AU2021104914A4 - SYNTHESIS OF 2-BENZYLBENZO[d] THIAZOLE-6-SULFONAMIDE DERIVATIVES AS POTENTIAL ANTI-INFLAMMATORY AGENT - Google Patents

Abstract

In the present Invention we have synthesized a series of novel Benzothiazole derivatives by using sulfa drugs.The Benzothiazole derivatives such as substituted 2-benzylbenzo[d]thiazole-6 sulfonamide were synthesized by a different procedure in which substituted benzyl bromide were reacted with sodium cyanide to formed substituted benzyl cyanide which were reacted with sulfuric acid to formed substituted benzyl acetic acid which were reacted with thionyl chloride to formed substituted benzyl acetyl chloride. These substituted benzyl acetyl chloride were reacted with sulfanilamide to form substituted 2-benzyl-N(-4-sulfamoylphenyl)acetamide which were further reacted with Lawessons reagent to formed substituted 2-benzyl-N(-4 sulfamoylphenyl)ethanethioamide. The cyclization of substituted 2-benzyl-N(-4 sulfamoylphenyl)ethanethioamide were prepared in the prensence of Dess-Martin priodinane with dichloromethane and then prepared Benzothiazole nucleus. The chemical structures of the synthesized compounds were confirmed by means of IR, H-NMR, Mass spectral. These compounds were screened for anti-inflammatory activity by carrageenan induced paw oedema method in rats at a dose of 10 mg/kg body weight. Among the tested compounds of benzothiazole derivatives, compounds Rm 2, Rm 3, Rm5 , Rm8 & Rmg exhibited some anti-inflammatory activity but compounds Rmi, Rm 4, Rm6 , Rm8 & Rmio were more potent when compared to standard drug Aspirin.

Description

TITLE OF INVENTION SYNTHESIS OF 2-BENZYLBENZO[d] THIAZOLE-6-SULFONAMIDE DERIVATIVES AS POTENTIAL ANTI-INFLAMMATORY AGENT

BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide and are especially valued for their analgesic, antipyretic and anti-inflammatory properties. However, despite the great benefits associated with NSAID use, up to 25% of patients taking NSAIDs chronically experience upper gastrointestinal (UGI) adverse effects.

Inflammation is a complex pathological condition associated with exaggerated human immune system involving various activated immune cells and bio-molecules. Treatment of inflammatory diseases particularly chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease etc. has been a big challenge for scientists as there are no safe drugs available for cure. Current therapeutic approaches to the treatment of inflammatory diseases are centered on cycloxygenase (both COX-1 and 2) proinflammatory enzymes but present available drugs of this category are associated with undesirable gastrointestinal and cardiovascular side effects.

The use of non- steroidal anti- inflammatory drug is well recognized for regional inflammatory disorders such as muscle pain, osteoarthritis and rheumatoid arthritis. A heterocyclic compound is one which possesses a cyclic structure with at least two different kinds of hetero atoms in the ring. Heterocyclic compounds are very widely distributed in nature and are essential to life in various ways.

Benzothiazole is one of the most important heterocyclic compounds, weak base, having varied biological activities and still of great scientific interest now a days. They are widely found in bioorganic and medicinal chemistry with application in drug discovery.

Benzothiazole is a privileged bicyclic ring system. Due to its potent and significant biological activities it has great pharmaceutical importance; hence, synthesis of this compound is of considerable interest. The small and simple benzothiazole nucleus if present in compounds involved in research aimed at evaluating new products that possess interesting biological activities. Benzothiazoles are fused membered rings, which contain the heterocycles bearing thiazole. Sulphur and nitrogen atoms constitute the core structure of thiazole and many pharmacologically and biologically active compounds.

Thiazole is structurally related to thiophene and pyridine, but in most of its properties it resembles to the latter. Thiazole is a heterocyclic compound. Thiazole ring is a five- member ring consists of one nitrogen and one sulfur atom in the ring. Thiazole and their analogues such as benzothiazole play an essential role as a template in the development of tremendous derivatives of thaizole which have different pharmacological activity and useful in the treatment of various disease.

Thiazole (a) was first described by Hantzsch and Waber in 1887. Popp confirmed its structure in 1889. The numbering in thiazole starts from the sulphur atom. The basic structure of benzothiazole (b) consist of benzene ring fused with 4, 5 position of thiazole (Shivaraj, H. et al 2010).

S (a) (b)

Structure of Thiazole and Benzothiazole

The benzothiazole ring is present in various marine or terrestrial natural compounds, which have useful biological activities (Hutchinson, I. et al 2001). Benzothiazole is a colorless, slightly viscous liquid with a melting point of 2°C, and a boiling point of 227-228 °C. The density of benzothiazole is 1.238 g/ml (25°C). Benzothiazole has no household use. It is used in industry and research work purpose which are very beneficial for development.

A considerable amount of research is directed towards a potent, more specific and less toxic anti-Inflammatory drug. Substituted benzothiazole have received considerable attention during last two decades as they are endowed with variety of pharmacological and biological activities, of which, most potent activity is anti-inflammatory, anti-microbial, anti-fungal, and analgesic activities and have wide range of therapeutic properties.

Prostaglandins made by COX-1 enzyme are protective prostaglandins, the presence of which leads to normal renal function in the kidney, whereas, prostraglandins made by COX-2 causes inflammation. Currently available NSAIDs (Nonsteroidal anti-Inflammatory drugs) inhibit both COX-1 and COX-2 enzymes. Inhibition of COX-1 reduces the basal production of cytoprotective PGE 2 and PGI 2 and hence causes ulceration. Therefore, complete inhibition of COX-1 is not preferred and drugs that inhibit the COX-2 enzyme are better anti Inflammatory agents.

Inflammation is defined as the local response of living mammalian tissues to injury due to any agent. The term inflammation is derived from Latin "Inflammare" meaning to burn. Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. This process may vary from a localized to a generalized response characterized by the accumulation of fluids and leukocytes leading to edema and pain. Inflammation is a process which begins with following a sub-lethal injury to mammalian tissue and ends with complete healing. Thus inflammation is a response to the tissue to an infection, irritation or foreign substance. It is the part of the host's defense, but when the response becomes too great, it may be worse and in extreme case it may be fatal. Inflammation is not a one event occurring in orderly sequence, not necessarily dependent on each other for their development. Especially mediators of inflammation and pain are Histamine, 5HT (serotonin), bradykinin, prostaglandins etc. Inflammation because of its frequent external obvious reaction has rich history that is intimately linked to the history of wounds, and infections. Inflammation is said to be protective response of living tissue. Despite its protective role in acute course, it might lead to affected tissue damage during chronicity. Therefore, the treatment with drugs to suppress inflammation is essential in order to prevent the deleterious effects on the affected tissue.

Types of inflammation: Depending upon the defence capacity of the host and duration of response

Acute inflammation: -It is a short duration and represents the early body reaction and is usually followed by repair. Its main features are accumulation of fluid and plasma at the affected site, intravascular activation of platelets, polymorphonuclear neutrophils as inflammatory cells.

Chronic inflammation: - It is of longer duration and occurs either after the causative agents of acute inflammation persist for a long time, or the stimulus is induces chronic inflammatory cells such as lymphocytes, plasma cells, and macrophages.

Description of Invention

In the present invention we have synthesize compound containing the features namely benzothiazole moiety fused with substituted sulphonamide to study their anti-Inflammatory activity.

SYNTHETIC SCHEME

SCHEME 1:

"" BrNaCN/DMSO Br~NDS NC H2SW4 yC0 COOH RX R EToAc R H20,A RR

12 13 11 SOCL 2 Reflux6-7hrs

COGl R

SCHEME 2:

0 C-CH2 NH 2 10% NaOH HN Cl /7 + R R S0 2NH 2 S0 2NH2

14 21 22

Lawsson"s Reagent

N2

SC -CH2 HN H2NO2S S Desmartin Periodinane / \ DCM

-\ S0 2NH2 24 R 23

Brief Description of Drawings

Other objects, features, and advantages of the embodiment will be apparent from the following description when read with reference to the accompanying drawings. In the drawings, wherein like reference numerals denote corresponding parts throughout the several views. Preferred embodiments of the present invention are herein further described, by way of non limiting example only, with reference to the accompanying tables, in which:

Table 1: Analytical Data Table

Table 2: Solubility of Synthesized Compounds

Table 3: Rf value of synthesized compounds

Table 4: IR spectral values of synthesized compounds

Table 5: 1H NMR spectral values of synthesized compounds are given

Table 6 The anti-inflammatory activity of compounds Rmi, Rm2, Rm 3 , Rm 4 , Rm 5 , Rm6 , Rmy, Rm, Rmg and Rmio at different time intervals using carrageenan-induced paw oedema in rats compared to indomethacin.

Figure 1 IR SPECTRA OF MOST POTENTIAL SYNTHESISED COMPOUND

Figure 2 H IN.M.R Spectra of MOST POTENTIAL Synthesized Compound

Figure-3 MASS SPECTRA OF MOST POTENTIAL SYNTHESISED COMPOUND

MODES FOR CARRYING OUT THE PREFERRED EMBODIMENTS

The embodiments herein and the various features and advantageous details thereof are explained more fully with reference to the non-limiting embodiments that are illustrated in the accompanying drawings and detailed in the following description. Descriptions of well known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

As used herein, the singular forms "a", "an", "the" include plural referents unless the context clearly dictates otherwise. Further, the terms "like", "as such", "for example", "including" are meant to introduce examples which further clarify more general subject matter, and should be contemplated for the persons skilled in the art to understand the subject matter. Although this invention has been described in conjunction with the exemplary embodiments' below, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, the exemplary embodiments of the invention as set forth above are intended to be illustrative and not limiting. Various changes may be made without departing from the spirit and scope of the invention.

Chemicals- The chemicals used in present project work were of AR grade and LR grade purchased from Sigma Aldrich and Merck.

Benzyl bromide Desmartin periodinane DMSO

2-hydoxy benzyl bromide Sulphanilamide NaCN

2-methoxy benzyl bromide Lawesson's reagent Na2SO4

3-bromo benzyl bromide Ethyl acetate NaCl

4-bromo benzyl bromide Toluene SOCl2

2-fluoro benzyl bromide n-Hexane H2SO4

4-fluoro benzyl bromide Methyl alcohol NaOH

2,5-difluoro benzyl bromide Ethyl alcohol CH2Cl2

4 nitro benzyl bromide Acetone CCl4

p-chloro benzyl bromide Nitrogen cylinder CHCl3

PROCEDURE

STEP 1: SYNTHESIS OF BENZYL CYANIDE DERIVATIVES:

Br NaCN/DMS R CN R C:-'rEToAc R 11 12

A solution of compound 11(5.26 gm; 20 mmol) in dry DMSO (5ml) was added dropwise to a rapid stirred mixture of NaCN (1.06 gm; 21.6 mmol) in 10 ml DMSO and the reaction mixture was stirried for 5 hrs at room temperature. Water (50 ml) was added and the solution was extracted with ethyl acetate (3x85 ml). The combined organic layer were washed with 30 ml brine and dried over anhydrous Na2SO4. The solution was filtered and the solvent was evaporated to yield compound 12.

STEP 2: SYNTHESIS OF BENZYL ACETIC ACID DERIVATIVES:

CN H2SO4 COOH R K.- 112o,A R 12 13

To a stirred suspension of compound 12 (3.4 mmol) in water(2.5 ml) conc. H2SO4(2.5 ml) was added after stirring for 1.5 hr under reflux.The reaction mixture was cooled to room temperature. The combined organic layer was washed withbrine water,dried over Na2SO4 and concentrated in vacuo to yield compound 13 as a pale orange solid, which was used for the next reaction without purification.

STEP 3: SYNTHESIS OF BENZYL ACETYL CHLORIDE DERIVATIVES:

COOH SOCL 2 COCI

R Reflux 6-7 hrs R 13 14

It is prepared by the reaction of compound13 (1 mole) compounds with thionyl chloride (1 mole). The reaction release HCl and SO 2 gas at room temperature. When reaction is complete then benzene is added and the reaction mixture is refluxed for 6-7 hrs at 30° 40°C

STEP 4: SYNTHESIS OF 2-PHENYL-N (-4-SULFAMOYLPHENYL) ACETAMIDE DERIVATIVES:

O C-CH 2

NH 2 10% NaOH S COCil__ _

RR R S0 2NH 2 S0 2 NH2

14 21 22

1.04 gm of sulphanilamide was added to 15ml of 10% NaOH solution and then 1.7 gm of compound 14 was added and shakes virgously for 20-30 min. The reaction was monitored by TLC. The reaction mixture was warmed on water bath to give compound 22.

STEP 5: SYNTHESIS OF 2-PHENYL-N-(4-SULFAMOYLPHENYL) ETHANETHIOAMIDE DERIVATIVES:

C2 I*C-CH2 HN Lawsson"s Reagent HN

R N2 R S0 2NH 2 S0 2NH 2

22 23 Lawesson's reagent (1.21gm; 1 mole) was added to a stirred solution of compound 22 (1 gm; 1 mole) in toluene. The mixture was stirred at 100°C for 3 hrs under N 2 . The reaction was monitored by TLC.

STEP 6: SYNTHESIS OF 2-BENZYLBENZO[d]THIAZOLE-6-SULFONAMIDE DERIVATIVES:

S C-CH 2 HN Desmartin Periodinane H2N02S S

R N

S0 2 NH 2 DCM 24 R

23

Dess-Martin priodinane (5.5 mmol) was added to a stirred solution of compound 23 (5.0 mmol) in CH2 Cl2 at room temperature. The progress of reaction was monitered by TLC. After completion, it was quenched with water (2x5 ml) and the reaction mixture was extracted with CH2 C 2(2x10ml). The combined organic layer was dried with anhydrous Na2 SO 4, and the solvent was removed in vacuo, to afford the crude product which was purified by the column chromatography on silica gel using petroleum ether/ethyl acetate (8:2) as eluent to give compound 24.

LIST OF COMPOUNDS SYNTHESISED:

1) Compound Rmi

H 2 NO 2 S s

N

Name: - 2-benzylbenzo[d]thiazole-6-sulfonamide

2) Compound Rm 2

H 2 NO 2 S s / OH

Name: - 2-(2-hydroxybenzyl)benzo[d]thiazole-6-sulfonamide

3) Compound Rm 3

H 2 NO 2 S s / OCH 3 CCN

Name: - 2-(2-methoxybenzyl)benzo[d]thiazole-6-sulfonamide

4) Compound Rm 4

H 2 NO 2 S s

Br

Name: - 2-(3-bromobenzyl)benzo[d]thiazole-6-sulfonamide

5) Compound Rm5

H 2 NO 2 S S

Br

Name: - 2-(4-bromobenzyl)benzo[d]thiazole-6-sulfonamide

6) Compound Rm6

H 2 NO 2 S s / F

Name: - 2-(2-fluorobenzyl)benzo[d]thiazole-6-sulfonamide

7) Compound Rm 7

H 2 NO 2 S S

F

Name: - 2-(4-fluorobenzyl)benzo[d]thiazole-6-sulfonamide

8) Compound Rm8

H 2 NO 2 S s F

F

Name: - 2-(2,5 difluorobenzyl)benzo[d]thiazole-6-sulfonamide

9) Compound Rmg

H 2 NO 2 S s N

N02

Name: - 2-(4-nitrobenzyl)benzo[d]thiazole-6-sulfonamide

) Compound Rmio

H 2 NO 2 S s

C1

Name: - 2-(4-chlorobenzyl)benzo[d]thiazole-6-sulfonamide

IDENTIFICATION AND CHARACTERIZATION

The identification and characterization of the prepared compounds were carried out by the following procedure to as certain that all prepared compound have different chemicals nature than the respective parent compounds.

Melting point, Solubility & Thin Layer Chromatography (TLC)

Melting point Determination:

Melting point of the organic compound was determined by open capillary with either using Thiel's melting point tube (capillary tube method) or thermionic melting point apparatus.

Melting point is a valuable criteria for an organic compound as a pure crystal is having definite and sharp melting point. The purity should not be assumed but must be established by observation of any change in the melting point when the compound is subjected to purification by recrystallisation. The melting point of synthesized compounds are given in below see Table 1

Solubility:- The solubility of synthesized compound were tested in various solvents. The solubility of synthesized compounds are given in below see table 2

Thin Layer Chromatography (TLC) :- TLC plates were prepared by using Merck Silica Gel 60.Slurry was prepared in distilled water and then layer was spread out on TLC glass slides. Allowed for dry and kept into the oven for 30 min at 110 °C. Visualization was done in iodine chamber.

Rf values were calculated by the given formula

Distance travelled by solute from origin line Rf - Distance travelled by solute from origin line

The mobile phase used for TLC was n-hexane: ethyl acetate:: 9:1 and CCl4:methanol::1:1 and benzene: ethanol::9:1.

The calculated Rf value of synthesized compounds are given below see the Table 3

SPECTRAL STUDIES:

IR Spectra: The peaks in IR spectra gives an idea the probable structure of the compound IR region ranges between 4000-666 cm .Quanta of radiation from this region lof the spectrum corresponds to energy difference between different vibrational levels of molecules. The compounds were recorded on PERKIN ELMER FTIR-spectrum spectrophotometer shows different vibration levels of molecules. The IR spectral values of synthesized compounds are given in drawing section in Table 4

1H NMR Spectra:

NMR spectroscopy enables us to record differences in magnetic properties of the various magnetic nuclei present, and to deduce in the large measure about the position of these nuclei are within the molecule. We can deduce how many different kinds of environment are there in the molecules and also which atoms are present in neighbouring groups.

The proton NMR spectra enable us to know different chemical and magnetic environments corresponding to protons in a molecule. IH NMR of the title compounds was recorded on BRUCKER 300 MHZ instrument. The IH NMR spectral values of synthesized compounds are given in Drawings section see Table 5

Mass Spectroscopy

The electrospray mass spectra were recorded on a WATER-Q-T of Premier-HAB213. mlz value of compound Rm6 is 322.0210.

BIOLOGICAL EVALUATION

Among the many methods used for screening of anti-inflammatory drugs, one of the most commonly employed techniques is based upon the ability of such agents to inhibit the edema produced in the hind paw of the rat after injection of a phlogistic agent. Many phlogistic agents (irritants) have been used, such as brewer's yeast, formaldehyde, dextran, egg albumin, kaolin, Aerosil, sulfated polysaccharides like carrageenan or naphthoyl heparamine.

Carragenan is a sulphated polysaccharide extract of sea weed called carrageenan or irish moss, the red algae obtained from Chondrus cripus (Rhodophylaceae) Carrageenan induced edema is commonly used as an experimental animal model of acute inflammation and is believed to be biphasic. The first phase is due to released of histamine and serotonin, the second phase is caused by the released of bradykinin, protease, prostaglandin and lysosome. It has been reported that the second phase of edema is sensitive to most clinically effective anti-inflammatory agents. Carrageenan rat paw oedema is a suitable test for evaluating anti-inflammatory drugs which has been frequently used to assess the anti-oedematous effect of drug.

ANTI-INFLAMMATORY ACTIVITY (CARRAGEENAN- INDUCED PAW OEDEMA MODEL)

Animals: White Albino Rats of Wister strain of either sex (150-200gm). Reference Standard Drug: Indomethacine(10 mg/kg body weight). Chemical used for induction of inflammation: Carrageenan (1 %) solution, DMSO Compounds: Rmi, Rm 2, Rm 3 , Rm 4, Rm 5 , Rm, RMRm 8,Rm, Rm o, Numbers of Animals used: Animals for control groups 04 numbers Animals for standard drug 04 numbers Animals for test drugs 04+04+ 04+ 04+ 04+ 04+ 04+ 04+ 04+ 04 numbers

Procedure: Rats were maintained on laboratory stock diet. They were fasted for 24 hours before starting the experiment. Rats were divided into four groups each comprised of six rats. The groups are: 1. Control group- four rats receive 1ml of DMSO. 2. Test groups- divided into first to ten groups, each containing four rats, receive 100mg of test drug/kg rat body weight dissolves in 1ml of DMSO. 3. Standard group: - Six rats receive oral dose of 10 mg of Indomethacin / kg rat body weight dissolve in 1 ml of DMSO.

The synthesized compounds Rmi, Rm 2 , Rm 3 , Rm 4 , Rm5 , Rm6 , Rm 7 , Rm 8 , Rm, Rmio, were selected for evaluated for their anti-inflammatory activity using carrageenan- induced paw edema described by Debranjan, D. et al carried out using Digital Plethysmometer. The tested compounds and reference drug (Indomethacin) were administered orally at a dose level of 100mg/kg. After an hour of oral medication, all rats were injected with 1% carrageenan suspension (0.05 ml / animal) into the sub-planter surface of the right hind paw. The thickness of both paws was measured at different time intervals of zero, 1h, 2h and 3h, after carrageenan injection (Kharat, N. et al 2010). The anti-inflammatory activity of the tested compounds and Indomethacin were calculated as the percentage decrease in edema thickness induced by carrageenan and was determined with the following formula

Vc - Vt Percentage inhibition = x 100 Vc

Where Ve = increase in paw volume of control group, Vt = increase in paw volume of drug treated group.

The final result obtained from the complete work of project, that the synthesized compounds were act as potential anti-inflammatory agents. Which were characterized by different parameters such as TLC, melting point, solubility, Rf value, recrystallization etc. and the analysed by the spectral analysis such as IR, 1 H NMR, Mass spectroscoppy. After complete identification of the synthesized compounds were determined their activity. For the anti inflammatory activity of the synthesized compounds we were used the carrageenan induced paw oedema model in rats. We were synthesized the benzothiazole derivatives from sulfa drug (sulfanilamide) by different synthetic procedures. The melting point of synthesized compounds were determined by Capillary Fusion method. The IR spectra of synthesized compounds were obtained from PERKIN ELMER FTIR-spectrum spectrophotometer. From the IR spectra we obtained that the benzothiazole derivatives have been found NH (1) amine, C=N, C-S-C, types of vibrations (cm-) which were essential for this type of derivatives. The 1H NMR analysis of synthesized compounds were observed from IIT Delhi. 1H NMR spectra were recorded on Brucker NMR instrument using TMS as reference and d6 DMSO as solvent. The 6 values (in ppm) of synthesized compounds from NMR spectra were predicted and show that the synthesized compounds having possible hydrogens which were confirmed by the chemdraw software.

Anti-inflammatory activity: (Carrageenan Induced Paw Oedema Model)

The anti-inflammatory activity of the synthesized benzothiazole derivatives of compounds were determined by the carrageenan induced paw oedema methods in rats. The anti-inflammatory activity of the synthesized compounds were observed in respect to the standard anti-inflammatory drug Indomethacin. The all synthesized compounds Rmi-RmiO were selected for anti-inflammatory activity in a dose 100 mg/kg body weight. The compounds Rmi, Rm4 , Rm, Rm 7 and Rmio were show very slightly effect of activity., which was shown in Table 7.1. So that the compounds Rmi, Rm 4 , Rm6 , Rm 7 and RmiO were potent anti-inlammatory agents of benzothiazole derivatives.

The purpose of the present work was to synthesize, characterize and evaluate the biological activity of the substituted benzothiazole derivatives. During this period, I was able to successfully synthesized derivatives Rmi-RmiO. The synthesized compounds were characterized by melting point, TLC, FTIR, 1H NMR and Mass Specta.

From the data of the anti-inflammatory activity it is clearly concluded that the synthesized compounds are promisingly significant and good anti-inflammatory agents. From the results of screening it is clearly indicated that the compound Rmi i.e. benzyl bromide which is attached to benzothiazole molecule had shown the potent activity, and Rm 4 , Rm6 , Rm 7 and Rmio, i.e.-3-bromo benzyl, 2-flouro benzyl, 4-flouro benzyl, & p-chloro benzyl attached to benzothiazole molecule had shown the potent activity.

The above results establish the fact that benzothiazole can be a rich source for exploitation.

SUMMARY

Many important biochemical compounds and drugs of natural origin contain heterocyclic rings. The presence of a heterocyclic ring in such diverse type of compounds is strongly indicative of profound effects of such molecules to exert physiological activity and recognition of this is reflected abundantly in efforts to find useful synthetic drugs. So synthesis of newer chemical entities has become imperative.

The main focus of this Invention has been to design a benzothiazole moiety to arrive at a newer pharmacophore which has potential activity. Benzyl benzothiazole derivatives are an interesting group of compounds with a wide range of biological activity. The biological activities of this class of compounds that are reported in literature are anti-inflammatory, antimicrobial, anticancer, anticonvulsant, anthelmintic and anti-diabetic activities.

Substituted benzyl cyanide was synthesized by the substituted benzyl bromide and NaCN in the presence of EtoAc in DMSO which was further treated with conc. H 2 SO4 in H 2 0 to get substituted benzyl acetic acid which was treated with SO 2 to get substituted benzyl acetyl chloride. This compound treated with sulphonamide in the presence 10% NaOH solution to get substituted 2-phenyl-N-(-4-sulfamoylphenyl) Acetamide which was further treated with Lawsson's Reagent in N2 atmosphere to get substituted 2-phenyl-N-(-4 sulfamoylphenyl)ethanethioamide. This compound was cyclised by Dess-Martin priodinane in DCM as a solvent to get substituted 2-benzylbenzo[d]thiazole-6-sulfonamide.

The yield of different synthesized compounds were found to be in the range of 77-82% and the characterization was done by melting point, TLC. Characteristics IR bands show several functional vibrations which confirm the completion of reaction. Some structures were confirmed by 1H NMR and Mass spectra. All the tested compounds showed to weak to strong anti-inflammatory activity. Rmi, Rm4 , Rm, Rm 7 and Rmo have showed potent anti inflammatory activity.

Claims (7)

1. Claim: 1. Herein we have synthesized a 2-BENZYLBENZO[d] THIAZOLE-6 SULFONAMIDE DERIVATIVES As Potential Anti-Inflammatory Agent.
2. 2. The compounds synthesized in 1 have a novel mechanism of action.
3. 3. The synthesized compounds in 1 have simple pharmacokinetic profile and no interactions with existing drugs.
4. 4. The synthesized compounds which are claimed in 1 have potential Anti-Inflammatory Activity.
5. 5. The synthesized compounds claimed in 1 have low toxicity and wide therapeutic window.
6. 6. The synthesized compounds claimed in 1 have low cost of preparation.
7. 7. We also claim procedure for synthesis of 2-BENZYLBENZO[d] THIAZOLE-6 SULFONAMIDE DERIVATIVES.

   DISCRIPTION OF DRAWINGS 04 Aug 2021

   Table 1: Analytical Data Table

   Compounds Structure M.P (0C) (M.W) Yield (%) Rm1 H2NO 2S S

   N 172- 305 77% 1750C 2021104914

   Rm2 H2NO 2S S OH N 190 0C 321 80%

   Rm3 H2NO 2S S OCH 3 N 195-200 334 78% 0 C

   Rm4 H2NO 2S S

   N 130 0C 382 81% Br

   Rm5 H2 NO 2S S

   N 185 0C 382 84%

   Br

   Rm6 H2NO 2S S F N 150 0C 322 79%

   Rm7 H2 NO 2S S

   N 155 0C 322 82%

   F

   Rm8 H2 NO 2S S F N 145 0C 331 77%

   F

   Rm9 H2 NO 2S S

   N 175-180 349 80% 2021104914

   0 C NO2

   Rm10 H2 NO 2S S

   N 180-185 338 81% 0 C Cl

   Table 2: Solubility of Synthesized Compounds

   S.NO COMPOUND SOLUBLE INSOLUBLE

   1 Rm1 DMSO, methanol Water, ethanol, ethyl acetate, acetone, benzene, chloroform 2 Rm2 DMSO, acetone, methanol Water, ethanol, ethyl acetate, hexane, benzene, chloroform 3 Rm3 DMSO, ethyl acetate Water, alcohol, ethyl acetate, acetone, benzene, chloroform 4 Rm4 DMSO, ethyl acetate, alcohol, Water, hexane, acetone benzene, chloroform 5 Rm5 DMSO, ethyl acetate, alcohol, Water, hexane, Acetone benzene, chloroform 6 Rm6 DMSO, ethyl acetate, alcohol, Water, hexane, Acetone benzene, chloroform 7 Rm7 DMSO, ethyl acetate, alcohol, Water, hexane,

   Acetone benzene, chloroform 8 Rm8 DMSO, ethyl acetate, alcohol, Water, hexane, Acetone benzene, chloroform 9 Rm9 DMSO, ethyl acetate, methanol, Water, hexane, benzene, chloroform, acetone, ethanol 10 Rm10 DMSO, methanol, acetone Water, benzene, 2021104914

   chloroform, ethanol, ethyl acetate

   Table 3: Rf value of synthesized compounds

   So. No. Synthesized Compounds Rf values 1 Rm1 0.70 2 Rm2 0.68 3 Rm3 0.64 4 Rm4 0.75 5 Rm5 0.80 6 Rm6 0.66 7 Rm7 0.72 8 Rm8 0.77 9 Rm9 0.80 10 Rm10 0.78

   Table 4: IR Spectral Values of Synthesized Compounds

   Compoun Structure I.R ds Rm1 H2NO 2S S 3370 (-NH2), 1650 (C= N),

   N 1294 (C-N), 795 (C-S-C)

   Rm2 H2NO 2S S 3372 (-NH2), 1655 (C= N), OH N 1275(C-N), 756 (C-S-C), 3450 (-OH)

   Rm3 H2NO 2S S 3392 (-NH2), 1652 (C= N), OCH 3 N 1280 (C-N), 795 (C-S-C), 1375 (-CH3) 2021104914

   Rm4 H2NO 2S S 3376 (-NH2), 1662 (C= N),

   N 1291 (C-N), 795 (C-S-C), Br 650 (-Br)

   Rm5 H2 NO 2S S 3375 (-NH2), 1660 (C= N),

   N 1255 (C-N), 795 (C-S-C), 650 (-Br) Br

   Rm6 H2NO 2S S 3370 (-NH2), 1676 (C= N), F N 1255 (C-N), 767 (C-S-C), 1029 (-F)

   Rm7 H2 NO 2S S 3338 (-NH2), 1660 (C= N),

   N 1266 (C-N), 767 (C-S-C), 1029 (-F) F

   Rm8 H2 NO 2S S 3348 (-NH2), 1665 (C= N), F N 1265 (C-N), 765 (C-S-C), 1029 (-F) F

   Rm9 H2 NO 2S S 3332 (-NH2), 1644 (C= N),

   N 1259 (C-N), 754 (C-S-C), 1512 (-NO2). NO2

   Rm10 H2 NO 2S S 3334 (-NH2), 1650 (C= N),

   N 1291 (C-N), 771 (C-S-C), 724 (-Cl) Cl 2021104914

   Table 5: 1H N.M.R Spectral Values of Synthesized Compounds

   Compounds Structure Frequency, δ Values Solvent Rm1 H2NO 2S S δ 3.81 (s,2H,CH2),

   N 300 ,DMSO 7.23-7.33 (s,5H,Ar-H), 7.84-8.41 (s,3H,Ar-H), 7.39 (s,2H,NH2). Rm2 H2NO 2S S δ 3.81 (s,2H,CH2), OH N 300 ,DMSO 6.83-7.07 (s,4H,Ar-H), 7.84-8.41 (s,3H,Ar-H), 7.39 (s,2H,NH2), 9.68 (s,1H,OH). Rm3 H2NO 2S S δ 3.81 (s,2H,CH2), OCH 3 N 300 ,DMSO 3.83 (s,3H,CH3), 6.87-7.12 (s,3H,Ar-H), 7.84-8.41 (s,3H,Ar-H), 7.39 (s,2H,NH2). Rm4 H2NO 2S S δ 3.81 (s,2H,CH2),

   N 300 ,DMSO 7.17-7.41 (s,4H,Ar-H), Br 7.84-8.41 (s,3H,Ar-H), 7.39 (s, 2H, NH2).

   Rm5 H2 NO 2S S δ 3.81 (s,2H,CH2),

   N 300 ,DMSO 7.12-7.85 (s,4H,Ar-H), 7.84-8.41 (s,3H,Ar-H), Br 7.39 (s,2H,NH2).

   δ 3.81 (s,2H,CH2), 04 Aug 2021

   Rm6 H2NO 2S S F N 300 ,DMSO 7.10-7.56 (s,4H,Ar-H), 7.84-8.41 (s,5H,Ar-H), 7.39 (s,2H,NH2). Rm7 H2 NO 2S S δ 3.81 (s,2H,CH2),

   N 300 ,DMSO 7.12-7.21 (s,4H,Ar-H), 7.84-8.41 (s,3H,Ar-H), 2021104914

   F 7.39 (s,2H,NH2).

   Rm8 H2 NO 2S S δ 3.81 (s,2H,CH2), F N 300 ,DMSO 6.75-7.10 (s,3H,Ar-H), 7.84-8.41 (s,3H,Ar-H), F 7.39 (s,2H,NH2).

   Rm9 H2 NO 2S S δ 3.81 (s,2H,CH2),

   N 300 ,DMSO 7.49-8.14 (s,4H,Ar-H), 7.84-8.41 (s,3H,Ar-H), NO2 7.39 (s,2H,NH2).

   Rm10 H2 NO 2S S δ 3.81 (s,2H,CH2),

   N 300 ,DMSO 7.17-7.37 (s,5H,Ar-H), 7.84-8.41 (s,3H,Ar-H), Cl 7.39 (s,2H,NH2).

   Table 6 The anti-inflammatory activity of compounds Rm1, Rm2, Rm3, Rm4, Rm5, Rm6, Rm7, Rm8, Rm9 and Rm10 at different time intervals using carrageenan-induced paw oedema in rats compared to indomethacin.

   Paw volume (ml) at time after carrageenan Treatment N (Mean ± S.E.M) %I at 3hr

   Initial 1hr 2hr 3hr

   Control 4 0.122 ± 0.140 ± 0.152 ± 0.195 ± ------- 0.0041 0.0035 0.0021 0.0025

   Standard 4 0.135 ± 0.170 ± 0.152 ± 0.135 ± 30.77 *** 0.0025 0.0035 0.0021 0.0025

   Rm1 4 0.140 ± 0.180 ± 0.152 ± 0.145 ± 25.65 *** 0.0035 0.0035 0.0021 0.0025

   Rm2 4 0.140 ± 0.152 ± 0.180 ± 0.185 ± 5.13 0.0035 0.0021 0.0035 0.0025 2021104914

   Rm3 4 0.135 ± 0.152 ± 0.170 ± 0.183 ± 6.15 0.0025 0.0021 0.0035 0.0020

   Rm4 4 0.140 ± 0.170 ± 0.160 ± 0.148 ± 24.10 *** 0.0035 0.0035 0.0035 0.0017

   Rm5 4 0.135 ± 0.152 ± 0.180 ± 0.180 ± 7.69 0.0025 0.0021 0.0035 0.0025

   Rm6 4 0.145 ± 0.170 ± 0.152 ± 0.150 ± 23.08 *** 0.0025 0.0035 0.0021 0.0035

   Rm7 4 0.140 ± 0.180 ± 0.160 ± 0.152 ± 22.02 *** 0.0035 0.0035 0.0035 0.0021

   Rm8 4 0.140 ± 0.152 ± 0.170 ± 0.182 ± 6.67 0.0035 0.0021 0.0035 0.0035

   Rm9 4 0.135 ± 0.160 ± 0.180 ± 0.181 ± 7.18 0.0025 0.0035 0.0035 0.0036

   Rm10 4 0.145 ± 0.180 ± 0.160 ± 0.144 ± 26.15 *** 0.0025 0.0035 0.0035 0.0048

   Data represent: - Mean ± S.E.M = Standard Error Mean, N= numbers of animals, % I= Percentage reduction of oedema, *** = significant (P ˂ 0.05)

   Figure 1 IR SPECTRA OF MOST POTENTIAL SYNTHESISED COMPOUND:

   Figure 2 H1 N.M.R Spectra of MOST POTENTIAL Synthesized Compound :

   Figure-3 MASS SPECTRA OF MOST POTENTIAL SYNTHESISED COMPOUND :