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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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LL 3858, SUDOTERB


SUDOTERB.png

Figure imgf000023_0002

LL 3858, SUDOTERB

UNII-SK2537665A;

CAS 676266-31-2;

N-[2-methyl-5-phenyl-3-[[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]methyl]pyrrol-1-yl]pyridine-4-carboxamide;

N-[2-Methyl-5-phenyl-3-[[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]methyl]-1H-pyrrol-1-yl]-4-pyridinecarboxamide

Sudoterb(TM)

Molecular Formula: C29H28F3N5O
Molecular Weight: 519.572 g/mol
  • Originator Lupin
  • Class Antituberculars; Isonicotinic acids; Pyrroles
  • Mechanism of Action Undefined mechanism
  • Orphan Drug Status No
  • New Molecular Entity Yes

Highest Development Phases

  • No development reported Tuberculosis

Most Recent Events

  • 23 Jul 2015 No recent reports on development identified – Phase-II for Tuberculosis in India (unspecified route)
  • 11 Dec 2013 Lupin completes a phase II trial in Tuberculosis in India prior to December 2013 (CTRI2009-091-000741)
  • 31 Jul 2010 Lupin completes enrolment in its phase II trial for Tuberculosis in India (CTRI2009-091-000741)

img

Sudoterb HCl
CAS: 1044503-04-9 (2HCl)
Chemical Formula: C29H30Cl2F3N5O
Molecular Weight: 592.4882

Image result

Image result for sudoterb

SYNTHESIS

WO 2006109323

Tuberculosis (TB) is a contagious disease, which usually runs a protracted course, ending in death in majority of the cases, with relapse being a common feature of the disease. It is one of the most important causes of prolonged disability and chronic ill health. It is caused by the tubercle bacillus Mycobacterium tuberculosis, which is comparatively difficult to control. Drugs such as isoniazid, rifampicin, pyrazinamide, ethambutol streptomycin, para- aminosalisylic acid, ethionamide, cycloserine, capreomycin, kanamycin, thioacetazone etc. have been and are being currently used to treat TB. Amongst these, isoniazid, rifampicin, ethambutol and pyrazinamide are the first-line drugs of choice, which are administrated either as a single drug formulation or as a fixed-dose combination of two or more of the aforesaid drugs. Even though, each of the abovementioned first-line drug regimen is highly effective for treatment of TB, however, they are associated with shortcomings, such as unpleasant side- effects and relatively long course of treatment. The later one results in non-compliance of the patient to the treatment leading often to failure of the treatment and most importantly, development of drug resistance. The development of drug resistance has long constituted a principal difficulty in treating human tuberculosis. The second-line drugs, on the other hand are less effective, more expensive and more toxic.

It is estimated that in the next twenty years over one billion people would be newly infected with TB, with 35 million people succumbing to the disease (WHO Fact Sheet No. 104, Global

Alliance for TB Drug Development- Executive Summary of the Scientific Blueprint for TB

Development : http://www.who.int/inf-fs/en/factl04.hfaiil). With the emergence of HIV related

TB, the disease is assuming alarming proportions as one of the killer diseases in the world today.

A major thrust in research on antimycobacterials in the last decade has witnessed the development of new compounds for treatment of the disease, a) differing widely in structures, b) having different mode/mechanism of action, c) possessing favourable pharmacokinetic properties, d) which are safe and having low incidence of side-effects, and e) which provide a cost-effective dosage regimen.

Several new class of compounds have been synthesized and tested for activity against Mycobacterium tuberculosis, the details of chemistry and biology of which could be found in a recent review by B. N. Roy et. al. in J. Ind. Chem. Soc, April 2002, 79, 320-335 and the references cited therein.

Substituted pyrrole derivatives constitute another class of compounds, which hold promise as antimycobacterial agents. The pyrrole derivatives which have been synthesized and tested for antitubercular as well as non-tubercular activity has been disclosed by : a) D. Deidda et. al. in Antimicrob. Agents and Chemother., Nov 1998, 3035-3037. This article describes the inhibitory activity shown by one pyrrole compound, viz. BM 212 having the structure shown below, against both Mycobacterium tuberculosis including drug-resistant mycobacteria and some non-tuberculosis mycobacteria.

Figure imgf000004_0001

The MIC value (μg/ml) against the M. tuberculosis strain 103471 exhibited by BM 212 was 0.70 as against 0.25 found for isoniazid.

b) M. Biava et. al. in J. Med. Chem. Res., 1999, 19-34 have reported the synthesis of several analogues of BM 212, having the general formula (The compounds disclosed by M. Biava et. al. inJ. Med. Chem. Res., 1999, 19-34.) shown hereunder

Figure imgf000005_0001

wherein,

Figure imgf000005_0002

X is H, . CH2— (Oy-Cl ; CH2-(CH2)4-CH3

Figure imgf000005_0003
Figure imgf000005_0004

Z is H ; Y

and the in vitro antimicrobial activity of the compounds against Candida albicans, Candida sp, Cryptococcus neoforma s, Gram- positive or Gram-negative bacteria, isolates of pathogenic plant fungi, Herpes simplex virus, both HSV1 and HSN2, M. tuberculosis, M. smegmαtis, M. mαrinum and M. αvium.

However, the MIC values (μg/ml) of these compounds against the M. tuberculosis strain 103471 are found to be inferior to BM 212 and are in the range of 4-16.

M. Biava et. al. in Bioorg. & Med. Chem. Lett., 1999, 9, 2983-2988. This article describes the synthesis of pyrrole compounds of formula (: The compounds disclosed by M. Biava et. al. in Bioorg. & Med. Chem. Lett., 1999, 9, 2983-2988) shown hereunder

Figure imgf000006_0001

wherein,

X is H or Cl Y is H or Cl

R is N-methyl piperazinyl or thiomorphinyl

and their respective in vitro activity against M. tuberculosis and non-tuberculosis species of mycobacteria .

However, the MIC values (μg/ml) of these compounds against the M. tuberculosis strain 103471 are found to be inferior to BM 212 and are in the range of 2-4.

d) F. Cerreto et. al. in Eur. J. Med. Chem., 1992, 27, 701-708 have reported the synthesis of certain 3-amino-l,5-diary-2 -methyl pyrrole derivatives and their in vitro anti-fungal activity against Candida albicans and Candida sp. However, there is no report on the activity of such compounds against M. tuberculosis.

e) C. Gillet et. al. in Eur. J. Med. Chem.-Chimica Therapeutica, March- April 1976, ϋ(2), 173-181 report the synthesis of several pyrrole derivatives useful as anti-inflammatory agents and as anti-allergants.

f) R. Ragno et. al., Bioorg. & Med. Chem., 2000, 8, 1423-1432. This article reports the synthesis and biological activity of several pyrrole derivatives as well as describes a structure activity relationship between the said pyrrole compounds and antimycobacterial activity. The compounds (The compounds disclosed by R. Rango et. al., Bioorg. & Med. Chem., 2000, 8, 1423-1432)synthesized and tested by the authors is summarized hereunder

Figure imgf000007_0001

wherein,

X is COOH, COOEt, CONHNH2, CH2OH, CH(OH)C6H5, NO2

Figure imgf000007_0002

Y is H, CH3, OCH3, CH2, SO2, or a group of formula

Figure imgf000007_0003

wherein,

R is H, Cl, C2H5, or OCH3 and R1 is H, Cl, F, CH3, or NO2,

A is H or R

Z is a group of formula,

Figure imgf000007_0004

R2 is H, Cl, OH, or OCH3 and R3 is H or Cl

None of the abovementioned disclosures report or suggest the in vivo efficacy including toxicity of any of the compounds described therein against experimental tuberculosis in animal model. Moreover, the higher MIC values of the compounds reported suggest that they may not be very effective in inhibition of Mycobacterium tuberculosis.

NO PIC

Sudershan Kumar Arora

sudershan arora, Formerly: President R&D, Ranbaxy Lab Limited,

Experience

Inventors Sudershan Kumar AroraNeelima SinhaSanjay JainRam Shankar UpadhayayaGourhari JanaShankar AjayRakesh Kumar Sinha
Applicant Lupin Limited

PATENT

WO 2004026828

https://www.google.com/patents/WO2004026828A1?cl=en

PATENT

US 20050256128

PATENT

https://encrypted.google.com/patents/WO2005107809A2?cl=en

Thus the invention relates to an antimycobacterial combination comprising a therapeutically effective amount of N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2- methy 1-5 -phenyl- pyrrolyl)-4-pyridylcarboxamide of formula (I) or a pharmaceutically acceptable non- toxic salt thereof

Figure imgf000011_0001

and a therapeutically effective amount of one or more first line antitubercular drugs selected from the group consisting of isoniazid, rifampicin, ethambutol and pyrazinamide. Further according to the invention there is provided a process for preparation of an antimycobacterial pharmaceutical composition comprising combining a compound of formula I or a pharmaceutically acceptable salt thereof

Figure imgf000011_0002

and one or more of the first line antitubercular drugs using a dry granulation method, a wet granulation method or a direct compression method. The present invention further provides an antimycobacterial combination comprising a therapeutically effective amount of N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2- methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide of formula (I) the compound of formula (I) or a pharmaceutically acceptable non-toxic salt thereof

Figure imgf000012_0001

and a therapeutically effective amount of one or more first line antitubercular drugs selected firom isoniazid, rifampicin, ethambutol and pyrazinamide for treatment of multi-drug resistant tuberculosis including latent tuberculosis. The present invention provides an antimycobacterial combination comprising a therapeutically effective amount of N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2- methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide of formula (I) or a pharmaceutically acceptable non-toxic salt thereof

Figure imgf000012_0002

and a therapeutically effective amount of one or more first line antitubercular drugs selected from isoniazid, rifampicin, ethambutol and pyrazinamide for treatment and/or inhibition of one or more mycobacterial conditions/ cells including but not limited to sensitive and multi- drug resistant strains of Mycobacterium tuberculosis, Mycobacterium avium – intracellular complex, M. fortutium, M. kansasaii and other related mycobacterial species.

ynthesis of Compound of Formula (I) The compound of formula (I) and the pharmaceutically acceptable salts thereof can be synthesized by any known method including but not limited to the methods disclosed in our PCT Application No. PCT/IN02/00189 (WO 04/026828 Al), which is incorporated herein by reference. An example of the preparation of N-(3-[[4-(3-trifluoromethylphenyl) piperazinyl]methyl]-2-methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide is as follows:

Preparation of N-(3 ~[[4-(3 -trifluoromethylphenyl)piperazinyl]methyl)] -2-methyl-5 – phenylpyrrolyl)-4-pyridylcarboxamide

Step l 1 -(4-chlorophenyl)pentane- 1 ,4-dione To a well stirred suspension of anhydrous aluminium chloride (27.0gm, 205.9mmol) in

126ml. of chlorobenzene was added oxopentanoylchloride (23.0gm, 171.6 mmol) drop-wise, over a period of 30-35 minutes at room temperature (25-30EC). The reaction mixture was stirred at the same temperature for 1 hour. After decomposition of the reaction mixture by the addition of solid ice and hydrochloric acid (10ml) the precipitated solid was filtered and the filtrate evaporated on a rotary evaporator to remove all the solvents. The residue was dissolved in ethyl acetate (400 ml), washed with water (2 x 100ml.), brine (100 ml.) and dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained was chromatographed over silica gel (100-200 mesh) using chloroform as eluent to give 8.6gm (24.07%) of the title compound.

Step 2 N-(5-methyl-2-phenylpyrrolyl)-4 pyridylcarboxamide

A mixture of 1- (chlorophenyl)pentane-l,4-dione (6.0g, 28.50 mmol, as obtained in Step-1) and isonicotinic hydrazide (4.30gm, 31.35 mmol) in benzene (6.0 ml.) was refluxed by over molecular sieves. After two hours, benzene was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with water (2 x 100 ml.) and brine (1 x 50 ml.). The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained as purified by column chromatography over silica gel (100-200 mesh) using 0.2% methanol in chloroform as eluent to give 3.50gm (39.42%) of the title compound.

Step 3 N-(3 – { [4-(3-trifuoromethylphenyl)piperazinyl]methyl} -2-methyl-5 -phenylpyrrolyl)-4- pyridylcarboxamide

To a stirred solution of N-(5-methyl-2-phenylpyrrolyl)-4-pyridylcarboxamide (0.300gm, 1.083 mmol, as obtained in Step-2) in acetonitrile (5.0 ml.) was added a mixture of l-(3-trifluoromethylphenyl)piperazine hydrochloride (0.288gm, 1.083mmol), 40% formaldehyde (0.032gm, 1.083 mmol) and acetic acid (0.09 ml), drop-wise. After the completion of addition, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized with sodium hydroxide (20% aq. Soln.) and extracted with ethyl acetate (2 x 50 ml.). The combined ethyl acetate extract was washed with water (2 x 25 ml.), brine (1-χ 20 ml.), and dried over anhydrous sodium sulfate and the solvent evaporated off. TLC of the crude product indicated two spots, which were separated by column chromatography over silica gel (100-200mesh). The more polar compound a eluted out using 80% ethyl acetate- hexane mixture was obtained in 24.34 % (0.130 gm) and was identified as N-(3-{[4-(3- trifluoromethylphenyl)piperazinyl]methyl}-2-methyl-5-phenylpyrrolyl)-4- pyridylcarboxamide m.p.80-82°C, MS: m/z 520 (M+l)

1HNMR(CDC13, *): 2:13 (s, 3H,CH3), 2.60 (bs, 4H, 2xN-CH2), 3.18 (bs, 4H, 2xN-CH2), 3.41 (s, 2H, N-CH2), 6.24 (s, lH,H-4), 6.97-7.03 (4H, m, ArH), 7.22-7.29 (m, 5H,AιΗ), 7.53 (d, 2H, J=6Hz, pyridyl ring), 8.50 (bs, 1H,NH D2O exchangeable), 8.70 (d, 2H, J=6Hz, pyridyl ring).

PATENT

WO 2006109323

Compounds of Formula I are known from PCT International Patent Application WO 2004026828, and were screened for antimycobacterial activity, in various in vitro and in vivo models in mice and guinea pigs. Several compounds exhibited strong antimycobacterial activity against sensitive and MDR strains of Mycobacterium tuberculosis in the in vitro and in vivo experiments. Further the compounds of Formula I were also found to be bioavailable, less toxic and safe compared to available anti TB drugs in various animal models.

Thus compounds of Formula I are useful for the effective treatment of Mycobacterium tuberculosis infection caused by sensitive/MDR strains. PCT International Patent Application WO 2004026828 also discloses the synthesis of compounds of Formula I,

Figure imgf000004_0001

wherein,

Ri is phenyl or substituted phenyl

R2 is selected from a group consisting of i) phenyl which is unsubstituted or substituted with 1 or 2 substituents, each independently selected from Cl, F, or, ii) pyridine, or iii) naphthalene, or iv) NHCOR4 wherein R4 is aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl. R3 is selected from a group of formula

/~-\ /-Un

— N N-R5 and — N X

wherein R5 is phenyl which is unsubstituted or substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, Ci-C4 alkyl, Ci-C4 alkoxy, nitro, amino, haloalkyl, haloalkoxy etc.; unsubstituted or substituted benzyl; unsubstituted or substituted heteroaryl; unsubstituted or substituted heteroaroyl; unsubstituted or substituted diphenylmethyl,

n = 0-2 and X = -NCH3, CH2, S, SO, or SO2

Such that when R2 is phenyl, which is unsubstituted or substituted with 1 or 2 substituents, each independently selected from Cl, F; R5 is not Ci-C4 alkyl, or X is not -NCH3, CH2, S, SO, or SO2, when n = 1, or X is not -CH2 when n = 0 which comprises reacting the compound of Formula Il

»o-i >-CH, (H)

O O

with thionyl chloride, followed by reaction with RiH (wherein Ri is phenyl or substituted phenyl) in presence of aluminium chloride, and then condensation with R2NH2 (wherein R2 is as described above) in presence of p-toluenesulphonic acid to yield the corresponding unsubstituted pyrrole derivatives of Formula V,

Figure imgf000005_0001

which on further treatment with suitable secondary amines in the presence of formaldehyde and acetic acid afforded the desired pyrrole derivatives of Formula I,

Figure imgf000006_0001

which, on reacting with hydrochloric acid give a hydrochloride salt of compound of Formula Ia. wherein m = 1-2, Ri, R2 and R3 are the same as defined earlier. The above-mentioned methods in the prior art for the synthesis of compound of the Formula I suffer from the limitations,

1. In methods described in PCT International Patent Application WO 2004026828 for the synthesis of compounds of Formula I, positional isomers, the compound of Formula I’, are formed. The necessity of their removal through column chromatography decreases the yield of final pure product.

Figure imgf000006_0002

2. The synthesis of oxopentanoyl chloride (compound of Formula III) for the synthesis of compound of Formula I has been described in J. Org. Chem.

1960, 25, 390-392. It comprises reaction of levulinic acid with thionyl chloride at 50 0C for 1h, which results in poor yield.

3. In method described in PCT International Patent Application WO 2004026828 for the synthesis of 1-aryl-pentane-1,4-dione (compound of Formula IV), impurities are formed and purification involves column chromatography which decreases the yield of the product. 4. The synthesis of the intermediate of Formula V requires the use of benzene and high temperature conditions, which involves the formation of undesired by- products.

5. The above-mentioned methods in prior art for the synthesis of all the intermediates and final compounds of Formula I involves column chromatography for purification, which is cumbersome, tedious and not practicable on an industrial scale.

Example 1: Preparation of /V-(2-methyl-5-phenyl-3-f4-C3-trifluoromethyl-phenyl)- piperazin-1-ylmethyli-pyrrol-i-ylHsonicotinamide hydrochloride

Step (a): Preparation of 4-oxo-pentanoyl chloride

To a stirred mixture of levulinic acid (340.23 g, 2.93 mol) and Λ/./V- dimethylformamide (6.8 mL, catalytic amount) was added thionyl chloride (367.36 g, 3.087 mol, 1.05 equivalent) drop-wise at 20-30 0C in 1.5-2.0 h. After the complete addition of thionyl chloride, the reaction mixture was stirred at same temperature for 0.5 h (completion of reaction or formation of acid chloride was monitored by GC). After the completion of reaction, thionyl chloride was distilled off under reduced pressure at 20-30 0C. Traces of thionyl chloride were removed by adding benzene (136 mL) under reduced pressure at 30-35 0C and residue was dried at reduced pressure (1-2 mm) at 20-30 0C for 30-60 min to yield 370 g (93.8%) of 4-oxo-pentanoyl chloride as light orange oil. Step (b): Preparation of 1-phenyl-pentane-1,4-dione

Figure imgf000016_0001

(B) (A)

To a stirred suspension of benzene (3700 mL, 10 T w/v of acid chloride) and anhydrous aluminium chloride (440.02 g, 3.30 mol, 1.20 equivalent) was added A- oxo-pentanoyl chloride (370 g, 2.75 mol) drop-wise; the rate of addition was regulated so that the addition required 1.5-2 h and the temperature of the reaction mixture was kept at 25-35 0C. The reaction was completed in 2 h and monitored by GC. After completion of reaction, the reaction mixture was added slowly into cold (5-10 0C) 5% HCI (3700 mL) solution maintaining the temperature below 30 0C. The layers were separated; aqueous layer was extracted with ethyl acetate (1×1850 mL). The combined organic phase was washed with water (1 *1850 mL), 5% NaHCO3 solution (1×1850 mL), water (1×1850 mL), 5% NaCI solution (1×1850 mL), dried (Na2SO4), filtered and concentrated under reduced pressure at 35-40 0C, which was finally dried under reduced pressure (1-2 mm) at 35-400C to yield 185.6 g (38.3%) of 1-phenyl-pentane-1,4-dione as thick oil.

Step (c): Preparation of /V-(2-methyl-5-phenyl-pyrrol-1-yI)-isonicotinamide

A mixture of 1-(phenyl)-pentane-1,4-dione (185 g, 1.05 mol), isonicotinic hydrazide (158.4 g, 1.155 mol, 1.1 equivalent), p-toluenesulphonic acid (1.85 g, 1% w/w) and dichloromethane (1850 ml_) was heated under reflux at 40-50 0C under azeotropic distillation for 2-3 h (water was collected in dean stark apparatus). The completion of reaction was monitored by HPLC. After cooling to 25-30 0C the resulting mixture was washed with saturated NaHCO3 solution (1×925 mL), aqueous layer was back extracted with EtOAc (1×925 ml_). The combined organic layers were washed with water (1×925 mL), 5% brine solution (1×925 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to obtain the solid product, which was further dried under reduced pressure (1-2 mm) at 35-40 0C. To this, cyclohexane (925 mL) was added and stirred for 25-30 min, solid separated out was filtered washed with cyclohexane (370 mL). This process was repeated two times more with the same amount of cyclohexane and finally solid was dried under reduced pressure (1-2 mm) at 40-500C; yield 162.23 g (55.7%). White solid, mp 177-179 0C. 1H NMR (CDCI3): δ 2.10 (s, 3H), 5.98 (d, J = 3.4 Hz, 1H), 6.22 (d, J = 3.7 Hz, 1H), 7.237.28 (m, 5H), 7.50 (d, J = 5.6 Hz, 2H), 8.55 (d, J = 5.0 Hz, 2H), 9.82 (s, 1H). MS: m/z (%) 278 (100) [M+1]. Anal. Calcd for C17H15N3O (277.32): C, 73.63; H, 5.45; N, 15.15. Found: C, 73.92; H, 5.67; N, 15.29.

Step (d): Preparation of /V-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl- phenyl)-piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide

To a stirred solution of Λ/-(2-methyl-5-phenyl-pyrrol-1-yl)-isonicotinamide (160 g, 0.577 mol) in acetonitrile (1600 mil), was added drop-wise through pressure equalizing funnel a mixture of 1-(3-trifluoromethyl-phenyl)-piperazine monohydrochloride (153.75 g, 0.667 mol, 1.155 equivalent), formaldehyde (17.34 g, 0.577 mol, 1.0 equivalent) and acetic acid (480 mL) at 25-30 0C over a period of 60-90 min. The resulting reaction mixture was stirred for 14-16 h at same temperature and completion of reaction was monitored by TLC. After the completion of reaction, reaction mixture was treated with 20% aqueous NaOH solution (2600 mL). Layers were separated, EtOAc (4000 mL) was added to organic layer, washed with water (2×2000 mL), brine (2×1250 mL), dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure at 35-38 0C and then dried under reduced pressure (1-2 mm) to yield the mixture of Λ/-{5-methyl-2-phenyl-3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-pyrrol- 1-yl}-isonicotinamide (A) and Λ/-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl- phenyl)-piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide (B), yield 289 g (97.8%). The ratio of A and B was determined by reverse phase HPLC, which was found to be 19.4% and 76.7%, respectively.

Step (e): Purification of yV-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl-phenyl)- piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide i) The mixture of A and B obtained from Step (d) (279 g) was dissolved in EtOAc (1960 ml_, 7 times) by heating at 50-60 0C. To this activated charcoal (14 g) was added and stirred for 10 min at the same temperature, filtered the activated charcoal through celite bed at 50-60 0C, washed with EtOAc (560 mL). After cooled to 25-30 0C, cyclohexane (2800 mL) was added to the filtrate and stirred the reaction mixture for 14-15 h at 20-35 0C. Solid separated out was filtered, washed with cyclohexane (3500 mL) and dried under reduced pressure (1-2 mm) for 4-5 hours. Yield 151 g (52%). Ratio of A and B was found to be 1.7% and 96.6%, respectively.

ii) The mixture of A and B obtained from Step (e)(i) (151 g) was dissolved in

EtOAc (755 mL, 5 times) by heating at 50-60 0C. After cooled to 25-30 0C, cyclohexane (1510 mL) was added and stirred the reaction mixture for 14-15 h at 20-35 0C. Solid separated out was frltered, washed with cyclohexane (3000 mL) and dried under reduced pressure (1-2 mm) for 4-5 hours. Yield 140 g (92%). Ratio ofA and B was found to be 0.2% and 98.1%, respectively.

Off white solid, mp 191-193 0C. 1H NMR (CDCI3): δ 2.13 (s, 3H), 2.60 (br s, 4H), 3.13 (br s, 4H), 3.41 (s, 2H), 6.24 (s, 1H), 6.977.29 (m, 9H), 7.53 (d, J = 5.6 Hz, 2H), 8.50 (S, 1H), 8.70 (d, J = 5.6 Hz, 2H). 13C NMR (CDCI3): δ 165.93, 151.77, 150.86, 139.74, 133.02, 131.99, 131.43, 129.92, 129.01, 127.79, 127.49, 121.74, 119.09, 116.18, 115.05, 112.48, 109.51, 54.87, 52.99, 48.93, 9.77. MS: m/z (%) 520 (100) [M+U Anal. Calcd for C29H28F3N5O (519.56): C, 67.04; H, 5.43; N, 13.48. Found: C, 67.36; H, 5.71; N, 13.69.

The free base Λ/-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl-phenyl)-piperazin-1- ylmethyl]-pyrrol-1-yl}-isonicotinamide is obtained in a crystalline form having characteristic powder X-ray diffraction pattern given in Figure 1 with 2Θ values 4.85, 5.99, 6.83, 7.34, 9.15, 9.78, 10.93, 11.98, 13.17, 13.98, 14.33, 14.75, 15.73, 16.42, 17.11. 17.72, 17.95, 18.32, 19.11, 19.75, 20.32, 21.36, 22.04, 23.19, 25.17

Step (f): Preparation of /V-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl-phenyl)- piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide hydrochloride

To a stirred solution of 6% w/v HCI-EtOAc solution (821.8 mL, 1.351 mol, 7.0 equivalent) in EtOAc (2000 mL) was added a solution of Λ/-{2-methyl-5-phenyl-3- [4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide (100 g, 0.193 mol) in EtOAc (2000 mL) through dropping funnel at 15-20 0C. When the addition was completed (~60 min), the reaction mixture was stirred at 10-150C for 1 h and then nitrogen gas was passed through reaction mass for 1 h until all the excess HCI fumes were removed. Solid so obtained was filtered through suction in an inert atmosphere, washed with ethyl acetate (2×500 mL), diisopropyl ether (2×500 mL) and dried in vacuum oven under reduced pressure (1-2 mm) at 35-40 0C for 15-20 h. Yield 115 g (99%).

Yellow solid, mp 177-179 0C. 1H NMR (DMSO-d6): δ 2.21 (s, 3H), 3.11-3.42 (m, 6H), 3.93-4.23 (m, 4H), 6.62 (s, 1H), 7.09-7.51 (m, 9H), 8.19-8.21 (d, 2H, J = 4.6 Hz), 8.95-8.97 (d, 2H1 J = 4.6 Hz), 11.30 (br s, 1H), 12.86 (s, 1H). MS: m/z (%) 520 (100) [M+1]. Anal. Calcd for C29H28F3N5O.2HCI.3H2O (646.53): C, 53.87; H, 5.61; N, 10.83. Found: C, 53.67; H, 5.59; N, 10.86.

The product obtained was amorphous in nature having the characteristic X-ray powder diffraction pattern given in Figure 2.

Cited Patent Filing date Publication date Applicant Title
WO2004026828A1 * Sep 20, 2002 Apr 1, 2004 Lupin Limited Pyrrole derivatives as antimycobacterial compounds
WO2005107809A2 * Aug 27, 2004 Nov 17, 2005 Lupin Limited Antimycobacterial pharmaceutical composition comprising an antitubercular drug
US3168532 * Jun 12, 1963 Feb 2, 1965 Parke Davis & Co 1, 5-diarylpyrrole-2-propionic acid compounds
Reference
1 * BIAVA M ET AL: “SYNTHESIS AND MICROBIOLOGICAL ACTIVITIES OF PYRROLE ANALOGS OF BM 212, A POTENT ANTITUBERCULAR AGENT” MEDICINAL CHEMISTRY RESEARCH, BIRKHAEUSER, BOSTON, US, vol. 9, no. 1, 1999, pages 19-34, XP008016949 ISSN: 1054-2523
2 * BIAVA, MARIANGELA ET AL: “Antimycobacterial compounds. New pyrrole derivatives of BM212” BIOORGANIC & MEDICINAL CHEMISTRY , 12(6), 1453-1458 CODEN: BMECEP; ISSN: 0968-0896, 2004, XP002390961
3 * PARLOW J.J.: “synthesis of tetrahydonaphthaenes. part II” TETRAHEDRON, vol. 50, no. 11, 1994, pages 3297-3314, XP002391102
4 * R. RIPS , CH. DERAPPE AND N. BII-HOÏ: “1,2,5-trisubstituted pyrroles of pharmacologic interest” JOURNAL OF ORGANIC CHEMISTRY, vol. 25, 1960, pages 390-392, XP002390960 cited in the application

REFERENCES

1: Didilescu C, Craiova UM. [Present and future in the use of anti-tubercular
drugs]. Pneumologia. 2011 Oct-Dec;60(4):198-201. Romanian. PubMed PMID: 22420168.

2: Nuermberger EL, Spigelman MK, Yew WW. Current development and future prospects
in chemotherapy of tuberculosis. Respirology. 2010 Jul;15(5):764-78. doi:
10.1111/j.1440-1843.2010.01775.x. Review. PubMed PMID: 20546189; PubMed Central
PMCID: PMC4461445.

3: LL-3858. Tuberculosis (Edinb). 2008 Mar;88(2):126. doi:
10.1016/S1472-9792(08)70015-5. Review. PubMed PMID: 18486049.

4: Ginsberg AM. Drugs in development for tuberculosis. Drugs. 2010 Dec
3;70(17):2201-14. doi: 10.2165/11538170-000000000-00000. Review. PubMed PMID:
21080738.

Patent ID

Patent Title

Submitted Date

Granted Date

US2016318925 IMIDAZO [1, 2-a]PYRIDINE COMPOUNDS, SYNTHESIS THEREOF, AND METHODS OF USING SAME
2016-02-29
US9309238 IMIDAZO [1, 2-a]PYRIDINE COMPOUNDS, SYNTHESIS THEREOF, AND METHODS OF USING SAME
2010-11-05
2012-08-30
US7491721 Antimycobacterial pharmaceutical composition
2005-11-17
2009-02-17
US2009118509 PREPARATION OF [2-METHYL-5-PHENYL-3-(PIPERAZIN-1-YLMETHYL)] PYRROLE DERIVATIVES
2009-05-07

///////////////LL 3858, SUDOTERB, TB, LUPIN

CC1=C(C=C(N1NC(=O)C2=CC=NC=C2)C3=CC=CC=C3)CN4CCN(CC4)C5=CC=CC(=C5)C(F)(F)F

New TB Drug Enters Trials Neglected Diseases: Milestone comes despite waning pharma interest


TBA-354

New TB Drug Enters Trials

Neglected Diseases: Milestone comes despite waning pharma interest
chemical and eng news
Volume 93 Issue 8 | p. 5 | News of The Week
Issue Date: February 23, 2015 | Web Date: February 19, 2015

For the first time in six years, a new tuberculosis drug candidate has entered human clinical trials. Supported by the nonprofit Global Alliance for TB Drug Development, Phase I testing of TBA-354 began on Feb. 19.

TBA-354 is a nitroimidazole, a class of drugs effective against drug-resistant TB. The compound arose from a collaboration among the TB Alliance and researchers at New Zealand’s University of Auckland and the University of Illinois, Chicago, to find a next-generation nitroimidazole with more potent bactericidal activity and more favorable pharmacokinetic properties

TBA 354

CAS No: 1257426-19-9, 1403987-02-9

436.34, C19 H15 F3 N4 O5

2-Nitro-6(S)-[6-[4-(trifluoromethoxy)phenyl]pyridin-3-ylmethoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]

5H-​Imidazo[2,​1-​b]​[1,​3]​oxazine, 6,​7-​dihydro-​2-​nitro-​6-​[[6-​[4-​(trifluoromethoxy)​phenyl]​-​3-​pyridinyl]​methoxy]​-​, (6S)​-

6S)-2-Nitro-6-({6-[4-(trifluoromethoxy)phenyl]-3-pyridinyl}methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

TBA-354 is a potent anti-tuberculosis compound; maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates.

TBA-354

Nitroimidazoles represent a promising new class of anti-tubercular agents with potential for the treatment of drug sensitive and drug resistant disease. Two first generation compounds (PA-824 and OPC67683) are currently in clinical development. To maximize the potential of this class for tuberculosis (TB), we conducted a medicinal chemistry program to identify a next generation nitroimidazole. Ultimately, we selected TBA-354 [(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine] for in-depth profiling and preclinical development.
TBA-354 is more potent than PA-824 against M. tuberculosis in vitro, and against acute and established murine TB. This potency advantage is maintained on dosing as monotherapy in the initial and continuation phases of treatment, and when administered in combination with moxifloxacin and pyrazinamide. TBA-354 possesses a favorable pharmacokinetic (PK) profile with good oral bioavailability and excellent exposures in preclinical species. Due to these combined advantages, predicted clinically therapeutic doses are once daily and low, differentiating TBA-354 as a next generation anti-tubercular nitroimidazole.

TBA-354 was discovered by the TB Alliance in partnership with the University of Auckland and the University of Illinois at Chicago. The TB Alliance is a not-for-profit product development partnership (PDP) that operates like a biopharmaceutical company. The medicinal chemistry that led to discovery of TBA-354 was conducted at the Auckland Society for Cancer Research Center at University of Auckland and the biology was conducted at the University of Illinois at Chicago. Further in-depth profiling of the compound was led by the TB Alliance in collaboration with Johns Hopkins University, University of Illinois at Chicago and RTI International. Financial support for this project was provided by the Bill & Melinda Gates Foundation and UK Aid. The work was presented at ICAAC 2012 in San Francisco on Sept 10th 2012.

TBA-354’s excellent efficacy and pharmacokinetic profile make it a promising candidate to deliver superior bactericidal results from a small daily pill. The evidence of TBA-354’s effectiveness was found in animal models of TB, which, while often predictive, have their limitations. Clinical trials are needed to evaluate TBA-354’s effectiveness against TB in patients. Before proceeding to clinical trials, the safety and tolerability of TBA-354 must be evaluated; these toxicology and safety pharmacology studies are underway and will provide more information concerning the potential of this compound.

One of the major challenges of TB treatment, as well as drivers of drug-resistance remains the length and complexity of current treatment. Defeating the TB pandemic will require new drugs that shorten and simplify treatment. Given the disproportionate skew of the TB burden in the developing world, all new TB treatments must also be inexpensive enough to facilitate scale-up. As the most potent anti-tubercular nitroimidazole under development to date, TBA-354 offers great promise in many ways. Its potency may enable the reduction of length, cost, and side-effects of TB treatment. It is compatible with commonly used AIDS medications in ways that some currently used TB treatments are not. Further, nitroimadzoles have already proven combinable with other experimental TB drugs to form novel treatments regimens with the potential to cure both drug-sensitive and MDR-TB.

TBA-354 belongs to the nitroimadazole class. Other drugs from this class have exhibited promising activity against TB bacteria in the lab and in clinical trials — two of the most advanced new TB drug candidates (PA-824and delamanid) belong to this class. Having shown greater potency compared to PA-824 and an improved pharmacokinetic profile compared to delamanid, along with other promising properties, TBA-354 offers the potential to shorten and simplify TB treatment further than therapies currently under clinical development. Its increased potency against TB could also reduce the cost, pill size, frequency and/or side effects of treatment with a nitroimidazole by achieving comparable efficacy with less drug amount. Importantly, because it belongs to a novel class of drugs, TBA-354 projects to be effective in treating both drug-sensitive and drug-resistant TB.

TBA-354 emerged from studies designed to identify a next generation nitroimidazole for TB

• It is the first new TB drug candidate to begin a Phase 1 clinical trial since 2009

• 1.5 million people die each year from TB, and more than nine million were diagnosed with the disease

FEB 2015 NEW YORK — The Global Alliance for TB Drug Development (TB Alliance) has commenced the first human trial of a new tuberculosis (TB) drug candidate, designated TBA-354, the not for profit organization announced Wednesday..

It is the first new TB drug candidate to begin a Phase 1 clinical trial since 2009.

The World Health Organization reported that 1.5 million people die each year from TB, and more than nine million were diagnosed with the disease. The lack of short, simple, and effective treatments is a significant obstacle to TB control.

Owing to lack of economic incentive to develop new tools, there are not enough promising drugs in the pipeline, which could hinder efforts to develop the appropriate treatments needed to combat the TB epidemic.

“There is a critical gap of new compounds for TB,” said Mel Spigelman, MD, President and CEO of TB Alliance.

“The advancement of TBA-354 into clinical testing is a major milestone, not only because of the potential it shows for improving TB treatment, but because it is the first new TB drug candidate to begin a Phase 1 clinical trial in six years.”

TBA-354 emerged from studies designed to identify a next generation nitroimidazole for TB. It comes from the nitroimidazole class of chemicals, known for being effective against drug-sensitive and drug-resistant tuberculosis.

The class also includes the experimental TB drug pretomanid (formerly PA-824), which is being tested as a component of other novel regimens in multiple clinical trials.

TB Alliance conducted the studies in collaboration with the University of Auckland and University of Illinois-Chicago. Once identified, TB Alliance further advanced TBA-354 through pre-clinical development and is now the sponsor of the Phase 1 study

“Our chemistry team has worked on this since 2006 when the TB Alliance approached us to help with this project,” said Professor Bill Denny, director of the Auckland Cancer Society Research Centre and a Principal Investigator of the Maurice Wilkins Centre at the University of Auckland. “We made several hundred compounds, from which TBA-354 was selected for clinical development in 2011.”

“It’s very pleasing for us to see this drug go all the way through to Phase one clinical trial. It’s a validation of our work designing this compound to create a new and improved drug for the treatment of tuberculosis,” stated Denny in a statement.

In preclinical studies, TBA-354 demonstrated more potent anti-bactericidal and sterilizing activity compared to pretomanid. Recruitment is under way to enroll nearly 50 U.S. volunteers for the randomized, double-blind Phase 1 trial, which will evaluate the safety, tolerability, pharmacokinetics, and dosing of TBA-354.

In late 2012 a promising New Zealand compound targeting treatment-resistant tuberculosis (TB) was selected as a drug candidate by international non-profit drug developer the Global Alliance for TB Drug Development (TB Alliance).

NZ TB drug selected

Image: Micrograph of Mycobacterium tuberculosis, the bacterium that causes tuberculosis. Image courtesy of Dr Ray Butler and Janice Carr (Centres for Disease Control).

New drug candidate TBA-354 was designed by scientists from the Auckland Cancer Society Research Centre (ACSRC) and Maurice Wilkins Centre in partnership with the TB Alliance and University of Illinois at Chicago. The TB Alliance expects to complete preclinical studies by early 2013, and then seek permission from the US Food and Drug Administration to begin human trials.

TB is second only to HIV/AIDS as the greatest infectious killer worldwide. While most cases and deaths occur in low and middle income countries, it is a major health concern in the Asia-Pacific region. Treatment regimens are complex, lengthy and challenging to follow and the disease is developing resistance to current antibiotics. If a new drug proves more effective than current treatments it may reduce the duration, cost and side effects of treatment.

Laboratory studies to date have been very promising, with TBA-354 proving much more potent and broad-spectrum than PA-824, the first-generation compound it was designed to improve upon. TBA-354 and PA-824 are members of the first new class of drugs developed for TB in nearly fifty years and the first designed to attack the persistent form.

the TB Alliance contracted the New Zealand scientists to develop second-generation compounds to overcome some of its known limitations. The New Zealanders optimised each part of the drug, and in the process developed a new method of synthesis that will simplify and reduce the cost of producing drugs of this class.

“TBA-354 is an improved, second-generation version of PA-824,” says Professor Bill Denny,
ACSRC Co-Director and a Maurice Wilkins Centre principal investigator. “It is much more
potent than PA-824, longer lasting, and has greater activity against resistant strains. Recent
trials show that PA-824 can dramatically shorten the treatment period for TB, and it’s
encouraging that in TBA-354 we have a compound that is clearly superior to it.”

“This has been an excellent and productive international collaboration, across groups with
different skills, where we have learned much that we can apply in future,” says Associate
Professor Brian Palmer of the ACSRC and Maurice Wilkins Centre, who led the project’s
chemistry team of Drs Adrian Blaser, Iveta Kmentova, Hamish Sutherland and Andrew
Thompson.

“New Zealand has an outstanding reputation in drug discovery and it’s exciting to see the
ACSRC’s expertise in cancer drug development being applied to the fight against one of
the most devastating infectious diseases in the world,” says Centre Director Professor
Rod Dunbar.

 http://www.google.co.in/patents/EP2459571A1?cl=en

[0093] E. Synthesis of (6S)-2-nitro-6-({6-[4-(trifluoromethoxy)phenyI]-3- pyridinyI}methoxy)-6,7-dihydro-5H-imidazo[2,l-A][l53]oxazine (6) by the method of Scheme 4.

Figure imgf000025_0001

NaH (60% w/w, 0.584 g, 14.6 mmol) was added to a solution of oxazine alcohol 41 (2.073 g, 1 1.2 mmol) and 2-chloro-5-(chloromethyl)pyridine (48) (2.0 g, 12.3 mmol) in anhydrous DMF (40 mL) at 5 0C. The resulting mixture was stirred at room temperature for 16 h and then quenched with water (150 mL). The precipitate was filtered off, washed with water and dried to give (65)-6-[(6-chloro-3-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5//-imidazo[2,l- ft][l,3]oxazine (49) (3.39 g, 97%) as a light yellow solid: mp 191-193 0C; 1H NMR [(CD3)2SO] δ 8.37 (d, J- 2.3 Hz, 1 H), 8.02 (s, 1 H), 7.79 (dd, J = 8.3, 2.4 Hz, 1 H), 7.51 (br d, J = 8.2 Hz, 1 H), 4.74 (d, J= 12.4 Hz, 1 H), 4.69-4.64 (m, 2 H), 4.47 (d, J= 1 1.8 Hz, 1 H), 4.29-4.21 (m, 3 H). HRESIMS calcd for C12Hi2ClN4O4 mlz [M + H]+ 313.0513, 311.0542, found 313.0518, 311.0545.

Chloride 49 (1.0 g, 3.22 mmol) and 4-(trifluoromethoxy)phenylboronic acid (44) (0.788 g, 3.82 mmol) were suspended in DME (50 mL) and an aqueous solution Of K2CO3 (2M, 10 mL) was added. The mixture was purged with N2 and then treated with Pd(dppf)Cl2 (50 mg, 0.068 mmol) and stirred at 85 0C in an N2 atmosphere for 1 day, monitoring by MS. Further 44 (0.150 g, 0.728 mmol) was added and the mixture was stirred at 85 0C in an N2 atmosphere for 1 day. The resulting mixture was diluted with water (50 mL), and extracted with EtOAc (3 x 100 mL). The dried (MgSO4) organic layers were adsorbed onto silica gel and chromatographed on silica gel, eluting with EtOAc. Trituration of the product in Et2O gave 6 (0.942 g, 67%) as a white powder: mp 217-219 0C; 1H NMR [(CD3)2SO] δ 8.63 (d, J = 1.7 Hz, 1 H), 8.20 (dt, J = 8.9, 2.1 Hz, 2 H), 8.03 (s, 1 H), 7.99 (dd, J = 8.2, 0.5 Hz, 1 H), 7.84 (dd, J = 8.2, 2.2 Hz, 1 H), 7.47 (dd, J = 8.8, 0.8 Hz, 2 H), 4.77 (d, J = 12.3 Hz, 1 H), 4.71-4.68 (m, 2 H), 4.49 (d, J= 11.7 Hz, 1 H), 4.31-4.26 (m, 3 H). Anal. (Ci9Hi5F3N4O5) C, H, N. HPLC purity: 98.9%.

…………………

PATENT

http://www.google.com/patents/US20120028973

 

…………………

PAPER

Journal of Medicinal Chemistry (2010), 53(23), 8421-8439

http://pubs.acs.org/doi/full/10.1021/jm101288t

217 – 219 °C MP

http://pubs.acs.org/doi/suppl/10.1021/jm101288t/suppl_file/jm101288t_si_001.pdf

(6S)-2-Nitro-6-({6-[4-(trifluoromethoxy)phenyl]-3-pyridinyl}methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (93).
1)via bromide 160 :
Reaction of bromide160and 4-(trifluoromethoxy)phenylboronic acidunder the Suzuki coupling conditions described in Procedure A, followed by chromatographyof the product on silica gel, eluting with EtOAc, gave93(70%) as a cream solid: mp 217-219°C;
1H NMR [(CD3)2SO]
δ8.63 (d,J =1.7 Hz, 1 H),
8.20 (dt,J =8.9, 2.5 Hz, 2 H),
8.03 (s,1 H),
7.99 (dd,J =8.2, 0.5 Hz, 1 H),
7.84 (dd,J =8.2, 2.2 Hz, 1 H),
7.47 (br d,J =8.8 Hz, 2H),
4.77 (d,J =12.3 Hz, 1 H),
4.74-4.67 (m, 2 H),
4.49 (br d,J =11.7 Hz, 1 H),
4.33-4.22(m, 3 H).
Anal. (C19H15F3N4O5) C, H, N.F

 

Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
§ Global Alliance for TB Drug Development, 40 Wall Street, New York, New York 10005, United States
J. Med. Chem., 2010, 53 (23), pp 8421–8439
DOI: 10.1021/jm101288t

Andrew M. Thompson

*Corresponding author. Phone: (+649) 923 6145. Fax: (+649) 373 7502. E-mail: am.thompson@auckland.ac.nz.

+64 9 373 7599

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REF

International Journal of Computational Biology and Drug Design (2014), 7(1), 1-30.

http://www.inderscience.com/info/inarticle.php?artid=58583

 

 

University of Auckland – Faculty of Medical & Health Science

 

Auckland Food Tasting and Market Tour

 

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Sanofi Gets US FDA Approval For Priftin, Rifapentine 利福喷汀 Tablets To Treat Latent TB Infection


 

 

French drug maker Sanofi  Tuesday said it has received approval from the U.S. Food and Drug Administration for its Priftin (rifapentine) tablets to treat latent tuberculosis infection, or LTBI.

CID 5462354.png

Following a priority review, FDA has approved Priftin in combination with isoniazid, or INH, for a new indication for treatment of LTBI in patients two years of age and older at high risk of progression to tuberculosis or TB disease.

http://www.rttnews.com/2424574/sanofi-gets-us-fda-approval-for-priftin-tablets-to-treat-latent-tb-infection.aspx#.VH4RHVxo9iA.linkedin

Rifapentine.svg

Rifapentine

Antibiotic DL 473IT;Cyclopentylrifampicin;DL 473;KTC 1;MDL 473;Prifitin;Priftin;R 77-3;Rifamycin AF/ACPP;

Rifapentine is an antibiotic drug used in the treatment of tuberculosis. It inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme.

For the treatment of pulmonary tuberculosis

3-(((4-Cyclopentyl-1-piperazinyl)imino)methyl)rifamycin

C47H64N4O12
61379-65-5
Rifapentine
Rifapentine.svg
Systematic (IUPAC) name
(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z,26E)-26-{[(4-cyclopentylpiperazin-1-yl)amino]methylidene}-2,15,17,29-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,27-trioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(28),2,4,9,19,21,25(29)-heptaen-13-yl acetate
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a602026
Legal status
?
Pharmacokinetic data
Bioavailability increases when administered with food
Identifiers
CAS number 61379-65-5 Yes
ATC code J04AB05
PubChem CID 5462354
DrugBank DB01201
ChemSpider 10482075 Yes
UNII XJM390A33U Yes
KEGG D00879 Yes
ChEBI CHEBI:45304 Yes
ChEMBL CHEMBL1660 Yes
NIAID ChemDB 007686
Synonyms 3{[(4-cyclopentyl-1-piperazinyl)imino]methyl}rifamycin
Chemical data
Formula C47H64N4O12 
Mol. mass 877.031 g/mol

Rifapentine (INN, marketed under the brand name Priftin by Sanofi-Aventis) is an antibiotic drug used in the treatment of tuberculosis.

Rifapentine was first synthesized in 1965 by the same company that produced rifampin. The drug was approved by the Food and Drug Administration (FDA) in June 1998.

 

Medical uses

A review of alternative regimens for prevention of active tuberculosis in HIV-negative individuals with latent TB found that a weekly, directly observed regimen of rifapentine with isoniazid for three months was as effective as a daily, self -administered regimen of isoniazid for nine months. But the rifapentine-isoniazid regimen had higher rates of treatment completion and lower rates of hepatotoxicity. However, the rate of treatment-limiting adverse events was higher in the rifapentine-isoniazid regimen. [1]

PRIFTIN (rifapentine) for oral administration contains 150 mg of the active ingredient rifapentine per tablet.

The 150 mg tablets also contain, as inactive ingredients: calcium stearate, disodium EDTA, FD&C Blue No. 2 aluminum lake, hydroxypropyl cellulose, hypromellose USP, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, propylene glycol, sodium ascorbate, sodium lauryl sulfate, sodium starch glycolate, synthetic red iron oxide, and titanium dioxide.

Rifapentine is a rifamycin derivative antibiotic and has a similar profile of microbiological activity to rifampin (rifampicin). The molecular weight is 877.04.

The molecular formula is C47H64N4O12.

The chemical name for rifapentine is rifamycin, 3-[[(4-cyclopentyl-1-piperazinyl)imino]methyl]-or 3-[N-(4-Cyclopentyl – 1-piperazinyl)formimidoyl] rifamycin or 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-cyclopentyl-l-piperazinyl)-formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-1,11(2H)-dione 21-acetate. It has the following structure:

PRIFTIN (rifapentine) structural formula illustration

 

Use in special populations

Pregnancy

Rifapentine has been assigned a Pregnancy Category C by the FDA. Rifapentine in pregnant women has not been studied, but animal reproduction studies have resulted in fetal harm and were teratogenic. If rifapentine and rifampin are used together in pregnancy, coagulation should be monitored due to a possible increased risk of maternal postpartum hemorrhage and infant bleeding. [2]

Adverse effects

Common side effects are hyperuricemia, pyuria, hematuria, urinary tract infection, proteinuria, neutropenia, anemia, and hypoglycemia. [2]

Contraindications

Rifapentine should be avoided in patients with an allergy to the rifamycin class of drugs. [2] This drug class includes rifampin and rifabutin. [3]

Interactions

Rifapentine induces metabolism by CYP3A4, CYP2C8 and CYP2C9 enzymes. It may be necessary to adjust the dosage of drugs metabolized by these enzymes if they are taken with rifapentine. Examples of drugs that may be affected by rifapentine include warfarin, propranolol, digoxin, protease inhibitors and oral contraceptives.[2]

History

Rifapentine was first synthesized in 1965 by the same company that produced rifampin. The drug was approved by the Food and Drug Administration (FDA) in June 1998. It is synthesized in one step from rifampicine.

 

Rifapentine was first synthesized in 1965 by the same company that produced rifampin. The drug was approved by the Food and Drug Administration (FDA) in June 1998.

(7S,11S,12S,13S,14R,15S,16R,17R,18R,26E)-26-{[(4-Cyclopentyl-1-piperazinyl)amino]methylene}-2,15,17,29-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,27-trioxo-8,30-dioxa-24-azatetracyclo [23.3.1.14,7.05,28]triaconta-1(28),2,4,9,19,21,25(29)-heptaen-13-yl acetate. Rifapentine is an antibiotic drug used in the treatment of tuberculosis.

Preparation of Rifapentine: this chemical can be prepared by 3-aldehyde rifamycin SV with 1-Amino-4-cyclopentylpiperazine. This reaction needs reagent tetrahydrofuran. The yield is 55 %

References

  1. Sharma SK et al . (2013). “Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB.”. Cochrane Database of Systematic Reviews 7: CD007545. doi:10.1002/14651858.CD007545.pub2. PMID 23828580.
  2. Sanofi-Aventis. (2010) Priftin (rifapentine): Highlights of Prescribing Information. Retrieved from http://products.sanofi.us/priftin/Priftin.pdf.
  3. CDC. (2013) Core Curriculum on Tuberculosis: What the Clinician Should Know. Retrieved from http://www.cdc.gov/TB/education/corecurr/default.htm
  4. http://www.mdpi.com/1424-8247/5/7/690/htm
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