WO2011089457A1 - Nouveaux composés médicinaux - Google Patents

Nouveaux composés médicinaux Download PDF

Info

Publication number
WO2011089457A1
WO2011089457A1 PCT/HU2011/000009 HU2011000009W WO2011089457A1 WO 2011089457 A1 WO2011089457 A1 WO 2011089457A1 HU 2011000009 W HU2011000009 W HU 2011000009W WO 2011089457 A1 WO2011089457 A1 WO 2011089457A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
pyrimidin
carbaldehyde
heterocyclic
pyrimidine
Prior art date
Application number
PCT/HU2011/000009
Other languages
English (en)
Inventor
István CSONKA
Vince Grolmusz
József RÉPÁSI
Zoltán SZABADKA
András Szabó
Máriusz KERTÉSZ
Original Assignee
Uratim Gyártó Korlátolt Felelősségű Társaság
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Uratim Gyártó Korlátolt Felelősségű Társaság filed Critical Uratim Gyártó Korlátolt Felelősségű Társaság
Publication of WO2011089457A1 publication Critical patent/WO2011089457A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention concerns novel compounds possessing the general formula
  • compositions containing an active substance possessing the general formula (I), and preparation thereof are effective in prevention and treatment of diseases caused by the bacterium Mycobacterium tuberculosis or other Mycobacteria.
  • the invention concerns compounds
  • R stands for any of the followings: hydrogen atom, halogen atom, hitrile group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group and its derivatives, alkoxy carbonyl group, cycloalkoxy carbonyl group, alkenyl oxycarbonyl group, alkynyl
  • alkyl carboxamide group cycloalkyl carboxamide group, alkenyl carboxamide group, alkynyl carboxamide group, aryl carboxamide group, heterocyclic carboxamide group and its derivatives, hydroxyl group, alkoxy carbonyl group, cycloalkoxy carbonyl group, alkenyloxy group, alkynyloxy group, aryloxy group, heterocyclic oxy group and its derivatives, amine group, alkylamine group, cycloalkyl amine group, alkenyl amine group, alkynyl amine group, arylamine group, heterocyclic amine group and its derivatives;
  • R' stands for hydrogen atom, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group and its derivatives, alkoxy carbonyl group, cycloalkoxy carbonyl group, alkenyl oxycarbonyl group, alkynyl oxycarbonyl group,
  • aryloxycarbonyl group, heterocyclic oxycarbonyl group and its derivatives alkyl carboxamide group, cycloalkyl carboxamide group, alkenyl carboxamide group, alkynyl carboxamide group, aryl carboxamide group, heterocyclic carboxamide group and its derivatives, hydroxyl group, alkoxy carbonyl group, cycloalkoxy carbonyl group,
  • alkenyloxy group alkynyloxy group, aryloxy group,
  • heterocyclic oxy group and its derivatives amine group, alkylamine group, cycloalkylamine group, alkenyl amine group, alkynyl amine group, arylamine group, heterocyclic amine group and its derivatives;
  • R' '' stands for any of the followings: hydrogen atom, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group and its derivatives, alkoxy carbonyl group, cycloalkoxy carbonyl group, alkenyl
  • alkylcarboxamide group cycloalkylcarboxamide group, alkenyl carboxamide group, alkynyl carboxamide group, arylcarboxamide group, heterocyclic carboxamide group and its derivatives, hydroxyl group, alkoxy carbonyl group, cycloalkoxy carbonyl group, alkenyloxy group, alkynyloxy group, aryloxy group, heterocyclic oxy group and its derivatives, amine group, alkylamine group,
  • R' ' and R' ' ' constitutes unsubstituted or substituted aromatic or unsubstituted or substituted heteroaromatic ring or cycloalkyl or
  • the invention moreover concerns the procedure for
  • Mycobacterium genus inhabit the surface waters and the upper levels of the soil; they are important, mostly saprophyte microorganisms that contribute to biodegradation of organic materials in the environment. Some Mycobacterium species, however, became pathogenic in the course of the evolution: in this respect, one should mention
  • Mycobacterium tuberculosis and Mycobacterium bovis as the most important pathogens in the Mycobacterium tuberculosis complex, that also contains the following other species: M. bovis bacillus Calmette-Guerin , M. africanum, M. microti, M. canetti, M. caprae.
  • tuberculosis disease and the human race have existed together for a very long time.
  • the eradication of tuberculosis is still far away, and newly appearing multi-drug resistant and extremely multi-drug resistant tuberculosis strains cause new difficulties in therapy (Gergely, R. Medicina Thoracalis 1998; 51:185-188; Hutas I. HIPPOCRATES Vol. I. (5) 260, 1999) .
  • the global health challenge caused by tuberculosis, can be characterized by the following numbers: every year 8 million new TB cases are diagnosed, and 2 million casualties are caused by tuberculosis.
  • One third of the human population carries the tuberculosis bacterium ⁇ WHO Report, 2001, Geneva) .
  • tuberculosis as a co-infection, increasing the number of new cases worldwide. About 15% of all AIDS sufferers die from tuberculosis .
  • MDR multi-drug resistant
  • the Mycobacterium tuberculosis bacterium When the Mycobacterium tuberculosis bacterium enters the lung by inhalation, it becomes internalized by phagocytosis into macrophages of the lung, i.e. the alveolar macrophages. The bacteria will survive in the macrophages, and may remain in the lung for years or disperse in the body of the host
  • macrophage can be in an active, dividing, or in a passive sleeping, or dormant state with very low metabolism.
  • anti-tuberculosis therapies apply multiple drugs through a period of 6 to 9 months in non-MDR strains, and up to 24 months in the case of MDR or XDR strains.
  • the aim of the present invention is to overcome the above mentioned difficulties with new anti-tuberculotic drug
  • alkyl carboxamide group cycloalkyl carboxamide group, alkenyl carboxamide group, alkynyl carboxamide group, aryl carboxamide group, heterocyclic carboxamide group and its derivatives, hydroxyl group, alkoxy carbonyl group, cycloalkoxy carbonyl group, alkenyloxy group, alkynyloxy group, aryloxy group, heterocyclic oxy group and its derivatives, amine group, alkylamine group, cycloalkyl amine group, alkenyl amine group, alkynyl amine group, arylamine group, heterocyclic amine group and its derivatives;
  • R' stands for hydrogen atom, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group and its derivatives, alkoxy carbonyl group, cycloalkoxy carbonyl group, alkenyl oxycarbonyl group, alkynyl oxycarbonyl group,
  • aryloxycarbonyl group, heterocyclic oxycarbonyl group and its derivatives alkyl carboxamide group, cycloalkyl carboxamide group, alkenyl carboxamide group, alkynyl carboxamide group, aryl carboxamide group, heterocyclic carboxamide group and its derivatives, hydroxyl group, alkoxy carbonyl group, cycloalkoxy carbonyl group, alkenyloxy group, alkynyloxy group, aryloxy group,
  • heterocyclic oxy group and its derivatives amine group, alkylamine group, cycloalkylamine group, alkenyl amine group, alkynyl amine group, arylamine group, heterocyclic amine group and its derivatives;
  • Q stands for halogen atom, or NR''R''', where R' ' es
  • R' '' stands for any of the followings: hydrogen atom, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group and its derivatives, alkoxy carbonyl group, cycloalkoxy carbonyl group, alkenyl oxycarbonyl group, alkynyl oxycarbonyl group, aryl
  • alkylcarboxamide group cycloalkylcarboxamide group, alkenyl carboxamide group, alkynyl carboxamide group, arylcarboxamide group, heterocyclic carboxamide group and its derivatives, hydroxyl group, alkoxy carbonyl group, cycloalkoxy carbonyl group, alkenyloxy group, alkynyloxy group, aryloxy group, heterocyclic oxy group and its derivatives, amine group, alkylamine group,
  • R' ' and R' ' ' constitutes unsubstituted or substituted aromatic or unsubstituted or substituted heteroaromatic ring or cycloalkyl or
  • compositions which contain as active substance one or more compounds possessing the general formula (I) and/or their pharmaceutically applicable organic or inorganic salt(s) at pharmaceutically applicable concentrations together with one or more pharmaceutically applicable diluting agent (s),
  • excipient ( s ) excipient ( s ) , and/or inert carrier (s) .
  • the term “excellentalkyl” stands for substituents possessing acyclic straight or branched chains of at most 20 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, 1-methyl-ethyl, i- propyl, tertiary butyl.
  • the alkyl group may be further
  • the term “padcycloalkyl” stands for substituents possessing cycloalkyl groups with 3-12 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the cycloalkyl group may be further substituted, i. e. it may contain any of the following substituents: F, CI, Br, OH, OMe, methyl, ethyl, CN,
  • the term facedaryl stands for substituents possessing either an aromatic monocyclic group of 6 carbon atoms or a aromatic bicyclic group of 10 carbon atoms, e.g. phenyl, 1-naphtyl or 2- naphtyl .
  • the aryl group may be further substituted, i. e. itmay contain any of the following substituents: F, CI, Br, OH,
  • alkenyl group may be further substituted, i. e. it may contain any of the following
  • alkynyl group may be further substituted, i. e. it may contain any of the following
  • heterocyclic stands for substituents possessing cyclic groups where one or more carbon atoms are substituted with nitrogen, oxygen or sulphur atoms, e.g. pyrrole,
  • heterocyclic group may be further substituted, i.e. it may contain any of the following
  • the compounds possessing the general formula (I) and the pharmaceutically applicable compositions containing their inorganic or organic salts in either solid or fluid forms may be administered by any of the following routes: peroral, parenteral (including subcutaneous, intramuscular,
  • the solid compositions to be administered by peroral route may be in the form of powder, capsule, pill (tablet) , film tablet, microcapsule, etc, and may contain as carrier materials like binders (e.g. gelatin, sorbitol, polyvinyl-pirrolidone) ; fillers (e.g. lactose, glucose, starch, calcium-phosphate, etc); auxiliary materials (e.g. magnesium-stearate, talcum, polyethylene-glycol, silicon-dioxide, etc) ; lubrication agents (e.g. sodium-lauryl-sulphate, etc), etc.
  • binders e.g. gelatin, sorbitol, polyvinyl-pirrolidone
  • fillers e.g. lactose, glucose, starch, calcium-phosphate, etc
  • auxiliary materials e.g. magnesium-stearate, talcum, polyethylene-glycol, silicon-dioxide, etc
  • lubrication agents
  • the fluid compositions to be administered by peroral route may be in the form of solutions, suspensions or emulsions which may contain as carrier materials e.g. suspending agents (e.g. gelatin, carboxy-methyl-cellulose, etc) ; emulgation agents (e.g. sorbitane monooleate, etc) stb.; solvents (e.g. water, oils, glycerol, propylene glycol, ethanol) ; preservatives (e.g. p-hydroxy-benzoate methyl-ester, etc), etc.
  • suspending agents e.g. gelatin, carboxy-methyl-cellulose, etc
  • emulgation agents e.g. sorbitane monooleate, etc
  • solvents e.g. water, oils, glycerol, propylene glycol, ethanol
  • preservatives e.g. p-hydroxy-benzoate methyl-ester, etc
  • parenteral compositions constitute solutions or suspensions, which contain the compounds
  • non-aqueous solutions e.g. in polyethylene glycol, polyvinyl pirrolidone, lecithin, peanut oil or sesame oil.
  • the solution may be lyophilized and re-dissolved in an adequate solvent just before administration.
  • compositions applicable via the nasal route covered by the present inventions may contain the compounds possessing the general formula (I) and/or their pharmaceutically applicable organic and inorganic salts in the form of aerosols, drops, gels and powders.
  • the aerosol compositions covered by the present invention may contain the compounds possessing the general formula (I) and/or their pharmaceutically applicable organic and inorganic salts in the form of a sterile solution or fine suspension prepared using a pharmaceutically adequate aqueous or nonaqueous solvent.
  • the sterile aerosol may be present in a container containing one dose or multiple doses, where the dosage or the refill is provided, and which is usually equipped with a vaporizer.
  • the closed container may also be adequate for dosage of unit doses; such as the single- dose nasal inhalator or the aerosol-container equipped with a dosing valve, disposable when emptied.
  • the aerosol-container is equipped with a dosing valve, then it contains some form of carrier gas, e.g. compressed gas (e.g. compressed air) or organic carrier gas (chlorinated or fluorinated hydrocarbon) . Dosage of the aerosol may also be administered by a vaporizer pump .
  • carrier gas e.g. compressed gas (e.g. compressed air) or organic carrier gas (chlorinated or fluorinated hydrocarbon) .
  • Dosage of the aerosol may also be administered by a vaporizer pump .
  • compositions applicable via the buccal route covered by the present invention may contain the compounds possessing the general formula (I) and/or their pharmaceutically
  • a carrier e.g. sugar, gum arabic, gum tragacanth, gelatin, glycerol, etc.
  • compositions covered by the present invention may also be administered via the rectal route.
  • Such compositions are usually in the form of suppositories, which contain the active ingredient mixed in a suppositorial carrier material, e.g. cocoa butter (theobroma cacao) or other known carrier.
  • a suppositorial carrier material e.g. cocoa butter (theobroma cacao) or other known carrier.
  • the suppositories are produced in the usual manner by first mixing the components with the melted carrier, then molding the mixture using adequate mould forms.
  • compositions covered by the present invention is also applicable as transdermal preparation, e.g. in the form of ointment, gel or patch.
  • compositions covered by the present invention are produced by i) mixing the active ingredient (containing the compounds possessing the general formula (I) and/or their pharmaceutically applicable organic and inorganic salts) and the carrier material (s) and ii) formulating the produced mixture into the form of any already described pharmaceutical preparation.
  • the methods to be applied for producing such pharmaceutical preparations are described in the art (e.g. in the above mentioned handbook ([Remington's
  • the present invention also covers the application of one or more pharmaceutical compositions, containing the compounds possessing the general formula (I) and/or their pharmaceutically applicable organic and inorganic salts in the form of any pharmaceutically applicable
  • the compounds covered by the present inventions were identified by using high-throughput in silico (i.e. computer- driven and -modeled) docking screen on the whole surface of the dUTPase enzyme from Mycobacterium tuberculosis, which is essential for viability of the bacterium.
  • the starting compound database contained over one million small molecular compounds present and described in electronic catalogues of chemical companies. This compound database was docked on the surface of the Mycobacterium tuberculosis dUTPase protein using our computer cluster and the docking software Frigate, developed by us. Results were evaluated using mathematical optimization by the Frigate software to reveal fitting data of the compounds to the surface of the Mycobacterium tuberculosis dUTPase protein.
  • the small molecular compounds were treated as flexible molecules and their locations in the three-dimensional space and their three-dimensional structures (considering all possible rotations along the rotatable chemical bonds) were optimized.
  • the compounds characterized with the best binding profiles were further screened based on important pharmacological properties (e.g. log P) .
  • Reaction scheme 1 The reaction was generalized for substituted derivatives of 2-aminopyridine as well.
  • reaction was generalized for pyrido [1, 2-a] pyrimidin- 2, 4-dione compounds produced using substituted derivatives of 2-aminopyridine as well.
  • the compound 2-R-amino-3-R-iminomethylpyrido [ 1, 2- a] pyrimidin-4-one can be generated by reacting 2-chloro-4- oxopyrido [ 1 , 2-a] pyrimidine-3-carbaldehyde in adequate polar solvent with primer amines as shown in reaction scheme 3.
  • the produced hydrochloric acid may be neutralized using either excess amines o
  • the 3-iminomethyl-group of the Schiff-base generated from primary amines may be reduced (using e.g. sodium borohydride) into aminomethyl-group (c.f. reaction scheme 4).
  • reaction scheme 5 the carbaldehyde group can be hydrated to generate carbaldehyde-hydrate (geminal diol) .
  • the compounds were characterized using thin layer chromatography (Merck TLC Silica gel 60 F 254 ) and NMR (11.7 Tesla Bruker Avance-500 (double channel) spectrometer, 300K, d6-DMSO solvent) .
  • the separated yellow precipitate is filtered and washed with 2x200 ml water and 2x100 ml dichloromethane, dried at 40 °C in vacuum. Yield: 92.7 g (0.44 mol, 91 % ) ;
  • the carbaldehyde group may be hydrated into carbaldehyde hydrate (geminal diol) .
  • the product was gained as 2-allylamino-4-oxopyrido [ 1 , 2- a] pyrimidine-3-carbaldehyde hydrate (Yield: 55 %, solid yellow product) .
  • the protein enzymes Mycobacterium tuberculosis dUTPase and Homo sapiens dUTPase were expressed in E. coli expression system and were purified to homogeneity as described previously (Varga et al. Biochem Biophys Res Commun. 2008 313:p. 8-13.; Varga et al. FEBS Lett. 2007 581: p. 4783-8.).
  • enzyme assay measurements To investigate the effects of several compounds, we carried out enzyme assay measurements. The potential dUTPase inhibitory effects of the compounds were investigated using the malachite green assay (McQuade, T. J. et al. , Anal Biochem. 2009 386: p. 244-50.).
  • the phosphate produced via the coupled reaction binds to malachite green and changes its colour.
  • the colour change is detected spectrophotometrically, thus we directly measure the concentration of the produced phosphate, thereby indirectly measuring the velocity of the enzymatic reaction and the extent of the inhibition.
  • the concentration of the enzyme was 50 nM.
  • tuberculosis dUTPase tuberculosis dUTPase. None of these compounds inhibited the human dUTPase enzyme.
  • Mycobacterium tuberculosis dUTPase protein does not form crystals in the absence of bound ligands.
  • the appearance of protein crystals in the presence of the compounds indicated that crystallization was facilitated by the binding of the compounds TB 807 or TB 808. This also indicates that the compounds TB 807 or TB 808 are present as bound to the protein in the crystals.
  • X-ray crystallographic data collection was performed on a Rigaku R-AXIS RAPID diffractometer ⁇ Mycobacterium tuberculosis dUTPase together with compound TB 807, full data set was collected, resolution 2.5 A, space group: P6 3 ) and also on synchrotron (ESRF Grenoble, beamline 14-4, Mycobacterium tuberculosis dUTPase together with compound TB 807, full data set was collected, resolution: 2 A or 1, 6 A, space group: P63) .
  • the XDS program and molecular replacement was used for data analysis and solving the phase problem.
  • tuberculosis dUTPase was used as the model (PDB ID: 3HZA) .
  • Example 8 Bacteriologic evaluations of the TB8
  • the compounds to be tested were dissolved in DMSO, and after sterile filtration, these were diluted with DMSO to produce ten distinct concentrations in the 0.05 - 100 ⁇ g/ml range.
  • the test tubes were then infected with diluted bacterium suspensions (100 ⁇ ) and these were incubated for 28 days in 37 °C.
  • the minimal inhibitory concentration i.e., the minimal compound concentration that prevents bacterial growth to turn the Sula media turbid was identified by visual inspection. Aliquots from the test tubes potentially containing still surviving bacteria were used to inoculate solid Lovenstein-Jensen medium (Lowenstein, E.
  • Table 9 MIC values of the TB8 derivatives in M.
  • Table 10 MIC values of the TB8 derivatives in M. kansasii :
  • Table 11 MIC values of some TB8 derivatives on multidrug- resistant M. tuberculosis culture
  • the cytotoxicity of the TB8 derivatives were examined in HepG2 (human hepatoma) , MonoMac6 (human monocyte) cell lines, on human PBMC (human peripheral blood monomorphonuclear ) cells, and on mouse bone marrow macrophage cells.
  • the cytostatic effects were examined on HepG2, onoMac6, and PBMC cell lines.
  • the cells were incubated at 37 °C for three hours, and then the compounds were washed out from the cells.
  • the cytostaticity test the cells were incubated at 37 °C for three days in 5% C0 2 atmosphere.
  • A means the difference in the absorbance averaged in the 4-8 parallel experiments.
  • Table 12 Comparison of the MIC and IC 50 values for some members of the TB8 family
  • Example 10 Examination of the interaction of drug compounds with lipid layers
  • the lipid mixed film consists of the mixture of the lipid and the drug compound in 5 to 1 molar ratio.
  • the concentration of the compound was 2xl0 ⁇ 6 M.
  • addition of the compound TB801 to the lipid did not result in any difference as compared to the drug- free lipid.
  • the second method penetration of drug into the lipid layer was detected by the change of surface pressure.
  • pure lipid monolayer was formed and following one compression/expansion cycle, the layer was compressed to a given value of surface pressure (15 and 20 mN/m) .
  • the compound was injected below the lipid layer and interaction between the compound and the lipd layer was evaluated based on eventual changes of surface pressure.
  • the solubility and the amphiphilicity of the TB 801 compound was also determined by measuring the octanol/water ratio log P app , and by measuring the surface tension of aqueous solutions containing the compound TB 801 (Table 12). The static surface tension was changed only in the 40 times more
  • the following materials are mixed: 0.01-50% drug compound possessing the general formula (I), 15-50% lactose, 15-50% potato starch, 5-15% polyvinylpyrrolidone, 1-5% talcum, 0.01- 3% magnesium-stearate, 1-3% colloidal silicon-dioxide, and 2-7 ultraamylopectin .
  • the mixture is granulated by the wet
  • Dragees and film tablets The pills produced as described above are coated with entero- or gastrosolvent film coating, or with sugar-containing coating and talcum. Dragees are coated with a mixture of bee wax and carnauba wax.
  • Capsules
  • Components 0.01-15% drug compound possessing the general formula (I), 0.1-2% sodium-hydroxide, 0.1-3% citric acid, 0.05- 0.2% nipagin (sodium methyl 4-hydroxy-benzoate) , 0.005-0.02% nipasol, 0.01-0.5% carbopol (polyacrylic acid), 0.1-5% 96% ethanol, 0.1-1% flavouring material, 20-70% sorbitol (70 % aqueous solution) and 30-50% distilled water.
  • Carbopol in small doses is added to an aqueous solution of nipagin and citric acid with extensive stirring of the mixture. The resulting solution is left to stand for 10-12 hours. Then, sodium hydroxide (dissolved in 1 ml distilled water) , the aqueous solution of sorbitol and finally the ethanol solution of raspberry-flavor is added during strong stirring. To the such prepared carrier material, the drug compound is added in small doses and is homogenized using immersion homogenizer. Finally the suspension is filled up to the final volume and the suspension syrup is produced in its final form using a colloid mill. e) Suppositories :
  • the content of the ampoules is dissolved right before use in sterile water or sterile physiological salt solution (0.9% sodium chloride) .

Landscapes

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

Abstract

L'invention concerne des nouveaux composés médicinaux représentés par la formule générale (I), des compositions pharmaceutiques de tels principes actifs ainsi que le procédé permettant de les fabriquer; R, X, A et Q étant tels que définis dans les revendications. Les nouveaux composés sont efficaces pour empêcher et/ou traiter des maladies provoquées par la bactérie Mycobacterium tuberculosis ou toute autre mycobactérie.
PCT/HU2011/000009 2010-01-21 2011-01-21 Nouveaux composés médicinaux WO2011089457A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU1000034A HUP1000034A2 (en) 2010-01-21 2010-01-21 Pyrido[1,2-a]pyrimidine derivatives and pharmaceutical preparations thereof having anti - mycobacterial activity
HUP1000034 2010-01-21

Publications (1)

Publication Number Publication Date
WO2011089457A1 true WO2011089457A1 (fr) 2011-07-28

Family

ID=44306426

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2011/000009 WO2011089457A1 (fr) 2010-01-21 2011-01-21 Nouveaux composés médicinaux

Country Status (2)

Country Link
HU (1) HUP1000034A2 (fr)
WO (1) WO2011089457A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002087589A1 (fr) * 2001-04-26 2002-11-07 Daiichi Pharmaceutical Co., Ltd. Medicament permettant d'inhiber une pompe d'elimination de medicament
US20070027164A1 (en) * 2003-01-29 2007-02-01 Stockwell Brent R Agents for treating neurodegenerative diseases
WO2010003533A2 (fr) * 2008-06-17 2010-01-14 Institut Pasteur Korea Composés anti-infectieux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002087589A1 (fr) * 2001-04-26 2002-11-07 Daiichi Pharmaceutical Co., Ltd. Medicament permettant d'inhiber une pompe d'elimination de medicament
US20070027164A1 (en) * 2003-01-29 2007-02-01 Stockwell Brent R Agents for treating neurodegenerative diseases
WO2010003533A2 (fr) * 2008-06-17 2010-01-14 Institut Pasteur Korea Composés anti-infectieux

Non-Patent Citations (33)

* Cited by examiner, † Cited by third party
Title
BIOCHEMICAL PHARMACOLOGY, vol. 21, no. 3, 1972, pages 303 - 316 *
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, no. 10, 2004, pages 2493 - 2497 *
BIOORGANIC & MEDICINAL CHEMISTRY, vol. 14, no. 6, 2006, pages 1993 - 2004 *
BIOORGANIC & MEDICINAL CHEMISTRY, vol. 8, no. 4, 2000, pages 751 - 768 *
DATABASE CA GEORGE, THOMAS ET AL.: "Synthesis of pyrido [1, 2-a]pyrimido[4, 5-b]pyridine and related tricyclic systems", accession no. STN Database accession no. 75:88564 *
DATABASE CA GOTOH, MITSUHIRO ET AL.: "Inramolecular 1, 3-dipolar cycloaddition at the periphery of heterocyclic systems. Part 2. A mechanistic proposal for the facile oxime-nitrone isomerization at the periphery of pyridine and pyrido[1,2-a]- pyrimidine systems", accession no. STN Database accession no. 124:202156 *
DATABASE CA GURNOS, JOHNES ET AL.: "The Vilsmeier reaction of fully conjugated carbocycles and heterocycles", accession no. STN Database accession no. 149:575981 *
DATABASE CA HORVATH, AGNES ET AL.: "Nitrogen bridgehead compounds. Part 65. Vilsmeier-Haack formylation of 4H-pyrido [I, 2-a] pyrimidin-4-ones. Part 6", accession no. STN Database accession no. 107:58966 *
DATABASE CA KAUL, C.L. ET AL.: "Antihypertensive and monoamine oxidase inhibitory activity of 3-amino-2-oxazolidinone (3AO) and its condensation product with 2-substituted-3- formyl-4-oxo-(4H)-pyrido[l, 2-a]pyrimidines", accession no. STN Database accession no. 76:135864 *
DATABASE CA MAGYAR, KALMAN ET AL.: "Monamine oxidase-inhibitory activity of new homopyrimidazole derivatives", accession no. STN Database accession no. 82:120801 *
DATABASE CA NAKAYAMA, KIYOSHI ET AL.: "MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 4: Addressing the problem of poor stability due to photoisomerization of an acrylic acid moiety", accession no. STN Database accession no. 141:71507 *
DATABASE CA NOGUCHI, MICHIHIKO ET AL.: "A facile and stereoselective azepine-ring formation at the periphery ofpyridone and pyrido[l, 2-a pyrimidone systems via intramolecular imine and carbonyl ene reactions", accession no. STN Database accession no. 126:8060 *
DATABASE CA NOGUCHI, MICHIHIKO ET AL.: "Acid-catalyzed [4 + 2] cycloaddition reaction of 2- (alk-2-enyl) amino-3-(N-arylimino) methyl-4-oxo-4H-pyrido [1, 2-a] pyrimidines", accession no. STN Database accession no. 127:278180 *
DATABASE CA NOGUCHI, MICHIHIKO ET AL.: "An asymmetry induced azepine-ring formation through the ene reactions at the periphery of heterocyclic systems", accession no. STN Database accession no. 126:8062 *
DATABASE CA NOGUCHI, MICHIHIKO ET AL.: "Competitive thermal ene reaction and Deils-Alder reactions of 2-[N-(alk-2-enyl)benzylamino]-3-vinylpyrido[1, 2-a]pyrimidin-4 (4H)- ones", accession no. STN Database accession no. 147:95617 *
DATABASE CA NOGUCHI, MICHIHIKO ET AL.: "Mechanistic considerations on the azepine-ring formation through the ene reactions at the periphery of heterocyclic systems", accession no. STN Database accession no. 126:144245 *
DATABASE CA ROMAI, G ET AL.: "Synthesis, antiplatelet activity and comparative molecular field analysis of substituted 2-amino-4H-pyrido[l, 2-a]pyrimidin-4-oncs, their congeners and isosteric analogues", accession no. STN Database accession no. 133:68351 *
DATABASE CA SUN, BIN ET AL.: "Intramolecular 1, 3-polar cycloaddition at the periphery of heterocyclic systems. Part 4. A facile cyclopropane ring-formation by the thermal reaction of 2-(alk-2- enylamino)-4-oxo-4H-pyrido[1, 2-a]pyrimidine-3-carboxaldehydes with tosylhydrazine", accession no. STN Database accession no. 126:144246 *
DATABASE CA YOSHIDA, KEN-ICHI ET AL.: "MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 5: Carbon-substituted analogues at the C-2 position", accession no. STN Database accession no. 144:366386 *
DATABASE CA ZHANG, YUCHI ET AL.: "A convenient synthesis of 2-functionalized pyrrolo[2, 3-d]- pyrido[l, 2-a]pyrimidines", accession no. STN Database accession no. 146:401932 *
HETEROCYCLES, vol. 70, 2006, pages 181 - 184 *
JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 23, no. 5, 1986, pages 1295 - 1298 *
JOURNAL OF ORGANIC CHEMISTRY, vol. 36, no. 15, 1971, pages 2192 - 2194 *
NOGUCHI, MICHIHIKO ET AL.: "Acid-catalyzed [4 + 2] cycloaddition reaction of 2- (alk-2-enyl) amino-3-(N-arylimino) methyl-4-oxo-4H-pyrido [1, 2-a] pyrimidines", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 70, no. 9, 1997, pages 2201 - 2207 *
NOGUCHI, MICHIHIKO ET AL.: "Competitive thermal ene reaction and Deils-Alder reactions of 2-[N-(alk-2-enyl)benzylamino]-3-vinylpyrido[1, 2-a]pyrimidin-4 (4H)- ones", TETRAHEDRON, vol. 63, no. 21, 2007, pages 4548 - 4557 *
ORGANIC REACTIONS, vol. 49, 1997 *
ORVOSTUDOMANY, vol. 25, no. 2, 1974, pages 143 - 150 *
SHIRAI, MASASHI ET AL.: "Reaction of 2-substituted-4-oxo-4H-pyrido [1, 2-a] pyrimidine-3-carbaldehyde oximes with electron-deficient olefins and acetylenes.", TETRAHEDRON, vol. 59, 2003, pages 4113 - 4121 *
SYNTHESIS, vol. 1, 1997, pages 53 - 56 *
TETRAHEDRON, vol. 52, no. 3, 1996, pages 887 - 900 *
TETRAHEDRON, vol. 52, no. 41, 1996, pages 13081 - 13096 *
TETRAHEDRON, vol. 52, no. 41, 1996, pages 13097 - 13110 *
TETRAHEDRON, vol. 52, no. 41, 1996, pages 13111 - 13120 *

Also Published As

Publication number Publication date
HUP1000034D0 (en) 2010-03-29
HUP1000034A2 (en) 2011-09-28

Similar Documents

Publication Publication Date Title
US10568867B2 (en) Compounds and pharmaceutical compositions thereof for the treatment of cystic fibrosis
ES2968810T3 (es) Agentes moduladores del regulador de la conductancia transmembrana de la fibrosis quística
CN103717599B (zh) 吲唑
US20200138798A1 (en) Methods of treatment for cystic fibrosis
TW202115092A (zh) 囊腫纖維化跨膜傳導調節蛋白之調節劑
US20210009560A1 (en) Crystalline forms of modulators of cftr
US20110166123A1 (en) Novel compositions and methods of use
US20100016379A1 (en) Terephthalamate Compounds and Compositions, and Their Use as HIV Integrase Inhibitors
JPS60226882A (ja) 新規ピリミドピリミジン誘導体
TW201625618A (zh) 抑制瞬時受體電位ａ１離子通道
TW200900395A (en) Heteroarylamide pyrimidone compounds
WO2012011840A1 (fr) N,n'-diarylurées et n,n'-diarylthiourées cycliques, antagonistes de récepteurs d'androgènes, agent anti-cancer et procédé de production et d'application
CN109516989A (zh) 一类抑制并降解cdk的化合物
CN116669734A (zh) 一种嘧啶并五元氮杂环类衍生物的晶型及其制备方法
TWI305534B (en) 1-[alkyl], 1-[(heteroaryl)alkyl] and 1-[(aryl)alkyl]-7-(pyrimidin)-4-yl)-imidazo[1,2,a]pyrimidin-5(1h)-one derivatives
CN111868063A (zh) PI4KIIIβ抑制剂
US10065965B2 (en) Imidazo[1,2-B][1,2,4]triazine derivatives as antiparasitic agents
CN112055714A (zh) 二甲基氧膦类化合物
US8044066B2 (en) Derivatives of pyrrolopyridine-2-carboxamides, preparation thereof and therapeutic application thereof
CN110357905B (zh) 作为蛋白激酶抑制剂的大环类衍生物及其制备方法和用途
WO2011089457A1 (fr) Nouveaux composés médicinaux
CN109963853A (zh) 一类具有降解酪氨酸蛋白激酶jak3活性的化合物
WO2000077003A1 (fr) Composes de pyrrolopyridazine optiquement actifs
Rajasekaran et al. Synthesis, antitubercular, antibacterial and antioxidant activity of some 2-phenyl-3-substituted quinazolin-4 (3H)-ones
US20140378428A1 (en) 2,5-Disubstituted-Pyridyl Nicotinic Ligands, and Methods of Use Thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11734419

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11734419

Country of ref document: EP

Kind code of ref document: A1