WO2004050621A2 - Inhibiteurs de kinases pour le traitement d'une maladie - Google Patents

Inhibiteurs de kinases pour le traitement d'une maladie Download PDF

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WO2004050621A2
WO2004050621A2 PCT/US2003/036988 US0336988W WO2004050621A2 WO 2004050621 A2 WO2004050621 A2 WO 2004050621A2 US 0336988 W US0336988 W US 0336988W WO 2004050621 A2 WO2004050621 A2 WO 2004050621A2
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group
compound
substituted
alkyl
halogen
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PCT/US2003/036988
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English (en)
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WO2004050621A3 (fr
Inventor
Steven W. Andrews
Michael E. Garst
Xialing Guo
Jonathan J. Hebert
Thomas Malone
Julie A. Wurster
Iii Clarence Eugene Hull
Yuan-Xing Guo
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Allergan, Inc
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Priority claimed from US10/307,097 external-priority patent/US6699863B1/en
Priority claimed from US10/389,416 external-priority patent/US6747025B1/en
Application filed by Allergan, Inc filed Critical Allergan, Inc
Priority to JP2004570761A priority Critical patent/JP4879492B2/ja
Priority to DE10393799T priority patent/DE10393799T5/de
Priority to BR0316744-5A priority patent/BR0316744A/pt
Priority to CA002507780A priority patent/CA2507780A1/fr
Priority to GB0511267A priority patent/GB2410744B/en
Priority to AU2003295658A priority patent/AU2003295658A1/en
Publication of WO2004050621A2 publication Critical patent/WO2004050621A2/fr
Publication of WO2004050621A3 publication Critical patent/WO2004050621A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to prodrugs of compounds capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction.
  • the present invention is also directed to methods of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or non-receptor class, for the prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic, and blood vessel proliferative disorders.
  • PTKs Protein tyrosine kinases
  • 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 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 homeostasis, and responses to the extracellular microenvironment).
  • ligand specific growth factor
  • ligand 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 homeostasis, and responses to the extracellular microenvironment).
  • tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules.
  • SH2 serosine kinases
  • Several intracellular substrate proteins that associate with receptor tyrosine kinases (RTKs) have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such domain but serve as adapters and associate with catalytically active molecules. The specificity of the interactions between receptors or proteins and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue.
  • Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
  • the RTKs comprise a large family of transmembrane receptors with diverse biological activities.
  • the intrinsic function of RTKs is activated upon ligand binding, which results in phophorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses.
  • RTK subfamilies At present, at least nineteen (19) distinct RTK subfamilies have been identified.
  • One RTK subfamily designated the HER subfamily, is believed to be comprised of EGFR, HER2, HER3 and HER4.
  • Ligands to the Her subfamily of receptors include epithelial growth factor (EGF), TGF- , amphiregulin, HB-EGF, betacellulin and heregulin.
  • a second family of RTKs designated the insulin subfamily, is comprised of the INS-R, the IGF-1R and the IR-R.
  • a third family, the "PDGF" subfamily includes the PDGF ⁇ and ⁇ receptors, CSFIR, c-kit and FLK-II.
  • Another subfamily of RTKs, identified as the FLK family is believed to be comprised of the Kinase insert Domain-Receptor fetal liver kinase- 1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosine kinase 1 (flt-1). Each of these receptors was initially believed to be receptors for hematopoietic growth factors.
  • Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFRl, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-met and Ron).
  • the non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. At present, over twenty- four individual non-receptor tyrosine kinases, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes Fps, Fak, Jak, Ack and LIMK) have been identified. At present, the Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of PTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • Prodrugs are derivatives of drugs, which after administration undergo conversion to the physiologically active species. This conversion may be due caused by hydrolysis in the physiological environment, or be due to enzymatic hydrolysis.
  • the following literature is cited: Design of Pro-drugs (Bundgaard H. ed.) 1985 Elsevier Science Publishers BN. (Biomedical Devision), Chapter 1; Design of Prodrugs :Bioreversible derivatives for various functional groups and chemical entities (Hans Bundgaard); Bundgaard et al. Int.J. of Pharmaceutics 22 (1984) 45-56 (Elsevier); Bundgaard et al Int. J.
  • FIGURES Figure 1 shows the general scheme for the preparation of the compounds of this invention, in particular the compounds of Examples 2-6, 8 and 9.
  • FIG 2 shows the general scheme for the preparation of the compounds of this invention, in particular the compounds of Examples 12 and 13.
  • Figure 3 shows the general scheme for the preparation of the compounds of this invention, in particular the compounds of Examples 15, 16, 19 and 21.
  • the present invention relates to organic molecules capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction.
  • Such compounds are useful for the treatment of diseases related to unregulated TKS transduction, including cell proliferative diseases such as cancer, atherosclerosis, restenosis, metabolic diseases such as diabetes, inflammatory diseases such as psoriasis and chronic obstructive pulmonary disease, vascular proliferative disorders such as diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity, autoimmune diseases and transplant rejection.
  • the compounds of the present invention have the formula I:
  • fragment B represents a tyrosine kinase inhibitor or serine threonine kinase inhibitor containing a nitrogen atom capable of reacting with formaldehyde, a substituted aldehyde or substituted ketone and an amine to provide a compound of formula I and wherein;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl radicals, wherein said substituted hydrocarbyl may be substituted with heteroatoms selected from the group consisting of halogen, e.g. fluoro, chloro, bromo, or iodo, nitrogen, phosphorus, sulfur and oxygen, or R 3 and R 4 together with the nitrogen atom may form a cyclic ring, which ring may be substituted with said heteroatoms, e.g.
  • R 3 and R 4 may be selected from the group consisting of hydrogen, alkyl, alkoxy, alkyloxyalkyl, aryl, aryloxy, alkylaryl and alkaryloxy; and R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl and aryl radicals. Preferably, R 5 and R 6 are hydrogen.
  • X is O or C(R 2 ) 2 ; Y is [C(R 2 ) 2 ] c ; A is NR 2 or absent;
  • R 1 is selected from the group consisting of halogen, hydroxy, NO 2 , CN, hydrocarbyl and substituted hydrocarbyl radicals, wherein said substituted hydrocarbyl may be substituted with heteroatoms selected from the group consisting of halogen, e.g. fluoro, chloro, bromo, or iodo, nitrogen, phosphorus, sulfur and oxygen, e.g. Ci to C alkyl and aryl, e.g. phenyl, and when b is 1, R 1 is preferably chloro; R 2 is selected from the group consisting of hydrogen, Ci to C 8 alkyl,
  • R is selected from the group consisting of halogen, hydrocarbyl and substituted hydrocarbyl radicals, wherein said substituted hydrocarbyl may be substituted with heteroatoms selected from the group consisting of halogen, e.g. fluoro, chloro, bromo, or iodo, nitrogen, phosphorus, sulfur and oxygen, e.g.
  • F, hydroxy, and - alkyl or CR R may represent a carbocyclic ring of from 3 to 6 carbons, preferably R 8 and R 9 are H or CH 3 , preferably in the compounds of Formula m when a is 1, R is dimethyl amino and in the compounds of Formula II when a is 1, R is morpholonyl; R 3 , R 4 , R 5 and R 6 , are as defined above; R 10 is hydrogen, Ci to C 8 alkyl or arylalkyl; a is 0 or an integer of from 1 to 3; b is 0 or an integer of from 1 to 3; c is an integer of from 1 to 2; d is 0 or an integer of from 1 to 5 e is an integer of from 2 to 5 the wavy line represents a E or Z bond; and
  • Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl, wherein said substituted hydrocarbyl or said substituted heteroaryl may be substituted with heteroatoms selected from the group consisting of halogen, e.g. fluoro, chloro, bromo, or iodo, nitrogen, phosphorus, sulfur and oxygen, e.g. Ar may be selected from the group consisting of monocyclic and bicyclic aryl and heteroaryl, including both fused and non-fused dicyclic aryl or heteroaryl, e.g. phenyl, naphthyl, pyridyl, pyrrolyl, furyl, thienyl, etc. and substituted derivatives thereof; and pharmaceutically acceptable salts thereof.
  • halogen e.g. fluoro, chloro, bromo, or iodo
  • Ar may be selected from the group consisting of monocyclic and bicyclic aryl and hetero
  • Ar is a monocyclic aryl or heteroaryl, e.g., phenyl or pyrrolyl.
  • R 5 and R 6 are hydrogen.
  • R 3 is H and R 4 is selected from the group consisting of alkyl, e.g. n-butyl, or alkyloxyalkyl, e.g. methyloxypropyl, or R 3 and R , together with the nitrogen atom forms a cyclic ring having 5 or 6 members, e.g., a 6 member ring, which may include an enchained oxygen or nitrogen atom, e.g. R 3 and R 4 may, together with the nitrogen atom may be morpholinyl or piperidinyl and said morpholinyl or said piperidinyl ring may be substituted with one or more lower alkyl groups, e.g., methyl.
  • X is O and Y is CH and R may be di(lower)alkyl amino, e.g., dimethyl amino.
  • Ar is phenyl or pyrrolyl and R may be lower alkyl, e.g., methyl, or morpholinyl.
  • R 3 and R 4 together with the nitrogen atom form a cyclic ring having from 3 to 8, e.g., 5 or 6, members and more preferably said cyclic ring includes an enchained oxygen atom or a second nitrogen atom. That is, R 3 and R 4 together with the nitrogen atom may be pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • R 3 is hydrogen and R 4 is alkyl or alkyloxyalkyl.
  • R 3 ' are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R 2 , SO 2 (R 2 ) 2 , SO 3 R 2 , SR 2 , NO 2 , N(R 2 ) 2 , OH, CN, C(O)R 2 , OC(O)R 2 , NHC(O)R 2 , (CH 2 ) d CO 2 R 2 , and (CH 2 ) d CON(R 2 ) 2 ;
  • R' is hydrogen, alkyl, aryl, alkylaryl, haloalkyl, (CR 8 R 9 ) d C(O)OR 2 , (CR 8 R 9 ) e OR 2 , or (CR 8 R 9 ) e N(R 2 ) 2 , or
  • R 11 is R 1 or R ⁇ taken together with the nitrogen atom may be a 5 or 6 membered ring which may have an enchained oxygen atom or a second nitrogen atom, for example morpholinyl, piperidinyl piperzinyl, etc.
  • Ar is a five membered heteroaryl ring selected from the group consisting of furyl, thiophene, pyrrole, 2,4-dimethylpyrrole, 2,4-dimethyl-3-pyrrole-propionic acid, pyrazole, imidazole, 1, 2, 3-triazole, 1, 2, 4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1, 2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4- thiadiazole, 1,2,5-thiatriazole, and tetrazole, optionally substituted at one or more positions with R 2 , O(
  • R 2 , R 7 , R 8 and R 9 are as defined above.
  • Ar is a five membered heteroaryl ring selected from the group consisting of furyl, thiophene, pyrrole, 2,4-dimethylpyrrole, pyrazole, imidazole, 1, 2, 3-triazole, 1, 2, 4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1, 2,3- oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4- oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5- thiatriazole, and tetrazole, optionally substituted at one or more positions with with with
  • X is O or CH ;
  • Y is [C(R 2 ) 2 ] c ;
  • R 1 is selected from the group consisting of halogen, hydroxy, C t to C alkyl
  • R 2 is selected from the group consisting of hydrogen, Q to C 8 alkyl, ,
  • R is selected from the group consisting of halogen, to C 8 alkyl, CF 3 , OCF 3 , OCF 2 H, (CR 8 R 9 ) d C(O)OR 2 , (CR 8 R 9 ) d C (O)N(R 2 ) 2 , HNC(O)R 2 , HN -C(O)OR 2 ,
  • the present invention is further directed to pharmaceutical compositions comprising a pharmaceutically effective amount of the above-described compounds and a pharmaceutically acceptable carrier or excipient.
  • a composition is believed to modulate signal transduction by a tyrosine kinase, either by inhibition of catalytic activity, affinity to ATP or ability to interact with a substrate.
  • compositions of the present invention may be included in methods for treating diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as diabetic retinopathy.
  • diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as diabetic retinopathy.
  • “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Alkyl refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
  • Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.
  • Alkenyl refers to a straight-chain, branched or cyclic unsaturated hydrocarbon group containing at least one carbon-carbon double bond.
  • the alkenyl group has 1 to 12 carbons. More preferably it is a lower alkenyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
  • Alkynyl refers to a straight-chain, branched or cyclic unsaturated hydrocarbon containing at least one carbon-carbon triple bond.
  • the alkynyl group has 1 to 12 carbons. More preferably it is a lower alkynyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
  • “Alkoxyl” refers to an "O-alkyl” group.
  • Aryl refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups.
  • the aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO 2 , amine, thioether, cyano, alkoxy, alkyl, and amino.
  • Alkaryl refers to an alkyl that is covalently joined to an aryl group.
  • the alkyl is a lower alkyl.
  • Carbocyclic aryl refers to an aryl group wherein the ring atoms are carbon.
  • Heterocyclic aryl refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.
  • Hydrocarbyl refers to a hydrocarbon radical having only carbon and hydrogen atoms.
  • the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and most preferably from 1 to 7 carbon atoms.
  • Substituted hydrocarbyl refers to a hydrocarbyl radical wherein one or more, but not all, of the hydrogen and/or the carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical including a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g. fluoro, chloro, cyano, nitro, hydroxyl, oxa, oxo, phosphate, thiol, etc.
  • Amide refers to -C(O)-NH-R, wherein R is alkyl, aryl, alkylaryl or hydrogen.
  • Thioamide refers to -C(S)-NH-R, wherein R is alkyl, aryl, alkylaryl or hydrogen.
  • “Amine” refers to a -N(R')R" group, wherein R' and R" are independently selected from the group consisting of alkyl, aryl, and alkylaryl.
  • Thioether refers to -S-R, wherein R is alkyl, aryl, or alkylaryl.
  • the compounds of the present invention are selected from the compounds of Table 1 - Table 3, below.
  • the present invention relates to compounds capable of regulating and/or modulating tyrosine kinase signal transduction and more particularly receptor and non-receptor tyrosine kinase signal transduction.
  • 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 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 and responses to the extracellular microenvironment) .
  • tyrosine phosphorylation sites in growth factor receptors function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules.
  • SH2 serosine kinases
  • Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (or other disorders related to uncontrolled angiogenesis and/or vasculogenesis, e.g. macular degeneration).
  • neoplasia such as carcinoma, sarcoma, leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (or other disorders related to uncontrolled angiogenesis and/or vasculogenesis, e.g. macular degeneration).
  • This invention is therefore directed to compounds which regulate, modulate and/or inhibit tyrosine kinase signal transduction by affecting the enzymatic activity of the RTKs and/or the non-receptor tyrosine kinases and interfering with the signal transduced by such proteins.
  • the present invention is directed to compounds which regulate, modulate and/or inhibit the RTK and/or non-receptor tyrosine kinase mediated signal transduction pathways as a therapeutic approach to cure many kinds of solid tumors, including but not limited to carcinoma, sarcoma, leukemia, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma.
  • 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.
  • Example 12 of the invention has been studied using buffers at pH 1, pH 3 and pH 7.
  • Example 12 prepared in acetonitrile at 200 ⁇ g/mL and diluted to 20 ⁇ g/mL in buffers at pH 1, pH 3 and pH 7.
  • Example 12 was measured to have a half -life (t 2 ) of approximately 20 hours at pH 3 and 38 hours at pH 1.
  • the half -life (t 2 ) of Example 12 at pH 7.4 was less than 30 minutes.
  • HUVEC human umbilical vein endothelial cells
  • Casetics were seeded in 96-well fibronectin coated black- walled plates overnight at 37°C/5%CO 2 . Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37°C. Cells were washed 4 times (Original Cell Wash,
  • Test compounds were reconstituted in
  • test agents For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 ⁇ M) or at concentrations ranging from 0.01 to 10.0 ⁇ M followed by VEGF stimulation (5ng/mL). Changes in fluorescence at 516 nm were measured simultaneously in all 96 wells using a cooled CCD camera. Data were generated by determining max-min fluorescence levels for unstimulated, stimulated, and drug treated samples. IC 50 values for test compounds were calculated from % inhibition of VEGF stimulated responses in the absence of inhibitor.
  • the cytoplasmic domain of the human VEGF receptor (VEGFR-2) was expressed as a Histidine-tagged fusion protein following infection of insect cells using an engineered baculovirus. His-VEGFR-2 was purified to homogeneity, as determined by SDS-PAGE, using nickel resin chromatography. Kinase assays were performed in 96 well microtiter plates that were coated overnight with 30 ⁇ g of poly-Glu-Tyr (4:1) in lOmM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates were incubated with 1% BSA and then washed four times with PBS prior to starting the reaction.
  • PBS Phosphate Buffered Saline
  • reactions were carried out in 120 ⁇ L reaction volumes containing 3.6 ⁇ M ATP in kinase buffer (50mM Hepes buffer pH 7.4, 20mM MgCl 2 , 0.1 mM MnCl 2 and 0.2 mM Na 3 VO 4 ).
  • Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 0.5 ng of purified protein. Following a ten minute incubation at 25° C, the reactions were washed four times with PBS containing
  • IC 50 values for compound inhibition were calculated directly from graphs of optical density (arbitrary units) versus compound concentration following subtraction of blank values.
  • mice Male Hartley guinea pigs (300-600 g) were anesthetized with isofluorane, sheared, and given a single dose of drug or the respective vehicle. The guinea pigs were dosed orally unless indicated otherwise in Table 3. Ten minutes prior to the end of drug treatment, guinea pigs were anesthetized with isofluorane, and 0.5% Evans blue dye (EBD) in PBS (13-15 mg/kg dose of EBD) was injected intravenously. After 5 minutes, triplicate intradermal injections of 100 ng rhVEGF 165 in 100 ⁇ l PBS and of 100 ⁇ l PBS alone were administered on the flank. After 20 minutes, each animal was euthanized with Pentosol, and the skin containing the intradermal injection sites was removed for image analysis.
  • EBD Evans blue dye
  • CNV Laser-induced Choroidal Neovascularization
  • FTTC-dextran 10 mg/ml FTTC-dextran (MW 2x10 ).
  • images were obtained from the flat mounts of the RPE-choroid-sclera from each eye, and the area occupied by hyperfluorescent neovessels within each laser lesion was measured using ImagePro 4 software.
  • the percent inhibition data was plotted as a function of oral dose, using the 'best-fit' analysis within Microsoft Excel software. The IDso value was verified visually by using the plotted data (horizontal line from 50% y value, at intersection with best-fit line drop vertical line to x axis (dose). The results of said assays are set forth in Table 4- 6, below.
  • the organic layer was removed and the aqueous layer washed with ethyl acetate (15 mL).
  • the aqueous layer was made basic to pH 8 with saturated NaHCO 3 and extracted with ethyl acetate.
  • the ethyl acetate layer was washed with H 2 O, brine and dried with Na SO .
  • the organic layer was concentrated and the residue was crystallized from ethyl acetate /hexane to give the title compound (38 mg, 21%) as a bright yellow solid.
  • the reaction mixture was cooled to room temperature and partitioned between 30 mL dilute HC1 and 20 mL Ethyl acetate. The organic layer was removed and the aqueous layer washed with 15 mL ethyl acetate. The aqueous layer was made basic to pH 8 with saturated NaHCO 3 and extracted with ethyl acetate. The ethyl acetate layer was washed with H 2 O, brine and dried over anhydrous Na 2 SO 4 . The ethyl acetate layer was filtered and then concentrated.
  • the filtrate was partitioned between dilute HC1 and ethyl acetate.
  • the organic layer was removed and the aqueous layer washed with 15 mL Ethyl acetate.
  • the aqueous phase was made basic to pH 8 with saturated NaHCO 3 and extracted with ethyl acetate.
  • the ethyl acetate layer was washed with H 2 O, brine and dried over anhydrous Na 2 SO 4 .
  • the solvent was removed in vacuo to give 58 mg of yellow oil.
  • the oil was purified by chromatography (silica gel, l:l/hexane:ethyl acetate) to give the title compound (51.6 mg, 31%) as a yellow solid.

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Abstract

La présente invention concerne des molécules organiques permettant de moduler une transduction de tyrosine kinase en vue de réguler, moduler et/ou inhiber une prolifération cellulaire anormale.
PCT/US2003/036988 2002-11-27 2003-11-19 Inhibiteurs de kinases pour le traitement d'une maladie WO2004050621A2 (fr)

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JP2004570761A JP4879492B2 (ja) 2002-11-27 2003-11-19 疾患の治療のためのキナーゼ阻害剤
DE10393799T DE10393799T5 (de) 2002-11-27 2003-11-19 Kinaseinhibitoren für die Behandlung von Erkrankungen
BR0316744-5A BR0316744A (pt) 2002-11-27 2003-11-19 Inibidores de cinase para o tratamento de doença
CA002507780A CA2507780A1 (fr) 2002-11-27 2003-11-19 Inhibiteurs de kinases pour le traitement d'une maladie
GB0511267A GB2410744B (en) 2002-11-27 2003-11-19 Kinase inhibitors for the treatment of disease
AU2003295658A AU2003295658A1 (en) 2002-11-27 2003-11-19 Indol derivatives and their use as kinase inhibitors

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US10/307,097 US6699863B1 (en) 2002-11-27 2002-11-27 Kinase inhibitors for the treatment of disease
US10/389,416 US6747025B1 (en) 2002-11-27 2003-03-13 Kinase inhibitors for the treatment of disease
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WO2007087419A2 (fr) * 2006-01-24 2007-08-02 Allergan, Inc. Hétérocyclyl-1,3-dihydro-indol-2-ones insaturées et substituées à 3-5 éléments et leurs dérivés en tant qu'inhibiteurs de kinase
WO2007109596A2 (fr) * 2006-03-22 2007-09-27 Allergan, Inc. Dihydroindolones hétéroaryles comme inhibiteurs de kinases
JP2008539190A (ja) * 2005-04-28 2008-11-13 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 炎症性疾患の治療用の新規化合物
CN104211632A (zh) * 2013-05-31 2014-12-17 中国人民解放军军事医学科学院放射与辐射医学研究所 具有酪氨酸激酶抑制活性的2-吲哚酮衍生物及其制备方法与应用
US10149893B2 (en) 2013-09-24 2018-12-11 Allergan, Inc. Methods for modifying progression of osteoarthritis

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008539190A (ja) * 2005-04-28 2008-11-13 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 炎症性疾患の治療用の新規化合物
US8865682B2 (en) 2006-01-24 2014-10-21 Allergan, Inc. Substituted 3-(5-membered unsaturated heterocyclyl-1, 3-dihydro-indol-2-one's and derivatives thereof as kinase inhibitors
WO2007087419A2 (fr) * 2006-01-24 2007-08-02 Allergan, Inc. Hétérocyclyl-1,3-dihydro-indol-2-ones insaturées et substituées à 3-5 éléments et leurs dérivés en tant qu'inhibiteurs de kinase
US9758509B2 (en) 2006-01-24 2017-09-12 Allergan, Inc. Substituted 3-(5-membered unsaturated heterocyclyl-1, 3-dihydro-indol-2-one's and derivatives thereof as kinase inhibitors
WO2007087419A3 (fr) * 2006-01-24 2007-09-13 Allergan Inc Hétérocyclyl-1,3-dihydro-indol-2-ones insaturées et substituées à 3-5 éléments et leurs dérivés en tant qu'inhibiteurs de kinase
US9657005B2 (en) 2006-01-24 2017-05-23 Allergan, Inc. Substituted 3-(5-membered unsaturated heterocyclyl-1, 3-dihydro-indol-2-one's and derivatives thereof as kinase inhibitors
US8338415B2 (en) 2006-01-24 2012-12-25 Allergan, Inc. Substituted 3-(5-membered unsaturated heterocyclyl-1, 3-dihydro-indol-2-one's and derivatives thereof as kinase inhibitors
US8367664B2 (en) 2006-01-24 2013-02-05 Allergan, Inc. Substituted 3-(5-membered unsaturated heterocyclyl-1, 3-dihydro-indol-2-one's and derivatives thereof as kinase inhibitors
US8877923B2 (en) 2006-01-24 2014-11-04 Allergan, Inc. Substituted 3-(5-membered unsaturated heterocyclyl-1, 3-dihydro-indol-2-ones and derivatives thereof as kinase inhibitors
US8455535B2 (en) 2006-03-22 2013-06-04 Allergan, Inc. Heteroaryl dihydroindolones as kinase inhibitors
WO2007109596A2 (fr) * 2006-03-22 2007-09-27 Allergan, Inc. Dihydroindolones hétéroaryles comme inhibiteurs de kinases
US7977351B2 (en) 2006-03-22 2011-07-12 Allergan, Inc. Heteroaryl dihydroindolones as kinase inhibitors
WO2007109596A3 (fr) * 2006-03-22 2008-02-07 Allergan Inc Dihydroindolones hétéroaryles comme inhibiteurs de kinases
CN104211632A (zh) * 2013-05-31 2014-12-17 中国人民解放军军事医学科学院放射与辐射医学研究所 具有酪氨酸激酶抑制活性的2-吲哚酮衍生物及其制备方法与应用
US10149893B2 (en) 2013-09-24 2018-12-11 Allergan, Inc. Methods for modifying progression of osteoarthritis

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BR0316744A (pt) 2005-10-18
GB2410744A (en) 2005-08-10
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AU2003295658A1 (en) 2004-06-23
GB2410744B (en) 2006-04-12
DE10393799T5 (de) 2005-10-13

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