WO2005080335A1 - 3-3-di-substituted-oxindoles as inhibitors of translation initiation - Google Patents

3-3-di-substituted-oxindoles as inhibitors of translation initiation Download PDF

Info

Publication number
WO2005080335A1
WO2005080335A1 PCT/US2005/004373 US2005004373W WO2005080335A1 WO 2005080335 A1 WO2005080335 A1 WO 2005080335A1 US 2005004373 W US2005004373 W US 2005004373W WO 2005080335 A1 WO2005080335 A1 WO 2005080335A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
group
nhso
human
Prior art date
Application number
PCT/US2005/004373
Other languages
English (en)
French (fr)
Inventor
José A. HALPERIN
Amarnath Natarajan
Huseyin Aktas
Yun-Hua Fan
Han Chen
Original Assignee
President And Fellows Of Harvard College
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 President And Fellows Of Harvard College filed Critical President And Fellows Of Harvard College
Priority to EP05722960A priority Critical patent/EP1718611A4/en
Priority to CA002555812A priority patent/CA2555812A1/en
Priority to JP2006553263A priority patent/JP4989976B2/ja
Priority to AU2005214338A priority patent/AU2005214338B2/en
Publication of WO2005080335A1 publication Critical patent/WO2005080335A1/en
Priority to US11/463,421 priority patent/US7737172B2/en
Priority to US12/368,588 priority patent/US7846962B2/en
Priority to US12/796,831 priority patent/US8268879B2/en
Priority to US12/796,787 priority patent/US8088816B2/en
Priority to US12/916,956 priority patent/US8044089B2/en
Priority to US13/233,074 priority patent/US8354440B2/en

Links

Classifications

    • 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
    • C07D209/32—Oxygen atoms
    • C07D209/36—Oxygen atoms in position 3, e.g. adrenochrome
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P31/12—Antivirals
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • 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
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • 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
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to novel compounds which inhibit translation initiation, pharmaceutical compositions of the novel compounds, and methods of treating medical disorders.
  • Translation the mRNA-directed synthesis of proteins, occurs in three distinct steps: initiation, elongation and termination.
  • Translation initiation is a complex process in which the two ribosomal subunits and methionyl tRNA (met-tRNA) assemble on a properly aligned mRNA to commence chain elongation at the AUG initiation codon.
  • the established scanning mechanism for initiation involves the formation of a ternary complex among eukaryotic initiation factor 2 (eIF2), GTP and met-tRNA.
  • eIF2 eukaryotic initiation factor 2
  • GTP eukaryotic initiation factor 2
  • met-tRNA met-tRNA
  • This complex recruits mRNA in cooperation with other initiation factors such as eukaryotic initiation factor 4E (eIF4E), which recognizes the 7-methyl- guanidine cap (m- 7 GTP cap) in an mRNA molecule and forms the 48 S pre-initiation complex. Cap recognition facilitates the 43S complex entry at the 5' end of a capped mRNA. Subsequently, this complex migrates linearly until it reaches the first AUG codon, where a 60S ribosomal subunit joins the complex, and the first peptide bond is formed (Pain (1996) Eur. J. Biochem., 236:747-771).
  • eIF4E eukaryotic initiation factor 4E
  • mRNAs with complex, highly structured 5' UTRs include a disproportionately high number of proto-oncogenes such as the Gl cyclins, transcription and growth factors, cytokines and other critical regulatory proteins.
  • mRNAs that encode globins, albumins, histones and other housekeeping proteins rarely have highly structured, GC-rich 5' UTRs (Kozak (1994) Biochimie, 76; 815-21 ; Kozak (1999) Gene, 234: 187-208).
  • the fact that genes encoding for regulatory but not for housekeeping proteins frequently produce transcripts with highly structured 5' UTRs indicates that extensive control of the expression of regulatory genes occurs at the level of translation. In other words, low efficiency of translation is a control mechanism which modulates the yield of proteins such as cyclins, mos, c-myc, VEGF, TNF, among others, that could be harmful if overproduced.
  • Translation initiation is a critical step in the regulation of cell growth because the expression of most oncogenes and cell growth regulatory proteins is translationally regulated.
  • One approach to inhibiting translation initiation has recently been identified using small molecule known as translation initiation inhibitors.
  • Figure 1 sets forth a summary of the anti-cancer mechanism of action of translation initiation inhibitors such as clotrimazole (CLT) and the diaryloxindole (DAO) compounds of the present invention.
  • CLT inhibits translation initiation by sustained depletion of intracellular Ca 2+ stores.
  • EPA polyunsaturated fatty acid eicosapentaenoic acid
  • EPA is a ligand of peroxisome proliferator-activated receptor gamma (PPAR ⁇ ), a fatty acid-activated transcription factor.
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • EPA and other ligands of PPAR ⁇ such as troglitazone and ciglitazone, inhibit cell proliferation, they do so in a PPAR ⁇ -independent manner (Palakurthi et al. (2000) Cancer Research, 60:2919; and Palakurthi et al. (2001) Cancer Research, 61 :6213, incorporated herein by reference in their entirety for all purposes).
  • Embodiments of the present invention are directed to compounds that inhibit translation initiation, and the use of such compounds for treating (1) proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infections are disclosed. Certain examples are directed to the use of a combination of the compounds described herein for treating (1) proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infections. [09] In at least certain examples, DAO compounds are provided.
  • diaryloxindole AND “DAO” are intended to include substituted diphenyloxindole compounds such as, for example, 3-(5-tert-butyl-2-hydroxy-phenyl)-3-phenyl-l,3- dihydro-indol-2-one-type compounds.
  • diaryloxindole compounds of the present invention are set forth in Formula I.
  • the diaryloxindole compounds of the present invention deplete intracellular calcium stores.
  • diaryloxindole compounds are effective to inhibit translation initiation.
  • the diaryloxindole compounds of the present invention include compounds comprising Formula I to Formula XIV, and/or the active and partially active compounds set forth in Tables 1 - 14 and Figures 4A-4B.
  • a method of treating a proliferative disorder by providing and/or administering a diaryloxindole compound to a mammal e.g., a human or a non-human (e.g., a non-human primate)
  • a mammal e.g., a human or a non-human (e.g., a non-human primate)
  • the proliferative disorder is cancer.
  • a method of treating a viral infection by providing and/or administering a diaryloxindole compound to a mammal, e.g. a human or a non-human mammal is provided.
  • kits are provided for the treatment of (1) proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infections.
  • the kits comprise a diaryloxindole compound, a pharmaceutically acceptable carrier, and optionally, instructions for use.
  • the pharmaceutical composition can be administered to a human subject or a non-human subject depending on the disorder to be treated.
  • Figure I depicts a schematic of the anti-cancer mechanism of action for translation initiation inhibitors such as clotrimazole (CLT) and diaryloxindole (DAO).
  • CLT clotrimazole
  • DAO diaryloxindole
  • FIGS 2A-2B depict compound 1181 activity.
  • A depicts calcium (Ca 2+ ) release in a dose dependent manner as compared to CLT from intracellular stores measured using dye-loaded cells.
  • B depicts depletion of endoplasmic reticulum (ER) Ca 2+ in stable cells lines carrying ER-targeted Ca -sensitive chameleon proteins exposed to compound 1181, in accordance with certain examples. These proteins emit light and the Ca 2+ content is measured by fluorescent resonance energy transfer (FRET).
  • FRET fluorescent resonance energy transfer
  • FIGS. 3A-3C depict compound 1181 activity.
  • A depicts the drug induced phosphorylation of eIF2 ⁇ protein in control (lane 1), positive control (lane 2) and 1 181 (lane 3) measured using Western blot analysis.
  • B shows the in vitro anticancer effect of 1 181 in human lung cancer cells (A549) measured using sulfur rhodamine B (SRB) assay.
  • C graphically depicts depletion of ternary complex in transgenic KLN cells exposed to compound 1181.
  • Figures 4A-4B depict a general schematic for the synthesis of peptides that contain the diaryloxindole moiety.
  • Figure 5 graphically depicts a decrease in squamous cell carcinoma (KLN) tumor mass from DBA/2J mice after six weeks of treatment by oral administration with compound 1181 at 320 mg/kg/day.
  • KLN squamous cell carcinoma
  • diaryloxindole compounds that inhibit translation (e.g., translation initiation) are provided. Such compounds are useful for the treatment of (1) proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infections.
  • the compounds and compositions provided below are effective to inhibit translation (e.g., translation initiation) at least to the extent necessary for effective treatment of one or more disorders described herein. While in certain examples translation may be substantially inhibited such that little or no activity results, in other examples the inhibition is at least sufficient to relieve and or alleviate the symptoms from a selected disorder to be treated.
  • translation e.g., translation initiation
  • the inhibition is at least sufficient to relieve and or alleviate the symptoms from a selected disorder to be treated.
  • Ri is selected from the group consisting of (halo)alky, (un)substituted (alkyl)aryl, halogen, CN, COOH, alkenyl, alkynyl, alkoxy, cycloalkoxy, H, 2-OH, 2-Me, 2-OMe, 2-CH 2 CO 2 H, 2-NHFmoc, 2-NHSO 2 CH 2 Ph (wherein Ph is phenyl), 2-NHSO 2 CH 3 , 2-NHSO 2 (4-tBu)Ph, 2-NHSO 2 (4-NHAc)Ph, 2- NHSO 2 (3-CF 3 )Ph, 2-NHSO 2 (4-NO 2 )Ph, 2-NHSO 2 (4-OMe)Ph, 2-NHSO 2 (4-Br)Ph, 2- NHSO 2 (4-I)Ph, 2-NHSO 2 (4-Ph)Ph, 2-NHSO 2 (4-OPh)Ph, 2-NHAc, 2-NHCO(4- tBu)Ph, 3-
  • NHCOAr, H wherein X is selected from the group consisting of H, -SO 2 -Camphor, -CO(CH 2 ) 6 COOH, - CO(CH 2 ) 3 CONHOH, -CH 2 CH 2 NHBoc, -CO(CH 2 ) 3 COOH, -CH 2 COOH, -CH 2 CO- Leu-Phe-CH 2 OH, -CH 2 COOMe, 2-OH, 2-Me, 2-NHFmoc, 2-NHSO 2 CH 2 Ph, 2- NHSO 2 CH 3 , 2-NHSO 2 (4-tBu)Ph, 2-NHSO 2 (4-NHAc)Ph, 2-NHSO 2 (3-CF 3 )Ph, 2- NHSO 2 (4-NO 2 )Ph, 2-NHSO 2 (4-OMe)Ph, 2-NHSO 2 (4-Br)Ph, 2-NHSO 2 (4-I)Ph, 2- NHSO 2 (4-Ph)Ph, 2-NHSO 2 (4-OPh)Ph, 2-NHAc
  • diaryloxindole compounds are represented by Formula I, set forth below.
  • A is selected from the group consisting of carbocyclic aromatic ring, heterocyclic ring and heteroaromatic ring
  • Ri is selected from the group consisting of (halo)alky, (un)substituted (alkyl)aryl, halogen, CN, COOH, alkenyl, alkynyl, alkoxy and cycloalkoxy
  • R 2 is selected from the group consisting of (un)substituted aryl, (un)substituted heterocyclic, (un)substituted heteroaromatic, Ar- NHSO 2 Ar and Ar-NHCOAr
  • R is selected from the group consisting of (un)substituted aryl, (un)substituted heterocyclic, (un)substituted heteroaromatic, Ar- NHSO 2 Ar and Ar-NHCOAr
  • t is selected from the group consisting of (un)substituted aryl, (un)substituted heterocyclic, (
  • diaryloxindole compounds are represented by Formula II, set forth below.
  • R ⁇ is selected from the group consisting of H, 5-bromo, 5-chloro, 7-bromo, 5-iodo, 5-OCF 3 , 5-sulfonic acid, 5-nitro, 4-bromo, 6-bromo, 5- ethyl, 7-ethyl, 4-ethyl, 6-ethyl, 7-iodo, 5-fluoro, 7-COOH and 7-COOMe, and R 2 is H.
  • Ri is 4-Cl and R 2 is selected from the group consisting of 7- formamide-N-[2-(4-Amino-phenyl)-ethyl], 7-COOH, 7-CH 2 OH and 7-CH 2 -N- imidazole.
  • diaryloxindole compounds are represented by Formula III, set forth below.
  • X is selected from the group consisting of oxygen, NH and CH 2
  • R is selected from the group consisting of 3'-CH 2 CH(CO 2 Me)NH 2 , 3'- CH 2 CH(CO 2 Me)NHFmoc, 3'-t-Bu, 3'-t-Bu, 3'-OH, 3'-O(CH 2 ) 3 CHCH 2 , 3'- o H O(CH 2 ) 4 Br, 3'-O(CH 2 ) 4 NMe 2 , 3'-O(CH 2 ) 4 N 3 , 3'-- ⁇ °, 3'-O(CH 2 ) 4 NH 2 , 3'-CF 3 , 3'-CH 3 , 3'-n-heptyl, 3'-n-nonyl3'-/-Bu, 3'- - -Propyl, 3'-n-Propyl, 3'-n-Octyl, 3'-Et, 3'-n-p
  • diaryloxindole compounds are represented by Formula IV, set forth below.
  • R is selected from the group consisting of 4-F, 4- O(CH 2 ) 3 CHCH 2 , 3-C1, 3-F, 3-Me, 2-Me and 2-OMe.
  • diaryloxindole compounds are represented by Formula V, set forth below.
  • R is selected from the group consisting of -SO 2 -camphor, -CO(CH 2 ) 6 COOH, -CO(CH 2 ) 3 CONHOH, -CH 2 CH 2 NHBoc, -CO(CH 2 ) 3 COOH, - CH 2 COOH, -CH 2 CO-Leu-Phe-CH 2 OH and -CH 2 COOMe.
  • diaryloxindole compounds are represented by Formula VI, set forth below.
  • R ⁇ is selected from the group consisting of 7-Br, 4-Cl, 5- Br, 5-NO 2 , 5-1, 5-OMe, 5-C1, 7-CF 3 , 5-NH 2 , 4-Br, 6-Br, H, 7-OMe, 7-1, 5-Et, 7-Et, 4- Et, 6-Et, 5-F, 5-N 3 , 7-COOH, 4-Cl, 6-C1 and 5-NHSO 2 -l-napthyl, and R 2 is H.
  • Ri is 4-Cl and R 2 is 7-COOH.
  • diaryloxindole compounds are represented by Formula VII, set forth below.
  • is selected from the group consisting of H, 2-OH, 3- O(CH 2 ) 4 NMe 2 , 3-O(CH 2 ) 4 N 3 , 3-t-Bu, 2-OMe, 3-OMe, 4-OH, 4-n-propyl, 4-/-Bu, 4-n- Bu, 4-O(CH 2 ) 2 OH, 4-OMe, 2-CH 2 CO 2 H and 4-t-Bu, and R 2 is H.
  • Ri is selected from the group consisting of 2-OH, 4-OMe, 3-t-Bu, 2-OMe, 2-OH, 4- OH, 4-OPh, 4-Ph and 4-NMe 2
  • R 2 is selected from the group consisting of 2-OH, 4-OH and 4-t-Bu.
  • diaryloxindole compounds are represented by Formula VIII, set forth below.
  • Ri is selected from the group consisting of H and 7- COOH
  • R 2 is selected from a group consisting of H, 2-Me, 3'-Me, 3-F and 3-CF 3
  • R 3 is selected from a group consisting of H, 2-NHFmoc, 2-NHSO 2 CH 2 Ph, 2- NHSO 2 CH 3 , 2-NHSO 2 (4-tBu)Ph, 2-NHSO 2 (4-NHAc)Ph, 2-NHSO 2 (3-CF 3 )Ph, 2- NHSO 2 (4-NO 2 )Ph, 2-NHSO 2 (4-OMe)Ph, 2-NHSO 2 (4-Br)Ph, 2-NHSO 2 (4-I)Ph, 2- NHSO 2 (4-Ph)Ph, 2-NHSO 2 (4-OPh)Ph, 2-NHAc, 2-NHCO(4-tBu)Ph and 3'- NHSO 2 (4-tBu)Ph.
  • diaryloxindole compounds are represented by Formula IX, set forth below.
  • R is selected from the group consisting of Ph, Me, -CH 2 - (4-Cl)Ph, -CH 2 CHCH 2 , -CH 2 OH, CH 2 COOH, CH 2 OCH 2 CHCH 2 , -SO 2 (4-O-n-Bu)Ph, -SO 2 (4-O-Ph)Ph, -SO 2 (4-NHAc)Ph, -SO 2 (4-CH 2 CH 2 CO 2 Me)Ph, -SO 2 (4-OMe)Ph and -SO 2 (4-t-Bu)Ph.
  • diaryloxindole compounds are represented by Formulae X-XII, set forth below.
  • diaryloxindole compounds are represented by Formula XIII, set forth below.
  • R is selected from the group consisting of 2-thiophene, - (CH 2 )nCH 3 , -CH 2 Ph, -CCH, -cyclohexyl and -C 6 F 5 (pentafluorophenyl).
  • diaryloxindole compounds are represented by Formula XIV, set forth below.
  • R is selected from the group consisting of H, 3-C1, 3-F, 3- Me and 3-t-Bu.
  • diaryloxindole compounds include, but are not limited to, compounds comprising Formula I to Formula XIV, and the active and/or partially active compounds set forth in Figures 4A-4B and Tables 1-14.
  • the compounds disclosed here can be used in the treatment of cellular proliferative disorders, such as cancer.
  • Treatment of cellular proliferative disorders is intended to include, but is not limited to, inhibition of proliferation including rapid proliferation.
  • cellular proliferative disorder includes, but is not limited to, disorders characterized by undesirable or inappropriate proliferation of one or more subset(s) of cells in a multicellular organism.
  • cancer refers to various types of malignant neoplasms, most of which can invade surrounding tissues, and may metastasize to different sites (see, for example, PDR Medical Dictionary 1st edition (1995), incorporated herein by reference in its entirety for all purposes).
  • abnormal tissue refers to an abnormal tissue that grows by cellular proliferation more rapidly than normal and continues to grow after the stimuli that initiated proliferation is removed. Id. Such abnormal tissue shows partial or complete lack of structural organization and functional coordination with the normal tissue which may be either benign (i.e., benign tumor) or malignant (i.e., malignant tumor).
  • treatment of cellular proliferative disorders is intended to include, but is not limited to, the prevention of the growth of neoplasms in a subject or a reduction in the growth of pre-existing neoplasms in a subject.
  • the inhibition also can be the inhibition of the metastasis of a neoplasm from one site to another.
  • the neoplasms are sensitive to one or more diaryloxindole compounds of the present invention.
  • viral infection refers to one or more cells which have been infected with a virus, such as a DNA or RNA animal virus.
  • RNA viruses include, but are not limited to, virus families such as picornaviridae (e.g., polioviruses), reoviridae (e.g., rotaviruses), togaviridae (e.g., encephalitis viruses, yellow fever virus, rubella virus), orthomyxoviridae (e.g., influenza viruses), paramyxoviridae (e.g., respiratory syncytial virus, measles virus, mumps virus, parainfluenza virus), rhabdoviridae (e.g., rabies virus), coronaviridae, bunyaviridae, flaviviridae, filoviridae, arenaviridae, bunyaviridae, and retroviridae (e.g., human T-cell lymphotropic viruses (HTLV), human immunodeficiency viruses (HIV)).
  • picornaviridae e.g., polioviruses
  • DNA viruses include, but are not limited to, virus families such as papovaviridae (e.g., papilloma viruses), adenoviridae (e.g., adenovirus), herpesviridae (e.g., herpes simplex viruses), and poxviridae (e.g., variola viruses).
  • virus families such as papovaviridae (e.g., papilloma viruses), adenoviridae (e.g., adenovirus), herpesviridae (e.g., herpes simplex viruses), and poxviridae (e.g., variola viruses).
  • the viral infection is caused by hepatitis B virus, hepatitis C virus, and/or HIV.
  • disorders associated with viral infections are disclosed.
  • Treatment of one or more disorders associated with viral infections is intended to include, but is not limited to, the use of a diaryloxindole compound described herein to reduce or alleviate one or more symptoms of a viral infection.
  • disorders associated with viral infection refers to the host's response to infection by one or more viruses.
  • Such responses include, but are not limited to neurological symptoms (e.g., encephalitis, meningoencephalitis, paralysis, myelopathy, neuropathy, aseptic meningitis, hemiparesis, dementia, dysphagia, lack of muscular coordination, impaired vision, coma, and the like), wasting symptoms (e.g., inflammatory cell infiltration, perivascular cuffing of blood vessels, demyelination, necrosis, reactive gliosis and the like), gastroenteritis symptoms (e.g., diarrhea, vomiting, cramps and the like), hepatitis symptoms (nausea, vomiting, right upper quadrant pain, raised liver enzyme levels (e.g., AST, ALT and the like), jaundice and the like), hemorrhagic fever symptoms (e.g., headache, fever, chills body pains, diarrhea, vomiting, dizziness, confusion, abnormal behavior, pharyngitis, conjunctivitis, red face, red neck, hemorrhage
  • non-proliferative, degenerative disorders associated with aberrant translation initiation using a diaryloxindole compound described herein to alleviate and/or reduce one or more symptoms associated with a non-proliferative, degenerative disorder
  • Treatment of non-proliferative, degenerative diseases is intended to include, but is not limited to, the use of diaryloxindole compounds.
  • non- proliferative degenerative disorder is intended to include, but is not limited to, diseases characterized by a loss of function of cells, tissues, and/or organs due to aberrant translation initiation.
  • Non-proliferative degenerative disorders include, but are not limited to, disorders such as Alzheimer's disease and insulin resistance.
  • calcium releaser refers to molecules which cause a sustained depletion of intracellular Ca 2+ stores and inhibit translation initiation.
  • Calcium releasers include, but are not limited to, molecules such as clotrimazole (CLT), fatty acids such as EPA, diaryloxindole compounds of the present invention (including, but not limited to compounds comprising Formula I to Formula XIV and the active and/or partially active compounds set forth in Figures 4A-4B and Tables 1- 14), and the like.
  • kits for treating one or more (1) proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infections are provided.
  • the kit may comprise one or more diaryloxindole compounds, or a combination of one or more diaryloxindole compounds.
  • the kit may comprise a pharmaceutically acceptable carrier.
  • the kit may also include instructions for treating (1) proliferative disorders, (2) non- proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infections.
  • the kit may also comprise, e.g., a buffering agent, a preservative, or a protein stabilizing agent.
  • the kit may also contain a control sample or a series of control samples which can be assayed and compared to the test sample contained.
  • Other suitable components for including in the kit will be selected by the person of ordinary skill in the art, given the benefit of this disclosure.
  • diaryloxindole compounds can be incorporated into pharmaceutical compositions suitable for administration.
  • Such compositions typically comprise the compounds disclosed here and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • Such pharmaceutical compositions may be administered by inhalation, transdermally, orally, rectally, transmucosally, intestinally, parenterally, intramuscularly, subcutaneously, intravenously or other suitable methods that will be readily selected by the person of ordinary skill in the art, given the benefit of this disclosure.
  • solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, CREMPHOR ELTM (BASF, Parsippany, N.J.), or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation can be vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier.
  • compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811, incorporated herein by reference in its entirety for all purposes.
  • compositions of the invention comprise one or more diaryloxindole compounds covalently linked to a peptide (i.e., a polypeptide comprising two or more amino acids) ( Figures 4A-4B).
  • Peptides may be assembled sequentially from individual amino acids or by linking suitable small peptide fragments. In sequential assembly, the peptide chain is extended stepwise, starting at the C-terminus, by one amino acid per step. In fragment coupling, fragments of different lengths can be linked together, and the fragments can also be obtained by sequential assembly from amino acids or by fragment coupling of still shorter peptides.
  • Methods include the azide method, the symmetric and mixed anhydride method, the use of in situ generated or preformed active esters, the use of urethane protected N-carboxy anhydrides of amino acids and the formation of the amide linkage using coupling reagents, such as dicyclohexylcarbodumide (DCC), diisopropylcarbodiimide (DIC), 1 -ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline (EEDQ), pivaloyl chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propane-phosphonic anhydride (PPA), N,N-bis (2-oxo-3- oxazolidinyl)amido phosphoryl chloride (BOP-C1), bromo-tris- pyrrolidinophosphonium hexafluorophosphate (PyBrop),
  • the coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4- aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), N-hydroxysuccinimide (HOSu), 2-hydroxypyridine and the like.
  • DMAP N,N-dimethyl-4- aminopyridine
  • HOBt N-hydroxy-benzotriazole
  • HOOBt N-hydroxybenzotriazine
  • HOSu N-hydroxysuccinimide
  • 2-hydroxypyridine 2-hydroxypyridine and the like.
  • a method involves contacting a cell with an agent that inhibits translation initiation.
  • An agent that inhibits translation initiation can be any one of the compounds described herein, such as a diaryloxindole compound.
  • the compound modulates the depletion of intracellular calcium stores.
  • Methods of modulating translation initiation can be performed in vitro (e.g., by culturing a cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). Certain examples disclosed herein are directed to methods of treating an individual afflicted with a disease or disorder characterized by aberrant translation initiation.
  • the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that inhibits translation initiation.
  • an agent e.g., an agent identified by a screening assay described herein
  • an individual afflicted with a disease or disorder is intended to include both human and non-human mammals.
  • non-human mammals include, but are not limited to, non-human primates, horses, cows, goats, sheep, dogs, cats, mice, rats, hamsters, guinea pigs and the like.
  • the present invention provides for both prophylactic and therapeutic methods of treating a subject for one or more (1) proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infection.
  • the invention provides a method for preventing in a subject, a disease or condition associated with one or more (1) proliferative disorders, (2) non- proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infection, by administering, to the subject one or more diaryloxindole compounds described herein to modulate one or more (1) proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infection.
  • Administration of a prophylactic agent can occur prior to the manifestation of symptoms, such that a disease or disorder is prevented or, alternatively, delayed in its progression.
  • Another aspect of the invention pertains to therapeutic methods of treating one or more (1) proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infection for therapeutic purposes.
  • a therapeutic method of the invention involves contacting a subject with a diaryloxindole compound that therapeutically treats one or more (1) proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infection.
  • One embodiment of the present invention involves a method of treating a translation initiation-associated disease or disorder which includes the step of administering a therapeutically and/or prophylactically effective amount of an agent which inhibits translation initiation to a subject.
  • a subject is administered a therapeutically and/or prophylactically effective amount that is effective to deplete intracellular calcium stores.
  • a therapeutically and/or prophylactically effective amount of agent ranges from about 0.001 to 30 mg/kg body weight, from about 0.01 to 25 mg/kg body weight, from about 0.1 to 20 mg/kg body weight, from about 1 to 10 mg/kg, from about 2 to 9 mg/kg, from about 3 to 8 mg/kg, from about 4 to 7 mg/kg, or from about 5 to 6 mg/kg body weight.
  • agent i.e., an effective dosage
  • an effective dosage ranges from about 0.001 to 30 mg/kg body weight, from about 0.01 to 25 mg/kg body weight, from about 0.1 to 20 mg/kg body weight, from about 1 to 10 mg/kg, from about 2 to 9 mg/kg, from about 3 to 8 mg/kg, from about 4 to 7 mg/kg, or from about 5 to 6 mg/kg body weight.
  • an effective dosage ranges from about 0.001 to 30 mg/kg body weight, from about 0.01 to 25 mg/kg body weight, from about 0.1 to 20 mg/kg body weight, from about 1 to
  • Treatment of a subject with a therapeutically and/or prophylactically effective amount of an inhibitor can include a single treatment or can include a series of treatments. It will also be appreciated that the effective dosage of in used for treatment may increase or decrease over the course of a particular treatment.
  • Tables 1-14 depict biological data of compounds synthesized describing the general synthetic strategy for the scaffold set forth at the top of each table.
  • the appropriate isatins were either commercially available or synthesized starting from appropriate anilines.
  • p-toluene sulfonic acid in dichloroethane allowed the condensation to occur smoothly, while the unactivated ring systems required the use of triflic acid, which is much stronger than p-toluene sulfonic acid.
  • Ca refers to Ca release from intracellular stores where a "+” denotes release and a "+/-" denotes inconclusive; eIF2 ⁇ -P refers to phosphorylation of eIF2 ⁇ measured by Western blot; SRB refers to the inhibitory concentration to reduce cell growth by 50% (IC 50 ) for growth inhibition of A549 lung cancer cells; and n.d. is not determined.
  • isatins and substituted isatins were synthesized by heating a solution of appropriately protected aniline (0.1 moles), chloral hydrate (0.11 moles), hydroxylamine hydrochloride (0.2 moles) in concentrated H 2 SO 4 (12.5 g) and water (700 mL) to 95°C for ten minutes. The solution was then kept at 4°C overnight. The cream colored isonitroso intermediate was filtered off, washed with water and dried. This compound was ground to a fine powder in a mortar and pestle, and added, with stirring, in portions over 30 minutes to concentrated H 2 SO 4 (40 g) maintained at 60-65°C. The mixture was then heated at 95°C for one hour and poured onto ice (300g). The resulting solid was filtered to give the appropriate substituted isatin.
  • 3-Aryl-3-hydroxy-substituted-oxindoles (intermediates set forth in tables 2-7 and 9-14) were synthesized by adding dropwise a 1M solution of alkyl or aryl magnesium halide (0.33 mole) to an appropriately substituted isatin (0.1 mole) in 60 mL THF at 0°C. The resulting mixture was allowed to warm to room temperature and let spin at room temperature for twelve hours. The reaction mixture was quenched with a saturated solution of NH 4 C1 (100 mL) and diluted with 100 mL of dichloromethane. The layers were separated, the organic layer was washed with water followed by brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to yield the product.
  • symmetric substituted di-aryloxindoles (final compounds set forth in Tables 1 and 8) were synthesized by adding two mL of substituted benzene to a mixture of appropriately substituted isatins (1 mmol) combined with three mL of freshly distilled triflic acid. The resulting mixture was stirred at room temperature for eight hours. The product mixture was poured over 25 g of ice and extracted into either chloroform or toluene. The organic solution was washed with water and then brine and dried over Na 2 SO 4 . Concentration in vacuo yielded the 3,3-diphenyl-substituted oxindoles.
  • unsymmetrically substituted di-aryloxindoles (final compounds set forth in Tables 2-7 and 9-13) were synthesized by adding freshly distilled triflic acid (1 mmol) in 1 mL dichloromethane to a mixture of appropriately substituted 3-aryl-3-hydroxy-oxindole (0.1 mmol) and appropriately substituted benzene dissolved in 1 mL dichloromethane.
  • the reaction was maintained at room temperature and monitored by thin-layer chromatography (TLC) and liquid chromatography-mass spectrometry (LCMS). Upon completion, the mixture was poured over ice (25 g) and extracted with dichloromethane. The organic layer was dried and concentrated in vacuo to yield the desired product.
  • TLC thin-layer chromatography
  • LCMS liquid chromatography-mass spectrometry
  • unsymmetrically substituted di-aryloxindoles (final compounds set forth in Tables 2-7 and 9-13) were also synthesized by adding p- toluenesulfonic acid (0.3 mmol) in 5 mL dichloromethane to a mixture of appropriately substituted 3-Aryl-3-hydroxy-oxindole (0.1 mmol) and appropriately substituted benzene dissolved in 10 mL dichloroethane.
  • the reaction was heated to 95°C and monitored by TLC and LCMS, upon completion the reaction mixture was cooled and filtered to remove the p-toluenesulfonic acid. The filtrate was concentrated in vacuo and purified to yield the desired product.
  • the mechanism of action of translation initiation inhibitors is set forth in Figure 1, and includes the depletion (complete or partial depletion) of intracellular calcium (Ca 2+ ) stores and phosphorylation of eIF2 ⁇ .
  • Compounds synthesized using the approaches described herein were screened for their ability to partially deplete intracellular Ca 2+ stores using FURA-2AM loaded cells (Benzaquen et al. (1995) Nature Medicine, 1 :534, incorporated herein by reference in its entirety for all purposes).
  • a limited subset of compounds were further screened for their ability to deplete endoplasmic reticulum (ER) Ca 2+ .
  • the Ca 2+ content of the ER was monitored using ER-targeted, Ca 2+ sensitive, recombinant proteins. These recombinant proteins emitted light by fluorescent resonance energy transfer (FRET) as a function of the Ca 2+ content of the medium.
  • FRET fluorescent resonance energy transfer
  • Such assays are previously described (Miyawaki, A.; Mizuno, H.; Llopis, J.; Tsien, R. Y.; Jalink, K. Cameleons as cytosolic and intra-organellar calcium probes, Oxford University Press: Oxford, London, 2001; pp 3-16, incorporated herein by reference in its entirety for all purposes).
  • Compounds that depleted Ca 2+ were further evaluated for their ability to phosphorylate eIF2 ⁇ .
  • eIF2 ⁇ phosphorylation was measured by Western blot analysis using the phospho-specific anti-eIF2 ⁇ antibody, as previously described (Aktas et al. (1998) Proc. Natl. Acad. Sci. USA, 95:8280, incorporated herein by reference in its entirety for all purposes).
  • Compounds that both depleted ER Ca 2+ and phosphorylated eIF2 ⁇ were tested in a lung cancer cell line (A549) for cell growth inhibition as previously described (Palakurthi et al. (2000) Cancer Research, 60:2919, incorporated herein by reference in its entirety for all purposes).
  • Compound 1181 (set forth in Table 2) was determined to be a Ca 2+ depleting translation initiation inhibitor, as it depleted ER-Ca , phosphorylated eIF2 ⁇ , inhibited growth of a cancer cell line (A549), and decreased squamous cell carcinoma tumor mass in mice ( Figures 2A-2B, 3A-3C and 5). Using compound 1181 for comparison, additional compounds were screened for their ability to inhibit translation initiation in a Ca 2+ depletion-dependent manner (Tables 1 to 14).
  • the plasma levels for this in mice were estimated using liquid chromatography and mass spectrometry (LC-MS).
  • Compound 1430 was orally administered at 160 mg/kg, 240 mg/kg, and 320 mg/kg to DBA/2J mice and the plasma concentration was measured at three time points, one hour, three hours, and six hours, and is set forth in Table 15.
  • the plasma was isolated from the mice by heart-lung puncture and the samples were processed and analyzed by LC-MS.
PCT/US2005/004373 2004-02-13 2005-02-11 3-3-di-substituted-oxindoles as inhibitors of translation initiation WO2005080335A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EP05722960A EP1718611A4 (en) 2004-02-13 2005-02-11 3-3-DI-SUBSTITUTED OXINDOLES AS INHIBITORS OF INITIATION OF TRANSLATION
CA002555812A CA2555812A1 (en) 2004-02-13 2005-02-11 3-3-di-substituted-oxindoles as inhibitors of translation initiation
JP2006553263A JP4989976B2 (ja) 2004-02-13 2005-02-11 翻訳開始阻害剤としての３−３−二置換オキシインドール
AU2005214338A AU2005214338B2 (en) 2004-02-13 2005-02-11 3-3-di-substituted-oxindoles as inhibitors of translation initiation
US11/463,421 US7737172B2 (en) 2004-02-13 2006-08-09 3-3-di-substituted-oxindoles as inhibitors of translation initiation
US12/368,588 US7846962B2 (en) 2004-02-13 2009-02-10 3-3-di-substituted-oxindoles as inhibitors of translation initiation
US12/796,831 US8268879B2 (en) 2004-02-13 2010-06-09 3-3-di-substituted-oxindoles as inhibitors of translation initiation
US12/796,787 US8088816B2 (en) 2004-02-13 2010-06-09 3-3-di-substituted-oxindoles as inhibitors of translation initiation
US12/916,956 US8044089B2 (en) 2004-02-13 2010-11-01 3-3-di-substituted-oxindoles as inhibitors of translation initiation
US13/233,074 US8354440B2 (en) 2004-02-13 2011-09-15 3-3-di-substituted-oxindoles as inhibitors of translation initiation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US54438404P 2004-02-13 2004-02-13
US60/544,384 2004-02-13

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/463,421 Continuation US7737172B2 (en) 2004-02-13 2006-08-09 3-3-di-substituted-oxindoles as inhibitors of translation initiation

Publications (1)

Publication Number Publication Date
WO2005080335A1 true WO2005080335A1 (en) 2005-09-01

Family

ID=34886031

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/004373 WO2005080335A1 (en) 2004-02-13 2005-02-11 3-3-di-substituted-oxindoles as inhibitors of translation initiation

Country Status (6)

Country Link
US (6) US7737172B2 (US08088816-20120103-C00036.png)
EP (1) EP1718611A4 (US08088816-20120103-C00036.png)
JP (1) JP4989976B2 (US08088816-20120103-C00036.png)
AU (1) AU2005214338B2 (US08088816-20120103-C00036.png)
CA (1) CA2555812A1 (US08088816-20120103-C00036.png)
WO (1) WO2005080335A1 (US08088816-20120103-C00036.png)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097107A3 (en) * 2004-04-08 2006-03-30 Bioimage As Diphenyl - indol-2-on compounds and their use in the treatment of cancer
WO2008129075A1 (en) * 2007-04-24 2008-10-30 Topotarget A/S Substituted 3-(4-hydroxyphenyl)-indolin-2-one-compounds
EP2010168A2 (en) * 2006-02-14 2009-01-07 The President and Fellows of Harvard College Histone deacetylase inhibitors
WO2010109008A1 (en) 2009-03-26 2010-09-30 Topotarget A/S Prodrugs of substituted 3-(4-hydroxyphenyl)-indolin-2-ones
US7932252B2 (en) 2004-05-12 2011-04-26 Chemocentryx, Inc. Aryl sulfonamides
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
CN102127002A (zh) * 2011-01-20 2011-07-20 华东师范大学 一种制备3,3-二芳基取代和3-烷基-3-芳基取代氧化吲哚衍生物的方法
US8178579B2 (en) 2001-05-09 2012-05-15 President And Fellows Of Harvard College Dioxanes and uses thereof
US8304451B2 (en) 2006-05-03 2012-11-06 President And Fellows Of Harvard College Histone deacetylase and tubulin deacetylase inhibitors
US8329945B2 (en) 1996-03-26 2012-12-11 President And Fellows Of Harvard College Histone deacetylases, and uses related thereto
US8435780B2 (en) 2000-03-03 2013-05-07 President And Fellows Of Harvard College Class II human histone deacetylases, and uses related thereto
US8440716B2 (en) 2008-07-23 2013-05-14 President And Fellows Of Harvard College Deacetylase inhibitors and uses thereof
US8716344B2 (en) 2009-08-11 2014-05-06 President And Fellows Of Harvard College Class- and isoform-specific HDAC inhibitors and uses thereof
US8754237B2 (en) 2006-02-14 2014-06-17 President And Fellows Of Harvard College Bifunctional histone deacetylase inhibitors
US8999289B2 (en) 2005-03-22 2015-04-07 President And Fellows Of Harvard College Treatment of protein degradation disorders
CN107072205A (zh) * 2014-09-10 2017-08-18 Epizyme股份有限公司 Smyd抑制剂
CN107635996A (zh) * 2015-06-19 2018-01-26 安斯泰来制药有限公司 咪唑并二氮*化合物
EP3912625A1 (en) * 2020-05-20 2021-11-24 Kaerus Bioscience Limited Novel maxi-k potassium channel openers for the treatment of fragile x associated disorders
US20220064152A1 (en) * 2020-08-31 2022-03-03 Trustees Of Boston University Novel fungal modulators
EP4119542A1 (en) * 2019-11-01 2023-01-18 FMC Corporation An efficient process for the synthesis of 2-amino-5-chloro-n,3-dimethylbenzamide

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2010253820A1 (en) 2009-05-28 2011-12-22 President And Fellows Of Harvard College N,N-diarylurea compounds and N,N'-diarylthiourea compounds as inhibitors of translation initiation
WO2014047437A1 (en) * 2012-09-20 2014-03-27 President And Fellows Of Harvard College 3-3-di-substituted-oxindoles as inhibitors of translation initiation
AU2014207272A1 (en) * 2013-01-18 2015-07-30 Neal D. Andruska Estrogen receptor inhibitors
US10420761B2 (en) 2013-03-15 2019-09-24 University Of Florida Research Foundation, Inc. Allosteric inhibitors of thymidylate synthase
US9718775B2 (en) 2014-03-14 2017-08-01 Milliken & Company Oxindole compounds and compositions comprising the same
US10076267B2 (en) 2014-10-03 2018-09-18 General Electric Company Methods and systems for improved navigation
WO2016209688A1 (en) 2015-06-24 2016-12-29 University Of Florida Research Foundation, Incorporated Compositions for the treatment of cancer and uses thereof
AU2019299221A1 (en) * 2018-07-03 2021-02-04 The Board Of Trustees Of The University Of Illinois Activators of the unfolded protein response
CN113548999B (zh) * 2020-04-24 2023-04-28 复旦大学 消旋和手性3-(2,3-丁二烯基)氧化吲哚酮类化合物及制备方法及应用
WO2021222738A1 (en) * 2020-05-01 2021-11-04 The Board Of Trustees Of The University Of Illinois Compounds for estrogen receptor positive cancers
CN114057624B (zh) * 2021-12-10 2023-09-12 贵州大学 一种茶香酮拼接氧化吲哚类化合物及其制备方法及应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003176269A (ja) * 2001-12-12 2003-06-24 Mitsubishi Pharma Corp 環状アミド化合物およびその医薬用途

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES426436A1 (es) 1974-05-18 1976-07-01 Andreu Sa Dr Procedimiento para la obtencion de derivados de la 3,3-bis (4-hidroxifenil)-2-indolinona.
JPS55129284A (en) * 1979-03-27 1980-10-06 Shionogi & Co Ltd 3-(1-imipazolyl)indolin-2-one
US4522811A (en) * 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
SU1823440A1 (ru) 1990-10-18 1996-11-20 Киевский научно-исследовательский филиал Государственного научно-исследовательского и проектного института хлорной промышленности N-производные 3,3-бис-(4-оксиарил)индолин-2-она в качестве модификаторов поликарбоната
US5849780A (en) * 1992-01-30 1998-12-15 Sanofi 1-benzenesulfonyl-1-1,3-dihydroindol-2-one derivatives, their preparation and pharmaceutical compositions in which they are present
JPH07301916A (ja) 1994-04-28 1995-11-14 Nippon Zeon Co Ltd ポジ型レジスト組成物
JPH08183853A (ja) 1994-12-28 1996-07-16 Nippon G Ii Plast Kk ポリカーボネート、ポリカーボネート組成物およびこれらの製造方法
DE19638888A1 (de) * 1996-09-23 1998-03-26 Bayer Ag Cokatalysatoren für die Bisphenolsynthese
JP4035286B2 (ja) 2000-12-11 2008-01-16 本州化学工業株式会社 イサチンビス（ｏ−クレゾール）の製造方法
JP4035287B2 (ja) 2000-12-11 2008-01-16 本州化学工業株式会社 イサチンビス（ｏ−クレゾール）の製造方法
DE10202874A1 (de) 2002-01-25 2003-08-07 Basf Ag Verfahren zur Herstellung von 3,3-Bis-(4-hydroxyaryl)- oxindolen
CA2478172A1 (en) * 2002-03-15 2003-09-25 Eli Lilly And Company Dihydroindol-2-one derivatives as steroid hormone nuclear receptor modulators
WO2005097107A2 (en) 2004-04-08 2005-10-20 Topotarget A/S Diphenyl - indol-2-on compounds and their use in the treatment of cancer
AU2006210778B2 (en) 2005-01-31 2011-11-03 Trustees Of The University Of Pennsylvania Tumor necrosis factor inhibitors
WO2008071387A1 (en) 2006-12-11 2008-06-19 Topotarget A/S Prodrugs of diphenyl ox- indol- 2 -one compounds for the treatment of cancers
CA2684552A1 (en) 2007-04-24 2008-10-30 Topotarget A/S Substituted 3-(4-hydroxyphenyl)-indolin-2-one compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003176269A (ja) * 2001-12-12 2003-06-24 Mitsubishi Pharma Corp 環状アミド化合物およびその医薬用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HALPERIN J.A. ET AL: "Novel Arylsulfoanilide-Oxindole Hybrid as an Anticancer Agent that Inhibits Translation Initiation", J MED CHEM, vol. 47, no. 21, October 2004 (2004-10-01), pages 4979 - 4982, XP008047796 *
KLUMPP D.A ET AL: "Preparation of 3,3-Diaryloxindoles by Superacid-Induced Condensations of Isatinsand Aromatics with a Combinatorial Approach", JOURNAL OF ORGANIC CHEMISTRY, vol. 63, no. 13, March 1998 (1998-03-01), pages 4481 - 4484, XP002244340 *
See also references of EP1718611A4 *

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8329945B2 (en) 1996-03-26 2012-12-11 President And Fellows Of Harvard College Histone deacetylases, and uses related thereto
US8362084B2 (en) 1996-03-26 2013-01-29 President And Fellows Of Harvard College Histone deacetylases, and uses related thereto
US8399233B2 (en) 1996-03-26 2013-03-19 President And Fellows Of Harvard College Histone deacetylases, and uses related thereto
US8329946B2 (en) 1996-03-26 2012-12-11 President And Fellows Of Harvard College Histone deacetylases, and uses related thereto
US8426592B2 (en) 1996-03-26 2013-04-23 President And Fellows Of Harvard College Histone deacetylases, and uses related thereto
US8895284B2 (en) 2000-03-03 2014-11-25 President And Fellows Of Harvard College Class II human histone deacetylases, and uses related thereto
US8435780B2 (en) 2000-03-03 2013-05-07 President And Fellows Of Harvard College Class II human histone deacetylases, and uses related thereto
US8178579B2 (en) 2001-05-09 2012-05-15 President And Fellows Of Harvard College Dioxanes and uses thereof
WO2005097107A3 (en) * 2004-04-08 2006-03-30 Bioimage As Diphenyl - indol-2-on compounds and their use in the treatment of cancer
US7932252B2 (en) 2004-05-12 2011-04-26 Chemocentryx, Inc. Aryl sulfonamides
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US8999289B2 (en) 2005-03-22 2015-04-07 President And Fellows Of Harvard College Treatment of protein degradation disorders
US9572854B2 (en) 2005-03-22 2017-02-21 President And Fellows Of Harvard College Treatment of protein degradation disorders
US10172905B1 (en) 2005-03-22 2019-01-08 President And Fellows Of Harvard College Treatment of protein degradation disorders
US10172821B2 (en) 2006-02-14 2019-01-08 President & Fellows of Harvard College Dana-Farber Cancer Institute, Inc. Histone deacetylase inhibitors
EP2010168A2 (en) * 2006-02-14 2009-01-07 The President and Fellows of Harvard College Histone deacetylase inhibitors
US8383855B2 (en) 2006-02-14 2013-02-26 President And Fellows Of Harvard College Histone deacetylase inhibitors
AU2007214458B2 (en) * 2006-02-14 2012-04-19 Dana-Farber Cancer Institute, Inc. Histone deacetylase inhibitors
US9724321B2 (en) 2006-02-14 2017-08-08 President & Fellows Of Harvard College Histone deacetylase inhibitors
US8754237B2 (en) 2006-02-14 2014-06-17 President And Fellows Of Harvard College Bifunctional histone deacetylase inhibitors
EP2010168A4 (en) * 2006-02-14 2011-06-01 Harvard College Histone deacetylase INHIBITORS
AU2007214458C1 (en) * 2006-02-14 2012-12-06 Dana-Farber Cancer Institute, Inc. Histone deacetylase inhibitors
US8304451B2 (en) 2006-05-03 2012-11-06 President And Fellows Of Harvard College Histone deacetylase and tubulin deacetylase inhibitors
WO2008129075A1 (en) * 2007-04-24 2008-10-30 Topotarget A/S Substituted 3-(4-hydroxyphenyl)-indolin-2-one-compounds
US8440716B2 (en) 2008-07-23 2013-05-14 President And Fellows Of Harvard College Deacetylase inhibitors and uses thereof
US9434686B2 (en) 2008-07-23 2016-09-06 President And Fellows Of Harvard College Deacetylase inhibitors and uses thereof
WO2010109008A1 (en) 2009-03-26 2010-09-30 Topotarget A/S Prodrugs of substituted 3-(4-hydroxyphenyl)-indolin-2-ones
US9540317B2 (en) 2009-08-11 2017-01-10 President And Fellows Of Harvard College Class- and isoform-specific HDAC inhibitors and uses thereof
US8716344B2 (en) 2009-08-11 2014-05-06 President And Fellows Of Harvard College Class- and isoform-specific HDAC inhibitors and uses thereof
US10059657B2 (en) 2009-08-11 2018-08-28 President And Fellows Of Harvard College Class-and isoform-specific HDAC inhibitors and uses thereof
CN102127002B (zh) * 2011-01-20 2012-06-27 华东师范大学 一种制备3,3-二芳基取代和3-烷基-3-芳基取代氧化吲哚衍生物的方法
CN102127002A (zh) * 2011-01-20 2011-07-20 华东师范大学 一种制备3,3-二芳基取代和3-烷基-3-芳基取代氧化吲哚衍生物的方法
CN107072205A (zh) * 2014-09-10 2017-08-18 Epizyme股份有限公司 Smyd抑制剂
CN107635996A (zh) * 2015-06-19 2018-01-26 安斯泰来制药有限公司 咪唑并二氮*化合物
CN107635996B (zh) * 2015-06-19 2020-05-26 安斯泰来制药有限公司 咪唑并二氮*化合物
EP4119542A1 (en) * 2019-11-01 2023-01-18 FMC Corporation An efficient process for the synthesis of 2-amino-5-chloro-n,3-dimethylbenzamide
EP3912625A1 (en) * 2020-05-20 2021-11-24 Kaerus Bioscience Limited Novel maxi-k potassium channel openers for the treatment of fragile x associated disorders
WO2021234084A1 (en) * 2020-05-20 2021-11-25 Kaerus Bioscience Limited Maxi-k potassium channel openers for the treatment of fragile x associated disorders
US20220064152A1 (en) * 2020-08-31 2022-03-03 Trustees Of Boston University Novel fungal modulators
US11773086B2 (en) * 2020-08-31 2023-10-03 Trustees Of Boston University Fungal modulators

Also Published As

Publication number Publication date
US8044089B2 (en) 2011-10-25
EP1718611A4 (en) 2009-09-23
US20090299058A1 (en) 2009-12-03
JP4989976B2 (ja) 2012-08-01
US20120077759A1 (en) 2012-03-29
US20070099976A1 (en) 2007-05-03
US20100249201A1 (en) 2010-09-30
JP2007522234A (ja) 2007-08-09
US8354440B2 (en) 2013-01-15
US7846962B2 (en) 2010-12-07
CA2555812A1 (en) 2005-09-01
US20100256388A1 (en) 2010-10-07
US8088816B2 (en) 2012-01-03
AU2005214338B2 (en) 2011-11-10
US7737172B2 (en) 2010-06-15
EP1718611A1 (en) 2006-11-08
US8268879B2 (en) 2012-09-18
US20110046367A1 (en) 2011-02-24
AU2005214338A1 (en) 2005-09-01

Similar Documents

Publication Publication Date Title
AU2005214338B2 (en) 3-3-di-substituted-oxindoles as inhibitors of translation initiation
AP623A (en) Substituted n-(indole-2-carbonyl)-glycinamides and derivatives as antidiabetic agents.
JP3277147B2 (ja) グリコーゲン・ホスホリラーゼインヒビターを用いる、非−心虚血と関連する組織損傷の軽減方法
TWI229073B (en) Pyrrole substituted 2-indolinone protein kinase inhibitors
KR20010042330A (ko) 치환된 인돌알칸산
TW200402291A (en) Antiallergic
US8304421B2 (en) Indole compounds and their use as radiation sensitizing agents and chemotherapeutic agents
US6372742B1 (en) Substituted indole compounds and methods of their use
US11001557B2 (en) Antiviral drug for severe fever with thrombocytopenia syndrome
WO2014047437A1 (en) 3-3-di-substituted-oxindoles as inhibitors of translation initiation
US10450295B2 (en) Method of using an indolinone molecule and derivatives for inhibiting liver fibrosis and hepatitis
WO2019034179A1 (zh) 一种含吲哚环的ido抑制剂及其制备方法
US20080200557A1 (en) Method for Inhibiting Lipid Peroxidation
TWI274751B (en) Acyloxypyrrolidine derivatives, preparation thereof and application thereof in therapeutics
JP2002531504A (ja) Ｍｙｔ１キナーゼ阻害剤
WO2018076537A1 (zh) D-3-磷酸甘油酸脱氢酶别构抑制剂及其应用
RU2610275C2 (ru) Производное глутаримидов, его применение, фармацевтическая композиция на его основе, способ его получения
US11730712B2 (en) Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and derivatives thereof, and their use for the prevention or treatment of disease
US8133913B2 (en) Substituted indeno [1,2-b]indole derivatives as novel inhibitors of protein kinase CK2 and their use as tumor therapeutic agents, cytostatics and diagnostic aids
RU2610274C2 (ru) Производное глутаримидов, его применение, фармацевтическая композиция на его основе, способ его получения
JPH1149769A (ja) ヘテロ５員環縮合ベンゼン系テロメラーゼ阻害剤
KR20050019896A (ko) 아실옥시피롤리딘 유도체, 및 ｖ1ｂ 수용체 또는 ｖ1ｂ 및ｖ1ａ 수용체 모두의 리간드로서의 그의 용도

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 11463421

Country of ref document: US

Ref document number: 2006553263

Country of ref document: JP

Ref document number: 2555812

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2005722960

Country of ref document: EP

Ref document number: 2005214338

Country of ref document: AU

NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Ref document number: DE

ENP Entry into the national phase

Ref document number: 2005214338

Country of ref document: AU

Date of ref document: 20050211

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2005214338

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2005722960

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 11463421

Country of ref document: US