberculosis as well reduce morbidity and mortality due to the disease. Moreover, this can be a strategy to overcome multi drug resistant bacilli, which is increasingly making conventional treatment regimens ineffective. Objective of the present invention

The main objective of the present invention is to provide compounds of formula 1 exhibiting anti tubercular activity.

Therefore the objective of the invention is to provide compounds that are active against the mycobacterium in their dormant phase.

Another objective of the invention is to provide a process for the synthesis of said compounds.

Summary of the invention:

Accordingly, the present invention relates to compounds of formula 1 exhibiting anti tubercular activity in dormant stage and the present invention also provides a process for the preparation thereof.

Formula 1

wherein, R is H, halogen, dihalogen, O-alkyl, di- O-alkyl , Ri is phenyl, chlorophenyl, nitrophenyl, diclorophenyl, cycloalkyl preferably cyclohexyl , X is O or S.

In an embodiment of the present invention the general formula 1 is represented by the following compounds:

N-(3-chlorophenyl)-4-(2,4-dichlorophenyl)-6-methyl-2-oxo-l ,2,3,4- tetrahydropyrimidine-5-carboxamide( 1 )

N-(4-nitro-phenyl)4-(2,4-dichloro-phenyl)-6-methyl-2-oxo-l ,2,3,4-tetrahydropyrimidine-5- Carboxamide. (2)

N-(2,3-dichloro-phenyl)4-(2,4-dicUoro-phenyl)-6-methyl-2-oxo-l ,2,3,4-tetrahydropyrimidine- 5-carboxamide. (3)

N-cyclohexyl -4-phenyl -6-Methyl- 2-oxo - 1 ,2,3, 4-tetrahydropyrimidine-5- carboxamide (4)

N-(3-chloro-phenyl) -4-phenyl -6-Methyl- 2-oxo -l ,2,3,4-tetrahydropyrimidine-5- carboxamide. (5)

N-(3-chloro-phenyl)-4-phenyl 6-Methyl-2-thioxo- 1 ,2,3,4-tetrahydro-pyrimidine-5- carboxamide (6)

N-(4-nitro-phenyl)-4-phenyl -6-Methyl-2-oxo- 1 ,2,3,4-tetrahydro-pyrimidine-5- carboxamide (7).

N-(3-cUorophenyl)-4-(3-chlorophenyl)-6-methyl-2-oxo-l ,2,3,4-tetrahydropyrmiidine- 5-carboxamide. (8) N-(2,3-dicUoro-phenyl)-4-(3-chloro-phenyl)-6-methyl-2-oxo-l ,2,3,4-tetrahydro-pyrimidine- 5-carboxamide.( 9)

N-(3 -chloro-phenyl)-4-(3 ,4-dimethoxyphenyl)-6-methyl-2-oxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 - carboxamide.( 10)

N,4-bis(3-cUorophenyl)-6-methyl-2-thioxo-l ,2,3,4-tetrahydropyrimidine-5- carboxamide. (1 1)

N-(2,3-dichlorophenyl)-4-(3-chlorophenyl)-6-methyl-2-thioxo-l ,2,3,4-tetrahydropyrimidine- 5-carboxamide. (12)

N-(2,3-dichloro-phenyl)-4-(2,4-dichloro-phenyl)-6-methyl-2-thioxo-l ,2,3,4- tetrahydropyrimidine-5 -carboxamide. (13)

N-(2,3-dichlorophenyl)-6-methyl-4-phenyl-2-thioxo- 1 ,2,3, 4-tetrahydropyrimidine-5- carboxamide. (14)

N-(3-nitrophenyl)-6-methyl-4-phenyl-2-thioxo-l ,2,3,4-tetrahydropyrimidine-5- carboxamide. (15)

N-(4-nitrophenyl)-4-(3-chlorophenyl)-6-methyl-2-oxo-l ,2,3,4-tetrahydropyrimidine-5- carboxamide. ( 16)

N-(4-mtro-phenyl)-6-methyl-4-phenyl-2-thioxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide. (17)

N-(3-chloro-phenyl)-4-(2,4-dichloro-phenyl)-6-methyl-2-thioxo-l , 2,3,4- tetrahydropyrirnidine-5-carboxamide. (18)

N-cyclohexyl-6-methyl-4-phenyl-2-tmoxo-l ,2,3,4-tetrahydropyrimidine-5- carboxamide. (19)

N-(4-nitro-phenyl)-4-(2,4-dichloro-phenyl)-6-methyl-2-thioxo-l , 2,3,4- tetrahydropyrimidine-5-carboxamide. (20) N-(2,3-dichloro-phenyl)-6-methyl-2-oxo-4-phenyl- 1 ,2,3 ,4-tetrahydropyrimidine-5- carboxamide. (21)

N-(3-nitTO-phenyl)-4-(3-chloro-phenyl)-6-methyl-2-oxo-l ,2,3,4-tetrahydropyrimidine- 5-carboxamide. (22) N-cyclohexyl-4-(2,4-dichloro-phenyl)-6-methyl-2-thioxo-l ,2,3,4-tetrahydropyrimidine- 5-carboxamide. (23)

N-cyclohexyl-4-(2,4-dicUoro-phenyl)-6-methyl-2-oxo-l ,2,3,4-tetrahydropyrimidine-5- carboxamide. (24)

19 20 21

22 23 24

In another embodiment of the present invention compounds of general formula 1 exhibiting anti tubercular activity are disclosed. In another embodiment of the present invention the said compound is used against Mycobacterium in the dormant phase.

In another embodiment of the present invention a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula las claimed in claim 1.

In another embodiment of the present invention a process for the preparation of compounds of formula 1 as claimed in claim 1 , wherein the said process comprising of: In another embodiment of the present invention a pharmaceutical composition comprising a pharmaceutically acceptable excipients and an effective amount of a compound of formula las claimed in claim 1.

In another embodiment of the present invention a process for the preparation of compounds of formula 1 as claimed in claim 1 , wherein the said process comprising of:

(a) mixing a reactant selected from substituted acetoacetanilide or benzylacetoacetate, a substituted aldehyde and urea in a solvent , preferably absolute ethanol;

(b) heating the reaction mixture as obtained in step (a) at temperature ranging between 60-100°C for a period ranging between 4-8 hours;

(c) adding p-TSA( p- toluene sulphonic acid) or cone. HC1 into reaction mixture as obtained in step (b) followed by refluxing at temperature ranging between 60-100 ° C for a period ranging between4-8 hours; (d) cooling the reaction mixture as obtained in step ( c) followed by separating the solid by filteration, washing with alcohol to obtain compounds no. 1-3, 5-18 and 20-22 or benzylester of tetrahydropyrimidone;

(e) synthesizing tetrahydropyrimidone- 5- carboxylic acid from benzylester of tetrahydropyrimidone as obtained in step (d) either by stirring benzylester of tetrahydropyrimidone as obtained in step (d), 5%Pd C and ammonium formate into methanol under nitrogen atmosphere for a period ranging between 8-10 hrs at temperature ranging between 55-65 °C followed by adjusting pH 9 by basic solution preferably aq OH, filtering the reaction to obtain filterate, followed by adjusting pH 4 using acidic solution preferably aq HC1 to obtain tetrahydropyrimidone- 5- carboxylic acid or by hydrolysis of the benzylester of tetrahydropyrimidone as obtained in step (d) by NaOH or KOH;

(f) stirring tetrahydropyrimidone- 5- carboxylic acid as obtained in step (f) and NN'-Dicyclohexylcarbodiimide (DCC) for a period ranging between 6- 12 hours at temperature ranging between 50-65° C and subsequently adding DMF solution of corresponding amine preferably cyclohexylamine in the it and continuing stirring at temperature ranging between 55-65°C followed by adding methanol into the reaction mixture;

(g) filtering the reaction mix as obtained in step (g) to remove dicyclohexyl urea followed by removal of methanol to obtain compounds no.4, 19, 23 and 24.

In another embodiment of the present invention substituted acetoacetanilide used in step ( a) is selected from the group consisting of 3-chloroacetoacetanilide, 4- nitroacetoacetanilide, 2,3-dichloroacetoacetanilide and 3-nitroacetoacetanilide

In another embodiment of the present invention substituted aldehyde used in step (a) is selected from the group consisting of 2,4-dichlorobenzaldehyde, benzaldehyde, 3- chlorobenzaldehyde and 3,4-dimethoxybenzaldehyde

In another embodiment of the present invention mole ratio of substituted acetoacetanilide, substituted aldehyde and urea is 1 : 1 : 1.5.

In another embodiment of the present invention yield of compound of general formula 1 is in the range of 42-60%. Brief description of drawings

Scheme 1 : Process for the preparation of respective tetrahydropyrimidones/tetrahydrothiopyrimidone Detailed description of the invention

The invention will now be described in detail so that various aspects thereof may be more fully understood and appreciated.

The present invention provides novel antitubercular compounds of Formula 1 effective against Mycobacterium bacilli in their dormant stage.

Formula 1

In a preferred aspect, the present invention provides 5-(substituted) phenylcarbamoyl-4- (substituted)phenyl-6-methyl- l ,2,3,4-tetrahydropyrimid-2-one and 2-thione as antitubercular molecules of Formula 1 as given below in Table 1.

In yet another preferred aspect, the present invention provides 5 -(substituted) cycloalkyl-4-(substituted) phenyl-6-methyl-l ,2,3,4-tetrahydroprimidine-2-one and 2- thione compounds of Formula 1.

The compounds of Formula 1 are prepared by a process using modified Biginelli reaction. The process includes reacting substituted acetoacetanilides (lmole eq) with urea/thiourea ( 1.5 mole eq) and substituted benzaldehydes (1 mole eq) in presence of catalytic amount of p-toluene sulphonic acid(p-TSA) using absolute ethanol as a solvent to give the respective tetrahydropyrimidones/tetrahydrothiopyrimidone.

Thus, a mixture of substituted acetoacetanilides, urea/thiourea and substituted benzaldehydes in a molar ratio 1 : 1.5: 1 are dissolved in absolute ethanol and heated until a clear solution followed by addition of catalytic amount of p-TSA and further refluxed for about 3-5 hrs. The solid separated is washed with alcohol and dried to obtain respective tetrahydropyrirnidones/tetrahydrothiopyrimidone.

The substituted acetoacetanilides are obtained by conventional process involving reacting substituted aromatic amine with ethyl / /-butyl acetoacetate in a solvent.

The synthesized compounds of the current invention given above are further characterized by their spectral data (IR/NMR).

The tetrahydropyrimidones/tetrahydrothiopyrimidone derivatives of the present invention can advantageously be used to treat the pathological conditions or the diseases caused by Mycobacterium.

In an aspect, the anti tubercular potential of the novel compounds of the current invention is tested on a whole cell based assay carried out in microplate format. Nitrate reductase activity is used to represent the dormant stage whereas absorbance of the culture at 620nm is used to represent the actively growing stage of the bacilli during the screening protocol.

The antimycobacterial activity against dormant stage of the compounds of the present invention were tested for their activity in the growth phase as well as in the dormant phase and the inhibitory activity is given below in Table 1 and Table 2.

According to Filippini et al. in "ANTIMICROBIAL AGENTS AND

CHEMOTHERAPY, June 2010, p. 2712-2715, Mycobacterium bacilli can actively grow in presence of oxygen in medium. In people with latent tuberculosis (TB), a group estimated to be one-third of the world's population, Mycobacterium tuberculosis is presumed to lie in a nonreplicating (dormant) state in caseous lesions of the lungs, with little access to oxygen, or in extrapulmonary sites containing adipose

tissue. Nonreplicating M. tuberculosis may be obtained by adaptation of replicating cultures to hypoxia through the self-generated formation of an oxygen gradient (Wayne model) or inside adipocytes .

V. Virsodia et al reported the synthesis and evaluation of substituted N-phenyl-6- methyl-2-oxo-4-phenyl-l ,2,3,4-tetrahydropyrimidine-5-carboxamides as anti tubercular agents. But these agents have been found to be active against the tested Mycobacterium strain in its active or growing phase (EJMC compounds (01-05), Table 3.

The antimycobacterial activity of compound 8 at dormant stage is observed at concentration of less than 4.5 ug/ml. In a preferred aspect, the present invention provides N,4 bis(3-chlorophenyl)-6methyl- 2-oxo-l ,2,3,4, tetrahydropyrimidine5-carboxamide which is effective against dormant stage of the Mycobacterium .

In an aspect, the invention relates to a pharmaceutical composition comprising of the active ingredient of Formula 1 , as defined above either alone or as its salts along with pharmaceutically acceptable excipients.

The pharmaceutical composition according to the invention can be in the form of a solid, for example, powders, granules, tablets, capsules or can be present in the liquid form such as solutions, emulsions, suspensions etc or as an injectable composition. The invention provides the use of the compounds of formula 1 and/or derivative thereof against potent mycobacterium in their dormant stage.

In an aspect the invention provides use of the compound of formula 1 and/or derivative thereof in preparing medicament or pharmaceutical composition against mycobacterium in dormant stage.

The tetrahydropyrimidones/tetrahydrothiopyrimidone derivatives of formula 1 and pharmaceutical compositions containing them may, according to the invention, be administered using any amount, any form of pharmaceutical composition and any route of administration effective for the treatment. After formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, as known by those of skill in the art, the pharmaceutical compositions of this invention can be administered by any means that delivers the active pharmaceutical ingredient (s) to the site of the body whereby it can exert a therapeutic effect on the patient.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of examples and for purpose of illustrative discussion of preferred embodiments of the invention only and are not limiting the scope of the invention.

Examples:

Experimental:

Biginelli reaction: General procedure

METHOD A

A mixture of ( 1 mEq) substituted acetoacetanilide, (1 mEq) of substituted benzaldehyde and (1.5 mEq) of urea in 2 ml of absolute alcohol was heated until a clear solution was obtained in one hour and then catalytic amount of pTSA (p-toluene sulphonic acid) (15 mgs) at 78 ⁰ C was added to it. The mixture was refluxed for 4.5 hours (or until no starting material was absent on TLC). The product precipitated out after some time. The product was separated by filtration and washed with alcohol (3x5ml). The product was dried in an oven at 60°C. The same procedure can be used to synthesize all the derivatives. Some derivatives require more than a catalytic amount of p-toluene sulphonic acid (pTSA).

METHOD B - Tetrqhydropyrimidone synthesis via carboxylic acid intermediate

(Compound 4, 19, 23, 24)

Step 1 : - Synthesis of Benzyl acetoacetate.

Benzyl acetoacetate was synthesized by refluxing /-butyl acetoacetate and benzyl alcohol in toluene for 9 hrs.

Step 2: - Synthesis of Benzyl ester of tetrahydropyrimidone.

A mixture of 1 equivalent each of benzyl acetoacetate, benzaldehyde , 1.5 equivalents of urea , 10ml of absolute alcohol and 5 drops of cone. HCl was refluxed for a period of 4 hours. After completion of reaction (monitored by TLC). The mixture was cooled a bit and then dumped in mixture of ice water. The resulting precipitate was filtered and recrystallised from boiling alcohol.

Step 3: - Synthesis of tetrahydropyrimidone-5-carboxyllic acid.

Under nitrogen atmosphere 1 equivalent of benzyl ester of tetrahydropyrimidone, 5% Pd/C (10 % w/w) and ammonium formate (10 equivalents) and 5ml dry methanol were stirred for 8 hours at 60°C (or till no ester was seen in TLC). 0.5M OH solution was added till pH 9. The reaction mixture was filtered through celite. The residue was washed with methanol and the pH of the filtrate was adjusted to 4 using 2M HCl. The residue was filtered and washed with water to obtain tetrahydropyrimidone-5- carboxyllic acid. This reaction was not used for the thiourea condensation products as sulphur causes deactivation of Pd/C. The acid of thiooxo pyrimidones has to be synthesized by hydrolysis of the ethyl ester of the corresponding ester derivatives by NaOH or KOH. Step 4: - Synthesis of tetrahydropyrimidone-5-carboxamide.

Under nitrogen atmosphere 1 equivalent of tetrahydropyrimidone-5-carboxyllic acid and 1.2 Equivalents of dicylohexyl carboimide (DCC) in 5 ml dry DMF was stirred for 0.5 hours at 45°C and to it previously weighed solution of amine in dry DMF (1 equivalent) was added. The stirring was continued for 24 hours or until all acid is consumed. After 24 hours methanol was added to the reaction mixture and filtered to remove the dicyclohexyl urea. The methanol was removed to obtain tetrahydropyrimidone-5-carboxamide.

Examples of compounds synthesized by above two methods are as follows:

Examplel : N-(3-chlorophenyl)-4-(2, 4-dichlorophenyl)-6-methyl-2-oxo-l, 2,3,4- tetrahydropyrimidine-5-carboxamide. (1)

Synthesized using experimental procedure method "A". (3-chloroacetoacetanilide, 2,4- dichlorobenzaldehyde)

Yield: 46%; m.p. 201 -202 °C; IR (KBr, cm^-1): 3227, 2953, 1703, 1680, 1472, 1236, 772; Ή NMR (400 MHz, DMSO-<¾ δ ppm 1.71 (s, 3H, CH₃), 5.49 (s, 1 H, CH)7.02- 7.53 (m, 7H, Ar-H), 7.6(s, lH, NH), 8.95(s,lH, NH) 9.45 (s, 1 H, NH). Example 2: N-(4-nitro-phenyl)4-(2,4-Dichloro-phenyl)-6-methyl-2-oxo-l ,2,3,4- tetrahydropyrimidine-5-Carboxamide. (2)

Synthesized using experimental procedure method "A". (4-nitroacetoacetanilide, 2,4- dichlorobenzaldehyde) Yield: 55%; m.p. 225-227 °C; IR (KBr, era^"1): 3375, 2924, 1693, 1545, 1237, 756; Ή NMR (400 MHz, DMSO-<¾ δ ppm2.05 (s, 3H, CH₃), 5.78 (s, I H, CH), 7.42-8.17 (m, 7H, Ar-H), 7.69 (s, I H, NH), 9.03 (s, IH, NH), 10.32 (s, I H, NH ).

Example 3: N-(2,3-dichloro-phenyI)4-(2,4-DichIoro-phenyl)-6-methyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxamide. (3)

Synthesized using experimental procedure method "A".(2,3-dichloroacetoacetanilide, 2,4-dichlorobenzaldehyde)Yield: 60%; m.p. 264-266 °C; IR (KBr, cm^-1): 3286, 2928, 1707, 1458, 1214, 765; Ή NMR (400 MHz, DMSO-<¾ δ ppm 2.14 (s, 3H, CH₃), 5.74 (s, I H, CH), 7.36-7.70 (m,6 H, Ar-H), 7.46 (s, I H, NH), 8.95 (s, I H, NH), 9.45 (s, I H, NH).

Example 4: N-cyclohexyl -4-pheoyl -6-Methyl- 2-oxo -1,2,3,4- tetrahydropyrimidine-5-carboxamide (4)

Synthesized using experimental procedure method "B".(Cyclohexylamine, Benzaldehyde)Yield: 54%; m.p. 192-194 °C; IR (KBr, cm^-1): 3281 , 2924, 1710, 1568, 1254, 756; Ή NMR (400 MHz, DMSO-<¾ S ppm 1.1 (m, 6H, cyclohexyl), 1.61 (m, 5H, cyclohexyl), 1.94 (s, 3H, CH₃), 5.28 (s, I H, CH), 7.22-7.3 (m, 5H, Ar-H), 7.45 (m, 2H, NH), 8.5 (s, IH, NH).

Example 5: N-(3-chloro-phenyl) -4-phenyl -6-Methyl- 2-oxo -1,2,3,4- tetrahydropyrimidine-5-carboxamide. (5)

Synthesized using experimental procedure method "A". (3-chloroacetoacetanilide, Benzaldehyde)Yield: 51%; m.p. 236-237 °C; IR (KBr, cm^"1): 3281 , 2924, 1710, 1566, 1248, 775; Ή NMR (400 MHz, DMSC ¾ δ ppm 1.7 (s, 3H, CH₃), 5.06 (s, I H, CH), 6.69-6.73 (d, IH, Ar-H), 6.88-6. 95 (m, 6H, Ar-H), 7.3 (s, I H, Ar-H), 7.58 (d, IH, Ar, 7.1 (s, I H, NH), 8.47 (s, IH, NH), 9.41 (s, I H, NH) . Example 6: N-(3-chloro-phenyl)-4-phenyl 6-Methyl-2-thioxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxamide (6)

Synthesized using experimental procedure method "A". (3-chloroacetoacetanilide, Benzaldehyde)Yield: 42%; m.p. 140-142 °C; IR (KBr, cm^-1): 3176, 2923, 1670, 1570, 1502, 1 121 ; Ή NMR (400 MHz, OMSO-d₆) δ ppm 2.07 (s, 3H, CH₃), 5.4 (s, I H, CH), 7.09(d, I H, Ar-H), 7.24-7.36(m, 6H, Ar-H), 7.46(d, I H, Ar-H), 7.74(s, I H, Ar-H), 9.49(s, IH, NH), 9.93 (s, IH, NH), 10.08 (s, IH, NH).

Example 7: N-(4-nitro-phenyI)-4-phenyI -6-Methyl-2-oxo- 1,2,3,4-tetrahydro- pyrimidine-5-carboxamide (7) Synthesized using experimental procedure method "A". (4-nitroacetoacetanilide, Benzaldehyde) Yield: 42%; m.p. 217-219 °C; IR (KBr, cm^{" 1}): 3520, 3361 , 1605, 1570, 1502, 1 121 ; Ή NMR (400 MHz, DMSO-</₆) δ ppm 2.04 (s, 3H, CH₃), 5.41 (s, I H, CH), 7.2-7.33(m, 5H, Ar-H), 7.75-7.8(d, 2H, Ar-H), 8.1 1-8.16 (d, 2H, Ar-H), 8.89 (s, IH, NH), 8.90 (s, I H, NH), 10.12 (s, I H, NH). Example 8: N-(3-chlorophenyl)-4-(3-chlorophenyl)-6-methyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide. (8)

Synthesized using experimental procedure method "A". (3-chloroacetoacetanilide, 3- chlorobenzaldehyde) Yield: 45%; m.p. 180-182 °C; IR (KBr, cm^"1): 3240, 1633, 1597, 1502, 1 1 1 1 ; Ή NMR (400 MHz, DMSO-^) δ ppm 2.05 (s, 3H, CH₃), 5.39 (s, IH, CH), 7.08 (m, I H, Ar-H), 7.29-7.38(m, 6H, Ar-H), 7.72(s, IH, NH), 7.73(s, I H, Ar-H), 8.89(s, IH, NH), 9.49(s, I H, NH).

Example 9: N-(2,3-dichloro-phenyl)-4-(3-chloro-phenyl)-6-methyI-2-thioxo-l,2,3,4- tetrahydro-pyrimidine-5-carboxamide.( 9)

Synthesized using experimental procedure method "A". (2,3-dichloroacetoacetanilide, 3 -chlorobenzaldehyde) Yield: 52%; m.p. 182-183 °C; IR (KBr, cm^-1): 3232, 2953, 1685, 1580, 1502, 1 121 , 771 ; Ή NMR (400 MHz, DMSO-<¾ δ ppm 2.13 (s, 3H, CH₃), 5.34 (s, IH, CH), 7.31 (m, 8H, Ar-H), 7.69 (s, I H, NH), 8.89 (s, I H, NH), 9.3 (s, IH, NH). Example 10: N-(3-chloro-phenyl)-4-(3,4-dimethoxyphenyl)-6-raethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide.( 10)

Synthesized using experimental procedure method "A".(3-chloroacetoacetanilide, 3,4- dimethoxybenzaldehyde) Yield: 58%; m.p.259-262 °C; IR ( Br, cm^"1): 3247, 2953, 1630, 1580, 1502, 721 ; Ή NMR (400 MHz, OMSO-d₆) δ ppm 2.04 (s, 3H, CH₃), 3.66(s, 3H OCH₃),3.71(s, 3H OCH₃) 5.36 (s, IH, CH), 6.8 (dd, I H, CH 2, 8Hz ), 6.8(d, I H, Ar-H, 8Hz ) 6.9(d, I H, Ar-H, 8Hz) 7.07(dd, IH, Ar-H 2, 8Hz ) 7.28 (t, IH, Ar-H), 7.44 (dd, I H, Ar-H, 2, 8Hz ) 7.75 (s, I H, Ar-H), 7.57 (s, IH, NH), 8.75 (s, IH, NH), 9.75 (s, IH, NH). Example 11: N,4-bis(3-chlorophenyl)-6-methyl-2-thioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide. (11)

Synthesized using experimental procedure method "A". (3-chloroacetoacetanilide, 3- chlorobenzaldehyde)Yield: 55%; m.p. 157-159 °C; IR (KBr, cm^"1): 3232, 2953, 1685, 1580, 1502, 1 121 , 771 ; Ή NMR (400 MHz, DMSO-<¾ δ ppm 2.08 (s, 3H, CH₃), 5.39 (s, I H, CH), 7.08(s, I H, Ar-H), 7.2-7.4 (m, 6H, Ar-H), 7.73 (s, I H, Ar-H), 9.52 (s, I H, NH), 9.58 (s, I H, NH), 10.14 (s, I H, NH).

Example 12; N-(2,3-dichlorophenyl)-4-(3-chlorophenyl)-6-methyl-2-thioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide. (12)

Synthesized using experimental procedure method "A". (2,3-dichloroacetoacetanilide, 3-chlorobenzaldehyde)Yield: 51%; m.p. 194-196 °C; IR (KBr, cm^-1): 3232, 2953, 1685, 1565, 1517, 1 182, 774; Ή NMR (400 MHz, DMSO-e^) δ ppm 2.21 (s, 3H, CH₃), 5.42 (s, IH, CH), 7.3-7.49 (m, 7H, Ar-H)„ 9.62 (s, IH, NH), 9.64 (s, I H, NH), 10.21 (s, IH, NH).

Example 13: N-(2,3-dichloro-phenyl)-4-(2,4-dichloro-phenyl)-6-methyl-2-thioxo- l,2,3,4-tetrahydropyrimidine-5-carboxamide. (13)

Synthesized using experimental procedure method "A". (2,3- dichloroacetoacetanilide,2,4-dichlorobenzaldehyde)Yield: 51%; m.p. 236-237 °C; IR (KBr, cm^"1): 3400, 3238, 2953, 1685, 1567, 1516, 1 181 , 773; Ή NMR (400 MHz, DMSO-i _tf) δ ppm 2.14 (s, 3H, CH₃), 5.74 (s, I H, CH), 7.31(t, IH, Ar-H), 7.36 (dd, 1 H, Ar-H, 8Hz ), 7.4 (s, IH, Ar-H), 7.46 (dd, I H, Ar-H, 2 Hz,8Hz ), 7.51 (dd, IH, Ar-H, 2Hz, 8Hz ), 9.41 (s, IH, NH), 9.71 (s, IH, NH), 10.16 (s, IH, NH).

Example 14: N-(2,3-dichlorophenyl)-6-methyl-4-phenyl-2-thioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamlde. (14)

Synthesized using experimental procedure method "A". (2,3-dichloroacetoacetanilide, Benzaldehyde)Yield: 52%; m.p. 208-209 °C; IR ( Br, cm^"1): 3387, 3251 , 2953, 1633, 1567, 1516, 1271 , 773; Ή NMR (400 MHz, DMSO-<¾ δ ppm 2.18 (s, 3H, CH₃), 5.4 (s, I H, CH), 7.31 -7.4(m, 7H, Ar-H), 9.49 (s, IH, NH), 9.5 (s, I H, NH), 10.08 (s, I H, NH).

Example 15 : N-(3-nitwphenyl)-6-methyl-4-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine-5-carboxamide. (15)

Synthesized using experimental procedure method "A".(3-nitroacetoacetanilide, Benzaldehyde)Yield: 40%; m.p.154-156 °C; IR (KBr, cm^" '):3362, 3251 , 2953, 1531 , 1633, 1567, 1245, 1205,752 Ή NMR (400 MHz, DMSO-i¾ δ ppm 2.1 1 (s, 3H, CH₃), 5.4 (s, I H, CH), 7.25-7.38(m, 5H, Ar-H), 7.56(t, I H, Ar-H, 8Hz), 7.86(dd, IH, Ar-H, 2,8 Hz), 7.92(dd, IH, Ar-H, 2,8 Hz), 8.58(s, IH, Ar-H), 9.5 (s, IH, NH), 10.1(s, I H, NH), 10.18 (s, ΙΗ, ΝΗ).

Example 16: N-(4-nitrophenyl)-4-(3-chlorophenyl)-6-methyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide. (16)

Synthesized using experimental procedure method "A". (4-nitroactoacetanilide,3- chlorobenzaldehyde) Yield: 48%; m.p.275-276 °C; IR (KBr, cm^"'):3362, 3251 , 2953, 1531 , 1633, 1559, 1245, 1205, 752; "H NMR (400 MHz, DMSO-c¾ δ ppm 2.1 1 (s, 3H, CH₃), 5.4 (s, IH, CH), 7.31-7.36(m, 4H, Ar-H),7.80(s, IH, NH), 7,82(d, 2H, Ar-H, 8Hz), 8.22(d, 2H, Ar-H, 8Hz) 9.03 (s, IH, NH), 10.02 (s, IH, NH). Example 17: N-(4-nitro-phenyl)-6-methyl-4-phenyl-2-thwxo-l, 2,3,4- tetrahydropyrimidine-5-carboxamide. (17)

Synthesized using experimental procedure method "A". (4- nitroactoacetanilide,Benzaldehyde) Yield: 48%; m.p.231-233 °C; IR ( Br, cm^"'):3468,3369, 3238, 2953, 1685, 1540, 1516, 1203, 1 181 , 746; Ή NMR (400 MHz, DMSO-<¾ δ ppm 2.08 (s, 3H, CH₃), 5.39 (s, I H, CH), 7.08-7.43(m, 7H, Ar-H), 9.52 (s, IH, NH), 9.96 (s, I H, NH), 10.14 (s, IH, NH).

Example 18: N-(3-chloro-phenyl)-4-(2,4-dichloro-phenyl)-6-methyl-2-thioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide. (18)

Synthesized using experimental procedure method "A".(3-chloroactoacetanilide, 2,4- dichlorobenzaldehyde) Yield: 58%; m.p. 215-217 °C; IR (KBr, cm^""1): 3403, 3232, 2953, 1685, 1581 , 1 181 , 773;Ή NMR (400 MHz, DMSO-<¾ δ ppm 2.03 (s, 3H, CH₃), 5.74 (s, IH, CH), 7.07 (d, IH, Ar-H, 8Hz) 7.28(d, I H, Ar-H, 8Hz), 7.39-7.46(m,2H, Ar-H and s, I H, NH), 7.54 (s, I H, Ar-H),7.61 (s, I H, Ar-H),7.71 (s, I H, Ar-H), 8.92 (s, IH, NH), 9.89 (s, I H, NH).

Example 19: N-cyclohexyl-6-methyl-4-phenyl-2-thioxo-l,2,3,4-tetrahydropyrimidine- 5-carboxamide. (19)

Synthesized using experimental procedure method "A". (Cyclohexylamine,Benzaldehyde) Yield: 48%; m.p.261-262 °C; IR (KBr, cm^-1): 3381 , 3285, 2924, 1710, 1568, 1254, 756; Ή NMR (400 MHz, DMSO-i ₆) δ ppm 1.1 (m, 6H, cyclohexyl), 1.61 (m, 5H, cyclohexyl), 1.97 (s, 3H, CH₃), 5.28 (s, I H, CH), 7.19-7.23 (m, 5H, Ar-H), 7.55 (s, IH, NH), 9.28(s, IH, NH), 9.8 (s, IH, NH).

Example 20: N-(4-nitro-phenyl)-4-(2,4-dichlow-phenyl)-6-methyl-2-thioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide. (20)

Synthesized using experimental procedure method "A".(4-nitroacetoacetanilide, 2,4- dichlorobenzaldehyde) Yield: 54%; m.p. 183-185 °C; IR (KBr, cm^-1): 3395, 3238, 2953, 1685, 1567, 1516, 1 161 , 773; Ή NMR (400 MHz, DMSO-c/g) δ ppm 2.05 (s, 3H, CH₃), 5.79 (s, IH, CH), 7.3 l(t, I H, Ax-H), 7.42-7.44 (dd, IH, Ar-H, 8Hz ),7 .46-7.48 (dd, I H, Ar-H, 8Hz ), 7.54 (s, I H, Ar-H), 7.61 (s, IH, Ar-H), 7.7 (s, IH, NH), 7.74- 7.76 (d, IH, Ar-H, 8Hz ), 8.15-8.17 (d, IH, Ar-H, 8Hz ), 9.04 (s, IH, NH), 10.32 (s, IH, NH).

Example 21 : N-(2,3-dichloro-phenyl)-6-methyl-2-oxo-4-phenyl-l, 2,3,4- tetrahydropyrimidine-5-carboxamide. (21)

Synthesized using experimental procedure method "A". (2,3- dichloroacetoacetanilide,Benzaldehyde) Yield: 52%; m.p. 261 -263 °C; IR (KBr, cm^-1): 3402, 3228, 2953, 1633, 1271 , 773; Ή NMR (400 MHz, DMSO-</₆) δ ppm 2.16 (s, 3H, CH₃), 5.38 (s, I H, CH), 7.28-7.45 (m, 7H, Ar-H), 7.67 (s, IH, NH), 8.86 (s, I H, NH), 9.21 (s, Ι Η, ΝΗ).

Example 22: N-(3-nitro-phenyl)-4-(3-chloro-phenyl)-6-methyl-2-oxo-l, 2,3,4- tetrahydropyrimidine-5-carboxamide. (22)

Synthesized using experimental procedure method "A". (3-nitroacetoacetanilide,3- chlorobenzaldehyde)Yield:52%; m.p. 221-223 °C; IR (KBr, cm^-1): 3402, 3228, 2953, 1633, 1567, 1516, 1271 , 773; Ή NMR (400 MHz, DMSO-</₆) δ ppm 2.07 (s, 3H, CH₃), 5.47 (s, IH, CH), 7.20-7.9 (m, 8H, Ar-H), 8.57 (s, I H, NH), 8.95 (s, IH, NH), 10.41 (s, IH, NH). Example 23: N-cyclohexyl-4-(2,4-dichloro-phenyl)-6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine-5-carboxamide. (23)

Synthesized using experimental procedure method "A". (Cyclohexylamine, 2,4- dichlorobenzaldehyde)Yield: 58%; m.p 255-257 °C; IR (KBr, cm^"1): 3281 , 2924, 1710, 1568, 1254, 756; Ή NMR (400 MHz, DMSO-i¾ δ ppm 1.1 (m, 6H, cyclohexyl), 1.61 (m, 5H, cyclohexyl), 2.16 (s, 3H, CH₃), 5.38 (s, IH, CH), 7.31(d, I H, Ar-H, 8Hz), 7.47(dd, IH, Ar-H, 2Hz, 8Hz), 7.56(d, I H, Ar-H, 8Hz), 7.68 (s, IH, NH), 9, 18 (s, IH, NH), 9.9 (s, IH, NH).

Example 24: N-cyclohexyl-4-(2,4-dichloro-phenyl)-6-methyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide. (24)

Synthesized using experimental procedure method "B". (Cyclohexylamine, 2,4- dichlorobenzaldehyde)Yield: 58%; m.p 235-237 °C; IR (KBr, cm^-1): 3281 , 2924, 1710, 1568, 1254, 756; Ή NMR (400 MHz, DMSO-i¾ δ ppm 1.1 (m, 6H, cyclohexyl), 1.61 (m, 5H, cyclohexyl), 1.93 (s, 3H, CH₃), 5.6 (s, 1H, CH), 7.39(d, 2H, Ar-H, 8Hz), 7.43(dd, 1H, Ar-H, 2Hz, 8Hz), 7.53(d, 1H, Ar-H, 8Hz), 7.37 (s, l H, NH), 7.47 (s, 1H, NH), 8.93 (s, 1H, NH).

Example 25:

A protocol, which can identify inhibitors of active as well as dormant tubercle bacilli was used to screen the compounds. Nitrate reductase activity was used to represent the dormant stage whereas absorbance of the culture at 620nm was used to represent the actively growing stage of the bacilli in this screening protocol. 2.5□ 1 of lOmg/ml of compound solution in DMSO was aseptically transferred to individual wells of sterile 96-well plates. 247.5 D l of M. bovis BCG

(ATCC 35745was acquired from R& D Dision of M/S Astrazeneca of Bangalore) culture containing ~10⁵cells/ml, supplemented with 40mM NaN0₃ was aseptically transferred to each well to make up the total volume to 250□ I and the plate was covered with a sealer. 125 D 1 space was left in each well to make the headspace to culture volume ratio exactly 0.5. After sealing, these culture plates were incubated at 37°C in an incubator. After 8 days of incubation, culture OD was read at 620nm. Then, 80D 1 of culture was taken out from each well and transferred to a separate 96 well plate. Then, 80□ I of 1 % sulphanilic acid and 80 Dl of 0.1% N-(l -napthyl) Ethylenediamine Dihydrochloride solution were added in each well and the plate was incubated for 15 minutes at room temperature to develop pink color. The color was read in Spectramaxplus 384,Molecular Devices, USA at 540nm to measure Nitrate Reductase activity.

Example 26:

The compounds of the invention were tested for their activity in the growth phase of the bacilli and the results are tabulated herein. The table includes the IC50 values and the dose response curve for the compounds. Table 1. Table 1

Example 27:

The compounds of the invention were tested for their activity in the dormant phase of the bacilli and the results are tabulated herein. The table 2 includes the IC50 values and the dose response curve for the compounds.

Table 2

Example 28: Example 28: Inhibition data for European Journal of Medicinal Chemistry (EJMC) compounds (01 -05) (V. Virsodia et al)

Table 3

Agents known in prior art have been found to be active against the tested Mycobacterium strain only in its active or growing phase.

To address the issue relating to tuberculosis, the present invention has now overcome the problem with novel tetrahydropyrimidones/ tetrahydrothiopyrimidone derivatives of Formula I, effective against the Mycobacterium in their dormant stage.

Claims

We claim,

1. Compounds of general formula 1

Formula 1

wherein, R is H, halogen, dihalogen, O-alkyl, di- O-alkyl , R| is phenyl, chlorophenyl, nitrophenyl, diclorophenyl, cycloalkyl preferably cyclohexyl , X is O or S.

2. Compounds as claimed in claim 1 , wherein the general formula 1 is represented by

the following compounds:

N-(3-chlorophenyl)-4-(2,4-dichlorophenyl)-6-methyl-2-oxo-l , 2,3,4- tetrahydropyrimidine-5-carboxamide( 1 )

N-(4-nitro-phenyl)4-(2,4-dichloro-phenyl)-6-methyl-2-oxo- 1 ,2,3 ,4-tetrahydropyrimidine-5- Carboxamide. (2)

N-(2,3-dicUoro-phenyl)4-(2,4-dichJoro-phenyl)-6-methyl-2-oxo- l ,2,3,4-tetrahydropyrimidine- 5-carboxamide. (3)

N-cyclohexyl -4-phenyl -6-Methyl- 2-oxo -l ,2,3,4-tetrahydropyrimidine-5- carboxamide (4)

N-(3-chloro-phenyl)-4-phenyl 6-Methyl-2-thioxo- 1 ,2,3, 4-tetrahydro-pyrimidine-5- carboxamide (6)

N-(4-nitro-phenyl)-4-phenyl -6-Methyl-2-oxo- 1 ,2,3,4-tetrahydro-pyrimidine-5- carboxamide (7). N-(3-chlorophenyl)-4-(3-cUorophenyl)-6-methyl-2-oxo-l ,2,3,4-tetrahydropyrimidine- 5-carboxamide. (8)

N-(2,3-dichloro-phenyl)-4-(3-chloro-phenyl)-6-methyl-2-oxo-l ,2,3,4-tetrahydro- pyrimidine-5-carboxamide.( 9)

N-(3-chloro-phenyl)-4-(3 ,4-dimethoxyphenyl)-6-methyl-2-oxo- 1 ,2,3 ,4- tetrahydropyrimidine-5-carboxamide.( 10)

N,4-bis(3-chlorophenyl)-6-methyl-2-thio xo- 1 ,2,3, 4-tetrahydropyrimidine-5- carboxamide. (1 1)

N-(2,3-dichlorophenyl)-4-(3-chlorophenyl)-6-methyl-2-thioxo-l , 2,3,4- tetrahydropyrimidine-5-carboxamide. (12)

N-(2,3-dichloro-phenyl)-4-(2,4-dichloro-phenyl)-6-methyl-2-thioxo-l , 2,3,4- tetrahydropyrimidine-5-carboxamide. (13)

N-(2,3-dichlorophenyl)-6-methyl-4-phenyl-2-thioxo-l ,2,3,4-tetrahydropyrimidine-5- carboxamide. (14)

N-(3 -nitrophenyl)-6-methyl-4-phenyl-2-thioxo- 1 ,2 ,3 ,4-tetrahydropyrimidine-5 - carboxamide. ( 15)

N-(4-nitro-phenyl)-6-methyl-4-phenyl-2-thioxo-l ,2,3,4-tetrahydropyrimidine-5- carboxamide. (17)

N-(3-chloro-phenyl)-4-(2,4-dichloro-phenyl)-6-methyl-2-thioxo-l ,2,3,4- tetrahydropyrimidine-5-carboxamide. (18)

N-cyclohexyl-6-methyl-4-phenyl-2-thioxo-l ,2,3,4-tetrahydropyrimidine-5- carboxamide. ( 19) N-(4-nitro-phenyl)-4-(2,4-dichloro-phenyl)-6-methyl-2-thioxo-l , 2,3,4- tetrahydropyrimidine-5-carboxamide. (20)

N-(2,3-dichloro-phenyl)-6-methyl-2-oxo-4-phenyl- 1 ,2,3, 4-tetrahydropyrimidine-5- carboxamide. (21) N-(3-nitro-phenyl)-4-(3-cUoro-phenyl)-6-methyl-2-oxo-l ,2,3,4-tetrahydropyrimidine- 5-carboxamide. (22)

N-cyclohexyl-4-(2,4-dichloro-phenyl)-6-methyl-2-thioxo- 1 ,2,3 ,4-tetrahydropyrimidine- 5-carboxamide. (23)

N-cyclohexyl-4-(2,4-dichloro-phenyl)-6-methyl-2-oxo-l ,2,3,4-tetrahydropyrimidine-5- carboxamide. (24)

4 5 6

16 17 18

19 20 21

22 23 24 3. Compounds of general formula 1 as claimed in claim 2 exhibiting and tubercular activity.

4. Compound of Formula 1 , as claimed in claim 2, wherein the said compound is used against Mycobacterium in the dormant phase.

5. A pharmaceutical composition comprising an effective amount of a compound of formula las claimed in claim land a pharmaceutically acceptable excipient.

A process for the preparation of compounds of formula 1 as claimed in claim 1 , wherein the said process comprising of:

a) mixing a reactant selected from substituted acetoacetanilide or benzylacetoacetate, a substituted aldehyde and urea in mole ratio 1 : 1 : 1.5 in a solvent , preferably absolute ethanol;

b) heating the reaction mixture as obtained in step (a) at temperature ranging between 60-100°C for a period ranging between 4-8 hours; c) adding p-TSA( p- toluene sulphonic acid) or cone. HC1 into reaction mixture as obtained in step (b) followed by refluxing at temperature ranging between 60-100 ⁰ C for a period ranging between4-8 hours; d) cooling the reaction mixture as obtained in step ( c) followed by separating the solid by Alteration, washing with alcohol to obtain compounds no. 1 -3, 5-18 and 20-22 or benzylester of tetrahydropyrimidone;

e) synthesizing tetrahydropyrimidone- 5- carboxylic acid from benzylester of tetrahydropyrimidone as obtained in step (d) either by stirring benzylester of tetrahydropyrimidone as obtained in step (d), 5%Pd/C and ammonium formate into methanol under nitrogen atmosphere for a period ranging between 8-10 hrs at temperature ranging between 55-65 °C followed by adjusting pH 9 by basic solution preferably aq KOH, filtering the reaction to obtain filterate, followed by adjusting pH 4 using acidic solution preferably aq HC1 to obtain tetrahydropyrimidone- 5- carboxylic acid or by hydrolysis of the benzylester of tetrahydropyrimidone as obtained in step (d) by NaOH or KOH; f) stirring tetrahydropyrimidone- 5- carboxylic acid as obtained in step (f) and NN'-Dicyclohexylcarbodiimide (DCC) for a period ranging between 6-12 hours at temperature ranging between 50-65° C and subsequently adding DMF solution of corresponding amine preferably cyclohexylamine in the it and continuing stirring at temperature ranging between 55-65°C followed by adding methanol into the reaction mixture;

g) filtering the reaction mix as obtained in step (g) to remove dicyclohexyl urea followed by removal of methanol to obtain compounds no.4, 19, 23 and 24.

A process as claimed in claim 6, wherein substituted acetoacetanilide used in step ( a) is selected from the group consisting of 3-chloroacetoacetanilide, 4- nitroacetoacetanilide, 2,3-dichloroacetoacetanilide and 3-nitroacetoacetanilide.

8. A process as claimed in claim 6, wherein substituted aldehyde used in step (a) is selected from the group consisting of 2,4-dichlorobenzaldehyde, benzaldehyde, 3-chlorobenzaldehyde and 3,4-dimethoxybenzaldehyde.

9. A process as claimed in claim 6, wherein yield of compound of general formula 1 is in the range of 42-60%.

10. Use of the compound as claimed in any of the previous claims against the Mycobacterium in their dormant stage.

1 1. Use of the compound as claimed in any of the previous claims in preparing medicament or pharmaceutical composition against mycobacterium in dormant stage.