WO2021161084A1 - N-(4-fluorophenyl)-5-phenyl-[1,2,4] triazolo [1,5-a] pyridine-2-carboxamide derivatives and their synthesis thereof - Google Patents
N-(4-fluorophenyl)-5-phenyl-[1,2,4] triazolo [1,5-a] pyridine-2-carboxamide derivatives and their synthesis thereof Download PDFInfo
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- 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
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- 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
Abstract
The present invention relates to the development of novel N-(4-fluorophenyl)-5-phenyl- [1,2,4]triazolo[1,5-a]pyridine-2-carboxamide derivatives for their different pharmacological activities. It particularly relates to the development of N-(4-fluorophenyl)-5-phenyl- [1,2,4]triazolo[1,5-a]pyridine-2-carboxamide derivatives as antiviral, anticancer, antifungal, hypoglycemic, anti-tubercular, sedative, anti-type 2 diabetes activity. It specifically relates to the N-(4-fluorophenyl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide derivatives for treatment of H37Rv and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB). The present invention also relates to the process for synthesis of N-(4-fluorophenyl)- 5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide derivatives. The invention further relates to method for treatment of method for treatment of diseases such as tuberculosis, type 2 diabetes, bacterial, viral and fungal infections. Invention addresses the challenges in working with chemical processes and products by inventing novel reaction methodology that can maximize the desired products and minimize by-products, designing new synthetic schemes that can simplify operations in chemical productions and seeking nontoxic reagent that are inherently environmentally and ecologically benign. Synthesis of novel N-(4- fluorophenyl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide derivatives is being employed to develop a novel synthetic methodology and their pharmacological applications. Novel series of N-(4-fluorophenyl)-5-phenyl-[1,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives were designed synthesized evaluated for their in vitro anti-mycobacterial activity against H37Rv and multi-drug-resistant (MDR) strains of mycobacterium tuberculosis (MTB). All the synthesized compounds were characterized by spectroscopic methods like Mass, NMR and elemental analysis.
Description
N-(4-FLUOROPHENYL)-5-PHENYL-[l 2,4] TRIAZOLO [1,5-a] XA\IIDE DERIVATIVES AND THEIR
THESIS THEREOF FIELD OF THE INVENTION
The present invention relates to the development of novel N-(4-fluorophenyl)-5-phenyl- [l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives for their different pharmacological activities. It particularly relates to the development of N-(4-fluorophenyl)-5-phenyl- [l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives as antiviral, anticancer, antifungal, hypoglycemic, anti-tubercular, sedative, anti-type 2 diabetes activity. It specifically relates to the N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives for treatment of H37Rv and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB). The present invention also relates to the process for synthesis of N-(4-fluorophenyl)- 5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives. The invention further relates to method for treatment of method for treatment of diseases such as tuberculosis, type 2 diabetes, bacterial, viral and fungal infections.
BACKGROUND OF THE INVENTION
In modern science the branch of chemistry shows more important role. Organic chemistry is the branch of chemistry, it is having a wider application in synthesis of novel organic molecules and their biological applications [S. M. Mallikarjuna, C.Sandeep, B. Padmashali, Der Pharma Chemica, 2016, 8, 262-268, H. K. Nagesh, B. Padmashali, C. Sandeep, T. E. Musturappa, M. R. Lokesh, Der Pharma Chemica, 2015, 7, 129-136, H. K. Nagesh, B. Padmashali, C, Sandeep, T. M. C. Yuvaraj, M. B. Siddesh, S. M. Mallikarjuna, Int J of Pharm Sci Review and Research, 2014, 28, 6-10, M. B. Siddesh, B. Padmashali, K. S. Thriveni,C. Sandeep, Heterocyclic Letters, 2014, 4, 503-514, M. B. Siddesh, B. Padmashali, K. S. Thriveni, C. Sandeep, B. C. Goudarshivnnanava, J of Appli Chem, 2013, 2, 1281-1288, M. B. Siddesh, B. padmashali, K. S. Thriveni, C. Sandeep, 2014b. Journal of Chemical science Vol. 126, 2014, pp. 821-826, K. S. Thriveni, B. Padmashali, M. B. Siddesh, C. Sandeep, Indian J. Pharm. Sci., 2014, 76, 332-338, Basavaraj Padmashali, B.N. Chidananda, Bhanuprakash G, Siddesh M. Basavaraj, Sandeep Chandrashekharappa, Katharigatta N. Venugopala. Vol 9(05), 2019, 133-140, C. Sandeep, K. N. Venugopala, S. K. Nayak, R. Gleiser,D. A. Garcia, H. M. Kumalo,R. S. Kulkarni, F. M. Mahomoodally, R. Venugopala, M. K. Mohan, B. Odhav, J. Mol. Struct., 2018, 1156, 377-384, C. Sandeep, K. N. Venugopala, R. M. Gleiser, A. Chetram, B. Padmashali, R. S. Kulkarni, R. Venugopala, B. Odhav, Chem. Biol. Drug
Des., 2016, 88, 899-904, C. Sandeep, K. N. Venugopala, C.Tratrat, F. M. Mahomoodally, B. E. Aldhubiab, M. Haroun, R. Venugopala, M. K. Mohan, R. S. Kulkarni, M. V. Attimarad, S. Harsha, B. Odhav, 2018, New J. of Chem., 2018, 42, 4893-4901, Sandeep C, Katharigatta N. Venugopala, Mohammed A. Khedr , Basavaraj Padmashali, Rashmi S. Kulkarni, Rashmi Venugopala, Bharti Odhav, Indian Journal of Pharmaceutical Education and Research 2016, Vol 51, Issue 3, 452-460, C. Sandeep, B. Padmashali, R. S. Kulkarni, J. Appl. Chem. (Lumami, India), 2013, 2, 1049-1056, C. Sandeep, B. Padmashali, K. N. Venugopala, R. S. Kulkarni, R. Venugopala, B. Odhav, Asian J. of Chem., 2016, 28, 1043-1048, S.M. Mallikaquna, C. Sandeep, Basavaraj Padmashali, IJPSR, 2017; Vol. 8(7): 2879-2885, S.K. Rashmi, T.H. Suresha Kumara, Gopalpur Nagendrappa, H.B.V. Sowmya, P.S. Sujan Ganapathy, C. Sandeep, Sunil S. More, International Journal of Pharmacy and Pharmaceutical Sciences 2015, 7 (2); 493-497, F. J. Swinborne, J. H. Hunt and G. Klinkert. Adv. Heterocycl. Chem., 1978, 23, 103-170, S.M. Mallikaquna, Basavaraj Padmashali, C. Sandeep, International Journal of Pharmacy and Pharmaceutical Sciences 2014, 6 (7); 423- 427, Sandeep Chandrashekharappa , Katharigatta N. Venugopala, Rashmi Venugopala, Basavaraj Padmashali, Journal of applied pharmaceutical science Vol. 9(02), 2019, pp 124- 128, Katharigatta N. Venugopala, Christophe Tratrat, Sandeep Chandrashekharappa, Mahesh Attimarad, NagarajaSreeharsha, Anroop B. Nair, ShinuPottathil, Rashmi Venugopala, Omar Husham Ahmed Al-Attraqchi, Mohamed A. Morsy,MichelyneHaroun, Bharti Odhav, Indian Journal of Pharmaceutical Education and Research, Vol 53, Issue 2, 2019, 121-128, Mohammed A. Khedr, Sandeep Chandrashekharappa„SubhrajyothiBhandary, Deepak Chopra, Bandar E Aldhubiab, Mahesh Attimarad, Bharti Odhav, Katharigatta N. Venugopala, Journal of bimolecular structure and Dynamics, 2017, Vol 36, Issue 8,1-16, Katharigatta N. Venugopala, Mohammed A. Khedr, MelendhranPillay, Susanta K. Nayak, Sandeep Chandrashekharappa, Bandar E. Aldhubiab , SreeHarsha, Mahesh Attimard, Bharti Odhav, Journal of biomolecular structure and Dynamics.2018 1-13, K. N. Venugopala, C. Sandeep, M. Pillay, H. Hassan Abdallah, F. M. Mahomoodally, S. Bhandary, D. Chopra, M. Attimaradl, B. E. Aldhubiab, A. B. Nair, N. Sreeharsha, M. A. Morsy, S. Pottathil, R. Venugopala, B. Odhav, K. Mlisana, Plosone, 2019, 1-22, W. Flitsch. in Comprehensive Heterocyclic Chemistry, edited by A. R. Katritzky and C. W. Rees, Vol. 4, p. 443. Pergamon Press, Oxford (1984), C. Sandeep, B. Padmashali, S. K. Rashmi, S. M. Mallikaquna, M. B. Siddesh, H. K. Nagesh, K. S. Thriveni, Heterocyclic Letters, 2014, 4, 371-376, C. Sandeep,
B. Padmashali, R. S. Kulkarni, Tetrahedron Lett., 2013, 54, 6411-6414, Raghu Ningegowda,
C.V. Kavitha, B.S.Priya, S.L. Gaonkar, M.V. Tejesvi, K.S. Rangappa and S.
Nanjundaswamy. Letters in Drug Design & Discovery. 2009, 6(7), 502-507, Raghu Ningegowda^ Amit Grover, Basappa, S.Ranjith, Kanchugarakoppal S.Rangappa, B.S.Priya. S. Nanjundaswamy.. Invest New Drugs. 2010, 28, 754-765, Raghu Ningegowda, Nanjunda Swamy. S, Raghu Ram Achar, Basappa, S.L. Gaonkar, S.Ranjith, George W. Yip, B.S.Priya, Asian Journal of Biochemical and Pharmaceutical Research. 2015, 2, (5), 186-197, Raghu Ningegowda, Savitha Bhaskaran, Ayyiliath.M.Sajith, Chandrashekar Aswathanarayanappa, M. Syed Ali Padusha, Nanjunda Swamy S, B. S. Priya, 4 us. J. of Chemistry, 70(1): 44-51, 2017, Raghu Ningegowda , Nanjunda Swamy Shivananju , P. Rajendran , Basappa , Feng Li , Raghu Ram Achar, Ramar Perumal Sarny , Pradeep Bist , Lina Hsiu Kim Lim, Gautam Sethi , Babu Shubha Priya. Apoptosis, 2017, 22(1), 145-157, Shubhavathi T, Mallesha Ningegowda, Nanjundaswamy S, Raghu Ningegowda, Ranjith S. B.S Priya. “European Journal of Chemistry, 2016, 7(4)-391-396, Chandrashekar Aswathanarayanappa, Eswarappa Bheemappa, Yadav D Bodke, Raghu Ningegowda, _Peethambar S K. Inventi Rapid: Med Chem. 2012, 2, 90-93, Chandrashekar Aswathanarayanappa, Eswarappa Bheemappa, Yadav D. Bodke, Venkatesh K. Bhovi, Raghu Ningegowda, M. C. Shivakumar, S. K. Peethambar, Sandeep Telkar. Med Chem Res. 2013, 22, 78-87, Chandrashekar Aswathanarayanappa, Eswarappa Bheemappa, Yadav D Bodke, Peethambar S.K, Srinivas P.V., Raghu Ningegowda. Arch. Pharm. Chem. Life Sci. 2013, 346, 7, 1-9, Chandrashekar Aswathanarayanappa, Eswarappa Bheemappa, Yadav D. Bodke, Shankarappa Biradar, Arun Sindhe, Sannenahalli Krishnegowda Peethambar, Raghu Ningegowda. International Journal of PharmTech Research. 2014, 6 (4), 1245-1255, Chandrashekar Aswathanarayanappa, Eswarappa Bheemappa, Yadav D Bodke, Raghu Ningegowda, Der Pharma Chemica, 2012, 4(l):399-406, Ranjith S. Raghu Ningegowda.Naniundaswamv S, B.S Priya European Journal of Chemistry, 9(4)2018, 353-359].
Heterocyclic chemistry is a branch of organic chemistry it deals with the synthesis of heterocyclic compounds containing hetero atoms like Nitrogen, oxygen and sulphur. They possess a wide range of biological applications. In this classes of heterocyclic compounds nitrogen containing heteroatoms are having wide range of synthesis and biological applications in organic and medicinal chemistry. The important nitrogen containing heterocyclic compounds like Pyrrolidine, Piperazine, Piperidine, morhpoline, imidazole, pyrazole, pyridine, pyrimidine and triazoles are important class of compounds. The triazole compounds having broad application in synthesis as well pharmacological properties in medicinal chemistry. The ethyl 5-bromo-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (4) is a key component of large molecule of pharmaceutical application. The synthesis of this type
of heterocycles has been previously reported in the literature by several synthetic methods such as amination of 2-aminopyridine with hydroxylamine-O-sulphonic acid (HSA), followed by cyclization with formic acid (18-27% overall yield) [[39] K. T. Potts, H. R. Burton, J. Bhattacharyya, J. Org. Chem. 1966, 31, 260-265], reaction of 2-aminopyridines with DMF-dimethyl acetal (DMF-DMA) followed by cyclization eith HAS (26-87% yield) [Y.-I. Lin, S. A. Lang, J. Org. Chem. 1981, 46, 3123-3124], cyclization of N-iminopyridine with HCN (2% yield) [T. Okamoto, M. Hirobe, Y. Tamai, E. Yabe, Chem. Pharm. Bull. 1966, 14, 506], isomerization of [l,2,4]-triazolo[4,3-a]pyridines in the presence of formic acid [K. T. Potts, C. R. Surapaneni, J. Heterocycl. Chem. 1970, 7, 1019], reaction of 2- aminopyridines with DMF-DMA and hydroxylamine, followed by cyclization with polyphosphoric acid (PPA) (54% overall yield) [S. Polanc, B. Vercek, B. Sek, B. Stanovnik, M. Tisler, J. Org.Chem. 1974, 39, 2143 2147], and acetylation of formamidoximes followed by heating in aqueous solution [B. Vercek, B. Stanovnik, M. Tisler, Z. Zrimsek, Org. Prep. Proc.lnt. 1978, 10, 293-295], There are a number of significant disadvantages to these methods, including low yields and scope limitation. In the particular, triazoles prepared from 2-aminopyridines bearing a substituent on the 6 position are especially challenge and the cyclization methods previously reported very limited success to prepare these types of compounds. We achieved this with good percentage of yield.
In continuation of our effort to identify novel potent anti-TB agents of synthesized compounds against both H37Rv and multi-drug-resistant (MDR) strains of mycobacterium tuberculosis (MTB). In the present invention we explore the impact of the functionalization at position 6 of a novel series of N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide derivatives on the anti-TB activity against both H37Rv and multi-drug-resistant (MDR) strains of mycobacterium tuberculosis (MTB).
Though there prior art reports which reported the several heterocyclic compounds and their derivatives as antibacterial or antiviral agents but none of the prior arts in the literature reported or disclosed the N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide derivatives which act as antibacterial, antiviral, anticancer, antifungal, hypoglycemic, anti-tubercular, sedative, anti-type 2 diabetes activity along with not having the drawbacks or limitations of the prior art or existing compounds. There exists several drawbacks or limitations with the prior art compounds to act as antibacterial, antiviral, anticancer, antifungal, hypoglycemic, anti-tubercular, sedative, anti-type 2 diabetes activity . Therefore, the present inventors have developed the as N-(4-fluorophenyl)-5-phenyl- [l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivative as antiviral, anticancer, antifungal,
hypoglycemic, anti-tubercular, sedative, anti-type 2 diabetes activity for treatment of bacterial, viral and fungal infections along with the developed compounds not having the drawbacks or limitations of the prior art or existing compounds. The invention also includes the development of suitable eco-friendly method for synthesis of N-(4-fluorophenyl)-5- phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives which act as antibacterial, antiviral, anticancer, antifungal, hypoglycemic, anti-tubercular, sedative, anti-type 2 diabetes activity.
OBJECTIVES OF THE INVENTION
The primary object of the present invention is the development of N-(4-fluorophenyl)-5- phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives and their various pharmacological applications.
The other object of the present invention is the development of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives against H37Rv and MDR strains of Mycobacterium tuberculosis.
The other object of the present invention is development of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives as antiviral, anticancer, antifungal, hypoglycemic, anti-tubercular, sedative, anti-type 2 diabetes activity.
The other object of the present invention is the development of a multistep synthetic method for preparation of N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives.
The other object of the present invention is to develop more efficient, mild technology and environment friendly reaction for synthesis of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives.
The other object of the present invention is the characterization of intermediates and final products by using spectroscopic methods like 1 H-NMR. 13C-NMR, LC-MS, IR & elemental analysis in development of N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide derivatives.
The other object of the present invention is development of coupling of different substituted aromatic boronic acid on the pyridine ring of l,2,4[l,5-a]pyridine via Suzuki coupling to check the impact of the substituent on the efficacy of the compounds.
The other object of the present invention is the development of compositions for the treatment of tuberculosis caused by H37Rv and MDR strains of Mycobacterium tuberculosis.
The other object of the present invention is the development of the method for treatment of tuberculosis caused by H37Rv and MDR strains of Mycobacterium tuberculosis.
The other object of the present invention is the development of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives which are cost-effective as they are synthesized by using cheap raw materials.
The other object of the present invention is the development of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives against H37Rv and MDR strains of Mycobacterium tuberculosis, which are easy to use with little technical expertise.
The other object of the present invention is the development of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives against H37Rv and MDR strains of Mycobacterium tuberculosis, which are safe and practical to use.
STATEMENT OF THE INVENTION
Compound of N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivative having the formula (I):
I
Wherein
R = 2-F, 2-OMe, 2-Cland 5-CF3, 4-OCF3, 4- Vinyl, 4H, 3-F and 2-Ethoxy. .
The halogen is selected from fluorine (F) or chlorine (Cl).
Pharmaceutical composition comprising the compound of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivative having the formula (I)and pharmaceutically acceptable excipients or carriers.
Process for synthesis of compound of N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5- a]pyridine-2-carboxamide derivative of formula (I) comprising:
a. synthesis of 6-bromo-2-imino-l-(((mesitylsulfonyl)oxy)amino)-2,3- dihydropyridin-l-ium (3) by reacting 2-amino 6 Bromo pyridine (2) with O- (mesitylsulfonyl)hydroxylamine (1) ; b. then synthesis of intermediate ethyl 5-bromo-[l,2,4]triazolo[l,5-a]pyridine-2- carboxylate (4) from using 6-bromo-2-imino-l-(((mesitylsulfonyl)oxy)amino)- 2,3-dihydropyridin-l-ium (3) with Diethyl oxalate; c. then synthesis of intermediate (5) by using the hydrolyzed product of ethyl 5- bromo- [1,2,4] triazolo[ 1 ,5-a]pyridine-2-carboxylate (4) ; d. then synthesis of intermediate amide (6) by using the intermediate (5) and 4- Fluoro aniline or derivatives of aniline; e. then reacting the intermediate amide (6) with various substituted phenyl boronic acid (7a-h) to form compound of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivative of formula (I).
The 6-bromo-2-imino-l-(((mesitylsulfonyl)oxy)amino)-2,3-dihydropyridin-l-ium (3) is synthesized by using 2-amino 6 Bromo pyridine (2) and 0-(mesitylsulfonyl)hydroxylamine (1) in presence of different chlorinated solvents at ambient temperature.
The ethyl 5-bromo-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (4) is synthesized by using 6- bromo-2-imino-l-(((mesitylsulfonyl)oxy)amino)-2,3-dihydropyridin-l-ium (3) and diethyl oxalate by cyclization with various bases and solvents.
The intermediate amide (6) is synthesized by using hydrolyzed product of ethyl 5-bromo-
[1.2.4]triazolo[l,5-a]pyridine-2-carboxylate (4) and 4-Fluoro aniline or derivatives of aniline in presence of different de-hydrating agents like EDCI, T3P, F1BTU, F1ATU.
The compound of N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivative formula (I) is synthesized by reacting the final C-C bond formation compounds intermediate (6) with various substituted phenyl boronic acid (7a-h) and Pyridine ring via Suzuki coupling using various palladium catalyst and ligands.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the development of novel N-(4-fluorophenyl)-5-phenyl-
[1.2.4]triazolo[l,5-a]pyridine-2-carboxamide derivatives for their different pharmacological activities. It particularly relates to the development of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives as antiviral, anticancer, antifungal, hypoglycemic, anti-tubercular, sedative, anti-type 2 diabetes activity. It specifically relates to
the N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives for treatment of H37Rv and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB). The present invention also relates to the process for synthesis of N-(4-fluorophenyl)- 5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives. The invention further relates to method for treatment of method for treatment of diseases such as tuberculosis, type 2 diabetes, bacterial, viral and fungal infections.
All chemicals were obtained from Sigma- Aldrich Co. Thin-layer chromatography (TLC) was performed on silica gel (Sigma-Aldrich Co.) on TLC aluminum foils using n-hexane and ethyl acetate as a solvent. The samples were visualized in an iodine chamber and ultraviolet (UV) chamber. 1 H-NMR spectra were recorded on Bruker AVANCE III 400 MHz instruments using DMSO d6 as a solvent. Chemical shifts (d) were recorded in parts per million (ppm) downfield from tetramethylsilane; then, the coupling constants (f) were recorded in Hertz. Splitting patterns for singlet (s), doublet (d), quartet (q), and multiplet (m) are abbreviated. Elemental analysis was performed using a Thermo Finnigan FLASH EA 1112 CHN analyzer. Mass spectra were recorded using the LC-MS-Agilent 1100 series with MSD (an ion trap) using 0.1% aqueous trifluoroacetic acid in an acetonitrile system on the C18-BDS column.
Synthesis of O-(mesitylsulfonyl) hydroxylamine (1) using mesitylene, chlorosulphonic acid, fcrf-butyl hydroxycarbamate and trifluroacetic acid in conventional and microwave methods. Synthesis and optimization of 6-bromo-2-imino-l-(((mesitylsulfonyl)oxy)amino)-2,3- dihydropyridin-l-ium (3) using 2-amino 6 Bromo pyridine (1) and O- (mesitylsulfonyl)hydroxylamine (2) with different chlorinated solvents at ambient temperature. Synthesis and optimization of key synthetic intermediate ethyl 5-bromo- [l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (4) using 6-bromo-2-imino-l- (((mesitylsulfonyl)oxy)amino)-2,3-dihydropyridin-l-ium (3) and diethyl oxalate by cyclization with various bases and solvents. Synthesis and optimization of key intermediate amide using hydrolysed product of ethyl 5-bromo-[l,2,4]triazolo[l,5-a]pyridine-2- carboxylate (4) and 4-Fluoro aniline or derivatives of aniline using different de-hydrating agents like EDCI, T3P, HBTU, HATU. Synthesis and optimization of final C-C bond formation compounds with various substituted phenyl boronic acid (7a-r) (both electron donating and withdrawing) and Pyridine ring via Suzuki coupling using various palladium catalyst and ligands. In-vitro and SAR studies of all final synthesized compounds have been descripted in the table.
Scheme 1:
WORKING EXAMPLES-Synthetic procedure: Preparation of 6-bromo-2-imino-l-(((mesitylsulfonyl)oxy)amino)-2,3-dihydropyridin-l- ium (3):
To a stirred solution of l(50g, 0.289mol) in 250 ml of anhydrous Dichloromethane was added 2, 4, 6-trimethylbenzene-l-sulfonyloxy amine2(62.2g, 0.289mol) at room temperature. The reaction mixture was stirred at 27°C under Nitrogen atmosphere for 16hrs. The completion of reaction was monitored by TLC. After reaction the reaction mixture was filtered using
Buchner funnel to separate the solid and washed the solids with 100ml of Dichloromethane, dried under vacuum for lhr at 30°C to afford to get 75g of 3 as a white solid (% yield 69.34). Yield = 75g, % of Yield=69.34. Mol. F rmulaCnHiftBiNiO S. Mol. Wt=374.25.
LC-MS: [m/z]+ = 375.10.
Preparation of ethyl 5-bromo-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (4):
To a stirred solution of 3(75g,0.200mol) in 400 ml of Absolute Ethanol was added Potassium hydroxide(13.44g, 0.240mol) stirred for 10 min, reaction mixture turns to black colour, then added Diethyl oxalate(87.66g, 0.600mol) drop wise into the reaction mixture. The reaction mixture was stirred at 27°C under Nitrogen atmosphere for 24hrs, the completion of reaction was monitored by TLC. After completion of reaction, remove the ethanol using reduced pressure. The crude compound was purified by column chromatography using 60-120 mesh silica gel as a stationary phase and petroleum ether and ethyl acetate as a eluent. The compound eluted at 50% Ethyl acetate. After distillation of solvent to get the 46g of product 4 obtained as light yellow colour solid (% of Yield = 85.18).
Yield = 46g, % of Yield = 85.18, Mol. Formula^HgBrNsCh, Mol. Wt = 270.08.
LC-MS: [m/z]+ = 270.92.
Preparation of 5-bromo-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylic acid (5):
To a stirred solution of compound 4 (46g, 0.170 mol) in 230 ml of anhydrous THF was treated with 230 ml of 6N HC1. The reaction mixture was heated to reflux for lOhr. the completion of reaction was monitored by TLC. After completion of reaction evaporate the solvent by reduced pressure to get 35g of compound 5 as a white solid (% of yield =84.91). Yield = 35g, % of yield =84.91. Mol. Formula =C7H4BrN3(¾ , Mol. Wt= 242.03.
LC-MS: [m/z]+ = 243.12.
Preparation of 5-bromo-N-(4-fluorophenyl)-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide (6):
To a stirred solution of 5 (35g, 0.144mol) in anhydrous 350 ml of dichloromethane. To this added triethylamine (21.94g, 0.216 mol) and stirred for 10 min, then added l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide, (24.59g, 0.237mol), 1-Hydroxy Benzotriazole (5.83g, 0.0432mol) and 4-Fluoro aniline (24.0g, 0.216mol). The reaction mixture was stirred at room temperature for 12hrs under Nitrogen atmosphere, the completion of reaction was monitored by TLC. Reaction mixture was washed with water (2x500ml), and 10% sodiumbicarbonate
solution (1x100ml), brine solution(lx 100ml), dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude residue is adsorbed on to silica gel, purified by column chromatography using 9:1 chloroform: methanol as eluent to get pure 42.5 g of compound 5 (% of Yield= 87.70).
Yield=42.5g, % of Yield= 87.70, Ci3H8BrFN40, Mol. Wt.: 335.13. LC-MS: [m/z]+ = 336.23
General procedure for the preparation of N-(4-fluorophenyl)-5-phenyl- [l,2,4]triazolo[l,5-a]pyridine-2-carboxamide [I (a-h)]:
A 100ml 2 necked flask equipped with a temperature probe and a septum was charged with toluene (20ml), water (2ml), ethanol (2ml) under argon atmosphere. The flask was charged with5-bromo-N-(4-fluorophenyl)-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide 6
(2g,0.00596mol), Substituted phenyl boronic acid (1.5 eq), sodium carbonate (3.0 eq). Degassed the reaction mixture for about 5min with nitrogen and tetra triphenylphosphine palladium (0) was added (0.05 eq). The reaction mixture was then allowed to warm to 110°C and stirred for 9hrs under argon atmosphere. Completion of reaction was monitored by TLC. The reaction mass was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100ml), and washed with water (100 mlx2), brine (50ml), dried over anhydrous sodium sulphate, filtered and evaporated with reduced pressure. The crude residue was purified by silica column using 9:1 Petroleum ether and ethyl acetate as eluent.
Preparation of 5-(2-fluorophenyl)-N-(4-fluorophenyl)-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide [1(a)]:
The general experimental procedure described afforded I (a) from -bromo-N-(4- fluorophenyl)-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide6(2g, 0.00596mol) in toluene(20ml), water(2ml), ethanol(2ml), 2-Fluoro phenyl boronic acid (1.25g, 0.00894mol), sodium carbonate(1.89g. 0.0178mol), and palladium catalyst was added (0.34g, 0.000298 mol).
Yield= 1.45g, % of Yield =69.37%, Description = Light yellow color solid,
H1 -NMR-400MHZ, DMSO-d6: d 7.18(t, J=0.92Hz, 2H) 7.43-7.48(m,3H) 7.66-7.68(m,lH) 7.85(t, J=0.52Hz,lH) 7.87-7.92(m,3H) 8.03(d, J=0.92Hz, 1H) 10.82 (s,lH).
LC-MS: [m/z]+= 351.1.
Mol.Formula:Ci9H12F2N40, Mol. Wt.: 350.32
Anal. Calculated: C, 65.14; H, 3.45; F, 10.85; N, 15.99; O, 4.57, Found: C, 65.12; H, 3.47; F, 10.83; N, 15.96; O, 4.59.
Preparation of N-(4-fluorophenyl)-5-(2-(trifluoromethoxy)phenyl)-[l,2,4]triazolo[l,5- a]pyridine-2-carboxamide[I(b)] :
The general experimental procedure described afforded 1(b) from -bromo-N-(4- fluorophenyl)-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide6(2g, 0.00596mol) in toluene(20ml), water(2ml), ethanol(2ml), 2-Methoxy phenyl boronic acid (1.84g, 0.00894mol), sodium carbonate(1.89g. 0.0178mol), and palladium catalyst was added (0.34g, 0.000298 mol).
Yield= 1.80g, % of Yield =72.50, Description = White solid,
H1 -NMR-400MHZ, DMSO-d6: 57.20 (t, J=8.04Hz, 2H) 7.45(d, J=6.48Hz, 1H) 7.64(s, 2H) 7.75-7.94(m, 5H) 8.06(d, J=8.8Hz, 1H) 10.87(s, 1H). LC-MS: [m/z]+= 416.9. Mol.Formula:C2oHi2F4N402 , Mol. Wt.: 416.33 Anal. Calculated: C, 57.70; H, 2.91; F, 18.25; N, 13.46; O, 7.69.
Found: C, 57.72; H, 2.89; F, 18.27; N, 13.49; O, 7.72.
Preparation of 5-(2-chloro-5-(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide [1(c)] :
The general experimental procedure described afforded 1(c) from -bromo-N-(4- fluorophenyl)-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide 6 (2g, 0.00596mol) in toluene(20ml), water(2ml), ethanol(2ml), 2-chloro-5-(trifluoromethyl)phenylboronic acid (2.0g, 0.00894mol), sodium carbonate(1.89g. 0.0178mol), and palladium catalyst was added (0.34g, 0.000298 mol).
Yield= 1.95g, % of Yield =75.20, Description = White solid,
FI1 -NMR-400MF1Z, DMSO-d6: 57.19 (t, J=8.92Hz, 2H) 7.52(dd, .1,= 0.72Hz, J2= 6.92Hz, 1H) 7.79-7.88(m, 2H) 7.92-7.99(m, 2H) 8.04(dd, J!=1.92Hz, J2=8.58Hz, 1H) 8.09(dd, J =0.64Hz, J2=8.9HZ, lH) 8.17(d, J=1.4Hz,lH) 10.83(s,lH). LC-MS; [m/z] += 434.9.
Mol.Formula: C20H11CIF4N4O. Mol. Wt.: 434.77
Anal. Calculated: C, 55.25; H, 2.55; Cl, 8.15; F, 17.48; N, 12.89; O, 3.68
Found: C, 55.22; H, 2.57; Cl, 8.13; F, 17.50; N, 12.87; O, 3.70.
Preparation of N-(4-fluorophenyl)-5-(4-(trifluoromethoxy)phenyl)-[l,2,4]triazolo[l,5- a]pyridine-2-carboxamide [1(d)]:
The general experimental procedure described afforded 1(d) from -bromo-N-(4- fluorophenyl)-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide6(2g, 0.00596mol) in
toluene(20ml), water(2ml), ethanol(2ml), 4-(trifluoromethoxy)phenylboronic acid (1.84g, 0.00894mol), sodium carbonate(1.89g. 0.0178mol), and palladium catalyst was added (0.34g, 0.000298 mol).
Yield = 1.85g, % of Yield = 74.50, Description = White solid.
H1 -NMR-400MHZ, DMSO-d6: 57.20 (t, J=6.96Hz, 2H) 7.56(dd, J =0.52Hz, J2=7.04Hz, 1H) 7.61(dd, J =1.10Hz, J2=8.64Hz, 2H) 7.87-7.92(m, 3H) 7.99(dd, J =0.44Hz, J2=8.88Hz, 1H) 8.16(dd,J1=2.72Hz, J2=9.16Hz, 2H) 10.82(s,lH). LC-MS: [m/z]+= 416.9.
Mol. Formula: C2oH12F4N402, Mol. Wt.: 416.33 LC-MS: [m/z]+ = 416.92.
Anal. Calculated :C, 57.70; H, 2.91; F, 18.25; N, 13.46; O, 7.69.
Found: C, 57.73; H, 2.93; F, 18.27; N, 13.48; O, 7.70.
Preparation of N-(4-fluorophenyl)-5-(4-vinylphenyl)-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide[I(e)] :
The general experimental procedure described afforded 1(e) from -bromo-N-(4- fluorophenyl)-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide 6 (2g, 0.00596mol) in toluene(20ml), water(2ml), ethanol(2ml), 4-vinyl phenylboronic acid (1.32g, 0.00894mol), sodium carbonate(1.89g. 0.0178mol), and palladium catalyst was added (0.34g, 0.000298 mol).
Yield = 1.65g, % of Yield =77.46, Description = White color solid,
FI1 -NMR-400MF1Z, DMSO-d6: 55.40 (d, J=11.0Hz, 1H) 6.01(d, J=5.65Hz, 1H) 6.82-6.89(m, 1H) 7.19(t, J=1.8Hz, 2H) 7.53(dd, J =0.68Hz, J2=7.12Hz, 1H) 7.70(d, J=8.36Hz, 2H) 7.86-7.91(m, 3H) 7.95(dd, Jl=0.42Hz, J2=8.28Hz, 1H) 8.04(d, J=8.28Hz, 2H) 10.81(s, 1H) LC-MS:[m/z]+=358.9.
Mol. Formula = C2IHI5FN40, Mol. Wt.: 358.37 LC-MS = [m/z]+ = 358.95
Anal calculated: C, 70.38; H, 4.22; F, 5.30; N, 15.63; O, 4.46.
Found: C, 70.40; H, 4.24; F, 5.33; N, 15.60; O, 4.48.
Preparation of N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide [1(f)]:
The general experimental procedure described afforded 1(f) from -bromo-N-(4-fluorophenyl)- [l,2,4]triazolo[l,5-a]pyridine-2-carboxamide6(2g, 0.00596mol) in toluene(20ml),
water(2ml), ethanol(2ml), phenyl boronic acid (1.09g, 0.00894mol), sodium carbonate(1.89g. 0.0178mol), and palladium catalyst was added (0.34g, 0.000298 mol).
Yield = 1.45g, % of Yield =73.20, Description= Light yellow color solid.
H1 -NMR-400MHZ, DMSO-d6: 57.21 (t, J=6.76Hz, 2H) 7.50(dd, T=1.04Hz, J2=7.14Hz, 1H) 7.58-7.64(m, 3H) 7.87-7.91(m, 3H) 7.95(dd, J =0.96Hz, J2=8.9HZ,1H) 8.02(dd, T=1.64Hz, J2=7.56HZ, 2H) 10.82(S,1H). LC-MS [m/z]+=332.9.
Mol. Formula: Ci9H13FN40, Mol. Wt.: 332.33
Anal. Calculated: C, 68.67; H, 3.94; F, 5.72; N, 16.86; O, 4.81
Found: C, 68.70; H, 3.91; F, 5.70; N, 16.88; O, 4.80.
Preparation of 5-(3-fluorophenyl)-N-(4-fluorophenyl)-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide [1(g)]:
The general experimental procedure described afforded 1(g) from -bromo-N-(4- fluorophenyl)-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide 6 (2g, 0.00596mol) in toluene(20ml), water(2ml), ethanol(2ml), 2-Fluoro phenyl boronic acid (1.25g, 0.00894mol), sodium carbonate(1.89g. 0.0178mol), and palladium catalyst was added (0.34g, 0.000298 mol).
Yield= 1.55g, % of Yield =74.16, Description = White color solid,
H1 -NMR-400MHZ, DMSO-d6: 57.23 (t, J=8.92Hz, 2H) 7.47(t, J=1.84Hz, 1H) 7.58(dd, Ji=1.24Hz, J2=7.18HZ, lH) 7.63-7.67(m, 1H) 7.86-7.93(m,5H) 8.0(dd, Ji=1.2Hz, J2=8.92Hz, 1H) 10.84(s,lH). LC-MS: [m/z]+= 350.9
Mol. Formula: Ci9H12F2N40, Mol. Wt.: 350.32, LC-MS: [m/z] + = 350.23.
Anal. Calculated: C, 65.14; H, 3.45; F, 10.85; N, 15.99; O, 4.57,
Found: C, 65.13; H, 3.47; F, 10.83; N, 15.97; O, 4.55.
Preparation of 5-(2-ethoxyphenyl)-N-(4-fluorophenyl)-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide [1(h)]:
The general experimental procedure described afforded 1(h) from -bromo-N-(4- fluorophenyl)-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide6(2g, 0.00596mol) in toluene(20ml), water(2ml), ethanol(2ml), 2-Ethoxy phenyl boronic acid (1.48g, 0.00894mol), sodium carbonate(1.89g. 0.0178mol), and palladium catalyst was added (0.34g, 0.000298 mol).
Yield= 1.89g, % of Yield =84.37, Description = White color solid,
H1 -NMR-400MHZ, DMSO-d6: 51.01(t, J=6.96Hz, 3H) 4.06(q, J=6.92Hz, 2H) 7.12(t, J=7.44Hz, 1H) 7.16-7.24(m,3H) 7.33(dd, Jl=1.16Hz, J2=7.08Hz, 1H) 7.51-7.57(m,2H) 7.83- 7.89(m,3H) 7.95(dd, Jl=1.08Hz, J2=8.94Hz, 1H) 10.83(s,lH). LC-MS: [m/z]+= 377 Mol. Formula = C2iH17FN402, Mol. Wt.: 376.38, LC-MS: [m/z] + = 377.23 Anal. Calculated: C, 67.01; H, 4.55; F, 5.05; N, 14.89; O, 8.50.
Found: C, 67.03; H, 4.57; F, 5.03; N, 14.87; O, 8.52.
Preparation of 2, 4, 6-trimethylbenzene-l-sulfonyl chloride (10):
To a stirred solution of Mesitylene 9 (lOOg, 0.83 lmol) in 200 ml of dry chloroform was added chlorosulfonic acid (290.13g, 2.49mol) drop wise at 0-5 °C. Stirred the reaction mixture at 27°C for lhr under Nitrogen atmosphere. Reaction mixture was monitored by TLC, after completion of reaction, mixture was pour into 300ml ice water, filtered through celite and transferred the solution into separating funnel, washed the organic layer with brine solution (100ml), dried over sodium sulphate, filtered and evaporate under reduced pressure to get 65.9 g of a white crystalline solid (% of Yield = 65.90).
Yield = 65.9g, % of Yield = 65.90. Description= White solid.
Mol. Formula: C^nClCLS, Mol. Wt.: 218.7
Anal. Calculated: C, 49.43; H, 5.07; Cl, 16.21; O, 14.63; S, 14.66.
Found: C, 49.45; H, 5.05; Cl, 16.23; O, 14.60; S, 14.68.
Preparation of tert-butyl (mesitylsulfonyl)oxycarbamate (11):
To a stirred solution of 2, 4, 6-trimethylbenzene-l-sulfonyl chloridel0(50g, 0.228mol) in 500 ml of MTBE was added N-Boc Hydroxyl amine ( 30. lg, 0.228mol), Cool the reaction mixture to 0°C, Add triethyl amine (23.47g, 0.232mol) drop wise into the reaction mixture. The reaction mixture was stirred at 0°C for 2hr under Nitrogen atmosphere. After the completion of reaction monitored by TLC filtered off triethylamine hydrochloride through celite bed, washed the bed with MTBE( 100ml), distilled out MTBE under reduced pressure and triturated the obtained residue with n-Hexane(50ml), filtered the solid and dried in vacuo at 30°C to afford a 65g of white solid (% of Yield= 90.27).
Yield= 65g, % of Yield= 90.27. Mol.Formula:Ci4H2iN05S
Mol. Wt.: 315.39, LC-MS: [m/z] + = 316.30
Anal. Calculated: C, 53.32; H, 6.71; N, 4.44; O, 25.36; S, 10.17.
Found :C, 53.30; H, 6.69; N, 4.42; O, 25.38; S, 10.15.
Preparation 0-(mesitylsulfonyl)hydroxylamine (2):
Trifluoro acetic acid (200ml) was taken in a 500ml 3-necked round bottom flask, cooled to 0°C, then add tert-butyl (mesitylsulfonyl)oxycarbamate 11 portion wise into the flask containing TFA. Reaction mixture was stirred at 0°C for lhr under Nitrogen atmosphere. After completion of reaction monitored by TLC, transferred the reaction mixture into ice water (200ml) and stirred well for 15 min, the obtained solid was filtered and dried with vacuum to get 40g of compound 2 (% of Yield= 90.29).
Yield = 40g, % of Yield= 90.29.
Mol. Formula = C9H13NO3S, Mol. Wt.: 215.27 Anal. Calculated: C, 50.21; H, 6.09; N, 6.51; O, 22.30; S, 14.90.
Found: C, 50.19; H, 6.11; N, 6.53; O, 22.32; S, 14.88.
Pharmacology
Antimycobacterial evaluation protocol
The minimum inhibitory concentration (MIC90) that inhibits 90% of growth of the bacterial population was determined using the broth micro-dilution method against the Mtb H37RvMa strain (ATCC 27294), as described earlier (Singh et al., 2015, 2017).
Description: A 10 mL culture of the Mtb H37RvMa strain was grown to an optical density (OD6OO) of 0.6 - 0.7. Test compounds were reconstituted in DMSO to a concentration of 10 mM or 10/20 mg/mL. Duplicate two-fold serial dilutions of the test compounds were prepared across 10 wells in a 96-well microtiter plate, in a volume of 50 pL, after which, 50 pL of the diluted Mtb culture (1:500) was added to each well in the plate. The final volume per well was 100 pL. A positive growth (DMSO =< 2.5%), a negative growth (Rifampicin at 2xMIC: 0.150 pM), and a Rifampicin dose response (range 0.15 - 0.0002 pM) controls were used to measure any contamination and/or plate-to-plate variations. The micro titre plate was sealed in a secondary container and incubated at 37°C with 5% CO2 and humidification. The AlamarBlue (Bio-Rad) reagent was added to each well of the assay plate at day 7 and incubated further for 24 hours. The measurement of MIC values was done at day 8, either visually (the lowest concentration of compound displaying no visible growth was scored as the MIC90, blue colour - no growth, pink/purple colour - growth) or by measuring relative fluorescence (excitation 540 nm; emission 590 nm) using a SpecraMax i3x Plate reader. The raw fluorescent data were used to calculate % inhibition using a 4-parameter curve fit protocol (Softmax® Pro 6 Version 6.5.1).
Media used:
7H9 GLU ADC TW: Middlebrook 7H9 media (Difco™) supplemented with 0.2% Glucose (Sigma), Middlebrook albumin-dextrose-catalase (ADC) enrichment (BD, BBL) and 0.05% Tween 80 (Sigma).
Anti-mycobacterial results
Note: MIC (minimum inhibitory concentration). These isolates were found to be resistant to first-line antibiotics, rifampicin (1 pg/mL) and isoniazid (0.2 pg/mL).
The inhibitory activity of substituted novel N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine- 2-carboxamide derivatives against H37RV and MDR strains of MTB were reported. Our medicinal chemistry program toward the discovery of novel anti-TB compounds enabled the identification of key substituents in the N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivatives scaffold, which is responsible for generating a bioactive compound. The functionalization of the l,2,4]triazolo[l,5-a]pyddine moiety at the C-6 position by different substituted phenyl rings with C- C bond as well as the presence of 4-fluoro aniline amide formation in l,2,4]triazolo[l,5-a]pyridine halogen in the para position of the benzoyl ring at position C-2, were essential for displaying significant anti-TB activity.
Claims
1. Compound of N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide derivative having the formula (I):
Wherein
R = 2-F, 2-OMe, 2-Cland 5-CF3, 4-OCF3, 4- Vinyl, 4H, 3-F and 2-Ethoxy.
2. Compound as claimed in claim 1 wherein the halogen is selected from fluorine (F) and chlorine (Cl).
3. Compound as claimed in claim 1 wherein the compound selected is from the group consisting of :
1 (c)
4. Pharmaceutical composition comprising the compound as claimed in claim 1 and pharmaceutically acceptable excipients or carriers.
5. Process for synthesis of compound of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivative of formula (I) comprising: a. synthesis of 6-bromo-2-imino-l-(((mesitylsulfonyl)oxy)amino)-2,3- dihydropyridin-l-ium (3) by reacting 2-amino -6 -Bromo pyridine (1) with O- (mesitylsulfonyl)hydroxylamine (2) ; b. then synthesis of intermediate ethyl 5-bromo-[l,2,4]triazolo[l,5-a]pyridine-2- carboxylate (4) from using 6-bromo-2-imino-l-(((mesitylsulfonyl)oxy)amino)- 2,3-dihydropyridin-l-ium (3); c. then synthesis of intermediate (5) by using the hydrolysed product of ethyl 5- bromo- [1,2,4] triazolo[ 1 ,5-a]pyridine-2-carboxylate (4) ; d. then synthesis of intermediate amide (6) by using the intermediate (5) and 4- Fluoro aniline or derivatives of aniline; e. then reacting the intermediate amide (6) with various substituted phenyl boronic acid (7a-r) to form compound of N-(4-fluorophenyl)-5-phenyl-
[l,2,
4]triazolo[l,
5-a]pyridine-2-carboxamide derivative of formula (I).
6. Process for synthesis of compound of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivative of formula (I) as claimed in claim 5 wherein the 6-bromo-2-imino-l-(((mesitylsulfonyl)oxy)amino)-2,3- dihydropyridin-l-ium (3) is synthesized by using 2-amino 6 Bromo pyridine (2) and 0-(mesitylsulfonyl)hydroxylamine (1) in presence of different chlorinated solvents at ambient temperature.
7. Process for synthesis of compound of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivative of formula (I) as claimed as claimed in claim 5 wherein the ethyl 5-bromo-[l,2,4]triazolo[l,5-a]pyridine-2- carboxylate (4) is synthesized by using 6-bromo-2-imino-l- (((mesitylsulfonyl)oxy)amino)-2,3-dihydropyridin-l-ium (3) and diethyl oxalate by cyclization with various bases and solvents.
8. Process for synthesis of compound of N-(4-fluorophenyl)-5-phenyl-
[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivative of formula (I) as claimed in claim 5 wherein the intermediate amide (6) is synthesized by using hydrolyzed product of ethyl 5-bromo-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (4) and 4- Fluoro aniline or derivatives of aniline in presence of de-hydrating agents.
9. Process for synthesis of compound of N-(4-fluorophenyl)-5-phenyl- [l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivative of formula (I) as claimed in claim 5 wherein the compound of N-(4-fluorophenyl)-5-phenyl-[l,2,4]triazolo[l,5- a]pyridine-2-carboxamide derivative formula (I) is synthesized by reacting the final
C-C bond formation compounds intermediate (6) with various substituted phenyl boronic acid (7a-r) and Pyridine ring via Suzuki coupling using various palladium catalyst and ligands.
10. Process for synthesis of compound of N-(4-fluorophenyl)-5-phenyl- [l,2,4]triazolo[l,5-a]pyridine-2-carboxamide derivative of formula (I) as claimed in claim 5 wherein the compound synthesized is selected from the group consisting of :
11. Method for treatment of diseases comprising the using of compound as claimed in claim 1 for treatment of diseases selected from tuberculosis, type 2 diabetes, bacterial, viral and fungal infections.
12. Method for treatment of diseases according to claim 11 wherein the disease selected is tuberculosis.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4296674A1 (en) | 2022-06-20 | 2023-12-27 | Université Toulouse III - Paul Sabatier | Innovative molecules decreasing virulence of mycobacterium for the treatment of tuberculosis |
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