SYNTHESIS

Gautam Panda

PATENT

Indian Pat. Appl. (2012), IN 2010DE00685

Abstract:
The invention relates to Thiophene containing Trisubstituted Methanes (TRSMs) and a process for the preparation thereof. The invention particularly relates to a process for the preparation of substituted secondary and tertiary amino alkoxy diary! thiophenyl methanes and their use as potential antimycobacterial agents. Novel diaryl thiophenyl methanes of formula I have been prepared. The present invention provides novel diaryl thiophenyl methanes substituted with a secondary or tertiary amino alkoxy group and a process for the preparation of the said compounds of general formula I comprising general formula la and lb useful in antimycobacterial activity wherein R1 is selected from an aryl group or thophene moiety wherein the aryl group is selected from a group consisting of substituted phenyl groups such as methoxy phenyl, thiomethoxy phenyl, phenyl, p-chlorophenyl, p-fluorophenyl; R2 is selected from a group consisting of aminoalkoxyl, alkyl/dialkyl aminoalkoxy, cyclic alkyl aminoalkoxy. R3 is selected from a group consisting of H, lower alkyl, lower alkoxy group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl; R4 is selected from a group consisting of H,OH,methyl.

The invention relates to thiophene containing Trisubstituted Methanes (TRSMs) and a process for the preparation thereof. The invention particularly relates to a process for the preparation of substituted secondary and tertiary amino alkoxy diaryl thiophenyl methanes and their use as potential antimycobacterial agents. Novel diaryl thiophenyl methanes of formula I have been prepared.
The present invention provides novel diaryl thiophenyl methanes substituted with a secondary or tertiary amino alkoxy group and a process for the preparation of the said compounds of general formula I comprising formula la and lb useful in antimycobacterial activity wherein R1 is selected from an aryl group or thophene moiety wherein the aryl group is selected from a group consisting of substituted phenyl groups such as methoxy phenyl, thiomethoxy phenyl, phenyl, p-chlorophenyl, p-fluorophenyl; R2 is selected from a group consisting of aminoalkoxyl, alkyl/dialkyl aminoalkoxy, cyclic alkyl aminoalkoxy. R3 is selected from a group consisting of H, lower alkyl, lower alkoxy group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl ; R4 is selected from a group consisting of H,OH,methyl etc.
(Formula Removed)
Background of the Invention
Tuberculosis is a growing international health concern; it is the leading infectious cause of death in the world today (Dolin, P.J. et al Bull. WHO 1994, 72, 213; Daffe, M. et al Adv. Microb. Physiol 1998, 39, 131). It is estimated that worldwide 100 million people are infected annually.

Approximately ten million develop the disease, with five million of these progressing to the infectious stage and ultimately three million dying. Even though improved methods of prevention, detection, diagnosis and modern treatment have greatly reduced the number of people getting infected and dying from it, the emergence of multi-drug-resistant (MDR) strains and the global human immunodeficiency virus (HIV) augments the risk of developing TB many fold. Resistance has been described for all first-line drugs (isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin) and for several second-line and newer drugs (ethionamide, fluoroquinolones, macrolides, nitroimidazopyrans). Because MDR strains are the result of cumulative mutations, growth of Mycobacterium tuberculosis (MT) can successfully be controlled in the host by concomitant treatment with more than one drug. This has resulted in the development of new agents (Panda, G. et al Indian Journal of Chemistry, 2009, 48B, 1121-1127; Parai, M. K. et al Bioorganic & Medicinal Chemistry Letters, 2008, 18, 289-292) for the preparation of Disseminated Mycobacterium avium complex (DMAC) infection as well as combinations of both new and standard agents for its treatment. The search for more effective agents against Mycobacterium tuberculosis (MT) and Mycobacterium avium complex (MAC) is ongoing in an attempt to enhance survival and reduce morbidity, as proven by the high number of publications (Jing-Ping Lu et al J. Med. Chem., 2010, 53, 3, 1329-1337; Liqiang Chen et al J. Med. Chem., 2010, 53 (12), 4768-4778; Jiyoung A et al J. Med. Chem., 2009, 52 (17), 5485-5495; Maria-Teresa Gutierrez-Lugo et al J. Med. Chem., 2008, 51 (9), 2606-2612; Li Liu et al J. Med. Chem., 2010, 53 (7), 2882-2891 and references cited therein) and patents of new antituberculous drugs recently published. Preclinical data, such as in vitro measures of drug activity and pharmacokinetics, are used in the design of new treatment regimens. Assessment of pharmacodynamic activity from standard in vitro minimum inhibitory concentrations (MICs) alone is insufficient to predict in vivo potency. Achievable serum and tissue concentrations as well as pharmacokinetic characteristics must be considered.
Because of this, there is an urgent need for anti-TB drugs with improved properties such as enhanced activity against MDR strains, reduced toxicity, shortened duration of therapy, rapid mycobactericidal mechanism of action and the ability to penetrate host cells and exert anti-mycobacterial effects in the intracellular environment.
Following is the description of thiophene containing trisubstituted methanes having antimycobacterial activity.

PAPER

European Journal of Medicinal Chemistry (2015), 95, 357-368

http://www.sciencedirect.com/science/article/pii/S0223523415002032

Thiophene containing trisubstituted methanes [TRSMs] as identified lead against Mycobacterium tuberculosis

• Priyanka Singh^a,
• Sudipta Kumar Manna^a,
• Amit Kumar Jana^a,
• Tiash Saha^a,
• Pankaj Mishra^a,
• Saurav Bera^a,
• Maloy Kumar Parai^a,
• Srinivas Lavanya Kumar M^a,
• Sankalan Mondal^a,
• Priyanka Trivedi^b,
• Vinita Chaturvedi^b,
• Shyam Singh^b,
• Sudhir Sinha^{b, , ,} ,
• Gautam Panda^{a, , ,}

• ^a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, B.S. 10/1, Jankipuram Extension, Sitapur Road, Lucknow-226031, UP, India
• ^b Biochemistry Division, CSIR-Central Drug Research Institute, B.S. 10/1, Jankipuram Extension, Sitapur Road, Lucknow-226031, UP, India

Triarylmethanes (TRAMs) and thiophene containing trisubstituted methanes (TRSMs) have been reported by us, having potential against Mycobacterium tuberculosis andMycobacterium fortuitum strains, respectively. Further, extension through synthesis and biological evaluation of novel TRSMs resulted into an identified lead 36 (S006-830) [(diisopropyl-(2-{4-[(4-methoxy-phenyl)- thiophen-2-yl-methyl]-phenoxy}-ethyl)-amine)] with MIC: 1.33 mg/L, non-toxic against Vero C-1008 cell line with selectivity index >10,ex vivo efficacy equivalent to first line TB drugs-isoniazid (INH), rifampicin (RFM) and pyrazinamide (PZA) in the mouse and human macrophages, and lung CFU count of 2.2 × 10⁷ (approximately 15 fold lesser than untreated mice, 31 × 10⁷) with efficacies comparable to ethambutol (EMB) (1.27 × 10⁷) and PZA (1.9 × 10⁷). Further, S006-830 also showed potent bactericidal activity against multi-drug resistant and single-drug resistant clinical isolates of M. tuberculosis

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PAPER

Synthetic Communications (2014), 44(23), 3408-3413

Abstract