WO2016199172A2 - Nouveaux composés et leurs utilisations - Google Patents

Nouveaux composés et leurs utilisations Download PDF

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Publication number
WO2016199172A2
WO2016199172A2 PCT/IN2016/050179 IN2016050179W WO2016199172A2 WO 2016199172 A2 WO2016199172 A2 WO 2016199172A2 IN 2016050179 W IN2016050179 W IN 2016050179W WO 2016199172 A2 WO2016199172 A2 WO 2016199172A2
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Prior art keywords
amino
ethyl
indole
triazol
oxoethyl
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PCT/IN2016/050179
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English (en)
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WO2016199172A3 (fr
Inventor
Hanumant Bapurao Borate
Subhash Prataprao Chavan
Mahesh Madanrao PISAL
Ritesh Ashok ANNADATE
Dhiman Sarkar
Meghana Chintan ATHALYE
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Council Of Scientific & Industrial Research
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Publication of WO2016199172A2 publication Critical patent/WO2016199172A2/fr
Publication of WO2016199172A3 publication Critical patent/WO2016199172A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel compound of formula (I), (II) and (III). More particularly, the present invention relates to a novel compound of formula (I), (II) and (III) or a pharmaceutically acceptable salt thereof, process for preparation thereof and use of these compounds for the treatment of cancer and in cell imaging application.
  • Cancer is a generic term for a large group of diseases caused by uncontrolled growth and spread of cells that can affect any part of the body.
  • Chemotherapy is one of the most common forms of treatment for cancer which involves use of anticancer drugs that can destroy the cancer cells.
  • numerous treatment options are available for cancer, including chemotherapy, surgery and radiation for localized disease or a combination of said treatments. With the development of chemotherapy, survival and recovery rates of cancer patients have improved.
  • anticancer agents are problematic in terms of being highly toxic and thus severely damaging to normal cells.
  • many recent studies have focused on developing alternative anticancer substances capable of specifically suppressing proliferation of tumor cells. Unfornately, however, due to the prevalence of many different types of cancers and due to the complexity of cancers, there still remains a need to develop new anti-cancer therapeutics, including the development of compounds displaying anticancer activity.
  • Substituted 2,6-dicyanoanilines are an important class of compounds with acceptor- donor- acceptor (A-D-A) systems having varied and diverse applications.
  • the compounds find application in optical materials, in dyes, as intermediates in the synthesis of polymers, for chiral phases in chromatography, as precursors and reagents for regio selective or asymmetric syntheses.
  • 2,6-dicyanoaniline compounds with 2,6-dicyanoaniline as core group have been studied for various therapeutic activities and also find use as herbicides and insecticides. They also constitute molecular skeleton of a number of compounds with an array of structural variations some of which have been studied for potential medicinal use.
  • indole pyrrole-fused benzene (indole) derivatives have been considered as useful intermediates in drugs, pesticides and also as potential pharmaceuticals.
  • a large number of methods for the construction of the indole nucleus have been reported.
  • synthesis of indole and indole fused derivatives by novel approach is of current interest due to their promising activity.
  • PCT application no. 2003091214 disclosed substituted 3-amino-2-carboxylic acid indole and benzo(thiophene derivatives for use in treating allergy, asthma, rhinitis, dermatitis, B-cell lymphomas, tumors and diseases associated with bacterial, rhinovirus or respiratory syncytial virus (RSV) infections.
  • RSV respiratory syncytial virus
  • X and Y are the same or different and are independently selected from the group consisting of hydrogen, halogen, nitro, amino, hydroxy, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Ci_ 6 alkoxy, Ci_ 6 perfluoroalkyl, Ci_ 6 perfluoroalkoxy, phenyl and benzyl, wherein phenyl or benzyl is optionally substituted with one or two substituent's each independently selected from Cj- 6 alkyl, Ci- 6 perfluoroalkyl, halogen, hydroxy or Ci_ 6 perfluoroalkyl or Ci_ 6 perfluoroalkoxy;
  • PCT application no. 2000046199 disclosed the use of a 3-substituted indole compound of formula (I) ;
  • X is CH 2 or S0 2 and Ri
  • R 2 , R 3 , R4, R5, R 6 and R 7 are certain specified organic moieties, for use in the preparation of a medicament for the inhibition of monocyte chemoattractant protein- 1 and/or RANTES induced chemotaxis.
  • the problem to be solved by the present invention is to provide compounds that are useful in the treatment of cancer and in cell imaging applications.
  • the main objective of the present invention is to provide a novel compound of formula (I) or a pharmaceutically acceptable salt thereof and process for preparation thereof.
  • Another objective of the present invention is to provide a novel compound of formula (II) or a pharmaceutically acceptable salt thereof and process for preparation thereof.
  • Yet another objective of the present invention is to provide a novel compound of formula (III) or a pharmaceutically acceptable salt thereof and process for preparation thereof.
  • Still another objective of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising compound of formula (I) or (II) or (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent and/or carrier.
  • Yet still another objective of the present invention is to provide a method for the treatment of cancer in a subject in need thereof; comprising administering to the said subject a therapeutically effective amount of the compound of formula (I) or (II) or (III) or a pharmaceutically acceptable salt thereof.
  • Still another objective of the present invention is to provide use of compounds of formula (I) for cell imaging applications.
  • Yet still another objective of the present invention is to provide use of compounds of formula (I) in cell imaging applications.
  • Yet still another objective of the present invention is to provide use of compounds of formula (I), (II), (III) for the treatment of cancer.
  • R and R 1 are selected independently from hydrogen, (un)substituted alkyl,
  • R and R 1 together may form a cyclic ring
  • R is selected from (un)substituted 1,2,3-triazolyl, 1,2,4-triazolyl, mono, di or tri methoxy or halo substituted phenyl ; (benzyl)triazolyl , thienyl, benzofuranyl; 4-((l-(5-iodo- 2-methoxybenzyl)-lH-l,2,3-triazol-4-yl)methoxy)phenyl;
  • R 3 , R 4 is selected from hydrogen, alkyl, benzyl or allyl;
  • R is thienyl
  • R is (un) substituted 4-oxothieno[2,3-d]pyrimidin-3(4H)-yl
  • R is mono, di or tri methoxy or halo substituted phenyl
  • R 1 is not hydrogen and R, R 1 together may not form a cyclic ring
  • said compound of formula (I) is selected from 2-amino-4- (l-benzyl-lH-l,2,3-triazol-4-yl)-5-(4-oxo-6-propylthieno[3,2- ⁇ i]pyrimidin-3(4H)-yl)-6- (thiophen-2-yl)isophthalonitrile (1-1), 2-amino-4-(l-benzyl-lH-l,2,3-triazol-4-yl)-5-(6- hexyl-4-oxothieno[3,2- ⁇ i]pyrimidin-3(4H)-yl)-6-(thiophen-2-yl)isophthalonitrile (1-2), 2- amino-4-( 1 -benzyl- 1H- 1 ,2,3-triazol-4-yl)-6-(thiophen-2-yl)-5-( 1H- 1 ,2,4-triazol- 1 - yl)isophthalonitrile (1-3), 2-
  • said compound of formula (I) is used in cell imaging applications.
  • said compound of formula (I) is used for the treatment of cancer.
  • the present invention provides a novel substituted indole of formula (II);
  • R 5 and R 5 is selected from hydrogen, (un) substituted alkyl, benzyl, formyl, (un)substituted acetyl, (un)substituted allyl,
  • R 6 is selected from hydrogen, (un) substituted alkyl, (un)substituted triazolyl, (un)substituted aryl, imidazolyl, thienyl,
  • R 7 and R 8 is selected from hydrogen, (un)substituted alkyl, alkoxy, (un)substituted aryl, imidazolyl, thienyl, (un)substituted 1,2,3 -triazolyl, 1,2,4-triazolyl;
  • said compound of formula (II) is selected from ethyl 3- amino-6-( 1 -benzyl- 1H- 1 ,2,3-triazol-4-yl)-7-cyano-4-(2,4-difluorophenyl)- 1 -(2-ethoxy-2- oxoethyl)-5-(lH-l,2,4-triazol-l-yl)-lH-indole-2-carboxylate (2-1), ethyl 3-amino-4-(l- benzyl-lH-l,2,3-triazol-4-yl)-7-cyano-6-(2,4-difluorophenyl)-l-(2-ethoxy-2-oxoethyl)-5- (lH-l,2,4-triazol-l-yl)-lH-indole-2-carboxylate (2-2), ethyl 3-amino-6-(l-benzyl-lH-
  • said compound of formula (II) is used for the treatment of cancer.
  • the present invention provides a compound of formula (III);
  • R is selected from (un) substituted 4-oxothieno [2,3-d]pyrimidin-3(4H)-yl, 4-formyl- phenoxymethyl or 4-acetylphenoxymethyl, or a pharmaceutically acceptable salt thereof.
  • said compound of formula (III) is selected from 4-((l-(5- iodo-2-methoxybenzyl)-lH-l,2,3-triazol-4-yl)methoxy)benzaldehyde (3-1), l-(4-((l-(5- iodo-2-methoxybenzyl)-lH-l,2,3-triazol-4-yl)methoxy)phenyl)ethan-l-one (3-2) or 6-ethyl- 3-((l-(5-iodo-2-methoxybenzyl)-lH-l,2,3-triazol-4-yl)methyl)thieno[2,3-d]pyrimidin- 4(3H)-one (3-3).
  • said compound of formula (III) is used for the treatment of cancer.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or (II) or (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent and/or carrier.
  • the present invention provides a method for the treatment of cancer in a subject in need thereof; comprising administering to the said subject a therapeutically effective amount of the compound of formula (I) or (II) or (III) or a pharmaceutically acceptable salt thereof.
  • Fig 1 depicts the absorption spectra of compounds 1-15, 1-3 and 1-5.
  • Fig 2 depicts the emission spectra of compounds 1-15, 1-3 and 1-5 indicating the optical properties.
  • Fig 3 UV-visible absorption spectra of compounds 1-5, 1-6, 1-20 and 1-21.
  • Fig 4 Fluorescence spectra of compounds 1-5, 1-6, 1-20 and 1-21.
  • Fig 5 UV-visible absorption spectra of compounds 1-12, 1-14, 1-17, 1-22, 1-24 and 1-27.
  • Fig 6 Fluorescence spectra of compounds 1-12, 1-14, 1-17, 1-22, 1-24 and 1-27.
  • Fig 7 MCF-7 cells stained with compound 1-17 (100 ⁇ ⁇ > and SYTO 9 (A) Bright field; (B) Blue - compound 1-17, Green - SYTO 9 (Nucleus); (C) Merge image of (A) and (B).
  • Fig 8 MCF-7 cells stained with compound 1-17 (100 aglmL), SYTO 9 and Nile red (A) Bright field; (B) Blue - compound 1-17, Green - SYTO 9 (Nucleus); (C) Red - Nile red (Cell membrane), Green -SYTO 9; (D) Merge image of (A), (B) and (C).
  • Fig 9 MCF-7 cells stained with compound 1-18 (100 aglmL), SYTO 9 and Nile red (A) Bright field; (B) Blue - compound 1-18, Green - SYTO 9 (Nucleus); (C) Red - Nile red (Cell membrane), Green - SYTO 9 (Nucleus).
  • Fig 10 MCF-7 cells stained with compound 1-7 (100 ug/mL), SYTO 9 and Nile red (A) Bright field; (B) Blue - compound 1-7, Green - SYTO 9 (Nucleus); (C) Red - Nile red (Cell membrane), Green - SYTO 9 (Nucleus); (D) Merge image of (A), (B) and (C).
  • Fig 11 MDM-MB-231 cells stained with compound 1-17 (100 ⁇ g/mL) and SYTO 9
  • A Bright field with Blue - compound 1-17
  • B Blue - compound 1-17, Green - SYTO 9 (Nucleus)
  • C Blue - compound 1-17
  • D Merge image of (A), (B) and (C).
  • Fig 12 THP-1 cells stained with compound 1-19 (100 ⁇ g/mL), Annexin-V-FITC and Propidium iodide (PI)
  • A Bright field
  • B Green - Annexin-V-FITC (apoptosis), Red - PI (dead)
  • C Blue - compound 1-19, Red - PI (dead);
  • D Bright field with blue - compound 1-19
  • E - Merge image of (A), (B) and (C)
  • F - Merge image of (B) and (C).
  • Fig 13 THP-1 cells with induced apoptosis using Paclitaxel IC90 concentration, stained with compound 1-19 (100 ⁇ / ⁇ ), Annexin-V-FITC and Propidium iodide (PI)
  • A Bright field
  • B Green - Annexin-V-FITC (apoptosis), Red - Pl(dead)
  • C Blue - compound 1- 19, Red - PI (dead);
  • D Bright field with blue - compound 1-19;
  • E Blue - compound 1- 19;
  • F Merge image of (A) and (C).
  • Fig 14 MCF-7 cells stained with compound 1-19 (100 ⁇ / ⁇ _/), Annexin-V-FITC and Propidium iodide (PI)
  • A Bright field
  • B Green - Annexin-V-FITC (apoptosis), Red - Pl(dead)
  • C Blue - compound 1-19, Red - PI (dead);
  • D Blue - compound 1-19;
  • E - Merge image of (A) and (B);
  • F Merge image of (A) and (C).
  • Fig 15 MCF-7 cells with induced apoptosis using Doxorubicin IC50 concentration, stained with compound 1-19 (100 ⁇ / ⁇ ), Annexin-V-FITC and Propidium iodide (PI)
  • A Bright field
  • B Blue - compound 1-19
  • C Green - Annexin-V-FITC (apoptosis), Red - PI (dead) and Blue - compound 1-19
  • D - Merge image of (A) and (B);
  • E - Merge image of (A) and (C).
  • Fig 16 MDM-MB-231 cells with induced apoptosis using Doxorubicin IC90 concentration, stained with compound 1-19 (100 ⁇ aglmL), Annexin-V-FITC and Propidium iodide (PI)
  • A Bright field
  • B Green - Annexin-V-FITC (apoptosis)
  • C Green - Annexin-V-FITC (apoptosis), Red - PI (dead
  • D - Merge image of (A) and (B);
  • E Bright field with blue - compound 1-19 and red - PI (dead);
  • F - Merge image of (A) and (E).
  • Fig 17 Growth curve for human prostate cancer cell line DU-145 treated with compounds
  • compound NCL-ACT-SPC- 0025 is 2-24
  • compound NCL-ACT-SPC-0028 is 1-50
  • compound NCL-ACT-SPC-0029 is
  • the present invention provides to a novel compound of formula (I), (II) and (III) or a pharmaceutically acceptable salt thereof, process for preparation thereof and use of these compounds for the treatment of cancer. Further, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or (II) or (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent and/or carrier.
  • the present invention provides a compound of formula (I);
  • R and R 1 are selected independently from hydrogen, (un)substituted alkyl, (un)substituted aryl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thienyl, furanyl, thienopyrimidinonyl, benzimidazolyl or benzofuranyl, (un)substituted 4-oxothieno[2,3- d]pyrimidin-3(4H)-yl;
  • R and R 1 together may form a cyclic ring
  • R is selected from (un)substituted 1,2,3-triazolyl, 1,2,4-triazolyl, mono, di or tri methoxy or halo substituted phenyl; (benzyl)triazolyl, thienyl, benzofuranyl; 4-((l-(5-iodo- 2-methoxybenzyl)-lH-l,2,3-triazol-4-yl)methoxy)phenyl;
  • R 3 , R 4 is selected from hydrogen, alkyl, benzyl or allyl;
  • R 1 is (un) substituted 4-oxothieno[2,3-d]pyrimidin-3(4H)-yl; and
  • R is mono, di or tri methoxy or halo substituted phenyl,
  • R 1 is not hydrogen and R; R 1 together may not form a cyclic ring;
  • said compound of formula (I) is selected from 2-amino-4- (l-benzyl-lH-l,2,3-triazol-4-yl)-5-(4-oxo-6-propylthieno[3,2- ⁇ i]pyrimidin-3(4H)-yl)-6- (thiophen-2-yl)isophthalonitrile (1-1), 2-amino-4-(l-benzyl-lH-l,2,3-triazol-4-yl)-5-(6- hexyl-4-oxothieno[3,2- ]pyrimidin-3(4H)-yl)-6-(thiophen-2-yl)isophthalonitrile (1-2), 2- amino-4-( 1 -benzyl- 1H- 1 ,2,3-triazol-4-yl)-6-(thiophen-2-yl)-5-( 1H- 1 ,2,4-triazol- 1 - yl)isophthalonitrile (1-2), 2- amino-4-(
  • said compound of formula (I) is selected from 3-amino-5-(l -benzyl- lH-l,2,3-triazol-4-yl)-2',4'-difluoro-6-(4-oxo-6-pentylthieno [2,3- ⁇ i]pyrimidin-3(4H)-yl)-[l, -biphenyl]-2,4-dicarbonitrile (1-7), 2-amino-4-(l-benzyl- lH-l,2,3-triazol-4-yl)-5-hexylisophthalonitrile (1-17), 3-amino-5-(l-benzyl-lH- 1,2,3- triazol-4-yl)-2',4'-difluoro-[l, -biphenyl]-2,4-dicarbonitrile (1-18), 2-amino-4-(l-benzyl- lH-l,2,3-triazol-4-yl)-2',4
  • said compound of formula (I) is used in cell imaging applications.
  • said compound of formula (I) is used for the treatment of cancer.
  • the present invention provides a process for the synthesis of novel compounds of formula (I) which comprises stirring the reaction mixture of two carbonyl compounds and malononitrile in solvent in presence of morpholine at temperature in the range of 75 to 85°C for the period in the range of 8 to 16 hrs to afford compound of formula (I).
  • said process may optionally further comprise stirring the compound of formula (I) in tetrahydrofuran (THF) with sodium hydride (NaH) at temperature in the range of 50 to 60°C for the period in the range of 10 to 12 hrs followed by addition of methyl iodide and again stirred at temperature in the range of 25 to 30°C for the period in the range of 10 to 12 hrs to afford N,N-dimethylated compound of formula (I).
  • THF tetrahydrofuran
  • NaH sodium hydride
  • said carbonyl compound is selected from 1-benzyl-lH- l,2,3-triazole-4-carbaldehyde, 3-(2-oxo-2-(thiophen-2-yl)ethyl)-6-propylthieno[2,3- d]pyrimidin-4(3H)-one, 3-(2-oxo-2-(thiophen-2-yl)ethyl)-6-hexylthieno[2,3-d]pyrimidin- 4(3H)-one, l-(thiophen-2-yl)-2-(lH-l,2,4-triazol-l-yl)ethan-l-one, l-(2,4-difluorophenyl)- 2-( 1 H- 1 ,2,4-triazol- 1 -yl)ethan- 1 -one, 1 -(4-fluorophenyl)-2-( 1 H- 1 ,2,4-triazol- 1 -yl)ethan-
  • said reaction is carried out under argon atmosphere.
  • the present invention provides a novel substituted indole of formula (II);
  • R 5 and R 5 is selected from hydrogen, (un)substituted alkyl, benzyl, formyl,
  • R 6 is selected from hydrogen, (un) substituted alkyl, (un)substituted triazolyl, (un)substituted aryl, imidazolyl, thienyl,
  • R 7 and R 8 is selected from hydrogen, (un)substituted alkyl, alkoxy, (un)substituted aryl, imidazolyl, thienyl, (un)substituted 1,2,3 -triazolyl, 1,2,4-triazolyl;
  • said compound of formula (II) is selected from ethyl 3- amino-6-( 1 -benzyl- 1H- 1 ,2,3-triazol-4-yl)-7-cyano-4-(2,4-difluorophenyl)- 1 -(2-ethoxy-2- oxoethyl)-5-(lH-l,2,4-triazol-l-yl)-lH-indole-2-carboxylate (2-1), ethyl 3-amino-4-(l- benzyl-lH-l,2,3-triazol-4-yl)-7-cyano-6-(2,4-difluorophenyl)-l-(2-ethoxy-2-oxoethyl)-5-
  • said compound of formula (II) is selected from ethyl 3-amino-7-cyano-l-(2-ethoxy-2-oxoethyl)-5-octyl-6-(3,4,5-trimethoxyphenyl)- lH-indole-2-carboxylate (2-23) or ethyl 3-amino-7-cyano-l-(2-ethoxy-2-oxoethyl)-5-nonyl- 6-(3,4,5-trimethoxyphenyl)-lH-indole-2-carboxylate (2-24).
  • said compound of formula (II) is used for the treatment of cancer.
  • the present invention provides a process for the synthesis of novel compounds of formula (II) which comprises stirring the reaction mixture of compound of formula (I), ethyl bromoacetate and base in solvent at temperature in the range of 25 to 30°C and for the period in the range of 2 to 4 hrs to afford compound of formula (II).
  • said solvent is selected from acetonitrile or dimethylformamide (DMF).
  • said base is selected from potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate.
  • reaction is carried out under argon atmosphere.
  • present invention provides a compound of formula
  • R is selected from (un) substituted 4-oxothieno[2,3-d]pyrimidin-3(4H)-yl,
  • said compound of formula (III) is selected from 4-((l-(5- iodo-2-methoxybenzyl)-lH-l,2,3-triazol-4-yl)methoxy)benzaldehyde (3-1), l-(4-((l-(5- iodo-2-methoxybenzyl)-lH-l,2,3-triazol-4-yl)methoxy)phenyl)ethan-l-one (3-2), 6-ethyl-3- ((l-(5-iodo-2-methoxybenzyl)-lH-l,2,3-triazol-4-yl)methyl)thieno[2,3-d]pyrimidin-4(3H)- one (3-3).
  • said compound of formula (III) is 4-((l-(5- iodo-2-methoxybenzyl)-lH-l,2,3-triazol-4-yl)methoxy)benzaldehyde (3-1).
  • said compound of formula (III) is used for the treatment of cancer.
  • the present invention provides a process for the synthesis of novel compounds of formula (III) comprising click reaction of azido compound with propargyl compound in solvent in presence of copper(II) sulfate pentahydrate
  • said azido compound is selected from 2-(azidomethyl)-4- iodo- 1 -methoxybenzene .
  • said propargyl compound is selected from 4- propargyloxybenzaldehyde, 4-propargyloxyacetophenone, substituted 3-propargyl- thieno[2,3-d]pyrimidin-3(4H)-one.
  • said solvent is selected from t-butanol, water or mixture thereof.
  • the present invention provides compounds of formula (I) which show fluorescence properties.
  • the fluorescence properties of compounds of formula (I) are summarized in Table 1.
  • UV-visible absorption spectra of 2.5 x 10 "5 M solutions in acetonitrile, for representative compounds 1-5 and 1-6 and their corresponding N,N-dimethylated derivatives 1-20 and 1-21 are shown in Fig. 3 while fluorescence spectra for these compounds are shown in Fig. 4.
  • UV-visible absorption spectra, of 2.5 x 10 "5 M solutions in acetonitrile, for compounds 1-12, 1-14, 1-17, 1-22, 1-24 and 1-27 are shown in Fig. 5 while fluorescence spectra for these compounds are shown in Fig. 6.
  • the max values for amino compounds 1-5 and 1-6 are 367 and 365 nm while those for their corresponding N,N-dimethylated derivatives 1-20 and 1-21 are 395 and 390 nm showing that there is a red shift in absorption maxima due to enhanced electron-donating ability of the amino group after methylation. It is observed that the Stokes shifts for the amino compounds 1-5 and 1-6 are 47 and 46 nm while the stokes shifts for the corresponding N,N-dimethylated derivatives 1-20 and 1-21 are 74 and 75 nm indicating that the Stokes shift is increased after N,N-dimethylation of amino group. Similar trend is observed in case of the compounds 1-12 to 1-17 and 1-22 to 1-27.
  • the present invention provides novel compounds of formula (I) which are used for cell imaging applications. From the cell imaging analysis it is observed that some compounds are able to stain eukaryotic cells. The compounds 1-21, 1-18 and 1-7 are found to stain all the cells in contact. These compounds are found to specifically stain only the cytoplasm of the cells but not the nucleus. This is verified by using known counter stains like SYTO 9 (for nucleus) and Nile red (lipid molecules and cell membrane) as shown in figures 7 to 11.
  • one compound 1-19 is found to stain differently only some cells out of total cells. This differential staining was studied further using some known markers and inducers.
  • the cells are seeded and apoptosis / cell death is induced using known anti-cancer, cytotoxic compounds namely Paclitaxel and Doxorubicin at their IC50 and IC90 concentrations.
  • cytotoxic compounds namely Paclitaxel and Doxorubicin at their IC50 and IC90 concentrations.
  • Known markers like Annexin-VFITC for apoptosis and propidium iodide for dead cells are used along with the compound 1-19.
  • Standard staining protocol for Apoptosis/Necrosis using Annexin-V- FITC/PI is carried out with addition of this new compound 1-19.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) or (II) or (III) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent and/or carrier.
  • the carrier is typically used when the composition is prepared, and includes, but not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybezoate, talcum, magnesium stearate, mineral oil, or the like.
  • composition can additionally comprise stability improving material, viscosity improving or adjusting material, solubility improving material, sweetener, dye, palatability improving material, osmotic pressure variable salt, buffer solution, antioxidant and so on.
  • compositions of the present invention can be oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the inventive pharmaceutical composition is administered in the form of a unit dose containing its effective ingredient at an amount between about 1 mg and about 50 mg.
  • the total dose per day of the inventive pharmaceutical composition is within a range from about 1 mg to about 50 mg, and preferably from about 1 mg to about 30 mg.
  • a specific dose beyond such a range can be administered.
  • An optimal dose administered under a specific situation must be decided experimentally.
  • the inventive compounds can be administered once or several times at a dose.
  • a dose per day is administered once or twice per day.
  • inventive compounds can be administered alone or in conjunction with a pharmaceutically acceptable carrier and excipient.
  • inventive pharmaceutical composition can be formulated into excipient known in the art as well as a pharmaceutically acceptable carrier and diluents. This formulation can take the form of a unit dose by a method known in the pharmaceutical field for convenience.
  • the inventive pharmaceutical composition can be used in conjunction with one or more other therapeutically useful materials, for instance other anti-cancer drugs.
  • the present invention provides a method for the treatment of cancer in a subject in need thereof; comprising administering to the said subject a therapeutically effective amount of the compound of formula (I) or (II) or (III) or a pharmaceutically acceptable salt thereof.
  • This compound was prepared by procedure described for 1-20.
  • This compound was prepared by using the procedure similar to 1-20 with slight modification. The compound was stirred with NaH at room temperature and reacted further with allyl bromide at RT.
  • 2-bromomethyl-4-iodoanisole (Chem Asian J. 6, 1546-1556, 2011) (327 mg, 1 mmol) was dissolved in dimethyl formamide (5 ml) and sodium azide (78 mg, 1.2 mmol) was added to it under argon. Reaction mixture was stirred at 80°C for 4 hr, water was added in reaction mixture and extracted with ethyl acetate (2 x 15 ml). Organic layer was dried over Na 2 S0 4 and concentrated to obtain 2-azidomethyl-4- iodoanisole (231 mg, 80%).
  • the cell lines were grown in RPMI 1640 medium containing 10% fetal bovine serum and 2 mM L-glutamine.
  • cells were inoculated into 96 well microtiter plates in 90 ⁇ ⁇ at 5000 cells per well. After cell inoculation, the microtiter plates were incubated at 37°C, 5%C02, 95% air and 100 % relative humidity for 24 h prior to addition of experimental drugs.
  • Experimental drugs were solubilized in appropriate solvent to prepare stock of 10 " concentration.
  • four 10-fold serial dilutions were made using complete medium. Aliquots of 10 ⁇ of these different drug dilutions were added to the appropriate micro-titer wells already containing 90 ⁇ of medium, resulting in the required final drug concentrations.
  • GI50 Growth inhibition of 50 %
  • LC50 Concentration of drug causing 50% cell kill
  • GI50 Concentration of drug causing 50% inhibition of cell growth
  • TGI Concentration of drug causing total inhibition of cell growth
  • Human breast cancer cell line MCF-7 ATCC- HTB-22
  • Human breast cancer cell line MDA-MB-231 ATCC- HTB-26
  • Human monocytic cell line THP-1 ATCC-TIB-202
  • FBS Fetal bovine serum
  • DMEM Dulbecco's modified Eagle's medium
  • RPMI 1640 Minimum Essential Medium
  • C Cell culture: - Human breast cancer cell lines - MCF-7 and MDA-MB-231 and human monocytic cell line - THP-1 were obtained from National Centre for Cell Science (NCCS),
  • MCF-7 cells were maintained in MEM supplemented with 10% and MDA-MB-231 were maintained in DMEM supplemented with 10% FBS at 37°C in C02 incubator. These two adherent cell lines were passaged using trypsin-EDTA (Gibco) and sub-cultured at 1:3 ratio routinely. THP-1 were maintained in RPMI 1640 supplemented with 12% FBS and 0.15% NaHC03. This suspension cell line was passaged at 1:5 ratio routinely and stimulated with PMA (Sigma) for differentiation whenever required.
  • PMA Sigma
  • THP-1 phorbol 12-myristate 13-acetate
  • the cells were incubated with PMA for 24h at 37°C in C0 2 incubator and allowed to adhere to the well bottom surface. Upon differentiation, the cells gain adherent property and get attached to the well surface. The cells were allowed to attach and proliferate for 1 to 2 days.
  • the culture medium was then removed gently from the wells and replaced with pre- warmed PBS (pH 7.2) containing the desired compound to be screened at different concentrations (3, 10, 30 and The plate containing the cells and compounds was incubated for 20 minutes at 37°C in C0 2 incubator. The cells were then washed with pre-warmed PBS twice and replaced with 50 ⁇ PBS and viewed under fluorescent microscope (EVOS FL, Invitrogen) at 20X and 60X objective magnification.
  • E Apoptosis / Necrosis staining protocol: - Annexin-V-FITC conjugate (Invitrogen) was used for the assay along with Propidium iodide. A modified protocol was followed for Annexin-V-FITC staining.
  • Annexin binding buffer was prepared (lOmM HEPES, 140mM NaCl and 2.5mM CaC12, pH 7.4). Propidium iodide stock of lmg/mL (w/v) was prepared in DMSO. To 100 ⁇ _, of binding buffer, 5 ⁇ _, (v/v) Annexin-V-FITC and lpL (v/v) Propidium iodide (lmg/mL) was added and mixed. Culture media was gently removed from wells containing cells and 100 ⁇ _, of this binding buffer containing conjugate and PI was added to the well along with addition of the desired compound viz, COMPOUND 1-19. This was incubated at 37°C in C02 incubator for 15 minutes.
  • one compound viz. compound 1-19 was found to stain differently only some cells out of total cells. This differential staining was studied further using some known markers and inducers. In order to study the differential staining property of compound 1-19, the cells were seeded and apoptosis / cell death was induced using known anti-cancer, cytotoxic compounds namely Paclitaxel and Doxorubicin at their IC50 and IC90 concentrations. Known markers like Annexin- VFITC for apoptosis and Propidium iodide for dead cells were used along with the compound 1-19. Standard staining protocol for Apoptosis/Necrosis using Annexin- V-FITC/PI was carried out with addition of this new compound 1-19.
  • the compounds of the present invention possess excellent optical properties and can be used in the synthesis of indole and related compounds.
  • the compounds of formula (I) show fluorescence and are used in cell imaging applications.
  • the compounds of the present invention are used for the treatment of cancer.

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Abstract

L'invention concerne un nouveau composé de formule (I), (II) et (III) et son procédé de préparation. Une composition pharmaceutique comprenant le composé de formule (I) ou (II) ou (III) et l'utilisation desdits composés pour traiter le cancer et dans des applications d'imagerie cellulaire sont en outre décrites.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000046199A2 (fr) 1999-02-05 2000-08-10 Astrazeneca Ab Composes chimiques
WO2003091214A1 (fr) 2002-04-23 2003-11-06 Aventis Pharmaceuticals Inc. Derives d'acide carboxylique 3-substitue amino-1h-indole-2 et d'acide carboxylique 3-substitue amino-benzo(b)thiophene-2 utilises en tant qu'inhibiteurs de l'expression du gene de l'interleukine-4

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000046199A2 (fr) 1999-02-05 2000-08-10 Astrazeneca Ab Composes chimiques
WO2003091214A1 (fr) 2002-04-23 2003-11-06 Aventis Pharmaceuticals Inc. Derives d'acide carboxylique 3-substitue amino-1h-indole-2 et d'acide carboxylique 3-substitue amino-benzo(b)thiophene-2 utilises en tant qu'inhibiteurs de l'expression du gene de l'interleukine-4

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
AEFG HAMMAM ET AL.: "Novel fluoro substituted benzo[b]pyran with anti-lung cancer activity", IJC-B, vol. 44B, no. 09, September 2005 (2005-09-01), pages 1887 - 1893, XP008125939
B. NARSAIAH ET AL.: "Regioselective cyclization of unsymmetrical dicyanoanilines to novel 2,3-bifunctionalised indole regioisomers and their use in the synthesis of 4,5-dihydro[1,3]oxazino[5,4-b]indole-6-carbonitriles", TETRAHEDRON, vol. 61, no. 16, 2005, pages 3999 - 4008, XP025383156, DOI: doi:10.1016/j.tet.2005.02.046
BORATE ET AL.: "Synthesis of substituted 2,6-Dicyanoanilines and related compounds", ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL, vol. 44, 2012, pages 467 - 521, XP008167640, DOI: doi:10.1080/00304948.2012.715055
CHEM ASIAN J., vol. 6, 2011, pages 1546 - 1556
E YALÇMA ET AL.: "2,6-Dicyanoaniline based donor-acceptor compounds: the facile synthesis of fluorescent 3,5-diaryl/hetaryl-2,6-dicyanoanilines", ARKIVOC, April 2015 (2015-04-01), pages 202 - 218
H BORATE ET AL.: "One-step synthesis of 4-alkyl-3-aryl-2,6-dicyanoanilines and their use in the synthesis of highly functionalized 2,3,5,6,7- and 2,3,4,5,7-substituted indoles", TETRAHEDRON LETTERS, vol. 52, 2011, pages 5491 - 5493, XP028293801, DOI: doi:10.1016/j.tetlet.2011.08.064
HR SHATERIAN ET AL.: "Multicomponent synthesis of 3,5-diaryl-2,6-dicyanoanilines under thermal solvent-free conditions", MONATSH CHEM, vol. 141, no. 5, 2010, pages 557 - 560, XP019853472
S JAIN ET AL.: "A simple and clean synthesis of polysubstituted 2,6-Dicyanoanilines catalyzed by KF/alumina", JOURNAL OF THE KOREAN CHEMICAL SOCIETY, vol. 56, no. 6, 2012, pages 712 - 715
SINGH ET AL.: "Organocatalyzed straightforward synthesis of highly fluorescent 3,5-disubstituted 2,6-dicyanoanilines via domino annulation of a-enolicdithioesters with malononitrile", RSC ADV., vol. 3, 2013, pages 5345 - 5349
SKEHN ET AL.: "New colorimetric cytotoxicity assay for anticancer drug screening", J. NATL. CANCER INST., vol. 82, 1990, pages 1107, XP001022779, DOI: doi:10.1093/jnci/82.13.1107
SL CUI ET AL.: "Parallel synthesis of strongly fluorescent polysubstituted 2,6-dicyanoanilines via microwave-promoted multicomponent reaction", J. ORG. CHEM., vol. 70, no. 7, 2005, pages 2866 - 2869, XP055311365, DOI: doi:10.1021/jo047823h
VANICHA VICHAI ET AL.: "Sulforhodamine B colorimetric assay for cytotoxicity screening", NATURE PROTOCOLS, vol. 1, 2006, pages 1112 - 1116, XP055272660, DOI: doi:10.1038/nprot.2006.179

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