WO2016091228A1 - Substituted phenyltetrazole, its use and pharmaceutical preparation containing it - Google Patents
Substituted phenyltetrazole, its use and pharmaceutical preparation containing it Download PDFInfo
- Publication number
- WO2016091228A1 WO2016091228A1 PCT/CZ2015/000126 CZ2015000126W WO2016091228A1 WO 2016091228 A1 WO2016091228 A1 WO 2016091228A1 CZ 2015000126 W CZ2015000126 W CZ 2015000126W WO 2016091228 A1 WO2016091228 A1 WO 2016091228A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tetrazole
- dinitrophenyl
- alkyl
- general formula
- substituted
- Prior art date
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- 0 *c1cc(NC(C(CCCC2)CCCC2=C)=O)cc([N+]([O-])=O)c1 Chemical compound *c1cc(NC(C(CCCC2)CCCC2=C)=O)cc([N+]([O-])=O)c1 0.000 description 3
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- 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 relates to the new antituberculosis agents based on the nitro group- substituted phenyltetrazole, which are active against drug-susceptible and multidrug-resistant strains of mycobacteria.
- Tuberculosis is considered as a major global health problem, especially due to the increasing emergence of its multidrug resistant (MDR-TB) and extensively drug resistant (XDR-TB) forms.
- MDR-TB multidrug resistant
- XDR-TB extensively drug resistant
- TB is highly infectious disease caused by Mycobacterium tuberculosis ⁇ M.tb.), which is spread by air from the patients with pulmonary form of TB.
- Tuberculosis caused by Mycobacterium tuberculosis complex (MTB), belongs for many years to the most widespread infectious diseases in the world.
- M.tb Mycobacterium tuberculosis complex
- WHO Global Tuberculosis Report 2014
- TB the second greatest killer worldwide due to a single infectious agent.
- Treatment regimen of drug susceptible TB consist of the administration of isoniazid, rifampicin, pyrazinamide a ethambutol for 2 month followed by the administration of isoniazid and rifampicin for 4-6 months.
- Resistant forms of TB must be treated by second and third line antiTB drugs, such as fluoroquinolones, amikacin, kanamycin, streptomycin, cycloserine, ethionamide, p-aminosalicylic acid, for the period of 18 - 24 months.
- second and third line antiTB drugs such as fluoroquinolones, amikacin, kanamycin, streptomycin, cycloserine, ethionamide, p-aminosalicylic acid
- New antiTB drugs should possess new mechanism of action, which would overcome the possibility of cross resistances with common antiTB drugs.
- Nitroimidazole-oxazine PA-824 (Stover, C.K.; Warrener, P.; VanDevanter, D. R; Sherman, D.R.; Arain, T.
- nitro-dihydro-imidazooxazole OPC-67683 (Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M. OPC-67683, a nitro- dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLOS Medicine 2006 3, 2131-2143),
- Another antiTB active nitro group-bearing compounds are dinitrobenzamides (Christophe, T.; Jackson, M.; Jeon, H.K.; Fengerin, D.; Contreras-Dominguez, M.; Kim, J.; Genovesio, A.; Carralot, J.P.; Ewarm, F.; Kim, E.H.; Lee, S.Y.; Kang, S.; Seo, M.S.; Park, E.J.; Skovierova, H.; Pham, H.; Riccardi, G.; Nam, J.Y.; Marsollier, L.; Kempf, M.; Joly-Guillou, MX.; Oh, T.; Shin, W.K.; No, Z.; Nehrbass, U.; Brosch, R.; Cole, S.T.; Brodin, P.
- High content screening identifies decaprenyl-phosphoribose 2'epimerase as a target for intracellular antimycobacterial inhibitors.
- New substituted phenyltetrazoles of general formula (I) show significant activity against Mycobacterium tuberculosis, against non-tuberculous mycobacteria and also against clinically isolated multidrug resistant strains of M. tuberculosis.
- R is selected from the group consisting of: H, Q-Cn alkyl, phenyl-, or phenyl- substituted in positions 2, 3, 4 or 5, with one or more electron-acceptor groups comprising -N0 2 ,
- Another aspect of the invention is the use of the above mentioned nitro group-substituted phenyltetrazole of general formula (I) according to the current mvention as antituberculosis agent.
- Further aspect of the invention also relates to a pharmaceutical preparation containing the nitro group-substituted phenyltetrazole of general formula (I) as the active ingredient.
- the prepared compounds corresponding to general formula (I) were evaluated in Regional Institute of Public Health, Ostrava (Department for Diagnostic of Mycobacteria, Partyzanske namesti 7, 702 00 Ostrava) in in vitro conditions in Sula's semisynthetic liquid medium (SEVAC,ska) and the minimum inhibitory concentrations (MIC) were determined.
- the antimycobacterial activity was tested against Czech National Collection strains Mycobacterium tuberculosis CNCTC My 331/88, M. avium CNCTC My 330/88, and M kansasii CNCTC My 235/80, and a clinical isolate M. kansasii 6509/96.
- Isoniazid ( ⁇ ) was used as a standard in each assay. The results are shown in Table 2.
- MDR strains Mycobacterium tuberculosis
- the strains are labelled as M. tuberculosis 234/2005, M. tuberculosis 9449/2007, M. tuberculosis 8666/2010, M. tuberculosis Praha 1, M. tuberculosis Praha 4 and M. tuberculosis Praha 131 M. tuberculosis 7357/1998.
- These strains were clinically isolated from patients and are deposited in Regional Institute of Public Health, Ostrava (Department for Diagnostic of Mycobacteria, Partyzanske namesti 7, 702 00 Ostrava).
- the subject matter of the present invention comprises a highly antimycobacterially active low molecular weight tetrazole based compounds with a combination of a substituent -C3 ⁇ 4-R in the position 2 and 3,5-dinitrophenyl moiety bound in the position 5 of tetrazole.
- the starting dimethyl sulfate is a commercially available compound.
- the starting 5-(3,5- dinitrophenyl)-lH-tetrazole was prepared according to published procedure shown in Scheme 1 (Roh, J.; Artamonova, T. V.; Vavrova, K.; Koldobskii, G. I.; Hrabalek, A.Synthesis 2009, (13), 2175-2178).
- the starting benzyl bromide is a commercially available compound.
- the starting 5 -(3, 5- dinitrophenyl)-lH-tetrazole was prepared according to published procedure shown in Scheme 1 (Roh, J.; Artamonova, T. V.; Vavrova, K.; Koldobskii, G. I.; Hrabalek, K.:Synthesis 2009, (13), 2175-2178).
- the starting 4-methylbenzyl bromide is a commercially available compound.
- the starting 5- (3,5-dinitrophenyl)-lH-tetrazole was prepared according to published procedure shown in Scheme 1 (Roh, J.; Artamonova, T. V.; Vavrova, K.; Koldobskii, G. L; Hrabalek, A.:Synthesis 2009, (13), 2175-2178).
- Compound 8 was prepared using the above mentioned synthetic procedures from 5 -(3, 5- dinitrophenyl)-lH-tetrazole and 3,4-dichlorobenzyl chloride.
- the starting 5 -(3, 5- dinitrophenyl)-lH-tetrazole was prepared according to published procedure shown in Scheme 1.
- 3,4-Dichlorobenzyl chloride is a commercially available compound.
- Compound 10 was prepared using the above mentioned synthetic procedures from 5-(3,5- dinitrophenyl)-lH-tetrazole and propyl bromide.
- the starting 5-(3,5-dinitrophenyl)-lH- tetrazole was prepared according to published procedure shown in Scheme 1.
- Propyl bromide is a commercially available compound.
- Compound 11 was prepared using the above mentioned synthetic procedures from 5-(3,5- dinitrophenyl)-lH-tetrazole and dodecyl bromide.
- the starting 5-(3,5-dinitrophenyl)-lH- tetrazole was prepared according to published procedure shown in Scheme 1.
- Dodecyl bromide is a commercially available compound.
- Compound 12 was prepared using the above mentioned synthetic procedures from 5-(3,5- dinitrophenyl)-lH-tetrazole and 4-fluorobenzyl chloride.
- the starting 5-(3,5-dinitrophenyl)- lH-tetrazole was prepared according to published procedure shown in Scheme 1.
- 4- Fluorobenzyl chloride is a commercially available compound.
- Compound 13 was prepared using the above mentioned synthetic procedures from 5 -(3 ,5- dinitrophenyl)-lH-tetrazole and 3,4-difluorobenzyl chloride.
- the starting 5-(3,5- dinitrophenyl)-lH-tetrazole was prepared according to published procedure shown in Scheme 1 , 3,4-Difluorobenzyl chloride is a commercially available compound.
- Compound 14 was prepared using the above mentioned synthetic procedures from 5-(3,5- dinitrophenyl)-lH-tetrazole and 3,5-difluorobenzyl chloride.
- the starting 5-(3,5- dinitrophenyl)-lH-tetrazole was prepared according to published procedure shown in Scheme 1.
- 3,5-Difluorobenzyl chloride is a commercially available compound.
- Compound 15 was prepared using the above mentioned synthetic procedures from 5-(3,5- dinitrophenyl)-lH-tetrazole and 2-chloro-6-fluorobenzyl chloride.
- the starting 5-(3,5- dinitrophenyl)-lH-tetrazole was prepared according to published procedure shown in Scheme 1.
- 2-Chloro-6-fluorobenzyl chloride is a commercially available compound.
- Compound 16 was prepared using the above mentioned synthetic procedures from 5-(3,5- dinitrophenyl)-lH-tetrazole and 3-fluorobenzyl chloride.
- the starting 5-(3,5-dinitrophenyl)- lH-tetrazole was prepared according to published procedure shown in Scheme 1.
- 3-Fluorobenzyl chloride is a commercially available compound.
- 3-Bromobenzyl chloride is a commercially available compound.
- Compound 18 was prepared using the above mentioned synthetic procedures from 5-(3,5- dinitrophenyl)-lH-tetrazole and 3-methoxybenzyl chloride.
- the starting 5-(3,5- dinitrophenyl)-lH-tetrazole was prepared according to published procedure shown in Scheme 1.
- 3-Methoxybenzyl chloride is a commercially available compound.
- 3-Chlorobenzyl chloride is a commercially available compound.
- Example 1 ( " content of active substance 100 rug)
- Example 2 (content of active substance 200 mg " )
- Example 4 (content of active substance 400 mg )
- the active ingredient is mixed together with other individual excipients and the obtained mixture is compressed by regular manner using a conventional tablet machine.
- the therapeutically effective compound is mixed with lactose, potato starch and this mixture is granulated with povidone.
- the dried granulate is mixed then with sodium carboxymethylstarch, magnesium stearate, and talc.
- the obtained mixture is compressed by regular manner using a conventional tablet machine.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CZPV2014-892 | 2014-12-11 | ||
CZ2014-892A CZ306245B6 (cs) | 2014-12-11 | 2014-12-11 | Substituovaný fenyltetrazol, jeho použití a farmaceutický přípravek ho obsahující |
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WO2016091228A1 true WO2016091228A1 (en) | 2016-06-16 |
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PCT/CZ2015/000126 WO2016091228A1 (en) | 2014-12-11 | 2015-10-23 | Substituted phenyltetrazole, its use and pharmaceutical preparation containing it |
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CZ (1) | CZ306245B6 (cs) |
WO (1) | WO2016091228A1 (cs) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106038561A (zh) * | 2016-06-20 | 2016-10-26 | 中国药科大学 | 四氮唑取代芳香化合物在耐吡嗪酰胺结核病及结核病治疗中的医药用途 |
Citations (2)
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WO2010003533A2 (en) * | 2008-06-17 | 2010-01-14 | Institut Pasteur Korea | Anti-infective compounds |
WO2014161516A1 (en) * | 2013-04-04 | 2014-10-09 | Univerzita Karlova V Praze Farmaceuticka Fakulta V Hradci Kralove | Oxa- and thia-diazoles useful in the treatment of tuberculosis |
Family Cites Families (3)
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PE20120585A1 (es) * | 2009-02-03 | 2012-06-13 | Trius Therapeutics | Forma cristalina del fosfato de dihidrogeno r)-3-(4-(2-(2-metiltetrazol-5-il) piridin-5-il)-3-fluorofensil)-5-hidroximetil oxazolidin-2-ona |
US9730913B2 (en) * | 2011-10-13 | 2017-08-15 | The Johns Hopkins University | High affinity beta lactamase inhibitors |
CZ305622B6 (cs) * | 2013-04-04 | 2016-01-13 | Univerzita Karlova v Praze Farmaceutická fakulta v Hradci Králové | Substituovaný tetrazol, jeho použití a farmaceutický přípravek ho obsahující |
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- 2014-12-11 CZ CZ2014-892A patent/CZ306245B6/cs not_active IP Right Cessation
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- 2015-10-23 WO PCT/CZ2015/000126 patent/WO2016091228A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010003533A2 (en) * | 2008-06-17 | 2010-01-14 | Institut Pasteur Korea | Anti-infective compounds |
WO2014161516A1 (en) * | 2013-04-04 | 2014-10-09 | Univerzita Karlova V Praze Farmaceuticka Fakulta V Hradci Kralove | Oxa- and thia-diazoles useful in the treatment of tuberculosis |
Non-Patent Citations (11)
Title |
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CHRISTOPHE, T.; JACKSON, M.; JEON, H.K.; FENISTEIN, D.; CONTRERAS-DOMINGUEZ, M.; KIM, J.; GENOVESIO, A.; CARRALOT, J.P.; EWANN, F.: "High content screening identifies 'decaprenyl-phosphoribose 2 'epimerase -as a target for intracellular antimycobacterial inhibitors.", PLOS PATHOG, vol. 5, 2009, pages 1 - 10 |
J. CLAYDEN; N. GREEVES; S. WARREN; P. WOTHERS: "Organic Chemistry", 2001, OXFORD UNIVERSITY PRESS |
JOHN MCMURRY: "Organic Chemistry", 2004, BROOKS/COLE, A THOMSON LEARNING COMPANY |
L. G. WADE, JR.: "Organic Chemistry", 2006, PEARSON ,PRENTICE HALL INC. |
MAKAROV, V.; MANINA, G.; MIKUSOVA, K.; MOLLMANN, U.; RYABOVA, O.; SAINT-JOANIS, B.; DHAR, N.; PASCA, M.R.; BURONI, S.; LUCARELLI,: "Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis", SCIENCE, vol. 324, 2009, pages 801 - 804 |
MATSUMOTO, M.; HASHIZUME, H.; TOMISHIGE, ' T.; KAWASAKI, M.; TSUBOUCHI, H.; SASAKI, H.; SHIMOKAWA, Y.; KOMATSU, M.: "OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice.", PLOS MEDICINE, vol. 3, 2006, pages 2131 - 2143 |
ROH, J.; ARTAMONOVA, T. V.; VAVROVA, K.; KOLDOBSKII, G. I.; HRABALEK, A.:, SYNTHESIS, 2009, pages 2175 - 2178 |
ROH, J.; ARTAMONOVA, T. V.; VAVROVA, K.;; KOLDOBSKII, G. I.; HRABALEK, A., SYNTHESIS, 2009, pages 2175 - 2178 |
ROH, J; ARTAMONOVA, T. V.; VAVROVA, K.; KOLDOBSKII, G. I.; HRABALEK, A.:, SYNTHESIS, 2009, pages 2175 - 2178 |
STOVER, C.K.; WARRENER, P.; VANDEVANTER, D. R.; SHERMAN, D.R.; ARAIN, T.M.; LANGHORNE, M.H.; ANDERSON, S.W.; TOWELL, J.A.; YUAN, Y: "A small-molecule nitrimidazopyran drug candidate for the treatment of tuberculosis.", NATURE, vol. 405, 2000, pages 962 - 966 |
TIWARI, R.; MOLLMANN, U.; SANGHYUN, CH.; FRANZBLAU, S.G.; MILLER, P.A.; MILLER M.J.: "Design and syntheses of anti-tuberculosis agents inspired by BTZ043 using a scaffold simplification strategy", ACS MEDICINAL CHEMISTRY LETTERS, vol. 5, 2014, pages 587 - 591 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106038561A (zh) * | 2016-06-20 | 2016-10-26 | 中国药科大学 | 四氮唑取代芳香化合物在耐吡嗪酰胺结核病及结核病治疗中的医药用途 |
CN106038561B (zh) * | 2016-06-20 | 2019-03-01 | 中国药科大学 | 四氮唑取代芳香化合物在耐吡嗪酰胺结核病及结核病治疗中的医药用途 |
Also Published As
Publication number | Publication date |
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CZ2014892A3 (cs) | 2016-06-22 |
CZ306245B6 (cs) | 2016-10-26 |
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