WO2014174457A1 - Analogues d'acide pyrazole carboxylique en tant que candidats médicaments anti-mycobactériens - Google Patents

Analogues d'acide pyrazole carboxylique en tant que candidats médicaments anti-mycobactériens Download PDF

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WO2014174457A1
WO2014174457A1 PCT/IB2014/060936 IB2014060936W WO2014174457A1 WO 2014174457 A1 WO2014174457 A1 WO 2014174457A1 IB 2014060936 W IB2014060936 W IB 2014060936W WO 2014174457 A1 WO2014174457 A1 WO 2014174457A1
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methyl
pyrazole
chlorophenyl
carboxylic acid
dichlorophenyl
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Jayant Maroti GAJBHIYE
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Council of Scientific and Industrial Research CSIR
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to pyrazole carboxylic acid analogues of formula-I as potent anti -mycobacterial drug candidates. Particularly the invention provides novel pyrazole carboxylic acid analogues of formula-I, and pharmaceutically acceptable salts thereof for treatment of mycobacterial infections.
  • BACKGROUND AND PRIOR ART Tuberculosis (TB) is one of the deadliest diseases afflicting centuries. One third of the world's population is infected with TB. In 2011, nearly 9 million people around the world suffered from TB. There were around 1.4 million TB- related deaths worldwide. TB is a leading killer of people who are HIV infected.
  • Anti -tuberculosis drug resistance is a major public health problem that threatens progress made in TB care and control worldwide. Drug resistance arises due to improper use of antibiotics in chemotherapy of drug-susceptible TB patients. This improper use is a result of a number of actions including, administration of improper treatment regimens and failure to ensure that patients complete the whole course of treatment. Essentially, drug resistance arises in areas with weak TB control programmes. A patient who develops active disease with a drug-resistant TB strain can transmit this form of TB to other individuals. Multidrug-resistant (MDR) and extensively drug -resistant (XDR) tuberculosis are generally thought to have high mortality rates.
  • MDR multidrug-resistant
  • XDR extensively drug -resistant tuberculosis
  • Multidrug-resistant is the combination of at least four drugs to which the Mycobacterium tuberculosis isolate is likely to be susceptible.
  • the first group the oral first-line drugs
  • high-dose isoniazid, pyrazinamide, and ethambutol are thought of as an adjunct for the treatment of MDR and XDR tuberculosis.
  • the MDR TB patients with HIV/AIDS lack the immunity to fight the TB infection and are at great risk of developing drug resistance. Therefore research and funding is needed in the diagnosis, prevention and treatment of TB and MDR TB.
  • To combat continuous rise in multi-drug resistant TB scientific efforts are concentrated on inventing new agents for treatment of TB.
  • New drug discovery is a long and tedious process consuming several years and the regulatory approval process following drug discovery involves several tests and trials.
  • it would be highly beneficial and attractive to identify a candidate effective for treatment of TB such that the candidate has been approved as a drug by regulatory authorities. This would enable a quick introduction of the drug into the market for TB treatment.
  • Rimonabant a pyrazole carboxylic acid derivative was withdrawn from market, the reason for the withdrawal was that its benefits did not outweigh the risks. But the fact that it was marketed establishes that it is safe for administration in humans.
  • Rimonabant a pyrazole carboxylic acid derivative was discovered by Sanofi-Synthelabo in 1994 as the first potent, orally active, selective CBl cannabinoid receptor antagonist and sold under several trade names as an anorectic antiobesity drug, but withdrawn from the market due to its side effects. It is an inverse agonist for the cannabinoid receptor CBl . Its main effect is reduction in appetite. Rimonabant was the first selective CBl receptor blocker to be approved for use anywhere in the world.
  • BMI body mass index
  • Pyrazole derivatives are the subject of many research studies due to their widespread potential biological activities such as antimicrobial, antiviral, antitumor, antihistaminic, antidepressant, insecticides and fungicides.
  • WO 2007017125 describes pyrazolinecarboxamides of formula-I as CBl antagonists or inverse antagonists as therapeutical agents for the treatment of inflammation involving gene expression.
  • WO' 125 also describes preparation ofN-piperidinyl-5-(4-chlorophenyl)-l-(2,4-dichiorophenyl)-4,5- dihydropyrazole-3-carboxamide.
  • WO 2007009701 describes use of substituted pyrazole compounds of formula-I for the treatment of cardiovascular risk factors caused by metabolic syndrome in humans and animals
  • ⁇ 1743637 discloses use of substituted pyrazole compounds and combinations thereof for the treatment of metabolic syndrome.
  • Mohamed Jawed Ahsana et al. in European Journal of Medicinal Chemistry, vol 46, (11), Nov 2011, Pg. 5694-5697 discloses synthesis of a series of 3a,4-dihydro-3H- indeno [1,2-c] pyrazole-2-carboxamide analogues and evaluation of antitubercular activity thereof.
  • Rimonabant is an approved drug, with established safety. Rimonabant and its analogues are also shown to have promising activities and also are proved safe to human. Since Rimonabant was recently withdrawn from the market following postmarketing surveillance studies, which confirmed a risk of depressive disorders amongst users, there is need for modification or elimination of the carboxamide side chain, which is responsible for crossing the blood-brain barrier, might reduce these side effects. Therefore, the present inventors have modified the core structure of rimonabant i.e. pyrazole carboxylic acid to obtain a safe, alternative drug candidate for treatment of mycobacterial infections.
  • OBJECT OF THE INVENTION The main object of invention is to provide Pyrazole carboxylic acid analogues for the treatment of Mycobacterium Tuberculosis.
  • Still another object of the present invention is to introduce rimonabant and its analogues as potential drug candidates for treatment of mycobacterial infection.
  • Yet another object of the present invention is to provide a pharmaceutical composition for the treatment of mycobacterial infections in human.
  • the present invention provides the pyrazole carboxylic acid analogues of Formula 1, or stereoisomers, or esters or pharmaceutically acceptable salts thereof, for use as a medicament for treating mycobacterial infections,
  • Y represents heteroatom N, S or O
  • X represents hydrogen, or halogen
  • Ri represents (un)substituted aryl, hydrogen, where substituents are mono, di or tri halogen;
  • R 2 represents OH, (C1-C6) alkyl, (C1-C6) alkoxy, piperidine, 1 -amino piperidine, morpholine, pyridine-4-carbohydrazide, 1-methylpiperazine, 1-methylpiperazine, thiomorpholine, hydrazine, amino acids, Schiff bases, heterocycles;
  • R represents (C1-C4) linear or branched alkyl, hydrogen.
  • the pyrazole carboxylic acid analogues of Formula 1 encompasses the following compounds;
  • the minimum inhibitory concentration (MIC) of the pyrazole carboxylic acid analogues of Formula 1, against Mycobacterium tuberculosis (strain H37Rv) is in the range of 3 to 30 ⁇ g/ml and for Mycobacterium smegmantis the MIC is in the range of 1-35 ⁇ g/ml.
  • a pharmaceutical composition comprising pyrazole carboxylic acid analogues of the Formula I, together with pharmaceutically acceptable excipient(s) and/or vehicle(s), for the treatment of mycobacterial infections in human.
  • the pharmaceutical composition comprising pyrazole carboxylic acid analogues of general formula I, optionally with an additional antitubercular agent together with pharmaceutically acceptable excipient(s) and/or vehicle(s).
  • the Mycobacterium species is selected from the group consisting of Mycobacterium tuberculosis (strain H37Rv) and Mycobacterium smegmatis (strain MC2 155).
  • a method of treating or inhibiting or controlling growth of Mycobacterium species in human comprising administrating pyrazole carboxylic acid analogues of general formula-I, together with pharmaceutically acceptable excipient(s) and/or vehicle(s).
  • Y represents heteroatom N, S or O
  • X represents hydrogen, or halogen
  • Ri represents (un)substituted aryl, hydrogen, where substituents are mono, di or tri halogen;
  • R 2 represents OH, (C1-C6) alkyl, (C1-C6) alkoxy, piperidine, 1 -amino piperidine, morpholine, pyridine-4-carbohydrazide, 1-methylpiperazine, 1-methylpiperazine, thiomorpholine, hydrazine, amino acids, Schiff bases, heterocycles;
  • R represents (C1-C4) linear or branched alkyl, hydrogen.
  • the method of treating or inhibiting or controlling growth of Mycobacterium species in human comprising administrating pyrazole carboxylic acid analogues of general formula- 1, wherein the compounds are selected from the group consisting of ; i. 5 -(4-Chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methyl-N-(piperidin- 1 -yl)-l -H-pyrazole-3 - carboxamide (1)
  • the Mycobacterium species is selected from the group consisting of Mycobacterium tuberculosis (strain H37Rv) and Mycobacterium smegmatis (strain MC2 155).
  • the invention provides the pyrazole carboxylic acid analogues of Formula 1 or stereoisomers, or esters or pharmaceutically acceptable salts thereof, for use as a medicament for mycobacterial infections,
  • Y represents heteroatom N, S or O
  • X represents hydrogen, halogen
  • Ri represents (un)substituted aryl, hydrogen, where substituents are mono, di or tri halogen;
  • R 2 represents OH,(Cl-C6)alkyl, (C1-C6) alkoxy, piperidine, 1 -amino piperidine, morpholine, pyridine-4- carbohydrazide, 1-methylpiperazine, 1-methylpiperazine,
  • R represents (C1-C4) linear or branched alkyl, hydrogen.
  • the pyrazole carboxylic acid analogues of Formula 1, having anti-mycobacterial activity encompass the compounds as listed in table 1.
  • the anti-mycobacterial pyrazole carboxylic acid analogues of Formula- 1 are selected from the group consisting of;
  • the initial studies involved screening of Rimonabant (1) against Mycobacterium smegmatis, which showed a MIC value 13.56 ⁇ g/ml. Therefore, its 18-analogues were synthesized and few of them were screened against Mycobacterium smegmatis. They showed moderate to excellent activity (Table 1). Similarly Rimonabant and all the synthesized analogues were then screened for anti-bacterial activity against Mycobacterium tuberculosis (virulent strain H37Rv) in vitro. The precursor of Rimonabant, acid 2 showed improved MTB activity and ester 3 retains the activity as compared to Rimonabant.
  • analogues 2, 4, 7, 11 & 15-18 showed enhanced activity and the analogues 3, 5, 6, 8, 10, 12 & 19 retains the activity.
  • the analogues 9 and 13 showed drastic increase in MTB activity.
  • the analogue 14 came out to be a promising lead with highest activity. Compared with one of the first line anti-TB drug Ethambutol (MIC 3.25 ⁇ g/ml), the analogue 14 was found to be equally active. When compared to Pyrazinamide (MIC 50.0 ⁇ g/ml) all the 18 analogues were found to be more potent.
  • the analogue 13 was a simplified lead molecule. Based on the analogue 9, a simple replacement of chlorine by hydrogen might provide a more active analogue of 13.
  • the anti- mycobacterial activity of compounds of Formula-I against mycobacterial species is measured in the range of 1 to 50 ⁇ g/ml, particularly anti -mycobacterial activity against Mycobacterium tuberculosis (strain H37Rv) is evaluated in the range of 3 to 30 ⁇ g/ml and for Mycobacterium smegmantis the MIC is calculated in the range of 1-35 ⁇ g/ml,
  • the invention provides, novel pyrazole carboxylic acid analogues of Formula 1 having anti-mycobacterial activity as disclosed in above Table 1,
  • Y represents heteroatom N or O
  • Ri represents phenyl, 2-4 dichlorophenyl, 2-4 difluorophenyl
  • R 2 represents OH, ethyl, piperidine, 1-aminopiperidine, pyridine-4-carbohydrazide, 1- methylpiperazine; and R represents methyl, hydrogen.
  • novel anti-mycobacterial agents of formula-I are selected from the group consisting of;
  • the pyrazole carboxylic acid analogues of Formula 1 is Rimonabant or 5 -(4-Chlorophenyl)- 1 -(2,4-dichloro-phenyl)-4-methyl-N-(piperidin- 1 -yl)- lH-pyrazole-3 - carboxamide, wherein the minimum inhibitory concentration of Rimonabant against Mycobacterium smegmatis is 13.56 ⁇ g/ml and against Mycobacterium tuberculosis 25 ⁇ g/ml.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula 1, or its stereoisomers, esters or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier(s), diluent(s) vehicle(s), and/or excipient(s).
  • the compound of formula 1 disclosed herein is present in the composition in an amount which is effective to treat the disease or the condition caused by the bacterial strains mentioned above.
  • compositions of the invention can be prepared by combining compounds of Formula-I with appropriate pharmaceutically acceptable carriers, diluents or excipients, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels and microspheres.
  • the present invention relates to administering 'an effective amount' of the 'composition of invention' to the subject suffering from said disease.
  • compound of Formula 1 and pharmaceutical compositions containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease.
  • Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
  • compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a subject or patient may take the form of one or more dosage units.
  • the dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms.
  • excipients or carriers are selected from the group such as diluents, disintegrants, crosslinked polymers, binders, lubricants, coatings layer.
  • synergistic effect of instant pharmaceutical composition can be achieved in combination with additional known anti-tubercular drugs such as Rifampcin, Ethambutol, Pyrazinamide.
  • the invention provides a method of treating or inhibiting growth of a bacteria preferably Mycobacterium smegmatis and Mycobacterium tuberculosis in a subject (i.e. human or animal) comprising administrating anti-mycobacterial compounds of Formula-I, optionally with at least one additional active compound or anti-tubercular agent together with pharmaceutically acceptable excipients and/or vehicles.
  • the invention provides pyrazole carboxylic acid compounds of Formula-I for use in treating or inhibiting growth of a bacteria preferably Mycobacterium smegmatis and Mycobacterium tuberculosis in a subject.
  • a bacteria preferably Mycobacterium smegmatis and Mycobacterium tuberculosis.
  • the subject according to the invention is an animal or human.
  • the invention furnishes pyrazole carboxylic acid compounds of Formula-I for the preparation of medicament useful for treating or inhibiting the growth of Mycobacterium smegmatis and Mycobacterium tuberculosis in human.
  • Anti- mycobacterial activity assay Mycobacterium smegmatis MC 2 155 strain
  • Anti-mycobacterial activity of the compounds was performed with Mycobacterium smegmatis MC 2 155 strain by performing a growth inhibition assay by agar dilution followed turbidometry method. The assay was semi -throughput and conducted in a 96 well plate (sterile). Isolated single colonies of M. smegmatis MC 2 155 (ATCC 14468) grown on 7H10 agar plate were grown overnight in Middlebrook 7H9 medium (0.47% Middlebrook 7H9 broth base, 10% ADS, 0.2% glycerol, and 0.1% Tween-80) to mid exponential phase inoculated in 5 ml Middlebrook 7H9 medium.
  • Middlebrook 7H9 medium 0.47% Middlebrook 7H9 broth base, 10% ADS, 0.2% glycerol, and 0.1% Tween-80
  • the secondary culture was incubated overnight and allowed to grow at 37°C to early log phase (OD 60 o 3 ⁇ 4 0.3).
  • 98 ⁇ of l 1000-folds dilution of secondary culture was dispensed into 96-well microtiter plate per well along with 2 ⁇ 1 of test compound in triplicate.
  • 240 ⁇ of sterile water were added to each well of the peripheral rows of 96-well plate to minimize media evaporation during assay incubation.
  • the final concentration of the test compound (Rimonabant) in each well was 30 ⁇ .
  • MIC / Minimum Inhibitory Concentration is that concentration of compound which inhibits the 90 % growth of bacteria under optimum conditions.
  • the growth inhibition assays were carried out in the same analogy as explained above various concentrations of the test compounds prepared by serial dilutions 100 ⁇ , 50 ⁇ , 25 ⁇ , 12.5 ⁇ and 6.25 ⁇ (DMSO as solvent) to obtain the final concentrations of 46.37 ⁇ g/ml, 23.18 ⁇ g ml, 11.59 ⁇ g/ml, 5.79 ⁇ g/ml, 2.89 ⁇ g/ml respectively. From the rate of inhibition bacterial growth, the ascertained MIC of the compound was calculated.
  • the MIC value of the test compound JMG 005 i.e. Rimonabant is 13.56 ⁇ (29.24 ⁇ ⁇ 1.47).
  • the minimum inhibitory concentration (MIC) is defined as the minimum concentration of the compound required to completely inhibit the bacterial growth. Rifampicin, Ethambutol and Pyrazinamide were used as reference compounds. This method is similar to that recommended by the National Committee for Clinical Laboratory Standards 11 for the determination of minimum inhibitory concentration (MIC) in triplicate.
  • Compound 4 was synthesized from 2 according to the procedure applied to 1.
  • Compound 5 was synthesized from 2 according to the procedure applied to 1.
  • Compound 6 was synthesized from 2 according to the procedure applied to 1.
  • Compound 10 was synthesized from 9 according to the procedure applied to 1.
  • Compound 11 was synthesized by the procedure applied to 2.
  • Compound 12 was synthesized by the procedure applied to 2.
  • Compound 14 was synthesized from 7 according to the procedure applied to 1.
  • Com pound 15 was synthesized from 12 according to the procedure applied to 1.
  • Compound 16 was synthesized from 13 according to the procedure applied to 1.
  • Compound 18 was synthesized from 9 according to the procedure applied to 1.
  • Mode of administration Disperse the powder in water/juice.
  • Example 21 Rimonabant (1) Composition:
  • Mode of administration Disperse the powder in water/juice.
  • Example 22 Composition:
  • Mix active ingredient (JMG-14) and Magnesium stearate may be filled in a capsule of suitable size.
  • the capsule may be had with water of juice
  • Example 23 Composition:
  • Mix active ingredient (JMG-14) and Magnesium stearate may be filled in a capsule of suitable size.
  • the capsule may be had with water of juice
  • Example 24 Composition:
  • Mix active ingredient (Compound-11) and Magnesium stearate may be filled in a capsule of suitable size.
  • the tablet may be had with water of juice
  • Example 25 Composition:
  • the tablet may be had with water of juice
  • Example 26 Composition:

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Abstract

La présente invention concerne des analogues d'acide pyrazole carboxylique de Formule 1 ou des stéréo-isomères, ou des esters ou des sels pharmaceutiquement acceptables de ceux-ci, en tant qu'agents anti-mycobactériens puissants. L'invention concerne en outre la composition pharmaceutique comprenant les composés de Formule I pour le traitement d'infections mycobactériennes.
PCT/IB2014/060936 2013-04-23 2014-04-23 Analogues d'acide pyrazole carboxylique en tant que candidats médicaments anti-mycobactériens Ceased WO2014174457A1 (fr)

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WO2020103856A1 (fr) * 2018-11-20 2020-05-28 Shanghaitech University Inhibiteurs de mmpl3, compositions et utilisations associées
RU2795229C2 (ru) * 2018-11-20 2023-05-02 Шанхайтек Юниверсити Ингибиторы mmpl3, композиции на их основе и пути их применения
CN120025297A (zh) * 2025-02-26 2025-05-23 和径医药科技（上海）有限公司 分枝杆菌膜蛋白MmpL3抑制剂、其药物组合物及应用

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020103856A1 (fr) * 2018-11-20 2020-05-28 Shanghaitech University Inhibiteurs de mmpl3, compositions et utilisations associées
CN113166068A (zh) * 2018-11-20 2021-07-23 上海科技大学 MmpL3抑制剂、组合物及其用途
RU2795229C2 (ru) * 2018-11-20 2023-05-02 Шанхайтек Юниверсити Ингибиторы mmpl3, композиции на их основе и пути их применения
US11655238B2 (en) 2018-11-20 2023-05-23 Shanghaitech University MMPL3 inhibitors, compositions and uses thereof
RU2795229C9 (ru) * 2018-11-20 2023-05-30 Шанхайтек Юниверсити Ингибиторы mmpl3, композиции на их основе и пути их применения
CN113166068B (zh) * 2018-11-20 2024-08-16 上海科技大学 MmpL3抑制剂、组合物及其用途
CN120025297A (zh) * 2025-02-26 2025-05-23 和径医药科技（上海）有限公司 分枝杆菌膜蛋白MmpL3抑制剂、其药物组合物及应用

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