Description:FIELD OF THE INVENTION
The present invention relates to synthesis of novel 5-Amino-Salicylic Acid derivatives by using 3-methyl-2-thiophenecarboxaldehyde as an starting material and followed by N,N-dicyclohexylcarbodiimide. Further invention relates to novel 5-Amino-Salicylic Acid derivatives used for anti-inflammatory, analgesic, neuroprotective, and antitumor properties.

BACKGROUND OF INVENTION:
Mesalazine, also known as mesalamine or 5-aminosalicylic acid, is a medication used to treat inflammatory bowel disease, including ulcerative colitis and Crohn's disease. It is generally used for mildly to moderately severe disease. It is taken by mouth or rectally.

5-aminosalicylic acid derivatives are a class of drugs used to treat active ulcerative colitis (a condition which causes swelling and sores in the lining of the colon [large intestine] and rectum), mild-to-moderate Crohn's disease (a chronic inflammatory disease of the intestines, especially the colon and ileum, associated with ulcers and fistulae), and ulcerative proctitis (a mild form of ulcerative colitis).

They are also indicated to reduce inflammation and pain in rheumatoid arthritis (a chronic progressive disease, causing inflammation in the joints resulting in painful deformity and immobility) and to treat tuberculosis in combination with other active antitubercular medications.

Inflammatory diseases cause excessive production of chemicals such as “prostaglandins” (produced by the enzymes, cyclooxygenase, and lipoxygenase) responsible for inflammation in the colon. 5-aminosalicylic acid derivatives work by blocking the activity of cyclooxygenase and lipoxygenase, thereby reducing the production of prostaglandins.

It is previously known in the art that 5-ASA may also be produced by direct amination of salicylic acid by diazonium linking and splitting of the thus formed azo compounds. This method has also been employed in production of 5-ASA on an industrial scale. In such production, aniline is normally employed as the source of the diazonium salt, thus the use of sulphanilic acid is also described in the literature in the art. For splitting of the azo bonds, use has been made of dithionite or any analogous sulphur compound which has been added in such excessive amount that this has entailed a considerable hazard to the immediate environment in the industrial production of 5-ASA. According to a recently published method the azo compound obtained according to the above method may also be split electro-chemically in a basic environment. However, this method can only be used by manufacturers who have access to the highly specialized equipment required for industrial electro-chemical synthesis.

US4788331A discloses a novel method of preparing 5-amino salicylic acid (5-ASA) from salicylic acid, with sulphanilic acid as the auxiliary chemical. The reaction carried out according to the present invention by linking and splitting gives, as its final product, an extremely pure 5-amino salicylic acid well suited for pharmaceutical preparation.

None of the above mention prior art suggest that novel 5-Amino-Salicylic Acid derivatives by using 3-methyl-2-thiophenecarboxaldehyde as an starting material and followed by N,N-dicyclohexylcarbodiimide.

SUMMARY OF THE INVENTION
The present invention relates to synthesis of novel 5-Amino-Salicylic Acid derivatives by using 3-methyl-2-thiophenecarboxaldehyde as an starting material and followed by N,N-dicyclohexylcarbodiimide.

Further invention relates to novel 5-Amino-Salicylic Acid derivatives used for anti-inflammatory, analgesic, neuroprotective, and antitumor properties.

DETAILED DESCRIPTION OF THE INVENTION
Detailed Description of the Invention While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

Salicylic acid (SA) derivatives are widely used in the treatment of a wide range of diseases. Acetylsalicylic acid is the most commonly used drug in the world, 4-Aminosalicylic acid (4-ASA) was historically used as a systemic ant tuberculosis drug, and diflunisal is a powerful pain reliever and antipyretic. 5-Aminosalicylic acid (5-ASA), which was first synthesized at the end of the nineteenth century and used to make azo dyes, was later discovered to be a very valuable medicinal agent as well as a component of many biologically active agents. For pharmacological activity, 5-ASA is not metabolized to salicylic acid. It is not regarded as a true salicylate. 5-ASA, unlike other salicylates, does not cause upper gastrointestinal (GI) side effects. Furthermore, it was discovered to be particularly beneficial in the treatment of inflammatory bowel disease (IBD). Since we are interested in this compound and its derivatives, it is unique among salicylates and has a wide range of biological activities including anti-inflammatory, analgesic, neuroprotective, and antitumor properties.

Scheme 1 depicts the synthetic route for novel derivatives. The formation of Schiff bases and the coupling reaction are two steps that result in novel derivatives. A Schiff base is a nitrogen analogue of an aldehyde or ketone that has the C=O group replaced by the C=N-R group. Condensation of an aldehyde or ketone with a primary amine produces it.

Because amines are basic and tend to convert carboxylic acids to their highly unreactive carboxylates, direct conversion of a carboxylic acid to an amide is difficult. The carboxylic acid reacts with the DCC molecule to form a good leaving group, which is then displaced by an amine during nucleophilic substitution. DCC induced coupling, resulting in the formation of an amide linkage is an important reaction in the synthesis of peptides.
Scheme 1.-Synthesis of some novel 5-Amino-Salicylic Acid derivatives.
Where,
Table 1 : Novel 5-ASA derivatives containing amines
Compound Amines Compound Amines

A5

A6

A7

A8

Table 2 : List of compounds synthesized (A5 to A8)
Sr. No. RNH2(AMINE) Chemical name Derivatives
A5
N-benzyl-2-hydroxy-5-{[(E)-(3-methylthiophen-2-yl)methylidene]amino}benzamide

A6
2-hydroxy-5-{[(E)-(3-methylthiophen-2-yl)methylidene]amino}-N-phenylbenzamide

A7
N-cyclohexyl-2-hydroxy-5-{[(E)-(3-methylthiophen-2-yl)methylidene]amino}benzamide

A8 N-(2-aminophenyl)-2-hydroxy-5-{[(E)-(3-methylthiophen-2-yl)methylidene]amino}benzamide

Table 3: Physicochemical Data of Synthesized compounds (A4-A8)
Compound Molecular formula Molecular
Weight
g/mol
M.P. range (0C)
Mobile phase *RF value
A5 C20H18N2O2S 350.43 238-240 Methanol:Ethyl acetate:Water:7:2:1 0.1 to 1.00
A6 C19H16N2O2S 336.41 238-240 Methanol:Ethyl acetate:Water:7:2:1 0.1 to 1.00
A7 C19H22N2O2S 342.14 236-238 Methanol:Ethyl acetate:Water:7:3:1 0.1 to 1.00
A8 C19H17N3O2S 351.42 238-240 Methanol:Ethyl acetate:Water:7:3:1 0.1 to 1.00

Predictions of pharmacokinetics (ADME)
Molsoft, Molinspiration, and Swiss ADME tools were used to predict ADME characteristics of bioactive molecules. This method computes pharmacokinetic and toxicological participants based on the compound's construction.
Table 1: In silico ADMET screening for synthesized compound
Compound M.F. M.W. nHBA nHBD logP TPSA
(A0) Rule of Five
Accepted values -------------- <500
g/mol <5 <10 <5 <110 Max 4
A5 C20H18N2O2S 350.43 2 3 4.80 50.35 4
A6 C19H16N2O2S 336.41 2 3 4.80 49.02 4
A7 C19H22N2O2S 342.46 2 3 5.23 50.07 3
A8 C19H17N3O2S 351.42 2 3 4.03 68.42 4
Schiff Base C13H11NO3S 261.30 2 4 3.79 54.34 4

The chemicals used in the present work were AR grade and LR grade, purchased from Sigma Aldrich, Loba Chemie and used as for preparation of novel derivatives. The list of chemicals used were 5-aminosalicylic acid, methanol, acetic acid, 3-methyl-2-thiophenecarboxaldehyde, N,N-dicyclohexylcarbodiimide, 2-nitroaniline, 3-nitroaniline, 4-methylbenzylamine, 4-nitroaniline, a-napthylamine, Benzylamine, aniline, Cyclohexylamine, o-phenylenediamine etc. The water used was double distilled deionised water.

Examples:
General procedure:
Step-1. Synthesis of Schiff base:-
5-ASA (9.7 mmol) was dissolved in 15ml methanol in a beaker. (9.7 mmol) of 3-methyl-2-thiophenecarboxaldehyde was dissolved in 15ml methanol. Mix both solution in round bottom flask and 3-4 drop of acetic acid was also added. Reflux it for about 21/2hour. Reaction mixture was cooled to room temperature and placed in refrigerator for 24 hr. the precipitate solid was filtered and washed with methanol.

Step-2. Synthesis of 5ASA derivatives:-
To a magnetically stirred solution of carboxylic acid (1 mmol) in H2O was added 1 mmol of N,N-dicyclohexylcarbodiimide and the reaction mixture was stirred at room temperature for 1 h after this period, the amine (1 mmol) was added and the reaction mixture was stirred at room temperature for the indicated time until the starting materials were totally consumed as checked by TLC. Then, the solvent was separated by filtration and the solid washed several times with water in order to remove the by-product diisopropyl urea (DIU).

Identification and characterization of synthesized products:
The synthesized compounds were scaled for yield and purified by recrystallization with suitable solvent system. The purified compounds were assigned for physical constant determination and further subjected for spectral analysis like Infrared spectroscopy, Nuclear magnetic resonance spectroscopy and Mass spectroscopy.

Spectral Data:

A5: N-benzyl-2-hydroxy-5-{[(E)-(3-methylthiophen-2-yl)methylidene]amino}benzamide
IR (cm-1): 1677.77 (C=O), 3083.62 (N-H), 2623.68 (Aromatic C-H), 3651.55 (O-H), 1098.26 (C-S)
1H NMR (500 MHz, Chloroform-d) d 11.60 (s, 1H), d 8.75 (s, 1H), 8.03 (t, J = 5.6 Hz, 1H), 7.60 (d, J = 5.7 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.36 – 7.23 (m, 5H), 7.15 (dd, J = 8.6, 2.2 Hz, 1H), 7.03 – 6.98 (m, 1H), 6.96 (d, J = 8.7 Hz, 1H), d 5.44 (s, 1H), 4.53 (dt, J = 5.7, 0.8 Hz, 2H), 2.46 (s, J = 0.7 Hz, 3H).
Theoretical Mass : 350.43 Observed Mass :363.1257

A6: 2-hydroxy-5-{[(E)-(3-methylthiophen-2-yl)methylidene]amino}-N-phenylbenzamide
IR (cm-1): 1701.87 (C=O), 3099.05(N-H), 2985.27 (Aromatic C-H), 3345.89 (O-H), 1229.4 (C-S)
1H NMR (500 MHz, Chloroform-d) d 11.78 (s, 1H), d 9.55 (s, 1H), 8.75 (s, 1H), 7.71 – 7.65 (m, 2H), 7.60 (d, J = 5.7 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.36 – 7.29 (m, 2H), 7.18 – 7.11 (m, 2H), 7.03 – 6.98 (m, 1H), 6.96 (d, J = 8.6 Hz, 1H), d 5.37 (s, 1H), 2.46 (s, J = 0.7 Hz, 3H).
Theoretical Mass : 336.41 Observed Mass : 336.0612

A7: N-cyclohexyl-2-hydroxy-5-{[(E)-(3-methylthiophen-2-yl) methylidene] amino} benzamide
IR (cm-1): 1701.87 (C=O), 3099.05(N-H), 2985.27 (Aromatic C-H), 3345.89 (O-H), 1095.37 (C-S)
1H NMR (500 MHz, Chloroform-d) d 11.50 (s, 1H), d 8.75 (s, 1H), 7.60 (d, J = 5.7 Hz, 1H), 7.46 (s, 1H), 7.15 (dd, J = 8.6, 2.2 Hz, 1H), 7.01 (dt, J = 5.9, 0.9 Hz, 1H), 6.98 – 6.90 (m, 2H), 3.76 (dp, J = 7.9, 4.9 Hz, 1H), 2.46 (s, J = 0.7 Hz, 3H), 1.80 (dddd, J = 13.5, 8.6, 6.0, 4.8 Hz, 2H), 1.70 – 1.57 (m, 2H), 1.55 – 1.39 (m, 6H).
Theoretical Mass :342.14 Observed Mass : 342.1321

A8: N-(2-aminophenyl)-2-hydroxy-5-{[(E)-(3-methylthiophen-2yl)methylidene] amino} benzamide
IR (cm-1): 1683.55 (C=O), 3260.07(N-H), 2813.63 (Aromatic C-H), 3690.07 (O-H), 1143.58 (C-S)
1H NMR (500 MHz, Chloroform-d) d 11.84 (s, 1H), d 9.45 (s, 1H), d 8.75 (s, 1H), 7.60 (d, J = 5.7 Hz, 1H), 7.57 (dd, J = 7.9, 1.3 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.28 – 7.21 (m, 1H), 7.15 (dd, J = 8.6, 2.2 Hz, 1H), 7.03 – 6.93 (m, 3H), 6.84 (dd, J = 7.9, 1.4 Hz, 1H), 4.03 (s, 2H), 2.46 (s, J = 0.7 Hz, 3H).
Theoretical Mass : 351.42 Observed Mass : 364.0784

The present invention reveals the synthesis of some novel 5-Amino-Salicylic Acid derivatives by using 3-methyl-2-thiophenecarboxaldehyde as an starting material and followed by N,N-dicyclohexylcarbodiimide. The newly synthesized derivatives were confirmed by elemental analysis, mass, IR and NMR spectroscopy.

5-aminosalicylic acid derivatives are anti-inflammatory drugs that help to reduce symptoms of ulcerative colitis such as diarrhea, rectal bleeding, and stomach pain.

5-aminosalicylic acid derivatives are administered via the oral route, typically three times a day with or without food, and as a suppository and an enema to be used in the rectum typically once a day at bedtime.

5-aminosalicylic acid derivatives work in the following ways:
They belong to a class of drugs called “aminosalicylates” that work by reducing bowel inflammation.
In addition, they are antituberculosis antibiotic that works by stopping or slowing the growth of bacteria.

Mesalamine is also known as mesalazine or 5-aminosalicylic acid (5-ASA). It is an antiinflammatory drug used to treat inflammations of the digestive tract such as ulcerative colitis and mild to moderate Crohn's disease. Mesalamine is a bowel specific aminosalicylate drug that after oral administration is metabolized in the gut and has its predominant actions there. Consequently there are fewer side effects. It is now believed that mesalamine is the therapeutic moiety of sulfasalazine which is a conjugate of 5-aminosalicylic acid and sulfapyridine. The sulfapyridine moiety is thought to be the component responsible for a large percentage of the side effects seen with sulfasalazine. The therapeutic activity of mesalamine is not really known. It may be due to inhibition of lipoxygenase or to the inhibition of several inflammatory mediators. The most common adverse effects of mesalamine are gastrointestinal related or hypersensitivity reactions.
, Claims:Claim 1: A synthesis of novel 5-Amino-Salicylic Acid derivatives by using 3-methyl-2-thiophenecarboxaldehyde as an starting material and followed by N,N-dicyclohexylcarbodiimide.

Claim 2: The synthesis of novel 5-Amino-Salicylic Acid derivatives as claimed in claim 1, wherein the novel 5-Amino-Salicylic Acid derivatives used for anti-inflammatory, analgesic, neuroprotective, and antitumor properties.

Claim 3: The synthesis of novel 5-Amino-Salicylic Acid derivatives as claimed in claim 1, wherein the synthesis of novel 5-Amino-Salicylic Acid derivatives by using following steps