WO2011089456A1 - Novel medicinal compounds - Google Patents
Novel medicinal compounds Download PDFInfo
- Publication number
- WO2011089456A1 WO2011089456A1 PCT/HU2011/000008 HU2011000008W WO2011089456A1 WO 2011089456 A1 WO2011089456 A1 WO 2011089456A1 HU 2011000008 W HU2011000008 W HU 2011000008W WO 2011089456 A1 WO2011089456 A1 WO 2011089456A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ylmethyl
- phenylallyl
- methoxynaphtalen
- piperazine
- piperazin
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- 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
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Definitions
- the present invention concerns novel compounds possessing the general formula (I),
- 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, alkyl group, hydroxyl group, alkoxy group, alkylamine group, nitro group, nitrile group;
- 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, 2007, Genova) .
- tuberculosis as a co-infection, increasing the number of new cases worldwide. About 15% of all AIDS sufferers die from tuberculosis.
- DR multi-drug resistant
- XDR extensively 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.
- the most anti-tuberculotic drugs have bacteriostatic or bactericide effects in the inter-cellular space.
- the known anti-tuberculotic drugs enter the macrophages through diffusion, in a limited rate. Additionally, nonspecific toxicity and too fast metabolism may cause
- 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
- 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
- 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
- heterocyclic stands for substituents possessing cyclic groups where one or more carbon atoms are substituted with nitrogen, oxygen or sulphur atoms, e.g. pyrrole,
- the heterocyclic group may be further
- intravenous buccal, sublingual, nasal or rectal, or via topical administration.
- 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-pyrrolidone ) ; fillers (e.g. lactose, glucose, starch, calcium-phosphate, etc); auxiliary materials (e.g. magnesium-stearate, talcum, poliethylene-glycol, silicon-dioxide, etc) ; lubrication agents (e.g. sodium-lauryl-sulphate, etc), etc.
- carrier materials like binders (e.g. gelatin, sorbitol, polyvinyl-pyrrolidone ) ; fillers (e.g. lactose, glucose, starch, calcium-phosphate, etc); auxiliary materials (e.g. magnesium-stearate, talcum, poliethylene-glycol, silicon-dioxide, etc)
- 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
- sorbitane monooleate 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 pyrrolidone, 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
- 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) .
- condensation reaction using piperazine and aldehydes followed by reduction.
- piperazine containing 1-tert- butoxycarbonyl protecting group on on of the piperazine nitrogen atom was reacted with aromatic aldehyde; then the protecting group was removed the compound was reacted with cinnamic aldehyde.
- Naphtyl-piperazines were prepared via reductive amination using 1- tert-butoxycarbonyl piperazine and naphtyl-carbaldehyde followed by removal of the tert-butoxycarbonyl (BOC) protecting group (Reaction scheme 1) .
- the cinnamic naphtyl-methyl piperazines were prepared by reacting naphtyl-methyl piperazines with cinnamic . aldehydes via reductive amination (Reaction scheme 2) .
- the compounds were characterized using thin layer chromatography (Merck TLC Silica gel 60 F 2 s 4 ) and NMR (11.7 Tesla Bruker Avance-500 (double channel) spectrometer, 300K, d6-DMSO solvent) .
- Mass spectra were recorded using electrospray ion source, on a Bruker Esquire 3000+ iontrap equipment. Samples were dissolved in acetonitrile/water 1:1 (v/v) solvent, also containing 0.1% AcOH, and were injected at a flow rate of 10 ⁇ /min. Spectra were recorded in the positive mood, in the interval 50-3000 m/z, using 13,000 m/z/sec sampling speed.
- reaction mixture is evaporated using rotadest at decreased pressure.
- the evaporation residue is dissolved in the mixture of 120 ml saturated NaHC0 3 and 300 ml EtOAc and is stirred till phase separation.
- the organic phase is separated and is washed with 1x100 ml saturated NaHC0 3 solution then with 1x100 ml water, then it is dried on anhydrous Na 2 S0 4 and evaporated .
- 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.
- the compounds to be investigated were dissolved in DMSO result in a final stock concentration of 25 mM. Aliquots of this stock solution was added to the enzyme reaction mixtures In multiple cases, precipitation was observed.
- tuberculosis 2.5 mM
- 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 compound TB 1630. This also indicates that the compound TB 1630 is present as bound to the protein in the crystals.
- X-ray crystallographic data collection was performed on a synchrotron (ESRF Grenoble, beamline 14-4, Mycobacterium tuberculosis dUTPase together with compound TB 1630, full data set was collected, resolution 2 A) .
- 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 6 Bacteriologic evaluations of the TB 16
- the test tubes were then infected with diluted bacterium suspensions (100 ⁇ ) and these were incubated for 28 days in 37 °C. After the 28 days incubation period, the minimal inhibitory concentration (MIC) were determined, 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 8 The MIC values of the TB 16 derivatives in M.
- tuberculosis cultures
- tuberculosis bacterium were tested on multidrug-resistant bacterium strain (INH, RIF MDR A8 M. tuberculosis) .
- the MIC and CFU values were determined as we described above.
- Table 10 The MIC values of some TB 16 derivatives on multidrug-resistant M. tuberculosis culture:
- cytotoxicity and cytostaticity using colometric tetrazolium test 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, MonoMac6, 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% CO2 atmosphere.
- A means the difference in the absorbance averaged in the 4-8 parallel experiments.
- the following materials are mixed: 0.01-50% drug compound possessing the general formula (I), 15-50% lactose, 15-50% potato starch, 5-15% polyvinyl-pyrrolidone, 1-5% talcum, 0.01- 3% magnesium-stearate, 1-3% colloidal silicon-dioxide, and 2-7% ultraamylopectin .
- the mixture is granulated by the wet
- 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) .
Abstract
The invention concerns novel compounds possessing the general formula (I), pharmaceutical compositions containing any of these compounds as active ingredient, and preparation of these compounds, where R, Q, and A are defined in the claims. The new compounds are efficient in order to prevent and/or treat diseases caused by the bacterium Mycobacterium tuberculosis or any other Mycobacteria.
Description
NOVEL MEDICINAL COMPOUNDS
The present invention concerns novel compounds possessing the general formula (I),
pharmaceutical compositions containing an active substance possessing the general formula (I), and preparation thereof. The novel compounds are effective in prevention and treatment of diseases caused by the bacterium Mycobacterium tuberculosis or other Mycobacteria.
More precisely, the invention concerns compounds
possessing the general formula (I),
where
R stands for any of the followings: hydrogen atom, halogen atom, alkyl group, hydroxyl group, alkoxy group, alkylamine group, nitro group, nitrile group;
Q stands for -C≡C- or -HC=CR' - group, where R' stands for alkyl group,
A stands for any of the followings:
(i) unsubstituted phenyl or naphtalenyl group or phenyl or naphtalenyl group substituted with halogen atom, alkyl
group, hydroxyl group, alkoxy group, alkylamine group, nitro group, nitrile group, or
(ii) unsubstituted or alkyl group-substituted heterocycle; and organic or inorganic salts of compounds possessing the general formula (I).
The invention moreover concerns the procedure for
preparation of compounds possessing the general formula (I), as well as the application of compounds possessing the general formula (I) and its pharmaceutically applicable organic or inorganic salts and pharmaceutical compositions containing one or more of these compounds and its salts for prevention and/or treatment of diseases caused by the bacterium Mycobacterium tuberculosis or other Mycobacteria.
Most species of the 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. These bacteria differ substantially by their
virulence and host organisms, but their DNA is very similar: these bacteria show a 99.9% similarity at the DNA level {Brosch R. et al. Molecular genetics of Mycobacteria. Washington, D.C.: American Society for Microbiology, 2000:19-36; Brosch R. et al.
Proc Natl Acad Sci U S A 2002; 99:3684-3689. ; Zumla, A. et al. Pulmonary Medicine. 8 (3).-166-112, May, 2002).
The 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, 2007, Genova) .
From the 1980' s, numerous AIDS patients developed
tuberculosis as a co-infection, increasing the number of new cases worldwide. About 15% of all AIDS sufferers die from tuberculosis.
At the end of the twentieth century, drug-resistant tuberculosis strains appeared, causing further difficulties in the therapy: the multi-drug resistant ( DR) strains (that are resistant to the two first-line TB drugs, isoniazid and rifampicin) should be mentioned primarily, and the less frequent, but very hard to cure, extensively drug resistant (XDR) strains secondly.
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
organism. The tuberculosis bacterium surviving in the
macrophage can be in an active, dividing, or in a passive sleeping, or dormant state with very low metabolism.
Timely started therapy will cease further infections in the population of the host organism, and will prevent secondary drug resistance and later relapses by eradicating the bacteria. The appearance of resistant M. tuberculosis strains requires the revision of the current therapy protocols {William K. J. and Duncan K. Curr Mol Med. 2007 May;7 (3).-297-301) .
In neutral and slightly basic media, isoniazid, rifampicin and streptomycin are very efficient against M. tuberculosis. Pyrazinamide is efficient in the more acidic intra-cellular space.
The most anti-tuberculotic drugs have bacteriostatic or bactericide effects in the inter-cellular space. By the prior art, the known anti-tuberculotic drugs enter the macrophages through diffusion, in a limited rate. Additionally, nonspecific toxicity and too fast metabolism may cause
pharmacodynamic difficulties, and decrease the effects of the drugs. Usually, 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.
Most anti-tuberculotic drugs have limited effects against dormant bacilli. Increasing the metabolism or the diffusion of the drugs into the infected macrophages may speed up the
therapy and would allow the decrease of drug concentration applied, yielding fewer side effects.
The aim of the present invention is to overcome the above mentioned .difficulties with new anti-tuberculotic drug
preparations efficient in diseases caused by Mycobacterium tuberculosis, and other Mycobacteria in the lung and in other organs. The drug molecules will be efficient in the prevention and/or therapy of tuberculotic diseases.
We have found that the above goal can be potentially chieved by using new compounds possessing the general formula
stands for any of the followings: hydrogen atom, halogen atom, alkyl group, hydroxyl group, alkoxy group, alkylamine group, nitro group, nitrile group;
stands for -C≡C- or -HC=CR' - group, where R' stands for alkyl group,
stands for any of the followings:
unsubstituted phenyl or naphtalenyl group or phenyl or naphtalenyl group substituted with halogen atom, alkyl group, hydroxyl group, alkoxy group, alkylamine group, nitro group, nitrile group, or
(ii) unsubstituted or alkyl group-substituted heterocycle;
and organic or inorganic salts of compounds possessing the general formula (I) . In a representative presentation of the present invention, A stands for any group selected from the followings:
unsubstituted or alkyl group-substituted dihydrobenzofurane ; and organic or inorganic salts of compounds possessing the general formula (I) .
The compounds selected from the list below and possessing the general formula (I) constitute representative presentation of the present invention: 1- (4-Methoxynaphtalen-l-ylmethyl) -4- [ (E) -3-phenylallyl ] - piperazine dihydrochloride,
1- (2-Methoxynaphtalen-l-ylmethyl) -4- [ (E) -3-phenylallyl] - piperazine,
1- (6-Methoxynaphtalen-l-ylmethyl) -4- [ (E) -3-phenylallyl ] - piperazine,
1- (Naphtalen-l-ylmethyl) -4- [ (E) -3-phenylallyl] -piperazine dihydrochloride,
1- (Naphtalen-2-ylmethyl) -4- [ (E) -3-phenylallyl] -piperazine, 4-{4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -naphtalen-l-ol , l-{4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -naphtalen-2-ol,
2- (l-{ 4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -naphtalen-2- yloxy) -acetic acid methyl ester,
2- (-4-{4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -naphtalen-1- yloxy) -acetic acid methyl ester dihydrochloride,
4- { 4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -quinoline trihydrochloride,
7-methoxy-4- { 4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } - quinoline trihydrochloride,
3-{4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -3H-indole, 1- (Benzofuran-2-ylmethyl) -4- [ (E) -3-phenylallyl] -piperazine dihydrochloride,
1- (2, 3-dihydro-benzofuran-7-ylmethyl) -4- [ (E) -3-phenylallyl] - piperazine dihydrochloride,
1- (3-nitrobenzyl) -4- [ (E) -3-phenylallyl] -piperazine
dihydrochloride,
3- {4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -phenol,
4- { 4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -benzonitrile,
3- { 4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -phenylamine, 4 - { - [ (E)-3-Phenylallyl] -piperazin-l-ylmethyl } -benzamid,
4- { 4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -phenol,
4-{4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -benzoic acid dihydrochloride,
2- (4-{4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -phenoxyl ) - acetic acid methyl ester dihydrochloride,
(4-{ [ (E) -3- [4- (4-methoxynaphtalen-l-ylmethyl) -piperazin-l-yl] - propenyl } -phenyl) -dimethylamine trihydrochloride,
(4-{ (E) -3- [4- (2-methoxynaphtalen-l-ylmethyl) -piperazin-l-yl] - propenyl } -phenyl ) -dimethylamine,
1- (2-methoxynaphtalen-l-ylmethyl) -4- [ (E) -3- (3-methoxy-phenyl) - allyl] -piperazine dihydrochloride,
1- (4-methoxynaphtalen-l-ylmethyl) -4- [ (E) -3- ( 4-nitrophenyl ) - allyl] -piperazine,
1- (2-methoxynaphtalen-l-ylmethyl) -4- [ (E) -3- (4-nitrophenyl) - allyl] -piperazine,
4-{ (E) -3- [4- (2-methoxynaphtalen-l-ylitiethyl ) -piperazine-l-yl] - propenyl } -phenylamine trihydrochloride,
1- (4-methoxynaphtalen-l-ylmethyl) -4- [ (E) -3- ( 3-methoxyphenyl ) - allyl] -piperazine dihydrochloride,
1- [ (E) -3- (4-bromophenyl) -allyl] -4- (2-methoxynaphtalen-l- ylmethyl) -piperazine dihydrochloride,
1- [ (E) -3- (4-bromophenyl ) -allyl] -4- (4-methoxynaphtalen-l- ylmethyl) -piperazine dihydrochloride,
4-{ (E) -3- [4- (4-methoxynaphtalen-l-ylmethyl) -piperazin-l-yl ] - propenyl } -phenylamine trihydrochloride,
1- [ (E) -3- (3-Bromophenyl) -allyl] -4- (4-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
1- [ (E) -3- (2-Bromophenyl) -allyl] -4- ( 4-methoxynaphtalen-l- ylmethyl ) -piperazine hydrochloride,
1- [ (E) -3- (3-Bromophenyl) -allyl] -4- (2-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
1- [ (E) -3- (2-Bromophenyl ) -allyl] -4- (2-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
1- [ (E) -3- (3-chlorophenyl) -allyl] -4- ( 4-methoxynaphtalen-l- ylmethyl ) -piperazine hydrochloride,
1- [ (E) -3- (3-fluorophenyl) -allyl] -4- (4-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
1- [ (E) -3- (4-fluorophenyl) -allyl] -4- (4-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
1- (4-methoxynaphtalen-l-ylmethyl) -4- [ (E) -3- (2- trifluormethylphenyl) -allyl] -piperazine hydrochloride,
4- [ (E) -2-methyl-3-phenylallyl] -1- (4-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
4- [ (E) -2-methyl-3-phenylallyl] -1- (2-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
1- (4-Methoxynaphtalen-l-ylmethyl) -4- ( 3-phenylprop-2-ynyl ) - piperazine,
and the pharmaceutically applicable organic and inorganic salts of these compounds.
In addition, the invention concerns all such
pharmaceutical 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 ) , and/or inert carrier (s).
The term „alkyl" 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
substituted, i.e. it may contain any of the following
substituents: F, CI, Br, OH, OMe, methyl, ethyl, CN, COOH, COOMe, CONH2, and NH2.
The term „halogen" stands for any of the following substituents: fluorine, chlorine, bromine or iodine.
The term heterocyclic" stands for substituents possessing cyclic groups where one or more carbon atoms are substituted with nitrogen, oxygen or sulphur atoms, e.g. pyrrole,
pyrrolidine, pyrazole, imidazole, piridine, thiophene,
benzodioxane . The heterocyclic group may be further
substituted, i. e. it may contain any of the following
substituents: F, CI, Br, OH, OMe, methyl, ethyl, CN, COOH, COOMe, CONH2, and NH2.
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,
intravenous), buccal, sublingual, nasal or rectal, or via topical administration.
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-pyrrolidone ) ; fillers (e.g. lactose, glucose, starch, calcium-phosphate, etc); auxiliary materials (e.g. magnesium-stearate, talcum, poliethylene-glycol, silicon-dioxide, etc) ; lubrication agents (e.g. sodium-lauryl-sulphate, etc), etc.
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.
Representative forms of parenteral compositions constitute solutions or suspensions, which contain the compounds
possessing the general formula (I) and/or their
pharmaceutically applicable organic and inorganic salts as sterile solutions in aqueous solutions or parenterally
applicable non-aqueous solutions e.g. in polyethylene glycol, polyvinyl pyrrolidone, lecithin, peanut oil or sesame oil. As
an alternative application, the solution may be lyophilized and re-dissolved in an adequate solvent just before administration.
The 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. As an alternative, 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. If 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 .
The compositions applicable via the buccal route 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 pills, lozenges, or pastille, where the active ingredient is
formulated together with a carrier (e.g. sugar, gum arabic, gum tragacanth, gelatin, glycerol, etc) .
The 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. 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.
In addition, the pharmaceutical compositions covered by the present invention is also applicable as transdermal preparation, e.g. in the form of ointment, gel or patch.
The administration routes mentioned above as examples are described in the art (literature) by themselves as well (c.f. e.g. Remington's Pharmaceutical Sciences, Edition 18th, Mack Publishing Co., Easton, USA (1990)).
The pharmaceutical 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
Pharmaceutical Sciences] ) .
In addition, 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
formulations in order to prevent and/or treat diseases caused by the bacterium Mycobacterium tuberculosis or any other
Mycobacteria .
In addition, the present invention also covers
procedure (s) to prepare pharmaceutically applicable
compositions containing the compounds possessing the general formula (I) and/or their pharmaceutically applicable organic and inorganic salts to prevent and/or treat diseases caused by the bacterium Mycobacterium tuberculosis or any other
Mycobacteria .
In addition, the present invention also covers
pharmaceutical protocols to prevent and/or treat diseases caused by the bacterium Mycobacterium tuberculosis or any other Mycobacteria (such as tuberculotic diseases of the lung and other tissues) during which protocols patients suffering from such diseases are administered efficient, non-toxic doses of compounds possessing the general formula (I) and/or their pharmaceutically applicable organic and inorganic salts.
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.
During in silico docking, 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) .
Preparation of compounds possessing the general formula (I)
The compounds covered by the present invention and possessing the general formula (I) were prepared by
condensation reaction using piperazine and aldehydes, followed by reduction. In the first step, piperazine containing 1-tert- butoxycarbonyl protecting group on on of the piperazine nitrogen atom was reacted with aromatic aldehyde; then the protecting group was removed the compound was reacted with cinnamic aldehyde.
Some compounds were crystallized in the form of salts of hydrochloric acid.
Naphtyl-piperazines were prepared via reductive amination using 1- tert-butoxycarbonyl piperazine and naphtyl-carbaldehyde followed by removal of the tert-butoxycarbonyl (BOC) protecting group (Reaction scheme 1) .
(AcO)3BHNa
rt Re action scheme 1
The reaction was generalized for
a) substituted naphtyl-carbaldehydes ,
b) substituted benzaldehydes , and
c) heterocyclic carbaldehyde-derivatives .
The cinnamic naphtyl-methyl piperazines were prepared by reacting naphtyl-methyl piperazines with cinnamic . aldehydes via reductive amination (Reaction scheme 2) .
Reaction scheme 2
The reaction was generalized for:
a) ring-substituted cinnamic aldehydes,
b) allyl-chain substituted cinnamic aldehydes, and
c) analogues of cinnamic aldehydes containing triple bond in the side chain ( 3-phenylpropargylaldehydes ) .
Generated compounds
Using the above described procedures and based on the examples below, the compounds possessing the general formula (I) covered in the present invention are summarized in Tables 1-6.
The compounds were characterized using thin layer chromatography (Merck TLC Silica gel 60 F2s4) and NMR (11.7 Tesla Bruker Avance-500 (double channel) spectrometer, 300K, d6-DMSO solvent) .
Mass spectra were recorded using electrospray ion source, on a Bruker Esquire 3000+ iontrap equipment. Samples were dissolved in acetonitrile/water 1:1 (v/v) solvent, also containing 0.1% AcOH, and were injected at a flow rate of 10 μΐ/min. Spectra were recorded in the positive mood, in the interval 50-3000 m/z, using 13,000 m/z/sec sampling speed.
Elemental analysis of the compounds were performed using a VARIO EL III automated instrument.
Table 1 Naphtyl group substituted cinnamic naphtyl methyl piperazines
mass spectrum
TB 1602 l-(2- CHCl3:MeOH
Methoxynaphtalen- 95:5 1-ylmethyl) -4- Rf=0, 33
1
[ (E) -3-
C25H28°2
372.51 phenylallyl] - piperazine
TB 1603 l-(6- CHCl3:MeOH
Methoxynaphtalen- 95:5 1-ylmethyl) -4- Rf=0, 34
C25H28°2 [ (E)-3-
372.51
phenylallyl ] - piperazine
piperazine
415.41
di ydrochloride
TB 1605 1- (Naphtalen-2- CHCl3:MeOH ylmethyl)-4-[ (E)- 95: 5
C24H26N2 3-phenylallyl] - Rf=0, 51
342.49 piperazine
TB 1615 4-{4-[ (E)-3- CHCl3: eOH phenylallyl] - 95:5 piperazin-1- Rf=0, 69 ylmethyl } -
358.49
naphtalene-l-ol
TB 1616 l-{4-[ (E)-3- CHCl3:MeOH phenylallyl] - 95:5 piperazin-1- Rf=0, 13 ylmethyl}-
358.49 naphtalene-2-ol
Code Structure/ Name TLC elemental analysis/
mass spectrum
TB 1620 2-(l-{4-[ (E)-3- CHCl3:MeOH phenylallyl ] - 95:5 piperazin-1- Rf=0, 0 ylmethyl } -
naphtalen-2-
430.55
yloxy) -acetic acid
methyl ester
TB 1619 CIH 2-(-4-{4-[ (E)-3- CHCl3:MeOH phenylallyl] - 95:5 piperazin-1- Rf=0,23 ylmethyl}-
C27H20N2°3 *2HCI /0 naphtalen-1-
503.47 yloxy) -acetic acid
methyl ester
dihydrochloride
Table 2 Heterocyclic carbaldehyde derivatives
mass spectrum
TB 1608 3-{4-[ (E)-3- CHCl3:MeOH phenylallyl] - 9:1
C22H25N3 piperazin-1- Rf=0,28 331.46 ylmethyl}-3H- indole
piperazine
405.37
dihydrochloride
TB 1610 CIH 1- (2, 3-dihydro- CHCl3:MeOH benzofuran-7- 95:5 ylmethyl) -4- [ (E) - Rf=0, 19
Cj-HjgN *2HCI 3-phenylallyl] - 407.39 piperazine
dihydrochloride
Table 3 Substituted benzaldehyde derivatives
Code Structure/ Name Rf
elemental analysis/
mass spectrum
TB 1611 CIH Qt 1- ( 3-nitrobenzyl ) - CHCl3:MeOH
4- [ (E) -3-phenyl95:5 allyl] -piperazine Rf=0, 55
C20H23N3O2 *2HCI dihydrochloride
410.35
TB 1612 3-{4-[ (E)-3- CHCl3:MeOH phenylallyl] - 95: 5
C20H24N2O piperazin-1- Rf=0, 14 308.43
ylmethyl } -phenol
000008
20
mass spectrum
trihydrochloride
TB 1635 l-[ (E)-3-(3- CHCl3:MeOH
Bromophenyl ) - 95:5 allyl] -4- (4- Rf=0, 23
1
methoxynaphtalen- 1-ylmethyl ) - piperazine
hydrochloride
TB 1636 l-[ (E)-3-(2- CHCl3: eOH
Bromophenyl ) - 95:5 allyl] -4- (4- Rf=0, 40 methoxynaphtalen- 1-ylmethyl ) - piperazine
hydrochloride
TB 1638 l-[ (E)-3-(3- CHCl3:MeOH
A aw Bromophenyl ) - 95:5
I allyl] -4- (2- Rf=0, 43 methoxynaphtalen- 1-ylmethyl ) - piperazine
hidrichloride
TB 1639 l-[ (E)-3-(2- CHCl3:MeOH
Bromophenyl) - 95:5 allyl] -4- (2- Rf=0,35 methoxynaphtalen- 1-ylmethyl) - piperazine
hydrochloride
Table 6 3-Phenylpropargylaldehyde-szarmazekok
Code Structure/ Name Rf
elemental analysis/
mass spectrum
TB 1645 l-(4- Hexan:EtOA
Methoxynaphtalen- c
l-ylmethyl)-4-(3- .2:1
C25H26N20 phenylprop-2- Rf=0,22
370.50 o ynyl ) -piperazine
In all cases where the names and the structures of any compound presented in the tables above disagree, the structure (structural formula) has to be considered to be authoritative.
The invention will be specifically illustrated using the examples below, however, the invention is not limited to the examples below. EXAMPLES
Example 1
Preparation of 1- ( tert-butoxycarbonyl) -4- (2-methoxynaphtalen-l- ylmethyl) -piperazine (Reaction scheme)
10,0 g (53,7 mmol) 2-methoxynaphtaldehyde is dissolved in 100 ml dichloromethane . 10,1 g (53,7 mmol) 1-Boc-piperazine is added at room temperature and the mixture is stirred for 10 min. Then 14,8 g (69,8 mmol) sodium triacetoxyborohydride is added into the reaction mixture in small doses using strong stirring (exothermic reaction) at room temperature and the mixture is stirred for 3 hours at room temperature. The reaction is followed by TLC and after completion of the reaction, 100 ml saturated NaHC03 solution and 100 ml MTBE are added. After 15 min stirring, the organic phase is separated and is washed with 1x100 ml saturated NaHC03 solution then with 1x100 ml water, then it is dried on anhydrous Na2S04 and evaporated. The raw product is crystallized from 50 ml iso- propanol .
Yield: 14,76 g (77 %) white, crystalline product.
TLC: Rf=0,75 (CHC13:MeOH 95:5)
Example 2
Preparation of 1- (2-Methoxynaphtalen-l-yl-methyl) -piperazine (Reaction scheme 1)
14,7 g (41,2 mmol) 1- ( tert-butoxycarbonyl ) -4- ( 2- methoxynaphtalen-l-ylmethyl ) -piperazine is dissolved in 120 ml ethyl acetate, saturated with hydrochloric acid. The reaction mixture is stirred for 3 hours at room temperature. If the reaction is completed as followed by TLC ( chloroform: MeOH
95:5), then the reaction mixture is evaporated using rotadest at decreased pressure. The evaporation residue is dissolved in the mixture of 120 ml saturated NaHC03 and 300 ml EtOAc and is stirred till phase separation. The organic phase is separated and is washed with 1x100 ml saturated NaHC03 solution then with 1x100 ml water, then it is dried on anhydrous Na2S04 and evaporated .
Yield: 10,0 g (95%) white oil, solidifying during storage.
TLC: Rf=0,ll (CHC13:MeOH 95:5)
Example 3
Preparation of 1- (2-Methoxynaphtalen-l-ylmethyl) -4- [ (E) -3- (3- methoxyphenyl) -allyl] -piperazine hydrochloride (Reaction scheme 2)
1,00 g (6,17 mmol) 3-methoxycinnamic aldehyde and 1,60 g (6,17 mmol) 1- ( 2-methoxynaphtalen-l-ylmethyl ) -piperazine are
dissolved in 10 ml dichloromethane . The reaction mixture is stirred for 30 min at 25°C-on; then 0,35 ml (6,17 mmol) acetic acid is added followed by addition of 1,7 g (8,02 mmol) sodium triacetoxyborohydride in small doses (exothermic reaction) . The mixture is stirred for 2 hours at 25°C. If the reaction is completed as followed by TLC (chloroform: eOH 95:5), 15 ml saturated NaHC03 solution and 30 ml MTBE are added. After 10-15 min stirring, the organic phase is separated from the ether phase and is washed with 1x100 ml saturated NaHC03 solution
then with 1x100 ml water, then it is dried on anhydrous a2S04 and evaporated. The resulting 2,4g (95%) oily product is transformed into salt of hydrochloric acid using 20ml iso- propanol / hydrochloric acid.
TLC: Rf=0,32 (CHC13:MeOH 95:5). 1H-NMR : 8,30 (1H, d) , 8,14 (1H ,d), 7,95 (1H, d) , 7,54 (3H, m) , 7,33 (1 H, t) , 7,25 (1H, t) , 7,03 (2H, m) , 6,85 (1H, d) , 6,75 (1H, s), 6,42 (1H, m) , 4,80 (2H, m) , 4,00 (3H, s), 3,92 (2H, m) , 3,66 (3H, s), 3,39 (8H, m) .
The biological effects of the compounds covered by the present invention were investigated as follows.
Example 4 : Enzyme inhibition
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.). 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.
In parallel to the measurements with the Mycobacterium tuberculosis dUTPase enzyme, we also carried out similar investigations with the human dUTPase enzyme, as well. Using those methods, we determine the lowest inhibitor concentration where dUTPase inhibition is still observable. In all
experiments, the concentration of the enzyme was 50 nM.
The compounds to be investigated were dissolved in DMSO result in a final stock concentration of 25 mM. Aliquots of this stock solution was added to the enzyme reaction mixtures In multiple cases, precipitation was observed.
The measurements were performed with selected compounds and results are summarized in Table 7.
Table 7 : dUTPase-inhibitory effects of selected compounds
Code Minimal Inhibitory Remark
inhibitory effect on
concentration human dUTPase
for M. (measured at
tuberculosis 2.5 mM
dUTPase (mM) compound
concentration)
TB 1604 1.9 inhibition is precipitated
observed
TB 1605 2.3 no inhibition precipitated
TB 1620 1.9 no inhibition precipitated
TB 1625 1.7 inhibition is
observed
TB 1628 1.6 inhibition is precipitated
observed
TB 1629 1.6 inhibition is
observed
TB 1630 0.4 no inhibition
TB 1632 1.5 inhibition is precipitated
observed
TB 1635 1.5 inhibition is precipitated
observed
TB 1636 1.5 no inhibition precipitated
TB 1637 1.7 inhibition is precipitated
observed
TB 1638 1.5 inhibition is precipitated
observed
TB 1640 1.7 inhibition is precipitated
observed
TB 1642 1.7 inhibition is
observed
TB 1644 1.5 inhibition is
observed
TB 1645 1.7 inhibition is precipitated
observed
Example 5: Investigation of binding of the compounds to
Mycobacterium tuberculosis dUTPase by X-ray crystallography
For the ligand yielding the best results in the enzyme- inhibitory assays (Table 7), code-named TB 1630, we attempted a co-crystallization trial with the dUTPase enzyme, aiming to solve the molecular structure of the enzyme-complex.
Crystallization :
Crystallization of Mycobacterium tuberculosis dUTPase was carried out by co-crystallization in the presence of TB 1630 compound. We applied several alterations in the method
described in the literature (Varga et al. Biochem Biophys Res Commun. 2008 373:p. 8-13.) . Hanging-drop vapour diffusion method was applied and the complex of the enzyme and the compound was crystallized in the mixture of 50 mM Tris-HCl buffer, also containing 1.25-1.7 M ammonium-sulphate and 12 %
glycerol, at pH=7.5. The compound TB 1630 was present at 2.5 mM concentration in the complex. After 2-4 weeks, several protein crystals appeared.
Under these conditions, Mycobacterium tuberculosis dUTPase protein does not form crystals in the absence of bound ligands. Thus, the appearance of protein crystals in the presence of the compounds indicated that crystallization was facilitated by the binding of the compound TB 1630. This also indicates that the compound TB 1630 is present as bound to the protein in the crystals.
X-ray crystallographic data collection was performed on a synchrotron (ESRF Grenoble, beamline 14-4, Mycobacterium tuberculosis dUTPase together with compound TB 1630, full data set was collected, resolution 2 A) .
Structure determination
The XDS program and molecular replacement was used for data analysis and solving the phase problem. The very high resolution structure of a point mutant of Mycobacterium
tuberculosis dUTPase was used as the model (PDB ID: 3HZA) .
Refinement was carried out using the Refmac software from the CCP4 software package. Model building was performed using Coot. The determined structure indicated that the compound TB
1630 binds to the Mycobacterium tuberculosis dUTPase at a binding site that provides explanation for the enzyme
inhibitory and the biological effect. Example 6: Bacteriologic evaluations of the TB 16
derivatives : determining the minimal inhibitory concentration
(MIC) and the colony forming units (CFU) in M. tuberculosis and M. kansasii cultures
Using 4 week old fresh M. tuberculosis H37Rv (ATCC 27294) and Mycobacterium kansasii (ATCC 35775) cultures, 0.5 Mcfarland (1.5xl08 CFU/ml) (McFarland, J. Nephelometer J. Amer Med Ass, 1907. 14: p. 1176-1178.) suspensions were prepared in Sauton medium. The bacterial suspensions were diluted 103 and 104 times. 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 solutions were added to test tubes containing 5 ml Sula liquid medium (pH=6,5) (Sula, L. Bull World Health Organ, 1963. 29(5): p. 589-606; Sula, L. Bull World Health Organ, 1963. 29(5): p. 607-625). The test tubes were then infected with diluted bacterium suspensions (100 μΐ) and these were incubated for 28 days in 37 °C. After the 28 days incubation period, the minimal inhibitory concentration (MIC) were determined, 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.
Bakteriol Parasitenkd infektionskr hyg Abt I orig, 1931. 120: p. 127; Jensen, K. Bakteriol Parasitenkd infektionskr hyg Agt I Orig, 1932. 125: p. 222), and following an incubation period of 4-6 weeks, the colonies were counted; this way we identified the CFU value (colony forming units). The CFU value, multiplied by the dilution concentration, was compared to the initial bacterium number from the 0.5 McFarland suspension (1.5 x 108
CFU/ml) . The MIC and CFU values were determined in at least two. independent experiments in each case.
The experiments were conducted in the Bacteriologic
Reference Laboratory of Corden International Hungary Ltd. on the campus of the Koranyi Tuberculosis and Pulmonology
Institute, Budapest.
The results are given in Tables 8, 9 and 10.
Table 8: The MIC values of the TB 16 derivatives in M.
tuberculosis cultures:
TB 1626 5 10.5
TB 1627 5 12.0
TB 1628 5 10.2
TB 1629 20 40.2
TB 1630 5 10.1
TB 1631 8 15.3
TB 1631 10 19.1
TB 632 5 9.5
TB 1633 60 154.9
TB 1634 100 279.9
TB 1635 5 9.5
TB 1636 5 9.5
TB 1637 10 21.8
TB 1638 10 19.1
TB 1639 5 9.5
TB 640 10 21.8
TB 1641 5 10.4
TB 1642 5 10.8
TB 1643 10 21.6
TB 1644 10 19.5
TB 1645 20 45.1
Table 9: The MIC values of the TB 16 derivatives
kansasii cultures:
Those compounds that have low MIC values on the M.
tuberculosis bacterium were tested on multidrug-resistant bacterium strain (INH, RIF MDR A8 M. tuberculosis) . The MIC and CFU values were determined as we described above.
Table 10: The MIC values of some TB 16 derivatives on multidrug-resistant M. tuberculosis culture:
Example 7: In vitro cytotoxicity: Examination of
cytotoxicity and cytostaticity using colometric tetrazolium test (MTT) 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, MonoMac6, and PBMC cell lines.
In both types of trials, cell viability were determined by
MTT (3- (4, 5-dimethyltiazol-2-yl) -2, 5-diphenyl tetrazolium bromide) test {Gerlier, D. J Immunol Methods, 1986. 94(1-2): p. 57-63; Mosmann, T. J Immunol Methods, 1983. 65(1-2): p. 55-63; Slater et al., T. F. Biochim Biophys Acta, 1963. 77: p. 383- 93) .
In the case of HepG2 and MonoMac6 cell lines, aliquots from logarithmically dividing cell population were distributed on 96-well tissue-growth plate in 100 μΐ RPMI-1640 total medium (5xl03 cell/well) . In the case of the isolated human PBMC and the differentiated mouse bone marrow macrophage cells, on the day of the experiment we distributed the cells on the tissue- growth plate; 104 cells/well for mouse macrophage and 5*104
cells/well for human PBMC, both in serum-free RPMI-1640 medium.
After discarding 50 μΐ medium, we dissolved the compound to be tested in 150 μΐ serum-free medium, and after sterile- filtration, it was added to the cells in 4-8 parallel
experiments. In the cytotoxicity test, the cells were incubated at 37 °C for three hours, and then the compounds were washed out from the cells. In the cytostaticity test, the cells were incubated at 37 °C for three days in 5% CO2 atmosphere.
After the incubation period in both trials, 45 μΐ MTT solution were added to each wells (c = 2 mg/ml, solved in serum-free medium) . Following 3.5 hours of incubation, the tissue culture plate was centrifuged at 2000 rpm for 5 minutes, and the supernatant was carefully aspirated with a G30 needle, then it was discarded. The precipitated purple crystals were solved in 100 μΐ DMSO, and after 10 minutes agitation, the absorbance were determined at λ = 540 nm and 620 nm using ELISA plate reader spectrometer. The differences in the absorbance values measured at the two wavelengths were averaged (A) . The cytotoxicity and the cytostatic effects were computed with the following formula:
where A means the difference in the absorbance averaged in the 4-8 parallel experiments.
The measure of the cytotoxicity in percentage as the function of concentration was represented graphically, and by interpolation we gave the IC50 values in Table 10.
Table 11: Comparison of the MIC and IC50 alues for drug molecule TB 1601:
Example 8 : Production of pharmaceutical preparations a) Pills:
The following materials are mixed: 0.01-50% drug compound possessing the general formula (I), 15-50% lactose, 15-50% potato starch, 5-15% polyvinyl-pyrrolidone, 1-5% talcum, 0.01- 3% magnesium-stearate, 1-3% colloidal silicon-dioxide, and 2-7% ultraamylopectin . The mixture is granulated by the wet
granulation method and compressed into tablets. b) 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. c) Capsules:
The following materials are mixed thoroughly: 0.01-50% drug compound possessing the general formula (I), 1-5% sodium- lauryl-sulphate, 15-50% starch, 15-50% lactose, 1-3% colloidal
silicon-dioxide, and 0.01-3% magnesium-stearate . The mixture is pressed through a filter and is loaded into capsules. d) Suspensions :
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 :
0.01-15% drug compound possessing the general formula (I), and 1-20% lactose is mixed thoroughly, then this mixture is added to a fat preparation (final concentration of the fat in the suppositories will be 50-95%), suitable for production of suppositories (e.g. itepsol 4), melted and cooled down to 35 °C. The mixture such prepared is homogenized and is filled into cooled forms.
£) Lyophilized powder ampoule preparations:
Using bi-distilled water, adequate for injection, a 5 % aqueous solution of mannitol or lactose is prepared and sterile filtered. Using the same method, a 0.01-5% sterile solution of the drug compound possessing the general formula (I) . The two solutions are mixed under aseptic circumstances and 1 ml aliquots are filled into ampoules. The ampoule content is lyophilized and the ampoules are closed under nitrogen
atmosphere. The content of the ampoules is dissolved right before use in sterile water or sterile physiological salt solution (0.9% sodium chloride) .
Claims
Compounds possessing the general formula
R stands for hydrogen atom, halogen atom, alkyl group,
hydroxyl group, alkoxy group, alkylamine group, nitro group, nitrile group;
Q stands for -C≡C- or -HC=CR' - group, where R' stands for alkyl group,
A stands for:
(i) unsubstituted phenyl or naphtalenyl group or phenyl or naphtalenyl group substituted with halogen atom, alkyl group, hydroxyl group, alkoxy group, alkylamine group, nitro group, nitrile group, or
(ii) unsubstituted or alkyl group-substituted heterocycle; and pharmaceutically applicable organic or inorganic salts of compounds possessing the general formula (I).
2. Compounds possessing the general formula (I) where A stands for a heterocyclic group selected from unsubstituted or alkyl group substituted 2 , 3-dihydro-benzofuran, indole or quinoline group and pharmaceutically applicable organic or inorganic salts thereof.
3. The compounds according to the general formula (I) selected from
1- (4-Methoxynaphtalen-l-ylmethyl) -4- [ (E) -3-phenylallyl ] - piperazine dihydrochloride,
1- (2-Methoxynaphtalen-l-ylmethyl) -4- [ (E) -3-phenylallyl] - piperazine,
1- (6-Methoxynaphtalen-l-ylmethyl) -4- [ (E) -3-phenylallyl ] - piperazine,
1- (Naphtalen-l-ylmethyl ) -4- [ (E) -3-phenylallyl] -piperazine dihydrochloride,
1- (Naphtalen-2-ylmethyl) -4- [ (E) -3-phenylallyl] -piperazine,
4-{4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -naphtalene-l-ol ,
1- {4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -naphtalene-2-ol,
2- (l-{4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -naphtalen-2- yloxy) -acetic acid methyl ester,
2- (-4-{4-[(E) -3-phenylallyl] -piperazin-l-ylmethyl } -naphtalen-1- yloxy) -acetic acid methyl ester dihydrochloride,
4-{4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -quinoline trihydrochloride,
7-methoxy-4- { - [ (E) -3-phenylallyl ] -piperazin-l-ylmethyl } - quinoline trihydrochloride,
3- {4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -3H-indole, 1- (Benzofuran-2-ylmethyl ) -4- [ (E) -3-phenylallyl] -piperazine dihydrochloride,
1- (2, 3-dihydro-benzofuran-7-ylmethyl) -4- [ (E) -3-phenylallyl ] - piperazine dihydrochloride,
1- (3-nitrobenzyl) -4- [ (E) -3-phenyl-allyl ] -piperazine
dihydrochloride,
3-{4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -phenol,
4-{4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -benzonitrile, 3- { 4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -phenylamine,
4- { - [ (E) -3-Phenylallyl ] -piperazin-l-ylmethyl } -benzamid,
4- { - [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -phenol,
4-{4-[ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -benzoic acid dihydrochloride,
2- (4-{4- [ (E) -3-phenylallyl] -piperazin-l-ylmethyl } -phenoxyl ) - acetic acid methyl ester dihydrochloride,
(4-{ [ (E) -3- [4- ( -methoxynaphtalene-l-ylmethyl) -piperazin-l-yl ] - propenyl } -phenyl ) -dimethylamine trihydrochloride,
(4-{ (E) -3- [4- (2-methoxynaphtalene-l-ylmethyl) -piperazine-l-yl ] - propeniyl } -phenyl ) -dimethylamine,
1- (2-methoxynaphtalen-l-ylmethyl) -4- [ (E) -3- ( 3-methoxy-phenyl ) - allyl] -piperazine dihydrochloride,
1- (4-methoxynaphtalen-l-ylmethyl) -4- [(E) -3- ( 4-nitrophenyl ) - allyl] -piperazine,
1- (2-methoxynaphtalen-l-ylmethyl) -4- [ (E) -3- (4-nitrophenyl) - allyl] -piperazine,
4- { (E) -3- [4- (2-methoxynaphtalen-l-ylmethyl) -piperazine-l-yl] - propenyl } -phenylamine trihydrochloride,
1- (4-methoxynaphtalen-l-ylmethyl) -4- [ (E) -3- ( 3-methoxyiphenyl ) - allyl] -piperazine dihydrochloride,
1- [ (E) -3- (4-bromophenyl) -allyl] -4- (2-methoxynaphtalen-l- ylmethyl) -piperazine dihydrochloride,
1- [ (E) -3- (4-bromophenyl) -allyl] -4- ( 4-methoxynaphtalen-l- ylmethyl) -piperazine dihydrochloride,
4- { (E) -3- [4- (4-methoxynaphtalen-l-ylmethyl) -piperazin-l-yl] - propenyl } -phenylamine trihydrochloride,
1- [ (E) -3- (3-Bromophenyl) -allyl] -4- (4-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride, 1- [ (E) -3- (2-Bromophenyl) -allyl] -4- ( 4-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
1- [ (E) -3- (3-Bromophenyl) -allyl] -4- (2-methoxynaphtalen-l- ylmethyl) -piperazine hidrichloride,
1- [ (E) -3- (2-Bromophenyl) -allyl] -4- ( 2-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
1- [ (E) -3- (3-chlorophenyl) -allyl] -4- ( 4-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
1- [ (E) -3- (3-fluorophenyl) -allyl] -4- ( 4-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
1- [ (E) -3- (4-fluorophenyl) -allyl] -4- ( -methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
1- (4-methoxynaphtalen-l-ylmethyl) -4- [ (E) -3- (2- trifluormethylphenyl) -allyl] -piperazine hydrochloride,
4- [ (E) -2-methyl-3-phenylallyl] -1- ( 4-methoxynaphtalen-l- ylmethyl ) -piperazine hydrochloride,
4- [ (E) -2-methyl-3-phenylallyl] -1- (2-methoxynaphtalen-l- ylmethyl) -piperazine hydrochloride,
1- (4-Methoxynaphtalen-l-ylmethyl) -4- ( 3-phenylprop-2-ynyl ) - piperazine,
and the pharmaceutically applicable organic or inorganic salts of these compounds.
4. Use of the compounds according to any of Claims 1 to 3 possessing the general formula (I) and their pharmaceutically applicable organic or inorganic salts to prevent and/or treat diseases caused by the bacterium Mycobacterium tuberculosis or any other Mycobacteria.
5. Pharmaceutical preparation characterized by that it contains as active ingredient one or more compounds according to any of Claims 1 to 3, possessing the general formula (I) and/or their pharmaceutically applicable organic or inorganic salts in therapeutically effective amounts, in addition to one or more pharmaceutically applicable diluent, excipient and/or inert carrier.
6. Use of a pharmaceutical preparation according to Claim 5 to prevent and/or treat diseases caused by the bacterium Mycobacterium tuberculosis or any other Mycobacteria.
7. Process for manufacture of a pharmaceutical preparations to prevent and/or treat diseases caused by the bacterium Mycobacterium tuberculosis or any other Mycobacteria
characterized by that it contains as active ingredient one or more compounds according to any of Claims 1 to 3, possessing the general formula (I) and/or their pharmaceutically
applicable organic or inorganic salts.
8. Pharmaceutical treatment protocol characterized in
administration of a non-toxic dose of one or more compound according to any of Claims 1 to 3, possessing the general formula (I) and/or their pharmaceutically applicable salts patients suffering from disease caused by the bacterium
Mycobacterium tuberculosis or any other Mycobacteria.
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WO2005107809A2 (en) * | 2004-05-12 | 2005-11-17 | Lupin Limited | Antimycobacterial pharmaceutical composition comprising an antitubercular drug |
EP1857442A2 (en) * | 2002-09-20 | 2007-11-21 | Lupin Limited | Novel antimycobacterial compounds |
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WO2005107809A2 (en) * | 2004-05-12 | 2005-11-17 | Lupin Limited | Antimycobacterial pharmaceutical composition comprising an antitubercular drug |
Non-Patent Citations (4)
Title |
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DATABASE BEILSTEIN MALINKA, H.W. ET AL.: "Synthesis and preliminary screening of derivatives of 2-(4- arylperazin-1-ylalkyl)-3-oxoisothiazolo[5,4-b] pyridines as CNS and antimycobacterial agents", Database accession no. RN8648482 * |
KOSSAKOWSKI, JERZY ET AL.: "Synthesis and Evaluation of in Vitro Biological Activity of 4-Substituted Arylpiperazine Derivatives of 1, 7, 8, 9-Tetrachloro-10,10-dimethoxy- 4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione.", MOLECULES, vol. 14, 2009, pages 5189 - 5202 * |
PHARMAZIE, vol. 55, no. 6, pages 416 - 425 * |
XIN, HE ET AL.: "Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides.", BIOORG MED CHEM., vol. 15, no. 21, 2007, pages 6649 - 6658 * |
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