WO2000008202A9 - Modulateurs 3-methylidenyl-2-indolinone de proteine kinase - Google Patents

Modulateurs 3-methylidenyl-2-indolinone de proteine kinase

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Publication number
WO2000008202A9
WO2000008202A9 PCT/US1999/017845 US9917845W WO0008202A9 WO 2000008202 A9 WO2000008202 A9 WO 2000008202A9 US 9917845 W US9917845 W US 9917845W WO 0008202 A9 WO0008202 A9 WO 0008202A9
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WO
WIPO (PCT)
Prior art keywords
dihydroindol
group
indol
oxo
hydrogen
Prior art date
Application number
PCT/US1999/017845
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English (en)
Other versions
WO2000008202A3 (fr
WO2000008202A2 (fr
Inventor
Peng Cho Tang
Li Sun
Todd Anthony Miller
Congxin Liang
Ngoc My Tran
Anh Thi Nguyen
Asaad Nematalla
Original Assignee
Sugen Inc
Peng Cho Tang
Li Sun
Todd Anthony Miller
Congxin Liang
Ngoc My Tran
Anh Thi Nguyen
Asaad Nematalla
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 Sugen Inc, Peng Cho Tang, Li Sun, Todd Anthony Miller, Congxin Liang, Ngoc My Tran, Anh Thi Nguyen, Asaad Nematalla filed Critical Sugen Inc
Priority to CA002383623A priority Critical patent/CA2383623A1/fr
Priority to JP2000563824A priority patent/JP2002522452A/ja
Priority to AU54684/99A priority patent/AU5468499A/en
Priority to US09/762,198 priority patent/US6531502B1/en
Publication of WO2000008202A2 publication Critical patent/WO2000008202A2/fr
Publication of WO2000008202A3 publication Critical patent/WO2000008202A3/fr
Publication of WO2000008202A9 publication Critical patent/WO2000008202A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates generally to organic chemistry, biochemistry, pharmacology and medicine. More particularly, it relates to 3-methylidenyl-2-indolinone derivatives, and their physiologically acceptable salts and prodrugs, which modulate the activity of protein kinases ("PKs") and are expected to exhibit a salutary effect against disorders related to abnormal PK activity.
  • PKs protein kinases
  • PKs are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins.
  • the consequences of this seemingly simple activity are staggering; cell growth, differentiation and proliferation, i.e., virtually all aspects of cell life in one way or another depend on PK activity.
  • abnormal PK activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer) .
  • the PKs can be conveniently be broken down into two classes, the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs) .
  • PTKs protein tyrosine kinases
  • STKs serine-threonine kinases
  • growth factor receptors are cell-surface proteins. When bound by . growth factor ligand, growth factor receptors are converted to an active form which interacts with proteins on tn ⁇ inner surface of a cell membrane. This leads to phosphorylation on tyrosine residues of the receptor and other proteins and to the formation inside the cell of complexes with a variety of cytoplasmic signaling molecules that, in turn, effect numerous cellular responses such as cell division (proliferation) , cell differentiation, cell growth, expression of cellular metabolic processes to the extracellular microenvironmen , etc.
  • RTKs receptor tyrosine kinases
  • HER epidermal growth factor receptor
  • HER2 epidermal growth factor receptor
  • HER3 intracellular cytoplasmic catalytic domain that can phosphorylate tyrosine residues on proteins.
  • RTK subfamily consists of insulin receptor (IR) , insulin-like growth factor I receptor (IGF-1R) and insulin receptor related receptor (IRR) .
  • IR and IGF-1R interact with insulin, IGF-I and IGF-II to form a heterotetramer of two entirely extracellular glycosylated ⁇ subunits and two ⁇ subunits which cross the cell membrane and which contain the tyrosine kinase domain.
  • a third RTK subfamily is referred to as the platele ⁇ derived growth factor receptor (“PDGFR”) group, which includes PDGFR ⁇ , PDGFR ⁇ , CSFIR, c-kit and c-fms. These receptors consist of glycosylated extracellular domains composed of variable numbers of immunoglobin-like loops and an intracellular domain wherein the tyrosine kinase domain is interrupted by unrelated amino acid sequences.
  • flk fetus liver kinase
  • KDR/FLK-1 kinase insert domain- receptor fetal liver kinase-1
  • flk-lR fetal liver kinase-1
  • flt-4 fms-like tyrosine kinase 1
  • a further member of the tyrosine kinase growth factor receptor family is the fibroblast growth factor ("FGF") receptor subgroup.
  • FGF fibroblast growth factor
  • This group consists of four receptors, FGFR1-4, and seven ligands, FGF1-7. While not yet well defined, it appears that, like the PDGF receptors, the FGF receptors consist of a glycosylated extracellular domain containing a variable number of immunoglobin-like loops and an intracellular domain in which the tyrosine kinase sequence is interrupted by regions of unrelated amino acid sequences .
  • VEGF vascular endothelial growth factor
  • VEGF is a dimeric glycoprotein similar to PDGF but has different biological functions and target cell specificity in vivo.
  • VEGF is presently thought to play an essential role is vasculogenesis and angiogenesis .
  • CTK non-receptor tyrosine kinases
  • cellular tyrosine kinases This latter designation, abbreviated “CTK, " will be used herein.
  • CTKs do not contain extracellular and transmembrane domains.
  • Sc, Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak, Jak and Ack have been identified.
  • the Src subfamily appear so far to be the largest group of CTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • Src Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • STKs serine/threonine kinases
  • CTKs receptor kinases
  • STKs are the most common of the cytosolic kinases; i.e., kinases that perform their function in that part of the cytoplasm other than the cytoplasmic organelles and cytoskelton.
  • the cytosol is the region within the cell where much of the cell's intermediary metabolic and biosynthetic activity occurs; e.g., it is in the cytosol that proteins are synthesized on ribosomes.
  • RTKs, CTKs and STKs have all been implicated in a host of pathogenic conditions including, significantly, cancer.
  • pathogenic conditions which have been associated with PTKs include, without limitation, psoriasis, hepatic cirrhosis, diabetes, angiogenesis, restenosis, ocular diseases, rheumatoid arthritis and other inflammatory disorders, immunological disorders such as autoimmune disease, cardiovascular disease such as atherosclerosis and a variety of renal disorders.
  • PK regulated functions known to be PK regulated. That is, it has been suggested that malignant cell growth results from a breakdown in the mechanisms that control cell division and/or differentiation. It has been shown that the protein products of a number of proto-oncogenes are involved in the signal transduction pathways that regulate cell growth and differentiation. These protein products of proto-oncogenes include the extracellular growth factors, transmembrane growth factor PTK receptors (RTKs) , cytoplasmic PTKs (CTKs) and cytosolic STKs, discussed above.
  • RTKs transmembrane growth factor PTK receptors
  • CTKs cytoplasmic PTKs
  • STKs cytosolic STKs
  • Styryl compounds U.S. Pat. No. 5,217,999
  • styryl-substituted pyridyl compounds U.S. Pat. No. 5,302,606
  • quinazoline derivatives EP App. No. 0 566 266 Al
  • selenaindoles and selenides PCT WO 94/03427)
  • tricyclic polyhydroxylic compounds PCT WO 92/21660
  • benzylphosphonic acid compounds PCT WO 91/15495
  • the present invention relates generally to 3- methylidenyl-2-indolinones and their prodrugs and physiologically acceptable salts, which modulate the activity of receptor tyrosine kinases (RTKs) , non-receptor protein tyrosine kinases (CTKs) and serine/threonine protein kinases (STKs) .
  • RTKs receptor tyrosine kinases
  • CTKs non-receptor protein tyrosine kinases
  • STKs serine/threonine protein kinases
  • the present invention relates to the preparation and use of pharmaceutical compositions of the disclosed compounds and their physiologically acceptable salts and prodrugs in the treatment or prevention of PK driven disorders such as, by way of example and not limitation, cancer, diabetes, hepatic cirrhosis, cardiovasacular disease such as atherosclerosis, angiogenesis, immunological disease such as autoimmune disease and renal disease.
  • PK driven disorders such as, by way of example and not limitation, cancer, diabetes, hepatic cirrhosis, cardiovasacular disease such as atherosclerosis, angiogenesis, immunological disease such as autoimmune disease and renal disease.
  • A is carbon or nitrogen.
  • a "3 -methylidenyl-2-indolinone” refers to a molecule having the chemical structure :
  • A can be carbon or nitrogen.
  • a “pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or physiologically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • a “prodrug” refers to an agent which is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial.
  • prodrug might be a short polypeptide, for example, without limitation, a 2 - 10 amino acid polypeptide, bonded through a terminal amino group to a carboxy group of a compound of this invention wherein the polypeptide is hydrolyzed or metabolized in vivo to release the active molecule.
  • a “physiologically acceptable carrier” or a “pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • a “carrier” refers to a chemical compound which faciliates the incorporation of a compound of interest into cells and tissues.
  • An example, without limitation, of a carrier is dimethyl sulfoxide (DMSO) .
  • a “diluent” refers to a chemical compound, usually a liquid, which dissolves or disperses a compound of interest thereby reducing the concentration of the compound to less than that of the compound alone .
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • the present invention relate to 2- indolinones having chemical structure 1 . :
  • A is selected from the group consisting of carbon and nitrogen
  • Q is selected from the group consisting of
  • bonds a and b may be either single or double bonds as indicated by the dotted lines with the proviso that a and b are both single bonds or both double bonds in any one compound of this invention;
  • r is 1 when a and b are double bonds
  • r is 2 when a and b are single bonds
  • R° is selected from the group consisting of hydrogen, alkyl, -C(0)OR 19 and -C(0)R 19 ;
  • R 1 is selected from the group consisting of hydrogen, alkyl, aryl, alkoxy, halo, -C(0)OR 19 , - (CH 2 ) n OC (O) R 19 , -C(0)NR 19 and (CH 2 ) n R 20 , wherein:
  • R 19 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and aryl;
  • n 1, 2, 3 or 4;
  • R 20 is selected from the group consisting of hydroxy, halo, -OC(0)NR 21 R 22 ; -OC (S) NR 21 R 22 ; -OC (0) NHS0 2 R 21 , -C(0)OR 19 , -NR 21 R 22 and a heteroalicylic group containing at least one nitrogen atom in the ring, the ring being bonded to the adjacent CH 2 group through the nitrogen atom;
  • R 23 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl;
  • R 3 is selected from the group consisting of hydrogen, alkyl, trihalomethyl , alkoxy, aryl, aryloxy, heteroaryl, heteroalicyclic, hydroxy, halo, -S0 2 NR 21 R 22 , -NHS0 2 R 19 , - C(0)OR 19 , -NR 21 R 22 and -NHC (0) R 24 , wherein
  • R 24 is selected from the group consisting of alkyl, alkenyl , alkynyl , aryl , heteroaryl and heteroalicyclic ;
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkoxy and halo
  • R 5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, halo, aryl and heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, alkoxy, halo, cycloalkyl, aryl and, combined with R 18 , a heteroalicyclic group having the structure
  • y and y' are independently selected from the group consisting of hydrogen, alkyl and aryl;
  • R 7 is OR 18 , wherein R 18 is selected from the group consisting of alkyl, -(CH) n R 20 and, combined with R 6 or R 8 , a heteroalicyclic group having the structure
  • R 8 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaryl and, combined with R 18 , a heteroalicyclic ring having the structure
  • R 9 is selected from the group consisting of hydrogen, alkyl, alkoxy, halo and -NR 21 R 22 ;
  • R 10 is selected from the group consisting of alkyl and -C(0)0R 19 ;
  • R 11 is selected from the group consisting of hydrogen, alkyl and -C(0)0R 19 ;
  • R 12 is - ( CH 2 ) n R 20 ;
  • R 13 is either a bond through which Q is bonded to the rest of the molecule or, when it is not, a group selected from the group consisting of hydrogen and alkyl;
  • R 14 is either a bond through which Q is bonded to the rest of the molecule or, when it is not, a group selected from the group consisting of hydrogen, alkyl and -(CH 2 ) n R 20 ;
  • R 15 is either a bond through which Q is bonded to the rest of the molecule or, when it is not, hydrogen;
  • R 16 and R 17 when a and b are single bonds, are independently selected from the group consisting of hydrogen, alkyl and aryl and, when a and b are double bonds, R 16 is hydrogen and R 17 does not exist; and,
  • alkyl refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 1 to 20 carbon atoms (whenever a numerical range; e.g. "1-20", is stated herein, it means that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms) . More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more independently selected from the group consisting of halo hydroxy, unsubstituted lower alkoxy, aryl optionally substituted with one or more halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, aryloxy optionally substituted with one or more halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, 6-member heteroaryl having from 1 to 3 nitrogen atoms in the ring, the carbons in the ring being optionally substituted with one or more halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, 5-member heteroaryl having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon atoms of the group being optionally substituted with one or more halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower
  • a “cycloalkyl” group refers to a 3 to 8 member all- carbon monocyclic ring, an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring or a multicyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system.
  • cycloalkyl groups examples, without limitation, are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane and, cycloheptatriene .
  • a cycloalkyl group may be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more independently selected from the group consisting of unsubstituted lower alkyl, trihaloalkyl, halo, hydroxy, unsubstituted lower alkoxy, aryl optionally substituted with one or more halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, aryloxy optionally substituted with one or more halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, 6-member heteroaryl having from 1 to 3 nitrogen atoms in the ring, the carbons in the ring being optionally substituted with one or more halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, 5-member heteroaryl having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon atoms of the group being optionally substituted with one or more halo
  • alkynyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
  • the substituted group (s) is preferably one or more independently selected from the group consisting of unsubstituted lower alkyl, trihaloalkyl, halo, hydroxy, unsubstituted lower alkoxy, mercapto, (unsu ⁇ stituted lower alkyl) thio, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, nitro, N-sulfonamido, S- sulfonamido, R 25 S(0)-, R 25 S(0) 2 -, -C(0)OR 25 , R 25 C(0)0-, and -NR 25 R 26 , with R 25 and R 26 as defined above.
  • heteroaryl group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system.
  • heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine and carbazole.
  • the heteroaryl group may be substituted or unsubstituted.
  • the substituted group (s) is preferably one or more independently selected from the group consisting of unsubstituted lower alkyl, trihaloalkyl, halo, hydroxy, unsubstituted lower alkoxy, mercapto, (unsubstituted lower alkyl) thio, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, nitro, N-sulfonamido, S- sulfonamido, R 25 S(0)-, R 25 S(0) 2 -, -C(0)OR 25 , R 25 C(0)0-, and -NR 25 R 26 , with R 25 and R 26 as defined above.
  • heteroalicyclic group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi- electron system.
  • the heteroalicyclic ring may be substituted or unsubstituted.
  • the substituted group (s) is preferably one or more independently selected from the group consisting of unsubstituted lower alkyl, trihaloalkyl, halo, hydroxy, unsubstituted lower alkoxy, mercapto, (unsubstituted lower alkyl) thio, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, nitro, N- sulfonamido, S-sulfonamido, R 25 S(0)-, R 25 S(0) 2 -, -C(0)OR 25 , R 25 C(0)0-, and -NR 25 R 26 , with R 25 and R 26 as defined above.
  • a "hydroxy" group refers to an -OH group.
  • alkoxy refers to both an -O- (unsubstituted alkyl) and an -O- (unsubstituted cycloalkyl) group.
  • aryloxy refers to both an -O-aryl and an - O-heteroaryl group, as defined herein.
  • a “mercapto” group refers to an -SH group.
  • a “alkylthio” group refers to both an S- (unsubstituted alkyl) and an -S- (unsubstituted cycloalkyl) group.
  • a “arylthio” group refers to both an -S-aryl and an -S-heteroaryl group, as defined herein.
  • An “acyl” group refers to a -C(0)-R" group, where R" is selected from the group consisting of hydrogen, unsubstituted lower alkyl, trihalomethyl , unsubstituted cycloalkyl, aryl optionally substituted with one or more unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy, halo and
  • -NR 25 R 26 groups heteroaryl (bonded through a ring carbon) optionally substituted with one or more unsubstituted lower alkyl, trihaloalkyl, unsubstituted lower alkoxy, halo and -NR 25 R 26 groups and heteroalicyclic (bonded through a ring carbon) optionally substituted with one or more unsubstituted lower alkyl, trihaloalkyl, unsubstituted lower alkoxy, halo and -NR 25 R 26 groups.
  • aldehyde refers to an acyl group in which R" is hydrogen.
  • a “thioacyl” group refers to a -C(S)-R” group, with R" as defined herein.
  • ester refers to a -C(0)0-R" group with R" as defined herein except that R" cannot be hydrogen.
  • acetyl refers to a -C(0)CH 3 group.
  • a "halo” group refers to fluorine, chlorine, bromine or iodine.
  • trihalomethyl refers to a -CX 3 group wherein X is a halo group as defined herein.
  • a “cyano” group refers to a -C ⁇ N group.
  • a “methylenedioxy” group refers to a -0CH 2 0- group where the two oxygen atoms are bonded to adjacent carbon atoms .
  • An "ethylenedioxy” group refers to a -0CH 2 CH 2 0- where the two oxygen atoms are bonded to adj acent carbon atoms .
  • O-carbamyl refers to a -OC (O) NR 25 R 26 group with R 25 and R 26 as defined herein.
  • N-carbamyl refers to an R 25 OC (O) NR 26 - group, with R 25 and R 26 as defined herein.
  • O-thiocarbamyl refers to a -OC (S) NR 2S R 26 group with R 25 and R 26 as defined herein.
  • N-thiocarbamyl refers to a R 2S 0C (S) NR 26 - group, with R 25 and R 26 as defined herein.
  • amino group refers to an -NR 25 R 26 group, wherein R 25 and R 26 are both hydrogen.
  • C-amido refers to a -C(0)NR 25 R 26 group with R 25 and R 26 as defined herein.
  • N-amido refers to a R 2S C(0)NR 26 - group, with R 25 and R 26 as defined herein.
  • a "nitro” group refers to a -N0 2 group.
  • a presently preferred aspect of this invention is a compound in which Q is
  • Another presently preferred aspect of this invention is a compound in which Q is
  • R 1 is selected from the group consisting of hydrogen, lower alkyl and -C(0)OH
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)R 19 , -C(0)OR 19 , lower alkoxy, -NR 21 R 22 , -(CH 2 ) n R 20 and -NHC (0) OR 19 ;
  • R 3 is selected from the group consisting of hydrogen, hydroxy, halo, -NHC (0) O (lower alkyl) , -NHS0 2 R 19 , -NHC(0)R 24 , trihalomethyl, and aryl optionally substituted with one or more lower alkoxy groups ;
  • R 4 is hydrogen;
  • R 19 is selected from the group consisting of hydrogen and lower alkyl; n is 2 or 3 ;
  • R 20 is selected from the group consisting of hydroxy
  • R 21 and R 22 are independently selected from the group consisting of hydrogen and lower alkyl
  • R 24 is selected from the group consisting of hydrogen and lower alkyl .
  • R 1 is selected from the group consisting of hydrogen, lower alkyl and -C(0)OH;
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)R 19 , -C(0)OR 19 , lower alkoxy, -NR 21 R 22 , -(CH 2 ) n R 20 and -NHC (O) OR 19 ;
  • R 3 is selected from the group consisting of hydrogen, hydroxy, halo, -NHC (0) 0 (lower alkyl), -NHS0 2 R 19 , -NHC(0)R 24 , trihalomethyl, and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen;
  • R 19 is selected from the group consisting of hydrogen and lower alkyl; n is 2 or 3 ; R 20 is selected from the group consisting of hydroxy,
  • R 21 and R 22 are independently selected from the group consisting of hydrogen and lower alkyl;
  • R 24 is selected from the group consisting of hydrogen and lower alkyl;
  • R 5 is selected from the group consisting of hydrogen, lower alkyl, halo, five-member ring heteroaryl and aryl optionally substituted with one or more groups selected from the group consisting of lower alkyl, halo, hydroxy, -NR 21 R 22 and lower alkoxy;
  • R 6 is selected from the group consisting of hydrogen, lower alkyl, 3 to 7-member cycloalkyl, lower alkoxy, halo, aryl optionally substituted with one or more groups independently selected from the group consisting of lower alkyl, halo, hydroxy, -NR 21 R 22 and lower alkoxy and, combined with R 18 , a group having the structure
  • y and y' are either both hydrogen or both lower alkyl ;
  • R 7 is -OR 18 wherein R 18 is selected from the group consisting of lower alkyl, -(CH 2 ) n R 20 and, combined with R 6 or R 8 , a group having the structure
  • R 8 is selected from the group consisting of hydrogen, lower alkyl, 3 to 6-member ring cycloalkyl, lower alkoxy, halo, aryl optionally substituted with one or more groups selected from the group consisting of lower alkyl, lower alkoxy, halo, -NR 21 R 22 and -NHC (0) (lower alkyl), five-member heteroaryl having from 1 to 3 heteroatoms in the ring and 6-member heteroaryl having from 1 to 3 heteroatoms in the ring and, combined with R 18 a group having the structure
  • R 9 is selected from the group consisting of hydrogen, lower alkyl; hydroxy, lower alkoxy, halo and -NR 21 R 22 .
  • a further presently preferred aspect of this invention is a compound in which Q is
  • R 1 is selected from the group consisting of hydrogen, lower alkyl and -C(0)OH;
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)R 19 , -C(0)OR 19 , lower alkoxy, -NR 21 R 22 ,
  • R 3 is selected from the group consisting of hydrogen, hydroxy, halo, -NHC (O) 0 (lower alkyl) , -NHS0 2 R 19 , -NHC(0)R 24 , trihalomethyl, and aryl optionally substituted with one or more lower alkoxy groups ;
  • R 4 is hydrogen
  • R 19 is selected from the group consisting of hydrogen and lower alkyl; n is 2 or 3 ;
  • R 20 is selected from the group consisting of hydroxy, -C (0) OH , morpholin-4 -yl , piperidin- 1 -yl , piperazin- 1 - yl , pyrrolidin- 1 -yl and -NR 21 R 22 ;
  • R 21 and R 22 are independently selected from the group consisting of hydrogen and lower alkyl;
  • R 24 is selected from the group consisting of hydrogen and lower alkyl
  • R 5 is selected from the group consisting of hydrogen, lower alkyl, thien-2-yl, thien-3-yl and aryl optionally substituted with one or more lower alkoxy groups
  • R 6 is selected from the group consisting of hydrogen, lower alkyl, 5 or 6-member cycloalkyl, aryl optionally substituted with one or more lower alkoxy groups and, combined with R 18 , a group having the structure
  • y and y' are either both hydrogen or both lower alkyl
  • R 7 is -OR 18 , wherein R 18 is selected from the group consisting of lower alkyl, -(CH 2 ) n R 20 and, combined with R 6 or R 8 , a group having the structure
  • n 2 or 3;
  • R 20 is selected from the group consisting of hydroxy, -C(0)OH, morpholin-4-yl, piperidin-1-yl , piperazin-1-yl pyrrolidin-1-yl and -NR 21 R 22 ;
  • R 8 is selected from the group consisting of hydrogen, lower alkyl, 5 or 6-member ring cycloalkyl, lower alkoxy, aryl optionally substituted with a -NHC(O) (lower alkyl) group, thien-2-yl, thien-3-yl, pyridin-2-yl , pyridin-3-yl and, combined with R 18 , a group having the structure
  • R 9 is selected from the group consisting of hydrogen and lower alkyl .
  • Still another presently preferred aspect of this invention is a compound in which Q is:
  • R 1 is selected from the group consisting of hydrogen, lower alkyl and - (CH 2 ) n R 20 ; n is 2 or 3; R 20 is selected from the group consisting of hydroxy and -C(0)OH;
  • R 2 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, -S0 2 NR 21 R 22 and -C(0)OH;
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy and aryl optionally substituted with one or more lower alkoxy groups; and, R 4 is hydrogen.
  • R 1 is selected from the group consisting of hydrogen, lower alkyl and - (CH 2 ) n R 20 ; n is 2 or 3 ; R 20 is selected from the group consisting of hydroxy and -C(0)OH;
  • R 2 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, -S0 2 NR 21 R 22 and -C(0)OH;
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy and aryl optionally substituted with one or more lower alkoxy groups ;
  • R 4 is hydrogen
  • R 10 is selected from the group consisting of lower alkyl and
  • R 11 is selected from the group consisting of* hydrogen, lower alkyl and -C(0)OR 19 ;
  • R 12 is -(CH 2 ) n R 20 ;
  • R 19 is selected from the group consisting of hydrogen and lower alkyl ;
  • n is 2 or 3; and,
  • R 20 is selected from the group consisting of hydroxy, -C(0)OH, morpholin-4-yl, piperidin-1-yl , piperazin-1-yl , pyrrolidin-1-yl and -NR 21 R 22 .
  • R 1 is selected from the group consisting of hydrogen, lower alkyl and - (CH 2 ) n R 20 ; n is 2 or 3 ;
  • R 20 is selected from the group consisting of hydroxy and -C(0)OH
  • R 2 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, -S0 2 NR 21 R 22 and -C(0)OH;
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen
  • R 10 is selected from the group consisting of lower alkyl and
  • R 11 is selected from the group consisting of hydrogen, lower alkyl and -C(0)OR 19 ;
  • R 12 is -(CH 2 ) n R 20 ;
  • R 19 is selected from the group consisting of hydrogen and lower alkyl ; n is 2 ; and, R 20 is selected from the group consisting of -C(0)0H, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl , pyrrolidin-1-yl and -N (lower alkyl) 2 . It is also a presently preferred aspect of this invention that Q is
  • R 1 is selected from the group consisting of hydrogen and lower alkyl ;
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)OR 19 , -C(0)R 19 , -NR 21 R 22 , -S0 2 NR 21 R 22 and
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, morpholin-4-yl , piperidin-1-yl , piperazin-1-yl, pyrrolidin-1-yl and aryl optionally substituted with one or more lower alkoxy groups, ; and,
  • R 4 is hydrogen
  • a and b are both single bonds; r is 2 ; R 1 is selected from the group consisting of hydrogen and lower alkyl ;
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, morpholin-4-yl , piperidin-1-yl , piperazin-1-yl , pyrrolidin-1-yl and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen;
  • R 13 is a covalent bond through which Q is bonded to the rest of the molecule
  • R 14 is selected from the group consisting of hydrogen, lower alkyl and -(CH 2 ) n R 20 ;
  • R 15 is hydrogen;
  • R 16 and R 17 are independently selected from the group consisting of hydrogen and lower alkyl.
  • R 20 is -NR 21 R 22 wherein R 21 and R 22 are independently selected from the group consisting of hydrogen and lower alkyl.
  • a and b are both double bonds ; r is 1 ; R 1 is selected from the group consisting of hydrogen and lower alkyl ;
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)OR 19 , -C(0)R 19 , -NR 21 R 22 , -S0 2 NR 21 R 22 and
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, morpholin-4-yl , piperidin-1-yl , piperazin-1-yl, pyrrolidin-1-yl and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen
  • R 13 is a covalent bond through which Q is bonded to the rest of the molecule
  • R 14 is selected from the group consisting of hydrogen, lower alkyl and -(CH 2 ) n R 20 ;
  • R 15 and R 16 are hydrogen;
  • R 17 does not exist .
  • a and b are both double bonds; r is 1;
  • R 1 is selected from the group consisting of hydrogen and lower alkyl
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, morpholin-4-yl , piperidin-1-yl , piperazin-1-yl, pyrrolidin-1-yl and aryl optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen;
  • R 13 is selected from the group consisting of hydrogen and lower alkyl ;
  • R 14 is a covalent bond through which Q is bonded to the rest of the molecule;
  • R 15 and R 16 are hydrogen;
  • R 17 does not exist is another presently preferred aspect of this invention. It is a presently preferred aspect of this invention that, in a compound where Q is
  • a and b are double bonds ; r is 1; R 1 is selected from the group consisting of hydrogen and lower alkyl ;
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, halo, -C(0)OR 19 , -C(0)R 19 , -NR 21 R 22 , -S0 2 NR 21 R 22 and
  • R 3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, morpholin-4-yl , piperidin-1-yl , piperazin-1-yl, pyrrolidin-1-yl and ary optionally substituted with one or more lower alkoxy groups;
  • R 4 is hydrogen;
  • R 13 is selected from the group consisting of hydrogen and lower alkyl ;
  • R 14 is selected from the group consisting of hydrogen, lower alkyl and -(CH 2 ) n R 20 ;
  • R 15 is a covalent bond through which Q is bonded to the rest of the molecule;
  • R 16 are hydrogen;
  • R 17 does not exist .
  • a presently preferred embodiment comprises compounds selected from the group consisting of: 3- [2- (2-oxo-l,2-dihydro-indol-3-ylidenemethyl) -4,5,6,7- tetrahydro-lH-indol-3-yl] -propionic acid, 3- [2- (5-chloro-2-oxo-l, 2-dihydro-indol-3 -ylidenemethyl) - 4,5,6, 7-tetrahydro-lH-indol-3-yl] -propionic acid, 3-2- (5-bromo-2-oxo-l , 2-dihydro-indol-3-ylidenemethyl) - 4,5,6, 7-tetrahydro-lH-indol-3-yl] -propionic acid, 3- [2- (4-methyl-2-oxo-l, 2-dihydro-indol-3-ylidenemethyl) -4,5,6,7-t
  • An additional aspect of this invention is a combinatorial library of at least ten 3-methylidenyl-2- indolinone compounds that can be formed by reacting oxindoles of structure 5 with aldehydes of structure 6, 7 or 8:
  • R 14 , R 15 R 16 and R > 17 have the meanings set forth above,
  • a "combinatorial library” refers to all the compounds formed by the reaction of each compound of one dimension with a compound in each of the other dimensions in a multi-dimensional array of compounds.
  • the array is two dimensional and one dimension represents all the oxindoles of the invention and the second dimension represents all the aldehydes of the invention.
  • Each oxindole may be reacted with each and every aldehyde in order to form a substituted 3-methylidenyl-2- indolinone compound. All substituted 3-methylidenyl-2- indolinone compounds formed in this way are within the scope of the present invention.
  • the oxindole in the above combinatorial library is preferably selected from the group consisting of oxindole itself and substituted oxindoles such as, without limitation, ⁇ -bromooxindole, 5-hydroxyoxindole, 5- methoxyoxindole, ⁇ -methoxyoxindole, 5-phenylaminosulfonyl- oxindole, 4- [2- (2-isopropylphenoxy) ethyl] oxindole, 4- [2- (3- isopropylphenoxy) -ethyl] oxindole, 4- [2- (4-isopropylphenoxy) - ethyl] oxindole, 5-fluorooxindole, 6-fluorooxindole, 7- fluorooxindole, 6-trifluoromethyloxindole, 5-chlorooxindole, 6-chlorooxindole, 4-carboxyindole, 5-bromooxindole, 5-bro
  • the aldehyde in the above combinatorial library is preferably selected from the group consisting of 3-(l- Benzyl-5-formyl-2, -dimethyl-lH-pyrrol-3-yl) propionic acid, 3- (5-Formyl-l-methoxycarbonylmethyl-2 , 4-dimethyl-lH-pyrrol- 3-yl) propionic acid, 3- (5-Formyl-l, 2, 4-trimethyl-lH-pyrrol- 3-yl) propionic acid, 3- [5-Formyl-l- (3-methoxybenzyl) -2, 4- dimethyl-lH-pyrrol-3-yl] propionic acid methyl ester, 3-(l- Cyclohexylmethyl-5-formyl-2, 4-dimethyl-lH-pyrrol-3-yl) - propionic acid methyl ester, 3- [1- (2, 2-Dimethyl-propyl) -5- formyl-2, 4-dimethyl-lH-pyrrol-3-yl]
  • Another aspect of this invention provides a method for the synthesis of a 3-methylidenyl-2-indolinone of formula 1 comprising reacting an oxindole of formula 5 with an aldehyde of formula 6, 7 or 8 in a solvent, preferably in the presence of a base.
  • oxindole itself and substituted oxindoles such as, without limitation, 6-bromooxindole, 5-hydroxyoxindole, 5- methoxyoxindole, ⁇ -methoxyoxindole, 5-phenylaminosulfonyloxindole, 4- [2- (2-isopropylphenoxy) ethyl] oxindole, 4- [2- (3- isopropylphenoxy) -ethyl] oxindole, 4- [2- (4-isopropylphenoxy) - ethyl] oxindole, 5-fluorooxindole, ⁇ -fluorooxindole, 7- fluorooxindole, 6-trifluoromethyloxindole, 5-chlorooxindole, ⁇ -
  • aldehydes of structure ⁇ , 7 or 8 which may be reacted with oxindoles of structure 2 are, without limitation, 3- ( l-benzyl-5-formyl-2, 4-dimethyl-lH-pyrrol-3- yl) propionic acid, 3- (5-formyl-l-methoxycarbonylmethyl-2, 4- dimethyl-lH-pyrrol-3-yl) -propionic acid, 3- (5-formyl-1, 2, 4- trimethyl-lH-pyrrol-3-yl) -propionic acid, 3- [5-formyl-1- (3- methoxybenzyl) -2, -dimethyl-lH-pyrrol-3-yl] propionic acid methyl ester, 3- ( l-cyclohexylmethyl-5-formyl-2, 4-dimethyl- lH-pyrrol-3-yl) propionic acid methyl ester, 3-[l-(2,2- dimethylpropyl) -5-formyl-2, 4-dimethyl-
  • the base can be an inorganic or an organic base.
  • inorganic and organic bases are presented elsewhere herein.
  • the base is sodium acetate.
  • the "solvent" may be any solvent in which base and the other reactants are sufficiently soluble for reaction to take place.
  • Preferred solvents are polar protic solvents (defined elsewhere herein) such as water, methanol and ethanol.
  • the presently preferred solvent is water.
  • the reaction is carried out at temperatures of from about 60° C to about 180° C.
  • the temperature is between about 60° C and 180° C, more preferably between 80° C and 150° C, most preferably between 100 and 120° C.
  • the reaction is allowed to run for from 1 to 30 hours, preferably from 2 to 20 hours, most preferably from 4 to 15 hours.
  • step 2 a carboxylic acid group is converted to an amide group.
  • Procedures for accomplishing this conversion are well-known in the art.
  • the reaction of an amine with the carboxylic acid in the presence of 1, 1 ' -carbonyl diimidazole is the presently preferred method.
  • Any aprotic solvent may be used; in a presently preferred embodiment the solvent is a non-polar aprotic solvent, in particular dichoromethane .
  • the reaction may be carried out at room temperature or at an elevated temperature up to about 100° C; a presently preferred embodiment is to run the reaction at about room temperature.
  • Step 3 is the simultaneous reduction of the keto and the amido group using a reducing agent such as, for example and without limitation, lithium aluminum hydride.
  • the reaction is carried out in an aprotic solvent (defined elsewhere herein) .
  • a presently preferred solvent is tetrahydrofuran.
  • the reaction is carried out at temperatures from about room temperature to about 80° C, preferrably from about 50° C to about 70° C, most preferably, the reaction is carried out in tetrahydrofuran at reflux.
  • Step 4 is the well-known formylation of the aromatic pyrrole ring using phosphorus oxychloride and N,N-dimethyl formamide .
  • Step 5 the condensation of an aldehyde with an oxindole to form a 3-methylidenyl-2-indolinone of this invention is carried out in a solvent which may contain a base.
  • the base may be an organic or an inorganic base. If an organic base is used, preferably it is a nitrogen base. Examples of organic nitrogen bases include, but are not limited to, diisopropylamine, trimethylamine, triethylamine, aniline, pyridine, 1, 8-diazabicyclo- [5.4.1] undec-7-ene, pyrrolidine and piperidine.
  • inorganic bases are, without limitation, ammonia, alkali metal or alkaline earth hydroxides, phosphates, carbonates, bicarbonates, acetates, bisulfates and amides.
  • the alkali metals include, lithium, sodium and potassium while the alkaline earths include calcium, magnesium and barium.
  • the base is an alkali metal or an alkaline earth inorganic base, preferably, a alkali metal or an alkaline earth hydroxide.
  • the solvent in which the reaction is carried out may be a protic or an aprotic solvent, preferably it is a protic solvent.
  • a “protic solvent” is a solvent which has hydrogen atom(s) covalently bonded to oxygen or nitrogen atoms which renders the hydrogen atoms appreciably acidic and thus capable of being “shared” with a solute through hydrogen bonding.
  • Examples of protic solvents include, without limitation, water and alcohols.
  • aprotic solvent may be polar or non-polar but, in either case, does not contain acidic hydrogens and therefore is not capable of hydrogen bonding with solutes.
  • non-polar aprotic solvents are pentane, hexane, benzene, toluene, methylene chloride and carbon tetrachloride .
  • polar aprotic solvents are chloroform, tetrahydro-furan, dimethylsulfoxide and dimethylformamide .
  • the solvent is a protic solvent, preferably water or an alcohol such as ethanol.
  • the reaction is carried out at temperatures greater than room temperature.
  • the temperature is generally from about 30° C to about 150° C, preferably about 80°C to about 100° C, most preferable about 75° C to about 85° C, which is about the boiling point of ethanol.
  • a temperature range described herein is preferably within 10 degrees Celcius of the indicated temperature, more preferably within 5 degrees Celcius of the indicated temperature and, most preferably, within 2 degrees Celcius of the indicated temperature.
  • about 75° C is meant 75° C ⁇ 10° C, preferably 75° C ⁇ 5° C and most preferably, 75° C ⁇ 2° C.
  • Another aspect of this invention relates to a method for the modulation of the catalytic activity of a PK by contacting a PK with a compound of this invention or a physiologically acceptable salt or prodrug thereof.
  • PK refers to receptor protein tyrosine kinase (RTKs) , non-receptor or “cellular” tyrosine kinase (CTKs) and serine-threomne kinases (STKs) .
  • RTKs receptor protein tyrosine kinase
  • CTKs non-receptor or “cellular” tyrosine kinase
  • STKs serine-threomne kinases
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by, practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts.
  • modulation refers to the alteration of the catalytic activity of RTKs, CTKs and STKs.
  • modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTK, CTK cr STK is exposed or, more preferably, the inhibition of the catalytic activity of RTKs, CTKs and STKs.
  • catalytic activity refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylaticn of serine and threonine under the influence, direct or indirect, of STKs.
  • contacting refers to bringing a compound of this invention and a target PK together m such a manner that the compound can affect the catalytic activity of the PK, either directly, i.e., by interacting with the kinase itself, or indirectly, i.e., by interacting witn another molecule on which the catalytic activity of the kinase is dependent.
  • Such "contacting” can be accomplished “in vitro,” i.e., m a test tube, a petri dish or the like.
  • contacting may involve only a compound and a PK of interest or it may involve whole cells.
  • Cells may also be maintained or grown m cell culture dishes and contacted with a compound in that environment.
  • the ability of a particular compound to affect a PK related disorder i.e., the IC 50 of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted.
  • multiple methods exist, and are well -Known to those skilled in the art, to get the PKs in contact with the compounds including, but not limited to, direct cell micromjection and numerous transmembrane carrier techniques.
  • a further aspect of this invention is that the modulation of the catalytic activity of PKs using a compound of this invention may be carried out in vitro or in vivo.
  • In vitro refers to procedures performed m an artificial environment such as, e.g., without limitation, in a test tube or culture medium.
  • in vivo refers to procedures performed within a living organism such as, without limitation, a mouse, rat, rabbit ot human being.
  • a still further aspect of this invention is that the protein kinase whose catalytic activity is being modulated by a compound of this invention is selected from the group consisting of receptor protein tyrosine kinases, a cellular (or non-receptor) tyrosine kinases and serine- threonine kinases .
  • the receptor protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of EGF, HER2 , HER3 , HER4 , IR, IGF-1R, IRR, PDGFR ⁇ , PDGFR ⁇ , CSFIR, C-Kit, C-fms, Flk-IR, Flk4 ,
  • the cellular tyrosine kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of Src, Frk, Btk, Csk, Abl ,
  • ZAP70 Fes/Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • Another aspect of this invention is that the se ⁇ ne- threonme protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of CDK2 and Raf .
  • a pharmaceutical composition of a compound of this invention with a pharmaceutically acceptable carrier or excipient is yet another aspect of this invention.
  • Such pharmaceutical composition may contain both carriers and excipients as well as other components generally known to those skilled in the formulation of pharmaceutical compositions .
  • a method for treating or preventing a protein kinase related disorder in an organism comprising administering a therapeutically effective amount of a compound, salt or prodrug of this invention to an organism in need of such treatment is another aspect of this invention.
  • PK related disorder As used herein, "PK related disorder,” “PK driven disorder, “ and “abnormal PK activity” all refer to a condition characterized by inappropriate, i.e., under or, more commonly, over, PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs, (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth, or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth.
  • Over- activity of a PK refers to either amplification of the gene encoding a particular PK or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more of the symptoms of the cellular disorder increases) .
  • Under-activity is, of course, the converse, wherein the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases.
  • the terms “prevent”, “preventing” and “prevention” refer to a method for barring an organism from acquiring a PK related disorder in the first place.
  • the terms “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a PK mediated cellular disorder and/or its attendant symptoms. With regard particularly to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease will be reduced.
  • the term “organism” refers to any living entity comprised of at least one cell .
  • a living organism can be as simple as, for example, a single eukariotic cell or as complex as a mammal, including a human being.
  • the term “therapeutically effective amount” as used herein refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
  • a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and/or, (4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer.
  • the above- referenced protein kinase related disorder is selected from the group consisting of a receptor protein tyrosine kinase related disorder, a cellular tyrosine kinase disorder and a serine-threonine kinase related disorder.
  • the above referenced protein kinase related disorder is selected from the group consisting of an EGFR related disorder, a PDGFR related disorder, an IGFR related disorder and a flk related disorder.
  • the above referenced protein kinase related disorder is a cancer selected from the group consisting of squamous cell carcinoma, sarcomas such as Kaposi ' s sarcoma, astrocytoma, glioblastoma, lung cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer and glioma in a further aspect of this invention.
  • squamous cell carcinoma sarcomas such as Kaposi ' s sarcoma, astrocytoma, glioblastoma, lung cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer and glioma in a further aspect of this invention.
  • the above referenced protein kinase related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliteration disorder, von Hippel-Lindau disease, restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis, an inflammatory disorder and angiogenesis in yet another aspect of this invention.
  • Additional disorders which may be created or prevented using the compounds of this invention are immunological disorders such as autoimmune disease (AIDS) and cardiovasular disorders such as atherosclerosis.
  • AIDS autoimmune disease
  • cardiovasular disorders such as atherosclerosis.
  • a chemical compound that modulates the catalytic activity of a protein kinase may be identified by contacting cells expressing said protein kinase with a compound, salt or prodrug of the present invention and then monitoring said cells for an effect.
  • monitoring is meant observing or detecting the effect of contacting a compound with a cell expressing a particular PK.
  • the observed or detected effect can be a change in cell phenotype, m the catalytic activity of a PK or a change in the interaction of a PK with a natural binding partner.
  • Techniques for observing or detecting such effects are well-known m the art.
  • the above-referenced effect is selected from a change or an absence of change m a cell phenotype, a change or absence of change in the catalytic activity of said protein kinase or a change or absence of change m the interaction of said protein kinase with a natural binding partner in a final aspect of this invention.
  • Cell phenotype refers to the outward appearance of a cell or tissue or the biological function of the cell or tissue. Examples, without limitation, of a cell phenotype are cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis, and nutrient uptake and use. Such phenotypic characteristics are measurable by techniques well-known m the art.
  • a "natural binding partner” refers to a polypeptide that binds to a particular PK in a cell. Natural binding partners can play a role m propagating a signal in a PK-
  • SUBST ⁇ UTE SHEET (RULE26) mediated signal transduction process.
  • a change m the interaction of the natural binding partner with the PK can manifest itself as an increased or decreased concentration of the PK/natural binding partner complex and, as a result, in an observable change in the ability of the PK to mediate signal transduction.
  • a compound described herein, or its salt or prodrug might be combined with other chemotherapeutic agents for the treatment of the diseases and disorders discussed above.
  • a compound, salt or prodrug of th s invention might be combined with alkylating agents such as fluorouracil (5-FU) alone or m further combination with leukovonn; or other alkylating agents such as, without limitation, other pyrimidme analogs such as UFT, capecitabme, gemcitabme and cytarabme, the alkyl sulfonates, e.g., busulfan (used in the treatment of chronic granulocytic leukemia) , improsulfan and piposulfan; aziridmes, e.g., benzodepa, carboquone, meturedepa and uredepa; ethyleneimines and methylmelamines, e.g., altretamme, triethylenemelam e,
  • alkylating agents such as flu
  • Hodgkm's disease multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilm's tumor and rhabdomyosarcoma) , estramustme, lfosfamide, novemb ⁇ chm, prednimustme and uracil mustard (used m the treatment of primary thrombocytosis, non-Hodgkm 's lymphoma, Hodgkm's disease and ovarian cancer); and triaz es, e.g., dacarbazme (used m the treatment of soft tissue sarcoma) .
  • dacarbazme used m the treatment of soft tissue sarcoma
  • a compound, salt or prodrug of this invention might be expected to have a beneficial effect in combination with other antimetabolite chemotherapeutic agents such as, without limitation, folic acid analogs, e.g. methotrexate (used in the treatment of acute lymphocytic leukemia, choriocarcinoma, mycosis fungiodes breast cancer, head and neck cancer and osteogenic sarcoma) and pteropterin; and the purine analogs such as mercaptopurine and thioguanine which find use in the treatment of acute granulocytic , acute lymphocytic and chronic granulocytic leukemias.
  • folic acid analogs e.g. methotrexate (used in the treatment of acute lymphocytic leukemia, choriocarcinoma, mycosis fungiodes breast cancer, head and neck cancer and osteogenic sarcoma) and pteropterin
  • purine analogs such as mercaptopur
  • a compound, salt or prodrug of this invention might also be expected to prove efficacious in combination with natural product based chemotherapeutic agents such as, without limitation, the vinca alkaloids, e.g., vinblastin (used in the treatment of breast and testicular cancer) , vincristine and vindesine; the epipodophylotoxins, e.g., etoposide and teniposide, both of which are useful in the treatment of testicular cancer and Kaposi ' s sarcoma; the antibiotic chemotherapeutic agents, e.g., daunorubicin, doxorubicin, epirubicin, mitomycin (used to treat stomach, cervix, colon, breast, bladder and pancreatic cancer), dactinomycin, temozolomide, plicamycin, bleomycin (used in the treatment of skin, esophagus and genitourinary tract cancer) ; and the enzymatic chemotherapeutic agents such as L
  • a compound, salt or prodrug of this invention might be expected to have a beneficial effect used in combination with the platinum coordination complexes (cisplatin, etc.); substituted ureas such as hydroxyurea; methylhydrazine derivatives, e.g., procarbazine; adrenocortical suppressants, e.g., mitotane, aminoglutethimide; and hormone and hormone antagonists such as the adrenocorticoste ⁇ ods (e.g., predmsone) , progest s (e.g., hydroxyprogesterone caproate) ; estrogens (e.g., diethylstilbesterol) ; antiestrogens such as tamoxifen; androgens , e.g., testosterone propionate; and aromatase inhibitors (such as anastrozole.
  • substituted ureas such as hydroxyurea
  • methylhydrazine derivatives
  • combination of a compound of this invention might be expected to be particularly effective in combination with mitoxantrone or paclitaxel for the treatment of solid tumor cancers or leukemias such as, without limitation, acute myelogenous (non-lymphocytic) leukemia.
  • TABLE 1 shows the chemical structures of some exemplary compounds of this invention.
  • the compound numbers correspond to the Example numbers m the Examples section. That is, the synthesis of Compound 1 in Table 1 is described in Example 1.
  • the compounds presented in Table 1 are exemplary only and are not to be construed as limiting the scope of this invention in any manner.
  • TABLE 2 shows the results of biological testing of some exemplary compounds of this invention.
  • the results are reported in terms of IC 50 , the micromolar ( ⁇ M) concentration of the compound being tested which causes a 50% change m the activity of the target PKT compared to the activity of tne PTK m a control to which no test compound has been added.
  • the results shown indicate the concentration of a test compound needed to cause a 50% reduction of the activity of the target PTK.
  • the bioassays used are descr oed in detail below.
  • the PKs whose catalytic activity is modulated by the compounds of this invention include protein tyrosine kinases of which there are two types, receptor tyrosine kinases (RTKs) and cellular tyrosine kinases (CTKs) , and serine-threonine kinases (STKs) .
  • RTK mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand) , followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation.
  • Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic effects on the extracellular microenvironment , etc.) .
  • cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic effects on the extracellular microenvironment , etc.) .
  • STKs being primarily cytosolic, affect the internal biochemistry of the cell, often as a down-line response to a PTK event. STKs have been implicated in the signaling process which initiates DNA synthesis and subsequent mitosis leading to cell proliferation.
  • PK signal transduction results in, among other responses, cell proliferation, differentiation, growth and metabolism.
  • Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, glioblastoma and hemangioma, disorders such as leukemia, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy and other disorders related to uncontrolled angiogenesis and/or vasculogenesis .
  • PKs typically possess a bi-lobate structure wherein ATP appears to bind in the cleft between the two lobes in a region where the amino acids are conserved among PKs .
  • Inhibitors ⁇ of PKs are believed to bind by non-covalent interactions such as hydrogen bonding, van der Waals forces and ionic interactions in the same general region where the aforesaid ATP binds to the PKs.
  • the 2-indolinone component of the compounds of this invention binds in the general space normally occupied by the adenine ring of ATP. Specificity of a particular molecule for a particular PK may then arise as the result of additional interactions between the various substituents on the 2-indolinone core and the amino acid domains specific to particular PKs. Thus, different indolinone substituents may contribute to preferential binding to particular PKs.
  • the ability to select compounds active at different ATP (or other nucleotide) binding sites makes the compounds of this invention useful for targeting any protein with such a site.
  • the compounds disclosed herein may thus have utility as in vitro assays for such proteins as well as exhibiting in vivo therapeutic effects through interaction with such proteins.
  • the protein kinase is a protein tyrosine kinase, more particularly, a receptor protein tyrosine kinase.
  • receptor protein tyrosine kinases whose catalytic activity can be modulated with a compound of this invention, or salt thereof, are, without limitation, EGF, HER2 , HER3 , HER4 , IR, IGF-1R, IRR, PDGFR ⁇ , PDGFR ⁇ , CSFIR, C-Kit, C-fms, Flk- 1R, Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R.
  • the protein tyrosine kinase whose catalytic activity is modulated by contact with a compound of this invention, or a salt or a prodrug thereof, can also be a non-receptor or cellular protein tyrosine kinase (CTK) .
  • CTKs such as, without limitation, Src, Frk, Btk, Csk, Abl , ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk, may be modulated by contact with a compound or salt of this invention.
  • Still another group of PKs which may have their catalytic activity modulated by contact with a compound of this invention are the serine-threonine protein kinases such as, without limitation, CDK2 and Raf .
  • this invention relates to a method for treating or preventing a PK related disorder by administering a therapeutically effective amount of a compound of this invention, or a salt or a prodrug thereof, to an organism. It is also an aspect of this invention that a pharmaceutical composition containing a compound of this invention or a salt or prodrug thereof is administered to an organism for the purpose of preventing or treating a PK related disorder.
  • This invention is therefore directed to compounds that modulate PK signal transduction by affecting the enzymatic activity of RTKs, CTKs and/or STKs, thereby interfering with the signals transduced by such proteins. More particularly, the present invention is directed to compounds which modulate RTK, CTK and/or STK mediated signal transduction pathways as a therapeutic approach to the treatment of many kinds of solid tumors, including but not limited to carcinomas, sarcomas including Kaposi's sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma. Treatment or prevention of non-solid tumor cancers such as leukemia are also contemplated by this invention. Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers and bone cancers .
  • disorders related to inappropriate PK activity are cell proliferative disorders, fibrotic disorders and metabolic disorders.
  • Cell proliferative disorders which may be prevented, treated or further studied by the present invention include cancer, blood vessel proliferative disorders and mesangial cell proliferative disorders.
  • Blood vessel proliferative disorders refer to disorders related to abnormal vasculogenesis (blood vessel formation) and angiogenesis (spreading of blood vessels) . While vasculogenesis and angiogenesis play important roles in a variety of normal physiological processes such as embryonic development, corpus luteum formation, wound healing and organ regeneration, they also play a pivotal role in cancer development where they result in the formation of new capillaries needed to keep a tumor alive.
  • blood vessel proliferation disorders include arthritis, where new capillary blood vessels invade the joint and destroy cartilage, and ocular diseases, like diabetic retinopathy, where new capillaries in the retina invade the vitreous, bleed and cause blindness.
  • VEGF vascular endothelial growth factor
  • VEGF is not only responsible for endothelial cell proliferation, but also is the prime regulator of normal and pathological angiogenesis. See generally, Klagsburn & Soker, 1993, Current Biology, 3(10)699-702; Houck, et al . , 1992, J ⁇ Biol. Chem.. 267:26031-26037.
  • vasculogenesis and angiogenesis play important roles in a variety of physiological processes such as embryonic development, wound healing, organ regeneration and female reproductive processes such as follicle development in the corpus luteum during ovulation and placental growth after pregnancy.
  • Folkman & Shmg 1992, J. Biological Chem. , 267 (16) : 10931-34.
  • Uncontrolled vasculogenesis and/or angiogenesis has been associated with diseases such as diabetes as well as with malignant solid tumors that rely on vascularization for growth. Klagsburn & Soker, 1993, Current Biology. 3 (10) : 699-702 ; Folkham, 1991, J. Natl. Cancer Inst . , 82:4-6; Weidner, et al . , 1991, New Engl. J. Med.. 324:1-5.
  • VEGF endothelial cell proliferation and migration during angiogenesis and vasculogenesis indicates an important role for the KDR/FLK- 1 receptor in these processes .
  • Diseases such as diabetes mellitus (Folkman, 198, in Xlth Congress of Thrombosis and Haemostasis (Verstraeta, et al . , eds.), pp. 583-596, Leuven University Press, Leuven) and arthritis, as well as malignant tumor growth may result from uncontrolled angiogenesis. See e.g., Folkman, 1971, N. Engl . J. Med.. 285:1182-1186.
  • VEGF vascular endothelial growth factor
  • the receptors to which VEGF specifically binds are an important and powerful therapeutic target for the regulation and modulation of vasculogenesis and/or angiogenesis and a variety of severe diseases which involve abnormal cellular growth caused by such processes. Plowman, et al., 1994, DN&P, 7 (6) : 334-339. More particularly, the KDR/FLK-1 receptor's highly specific role in neovascularization make it a choice target for therapeutic approaches to the treatment of cancer and other diseases which involve the uncontrolled formation of blood vessels.
  • one aspect of the present invention relates to compounds capable of regulating and/or modulating tyrosine kinase signal transduction including KDR/FLK-1 receptor signal transduction in order to inhibit or promote angiogenesis and/or vasculogenesis, that is, compounds that inhibit, prevent, or interfere with the signal transduced by KDR/FLK-1 when activated by ligands such as VEGF.
  • KDR/FLK-1 receptor signal transduction in order to inhibit or promote angiogenesis and/or vasculogenesis
  • ligands such as VEGF
  • murme FLK-I binds human VEGF with the same affinity as mouse VEGF, and accordingly, is activated by the ligand derived from either species. Millauer et al . , 1993, Cell, 72:835-846; Quinn et al . , 1993, Proc. Natl. Acad. Sci. USA, 90:7533-7537. FLK-1 also associates with and subsequently tyrosine phosphorylates human RTK substrates (e.g., PLC- ⁇ or p85) when co-expressed in 293 cells (human embryonal kidney fibroblasts) .
  • RTK substrates e.g., PLC- ⁇ or p85
  • Models which rely upon the FLK-1 receptor therefore are directly applicable to understanding the KDR receptor.
  • use of the murme FLK-1 receptor in methods which identify compounds that regulate the murme signal transduction pathway are directly applicable to the identification of compounds which may be used to regulate the human signal transduction pathway, that is, which regulate activity related to the KDR receptor.
  • chemical compounds identified as inhibitors of KDR/FLK-1 in vitro can be confirmed in suitable in vivo models. Both in vivo mouse and rat animal models have been demonstrated to be of excellent value for the examination of the clinical potential of agents acting on the KDR/FLK-1 induced signal transduction pathway.
  • this invention is directed to compounds that regulate, modulate and/or inhibit vasculogenesis and/or angiogenesis by affecting the enzymatic activity of the KDR/FLK-1 receptor and interfering with the signal transduced by KDR/FLK-1.
  • the present invention is directed to compounds which regulate, modulate and/or inhibit the KDR/FLK-1 mediated signal transduction pathway as a therapeutic approach to the treatment of many kinds of solid tumors including, but not limited to, glioblastoma, melanoma and Kaposi ' s sarcoma, and ovarian, lung, mammary, prostate, pancreatic, colon and epidermoid carcinoma.
  • a further aspect of this invention relates to the inhibition of vasculogenesis and angiogenesis by other receptor-mediated pathways, including the pathway comprising the flt-1 receptor.
  • Receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand) , followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and autophosphorylation.
  • Binding sites are thereby created for intracellular signal transduction molecules which leads to the formation of complexes with a spectrum of cytoplasmic signalling molecules that facilitate the appropriate cellular response, e.g., cell division and metabolic effects to the extracellular microenvironment . See, Schlessinger and Ullrich, 1992, Neuron, 9:1-20.
  • the close homology of the intracellular regions of KDR/FLK-1 with that of the PDGF- ⁇ receptor (50.3% homology) and/or the related flt-1 receptor indicates the induction of overlapping signal transduction pathways.
  • the PDGF- ⁇ receptor members of the src family (Twamley et al., 1993, Proc. Natl. Acad. Sci. USA. 90:7696-7700), phosphatidylinositol-3 ' -kinase (Hu et al . , 1992, Mol . Cell. Biol., 12:981-990), phospholipase c ⁇ (Kashishian & Cooper, 1993, Mol . Cell. Biol ..
  • ras-GTPase-activating protein (Kashishian et al . , 1992, EMBO J.. 11:1373-1382), PTP-ID/syp (Kazlauskas et al . , 1993, Proc. Natl. Acad. Sci. USA, 10 90:6939-6943), Grb2 (Arvidsson et al . , 1994, Mol. Cell . Biol . , 14:6715-6726), and the adapter molecules She and Nek (Nishimura et al . , 1993, Mol . Cell. Biol ..
  • Fibrotic disorders refer to the abnormal formation of extracellular matrices.
  • fibrotic disorders include hepatic cirrhosis and mesangial cell proliferative disorders.
  • Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar.
  • An increased extracellular matrix resulting in a hepatic scar can also be caused by a viral infection such as hepatitis.
  • Lipocytes appear to play a major role in hepatic cirrhosis.
  • Other fibrotic disorders implicated include atherosclerosis.
  • Mesangial cell proliferative disorders refer to disorders brought about by abnormal proliferation of mesangial cells.
  • Mesangial proliferative disorders include various human renal diseases such as glomerulonephritis, diabetic nephropathy and malignant nephrosclerosis as well as such disorders as thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies .
  • the RTK PDGFR has been implicated in the maintenance of mesangial cell proliferation. Floege et al . , 1993, Kidney International 43:47S-54S.
  • PKs have been associated with cell proliferative disorders.
  • PKs such as, for example, members of the RTK family have been associated with the development of cancer.
  • Some of these receptors like EGFR (Tuzi et al . , 1991, Br . J. Cancer 63:227-233, Torp et al . , 1992, APMIS 100:713-719)
  • HER2/neu Slamon et al . , 1989, Science 244:707-712
  • PDGF-R (Kumabe et al . , 1992, Oncogene , 7:627-633) are over- expressed in many tumors and/or persistently activated by autocrine loops. In fact, in the most common and severe cancers these receptor over-expressions (Akbasak and Suner- Akbasak et al . , 1992, J. Neurol . Sci. , 111:119-133, Dickson et al., 1992, Cancer Treatment Res . 61:249-273, Korc et al., 1992, J. Clin. Invest. 90:1352-1360) and autocrine loops (Lee and Donoghue, 1992, J. Cell . Biol .
  • EGFR has been associated with squamous cell carcinoma, astrocytoma, glioblastoma, head and neck cancer, lung cancer and bladder cancer.
  • HER2 has been associated with breast, ovarian, gastric, lung, pancreas and bladder cancer.
  • PDGFR has been associated with glioblastoma and melanoma as well as lung, ovarian and prostate cancer.
  • the RTK c-met has also been associated with malignant tumor formation.
  • c- met has been associated with, among other cancers, colorectal, thyroid, pancreatic, gastric and hepatocellular carcinomas and lymphomas .
  • c-met has been linked to leukemia. Over-expression of the c-met gene has also been detected in patients with Hodgkins disease and Burkitts disease.
  • IGF-IR m addition to being implicated m nutritional support and in type- II diabetes, has also been associated with several types of cancers.
  • IGF- I has been implicated as an autocrine growth stimulator for several tumor types, e.g. human breast cancer carcinoma cells (Arteaga et al., 1989, J. Clin. Invest.
  • IGF-I insulin growth factor-I
  • gliomas While integrally involved in the normal growth and differentiation of the nervous system, also appears to be an autocrine stimulator of human gliomas. Sandberg- Nordqvist et al . , 1993, Cancer Res. 53:2475-2478.
  • IGF-IR insulin growth factor-IR
  • flbroblasts epithelial cells, smooth muscle cells, T- lymphocytes, myeloid cells, chondrocytes and osteoblasts (the stem cells of the bone marrow)
  • IGF- I insulin growth factor- I.
  • Goldrmg and Goldr g 1991, Eukaryotic Gene Expression, 1: 301-326.
  • Baserga suggests that IGF-IR plays a central role in the mechanism of transformation and, as such, could be a preferred target for therapeutic interventions for a broad spectrum of human malignancies. Baserga, 1995, Cancer Res .
  • STKs have been implicated in many types of cancer including, notably, breast cancer (Cance, et al . , Int. J. Cancer, 54:571-77 (1993)).
  • RTKs have been associated with diseases such as psoriasis, diabetes mellitus, endometnosis, angiogenesis, atheromatous plaque development, Alzheimer's disease, von Hippel-L dau disease, epidermal hyperproliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas.
  • diseases such as psoriasis, diabetes mellitus, endometnosis, angiogenesis, atheromatous plaque development, Alzheimer's disease, von Hippel-L dau disease, epidermal hyperproliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas.
  • EGFR has been indicated in corneal and dermal wound healing. Defects in Insulin-R and IGF-IR are indicated in type- I I diabetes mellitus.
  • a more complete correlation between specific RTKs and their therapeutic indications is set forth in Plowman et al., 1994, DN&P 7:334-339.
  • CTKs including, but not limited to, src, abl , fps , yes, fyn, lyn, lck, blk, hck, fgr and yrk (reviewed by Bolen et al . , 1992, FASEB J. , 6:3403-3409) are involved m the proliferative and metabolic signal transduction pathway and thus could be expected, and have been shown, to be involved many PTK-mediated disorders to which the present invention is directed.
  • mutated src v-src
  • pp60 c src transmits oncogenic signals of many receptors.
  • Over-expression of EGFR or HER2/neu in tumors leads to the constitutive activation of pp60 c src , which is characteristic of malignant cells but absent m normal cells.
  • mice deficient in the expression of c-src exhibit an osteopetrotic phenotype, indicating a key participation of c-src m osteoclast function and a possible involvement m related disorders.
  • Zap70 has been implicated m T-cell signaling which may relate to autoimmune disorders.
  • STKs have been associated with mflamation, autoimmune disease, immunoresponses, and hyperproliferation disorders such as restenosis, fibrosis, psoriasis, osteoarthritis and rheumatoid arthritis.
  • the compounds of this invention may provide an effective method of preventing such embryo implantation and thereby be useful as birth control agents.
  • a method for identifying a chemical compound that modulates the catalytic activity of one or more of the above discussed protein kinases is another aspect of this invention.
  • the method involves contacting cells expressing the desired protein kinase with a compound of this invention (or its salt or prodrug) and monitoring the cells for any effect that the compound has on them.
  • the effect may be any observable, either to the naked eye or through the use of instrumentation, change or absence of change in a cell phenotype.
  • the change or absence of change in the cell phenotype monitored may be, for example, without limitation, a change or absence of change in the catalytic activity of the protein kinase in the cells or a change or absence of change in the interaction of the protein kinase with a natural binding partner.
  • Examples of the effect of a number of exemplary compounds of this invention on several PTKs are shown in Table 2. The compounds and data presented are not to be construed as limiting the scope of this invention in any manner whatsoever. 3. PHARMACEUTICAL COMPOSITIONS AND USE
  • a compound of the present invention, a prodrug thereof or a physiologically acceptable salt of either the compound or its prodrug can be administered as such to a human patient or can be administered in pharmaceutical compositions in which the foregoing materials are mixed with suitable carriers or excipient (s) .
  • suitable carriers or excipient s
  • Techniques for formulation and administration of drugs may be found in "Remington's Pharmacological Sciences,” Mack Publishing Co., Easton, PA, latest edition. Routes of Administration.
  • administer refers to the delivery of a compound, salt or prodrug of the present invention or of a pharmaceutical composition containing a compound, salt or prodrug of this invention to an organism for the purpose of prevention or treatment of a PK-related disorder.
  • Suitable routes of administration may include, without limitation, oral, rectal, transmucosal or intestinal administration or intramuscular, subcutaneous, mtramedullary, mtrathecal, direct mtravent ⁇ cular, intravenous, mtravitreal, mtraperitoneal , mtranasal, or intraocular injections.
  • the preferred routes of administration ary oral and parenteral .
  • the liposomes will be targeted to and taken up selectively by the tumor. Composition/Formulation.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizmg processes.
  • compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the compounds of the invention may be formulated m aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known m the art.
  • the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient.
  • Pharmaceutical preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding other suitable auxiliaries if desired", to obtain tablets or dragee cores.
  • Useful excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as, for example, maize starch, wheat starch, rice starch and potato starch and other materials such as gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl -cellulose, sodium carboxymethylcellulose, and/or polyvmyl-pyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvmyl pyrrolidone, agar, or alg ic acid. A salt such as sodium algmate may also be used.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses .
  • Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push- fit capsules can contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers.
  • a filler such as lactose
  • a binder such as starch
  • a lubricant such as talc or magnesium stearate
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • Stabilizers may be added in these formulations, also.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane or carbon dioxide.
  • a suitable propellant e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane or carbon dioxide.
  • the dosage unit may be controlled by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds may also be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents .
  • Pharmaceutical compositions for parenteral administration include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound. Additionally, suspensions of the active compounds may be prepared in a lipophilic vehicle.
  • Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxy ethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example, subcutaneousiy or intramuscularly) or by intramuscular injection.
  • a compound of this invention may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a pharamcologically acceptable oil), with ion exchange resms, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt.
  • a non-limiting example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer and an aqueous phase such as the VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:D5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution.
  • This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of such a co- solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co- solvent components may be varied: for example, other low- toxicity nonpolar surfactants may be used instead of
  • Polysorbate 80TM the fraction size of polyethylene glycol may be varied, other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone, and other sugars or polysaccharides may substitute for dextrose.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. In addtion, certain organic solvents such as dimethylsulfoxide also may be employed, although often at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
  • the pharmaceutical compositions herein also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • salts m which the compound forms the positively charged moiety include, without limitation, quaternary ammonium (defined elsewhere herein) , salts such as the hydrochloride, sulfate, carbonate, lactate, tartrate, maleate, succinate wherein the nitrogen atom of the quaternary ammonium group is a nitrogen of the selected compound of this invention which has reacted with the appropriate acid.
  • Salts m which a compound of this invention forms the negatively charged species include, without limitation, the sodium, potassium, calcium and magnesium salts formed by the reaction of a carboxylic acid group in the compound with an appropriate base (e.g. sodium hydroxide (NaOH) , potassium hydroxide (KOH) , Calcium hydroxide (Ca(OH) 2 ) , etc. ) .
  • compositions suitable for use m the present invention include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose, i.e., the modulation of PK activity or the treatment or prevention of a PK-related disorder. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • the therapeutically effective amount or dose can be estimated initially from cell culture assays. Then, the dosage can be formulated for use in animal models so as to achieve a circulating concentration range that includes the IC 50 as determined in cell culture (i.e., the concentration of the test compound which achieves a half-maximal inhibition of the PK activity) . Such information can then be used to more accurately determine useful doses in humans .
  • Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the IC 50 and the LD 50 (both of which are discussed elsewhere herein) for a subject compound.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans .
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al . , 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.l).
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active species which are sufficient to maintain the kinase modulating effects. These plasma levels are referred to as minimal effective concentrations (MECs) .
  • MECs minimal effective concentrations
  • the MEC will vary for each compound but can be estimated from in vitro data, e.g., the concentration necessary to achieve 50-90% inhibition of a kinase may be ascertained using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compounds should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration and other procedures known in the art may be employed to determine the correct dosage amount and interval.
  • the amount of a composition administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc. Packaging.
  • compositions may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or of human or veterinary administration.
  • compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Suitable conditions indicated on the label may include treatment of a tumor, inhibition of angiogenesis, treatment of fibrosis, diabetes, and the like. 4.
  • the compounds of this invention may be readily synthesized using techniques well known in the chemical arts. It will be appreciated by those skilled in the art that other synthetic pathways for forming the compounds of the invention are available and that the following is offered by way of example and not limitation. General synthetic procedures.
  • 5 -Nitro-2 -oxindole (6.3 g) was hydrogenated in methanol over 10% palladium on carbon to give 3.0 g (60% yield) of the title compound as a white solid.
  • 5-Bromo-2 -oxindole 2-Oxindole (1.3 g) in 20 mL acetonitrile was cooled to -10 °C and 2.0 g N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at -10 °C and 2 hours at 0 °C . The precipitate was collected, washed with water and dried to give 1.9 g (90 % yield) of the title compound.
  • Dimethylsulfoxide (330 mL) was added to 7.9 g of sodium hydride followed by dropwise addition of 43.6 g diethyloxalate .
  • the mixture was heated to 100 °C for 1.0 hour and cooled to room temperature.
  • 2 -Nitro-4 -trifluoro methyltoluene (31.3 g) was added, the reaction stirred for 30 minutes at room temperature and then heated to 100 °C for 1 hour.
  • the reaction was cooled and poured into a mixture of saturated aqueous ammonium chloride, ethyl acetate and hexane.
  • the organic layer was washed with saturated ammonium chloride, water and brine, dried, and concentrated to give dimethyl 2- (2-nitro-4-trifluoromethylphenyl) malonate .
  • the diester was dissolved in a mixture of 6.4 g of lithium chloride and 2.7 mL of water in 100 mL of dimethylsulfoxide and heated to 100 °C for 3 hours.
  • the reaction was cooled and poured into a mixture of ethyl acetate and brine.
  • the organic phase was washed with brine, dried with sodium sulfate, concentrated and chromatographed on silica gel (10 % ethyl acetate in hexane) . The fractions containing product were evaporated to give 25.7 g of methyl 2 -nitro-4 -trifluoromethylphenylacetate .
  • reaction mixture was then stirred at 100 °C for 1.0 h and then cooled to room temperature.
  • 2 -Chloro-3 -methoxy carbonyl -nitrobenzene (2.15 g) was added to the above mixture in one portion and the mixture was heated to 100 °C for 1.5 h.
  • the reaction mixture was then cooled to room temperature and poured into ice water, acidified to pH 5, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 3.0 g of the dimethyl 2 -methoxy carbonyl- 6-nitrophenylmalonate .
  • Chloral hydrate (9.6 g) was dissolved 200 mL of water containing 83 g of sodium sulfate. The solution was warmed to 60 °C, a solution of 11.4 g of hydroxylamme hydrochloride in 50 mL of water was added and the mixture was held at 60 °C . In a separate flask, 6.4 g of 4-anisidine and 4.3 mL of concentrated hydrochloric acid in 80 mL of water was warmed to 80 °C . The first solution was added to the second and the mixture refluxed for 2 minutes after which it was cooled slowly to room temperature and then cooled in an ice bath. The tan precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 8.6 g ( 85% yield) of N- (2-hydroximinoacetyl) anisidine.
  • 3-Dibromo-7-azaoxindole (2.9 g) was dissolved in a mixture of 20 mL of acetic acid and 30 mL of acetonitrile. To the solution was added 6.5 g of zinc dust. The mixture was stirred for 2 hrs at room temperature. The solid was filtered from the mixture and the solvent evaporated. The residue was slurried with ethyl acetate. The ethyl acetate solution containing insoluble solid was passed through a short column of silica gel. The collected ethyl acetate solution was evaporated and the residue dried under vacuum to give 1.8 g (yield 91%) of 7-azaoxindole acetic acid salt .
  • Tetrakis (triphenylphosphine) palladium (0.8 g) was added to a mixture of 5 g 3-methoxyphenylboronic acid, 5 g 5-bromo-2-fluoro-nitrobenzene and 11 mL of 2 M sodium carbonate solution in 100 mL of toluene. The mixture was refluxed for 2 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate was washed with saturated sodium bicarbonate and brine and then dried and concentrated to give an oily solid.
  • reaction mixture was cooled and quenched with 300 mL of saturated ammonium chloride solution and extracted twice with ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude dimethyl 3 ' -methoxy-3-nitrobiphenyl-4-malonate as a pale yellow solid.
  • 6-Amino-2 -oxindole (2.2 g) , 4.0 g 2, 2 ' -dibromoethyl ether and 7.9 g sodium carbonate were refluxed in 20 ml ethanol overnight, concentrated and diluted with 50 ml of water. The mixture was extracted three times with 50 ml of ethyl acetate and the organic extracts combined, washed with 20 ml of brine, dried over anhydrous sodium sulfate and concentrated to dryness.
  • the anisole (1 equivalent) , dimethylformamide (1-3 equivalents) and phosphorus oxychloride (1-3 equivalents) are heated to 100° C for 1-3 hours.
  • the reaction mixture is cooled to room temperature and dichloromethane is added.
  • the mixture is cooled in ice and water is then added, followed by 4-12 equivalents of concentrated sodium hydroxide until a pH of 9-10 is reached.
  • the organic layer is separated and washed with water and then with brine, dried over anhydrous sodium sulfate and evaporated to give the crude aldehyde.
  • the crude aledehyde is dissolved in boiling hexane containing activated carbon and the hexane solution is decanted and filtered hot through a layer of silica gel.
  • Butyllithium (1.1 equiv.) was added to a suspension of (2-dimethylaminoethyl) triphenylphosphonium bromide in THF (0.2 M) at 0°C. After stirring for 30 minutes, lithium diethylamine (1.1 equiv.) was added dropwise followed by the cold suspension of 3-formyl-lH-indole-2-carboxylic acid ethyl ester (3.96 g, 18.2 mmol) in THF. The resulting orange suspension was stirred for 18 hours. The reaction was then quenched with saturated ammonium chloride and extracted with 10% MeOH in DCM.
  • 3- (3-Dimethylaminopropenyl) -IH- indole-2 -carboxylic acid ethyl ester was hydrogenated using 10% palladium over carbon to reduce the double bond followed by a lithium aluminum hydride (LAH) reduction of the ester group to an alcohol resulting in the formation of [3- (3 -dimethylamino- propyl) -IH-indol -2 -yl] methanol as an orange oil.
  • LAH lithium aluminum hydride
  • Lithium aluminum hydride (LAH, 4 equiv.) is added dropwise to a suspension of the appropriate amido-keto- tetrahydroindole (1 equiv.) in THF (0.5 M) . The mixture is refluxed overnight. The mixture is then cooled and water is added carefully until no more gas is generated, then a few drops of 15% NaOH/water is added. The mixture is then stirred at room temperature for 0.5 hr and filtered to remove insoluble materials. The filtrate is concentrated to give the amino-tetrahydroindole . Examples of syntheses of aminotetrahydroindolecarb- aldehydes
  • Step 1 A mixture of 5-aminolevulinic acid hydrochloride (1.68 g, 10 mmol), 1, 3-cyclohexanedione (1.12 g, 10 mmol) and sodium acetate (1.64 g, 20 mmol) in water (10 mL) was stirred at 110° C for 4 hr and then cooled. The precipitate which formed was collected by vacuum filtration, washed with 30% of ethanol in water and dried under vacuum to give 1.7 g (82%) of 3 - (4-oxo-4 , 5 , 6 , 7- tetrahydro-lH- indol -3-yl) -propionic acid.
  • Step 2 To a suspension of 10 g of the product of step 1 (48 mmol) in dichloromethane (60 mL) was added 9.3 g (57.6 mmol) of 1, 1 ' -carbonyldiimidazole . The mixture was stirred at room temperature for 2 hours and then 5.3 mL (48 mmol) 1-methylpiperazine and 8.4 mL (48 mmol) ⁇ , ⁇ -diisopropyl- ethylamine was added. The dark red reaction mixture was then stirred at room temperature overnight.
  • Step 3 LAH (2.6 g, 68 mmol) was added dropwise to a suspension of 3- [3- (4-methylpiperazin-l-yl) -3 -oxo-propyl] - 1, 5, 6, 7-tetrahydroindol-4-one (5g, 17 mmol) in THF (300 mL) . The mixture was then refluxed overnight . The mixture was then cooled and 2.6 mL each of water followed by a few drops of 15% NaOH was added. The reaction was stirred at room temperature for 30 min and then filtered to remove insolubles. The filtrate was concentrated to give 4.5 g (100%) of 3- [3- (4-methylpiperazin-l-yl) propyl] -4,5,6,7- tetrahydro-IH-indole.
  • Step 4 POCl 3 (1.8 mL, 18.9 mmol) was added dropwise to N,N-dimethylformamide (DMF, 3.8 mL, 51.6 mmol) at -5° C. The mixture was then allowed to come to room temperature and then stirred for 30 minutes after which it was again cooled to -5°C. A solution of 3- [3- (4-methylpiperazin-l-yl) - propyl] -4, 5, 6, 7-tetrahydro-lH- indole (4.5 g, 17.2 mmol) in DMF (9 mL) was added dropwise. The mixture was again allowed to come to room temperature and then stirred at that temperature overnight.
  • DMF N,N-dimethylformamide
  • Step 2 N, N-Dimethyl - 3 - (4-oxo-4 ,5,6, 7-tetrahydro-1H- indol-3-yl) -propionamide:
  • Step 4 3- (3-Dimethylaminopropyl) -4,5,6, 7-tetrahvdro- 1H- indole-2 -carbaldehyde :
  • Step 2 3- (3-0xo-3-pyrrolidin-l- ⁇ lpropyl) -1,5,6,7- tetrahydroindol-4-one :
  • Step 4 3- (3 -Pyrrolidin-1-ylpropyl) -4,5,6,7- tetrahvdro-lH- indole-2 -carbaldehyde :
  • Step 2 N, N-Diethyl - 3 - (4-oxo-4.5, 6 , 7 -tetrahydro- 1H- indol-3-yl) -propionamide:
  • Step 3 Diethyl- T3- (4.5 , 6 , 7-tetrahvdro-lH-indol-3-yl) - propyl1 -amine:
  • Step 1 A mixture of 5-aminolevulinic acid hydrochloride (1.68 g, 10 mmol) , 5 , 5 -dimethyl -1 , 3- cyclohexandione (1.4 g, 10 mmol) and sodium acetate (1.64 g, 20 mmol) in water (10 mL) was stirred at 110° C for 4 hr and then cooled. The precipitate which formed was collected by vacuum filtration, washed with 30% of ethanol (EtOH) in water and dried under vacuum to give 1.6 g (68%) of 3- (4- oxo-6-dimethyl -4 ,5,6, 7-tetrahydro- IH-indol-3 -yl) propionic acid.
  • Step 2 To a suspension of 1.18 g (5 mmol) of the product of step 1 in dichloromethane (25 mL) was added 0.97 g (6 mmol) of CDI . After stirring at room temperature for 2 hr, 2.1 mL (20 mmol) diethylamine was added. The mixture was stirred at room temperature overnight.
  • Step 3 LAH (0.57 g, 15.1 mmol) was added dropwise to a suspension of 3- (6, 6-dimethyl -4 -oxo-4 , 5, 6, 7-tetrahydro-
  • Step 2 except that the amine in Step 2 was pyrrolidine.
  • Step 2 6, 6-Dimethyl-3- (3 -oxo-3 -pyrrolidin-1- ylpropyl) -1,5,6, 7-tetrahvdroindol-4-one
  • Step 3 6, 6-Dimethyl-3- (3 -pyrrolidin-1-ylpropyl) - 4,5,6, 7-tetrahydro- IH-indole *HNMR (360 MHz, DMSO-d6) ⁇ 9.75 (br s, IH, NH) , 6.23 (d, IH) , 2.22-2.37 (m, 12H, 6xCH 2 ) , 1.55-1.66 (m, 6H, 3xCH 2 ) , 1.40 (m, 2H, CH 2 ) , 0.92 (s, 6H, 2xCH 3 ) .
  • Step 4 6 , 6-Dimethyl-3- (3-pyrrolidin-l- ⁇ lpropyl) - 4,5,6, 7-tetrahydro-lH-indole-2-carbaldehyde
  • Step 2 6 , 6-Dimethyl-3- ⁇ 3 - (4-methylpiperazin-l-yl) -3- oxo-propyl1 -1,5,6, 7-tetrah ⁇ droindol-4-one
  • Step 3 6 , 6-Dimethyl-3- f3- (4-methylpiperazin-l-yl) - propyll -4,5,6, 7-tetrahydro- IH- indole X HNMR (360 MHz, DMSO-d6) ⁇ 9.74 (br s, IH, NH) , 6.24
  • Step 4 6 , 6-Dimethyl -3- ⁇ 3 - (4-methylpiperazin-l-yl) - propyll -4,5,6, 7-tetrahvdro-lH-indole-2 -carbaldehyde
  • Step 2 6 , 6-Dimethyl-3- (3-morpholin-4-yl-3-oxoprop ⁇ l) - 1.5,6, 7-tetrahydroindol-4-one
  • X HNMR 360 MHz, DMSO-d6) ⁇ 10.94 (br s, IH, NH) , 6.49 (s, IH) , 3.42-3.50 (m, 8H, 4xCH 2 ) , 2.74 (m, 2H, CH 2 ) , 2.57 (s, 2H, CH 2 ) , 2.48 (m, 2H, CH 2 ) , 2.17 (s, 2H, CH 2 ) , 1.00 (s, 6H, 2xCH 3 ) .
  • Step 4 6 , 6-Dimethyl -3 - (3 -morpholin-4 -ylpropyl) - 4,5,6, 7-tetrah ⁇ dro-lH-indole-2 -carbaldehyde
  • Step 2 3- (6, 6 -Dimethyl -4 -oxo-4 ,5,6, 7 -tetrahydro- 1H- indol-3-yl) -N, N-dimethylpropionamide 'HNMR (360 MHz, DMSO-d6) ⁇ 10.93 (br s, IH, NH) , 6.48 (s, IH) , 2.94 (s, 3H, CH 3 ) , 2.79 (s, 3H, CH 3 ) , 2.72 (m, 2H, CH 2 ) , 2.57 (s, 2H, CH 2 ) , 2.48 (m, 2H, CH 2 ) , 2.17 (s, 2H, CH 2 ) , 1.00 (m, 6H, 2xCH 3 ) .
  • Step 3 [3- (6, 6-Dimethyl-4 ,5,6, 7 -tetrahydro- IH- indol - 3- ⁇ l) -propyll dimethylamine
  • Step 4 3- (3-Dimethylaminopropyl) -6 , 6-dimethyl - 4.5,6, 7-tetrahydro-lH-indole-2 -carbaldehyde
  • Example 1 3- (3.5-Diisopropyl-4-methoxybenzylidene) - 1, 3 -dihydroindol-2 -one
  • 5-Diisopropyl -4 -methoxybenzaldehyde was condensed with 5-chloro-2 -oxindole to give 0.3 g of 5-chloro-3- (3 , 5- diisopropyl -4 -methoxybenzylidene) -1, 3 -dihydroindol -2 -one as a yellow-orange solid.
  • Tin chloride dihydrate (225 g) was added to a solution of 2 ,4-dinitrophenylacetic acid (22.6 g) in ethanol (450 ml) . The mixture was heated at 90° C for 10 hours. The reaction mixture was cooled and adjusted to pH 11 with 12M sodium hydroxide. The solids were removed by filtration and the filtrate was concentrated. The residue was treated with ethanol (300 ml) . Insoluble materials were removed by filtration and washed with ethanol (5 x 60 ml) . The combined ethanol solutions were evaporated and the solid obtained was dried under vacuum to give 15g of 6-amino-2- oxindole as a brown powder.
  • 2-Oxindole (82.9 g) was suspended in 630 ml of acetic acid in a reaction vessel equipped with mechanical stirring and the mixture cooled to 10° C in an ice water bath.
  • Solid N-iodosuccinimide (175 g) was added in portions over 10 minutes. After the addition was complete the mixture was stirred for 1 hour at 10° C. The suspended solid which was always present became very thick at this time.
  • the solid was collected by vacuum filtration, washed with 100 ml of 50% acetic acid in water and then with 200 ml of water and subjected to vacuum filtration for 20 minutes to partially air dry it . The product was then dried under vacuum to give 93.5 g (36%) of 5-iodo-2-oxindole containing about 5% 2- oxindole by proton NMR.
  • 5-Isopropyl-4 -methoxy-2 -methylbenzaldehyde was condensed with 2-oxindole to give 0.25 g of 3 - (5-Isopropyl- 4 -methoxy-2 -methylbenzylidene) -1, 3 -dihydroindol -2 -one as a yellow-orange solid.
  • 3 -Cyclopentyl-4-methoxybenzaldehyde was condensed with 2-oxindole to give 0.25 g of 3- (3 -Cyclopentyl -4- methoxybenzylidene) -1, 3 -dihydro-indol -2 -one as a yellow- orange solid.
  • Example 11 3- (3 -Cyclopentyl-4 -methoxybenzylidene) -5- fluoro-1, 3 -dihydroindol-2 -one 2-Cyclopentylphenol was methylated and then formylated to give 3 -cyclopentyl -4 -methoxybenzaldehyde .
  • the aldehyde was condensed with oxindole to give 0.3 g of 3- (3-Cyclohexyl-4-methoxybenzylidene) -1 , 3 -dihydroindol - 2-one as a yellow-orange solid.
  • Example 13 5-Bromo-3- (6-methoxybiphenyl-3 -ylmethylene) - 1, 3 -dihydroindol-2 -one 2-Phenylanisole was formylated to give 4-methoxy-3- phenylbenzaldehyde .
  • Example 14 5-Chloro-3- (2, 3-dihydro-benzofuran-5- ylmethylene) -1, 3 -dihydroindol-2 -one 2 , 3-Dihydro-5-formylbenzofuran was condensed with 5- chloro-2 -oxindole to give 0.25 g of 5-Chloro-3 - (2 , 3- dihydro-benzofuran-5-ylmethylene) -1 , 3 -dihydroindol-2 -one as a yellow-orange solid.
  • Example 15 5-Chloro-3- (2 , 2 -dimethyl-chroman-6- ylmethylene) -1.3 -dihydroindol-2-one 2,2-Dimethyl-6-formylchromane was condensed with 5- chloro-2 -oxindole to give 0.3 g of 5-Chloro-3- (2 , 2- dimethylchroman-6-ylmethylene) -1, 3 -dihydroindol -2 -one as a yellow-orange solid.
  • Triphenylphosphine (7.47 g, 19.58 mmol) was added to a solution of 2 -cyclohexyl -4 -chlorophenol (6 g, 28.48 mmol) and 2-hydroxyethylmorpholine (3.5 g, 28.48 mmol) in tetrahydrofuran (50 ml) , followed by the dropwise addition of diethylazodicarboxylate (4.5 ml, 28.48 mmol). The mixture stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and triturated with dichloromethane/ hexanes and then washed with more hexanes.
  • the filtrate was extracted with 0.5N hydrochloric acid (200 ml) and brine (2 X 200 ml) .
  • the acid wash was basified with solid sodium bicarbonate to pH 9 and extracted with ethyl acetate (2 x 200 ml) .
  • the combined organic layers were washed with brine (200 ml) , dried over magnesium sulfate and concentrated.
  • the combined solids were dissolved in dichloromethane (25 ml) and precipitated with diethyl ether (500 ml) to afford 1.6g of a mustard yellow solid.
  • Example 18 N- [3- (4-Methoxy-3-thiophene-3- ylbenzylidene) -2-oxo-2 , 3-dihydro-lH-indol-6-yl] -acetamide Tetrakis (triphenylphosphine) palladium (0) (1.35 g) was added to a solution of 4-methoxy-3-bromobenzaldehyde (6.72 g) in toluene (45 ml) and ethanol (45 ml) , followed by addition of 2M aqueous sodium carbonate (80 ml) .
  • Example 19 3- (3 , 5 -Diisopropyl-4 -methoxybenzylidene) -5- methyl-1, 3 -dihydroindol-2 -one
  • a mixture of 5-methylisatin (15.0 g) and 60 ml of hydrazine hydrate was stirred at 140 - 160°C for 4 hours.
  • the reaction mixture was cooled to room temperature, poured into 300 ml of ice water and acidified to pH 2 with 6 N hydrochloric acid. After standing at room temperature for 2 days, a precipitate formed which was collected by vacuum filtration, washed with water and dried under vacuum to give 6.5 g (47 % yield) of 5 -methyl -2 -oxindole .
  • 5-Nitro-2-oxindole (6.3 g) was hydrogenated in methanol over 10% palladium on carbon to give 3.0 g (60% yield) of 5 -amino-2 -oxindole as a white solid.
  • 5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-amino-2 -oxindole to give 0.3 g of 5-Amino-3- (3 , 5- diisopropyl -4 -methoxybenzylidene) -1, 3 -dihydroindol -2 -one as a yellow-orange solid.
  • Example 22 3- (3 , 5-Diisopropyl-4-methoxybenzylidene) -6- fluoro-1.3 -dihydroindol-2 -one
  • a suspension of sodium hydride (2.6 g) and dimethylmalonate (14.5 g) in dimethylsulfoxide (160 ml) was stirred at 100°C for 1 hour.
  • the mixture was cooled to room temperature and 7.95 g of 2 , 5-difluoronitrobenzene was added and stirring was continued for 30 minutes.
  • the mixture was then heated to 100°C and stirred for 1 additional hour, then cooled to room temperature and poured into 400 ml of saturated ammonium chloride.
  • Triphenylphosphine (5.14 g, 19.58 mmol) was added to a solution of 3 , 5-diisopropyl -4 -hydroxybenzaldehyde (4 g, 19.58 mmol) in tetrahydrofuran (40 ml) followed by addition of 2-hydroxyethylmorpholine (2.57 g, 19.58 mmol) and then the dropwise addition of diethylazodicarboxylate (3.41 g, 19.58 mmol) . The mixture was stirred at room temperature for 12 hours. The reaction was concentrated under reduced pressure and partitioned between 2N hydrochloric acid (200 ml) and ethyl acetate (150 ml) .
  • the aqueous layer was extracted with ethyl acetate (2 x 150ml) , basified to pH 9 with solid sodium bicarbonate and extracted with ethyl acetate (3 x 150 ml) .
  • the organic layers were combined, dried over magnesium sulfate and concentrated to afford 900 mg (14%) of 3 , 5-diisopropyl-4- (2 -morpholin-4 -ylethoxy) - benzaldehyde as a yellowish oil.
  • Tetrakis (triphenylphosphine) palladium(O) (0.02 g, 0.02 mmol) was added to a solution of 3 - (3 -Bromo-4-methoxy- benzylidene) -1, 3 -dihydroindol -2 -one (0.2 g, 0.61 mmol) in toluene (1 ml) and ethanol (2 ml) , followed by addition of 2M aqueous sodium carbonate (1.2 ml, 2.4 mmol). To this mixture was added 3-acetamidophenylboronic acid (0.12 g, 0.67 mmol), and the mixture was heated to 100°C in a sealed tube and held there for 12 hours.
  • the reaction was then poured into water (50 ml) and extracted with ethyl acetate (2x100 ml) .
  • the combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml) .
  • the organic layer was dried over magnesium sulfate and concentrated.
  • 5-Isopropyl-4 -methoxy-2 -methylbenzaldehyde was condensed with 5-fluoro-2 -oxindole to give 0.25 g of 5- fluoro-3- (5-isopropyl-4-methoxy-2-methylbenzylidene) -1,3- dihydroindol -2 -one as a yellow-orange solid.
  • Tetrakis (triphenylphosphine) palladium (0) (0.24 g) was added to a solution of 4-methoxy-3-bromobenzaldehyde (1.5 g) in toluene (15 ml) and ethanol (15 ml) , followed by addition of 2M aqueous sodium carbonate (14 ml) .
  • thiophene-2-boronic acid (0.98 g) , and the mixture was heated to reflux. After 3 hours, the reaction was partitioned between water (100 ml) and ethyl acetate (250 ml) . The organic layer was washed with saturated aqueous sodium bicarbonate (75 ml) and brine (75 ml) , dried over magnesium sulfate and concentrated.
  • Example 34 5-Bromo-3- (2 , 2 -dimethylchroman-6 - ylmethylene) -1.3 -dihydroindol-2 -one 2-Oxindole (1.3 g) in 20 ml of acetonitrile was cooled to -10°C and 2.0 g of N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at -10°C and then 2 hours at 0°C. The precipitate which formed was collected, washed with water and dried to give 1.9 g (90% yield) of 5 -bromo-2 -oxindole .
  • Tetrakis (triphenylphosphine) palladium (0) (0.02 g, 0.02 mmol) was added to a solution of 3- ( 3 -bromo-4 -methoxybenzylidene) -1 , 3 -dihydroindol -2 -one (0.2 g, 0.61 mmol) in toluene (1 ml) and ethanol (1 ml) , followed by addition of 2M aqueous sodium carbonate (1.2 ml, 2.4 mmol) . To this mixture was added thiophene-3 -boronic acid (0.09 g, 0.67 mmol) and the mixture was held at 100°C in a sealed tube for 12 hours.

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Abstract

L'invention concerne de nouveaux composés 3-méthylidényl-2-indolinone ainsi que leurs sels physiologiquement acceptables et leurs promédicaments. Ces composés modulent l'activité des protéines kinases et par conséquent sont supposés convenir à la prévention et au traitement des troubles cellulaires liés à la protéine kinase, comme par exemple le cancer.
PCT/US1999/017845 1998-01-21 1999-08-04 Modulateurs 3-methylidenyl-2-indolinone de proteine kinase WO2000008202A2 (fr)

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CA002383623A CA2383623A1 (fr) 1998-08-04 1999-08-04 Modulateurs 3-methylidenyl-2-indolinone de proteine kinase
JP2000563824A JP2002522452A (ja) 1998-08-04 1999-08-04 蛋白質キナーゼの調節剤３−メチリデニル−２−インドリノン
AU54684/99A AU5468499A (en) 1998-08-04 1999-08-04 3-methylidenyl-2-indolinone modulators of protein kinase
US09/762,198 US6531502B1 (en) 1998-01-21 1999-08-04 3-Methylidenyl-2-indolinone modulators of protein kinase

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US12925698A 1998-08-04 1998-08-04
US09/129,256 1998-08-04
US9547098P 1998-08-05 1998-08-05
US60/095,470 1998-08-05
US10217898P 1998-09-28 1998-09-28
US60/102,178 1998-09-28
US11610799P 1999-01-15 1999-01-15
US60/116,107 1999-01-15

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US09/762,198 A-371-Of-International US6531502B1 (en) 1998-01-21 1999-08-04 3-Methylidenyl-2-indolinone modulators of protein kinase
US10/383,690 Division US6855730B2 (en) 1998-08-05 2003-03-10 3-methylidenyl-2-indolinone modulators of protein kinase

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WO2000008202A3 WO2000008202A3 (fr) 2000-05-18
WO2000008202A9 true WO2000008202A9 (fr) 2000-07-27

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JP2002522452A (ja) 2002-07-23
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CA2383623A1 (fr) 2000-02-17
WO2000008202A2 (fr) 2000-02-17

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