US20120189670A1 | 2012-07-26 | |||
US20130184317A1 | 2013-07-18 | |||
US20100056581A1 | 2010-03-04 |
CLAIMS We claim, 1. An aryl azo pyrazole derivatives, comprising the compound of structural formula I or a pharmaceutically acceptable salt thereof, in which R1 is an alkoxy or a halo group. 2. The aryl azo pyrazole derivatives as claimed in claim 1, wherein the alkoxy group is selected from methoxy, ethoxy, isopropoxy, tert-butoxy and phenoxy, more preferably a methoxy. 3. The aryl azo pyrazole derivatives as claimed in claim 1, wherein the halo group is selected from flouro, chloro, bromo and iodine, more preferably a flouro. 4. The aryl azo pyrazole derivatives as claimed in claim 1, wherein the derivative is (E)-4-(2-(1-(4-methoxybenzoyl)-3-methyl-5-oxo-1,5-dihydro- 4H-pyrazol-4-ylidene)hydrazinyl)-N-(pyrimidin-2- yl)benzenesulfonamide: 5. The aryl azo pyrazole derivatives as claimed in claim 1, wherein the another derivative is (E)-4-(2-(1-(4-fluorobenzoyl)-3-methyl-5-oxo-1, 5- dihydro- 4H-pyrazol-4-ylidene)hydrazinyl)-N-(pyrimidin-2- yl)benzenesulfonamide: 6. A process for preparation of compound of Formula-I as claimed in claim 1, comprising the following steps: a) Dissolving 100g of 0.4mol of sulfadiazine in 700ml solution of hydrochloric acid and cool the mixture to 0-5° C. b) Dissolving 41g of sodium nitrite in 200 ml of water and dropwise adding the solution into the mixture of step (a). c) Stirring the mixture of step (b) at 0-5° C for 30 minutes. d) Dissolving 238 g of sodium acetate in 600ml of water and stir to form a mixture. e) Dissolving 54.6g of 0.42mol ethyl acetoacetate to the solution of step (d) and maintaining the mixture at 0-5° C. f) Dropwise adding the mixture of step (c) into the mixture of step (e) while keeping the temperature 0-5 °C within 30 minutes. g) Stirring the reaction mixture of step (f) for 30 minutes. h) Filtering the reaction mixture of step (g) and washing it with 300ml of cold water. i) Drying the compound under vacuum at 45-50°C to get intermediate 3. j) Dissolving 84.8g of the intermediate 3 of step (i) and 36.0g of benzohydrazide into 840ml of acetic acid. k) Stirring the mixture of step (j) at 25-300C for 30 minutes and then heat it at 95-1000C under stirring for 40 hours. l) Cooling the mixture of step (k) to 400C and keep stirring at the same temperature for 1 hour. m) Filter the precipitated compound of step (l) and washing it with 200 ml of cold water. n) Drying the compound of step (m) under vacuum at 45-500C to get 30.9g of the crude compound. o) Suspending 30.9g of the crude compound of step (n) in 600ml of methanol and reflux the mixture under stirring for 2-3 hours. p) Cool the suspension of step (o) to 25-300C and is stirred for 1 hour. q) Filtering the compound of step (p) and washing it with 200ml of methanol and drying the compound under vacuum at 45-500C to get the pure compound with formula (I). 7. The aryl azo pyrazole derivatives as claimed in claim 1, wherein the said compound is used to prepare pharmaceutical composition comprising a pharmaceutically active compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 8. The aryl azo pyrazole derivatives as claimed in claim 1, wherein the pharmaceutical composition is used as an anti-microbial agent for treating microbial infection. 9. The aryl azo pyrazole derivatives as claimed in claim 1, wherein the said derivatives having LD504000mg/kg. |
In another embodiment, the present invention provides a method for the preparation of compound with formula (I), comprising the following steps: a) Dissolving 100g of 0.4mol of sulfadiazine in 700ml solution of hydrochloric acid and cool the mixture to 0-5° C. b) Dissolving 41g of sodium nitrite in 200 ml of water and dropwise adding the solution into the mixture of step (a). c) Stirring the mixture of step (b) at 0-5° C for 30 minutes. d) Dissolving 238 g of sodium acetate in 600ml of water and stir to form a mixture. e) Dissolving 54.6g of 0.42mol ethyl acetoacetate to the solution of step (d) and maintaining the mixture at 0-5° C. f) Dropwise adding the mixture of step (c) into the mixture of step (e) while keeping the temperature 0-5 ° C within 30 minutes. g) Stirring the reaction mixture of step (f) for 30 minutes. h) Filtering the reaction mixture of step (g) and washing it with 300ml of cold water. i) Drying the compound under vacuum at 45-50°C to get the final compound with formula (I). In another embodiment, the present invention provides a compound wherein the said compound is used to prepare a pharmaceutical composition comprising pharmaceutically active compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically accept able carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as Suitable and as understood in the art. The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, and suspension, for parenteral injection as a sterile solution, suspension, or emulsion, for topical administration as an ointment or cream or for rectal administration as a Suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight of the active ingredient, and, from 1 to 99.95% by weight, more preferably from 30 to 99.9 weight % of a pharmaceutically acceptable carrier, all percentages being based on the total composition. The pharmaceutical composition may additionally contain various other ingredients known in the art, for example, a lubricant, stabilizing agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant. In another embodiment, the present invention relates to methods of synthesizing the compound of formula (I-1) and the compound of formula (I-2) and the use of it in treating, ameliorating, or preventing a microbial infection. In another embodiment, the present invention relates to compounds of formula (I- 1) and formula (I-2) for treating, ameliorating, or preventing microbial inflammation. In another embodiment, the present invention relates to the compounds of formula (I-1) and formula (I-2) are showing antipyretic activity. Compounds described herein may be in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate forms. In addition, compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization Solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate. EXAMPLES The following working examples represent preferred embodiments of the present invention. All temperatures are expressed in degrees Centigrade unless otherwise indicated. Example 1: Method of synthesis of compound of formula (I):
Step 1: Preparation of ethyl (E)-3-oxo-2-(2-(4-(N-(pyrimidin-2-yl) sulfamoyl) phenyl) hydrazono) butanoate (Intermediate 3): a) Dissolving 100g of 0.4mol of 4-amino-N-(pyrimidin-2-yl) benzenesulfonamide in 700ml solution of hydrochloric acid and cool the mixture to 0-5° C. b) Dissolving 41g of sodium nitrite in 200 ml of water and dropwise adding the solution into the mixture of step (a). c) Stirring the mixture of step (b) at 0-5° C for 30 minutes. d) Dissolving 238 g of sodium acetate in 600ml of water and stir to form a mixture. e) Dissolving 54.6g of 0.42mol ethyl acetoacetate to the solution of step (d) and maintaining the mixture at 0-5° C. f) Dropwise adding the mixture of step (c) into the mixture of step (e) while keeping the temperature 0-5° C within 30minutes. g) Stirring the reaction mixture of step (f) for 30 minutes. h) Filtering the reaction mixture of step (g) and washing it with 300ml of cold water. i) Drying the compound under vacuum at 45-50°C to get Intermediate (3). Step 2: Preparation of compound with Formula (I): a) Dissolving 84.8g of Intermediate 3 and 36.0g of benzohydrazide into 840ml of acetic acid at room temperature. b) Stirring the reaction mixture of step (a) at 25-30 0 C for 30 minutes and then heat it at 95-100 0 C under stirring for 40 hours. c) Cooling the mixture of step (b) to 35-40 0 C and keep stirring at the same temperature for 1 hour. d) Filter the precipitated compound of step (c) and washing it with 200 ml of cold water. e) Drying the compound of step (d) under vacuum at 45-50 0 C to get 30.9g of the crude compound. f) Suspending 30.9g of the crude compound of step (e) in 600ml of methanol and reflux the mixture under stirring for 2-3 hours. g) Cool the suspension of step (f) to 25-30 0 C and is stirred for 1 hour. h) Filtering the compound of step (g) and washing it with 200ml of methanol and drying the compound under vacuum at 45-50 0 C to get the pure compound with formula (I). Example 2: Method of synthesis of derivative of formula (I-1) (E)-4-(2-(1-(4- methoxybenzoyl)-3-methyl-5-oxo-1, 5-dihydro-4H-pyrazol-4-ylidene) hydrazinyl)-N-(pyrimidin-2-yl) benzenesulfonamide: Step 1: Preparation of (E)-ethyl 3-oxo-2-(2-(4-(N-(pyrimidin 2yl) sulfamoyl) phenyl) hydrazono) butanoate (Intermediate-3): a) Dissolving 100g of 0.4mol of 4-amino-N-(pyrimidin-2-yl) benzenesulfonamide in 700ml solution of hydrochloric acid and cool the mixture to 0-5° C. b) Dissolving 41g of sodium nitrite in 200 ml of water and dropwise adding the solution into the mixture of step (a). c) Stirring the mixture of step (b) at 0-5° C for 30 minutes. d) Dissolving 289g of sodium acetate in 600ml of water and stir to form a mixture. e) Dissolving 54.6g of 0.42mol ethyl acetoacetate to the solution of step (d) and maintaining the mixture at 0-5° C. f) Dropwise adding the mixture of step (c) into the mixture of step (e) while keeping the temperature 0-5° C within 30minutes. g) Stirring the reaction mixture of step (f) for 30 minutes. h) Filtering the reaction mixture of step (g) and washing it with 300ml of cold water. i) Drying the compound under vacuum at 45-50°C to get Intermediate (3). Step 2: Preparation of (E)-4-(2-(1-(4-methoxybenzoyl)-3-methyl-5-oxo-1, 5- dihydro-4H-pyrazol-4-ylidene) hydrazinyl)-N-(pyrimidin-2-yl) benzenesulfonamide [Formula (I-1)]: a) Dissolving 84.8g of Intermediate 3 and 36.0g of 4- methoxybenzohydrazide into 840ml of acetic acid at room temperature. b) Stirring the reaction mixture of step (a) at 25-30 0 C for 30 minutes and then heat it at 95-100 0 C under stirring for 40 hours. c) Cooling the mixture of step (b) to 35-40 0 C and keep stirring at the same temperature for 1 hour. d) Filter the precipitated compound of step (c) and washing it with 200 ml of cold water. e) Drying the compound of step (d) under vacuum at 45-50 0 C to get 30.9g of the crude compound. f) Suspending 30.9g of the crude compound of step (e) in 600ml of methanol and reflux the mixture under stirring for 2-3 hours. g) Cool the suspension of step (f) to 25-30 0 C and is stirred for 1 hour. h) Filtering the compound of step (g) and washing it with 200ml of methanol and drying the compound under vacuum at 45-50 0 C to get the pure compound with formula (I-1) (E)-4-(2-(1-(4- methoxybenzoyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)- ylidene)hydrazinyl)-N-(pyrimidin-2-yl)benzenesulfonamide. Example 3: Method of synthesis of derivative of formula (I-2) (E)-4-(2-(1-(4- fluorobenzoyl)-3-methyl-5-oxo-1, 5-dihydro-4H-pyrazol-4-ylidene) hydrazinyl)-N-(pyrimidin-2-yl) benzenesulfonamide Step 1: Preparation of (E)-ethyl 3-oxo-2-(2-(4-(N-(pyrimidin 2yl) sulfamoyl) phenyl) hydrazono) butanoate (Intermediate-3): a) Dissolving 100g of 0.4mol of 4-amino-N-(pyrimidin-2-yl) benzenesulfonamide in 700ml solution of hydrochloric acid and cool the mixture to 0-5° C. b) Dissolving 41g of sodium nitrite in 200 ml of water and dropwise adding the solution into the mixture of step (a). c) Stirring the mixture of step (b) at 0-5° C for 30 minutes. d) Dissolving 238g of sodium acetate in 600ml of water and stir to form a mixture. e) Dissolving 54.6g of 0.42mol ethyl acetoacetate to the solution of step (d) and maintaining the mixture at 0-5° C. f) Dropwise adding the mixture of step (c) into the mixture of step (e) while keeping the temperature 0-5° C within 30minutes. g) Stirring the reaction mixture of step (f) for 30 minutes. h) Filtering the reaction mixture of step (g) and washing it with 300ml of cold water. i) Drying the compound under vacuum at 45-50°C to get Intermediate (3). Step 2: Preparation of (E)-4-(2-(1-(4-fluorobenzoyl)-3-methyl-5-oxo-1,5-dihydro- 4H-pyrazol-4-ylidene)hydrazinyl)-N-(pyrimidin-2-yl)benzenesu lfonamide (Formula I-2): a) Dissolving 100.0g of Intermediate 3 and 40.0g of 4- fluorobenzohydrazide into 100ml of acetic acid at room temperature. b) Stirring the reaction mixture of step (a) at 25-30 0 C for 30 minutes and then heat it at 95-100 0 C under stirring for 40 hours. c) Cooling the mixture of step (b) to 35-40 0 C and keep stirring at the same temperature for 1 hour. d) Filter the precipitated compound of step (c) and washing it with 200 ml of cold water. e) Drying the compound of step (d) under vacuum at 45-50 0 C to get 20.0g of the crude compound. f) Suspending 20.0g of the crude compound of step (e) in 1000ml of methanol and reflux the mixture under stirring for 2-3 hours. g) Cool the suspension of step (f) to 25-30 0 C and is stirred for 1 hour. h) Filtering the compound of step (g) and washing it with 200ml of methanol and drying the compound under vacuum at 45-500C to get the pure compound with formula (I-2) (E)-4-(2-(1-(4- fluorobenzoyl)-3-methyl-5-oxo-1,5-dihydro- 4H-pyrazol-4- ylidene)hydrazinyl)-N-(pyrimidin-2-yl)benzenesulfonamide. Example 4: Analysis of the derivatives a) (E)-4-(2-(1-(4-methoxybenzoyl)-3-methyl-5-oxo-1, 5-dihydro-4H-pyrazol-4- ylidene) hydrazinyl)-N-(pyrimidin-2-yl) benzenesulfonamide (Formula I-1): The chemical formula of the compound (E)-4-(2-(1-(4-methoxybenzoyl)-3-methyl- 5-oxo-1, 5-dihydro-4H-pyrazol-4-ylidene) hydrazinyl)-N-(pyrimidin-2-yl) benzenesulfonamide is C22H19N7O5S having the molecular weight 493.50. Figure 1 illustrates FT-IR results, Figure 3 illustrates the Mass spec and Figure 5 illustrates NMR results of Formula (I-1). b) (E)-4-(2-(1-(4-fluorobenzoyl)-3-methyl-5-oxo-1, 5-dihydro-4H-pyrazol-4- ylidene) hydrazinyl)-N-(pyrimidin-2-yl) benzenesulfonamide (Formula I-2): The chemical formula of (E)-4-(2-(1-(4-fluorobenzoyl)-3-methyl-5-oxo-1, 5- dihydro-4H-pyrazol-4-ylidene)hydrazinyl)-N-(pyrimidin-2-yl) benzenesulfonamide is C 21 H 16 FN 7 O 4 S having molecular weight 481.46. Figure 2 illustrates FT-IR results, Figure 4 illustrates the Mass spec and Figure 6 illustrates NMR results of Formula (I-2). Example 5: Toxicity Studies of the Derivatives a) Toxicity Prediction for derivative of Formula (I-1) Result: Based on the available results and toxicity prediction from the QSAR software, it is concluded that the compound is non-hepatotoxic, noncarcinogenic, non-immunotoxic, non-mutagenic and noncytotoxic with a probability of 0.51, 0.51, 0.96, 0.74 and 0.82, respectively. Based on the predicted LD50 (4000 mg/kg b.wt.) and class (class 5), it is concluded that the safety index of the compound is very wide and compound is expected to be nontoxicity under the conditions and procedures followed in the present QSAR study. b) Toxicity Prediction for derivative of Formula (I-2) Result: Based on the available results and toxicity prediction from the QSAR software, it is concluded that the compound is non-hepatotoxic, noncarcinogenic, non-immunotoxic and mutagenicity with a probability of 0.51, 0.57, 0.98, 0.82 and 0.69, respectively. Based on the predicted LD50 (4000 mg/kg b.wt.) and class (class 5), it is concluded that the safety index of the compound is very wide and compound is expected to be nontoxicity under the conditions and procedures followed in the present QSAR study. Example 6: Biological Evaluation Antifungal activity: The biological activity such as antifungal activity of compound of formula (I-1) & compound of formula (I-2) were tested on a potato dextrose agar (PDA) medium on each of these vegetable pathogenic strains. The fungicidal activity of compound of formula (I-1) & compound of formula (I-2) were studied at 1000 ppm concentration in vitro. Plant pathogenic organisms used were Aspergillus Niger, Nigrospora Species, Rhizopus Nigricum, Botrydepladia Theobromae and Fusarium Oxyporium. Such a Potato agar medium contained dextrose 20g, potato 200g, agar 20g and water 10 ml. The Compounds to be tested were hovering (1000 ppm) in a PDA medium and autoclaved at 100 °C for 14 minutes at 12 atm. pressure. Old cultures were employed five or more days. These Potato agar media were mixed into sterile Petri plates and the microorganisms were immunized after cooling the Petri plates. The % zonal inhibition calculated for fungi was after five days using the formula given below: % of inhibition = 100 (X-Y) / X Where, Y = test plate Area of colony X = control plate Area of colony Table 1: Antifungal activity of compound of formula (I-1) and compound of formula (I-2) Antibacterial activity: It was mixed with 0.3-0.8 ml of 48 hour mixed well and old culture especially by normal stirring before adding on the Petri dish sterilized (50 ml in each dish). Nutrient agar broth was added in an aqueous beaker and boiled to 55 °C with occasional shaking to form well mixing. The melted mass was allowed to mix (1.5 hour) and after the mixing the “cups” were made by pressing into the agar with spooning out the pressed part of agar and sterile cork borer. Into this cups 0.10 ml of prepared test solution (prepared by dissolving 10.0 gm of sample in 10 ml Dimethyl formamide) was added by micropipette which was sterile. The plates were noted by appropriate codes. Table 2: Antibacterial activity of compound of formula (I-1) and compound of formula (I-2)