US20090054501A1 - Azole compounds used as tuberculostatic and leishmanicide agents - Google Patents

Azole compounds used as tuberculostatic and leishmanicide agents Download PDF

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US20090054501A1
US20090054501A1 US12/064,241 US6424106A US2009054501A1 US 20090054501 A1 US20090054501 A1 US 20090054501A1 US 6424106 A US6424106 A US 6424106A US 2009054501 A1 US2009054501 A1 US 2009054501A1
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triazole
imidazole
fluorobenzoic
carboxylate
amino
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Nubia Boechat
Marilia dos Santos Costa
Maria Cristina da Silva Lourenco
Ivan Neves Jr
Marcelo da Silva Genestra
Vitor Francisco Ferreira
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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
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention refers to azole compounds pertaining to the 1,2,3-triazole and imidazole classes that can be used to treat tuberculosis and leishmaniasis, with the advantage of having high activity against microorganisms, more specifically against Mycobacterium tuberculosis and protozoa of Leishmania gender, agents that cause these diseases, as well as their salts, its stereoisomeric forms, racemic mixtures, pro-drugs, their metabolites; as well as pharmacological compositions containing at least one of these compounds or their salt as an active principle and to the use of such compositions as drugs to treat or inhibit diseases.
  • this invention also includes a treatment method or inhibition of tuberculosis and leishmaniasis, with the advantage of presenting a high activity against microorganisms, more specifically against Mycobacterium tuberculosis and protozoa of the Leishmania gender, comprising the administration of a pharmacologically effective quantity of at least one of these compounds or their salt, to the living being that needs the referred treatment or inhibition.
  • Neglected diseases is the classification attributed to diseases that do not present a satisfactory treatment, do not create interest in pharmaceutical industries and, besides that, government funding is insufficient to fight these kinds of diseases.
  • Tuberculosis, HIV/Aids and malaria are examples of neglected diseases, because although they affect individuals from developed countries, they mainly afflict populations of countries in development and they create only a peripheral interest from the pharmaceutical market.
  • the lack of investment from pharmaceutical industries in the development of new drugs for certain diseases is directly connected to the low capacity of purchase of populations of countries in development.
  • Tuberculosis is an infectious disease transmitted through the airway by a bacterium called Mycobacterium tuberculosis , also known as Koch bacillus in honor of the scientist Robert Koch, who isolated it in 1882.
  • Mycobacterium tuberculosis also known as Koch bacillus in honor of the scientist Robert Koch, who isolated it in 1882.
  • There are several forms of tuberculosis lung, meningeal, milliary, bone, renal, cutaneous, genital, etc), however, the most frequent form and the most contagious one is the pulmonary.
  • a patient with pulmonary tuberculosis, if not treated, can infect from 10 to 15 persons in a year.
  • tuberculosis From reports of the presence of fragments of the bacillus in Egyptian mummies in 2400 B.C., tuberculosis presently infects approximately one third of the world population and it is the main cause of death in countries in development. We estimate that 70% of the population in destitute countries is infected by the Koch bacillus , and every year, 7.5 million new cases are reported and 2.8 million of deaths. The high rate of incidence of the disease in these is closely connected to the precarious life conditions of the population. In India, for instance, which holds 15% of global populations, approximately 30% of the population is infected by the M. tuberculosis and tuberculosis kills 14 times more people than all tropical diseases.
  • HIV infection is one of the most significant risk factors known for tuberculosis infection.
  • TBMR multidrug-resistant tuberculosis
  • Tuberculosis is a serious disease, but it is curable in practically 100% of new cases, as long as modern chemotherapy principles are followed, the adequate association of drugs and their regular use, for sufficient time are the necessary means to avoid bacterial resistance and persistence.
  • SM streptomycin
  • R CHO
  • SM administered in higher doses can affect the central and peripheral nervous systems.
  • PAS p-amino-salicylic acid
  • INH (Formula III) is active orally and besides exhibiting a bacteriostatic action against the bacillus , it is highly active against the M. avium complex. Its minimum inhibitory concentration (MIC) is very low (0.02-0.06 ⁇ g/mL) fact that contributes to its efficacy.
  • rifampicin (Formula IV, which is part of a semi-synthetic antibiotics group derived from rifamicin B, insulated from Streptomyces mediterrani, is extremely effective against M. tuberculosis , with a MIC of 0.1 ⁇ g/mL to 1.0 ⁇ g/mL, and it presents a quick bactericide action in the elimination of persistent bacteria.
  • rifampicin (Formula IV) is the drug chosen to treat patients co-infected by TB/HIV.
  • rifampicin as other by products of this class, presents a significant pharmaceutical interaction with several of the anti-retroviral, especially with protease inhibitors that have their concentration decreased by the inducing action of rifampicin.
  • EMB ethambutol
  • Figure VII Other significant drug used in treating tuberculosis, since 1968, is ethambutol (EMB) (Figure VII) which is active against many variables of Mycobacterium .
  • EMB is a synthetic amino alcohol, firstly synthesized in 1960, with enantiomer as its stereo specific activity (Figure VII) with S,S configuration is the isomer that shows a tuberculostatic action, as the enantiomer R,R presents an undesirable action, since it causes blindness.
  • Drugs used in the tuberculosis can be classified as first line and second line drugs.
  • First line drugs are part of the TB primary treatment plan and consist of the four medications previously mentioned isoniazide, rifampicin, pyrazinamide and ethambutol. The adequate treatment of patients with combinations of these agents during long periods (six to nine months) leads to cure in 95% of TB cases.
  • drugs used in the second chemotherapy plan are: Thiacetazone, D-cycloserine, clofazimine, terizidone, kanamycin and amicacin.
  • Leishmaniasis depicts a complex of diseases with a significant clinical and epidemiological diversity. Caused by approximately 20 species of protozoa of the Leishmania gender, it is transmitted to men by the sting of the female mosquito of the Phebotomine species in Europe and of the Lutzomyia species in South and Central America.
  • the diseases present two clinical forms: integumental leishmaniasis and visceral leishmaniasis.
  • the Cutaneous Leishmaniasis (LC) is the most common of the manifestations and it is characterized by ulcerative nodular lesions. The onset of lesions appears where the vector insect stung, thus being more frequent in body areas exposed, for instance, limbs and face. The incubation period between the sting and the onset of the lesion can vary from a few weeks to months.
  • the cutaneous leishmaniasis disseminated (LCD) is characterized by multiple and small lesions, with or without central ulceration, sometimes with an acneiform aspect.
  • the diffuse form is a rare form of the disease detected in some of the Brazilian states, such as Maranhao, Para, Bahia and Mato Grosso.
  • the drugs presently recommended for the treatment of leishmaniasis are the pentavalent—the sodium stibogluconate (Pentostam®), the meglumine antimoniate(Glucantime®), the pentamidine and the amphotericin B and its three lipidic formulations—a liposomal amphotericin B, colloidal dispersion amphotericin B and a lipidic complex amphotericin B.
  • Pentamidine was introduced in 1952 in therapy and even today it used as a third choice drug. Its use as a leishmanicide agent is restricted due to its high toxicity that can cause adverse effects such as nausea, vomiting, headache, hypoglycemia and sudden death.
  • X is an atom of “C” or “N” when X is “N” radicals of the triazole ring are represented by:
  • R 1 COR 2 , CSR 3 , CN(R 4 ) R 5 or CF 2 R 6 ;
  • R 2 H, NHNH 2 , alkyl, aryl substituted or not, OH, NR 7 R 8 or OR 9
  • R 3 alkyl or aryl substitute or not
  • R 4 H, OH, alkyl or aryl substituted or not
  • R 2 NHNH 2 , OH, OR 3 , or NR 4 R 5
  • R 3 alkyl or aryl substituted or not
  • R 10 NHR 6 or NR 6 R 7
  • R 8 aryl substituted or not while radical R n can be located in any one or in more than one of the carbon atoms of the aromatic ring, and these radicals can be equal or different, represented by hydrogen, alkylic groups with 1 or more carbon atoms in a linear or branched chain alkenes or alkynes, hydroxyl, hydroxyalkyl or oxygenated functions in acyclic or cyclic systems forming an heterocyclic ring, free or substituted amines, thioalkyl, donators and/or removing groupings of electrons or halogens, thus “n” can vary from 1 to 5.
  • Another objective of this invention refers to the pharmaceutical composition comprising, as active principle, at least one of the 1,2,3-triazole and/or imidazole compounds represented by the general formula VIII.
  • Another objective of this invention is related to the use of such compositions as drugs to treat or inhibit tuberculosis and leishmaniasis.
  • Another objective of this invention refers to a method for treating or inhibiting tuberculosis and leishmaniasis.
  • the compounds 1,2,3-triazole and imidazole of formula VIII can be under the form of salts, stereoisomeric forms, racemic mixtures, pro-drugs and metabolites, and can be used as tuberculostatic and leishmanicide agents, to treat tuberculosis and leishmaniasis, with the advantage of presenting high activity against microorganisms.
  • This invention refers to the new 1,2,3-triazole and imidazole compounds included in the family of compounds represented by general formula VIII
  • X is an atom of “C” or “N” when X is “N” the radicals of the triazole ring is represented by:
  • R 1 COR 2 , CSR 3 , CN(R 4 )R 5 or CF 2 R 6 ;
  • R 2 H, NHNH 2 , alkyl, aryl substituted or not, OH, NR 7 R 8 or OR 9
  • R 3 alkyl or aryl substituted or not
  • R 4 H, OH, alkyl or aryl substituted or not
  • R 2 NHNH 2 , OH, OR 3 , or NR 4 R 5
  • R 3 alkyl or aryl substituted or not
  • R 10 NHR 6 or NR 6 R 7
  • R 8 aryl substituted or not
  • radical R n can be located in any one or in more than one of the carbon atoms of the aromatic ring, and these radicals can be equal or different, represented by hydrogen, alkylic groups with 1 or more carbon atoms in a linear or branched chain alkenes or alkynes, hydroxyl, hydroxyalkyl or oxygenated functions in acyclic or cyclic systems forming an heterocyclic ring, free or substituted amines, thioalkyl, donators and/or removing groupings of electrons or halogens, thus “n” can vary from 1 to 5.
  • compounds 1,2,3-triazole can be selected among:
  • imidazole compounds they can be preferably selected among:
  • Imidazole compounds presented in this invention can be synthesized according to processes known by experts in this area, as described in articles “Wamhoff, H.; Berressem, R.; Herrmann, S.; Heterocyclishe ⁇ - Enaminoester; 55 . Imidazo[ 4,5- d ]-, Thiazolo[ 5,4- d ]- und Thiazolo[ 4,5-d][1,3]oxazinone; Synthesis, 1993, 107-111” and “Jakobsen, Palle; Horneman, A.
  • compositions containing at least one 1,2,3-triazole and/or imidazole compounds of this invention, or a salt of it can be administered in the pharmaceutical form of solution, suspension, emulsion, ointment, cream, gel, tablet or capsule, oral, injection or topic use, prepared as of powder, solution or suspension of at least one of the compounds in an adequate concentration, and in a vehicle pharmaceutically acceptable, in order to create the adequate dosage form.
  • These compositions are employed in the treatment or inhibition of tuberculosis and leishmaniasis.
  • FIG. 1 Essay of antimicrobial activity of compounds 1,2,3-triazole type I and II
  • FIG. 2 Specific of proton RMN of derivatives 1,2,3-triazole 114i (type I) and 121i (type II).
  • FIG. 3 Specific of proton RMN derivatives 1, 2, 3-triazole 119 (type III).
  • FIG. 4 Specific of proton RMN derivatives imidazole 145d (di-substituted) and 149d (mono-substituted).
  • Type I and II 1,2,3-triazole derivatives were submitted to a primary biological evaluation, in vitro, regarding the inhibitory activity of the Mycobacterium tuberculosis H37Rv (ATCC-27294).
  • MABA Microplate Alamar Blue Assay
  • MABA Microplate Alamar Blue Assay
  • This method consists in an essay performed by the micro dilution in plates, using, as cell growth indicator, the Alamar Blue® indicator pigment, which is a fluorescent/colorimetric indicator with redox property.
  • the oxidized form is blue (non-fluorescent) and indicates the absence of bacterial growth.
  • the reduced form presents a pink color (fluorescent), indicates the proliferation of bacteria.
  • This methodology has been applied to determine the resistance profile of microbacteria to antimicrobials ( FIG. 1 ).
  • sterile micro plates with 96 wells were used in a way that each wells presented a total of 200 ⁇ L of a mixture composed by the adequate culture mean, of the compound to be tested and of the bacterial suspension.
  • the comparison pattern used was rifampicin, which presents a MIC equal to 1.0 ⁇ g/mL.
  • Table 2 shows the values defined for MIC, in ⁇ g/mL, and the inhibition percentage presented by each substance.
  • Table 2 Antimicrobial activity of type I and II compounds against M. tuberculosis H37Rv (ATCC 27294)
  • Type MIC Inhibition R I ( ⁇ g/mL) (%) II ( ⁇ g/mL) (%) 4-Cl 114a 5,0 na* 121a 40,0 nd 4-Br 114b 5,0 100 121b 20,0 75 4-CH 3 114c 2,5 100 121c 40,0 87 4-OCH 3 114d 10,0 100 121d 10,0 93 2,5- 114e 80,0 59 121e 80,0 74 di(OCH 3 ) 3-Cl 114f 10,0 100 121f 80,0 54 3,5-di (Cl) 114g 2,5 na 121g 80,0 55 3-CN 114h 20,0 na 121h 80,0 na 4-CN 114i 5,0 na 121i 20,0 na 4-NO 2 114j 20,0 na 121j 40,0 na 2-OCH 3 114l 40,0 94 121l 40,0 86 3,4- 114
  • the evaluation of the leishmanicide activity of the type I and II 1,2,3-triazole derivatives was made through in vitro essays against promastigote forms of Leishmania amazonensis , and after the incubation with compounds, live parasites are counted by fluorescence, thus obtaining as a result, the percentage of inhibition of the compounds evaluated.
  • the gem-difluormethyl 121f derivative Compared to pentamidine, which in a 1 60 ⁇ g/mL concentration presents an inhibition percentage of 53%, with the most active compound, the gem-difluormethyl 121f derivative with an inhibition percentage of 93% in a 10.0 ⁇ g/mL concentration.
  • 114f derivative, precursor of 121f also presented activity against the promastigote forms, with an inhibition percentage of 72%, however in a concentration superior to the pattern (pentamidine).
  • derivative 114j presented an inhibition percentage 11% lower than pentamidine with the same 160.0 ⁇ g/mL concentration and o 1211 did not present activity against the protozoa.
  • the derivate (114a) was prepared with 75.0% of output, as of the reaction of the diazomalonaldehyde with the 4-chloroaniline chloride, thus obtaining an amorphous white solid with fusion point at 159.0-161.0° C.
  • the derivative (114b) was prepared with 76.0% of output, as of the reaction of the diazomalonaldehyde with the 4-bromoaniline chloride, thus obtaining an amorphous white solid with fusion point at 190.0-191.0° C.
  • the derivative (114c) was prepared with 86.0% of output, as of the reaction of the diazomalonaldehyde with 4-methylaniline chloride, thus obtaining an amorphous white solid with fusion point at 105.0-106.0° C.
  • the derivative (114d) was prepared with 76.0% of output, as of the reaction of the diazomalonaldehyde with the 4-metoxyaniline chloride, thus obtaining an amorphous white solid with fusion point at 158, 6-161° C.
  • the derivative (114e) was prepared with 73.0% of output, as of the reaction of diazomalonaldehyde with the 2,5-dimethoxyaniline chloride (114e), thus obtaining an amorphous yellow solid with fusion point at 89.3-89.8° C.
  • the derivative (114f) was prepared with 73.0% of output, as of the reaction of diazomalonaldehyde with the 3-chlorideaniline chloride, thus obtaining an amorphous yellow solid with fusion point at 129.4-130.5° C.
  • the derivative (114g) was prepared with 73.0% of output, as of the reaction of diazomalonaldehyde with the 3,5-dichlorideaniline chloride, thus obtaining an amorphous white solid with fusion point at 156.0-157.0° C.
  • the derivative (114h) was prepared with 80.0% of output, as of the reaction of diazomalonaldehyde with the chloride of 3-cyanoaniline, thus obtaining an amorphous white solid with fusion point at 177.7-179.8° C.
  • the derivative (114i) was prepared with 75.0% of output, as of the reaction of diazomalonaldehyde with the 4-cyanoaniline chloride, thus obtaining an amorphous white solid with fusion point at 178.9-179.6° C.
  • the derivative (114j) was prepared with 80.0% of output, as of the reaction of diazomalonaldehyde with the 4-nitroaniline chloride (114j), thus obtaining an amorphous yellow solid with fusion point at 185.0-186.0° C.
  • the derivative (1141) was prepared with 66.0% of output, as of the reaction of diazomalonaldehyde with the 2-methoxyaniline chloride, thus obtaining an amorphous yellowish solid with fusion point at 108.0-109.5° C.
  • the derivative (114m) was prepared with 80.0% of output, as of the reaction of diazomalonaldehyde with the 3,4-dimethoxyaniline chloride, thus obtaining an amorphous yellow solid with fusion point at 170.0-171.0° C.
  • the derivative 121a was prepared with 95.0% of output, as of the reaction of fluoridation of the derivative 4-carboxaldehyde-1-(4-chlorophenyl)-1H-1,2,3-triazole (114a) with the diethylamino sulphur trifluoride, DAST, obtaining a white solid with fusion point of 122.0-124.0° C.
  • the derivative 121b was prepared with 95.0% of output, as of the reaction of the fluoridation of the derivative 4-carboxaldehyde-1-(4-bromophenyl)-1H-1,2,3-triazole (114b) with the diethylamino sulphur trifluoride, DAST, thus obtaining a white solid with fusion point at 141.0-144.0° C.
  • the derivative (121c) was prepared with 93.0% of output, as of the reaction of fluoridation of the derivative 4-carboxaldehyde-1-(4-methylphenyl)-1H-1,2,3-triazole (114c) with the diethylamino sulphur trifluoride DAST, thus obtaining a white solid with fusion point at 96.5-97.5° C.
  • the derivative 121d was prepared with 97.0% of output, as of the fluoridation reaction to the derivative 4-carboxaldehyde-1-(4-methoxyphenyl)-1H-1,2,3-triazole (114d) with the diethylamino sulphur trifluoride, DAST, thus obtaining a white solid with fusion point at 98.2-100.0° C.
  • the derivative 121e was prepared with 98.0% of output, as of the fluoridation reaction to the derivative 4-carboxaldehyde-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole (114e) with the diethylamino sulphur trifluoride, DAST, thus obtaining a white solid with fusion point at 78.0-79.0° C.
  • the derivative 121f was prepared with 93.0% of output, as of the reaction of fluoridation to the derivative 4-carboxaldehyde-1-(3-chlorophenyl)-1H-1,2,3-triazole (114f) with the diethylamino sulphur trifluoride, DAST, thus obtaining a white solid with fusion point at 57.6-58.2° C.
  • the derivative 121g was prepared with 98.0% of output, as of the reaction of fluoridation to the derivative 4-carboxaldehyde-1-(3,4-dichlorophenyl)-1H-1,2,3-triazole (114 g) with the diethylamino sulphur trifluoride, DAST, thus obtaining a white solid with fusion point at 83.0-85.0° C.
  • the derivative 121h was prepared with 97.0% of output, as of the reaction of fluoridation to the derivative 4-carboxaldehyde-1-(3-cyanophenyl)-1H-1,2,3-triazole (114h) with the diethylamino sulphur trifluoride, DAST, thus obtaining a white solid with fusion point at 119.0-120.0° C.
  • the derivative 121i was prepared with 98.0% of output, as of the reaction of fluoridation to the derivative 4-carboxaldehyde-1-(4-cyanophenyl)-1H-1,2,3-triazole (114i) with the diethylamino sulphur trifluoride, DAST, thus obtaining a white solid with fusion point at 126.0-128.0° C.
  • the derivative (121j) was prepared with 93.0% of output, as of the reaction of fluoridation to the derivative 4-carboxaldehyde-1-(4-nitrophenyl)-1H-1,2,3-triazole (114j) with the diethylamino sulphur trifluoride, DAST, thus obtaining an amorphous yellow solid with fusion point at 161.0-163.0° C.
  • the derivative 121l was prepared with 96.0% of output, as of the reaction of fluoridation to the derivative 4-carboxaldehyde-1-(2-methoxyphenyl)-1H-1,2,3-triazole (114l) with the diethylamino sulphur trifluoride, DAST, thus obtaining a white solid with fusion point at 65.0-66.0° C.
  • the derivative 121m was prepared with 95.0% of output of the reaction of fluoridation of the derivative 4-carboxaldehyde-1-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole (114m) with the diethylamino sulphur trifluoride, DAST, thus obtaining a white solid with fusion point at 62.5-63.5° C.
  • the derivative (119) was prepared with 73.0% of output, as of the reaction of diazomalonaldehyde with p-chlorideaniline, in an acid environment, thus obtaining an amorphous yellow solid with fusion point at 208° C.
  • the derivative (120) was prepared with 80.0% of output, as of the reaction of diazomalonaldehyde with the p-bromoaniline, in an acid environment, thus obtaining an amorphous yellow solid with fusion point at 208-210.0° C.
  • the imidazole derivatives with general formula XII and XIII were submitted to a primary biological evaluation, in vitro, regarding the inhibitory activity of Mycobacterium tuberculosis H37Rv (ATCC-27294).
  • MABA Microplate Alamar Blue Assay
  • sterile micro plates with 96 wells were used in a way that each well presented a total of 200 ⁇ L of a mixture composed by the adequate culture mean, of the compound to be tested and of the bacterial suspension.
  • the comparison pattern used was rifampicin, which presents a MIC equal to 1.0 ⁇ g/mL.
  • table 4 there is a list of the values assessed for MIC, ⁇ g/mL, of 146a, 140b, 146c and 146e derivatives.
  • the derivative 140a was obtained with 81% of output in the form of colorless crystals with fusion point at 203-205° C.
  • the derivative 140b was obtained with 87% of output in the form of colorless crystals with fusion point at 206-208° C.
  • the derivative 140c was obtained with 87% of output in the form of colorless crystals with fusion point at 225-227° C.
  • the derivative 140d was obtained with 78% of output in the form of colorless crystals with fusion point at 140-142.0° C.
  • the derivative 140d was obtained with 77% of output in the form of colorless crystals with fusion point at 178-181.0° C.
  • the derivative 146a was obtained with 83% of output in the form of transparent crystals with fusion point at 176.5° C.
  • the derivative 146c was obtained with 80% of output in the form of transparent crystals with fusion point at 199-200.0° C.
  • the derivative 146d was obtained with 83% of output in the form of transparent crystals with fusion point at 140-142.0° C.
  • the derivative 146e was obtained with 80% of output in the form of transparent crystals with fusion point at 178-181.0° C.
  • the derivative 148a was obtained with 74% of output in the form of crystals shaped as colorless needles with fusion point at 183-185.0° C.
  • the derivative 148b was obtained with 73% of output in the form of colorless crystals with fusion point at 223-224.0° C.
  • the derivative 148c was obtained with 75% of output in the form of crystals with fusion point at 174-177° C.
  • the derivative 148d was obtained with 77% of output in the form of crystals with fusion point at 141-142.0° C.
  • the derivative 148e was obtained with 77% of output in the form of crystals with fusion point at 179.0° C.
  • the derivative 149a was obtained with 76% of output in the form of crystals with fusion point at 166.0-167.0° C.
  • the derivative 149a was obtained with 80% of output in the form of crystals with fusion point at 171.0-172.0° C.
  • the derivative 149c was obtained with 74% of output in the form of crystals with fusion point at 156.0-157.0° C.
  • the derivative 149d was obtained with 80% of output in the form of crystals with fusion point at 76.0-77.0° C.
  • the derivative 149e was obtained with 75% of output in the form of transparent crystals with fusion point at 184.0° C.

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US12/064,241 2005-08-19 2006-08-21 Azole compounds used as tuberculostatic and leishmanicide agents Abandoned US20090054501A1 (en)

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US20130156827A1 (en) * 2010-07-09 2013-06-20 Xinjian Li Sodium alginate crosslinked slow-release moxifloxacin microsphere, the preparation method and the use thereof, and target vascular occlusive agent of the microsphere

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BRPI0503681A (pt) * 2005-08-19 2007-04-10 Fundacao Oswaldo Cruz compostos azóis usados como agentes tuberculostáticos e leishmanicidas, composições farmacêuticas contendo os mesmos, uso das respectivas composições farmacêuticas no tratamento ou inibição de doenças, bem como método de tratamento ou inibição de doenças
WO2017165139A1 (en) * 2016-03-25 2017-09-28 St. Jude Children's Research Hospital 1,4,5-substituted 1,2,3-triazole analogues as antagonists of the pregnane x receptor
EP3502109A1 (en) * 2017-12-20 2019-06-26 Consejo Superior De Investigaciones Científicas Triazole-phenyl-thiazole heterocycles as innovative inhibitors of trypanothione reductase and their use as leishmanicides
US20260092058A1 (en) 2024-09-30 2026-04-02 St. Jude Children's Research Hospital, Inc. Small Molecule Degraders and Fluorescent Probes of PXR

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US20050261333A1 (en) * 2002-08-14 2005-11-24 Astrazeneca A B Use of and some novel imidazopyridines

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BRPI0503681A (pt) * 2005-08-19 2007-04-10 Fundacao Oswaldo Cruz compostos azóis usados como agentes tuberculostáticos e leishmanicidas, composições farmacêuticas contendo os mesmos, uso das respectivas composições farmacêuticas no tratamento ou inibição de doenças, bem como método de tratamento ou inibição de doenças

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US20050261333A1 (en) * 2002-08-14 2005-11-24 Astrazeneca A B Use of and some novel imidazopyridines

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130156827A1 (en) * 2010-07-09 2013-06-20 Xinjian Li Sodium alginate crosslinked slow-release moxifloxacin microsphere, the preparation method and the use thereof, and target vascular occlusive agent of the microsphere
US9028847B2 (en) * 2010-07-09 2015-05-12 Beijing Shengyiyao Technology & Development Co., Ltd. Sodium alginate crosslinked slow-release moxifloxacin microsphere, the preparation method and the use thereof, and target vascular occlusive agent of the microsphere

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ZA200805562B (en) 2009-07-29
EP1976832A2 (en) 2008-10-08
WO2007019660A2 (en) 2007-02-22
US8436027B2 (en) 2013-05-07
US20110269803A1 (en) 2011-11-03
US20130274298A1 (en) 2013-10-17
BRPI0503681A (pt) 2007-04-10
WO2007019660A3 (en) 2009-04-23

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