WO2015114663A1 - Nouveaux composés thiéno [2,3-d] pyrimidin-4 (3h)-one à propriétés antimycobactériennes - Google Patents

Nouveaux composés thiéno [2,3-d] pyrimidin-4 (3h)-one à propriétés antimycobactériennes Download PDF

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WO2015114663A1
WO2015114663A1 PCT/IN2015/000054 IN2015000054W WO2015114663A1 WO 2015114663 A1 WO2015114663 A1 WO 2015114663A1 IN 2015000054 W IN2015000054 W IN 2015000054W WO 2015114663 A1 WO2015114663 A1 WO 2015114663A1
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pyrimidin
thieno
ethyl
substituted
propyl
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Hanumant Bapurao Borate
Ritesh Ashok ANNADATE
Sagar Bapurao DEOKATE
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Council Of Scientific & Industrial Research
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • the present invention relates to a novel thieno [2,3-d]pyrimidin-4(3H)-one compounds of Formula-I or its pharmaceutically acceptable salts, having significant anti-myco bacterial activity.
  • the invention further relates to a pharmaceutical composition comprising the same.
  • tuberculosis In recent age tuberculosis (TB) is a major global health problem and causes millions of fatalities each year. Mycobacterium tuberculosis is more fatal for human than any other single microbial species.
  • J.P. DUPIN et al. in Journal of physiology and pharmacology 2002, 53, 4, 625-634 reports the six-step synthesis of a series of benzothienopyrimidinone derivatives evaluated for potent thrombolytic activity. Further biological and biochemical screening of amino acid thienopyrimidinone derivatives for potential radioprotective character and screening of antimicrobial activity thereof, is reported in Phosphorus, Sulfur, and Silicon and the related elements volume 131 , issue 1 , 1997.
  • WO2007050726 provides thienopyrimidinones compounds of Formula II, for treating a patient suffering from an MCHR-1 modulated disease or disorder such as, for example, obesity, diabetes, depression or anxiety.
  • WO 2005032527 relates to benzo (4, 5) thieno (2, 3-d) pyrimidin-4-one compounds, their 5,6-dihydro and 5, 6, 7, 8-tetrahydro derivatives of Formula III.
  • US 7928111 disclose compounds including substituted thienopyrimidinone derivatives of formula IV, useful as sweet taste enhancers in comestible or medicinal compositions. It also provides screening methods for identifying modifiers of chemosensory receptors and their ligands.
  • US2010069362 discloses thienopyrimidone compound of Formula-V having an MCH receptor antagonistic action.
  • EP 2280952 relates to thienopyridone derivatives ⁇ of Formula-VI that are activators of AMPK-activated protein kinase (AMPK).
  • AMPK AMPK-activated protein kinase
  • the main objective of the present invention is to provide a novel scaffold comprising thieno pyrimidinone necessary to overcome the resistance to current TB drugs.
  • Another objective of the present invention is to provide a novel thieno[2,3-i/]pyrimidin- 4(3 /)-ones compounds of Formula-I or its pharmaceutically acceptable salts, enantiomers, analogues thereof having anti-myco bacterial activity comprising;
  • R 1 and R 2 may be same or different and independently selected from the group consisting of hydrogen, halogen, (un)substituted aryl, , (un)substituted C Ci 5 linear or branched alkyl group optionally substituted with hydroxy, amino, nitrile, nitro, carboxyl, carbonyl, ester, alkoxy group; (un)substituted C 1 -C15 linear or branched alkenyl; (un)substituted Ci-C )5 linear or branched alkynyl group;
  • R 1 and R 2 together form a 5 to 12 membered carbocyclic ring which may be substituted or unsubstituted;
  • R 3 is selected from the group consisting of hydrogen, (un)substituted (CJ-C ) linear or branched alkyl; (un)substituted Ci-Ci 5 linear or branched alkenyl; (un)substituted (C Ci 5 ) linear or branched alkynyl; -CH 2 -COOEt; .CH 2 -COOH; CH 2 COCH 2 R 4 ; CH 2 CH(OH)CH 2 R 4 wherein R 4 is selected from the group consisting of (un)substituted triazol-l-yi, halogen, hydroxy, amino, nitrile, nitro, carboxyl, carbonyl, ester, alkoxy, (un)substituted-aryl; CHR 5 COAr wherein R 5 represents hydrogen or (C r C ) alkyl and Ar represents (un)substituted aryl; (CH 2 ) conflictR 6 or (CH 2 )phobia R 7+ X "
  • Yet another objective of the present invention is to provide a novel thieno[2,3- i ]pyrimidin-4(3//)-ones compounds of Formula- 1, having significant anti-mycobacterial activity.
  • Still another objective of the present invention is to provide a pharmaceutical composition comprising an effective amount of compound of formu!a-I in association with one or more pharmaceutical excipients for treatment of bacterial infections including tuberculosis.
  • the present invention focusses on novel scaffold comprising thieno pyrimidinone necessary to overcome the resistance to current TB drugs.
  • the invention provides a novel thieno[2,3- ⁇ pyrimidin-4(3//)-ones compounds of Formula-I or its pharmaceutically acceptable salts, enantiomers, analogues thereof having anti- myco bacterial activity comprising;
  • R 1 and R 2 may be same or different and independently selected from the group consisting of hydrogen, halogen, (un)substituted aryl, (un)substituted C Cis linear or branched alkyl group optionally substituted with hydroxy, amino, nitrile, nitro, carboxyl, carbonyl, ester, alkoxy group; (un)substituted Ci-Cu linear or branched alkenyl; (un)substituted CpQs linear or branched alkynyl group;
  • R 1 and R 2 together form a 5 to 12 membered carbocyclic ring which may be substituted or unsubstituted;
  • R 3 is selected from the group consisting of hydrogen, (un)substituted (C r C I5 ) linear or branched alkyl; (un)substituted Ci-Cu linear or branched alkenyl; (un)substituted (Ci-C (5 ) linear or branched alkynyl; -CH 2 -COOEt; .CH 2 -COOH; CH 2 COCH 2 R 4 ; CH 2 CH(OH)CH 2 R 4 wherein R 4 is selected from the group consisting of (un)substituted triazol-1 -yl, halogen, hydroxy, amino, nitrile, nitro, carboxyl, carbonyl, ester, alkoxy, (un)substituted-aryl; CHR 5 COAr wherein R 5 represents hydrogen or (Ci-C 4 ) alkyl and Ar represents (un)substituted aryl; (CH 2 ) conflictR 6 or (CH 2 )terrorism R 7+
  • the invention provides a novel thieno[2,3- ⁇ pyrimidin-4(3 /)-ones compounds of Formula-I, having significant anti-mycobacterial activity.
  • the invention provides a pharmaceutical composition comprising an effective amount of compound of fonnula-
  • the invention relates to a novel thieno[2,3- ⁇ /] pyrimidin-4(3i/)- ones with general Formula-I or its pharmaceutically acceptable salts thereof having anti- mycobacterial activity comprising;
  • R 1 and R 2 may be same or different and independently selected from the group consisting of hydrogen, halogen, (un)substituted aryl, (un)substituted or substituted Q-Cis linear .or branched alkyl group optionally substituted with hydroxy, amino, nitrile, nitro, carboxyl, carbonyl, ester, alkoxy group; (un)substituted or substituted C r Ci 5 linear or branched alkenyl; (un)substituted or substituted C1-C15 linear or branched alkynyl group;
  • R 1 and R 2 together form a 5 to 12 membered carbocyclic ring which may be substituted or unsubstituted;
  • R 3 is selected from the group consisting of hydrogen, (un)substituted or substituted (Ci-C 15 ) linear or branched alkyl; (un)substituted or substituted C1 -C15 linear or branched alkenyl; (un)substituted or substituted (C,-Ci 5 ) linear or branched alkynyl; -CH 2 -COOEt; .CH 2 -COOH; CH 2 COCH 2 R 4 ; CH 2 CH(OH)CH 2 R 4 wherein R 4 is selected from the group consisting of (un)substituted or substituted triazolyl, halogen, hydroxy, amino, nitrile, nitro, carboxyl, carbonyl, ester, alkoxy, (un)substituted or substituted aryl; CHR s COAr wherein R 5 represents hydrogen or (Ci-Q) alkyl and Ar represents (un)substituted or substituted aryl; (CH
  • R 7 represents NMe 3 or pyridin-l-yl or 4- dimethylaminopyridin-l -yl
  • X represent F, Br, I and CI
  • R ' and R 3 is H
  • R 2 is selected from H, (C C 3 ) alkyl, linear or branched (C 5 -C 10 ) alkyl, propyl benzyloxy or Br
  • R 1 is methyl or ethyl
  • R 2 is selected from H, Br and R 3 is selected from H, n-propyl, isobutyl
  • R 7 represents NMe 3 or pyridin-l-yl or 4- dimethylaminopyridin-l -yl
  • X represent F, Br, I and CI
  • R 3 is H
  • R l and R 2 together form 5-7 membered saturated carbocyclic ring.
  • the antimycobacterial thieno[2,3-rf]pynmidin-4(3/ )-ones compounds of Formula-I encompasses library of compounds as given below in Table- 1.
  • the present invention relates to a synthesis of antimycobacterial thieno[2,3-d]pyrimidin-4(3H)-ones compounds of Formula-I , which can be prepared by the process known in the art.
  • the process comprises the steps of:, a) preparing substituted 2-aminothiophene-3- carboxylates (Formula VII) by employing Gewald synthesis; b) preparing thieno[2,3-d]pyrimidin- 4(3H)-ones (Formula VIII) in one step from substituted ethyl 2-aminothiophene-3-carboxylates (Formula VII) by heating with formamide and ammonium acetate or alternatively reacting ethyl 2- aminothiophene-3-carboxylates (Formula VII) with formic acid and ammonium acetate to obtain ethyl 2-formylaminothiophene-3-carboxylates (Formula IX) followed by treatment with formamide and ammonium formate to get the desired thieno [2,3-d]pyrimidin-4(3H)-ones (Formula VIII); and c) synthesizing variously substituted thieno[
  • Gewald reaction is carried out by condensing aldehyde or ketone Formula X) with ethyl cyanoacetate in the presence of elemental sulfur and organic base, in a suitable solvent to obtain substituted 2-aminothiophene-3-carboxylates (Formula VII).
  • the organic base is selected from the group consisting of triethylamine, diethylamine, pyridine, quinoline and the like; solvent is selected from DMF, DMSO, THF, acetone, acetonitrile or ethanol either alone or mixtures thereof.
  • Reagents and conditions a. Et 3 N, DMF or quinoline, EtOH; b. Formamide, ammonium acetate; c. Formic acid, ammonium acetate; d. Formamide, ammonium formate
  • Reagents and conditions a. R 3 X, K 2 C0 3 , DMF or acetonitrile, RT; b. BrCH 2 CH 2 Br, K 2 CC> 3 , DMF, RT; c Required thienopyrimidinone, K 2 C0 3 . DMF. RT: d. K 2 C0 3 . DMF. RT: e. NR 3 R 4 R S , MeOH, sealed tube, 50°C; f. NaN 3 , DMF, 80°C; g. Propargyl alcohol, t-BuOH, water, CuS0 4 .5H 2 0, sodium ascorbate, RT; h. Benzyl azide, t-BuOH, water, CuS0 4 .5H ? 0, sodium ascorbate, RT.
  • the bromide Xll served as intermediate for a number of substituted thieno [2,3-d] pyrimidin-4(3H)-ones XIII, XIV, XV, XVI etc.
  • the compounds prepared in the present invention can be subjected further to various reactions to get a large number of compounds for optimization of biological activity.
  • the compounds of the present invention are characterized by spectral analysis such as NMR, IR, Mass and UV, elemental analysis and melting point etc.
  • the bacterial infections according to the invention may be caused due to gram negative, gram positive bacteria preferably Mycobacterium smegmatis MC2155 strain, Mycobacterium bovis BCG and Mycobacterium tuberculosis H37Rv strain.
  • the thieno[2,3-d]pyrimidin-4(3H)-ones compounds of Formula-I exhibit anti-mycobacterial activity that inhibits the growth of Mycobacterium smegmatis MC2155, Mycobacterium bovis BCG or Mycobacterium tuberculosis H37Ry among other mycobacterium species/strains.
  • the percentage inhibition ranges from about 40 to 68% e.g. compounds 2, 20, 29, 39, 64 and 65.
  • the thieno [2,3-d] pyrimidin-4(3H)-ones comprising compounds 26, 38, 40, 41 , 43, 44 and 58-exhibited significant activity against Mycobacterium smegmatis/ Mycobacterium bovis BCG (inhibition in the range of 30-40% at 30 ⁇ ).
  • One of the thieno [2,3-d] pyrimidin-4(3H)-one 40 was screened against Mycobacterium tuberculosis H37Rv and exhibited antitubercular activity with MIC equal to 8 ⁇ g/mL
  • the present invention provides a pharmaceutical composition comprising of the active ingredient of Formula I or its pharmaceutically acceptable salts, along with pharmaceutically acceptable excipients or carriers, for the treatment of infections caused due to Mycobacterium smegmatis MC 2 155 strain, Mycobacterium bovis BCG and Mycobacterium tuberculosis 3 ⁇ 47Rv strain.in a subject.
  • the present invention provides a pharmaceutical composition for treating or preventing tuberculosis in a subject, comprising anti mycobacterial compounds of Formula 1 in association with at least one pharmaceutically acceptable excipient.
  • the excipients or carriers are selected from diluents, glidants, lubricants, solubilizers, stabilizer, preservatives, sugar, coating agent, flavors, fillers and other inactive ingredients.
  • the quantity of the compounds of Formula 1 used in pharmaceutical compositions of the present invention will vary depending upon the body weight of the patient and the mode of administration and can be of any effective amount to achieve the desired therapeutic effect.
  • the compound of the present invention can also be administered optionally with other antibacterial actives depending on the disease conditions.
  • the pharmaceutical composition according to the invention can be in the form of a solid such as pills, powders, granules, tablets, capsules, pellets, beads etc. or can be present in the liquid form such as solutions, emulsions, suspensions, syrup etc. or can be used in the form of inhalants or parenteral injection.
  • the pharmaceutical compositions containing compounds of Formula I may be administered using an effective amount, along with pharmaceutically acceptable excipients for the treatment of tuberculosis.
  • the quantity of active compound of Formula-I is in the range between 0.9% to 99% by weight of the composition.
  • the invention provides method of treating or preventing the growth of bacterial infections in a subject comprising administering an effective amount of compound of Formula I or its pharmaceutical salt in association with one or more pharmaceutical excipients.
  • the pharmaceutical composition can be administered by any means that delivers the active pharmaceutical ingredient(s) to the site of the body whereby it can exert a therapeutic effect on the patient.
  • the present invention relates to the use of compounds of Formula 1 for the preparation of medicament useful for treatment or prevention of tuberculosis
  • Example 1 Preparation of 6-methyl-thieno[2,3-d]pyrimidin-4(3/i/)-one (1):
  • reaction mixture was extracted with ethyl acetate (3 x 100 ml) and the extract was dried and concentrated to obtain ethyl 2-amino-5-methyl- thiophene-3-carboxylate (40 g, 50.16 %) as a brownish sticky liquid.
  • reaction mixture was then cooled to room temperature, ice was added and stirred for 30 min and the white solid obtained was filtered, washed with water followed by washing with ethyl acetate in pet ether (3 X 20 ml) to get 6-propylthieno[2,3- d]pyrirnidin-4(3H)-one as white powder, 8.9 g, (80. 90 %) .
  • Example 4 Preparation of 6-(n-pentyI)-thieno[2,3-rf]pyrimidin-4(3 /)-one (4) a) Preparation of ethyl 5-pentyl-2-aminothiophene-3-carboxylate:
  • reaction mixture was then cooled to room temperature, diluted with chilled water (800 ml) and stirred for 30 min to obtain a white solid product which was filtered, washed with water (3 X 300 ml) followed by washing with 20 % ethyl acetate in pet-ether (3 x 20 ml) to obtain 6-(n-pentyl)-thieno[2,3- i/]pyrimidin-4(3H)-one as off-white solid (74.89 g, 81.3 %).
  • Example 8 6-(n-Heptyl)-thieno[2,3- ⁇ pyrimidin-4(3//)-one (8)
  • Example 10 6-(n-DecyI)-thieno[2,3- ⁇ /]pyrimidin-4(3 )-one (10)
  • Example 11 6-(Oct-7-en-l-yI)thieno
  • Example 16 3,5,6,7,8,9-Hexahydro-4H-cyclohepta[4,5
  • the 3-substituted thieno[2,3-d]pyrimidin-4(3H)-ones were prepared from the corresponding thieno[2,3 /]pyrimidin-4(3H)-ones by reaction with required (un)substituted alkyl halides in presence of base.
  • thieno[2,3-d] pyrimidin-4(3H)-one compound 4 (9 gm, 0.0404 moles), 2 C0 3 ( 13.85 gm, 0.0404 moles) and TBAB (6.44 g, 0.02 mol) were taken and the mixture was flushed with argon. Allyl bromide (1.23 ml, 0.0144 moles) in ethyl acetate (100 ml) was added by cannula. This reaction mixture was refluxed at 80 °C for 12 hr. Reaction was monitored by TLC (ethyl acetate- pet ether, 50:50).
  • Example 20 3-Allyl-6-propylthieno[2,3-d]pyrimidin-4(3H)-one (20)
  • Example 29 6-Ethyl-3-isopropylthieno[2,3-d
  • Example 33 6-Pentyl-3-propylthieno[2,3-d[pyrimidin-4(3H)-one (33)
  • Example 35 3-Benzyl-6-ethylthieno[2,3-d
  • Example 36 3-Benzyl-6-pi opylthieno[2,3-d
  • Example 37 6-Methyl-3-(prop-2-yn-l-yl)thieno[2,3-d] pyrimidin-4(3H)-one (37)
  • Example 38 6-EthyI-3-(prop-2-yn-l-yl)thieno[2,3-d]pyrimidin-4(3H)-one (38)
  • Example 39 3-(Prop-2-yn-l-yl)-6-propyIthieno[2,3-d]pyrimidin-4(3H)-one (39)
  • Example 40 3-(Prop-2-yn-l -yl)-6-pentylthieno
  • Example 42 Ethyl 2-(6-ethyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yI)acetare (42)
  • Example 45 Preparation of 2-(6-ethyI-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetic acid (45)
  • Example 48 3-(2-BromoethyI)-3,5,6,7-tetrahydro-4H-cycIopenta
  • Example 50 Preparation of 6-methyl-3-vinylthieno
  • Example 51 6-Methyl-3-vinylthieno[2,3-rf
  • Example 52 3-(2-Bromoethyl)-6-methylthieno[2,3-rf]pyrimidin-4(3H)-one (53) :
  • Example 53 3-(2-Bromoethyl-6-heptylthieno[2,3-i/]primidin-4(3//)-one (54):
  • Example 54 3,3'-(Ethane-l,2-diyl)bis(6-heptylthieno
  • Example 55 3-(2-Bromoethyl)-3,5,6,7,8,9-hexahydro- cyclohepta[4,5
  • Example 56 3,3'-(Ethane-l,2-diyl)bis(6-heptyIthieno[2,3-d]pyrimidin-4(3H)-one) (57)
  • Compound 58 was prepared by stirring compound 46 with potassium carbonate in DMF at room temperature.
  • Example 58 3-(2-Azidoethyl)-6-ethylthieno[2,3-d]pyrimidin-4(3H)-one (59)
  • Example 61 Preparation of l-(2-(6-ethyl-4 ⁇ oxothieno[2,3-d]pyrimidin-3(4H)- yl)ethyl)pyridin-l-ium bro
  • Compound 62 was prepared by the procedure described for 4-(dimethylamino)-l -(2-(6-ethyl-4- oxothieno[2,3-d]pyrimidin-3(4H)-yl)ethyl)pyridin- l -ium bromide (61).
  • Example 62 Preparation of 6-chloro-4-(2-(6-ethyl-4-oxothieno ⁇ 2,3-71 pyrimidin- 3(4//)-yl)ethyl)-2//- benzo[b] [ l,4]oxazin-3(4/ )-
  • potassium carbonate 0.5 g, 0.00174 mol
  • tetrabutylammonium bromide 0.56 g, 0.00174 mol
  • 6-chloro-2/ -benzo[6][ l ,4]oxazin- 3(4/J)-one 0.44 g, 0.00264 mol
  • DMF 15 ml
  • Example 63 Preparation of 3-(3-chIoro-2-oxopropyl)-6-propylthieno
  • Example 64 Preparation of 3-(3-cliloro-2-oxopropyl)-6-pentylthieno[2,3-
  • Example 65 Preparation of 3-(3-chloro-2-hydroxypropyl)-6-pentyIthieno[2,3- ⁇ /]pyrimidin-4(3//)-one (66)
  • Example 66 Preparation of 3-(2-oxo-3-(l /-l,2,4-triazol-l-yl)propyl-6- pentylthieno
  • 1 ,2,4-triazole 1 gm, 15 mmol
  • compound 65 1 gm, 3.2 mmol
  • NaHC0 3 1.68 gm, 20 mmol
  • Example 67 Preparation of 3-(2-hydroxy-3-(lH-l,2,4-triazol-l-yl)propyl)-6- pentylthieno[2,3-i/]pyrimidin-4(3/ )-one (68):
  • 6-Methyl-thieno[2, 3-d]pyrimidin-4(3/J)-one 1 (5 g, 0.0301 mole) was taken in two necked R.B. flask with guard tube, acetic acid (25 ml) was added, stirred for 10 min and bromine ( 1.8 ml, 0.033 I mole) in acetic acid ( 1 8 ml) was added drop wise. After complete addition, the reaction mixture was stirred at 60 °C till reaction was completed. Reaction was monitored by TLC. After completion of the reaction, reaction mixture was cooled to room temperature and diluted with water. The solid obtained was filtered and dried to obtain 5-bromo-6-methylthieno[2, 3-d]pyrimidin-4(3//)-one (4.0 g, 54.20 %) as a white solid, M.P. 255-7 °C.
  • Example 70 5-Bromo-6-propylthieno[2,3-rflpyrimidin-4(3 )-one (71)
  • Example 71 5-Bromo-6-hexylthieno[2,3-tf
  • Example 73 3-((l-Benzyl-l H-l,2,3-triazol-4-yl)methyl)-6-ethylthieno[2,3- d]pyrimidin-4(3H)-one (74):
  • Example 74 Preparation of 6-ethyl-3-(2-(4-(hydroxymethyl)-lH-l,2,3-triazol-l- yl)ethyl)thieno
  • reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate, concentrated and purified by column chromatography to obtain 6-ethyl-3-(2-(4-(hydroxymethyl)-lH- l,2,3-triazol-l-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one 75 (2 g, 81.9%).
  • Example 75 Preparation of l-(2-(6-ethyl-4-oxothieno[2,3-d]pyrimidin-3(4H)- yl)ethyl)-lH-l,2,3-triazole-4-carbaldehyde (76)
  • Compound 76 was prepared from 75 by oxidation with IBX in DMSO at RT for 3 h.
  • Example 76 Preparation of 3-(l-(2,4-difluorophenyl)-l-oxopropan-2-yl)-6- ethylthieno[2,3-rf]pyrimidin-4(3H)-one (77)
  • Example 77 3-(l-(2,4-Difluorophenyl)-l-oxopropan-2-yI)-6-heptyIthieno
  • Mycobacterium smegmatis and Mycobacterium bovis BCG share considerable homology with Mycobacterium tuberculosis and were considered as appropriate models for study of anti-tubercular activity of compounds of formula I. Accordingly, the compounds synthesized were evaluated to ascertain their anti-mycobacterial capacity on M. smegmatis (MC 2 155) strain/ 'Mycobacterium bovis BCG strain. Primarily the activity was determined in the form of percentage inhibition following which the MIC was calculated for the compounds showing 30% or more growth inhibition. Initially, lOmM stock concentrations of the compounds were diluted with the required 100% (v/v) DMSO solution to achieve a working concentration of 1.5 mM.
  • the assay was performed in a 96 well format plate. 100 ⁇ of inoculum was incubated with 2% of working solution ( 1.5 mM of compound), making the final concentration of compound as 30 ⁇ .
  • the inoculum of M. smegmatis/ M. bovis BCG was maintained in Middlebrook 7H9 broth supplemented with ADS (Albumin-Dextrose-Saline) or OADC respectively. Prior to assay the inoculum was diluted 1 : 1000 times.
  • the inhibition was tested at increasing concentrations of compound from 6.25 ⁇ to 100 ⁇ . After the period of incubation, from the absorbance of the inoculum observed at 600 nm, MIC values were calculated as the lowest drug concentration, which showed 90% growth inhibition of the bacteria.
  • Peripheral wells of assay plate were filled with sterile distilled water to . avoid evaporation in assay wells.
  • the plates were sealed with parafilm and were incubated at 37°C for 7 days.
  • 5 ⁇ of a freshly prepared Alamar Blue reagent was added to all assay wells.
  • the assay plates were further incubated at 37°C for 24 h. Then the plates were observed visibly for conversion of dye. Appearance of blue color in the well was interpreted as no growth and a pink color was scored as growth. From the observation of growth in comparison to the control, the MIC was defined, as the lowest drug concentration required which inhibits color change from blue to pink.
  • Rifampicin and Isoniazid were chosen.
  • the thieno[2,3-d] pyrimidin-4(3H)-one 40 was screened against Mycobacterium tuberculosis MtbH37Rv and was found to have MIC equal to 8 pg/mL.
  • the compound 2 exhibited significant antimycobacterial activity.
  • Compounds with carbocyclic ring attached to the thiophene group such as compound 15, 48 and 56 showed moderate antimycobacterial activity.
  • N-alkylation of compound 2 afforded corresponding alkylated products out of which compound 29 was equally active as compound 2. Conversion of 2 into 35 and 42, by reaction with benzyl bromide and ethyl bromoacetate respectively, decreased the activity while 45 prepared by hydrolysis of 42 exhibited no activity.
  • the bromide 46 prepared by reaction of compound 2 with 1 ,2-dibromoethane exhibited moderate activity, the corresponding water-soluble quaternary ammonium salt 60 had no activity while 58 prepared from 46 showed significant antimycobacterial activity.
  • the 6-(n)-pentylthieno[2,3- d]pyrimidin-4(3H)-one as such did not exhibit antimycobacterial activity but compounds 43 and 44 prepared by its reaction with ethyl bromoacetate and bromoacetonitrile exhibited significant antimycobacterial activity.
  • the compounds 38, 39 and 40 prepared from the corresponding thieno[2,3-d]pyrimidin-4(3H)-one (2) also exhibited significant antimycobacterial activity.
  • thieno[2,3-d]pyrimidin-4(3H)-one with different structural features were synthesized and evaluated for their antimycobacterial activity.
  • the thieno [2, 3-d] pyrimidin-4(3H)- ones comprising compounds 2, 20, 26, 29, 38, 39, 40, 41, 43, 44, 58, 64 and 65 38, 39 and 40 exhibited significant activity against Mycobacterium smegmatis/ Mycobacterium bovis BCG (inhibition in the range of 30-4068% at 30 ⁇ ).
  • the present invention provides novel thieno[2,3-d]pyrimidin-4(3H)-one compounds of general formula (I) which show great potential as antitubercular agents against Mycobacterium tuberculosis H37Rv and multi drug resistant tubercular bacteria.
  • the compounds of the present invention are easy to synthesize and can be prepared by the processes known in the art.

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne de nouveaux composés thiéno[2,3-d] pyrimidin-4 (3H)-one de formule-I ou ses sels pharmaceutiquement acceptables à activité anti-mycobactérienne significative et une composition pharmaceutique de ceux-ci.
PCT/IN2015/000054 2014-01-30 2015-01-28 Nouveaux composés thiéno [2,3-d] pyrimidin-4 (3h)-one à propriétés antimycobactériennes WO2015114663A1 (fr)

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CN108358860A (zh) * 2018-02-08 2018-08-03 盐城辉煌化工有限公司 一种高收率合成丙硫菌唑的方法
US10758623B2 (en) 2013-12-09 2020-09-01 Durect Corporation Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10758623B2 (en) 2013-12-09 2020-09-01 Durect Corporation Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same
US11529420B2 (en) 2013-12-09 2022-12-20 Durect Corporation Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same
CN108358860A (zh) * 2018-02-08 2018-08-03 盐城辉煌化工有限公司 一种高收率合成丙硫菌唑的方法
CN108358860B (zh) * 2018-02-08 2023-11-21 辽宁众辉生物科技有限公司 一种高收率合成丙硫菌唑的方法

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