WO2020240272A1 - Préparation de nouvelles 1 h-pyrazolo [4,3-d] pyrimidines, leurs compositions, leur synthèse et leurs procédés d'utilisation pour le traitement de la tuberculose - Google Patents

Préparation de nouvelles 1 h-pyrazolo [4,3-d] pyrimidines, leurs compositions, leur synthèse et leurs procédés d'utilisation pour le traitement de la tuberculose Download PDF

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WO2020240272A1
WO2020240272A1 PCT/IB2019/056972 IB2019056972W WO2020240272A1 WO 2020240272 A1 WO2020240272 A1 WO 2020240272A1 IB 2019056972 W IB2019056972 W IB 2019056972W WO 2020240272 A1 WO2020240272 A1 WO 2020240272A1
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methyl
propyl
pyrazolo
pyrimidine
compound
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PCT/IB2019/056972
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English (en)
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Manojit Pal
Parimal Misra
Aparna Srikantam
Farhan Jalees Ahmad
Nasreen Zafar EHTESHAM
Seyed Ehtesham Hasnain
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Dr.Reddy's Institute Of Life Sciences
Jamia Hamdard University
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Publication of WO2020240272A1 publication Critical patent/WO2020240272A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention is related to heterocyclic compounds of Formula (I): their derivatives, analogs, tautomeric forms, stereoisomers, bioisosters, diastereomers, polymorphs, enantiomers, prodrugs and their pharmaceutically acceptable salts for the treatment of tuberculosis. Also disclosed is the process for preparing compounds of Formula (I), and intermediates useful for preparing compounds of Formula (I). BACKGROUND OF THE INVENTION
  • bacterial pathogens may be classified as either Grain-positive or Gram-negative pathogens.
  • Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity.
  • Tuberculosis is a chronic, infectious disease that is generally caused by infection with Mycobacterium tuberculosis. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If left untreated, serious complications and death typically result.
  • Mycobacterium tuberculosis is the bacterial agent responsible for human pulmonary tuberculosis. Mycobacterial dormancy results in a disease stage termed latent
  • tuberculosis An individual with latent tuberculosis may later develop a case of reactivated tuberculosis, and in fact, a majority of the tuberculosis cases reported is the result of reactivation of a latent mycobacterial infection and not an initial infection.
  • novel heterocyclic compounds of the present invention are represented by the general Formula (I)
  • R is independently selected from hydrogen, halogen, hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl;
  • Ar is an optionally substituted mono, bi or tri cyclic group preferably an aryl or heteroaryl group such as phenyl, naphthyl, indole, benzoxazole, benzotriazole and the likes thereof;
  • Het represents an optionally substituted heterocyclyl or heteroaryl group connected through a C-C bond.
  • Ar is substituted with phenyl or halo group
  • Ar is phenyl substituted with halo group selected from a group consisting of chloro and bromo;
  • R represents optionally substituted alkyl
  • R is selected from a group consisting of methyl, ethyl and propyl; Furthermore, Het is optionally a substituted heterocyclyl or heteroarylgroup;
  • Het is optionally a substituted indole group connected to the pyrimidine moiety through a C-C bond;
  • Het is indole bi substituted with halo and alkyl groups, or indole substituted with bromo or chloro group, or indole bi substituted with bromo and methyl or ethyl groups, or indole bi substituted with chloro and methyl or ethyl groups.
  • Het is selected from
  • R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
  • X is hydrogen or a halo group selected from fluoro, chloro, bromo, and iodo
  • Y is hydrogen or a halo group selected from fluoro, chloro, bromo, and iodo.
  • the invention also provides a formulation of the compounds of Formula I, comprising 0.2 to 0.9% of the compound, 10 to 30% of S mix consisting tween 80: PEG 400 at a ratio of 1:1 and 70 to 90% normal saline.
  • Example 8(g)sample 30mM-no growth in proportional to control.
  • Halogen refers to Fluorine, Chlorine, Bromine or Iodine.
  • lower alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon that may be substituted or unsubstituted.
  • alkyl include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, isobutyl and the likes thereof.
  • lower Alkoxy refers to a group–OR b whereinR b is hydrogen or alkyl as herein defined. Representative examples include but are not limited to methoxy, ethoxy and the likes thereof.
  • Aryl refers to optionally substituted unsaturated or partially saturated aromatic ring system having five to ten carbon atoms whichare monocyclic, bicyclic or polycyclic and may optionally be replaced by one or more heteroatoms selected from N, O and S.
  • exemplary aryl groups include phenyl, naphthyl, indanyl, biphenyl and the likes thereof.
  • cycloalkyl used herein, either alone or in combination with other radicals, denotes mono, bicyclic or polycyclic saturated, partially saturated hydrocarbon ring system of about 3 to 12 carbon atoms which may be substituted or unsubstituted.
  • cycloalkyl groups include but are not limited to cyclopopyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, perhydronapthyl, adamantyl,
  • noradamantylandspirobicyclic groups such as spiro (4,4)non-2-yl.
  • Heteroaryl refers to monocyclic aromatic ring systems or fused bicyclic aromatic ring systems comprising two or more aromatic rings, preferably two to three ring systems. These heteroaryl rings contain one or more nitrogen, sulfur and/or oxygen atoms where N-oxides sulfur oxides and dioxides are permissible heteroatom
  • the termin cludes ring(s) optionally substituted with halogens, nitro, amino, alkoxy, alkyl sulfonyl amino, alkylcarbonylamino, carboxy, alkyl carbonoyl, hydroxy, and alkyl.
  • heteroaryl groups include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, chromanyl, isochromanyl and the likes thereof.
  • Heterocyclyl refers to a stable 3 to 15 membered ring that is either saturated or has one or more degrees of unsaturation or unsaturated. These heterocyclic rings contain one or more heteroatoms selected from the group consisting of nitrogen sulfur and/or oxygen atoms where N-oxides, sulfur oxides and dioxides are permissible heteroatom substitutions. Such a ring is optionally fused to one or more of another heterocyclic ring(s), aryl ring(s) or cycloalkyl ring(s).
  • Examples of such groups are selected from the group consisting ofazetidinyl, acridinyl, pyrazolyl, imidazolyl, triazolyl, pyrrolyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, pyrazinyl,
  • Heterocyclylalkyl refers to a heterocyclic ring radical defined above, directly bonded to an alkyl group.
  • the heterocyclylalkyl radical is attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure.
  • R 3 and R 4 together along with the nitrogen they are attached with, form a 4 to 8 membered ring which can be substituted or unsubstituted.
  • the substituents in the aforementioned "substituted” groups cannot be further substituted.
  • the substituent on “substituted alkyl” is "substituted aryl”
  • the substituent on “substituted aryl” cannot be “substituted alkenyl”
  • Stepoisomers refer to certain compounds described herein containing one or more chiral centres or may otherwise be capable of existing as multiple stereoisomers.
  • Scope of the present invention includes pure stereoisomers as well as mixtures of stereoisomers such as purified enantiomers/diastereomers or enantiomerically/diastereomerically enriched mixtures.
  • “Bioisosteres” refers to compounds or groups that possess near molecular shapes and volumes, approximately the same distribution of electrons and which exhibit similar physical properties such as hydrophobicity. Bioisostereic compounds affect the same biochemically associated systems as agonist or antagonists and thereby produce biological properties that are related to each other.
  • “Pharmaceutically acceptable salts” forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, 2- dimethylaminoethanol, isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine, triethylamine,
  • “Pharmaceutically acceptable solvates” may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Compounds of the invention or “present invention” refers to the compounds of the present invention represented by general Formula (I) as here in defined, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their enantiomers, their appropriate N-oxides, their pharmaceutically acceptable salts, their pharmaceutically acceptable hydrates, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • the compounds of the present invention will be useful as antibacterial agents particularly in the treatment of tuberculosis.
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
  • Different polymorphs of a compound of general Formula (I) of present invention may be prepared by crystallization of the compound of Formula (I) under different conditions. For example making use of commonly used solvents or their mixtures for recrystallization, crystallization at different temperature ranges, different cooling techniques like very fast to very slow cooling during crystallization procedure, by exposing to room temp, by heating or melting the compound followed by gradual cooling and the like.
  • the presence of polymorphs may be determined by one or more methods like solid probe NMR spectroscopy, DSC, TGA, Powder X- Ray diffraction and IR.
  • the present invention also provides pharmaceutical compositions containing the compounds of invention as defined above, theirderivatives, analogs, tautomeric forms, stereoisomers, bioisosters, polymorphs,enantiomers, diastereomers, their
  • the pharmaceutical compositions according to the present invention are useful antibacterial agents.
  • the pharmaceutical composition may be tablets, capsules, powders, syrups, solutions, suspensions, sprays and the likes thereof and may contain flavorants, sweeteners etc., in a suitable solid or liquid carriers or diluents or in a suitable sterile media to form injectable solutions or suspensions. It is understood that in any of the above schemes, any reactive group in the substrate molecule may be protected according to any conventional procedure known in the prior art.
  • Suitable protecting groups comprise N-Boc, N-Cbz, N-Fmoc, alkyl, benzophenoneimine for protection of amino group, acetal protection for aldehyde, ketal protection for ketone.
  • the invention also encompasses prodrugs of compounds of the invention, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of compounds of invention, which are readily convertible in vivo into compounds of the invention.
  • the invention also encompasses the active metabolites of the compounds of the present invention of general Formula (I).
  • the compounds can be formulated and administered in a prodrug form, hi general, prodrugs comprise functional derivatives of the claimed compounds which are capable of being enzymatically activated or converted into the more active parent form.
  • the term "administering” encompasses the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Wihnan, 14 Biochem. Soc.
  • the present invention relates to novel heterocycliccompounds of Formula (I), their analogues, derivatives, tautomers, prodrugs, stereoisomers, enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable hydrates, pharmaceutically acceptable solvates and bioisosteres:
  • R is independently selected from hydrogen, halogen, hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl;
  • Ar is an optionally substituted mono, bi or tri cyclic group preferably an aryl or heteroaryl group such as phenyl, naphthyl, indole, benzoxazole, benzotriazole and the like;
  • Het represents an optionally substituted heterocyclyl or heteroaryl group connected through a C-C bond.
  • Ar is substituted with phenyl or halo group;
  • Ar is phenyl substituted with halo group selected from a group consisting of chloro and bromo;
  • R represents optionally substituted alkyl
  • R is selected from a group consisting of methyl, ethyl and propyl
  • Het is optionally a substituted heterocyclylor
  • Het is optionally a substituted indole group connected to the pyrimidine moiety through a C-C bond;
  • Het is indole bi substituted with halo and alkyl groups, orindole substituted with bromo or chloro group, or indole bi substituted with bromo and methyl or ethyl groups, or indole bi substituted with chloro and methyl or ethyl groups.
  • Het is selected from
  • R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
  • X is hydrogen or a halo group selected from fluoro, chloro, bromo, and iodo
  • Y is hydrogen or a halo group selected from fluoro, chloro, bromo, and iodo.
  • the present invention provides the following compounds: 5-(4-chlorophenyl)-7-(1H-indol-3-yl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine; 5-(4-chlorophenyl)-1-methyl-7-(1-methyl-1H-indol-3-yl)-3-propyl-1H-pyrazolo[4,3 d]pyrimidine;
  • the present invention relates to a process for the preparation of the compound of Formula (I) as shown below:
  • the compounds of the present invention are prepared by reacting compound of Formula a (prepared as shown in Example 1 step iii of WO2006058201 which is herein incorporated by reference) with phosphorous chloride in the absence or presence of a suitable solvent selected from benzene, toluene, xylene, THF, 1,4-dioxane, diethyl ether, diphenyl ether, dichloromethane, chloroform, 1,2-dichloroethane and the likes thereof to give compound of formula b which is then reacted with suitable‘Het’ compound in presence of aluminium chloride and suitable solvent selected fromnitrobenzene, THF, 1,4-dioxane, diethyl ether, diphenyl ether, dichloromethane, chloroform, 1,2-dichloroethane orthe likes thereof to given compound of Formula (I).
  • a suitable solvent selected from benzene, toluene, xylene, THF, 1,4
  • the compounds of the invention are useful for the treatment of infections in subjects, mammals in particular, including humans.
  • the compounds may be used for the treatment of infections of soft tissues, blood, skin, mouth, lungs, respiratory tract, urinary tract and reproductive tract.
  • the compounds of the invention are useful for the treatment of infections caused by microorganisms, such as but not limited to bacterial infection, especially Mycobacterium complex, more specifically Mycobacterium tuberculosis that causes tuberculosis.
  • the compounds of the present invention are delivered to the subjects by forms suitable for each administration route.
  • the compounds are administered as tablets, capsules, injection, drops, inhaler, ointment, foams suppository.
  • the route of administration is oral, parenteral or topical.
  • Topical or transdermal administration include powders, sprays, ointments, pastes creams, lotions, gels, solutions, patches and inhalants.
  • composition of the present invention is presented in unit dosage form generally in an amount that produces a therapeutic effect in the subject.
  • the compounds of the present invention are administered at a daily dose that is the lowest dose effective to produce a therapeutic effect.
  • the dosage will effect from about 0.0001 to about 100 mg per kg body weight per day.
  • the dosage will range from about 0.001 to 75 mg per kg body weight per day and more preferably, the dosage will range from about 0.1 to about 50 mg per kg body weight per day.
  • Each unit dose may be, for example, 5, 10, 25, 50, 100, 125, 150, 200 or 250 mg of the compound of the invention.
  • the effective daily dose of the compound is administered as two, three, four or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms.
  • the antibacterial compositions of the present invention may be administered by any method known in the art. Some examples of suitable modes of administration include oral, intravenous, intramuscular topical or any other parenteral mode of administration.
  • the present invention is directed to a method of formulating compounds of the present invention in a pharmaceutically acceptable carrier or excipient and may be administered in a wide variety of different dosage forms e.g. tablets, capsules, sprays, creams, lotions, ointments, aqueous suspensions syrups, and the like.
  • Such carriers may include one or more of solid diluents or fillers, sterile aqueous media, and various nontoxic organic solvents, etc.
  • tablets may contain various excipients such as one or more of microcrystalline cellulose, sodium citrate, calcium carbonate and the like, along with various disintegrants such as starch and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose and the like.
  • solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluents or solvent e.g. as solution in 1, 3 butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid find in the preparation of injectables.
  • aqueous solutions may be suitable for intravenous injection purposes.
  • the oily solutions may be suitable for intra articular, intramuscular, and/or subcutaneous injection purposes.
  • the compounds of the present invention may be administered topically that include transdermal, buccal, or sublingual application.
  • therapeutic compounds may be suitably admixed in a pharmacologically inert topical carrier such as a gel, an ointment, a lotion, and/or a cream.
  • topical carriers may include water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, and/or mineral oils.
  • the timing of the administration of the pharmaceutical composition may also be regulated.
  • the compounds may be administered intermittently or by controlled release.
  • MTCM Mycobacterium tuberculosis Chorismate Mutase
  • RV1885C encoding Mtb Chorismate Mutase
  • the amplification conditions were as follows: 94°C for 5 min for initial denaturation of DNA followed by 10 cycles of amplification, with each cycle consisting of denaturation at 94°C for 30 sec and annealing at 50°C for 30 sec and polymerization at 72°C for 60 sec followed by 30cyclesof amplification, with each cycle consisting of denaturation at 94°C for 30 sec and annealing at 60°C for 30 sec and polymerization at 72°C for 60 sec. The polymerization was continued at the end for 10 min at 72°C.
  • the amplified DNA was cloned into pET15b between the sites Nde1 and Xho1 and the recombinant DNA was isolated from E. coli DH5a [Journal of bacteriology, 188:8638, 2006].
  • the PET15b recombinant was transformed in BL21*DE3 for the production of MTCM.
  • the E. coli BL21*DE3 harboring the recombinant plasmid was grown in LB medium supplemented with ampicillin (100 ⁇ g/ml) at 37°C to an A 260 of ⁇ 0.6.
  • MTCM was induced with 30 ⁇ M IPTG at and kept for incubation at 25°C overnight as detailed in the above reference.
  • Example 2 Purification of MTCM Purification of MTCM was carried out according standard procedures [Journal of bacteriology, 188:8638, 2006].
  • the culture was scaled up to 1 liter and the cells were harvested by centrifugation at 4000rpm at 4°C, 15min. The pellet was resuspended in 10ml of 20% sucrose and 30mM TRIS-HCl pH8.0 and 1M EDTA was added to a final concentration of 1mM.
  • the suspension was mixed on a rotary shaker at 150rpm for 10 min at 25°C and centrifuged at 13000rpm for 15 min at 4°C.
  • the cell pellet was suspended in 4ml of ice cold 5mM MgSO 4 and kept on rotary shaker at 150rpm for 10 min at 25°C.
  • the cell suspension was centrifuged at 13000rpm for 15 min at 4°C .
  • the supernatant containing the periplasmic proteins was collected and buffered with 1M TRIS pH8.0 to a final concentration of 30mM [Journal of
  • CM enzyme was based on direct observation of conversion of chorismate to prephenate at OD 274nm [Methods Enzymol.
  • the reaction volume of the assay was maintained as 100 ⁇ l.1mM of the substrate, Chorismic acid (SIGMA cat # 1701) was pre-incubated at 37°C for 5 min in the buffer (containing 50 mMTris-HCl (pH 7.5), 0.5 mM EDTA, 0.1 mg/ml bovine serum albumin, and 10 mM b-Mercaptoethanol).
  • the reaction was started by adding 180pmol of CM enzyme to the prewarmed Chorismic acid solution. Inhibitory screening of the compounds against CM activity was measured at 100nM to 50 ⁇ M concentration of the effectors.
  • the reaction was allowed to proceed at 37°C and was terminated after 5 min with 100 ⁇ l of 1 N HCl. A blank with no enzyme for every reaction was kept as a control to account for the non enzymatic conversion of chorismate to prephenate.
  • Proportion control method of drug susceptibility testing 1. Preparation of bacterial suspension and controls: Pure, luxuriant, fresh culture of lab control,M. tuberculosis H37 Rv on Lowenstein Jensen slant was selected for the experiment. A loopfull of growth representative of as many colonies as possible was suspended in 1ml of sterile distilled water. A uniform suspension of bacterial cells was made by sufficient and gentle vortexing.
  • DC Direct control
  • PC Proportion control
  • Bacterial suspension matched for turbidity to the 0.5 Mc Farlandstandards was considered as the direct growth control and direct control diluted to 1/100 times with sterile distilled water is considered as proportion control.
  • bacteriological medium Medium used: BacT/ALERT ® MP (Biomerieux, Inc. Durham, NC, USA), a ready to use mycobacterial liquid culture medium (10 mL standard volume)
  • Inoculation of DC 0.5ml of DC is inoculated into MP bottle.
  • Reading for mycobacterial positive/negative growth MB/ BacT ® system was automated to read the presence of mycobacterial growth once in every 15 minutes. Positive or negative culture bottles were determined by the decision making software contained in the MB/BacT ® detection system. Reading for positive bottles was given along with the time of detection in days. All positive reading bottles were further tested by ZN smear microscopy and overnight culture on blood agar to rule out contamination. 6. Interpretation of antimycobacterial activity/drug susceptibility
  • Drug containing bottle was not detected positive within 15 days, or had a positive time for detection that was greater than that of the proportion control. Standard upper limit for reading bottles was taken as 15days.
  • Resistant Drug containing bottle was detected positive with time of detection that was equal to or greater than that of the direct control but equal to or less than the proportion controls. Experiment was valid only if the growth in direct and proportion controls occurred within 15 days of incubation.
  • Figures2-6 are 'on-screen' growth curves as shown on the MB/BacT monitor.
  • Unique barcode ID number of the bottle along with the result of positive or negative is provided.
  • X axis denotes the number of days for detection of positive/negative
  • Y axis denotes the number of reflectance units (RLU) as measured by the detection system (cut off is 1800 RLU, anything above is considered positive and indicated in red color on the monitor).
  • RLU is directly proportional and is an approximate indicative of the number of live Mycobacterial cells and their active multiplication.
  • Results show that positive RLU of proportion control started on day 3.6 and reached within 4 days to and maintained at 4000 RLU.
  • Growth curve with Example8(g) compound started on avg 12.4 at 10mM; Growth curve with 10mM drug concentration has reached up to 3500 RLU over a period of about 20days and has never reached the 4000RLU point as shown in the control.
  • Example 8(g) has inhibited the growth with 10mM four times longer. Considering the total drug testing period as 15days, 10mM has shown good inhibition of up to 12 days. Growth curve of proportion control and drugs are showing differences in terms of RLU and start points; clear indication of limited and delayed growth of M.tb cells may be due to the inhibitory activity of the Example 8(g). Isoniazide at con 0.25 mg/mL(approx.. 0.75 mM) and sample 8(g) at 30 mM did not show any growth. Example 5. The Pharmacokinetic properties of Example 8(g)
  • mice The molecule was moderately stable ( ⁇ 35% after 30 min) in mice microsomal stability assay and was highly plasma protein bound ( ⁇ 98%) but stable upto25% even after two hours.
  • the oral PK (30 mg/kg) in mice was also poor ( ⁇ 1mg/ml/hr) and oral
  • Example 7-13 The particle size data of the micelles is depicted in Figures 7-13 and DSC curve of Example 8(g) is shown in Figure 14: Example 7.
  • Example 8(g) shows ⁇ 33 ⁇ gms/ml and ⁇ 66 ⁇ gms/ml of the blood plasma level at 10mg/kg and 30mg/kg dose (Figure 15) respectively in mice which was ⁇ 33 fold and ⁇ 66 fold higher compared to oral PK done at 30mg/kg in mice( ⁇ 1 ⁇ g/ml) and also many fold higher than the IV PK done at 10mg/kg in mice ( ⁇ 4.7 ⁇ g/ml).
  • the IC 50 of the molecule is ⁇ 7.7 ⁇ M and the blood level of the formulated compound is ⁇ 153 ⁇ M(Mol. wt. of Example 8(g)is 430) at 30mg/kg and ⁇ 75 ⁇ Mat 10mg/kg respectively and the levels were much higher than the IC 50 value.
  • Example 8 General method of Synthesis of Compounds of the Invention

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Abstract

La présente invention concerne de nouveaux composés hétérocycliques de formule (I) : leurs dérivés, analogues, formes tautomères, stéréoisomères, bioisostères, diastéréomères, polymorphes, énantiomères, promédicaments et leurs sels pharmaceutiquement acceptables pour le traitement de la tuberculose. L'invention concerne également le procédé de préparation des composés de formule (I), et des intermédiaires utiles pour préparer des composés de formule (I).
PCT/IB2019/056972 2019-05-31 2019-08-19 Préparation de nouvelles 1 h-pyrazolo [4,3-d] pyrimidines, leurs compositions, leur synthèse et leurs procédés d'utilisation pour le traitement de la tuberculose WO2020240272A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2023148767A1 (fr) * 2022-02-01 2023-08-10 Dr Reddy's Institute Of Life Sciences Dérivés de 1h-pyrazolo[4,3-d]pyrimidine utilisés en tant qu'inhibiteurs de staphylococcus aureus
EP4296674A1 (fr) 2022-06-20 2023-12-27 Université Toulouse III - Paul Sabatier Molécules innovantes réduisant la virulence des mycobactéries pour le traitement de la tuberculose

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SUNKE RAJNIKANTH, NALLAPATI SURESH BABU, KUMAR JETTA SANDEEP, SHIVA KUMAR K., PAL MANOJIT: "Use of A1C13 in Friedel Crafts arylation type reactions and beyond: an overview on the development of unique methodologies leading to N-heteroarenes", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 15, no. 19, 2017, pages 4042 - 4057, XP055765753, DOI: 10.1039/c7ob00468k rsc.li/obc *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023148767A1 (fr) * 2022-02-01 2023-08-10 Dr Reddy's Institute Of Life Sciences Dérivés de 1h-pyrazolo[4,3-d]pyrimidine utilisés en tant qu'inhibiteurs de staphylococcus aureus
EP4296674A1 (fr) 2022-06-20 2023-12-27 Université Toulouse III - Paul Sabatier Molécules innovantes réduisant la virulence des mycobactéries pour le traitement de la tuberculose

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