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WO2023209678A1 - Dérivés d'aryl-azo-pyrazole utiles comme agent antimicrobien - Google Patents

Dérivés d'aryl-azo-pyrazole utiles comme agent antimicrobien Download PDF

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Publication number
WO2023209678A1
WO2023209678A1 PCT/IB2023/054471 IB2023054471W WO2023209678A1 WO 2023209678 A1 WO2023209678 A1 WO 2023209678A1 IB 2023054471 W IB2023054471 W IB 2023054471W WO 2023209678 A1 WO2023209678 A1 WO 2023209678A1
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Prior art keywords
compound
mixture
formula
pyrazole derivatives
dissolving
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PCT/IB2023/054471
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English (en)
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Arpan B. PATEL
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Zenal Pharmachem Llc
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Publication of WO2023209678A1 publication Critical patent/WO2023209678A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to compound of formula (I), or a pharmaceutically acceptable salt thereof. More particularly, the present invention relate to method of synthesizing the compounds and the use of those compounds in treating, ameliorating, or preventing a microbial infection and inflammation.
  • An antimicrobial agent is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals are used against fungi. They can also be classified according to their function.
  • microbicides agents that kill microbes are microbicides, while those that merely inhibit their growth are called bacteriostatic agents.
  • the present invention arose due to the inventor's interest in pyrazole heterocyclic moiety and developed novel Aryl azo Pyrazole derivatives as Antimicrobial Agent.
  • OBJECTIVES OF THE INVENTION The main objective of the present invention is to provide aryl azo pyrazole derivatives, compounds having the structural formula (I).
  • Another objective of the present invention is to provide aryl azo pyrazole derivatives (I) which can be used as antimicrobial and anti-inflammatory agent.
  • Another objective of the present invention is to provide a process of synthesizing the aryl azo pyrazole derivatives (I) SUMMARY OF THE INVENTION
  • the main aspect of the present invention is to provide aryl azo pyrazole derivatives, compounds represented by formula (I) or a pharmaceutical acceptable salt thereof; Wherein R 1 is methoxy or fluoro.
  • Another aspect of the present invention is to provide a derivative, 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 represented by formula (I-1)
  • the 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 represented by the formula (I- 2)
  • Another aspect of the present invention is to provide the process for preparing the compounds and derivatives having formula (I).
  • Another aspect of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the present invention is to provide the process of synthesizing the compound of formula (I) and the use of it in treating, ameliorating, or preventing a microbial infection or inflammation.
  • the compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydro iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, and ascorbate.
  • non-toxic acid addition salts i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydro iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine- (meglu mine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • Suitable base salts are formed from bases which form non-toxic salts.
  • Non-limiting examples of suitable base salts include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, Sodium, tromethamine and Zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • Antimicrobial Agent is agent that kills microorganisms or stops their growth. Microorganisms include bacteria, fungi, virus and parasite.
  • the main embodiment of the present invention relates to a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:
  • R 1 is an alkoxy or a halo group.
  • the alkoxy group is selected from methoxy, ethoxy, isopropoxy, tert-butoxy and phenoxy, more preferably a methoxy.
  • the halo group is selected from flouro, chloro, bromo and iodine, more preferably a flouro.
  • the aryl azo pyrazole 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, having the formula
  • the aryl azo pyrazole 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
  • 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.
  • step (e) Dissolving 54.6g of 0.42mol ethyl acetoacetate to the solution of step (d) and maintaining the mixture at 0-5° C.
  • step (d) Dropwise adding the mixture of step (c) into the mixture of step (e) while keeping the temperature 0-5 ° C within 30 minutes.
  • step (f) Stirring the reaction mixture of step (f) for 30 minutes.
  • step (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).
  • the present invention provides a compound wherein the said compound is used to prepare a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • the present invention relates to compounds of formula (I- 1) and formula (I-2) for treating, ameliorating, or preventing microbial inflammation.
  • 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.
  • 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.
  • 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.
  • step (e) 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.
  • step (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.
  • 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
  • (I-1) a) Dissolving 84.8g of Intermediate 3 and 36.0g of 4- methoxybenzohydrazide into 840ml of acetic acid at room temperature.
  • step (a) 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.
  • step (b) Cooling the mixture of step (b) to 35-40 0 C and keep stirring at the same temperature for 1 hour.
  • step (d) Filter the precipitated compound of step (c) and washing it with 200 ml of cold water.
  • step (d) Drying the compound of step (d) under vacuum at 45-50 0 C to get 30.9g of the crude compound.
  • step (e) Suspending 30.9g of the crude compound of step (e) in 600ml of methanol and reflux the mixture under stirring for 2-3 hours.
  • Cool the suspension of step (f) to 25-30 0 C and is stirred for 1 hour.
  • 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.
  • step (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.
  • 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)benzenesulfonamide (Formula I-2): a) Dissolving 100.0g of Intermediate 3 and 40.0g of 4- fluorobenzohydrazide into 100ml of acetic acid at room temperature.
  • step (a) 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.
  • step (b) Cooling the mixture of step (b) to 35-40 0 C and keep stirring at the same temperature for 1 hour.
  • step (d) Filter the precipitated compound of step (c) and washing it with 200 ml of cold water.
  • step (d) Drying the compound of step (d) under vacuum at 45-50 0 C to get 20.0g of the crude compound.
  • step (e) Suspending 20.0g of the crude compound of step (e) in 1000ml of methanol and reflux the mixture under stirring for 2-3 hours.
  • Cool the suspension of step (f) to 25-30 0 C and is stirred for 1 hour.
  • step (g) 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)
  • 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.
  • FIG. 1 illustrates FT-IR results
  • Figure 3 illustrates the Mass spec
  • 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
  • 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.
  • FIG. 2 illustrates FT-IR results
  • Figure 4 illustrates the Mass spec
  • 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.
  • 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.
  • 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.
  • % zonal inhibition 100 (X-Y) / X
  • Y test plate Area of colony
  • X control plate Area of colony
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de formule (I), ou un sel pharmaceutiquement acceptable de celui-ci. La présente invention concerne également les dérivés dudit composé de formule (I). La présente invention concerne un procédé de préparation des composés et l'utilisation de ces composés dans la prévention d'une infection microbienne et d'une inflammation.
PCT/IB2023/054471 2022-04-29 2023-04-28 Dérivés d'aryl-azo-pyrazole utiles comme agent antimicrobien WO2023209678A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100056581A1 (en) * 2006-05-09 2010-03-04 Mahesh Vithalbhai Patel Substituted Piperidino Phenyloxazolidinones
US20120189670A1 (en) * 2009-09-14 2012-07-26 Kirkpatrick D Lynn Pharmaceutical compositions and formulations including inhibitors of the pleckstrin homology domain and methods for using same
US20130184317A1 (en) * 2008-04-14 2013-07-18 Arizona Board Of Regents On Behalf Of The University Of Arizona Small molecule inhibitors of the pleckstrin homology domain and methods for using same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100056581A1 (en) * 2006-05-09 2010-03-04 Mahesh Vithalbhai Patel Substituted Piperidino Phenyloxazolidinones
US20130184317A1 (en) * 2008-04-14 2013-07-18 Arizona Board Of Regents On Behalf Of The University Of Arizona Small molecule inhibitors of the pleckstrin homology domain and methods for using same
US20120189670A1 (en) * 2009-09-14 2012-07-26 Kirkpatrick D Lynn Pharmaceutical compositions and formulations including inhibitors of the pleckstrin homology domain and methods for using same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE ANONYMOUS : "4-((1-benzoyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)diazenyl)-N-(pyrimidin-2-yl)benzenesulfonamide", XP093106791, retrieved from PUBCHEM *

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