WO2014128724A1 - Composés anti tuberculose et procédé de leur préparation - Google Patents

Composés anti tuberculose et procédé de leur préparation Download PDF

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Publication number
WO2014128724A1
WO2014128724A1 PCT/IN2014/000104 IN2014000104W WO2014128724A1 WO 2014128724 A1 WO2014128724 A1 WO 2014128724A1 IN 2014000104 W IN2014000104 W IN 2014000104W WO 2014128724 A1 WO2014128724 A1 WO 2014128724A1
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WO
WIPO (PCT)
Prior art keywords
compound
general formula
patient
tuberculosis
mixture
Prior art date
Application number
PCT/IN2014/000104
Other languages
English (en)
Inventor
Dumbala Srinivasa REDDY
Remya RAMESH
Original Assignee
Council Of Scientific & Industrial Research
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Council Of Scientific & Industrial Research filed Critical Council Of Scientific & Industrial Research
Publication of WO2014128724A1 publication Critical patent/WO2014128724A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom
    • 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 silicon analogs of alkaloid of general formula I a molecule which has remarkable biological properties.
  • present invention relates to process for the preparation of silicon analogs of alkaloid of general formula I, which are expected to change physico-chemical properties of alkaloid, in particular lipophilicity and in vivo metabolism, which in turn may lead to improved drug candidates. More particularly, present invention relates to silicon analogs of alkaloid of general formula I useful for the treatment of Mycobacterium tuberculosis.
  • the alkaloid called piperine isolated from peppers possesses very interesting biological properties which can be used for treating various diseases like cancer, depression, inflammation and skin problems like vitiligo.
  • piperine suffers from poor pharmacokinetics to become drug on its own.
  • Main object of the present invention is to provide silicon analogs of alkaloid of generalformula I a molecule which has remarkable biological properties.
  • Another object of the present invention is to provide a process for the preparation of silicon analogs of alkaloid of general formula I, which are expected to change physico- chemical properties of alkaloid, in particular lipophilicity and in vivo metabolism, which in turn may lead to improved drug candidates.
  • Another object of the present invention is to provide silicon analogs of alkaloid of general formula I useful for the treatment of various diseases like cancer, depression, inflammation etc.
  • Another object of the present invention is to provide silicon analogs of alkaloid of general formula I useful for the treatment or prevention of Tuberculosis or Mycobacterium tuberculosis.
  • R 1 , R 2 each are individually selected from H, hydroxy, alkoxy or
  • R 1 and R 2 may form alicyclic or aromatic ring which may additionally contain one or two hetero atoms;
  • R 3 , R 4 each are individually selected from alkyl, aryl, alkoxy, halo or
  • R 3 and R 4 may form alicyclic ring which may additionally contain an hetero atom
  • the alkoxy group has C I to C5 carbon atoms.
  • the alicyclic ring is 3 to 8 membered alicyclic ring.
  • the aromatic ring is 3 to 8 membered aromatic ring.
  • the alkyl group has C I to C5 carbon atoms.
  • the aryl group has 1 or 2 rings.
  • the hetero atom is selected from O, S or N.
  • the halo atom is chromo or bormo atom.
  • said compound are useful for the treatment of tuberculosis.
  • present invention provides a process for the preparation of compound of general formula I according to claim 1 comprising the steps of:
  • step (b) adding silapiperidine salt of general formula III to the mixture of step (a) and stirring at temperature in the range of 20 to 25°C for period in the range of 7 to 9 h;
  • step (b) quenching the mixture of step (b) by the addition of water and separating the organic layer followed by washing with saturated NaHCOe, HCl;
  • step (c) drying the separated mixture of step (c) over Na2SC>4 followed by concentrating and purifying by column chromatography using pet ether-ethyl acetate to obtain the compound 3 and 6 of general formula I;
  • coupling agents used is selected from the group consisting of DCC ( iV'-Dicyclohexylcarbodiimide), EDC ( l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide), HATU (l-[Bis(dimethylamino)methylene]- lH- 1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), HBTU (O-Benzotriazole- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyl-uronium-hexafluoro-phosphate), HOBT (Hydroxybenzotriazole) .
  • organic base used is selected from the group consisting of triethyl amine, diisopropylethylamine.
  • yield of the compound of general formula I is in the range of 75-90%.
  • alcohol used is ethanol.
  • present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising compound of Formula I along with pharmaceutically acceptable ingredients against Mycobacterium tuberculi.
  • Present invention provides silicon analogs of piperine of general formula I which has remarkable biological properties and is expected to show activities similar or better with improved pharmacokinetics parameters.
  • the introduction of Silicon atom, the novel compounds are expected to change physico-chemical properties, in particular lipophylicity and in vivo metabolism, which in turn may lead to improved drug
  • R 1 , R 2 each are individually selected from H, hydroxy, alkoxy or
  • R 1 and R 2 may form alicyclic or aromatic ring which may additionally contain one or two hetero atoms;
  • R 3 , R 4 each are individually selected from alkyl, aryl, alkoxy, halo or
  • R 3 and R 4 may form alicyclic ring which may additionally contain an hetero atom
  • alkoxy group has C I to C5 carbon atoms.
  • the alicyclic ring is 3 to 8 membered alicyclic ring.
  • the aromatic ring is 3 to 8 membered aromatic ring.
  • the alkyl group has C I to C5 carbon atoms.
  • the aryl group has 1 or 2 rings.
  • the hetero atom is selected from O, S or N.
  • the halo atom is chromo or bormo atom.
  • the present invention provides the synthesis for the preparation of analogs of piperine of general formula I with increased efficacy starting from the reaction of compound of general formula II with compound of general formula III and the said process comprises the steps of: a) adding coupling agents like DCC, EDC, HATU, HBTU or HOBT and any organic base such as triethyl amine or diisopropylethylamine to a solution of carboxylic acid precursor general formula II in dry DCM at 0 °C; b) adding silapiperidine salt of general formula III to the mixture of above and stirring it at room temperature for 8 h;
  • step (b) quenching the mixture of step (b) by the addition of water and separating the organic layer, by washing it with saturated NaHCC , IN HC1;
  • step (d) purifying the crude mixture of step (d) further by column chromatography using pet ether-ethyl acetate to obtain the compound of formula I in high yield.
  • a pharmaceutical composition comprising a compound of general formula I or a stereoisomer, or ester or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels and microspheres,
  • the present invention relates to administering 'an effective amount' of the 'composition of invention ' to the subject in need of the same ' .
  • compound of formula I and pharmaceutical compositions containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease.
  • Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
  • Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a subject or patient may take the form of one or more dosage units.
  • the dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms.
  • Another embodiment of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I along with pharmaceutically acceptable ingredients.
  • Another embodiment of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I along with pharmaceutically acceptable ingredients against Mycobacterium tuberculi.
  • Another embodiment of the present invention provides a method of treating a patient with tuberculosis, said method comprising administering to the patient, a therapeutically effective amount of the compound of Formula I described as herein.
  • Another embodiment of the present invention provides a method of treating a patient with tuberculosis, said method comprising administering to the patient, a therapeutically effective amount of any compound of Formula I described as herein in any of the embodiments of the invention.
  • Another embodiment of the present invention provides use of a compound of Formula I described as herein in any of the embodiment of the present invention for the treatment or prevention of tuberculosis.
  • Another embodiment of the present invention provides use of compound of Formula I for the preparation of a medicament.
  • Another embodiment of the present invention provides use of the medicament as for the treatment of a disease.
  • Another embodiment of the present invention provides use of the medicament as for the treatment of a disease wherein the disease is selected from tuberculosis, cancer, inflammation, depression, etc.
  • Another embodiment of the present invention provides a method of treating a patient with a disease, said method comprising administering to the patient, a therapeutically effective amount of the compound of formula I described as herein in any of the embodiments of the invention.
  • Another embodiment of the present invention a method of treating a patient with a disease, said method comprising administering to the patient, a therapeutically effective amount of the compound of formula I described as herein in any of the embodiments of the invention, wherein the disease is selected from group comprising of tuberculosis, cancer, inflammation, depression, etc.
  • Another embodiment of the present invention a method of .treating a patient with a disease, said method comprising administering to the patient, a therapeutically effective amount of the compound of formula I, wherein the disease is selected from group comprising of cancer, inflammation, depression, etc.
  • IR i (film): cm' 1 3031, 1624, 1504, 1489, 1441;
  • the compounds (3) and (6) were tested for antitubercular activity through inhibition of growth of the virulent strain of Mycobacterium tuberculosis 3 ⁇ 47Rv using Alamar-Blue assay method.
  • MIC values of the compounds against H37RV were determined in 7H9- OADC media supplemented with 0.5% glycerol and 1 mg ml' 1 tryptone at 37 °C in 96- well microtiter plates using the colorimetric resazurin microtiter assay, and growth was measured by visual readout, Rifampicin was used as a positive drug control.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pulmonology (AREA)
  • Oncology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des analogues de silicium de pipérine de formule I présentant une plus grande efficacité antibactérienne et leur préparation.
PCT/IN2014/000104 2013-02-19 2014-02-19 Composés anti tuberculose et procédé de leur préparation WO2014128724A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN0467/DEL/2013 2013-02-19
IN467DE2013 2013-02-19

Publications (1)

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WO2014128724A1 true WO2014128724A1 (fr) 2014-08-28

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015102025A1 (fr) * 2014-01-03 2015-07-09 Council Of Scientific & Industrial Research Fongicides à base de silicium et procédé de production desdits fongicides
WO2017141272A1 (fr) 2016-02-19 2017-08-24 Council Of Scientific & Industrial Research Composés cycliques à base de silicium et compositions pharmaceutiques pour le traitement du paludisme et de la toxoplasmose

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006103527A1 (fr) * 2005-03-31 2006-10-05 Council Of Scientific And Industrial Research Amide aromatique substitue de l’acide pentadienoique destine a etre associe avec des anti-infectieux
CN102125554A (zh) * 2010-01-14 2011-07-20 吉林大学 一种分支杆菌外输蛋白新抑制剂

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006103527A1 (fr) * 2005-03-31 2006-10-05 Council Of Scientific And Industrial Research Amide aromatique substitue de l’acide pentadienoique destine a etre associe avec des anti-infectieux
CN102125554A (zh) * 2010-01-14 2011-07-20 吉林大学 一种分支杆菌外输蛋白新抑制剂

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BUSWELL M ET AL: "The extraordinary reactions of phenyldimethylsilyllithium with N,N-disubstituted amides", ORGANIC & BIOMOLECULAR CHEMISTRY, ROYAL SOCIETY OF CHEMISTRY, GB, vol. 2, no. 20, 1 October 2004 (2004-10-01), pages 3006 - 3017, XP002721752, ISSN: 1477-0520, [retrieved on 20040927], DOI: 10.1039/B412768D *
DATABASE WPI Week 201218, Derwent World Patents Index; AN 2011-K35818, XP002726140 *
FERGAL N.MCNAMARA; ANDREW RANDALL; MARTIN J.GUNTHORPE: "Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1)", BRITISH JOURNAL OF PHARMACOLOGY, vol. 144, 2005, pages 781 - 790
LI-HUA MUA; BO WANGA; HAO-YANG REN; PING LIU; DAI-HONG GUO; FU-MENG WANG; LIN BAI; YAN-SHEN GUO: "Synthesis and inhibitory effect of piperine derivates on monoamine oxidase", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, 2012, pages 3343 - 3348, XP028410913, DOI: doi:10.1016/j.bmcl.2012.02.090
PATRICK ENGLEBIENNE; ANNE V. HOONACKER; C. V. HERST: "The Place of the Bioisosteric Sila-Substitution in Drug Design", ENGLEBIENNE & ASSOCIATES IN RESEARCH GATE, 2005
SANDEEP SHARMA; MANOJ KUMAR; SUJATA SHARMA; AMIT NARGOTRA; SURRINDER KOUL; INSHAD ALI KHAN: "Piperine as an inhibitor of Rv1258c, a putative multidrug efflux pump of Mycobacterium tuberculosis", J ANTIMICROB CHEMOTHER, vol. 65, 2010, pages 1694 - 1701
W. S. TAVARES; I. CRUZ; F. PETACCI; S. S. FREITAS; J. E. SERRAO; J. C. ZANUNCIO: "Insecticide activity of piperine: Toxicity to eggs of Spodoptera frugiperda (Lepidoptera: Noctuidae) and Diatraea saccharalis (Lepidoptera: Pyralidae) and phytotoxicity on several vegetables", JOURNAL OF MEDICINAL PLANTS RESEARCH, vol. 5, no. 21, 9 October 2011 (2011-10-09), pages 5301 - 5306

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015102025A1 (fr) * 2014-01-03 2015-07-09 Council Of Scientific & Industrial Research Fongicides à base de silicium et procédé de production desdits fongicides
US10053472B2 (en) 2014-01-03 2018-08-21 Council Of Scientific & Industrial Research Silicon-based fungicides and process for producing the same
WO2017141272A1 (fr) 2016-02-19 2017-08-24 Council Of Scientific & Industrial Research Composés cycliques à base de silicium et compositions pharmaceutiques pour le traitement du paludisme et de la toxoplasmose
US10562922B2 (en) 2016-02-19 2020-02-18 Council Of Scientific And Industrial Research Silicon based cyclic compounds and pharmaceutical compositions for treating malaria and toxoplasmosis

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