WO2005113561A1 - Cyclicsulfonate pyrrole indolinones en tant qu'inhibiteurs de kinase - Google Patents

Cyclicsulfonate pyrrole indolinones en tant qu'inhibiteurs de kinase Download PDF

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WO2005113561A1
WO2005113561A1 PCT/IB2005/001399 IB2005001399W WO2005113561A1 WO 2005113561 A1 WO2005113561 A1 WO 2005113561A1 IB 2005001399 W IB2005001399 W IB 2005001399W WO 2005113561 A1 WO2005113561 A1 WO 2005113561A1
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alkyl
group
ring
membered
independently selected
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PCT/IB2005/001399
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English (en)
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Peng Cho Tang
Todd Anthony Miller
Shahrzad Shirazian
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Sugen, Inc.
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Publication of WO2005113561A1 publication Critical patent/WO2005113561A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to certain indolinone compounds and their methods of synthesis.
  • the invention also relates to methods of modulating the function of protein kinases, in particular CDK2.
  • protein kinase using compounds of the invention and methods of treating diseases by modulating the function of protein kinases, in particular CDK2 protein kinase, and related signal transduction • pathways.
  • the second class consists of protein phosphatases which hydrolyze phosphate moieties from phosphoryl protein substrates.
  • the converse functions of protein kinases and protein phosphatases balance and regulate the flow of signals in signal transduction processes.
  • Protein kinases, and protein phosphatases are generally divided into two groups-receptor and non-receptor type proteins. Most-receptor-type protein phosphatases contain two conserved catalytic domains, each of which encompasses a segment of 240 amino acid residues. Saito, et al., 1991 , Cell Growth and Diff. 2:59-65. Receptor protein phosphatases can be subclassified further based upon the amino acid sequence diversity of their extracellular domains.
  • Protein kinases and protein phosphatases are also typically divided into three classes based upon the amino acids they act upon. Some catalyze the addition or hydrolysis of phosphate on serine or threonine only, some catalyze the addition or hydrolysis of phosphate on tyrosine only, and some catalyze the addition or hydrolysis of phosphate on serine, threonine, and tyrosine.
  • Kinases can regulate the catalytic activity of other protein kinases involved in cell proliferation. Protein kinases with inappropriate activity are also involved in some types of cancer.
  • the present invention is directed to certain indolinone compounds and methods of treating diseases mediated by protein kinases, in particular CDK2 protein kinase, using these compounds.
  • the invention provides a compound of Formula (I):
  • Z is oxygen or sulfur;
  • R :>5 is. hydrogen or alkyl;
  • R is hydrogen, alkyl or -C(R ) 2 NR R , wherein R is hydrogen or alkyl; and
  • R 3 and R 4 are independently alkyl or combine to form a heteroaiicyclic ring or a heteroaryl ring;
  • X is NR 9 or O, and
  • R 9 is (i) hydrogen; (ii) saturated or unsaturated aikyl optionally substituted with one, two or three substituents selected from the group consisting of halogen, trihalomethyl, alkoxy, carboxylate, amino, nitro, ester, and a five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring where each ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, amino, nitro, and
  • CONX 10 X 11 or of formula ⁇ (X 9 ) n9 --CSNX 10 X 11 , where X 7 and X 9 are each independently selected from the group consisting of alkyl and five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring where each of the ring is optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, amino, nitro, and ester; n7 and n9 are independently 0 or 1 ; and X 8 , X 10 , and X 11 , are each independently selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, and five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring where the ring is optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alky
  • a ketone of formula -(X 19 ) n19 -CO-X 20 where X 19 and X 20 are independently selected from the group consisting of alkyl and five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring where the alkyl and each ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring, halogen, trihalomethyl, carboxylate, amino, nitro, and ester; and n19 is 0 or 1 ;
  • X 21 and X 22 are independently selected from the group consisting of alkyl and five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring where the alkyl and each ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring, halogen, trihalomethyl, carboxylate, amino, nitro, and ester; and n21 is 0 or 1 ; with the proviso that Y does not include a lactone or lactam moiety, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • X is oxygen.
  • Z is oxygen.
  • Y is a pyrrole group, optionally substituted as described above.
  • Y is a phenyl group, optionally substituted as described above.
  • R 5 is hydrogen.
  • R 8 is hydrogen.
  • Z is oxygen, Y is a pyrrole group optionally substituted as described above, R 5 is hydrogen and R 8 is hydrogen.
  • Z is oxygen, Y is a phenyl group optionally substituted as described above, R 5 is hydrogen and R 8 is hydrogen.
  • the invention provides a compound of Formula (II):
  • R 5 is hydrogen or alkyl
  • R 8 is hydrogen, alkyl or -C(R 1' ) 2 NR 3' R 4' , wherein R 1 ' is hydrogen or alkyl
  • R 3 and R 4 are independently alkyl or combine to form a heteroalicyclic ring or a heteroaryl ring
  • A is selected from the group consisting of carbon, nitrogen, oxygen and sulfur and it is understood that when A is oxygen or sulfur, R 4 does not exist and there is no bond
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of (i) hydrogen or hydroxy
  • X 4 , X 5 , and X 6 are independently selected from the group consisting of alkyl and five- membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring; and n4 and n5 are independently 0 or 1 ; *
  • X 19 and X 20 are independently selected from the group consisting of alkyl and five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring where the alkyl and each ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring, halogen, trihalomethyl, carboxylate, amino, nitro, and ester; and n19 is 0 or 1;
  • X 21 and X 22 are independently selected from the group consisting of alkyl and five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring where the alkyl and each ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring, halogen, trihalomethyl, carboxylate, amino, nitro, and ester; and n21 is 0 or 1 ; or (xvi) two adjacent R 1 ,
  • R 1 and R 2 do not form a heteroaliphatic ring. In another preferred aspect of this embodiment, and in combination with any other preferred aspects, R 1 and R 2 do not form a ring.
  • A is nitrogen.
  • Z is oxygen.
  • R 5 is hydrogen.
  • R 8 is hydrogen. In another preferred aspect of this embodiment, and in combination with any other preferred aspects, A is nitrogen and R 4 is hydrogen. In another preferred aspect of this embodiment, and in combination with any other preferred aspects, A is nitrogen, Z is oxygen, and each of R 4 , R 5 and R 8 is hydrogen.
  • the invention provides a compound of Formula (III):
  • Z is oxygen or sulfur
  • R 6 is hydrogen or alkyl
  • R 7 is hydrogen, alkyl or -C(R 1' ) 2 NR 3' R 4' , wherein R 1' is hydrogen or alkyl; and R 3' and R 4' are independently alkyl or combine to form a heteroalicyclic ring or a heteroaryl ring;
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of
  • X 4 , X 5 , and X 8 are independently selected from the group consisting of alkyl and five- membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring; and n4 and n5 are independently 0 or 1 ; (viii) an amide or thioamide of formula ⁇ (X 7 ) n7 -NHCOX 8 , ⁇ (X 7 ) n7 --NHCSX 8 , ⁇ (X 9 ) n9 ⁇ CONX 10 X 11 , or of formula ⁇ (X 9 ) n9 ⁇ CSNX 10 X 11 , where X 7 and X 9 are each independently selected from the group consisting of alkyl and five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring where each of the ring is optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, halogen
  • R 1 and R 2 do not form a heteroaliphatic ring.
  • Z is oxygen.
  • R 6 is hydrogen.
  • R 7 is hydrogen.
  • Z is oxygen, and each of R 6 and R 7 is hydrogen.
  • the invention provides a pharmaceutical composition comprising any of the inventive compounds described herein, and a pharmaceutically acceptable excipient.
  • the invention provides a method of treating a disease mediated by a protein kinase, in particular CDK2 protein kinase, in a mammal, including a human, by administering to the mammal a pharmaceutical composition comprising any of the inventive compounds described herein and a pharmaceutically acceptable excipient.
  • the disease is cancer.
  • Types of cancer treatable with the present invention include squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal cancer.
  • diseases treatable with the present invention include diabetic retinopathy, a hyperproliferation disorder, von Hippel- Lindau disease, restenosis, fibrosis, psoriasis, inflammatory disorders such as rheumatoid arthritis, osteoarthritis, immunological disorders such as autoimmune diseases, cardiovasular disorders such as atherosclerosis and angiogenesis related disorders.
  • the diseases treated with the compounds of the present invention are preferably CDK2 related diseases.
  • the invention is directed to the use of any of the inventive compounds described herein, in the preparation of a medicament which is most preferably useful in the treatment of a disease mediated by abnormal protein kinase activity, preferably CDK2 kinase activity.
  • alkyl refers to an aliphatic hydrocarbon group.
  • the alkyl moiety may be a "saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties.
  • the alkyl moiety may also be an "unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety.
  • alkene refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkyl moiety, whether saturated or unsaturated, may be branched, non-branched, or cyclic.
  • the alkyl group has 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated). More preferably, it is a "medium" size alkyl having 1 to 10 carbon atoms.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group(s) is(are) preferably one or more group(s) individually and independently selected from hydroxy, alkoxy, mercapto, alkylthio, cyano, halo, carbonyl, nitro, and amino.
  • aromatic refers to a mono or bicyclic aromatic group of 6 to 12 carbon atoms which has at least one ring having a conjugated pi electron system e.g., phenyl, naphthyl or anthracene groups.
  • heteromatic refers to a mono or bicyclic aromatic group of 5 to 10 ring atoms wherein one, two or three rings atoms are selected from a group consisting of nitrogen, oxygen or sulfur, the remaining ring atoms being carbon e.g., pyridine, pyrrole, thiophene, indole, imidazole, quinoline, isoquinoline, pyrazine, furan, pyrimidine, oxazole, triazole, pyrazole and the like.
  • aliphatic ring refers to a saturated cyclic group of 3 to 10 carbon atoms e.g., cyclcopropane, cyclobutane, cyclopentane, cyclohexane and the like.
  • heteroaliphatic ring refers to a saturated cyclic group of 5 to 10 ring atoms wherein one, two or three ring atoms are selected from the group consisting of nitrogen, sulfur, sulfoxide, sulfone, ⁇ S0 2 0 ⁇ group or oxygen the remaining ring atoms being carbon e.g., tetrahydropyran, piperidine, pyrrolidine, piperazine, morpholine and the like.
  • amine refers to a chemical moiety of formula ⁇ NR a R b where R a and R are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and five-membered or six-membered aromatic or heteroaromatic ring, where the ring is optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, nitro, and ester moieties.
  • halogen refers to an atom selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  • trihalomethyl refers to the -CX 3 group, where X is a halogen, e.g., trifluoromethyl.
  • carboxylic acid or “carboxylate” refers to a chemical moiety with formula ⁇ (R) n ⁇ COOH, where R is selected from the group consisting of saturated or unsaturated alkyl and five- membered or six-membered aromatic or heteroaromatic ring and where n is 0 or 1.
  • esters refers to a chemical moiety with formula ⁇ (R) n ⁇ COOR', where R and R' are independently selected from the group consisting of saturated or unsaturated alkyl and five- membered or six-membered aromatic or heteroaromatic ring and where n is 0 or 1.
  • aldehyde refers to a chemical moiety with formula --(R) n --CHO, where R is selected from the group consisting of saturated or unsaturated alkyl and five-membered or six- membered aromatic or heteroaromatic ring and where n is 0 or 1.
  • alkoxy refers to a group -OR 0 where R 0 is unsubstituted lower alkyl e.g., methoxy, ethoxy, propoxy, butoxy, and the like.
  • fused bicyclic ring refers to a five- or six-membered heteroaliphatic ring fused with an aromatic or heteroaromatic ring.
  • “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • alkyl group optionally substituted with halogen means that the halogen may, but need not be present, and the description includes situations where the alkyl group is substituted with a halogen group and situations where the alkyl group is not substituted with the halogen group.
  • the compounds of Formulas (I), (II) or (III) may exhibit the phenomena of tautomerism and structural isomerism.
  • the compounds described herein may adopt an E or a Z configuration about the double bond connecting the 2-indolinone moiety to the pyrrole moiety or they may be a mixture of E and Z.
  • a "pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • the compound of Formula (I) may also act as a prodrug.
  • 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.
  • An example, without limitation, of a prodrug would be 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.
  • 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 “pharmaceutically acceptable excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • the term “pharmaceutically acceptable salts, solvates or hydrates” refers to those salts, solvates or hydrates which retain the biological effectiveness and properties of the parent compound.
  • PK refers to receptor protein tyrosine kinase (RTKs), non-receptor or “cellular” tyrosine kinase (CTKs) and serine-threonine kinases (STKs).
  • RTKs receptor protein tyrosine kinase
  • CTKs non-receptor or “cellular” tyrosine kinase
  • STKs serine-threonine kinases
  • Modulation or “modulating” refers to the alteration of the catalytic activity of protein kinases, in particular CDK2 kinase.
  • modulating refers to the activation of the catalytic activity, preferably the activation or inhibition of the catalytic activity of, protein kinases, in particular CDK2 kinase, depending on the concentration of the compound or salt to which the protein kinases, in particular CDK2 kinase, is exposed or, more preferably, the inhibition of the catalytic activity of protein kinases, in particular CDK2 kinase.
  • “Therapeutically effective amount” 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.
  • function refers to the cellular role of a protein kinase.
  • the protein kinase family includes members that regulate many steps in signaling cascades, including cascades controlling cell growth, migration, differentiation, gene expression, muscle contraction, glucose metabolism, cellular protein synthesis, and regulation of the cell cycle.
  • catalytic activity in the context of the invention, defines the rate at which a protein kinase phosphorylates a substrate. Catalytic activity can be measured, for example, by determining the amount of a substrate converted to a product as a function of time. Phosphorylation of a substrate occurs at the active-site of a protein kinase.
  • the active-site is normally a cavity in which the substrate binds to the protein kinase and is phosphorylated.
  • substrate refers to a molecule phosphorylated by a protein kinase.
  • the substrate is preferably a peptide and more preferably a protein.
  • the term “activates” refers to increasing the cellular function of a protein kinase.
  • the protein kinase function is preferably the interaction with a natural binding partner and most preferably catalytic activity.
  • the term “inhibit” refers to decreasing the cellular function of a protein kinase.
  • the protein kinase function is preferably the interaction with a natural binding partner and most preferably catalytic activity.
  • modulates refers to altering the function of a protein kinase by increasing or decreasing the probability that a complex forms between a protein kinase and a binding partner.
  • a modulator preferably increases the probability that such a complex forms between the protein kinase and the binding partner, more preferably increases or decreases the probability that a complex forms between the protein kinase and the binding partner depending on the concentration of the compound exposed to the protein kinase, and most preferably decreases the probability that a complex forms between the protein kinase and the binding partner.
  • a modulator preferably activates the catalytic activity of a protein kinase, more preferably activates or inhibits the catalytic activity of a protein kinase depending on the concentration of the compound exposed to the protein kinase, or most preferably inhibits the catalytic activity of a protein kinase.
  • the term "complex" refers to an assembly of at least two molecules bound to one another.
  • binding partner refers to a compound that binds to a protein kinase in cells. Binding partners can play a role in propagating a signal in a protein kinase signal transduction process. A change in the interaction between a protein kinase and a binding partner can manifest itself as an increased or decreased probability that the interaction forms, or an increased or decreased concentration of the protein kinase/binding partner complex.
  • a binding partner may be a natural binding partners, in which case the binding partner is one which binds to the protein kinase during a cell's normal function.
  • a protein kinase binding partner can bind to a protein kinase's intracellular region with high affinity. High affinity represents an equilibrium binding constant on the order of 10 "6 M or less.
  • a natural binding partner can also transiently interact with a protein kinase intracellular region and chemically modify it. Protein kinase natural binding partners are chosen from a group that includes, but is not limited to, SRC homology 2 (SH2) or 3 (SH3) domains, other phosphoryl tyrosine binding (PTB) domains, guanine nucleotide exchange factors, protein phosphatases, and other protein kinases.
  • the term "contacting" as used herein refers to mixing a solution comprising a compound of the invention with a liquid medium bathing the cells of the methods.
  • the solution comprising the compound may also comprise another component, such as dimethylsulfoxide (DMSO), which facilitates the uptake of the compound or compounds into the cells of the methods.
  • DMSO dimethylsulfoxide
  • the solution comprising the compound of the invention may be added to the medium bathing the cells by utilizing a delivery apparatus, such as a pipet-based device or syringe-based device.
  • the compounds of the invention preferably modulate the activity of the protein kinase in vitro.
  • the invention also features a method of identifying compounds that modulate the function of protein kinase, comprising the following steps: (a) contacting cells expressing the protein kinase with the compound; and (b) monitoring an effect upon the cells.
  • the effect upon the ceils is preferably a change or an absence of a change in cell phenotype, more preferably it is a change or an absence of a change in cell proliferation, even more preferably it is a change or absence of a change in the catalytic activity of the protein kinase, and most preferably it is a change or absence of a change in the interaction between the protein kinase with a natural binding partner, as described herein.
  • the term "monitoring” refers to observing the effect of adding the compound to the cells of the method. The effect can be manifested in a change in cell phenotype, cell proliferation, protein kinase catalytic activity, or in the interaction between a protein kinase and a natural binding partner.
  • effect describes a change or an absence of a change in cell phenotype or cell proliferation.
  • Effect can also describe a change or an absence of a change in the catalytic activity of the protein kinase.
  • Effect can also describe a change or an absence of a change in an interaction between the protein kinase and a natural binding partner.
  • cell phenotype refers to the outward appearance of a cell or tissue or the function of the cell or tissue.
  • cell phenotype examples include cell size (reduction or enlargement), cell proliferation (increased or decreased numbers of cells), cell differentiation (a change or absence of a change in cell shape), cell survival, apoptosis (cell death), or the utilization of a metabolic nutrient (e.g., glucose uptake). Changes or the absence of changes in cell phenotype are readily measured by techniques known in the art.
  • the invention features a method for identifying the compounds of the invention, comprising the following steps: (a) lysing the cells to render a lysate comprising protein kinase; (b) adsorbing the protein kinase to an antibody; (c) incubating the adsorbed protein kinase with a substrate or substrates; and (d) adsorbing the substrate or substrates to a solid support or antibody.
  • the step of monitoring the effect on the cells comprises measuring the phosphate concentration of the substrate or substrates.
  • the invention also features a method of regulating kinase signal transduction comprising administering to a subject a therapeutically effective amount of a compound of the invention as described herein.
  • the invention features a method of preventing or treating an abnormal condition in an organism, where the abnormal condition is associated with an aberration in a signal transduction pathway characterized by an interaction between a protein kinase and a natural binding partner, where the method comprises the following steps: (a) administering a compound of the invention as described herein; and (b) promoting or disrupting the abnormal interaction.
  • the organism is preferably a mammal and the abnormal condition is preferably cancer.
  • the abnormal condition is an angiogenesis-related disorder or a dermatologic, ophthalmic, neurologic, cardiovascular, or immune disorder.
  • Some specific abnormal conditions include hypertension, depression, generalized anxiety disorder, phobias, post-traumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson's disease, endocrine disorders, vasospasm, cerebellar ataxia, and gastrointestinal tract disorders.
  • the term "aberration,” in conjunction with a signal transduction process, refers to a protein kinase that is over- or under-expressed in an organism, mutated such that its catalytic activity is lower or higher than wild-type protein kinase activity, mutated such that it can no longer interact with a natural binding partner, is no longer modified by another protein kinase or protein phosphatase, or no longer interacts with a natural binding partner.
  • the term "promoting or disrupting the abnormal interaction” refers to a method that can be accomplished by administering a compound of the invention to cells or tissues in an organism. A compound can promote an interaction between a protein kinase and natural binding partners by forming favorable interactions with multiple atoms at the complex interface.
  • a compound can inhibit an interaction between a protein kinase and natural binding partners by compromising favorable interactions formed between atoms at the complex interface.
  • indolinone is used as that term is commonly understood in the art and includes a large subclass of substituted or unsubstituted compounds that are capable of being synthesized from an aldehyde moiety and an oxindole moiety.
  • Particular examples of compounds of the invention include the compounds shown in Table 1 : Table 1
  • Another aspect of the invention provides for a method for synthesizing compounds of the invention by reacting a compound of formula A with a compound of formula B or C
  • a base may be used.
  • the base is preferably a nitrogen base or an inorganic base.
  • “Nitrogen bases” are commonly used in the art and are selected from acyclic and cyclic amines.
  • nitrogen bases include, but are not limited to, ammonia, methylamine, trimethylamine, triethylamine, aniline, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, diisopropylethylamine, pyrrolidine, piperidine, and pyridine or substituted pyridine (e.g., 2,6-di- tertbutylpyridine).
  • “Inorganic bases” are bases that do not contain any carbon atoms. Examples of inorganic bases include, but are not limited to, hydroxide, phosphate, bisulfate, hydrosulfide (SH " ), and amide anions.
  • the base used may be pyrrolidine or piperidine.
  • the base may be the hydroxide anion, preferably used as its sodium or potassium salt.
  • the synthesis of the compounds of the invention generally takes place in a solvent.
  • the solvent of the reaction is preferably a protic solvent or an aprotic solvent.
  • protic solvents are those that are capable of donating a proton to a solute. Examples of protic solvents include, but are not limited to, alcohols and water.
  • “Aprotic solvents” are those solvents that, under normal reaction conditions, do not donate a proton to a solute.
  • Typical organic solvents such as hexane, toluene, benzene, methylene chloride, dimethylformamide, chloroform, tetrahydrofuran, are some of the examples of aprotic solvents.
  • Other aprotic solvents are also within the scope of the present invention.
  • the solvent of the reaction is an alcohol, which may preferably be isopropanol or most preferably ethanol. Water is another preferred protic solvent.
  • Dimethylformamide known in the chemistry art as DMF, is a preferred aprotic solvent.
  • the synthetic method of the invention preferably takes place at a temperature greater than room temperature.
  • the elevated temperature is preferably about 30-150 C C, more preferably is about 80-100°C, and most preferably is about 80-90°C, which is about the temperature at which ethanol boils (i.e., the boiling point of ethanol).
  • about a certain temperature it is meant that the temperature range is preferably within 10°C of the listed temperature, more preferably within 5 °C of the listed temperature, and most preferably within 2°C of the listed temperature. Therefore, by way of example, by "about 80°C” it is meant that the temperature range is preferably 80 ⁇ 10 °C, more preferably 80 ⁇ 5 °C, and most preferably 80 ⁇ 2°C.
  • the synthetic method of the invention may be accompanied by the step of screening a library for a compound of the desired activity and structure, thus, providing a method of synthesis of a compound by first screening for a compound having the desired properties and then chemically synthesizing that compound.
  • Methods of Modulating Kinases The invention also features a method of identifying compounds that modulate the function of protein kinase, comprising the following steps: (a) contacting cells expressing the protein kinase with the compound; and (b) monitoring an effect upon the cells.
  • the effect upon the cells is preferably a change or an absence of a change in cell phenotype, more preferably it is a change or an absence of a change in cell proliferation, even more preferably it is a change or absence of a change in the catalytic activity of the protein kinase, and most preferably it is a change or absence of a change in the interaction between the protein kinase with a natural binding partner, as described herein.
  • the invention features a method for treating a disease related to unregulated kinase signal transduction, where the method includes the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein.
  • the invention also features a method of regulating kinase signal transduction comprising administering to a subject a therapeutically effective amount of a compound of the invention as described herein. Furthermore, the invention features a method of preventing or treating an abnormal condition in an organism, where the abnormal condition is associated with an aberration in a signal transduction pathway characterized by an interaction between a protein kinase and a natural binding partner, where the method comprises the following steps: (a) administering a compound of the invention as described herein; and (b) promoting or disrupting the abnormal interaction.
  • the organism is preferably a mammal and the abnormal condition is preferably cancer.
  • the abnormal condition is an angiogenesis-related disorder or a dermatologic, ophthalmic, neurologic, cardiovascular, or immune disorder.
  • Some specific abnormal conditions include hypertension, depression, generalized anxiety disorder, phobias, post-traumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson's disease, endocrine disorders, vasospasm, cerebellar ataxia, and gastrointestinal tract disorders.
  • the present invention relates to compounds capable of regulating and/or modulating cellular signal transduction and, in preferred embodiments, receptor and non-receptor tyrosine kinase signal transduction.
  • ⁇ Receptor 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 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 to the extracellular microenvironment). See, Schlessinger and Ullrich, 1992, Neuron 9:303- 391. It has been shown that tyrosine phosphorylation sites in growth factor receptors function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules.
  • the specificity of the interactions between receptors and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. Songyang et al., 1993, Cell 72:767-778. These observations suggest that the function of each receptor kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor.
  • phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
  • Kinase signal transduction results in, among other responses, cell proliferation, differentiation and metabolism.
  • 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).
  • This invention is therefore directed to compounds which regulate, modulate and/or inhibit kinase signal transduction by affecting the enzymatic activity of the RKs and/or the non-receptor kinases and interfering with the signal transduced by such proteins. More particularly, the present invention is directed to compounds which regulate, modulate and/or inhibit the receptor tyrosine kinase (RTK) and/or non-receptor kinase mediated signal transduction pathways as a therapeutic approach to cure many kinds of tumors, including but not limited to carcinoma, sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma.
  • RTK receptor tyrosine kinase
  • 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.
  • this invention is related to treated of disorders mediated by CDK2 protein kinases.
  • a group of STKs that comprise a particularly attractive therapeutic target for cell proliferative disorders are the cyclin dependent kinases or CDKs.
  • CDKs play a prominent role in control of cellular proliferation. That is, the proliferation of all eukaryotic cells occurs through a continuum of events called the "cell cycle.” While in fact a continuum, for purposes of discussion, the cell cycle is conveniently broken down into four phases, G1 , S, G2 and M.
  • G 0 There is another phase, known as G 0 , which is not part of the cell cycle per se but rather is a quiescent state in which a cell resides prior to entering the cell cycle at G1.
  • G1 cellular activity is heavily dependent on the stimulating influence of external growth factors. It is during G1 that the machinery necessary for DNA replication is assembled. Between G1 and S is a critical point called the "restriction" point. At the restriction point a cell must decide whether it is prepared to continue with the cell cycle. If so, the cell commits to entry into S phase at which time it no longer requires the stimulation of external growth factors. Progress through the cell cycle is entirely intracellular from this point. It is in the S phase that DNA is replicated. At the end of S phase and entry into G2, a cell has 4N DNA content.
  • a cell begins preparation for M phase and cytokinesis. Progression through the cell cycle is regulated by CDKs. As the name suggests, in order to perform their functions, the CDKs require association with cyclin regulatory subunits. Presently, about nine CDKs and about 12 families of cyclins with which the CDKs can interact are known. Two or these, cyclin D/CDK4 and cyclin E/CDK2 are responsible for controlling entry of a cell into G1 from G 0 , passage of the cell through the restriction point and commitment to S phase. Progress through S phase is driven by cyclin E/CDK2 and cyclin A/CDK2, the latter of which promotes completion of S phase and entry into G2.
  • a negative response at any of these checkpoints results in arrest of the cell cycle which can be temporary, if repairs can be made, or permanent, that is, death of the cell, if repairs cannot be made.
  • These checkpoints are important because inappropriate cell cycle progress is a hallmark of cell proliferation disorders such as malignant tumor growth. Since CDKs are primarily responsible for driving cells through the cell cycle, including the checkpoints, their proper functioning is critical to proper cell proliferation. It is for this reason that CDKs have attracted much interest as therapeutic targets. While therapeutic potential exists in all the CDKs, CDK2 has come under particular scrutiny due to the apparently critical role that it play in the cell cycle. For example, it has been demonstrated that CDK2 dominant negative constructs can halt cell cycle progression completely (S.
  • Blood vessel proliferative disorders which can be treated or further studied by the present invention include cancers, blood vessel proliferative disorders and mesangial cell proliferative disorders.
  • Blood vessel proliferative disorders refer to angiogenic and vasculogenic disorders generally resulting in abnormal proliferation of blood vessels.
  • the formation and spreading of blood vessels, or vasculogenesis and angiogenesis, respectively, play important roles in a variety of physiological processes such as embryonic development, corpus luteum formation, wound healing and organ regeneration. They also play a pivotal role in cancer development.
  • Other examples of 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.
  • Fibrotic disorders refer to the abnormal formation of extracellular matrix. Examples of 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. Hepatic cirrhosis can cause diseases such as cirrhosis of the liver. An increased extracellular matrix resulting in a hepatic scar can also be caused by viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis.
  • fibrotic disorders implicated include atherosclerosis (see, below).
  • 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, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies PTKs have been associated with such cell proliferative disorders.
  • some members of the RTK family have been associated with the development of cancer.
  • Some of these receptors like the EGFR (Tuzi et al., 1991, Br. J.
  • the EGFR receptor 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.
  • the PDGF-R has been associated with glioblastoma, lung, ovarian, melanoma and prostate cancer.
  • the RTK c-met has been generally associated with hepatocarcinogenesis and thus hepatocellular carcinoma. Additionally, c-met has been linked to malignant tumor formation. More specifically, the RTK c-met has been associated with, among other cancers, colorectal, thyroid, pancreatic and gastric carcinoma, leukemia and lymphoma. Additionally, over-expression of the c- met gene has been detected in patients with Hodgkin's disease, Burkitt's disease, and the lymphoma cell line. The association between abnormalities in RTKs and disease are not restricted to cancer, however. For example, RTKs have been associated with metabolic diseases like psoriasis, diabetes mellitus, wound healing, inflammation, and neurodegenerative diseases.
  • These diseases include, but are not limited to hypertension, depression, generalized anxiety disorder, phobias, post-traumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive- compulsive disorder, panic disorder, memory disorders, Parkinson's disease, endocrine disorders, vasospasm, cerebellar ataxia, and gastrointestinal tract disorders.
  • the EGF-R is indicated in corneal and dermal wound healing. Defects in the Insulin-R and the IGF-1R are indicated in type-ll diabetes mellitus.
  • a more complete correlation between specific RTKs and their therapeutic indications is set forth in Plowman etal., 1994, DN&P 7:334-339.
  • CKs cellular kinases
  • src receptor type kinases
  • abl cellular kinases
  • fps cellular kinases
  • yes, fyn, lyn, lck, blk, hck, fgr, yrk are involved in the proliferative and metabolic signal transduction pathway and thus in indications of the present invention.
  • mutated src v-src
  • pp60 v"src oncoprotein
  • the proto-oncogene pp ⁇ O 0" ⁇ 0 transmits oncogenic signals of many receptors.
  • overexpression of EGF-R or HER2/neu in tumors leads to the constitutive activation of pp ⁇ O 0-1 ⁇ 0 , which is characteristic for the malignant cell but absent from the normal cell.
  • mice deficient for the expression of c-src exhibit an osteopetrotic phenotype, indicating a key participation of c-src in osteoclast function and a possible involvement in related disorders.
  • Zap 70 is implicated in T-cell signaling.
  • CTK modulating compounds to augment or even synergize with RTK aimed blockers is an aspect of the present invention.
  • RTKs and non-receptor type kinases have been connected to hyperimmune disorders.
  • the compounds of the present invention are also effective in treating diseases that are related to the PYK-2 protein. This protein, its cellular function, and diseases related to them are set forth in detail in U.S. Patent Number 5,837,524, issued November 17, 1998, and entitled "PYK2 RELATED PRODUCTS AND METHODS," and U.S.
  • Pharmaceutical Formulations And Routes Of Administration The compounds described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, latest edition.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • parenteral delivery including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • parenteral delivery including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • parenteral delivery including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions for use in accordance with the present invention thus 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.
  • Types of administration includes, injection, oral administration, buccal administration, inhalation, parenteral administration by injection, e.g., by bolus injection or continuous infusion, rectal administration, depot preparation by such as implantation (for example subcutaneously or intramuscularly) or by intramuscular injection
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's 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 in the art.
  • the compounds can be formulated readily 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, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more compound of the invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable 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, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • 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 preparations 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 filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • 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. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • the compounds may be formulated for parenteral administration by injection, 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 formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which 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.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example as an emulsion in an acceptable oil
  • ion exchange resins or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • 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. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, 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. Many of the PTK modulating compounds of the invention may be provided as salts with pharmaceutically compatible counterions.
  • compositions suitable for use in the present invention include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. 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. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models 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 PTK activity).
  • IC 50 the concentration of the test compound which achieves a half-maximal inhibition of the PTK activity.
  • Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED 50 .
  • Compounds which exhibit high therapeutic indices are preferred.
  • 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 of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range 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.1).
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the kinase modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • 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 the kinase using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, 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 which 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.
  • the examples below are non-limiting and are merely representative of various aspects and features of the present invention. The examples describe methods for synthesizing compounds of the invention and methods for measuring an effect of a compound on the function of protein kinases. Synthetic Examples General reaction scheme
  • Example 1 6,6-Dioxo-3,6,8,9-tetrahvdro-1 H7-oxa-6 ⁇ -thia-3-aza-cvclopentaralnaphthalen-2-one 4-Hydroxyethyl oxindole (5 g, 28.2 mmol) was dissolved in 20 mL of chlorosulfonic acid with stirring at room temperature. After 30 minutes, the reaction mixture was slowly added to 300 mL of ice water with stirring.
  • Example 2 General method for condensation of an oxindole with a pyrrole aldehyde: 6,6-Dioxo-3,6,8,9- tetrahydro-1 H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one (1.0 eq) and 1.05 - 1.20 eq of the pyrrole aldehyde were suspended in reagent ethanol at a concentration of 0.25 - 1.0 M. Piperidine (0.05 -2.0 eq) was added and the mixture refluxed for 1 - 4 hours. Thin layer chromatography was used to determine when most or all of the starting materials were consumed.
  • pyrrole aldehyde contained a carboxylic acid group
  • 1.0 - 2.0 eq of acetic acid was added and the refluxing continued for 10 minutes.
  • the reaction mixture was cooled to room temperature and the solids collected by vacuum filtration and washed with ethanol.
  • the solids were slurry-washed by heating and stirring in ethanol for 5 - 20 minutes.
  • the mixture was cooled to room temperature.
  • the solids were collected by vacuum filtration, washed with ethanol and dried under vacuum to give the condensed indolinone.
  • Example 3 4-methyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2H7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen- (1Z)-ylidenemethyl]-1H-pyrrole-3-carboxylic acid, was prepared using the general method of Example 2.
  • Example 3 4-methyl-5-[2,6,6-trioxo-3,6,8,9- tetrahydro-2H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-(1Z)-ylidenemethyl]-1H-pyrrole-3- carboxylic acid as a red-orange solid.
  • Example 4 ( ⁇ 4-methyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2H-7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-(1Z)-ylidenemethyl]-1Hpyrrole-3-carbonyl ⁇ -amino)-acetic acid ethyl ester, was prepared using the general method of Example 2.
  • Acetic acid (25.2 mg, 0.42 mmol) was added and the refluxing continued for 10 minutes.
  • the reaction mixture was cooled to room temperature and the solids collected by vacuum filtration and washed with ethanol. The solids were slurry-washed by refluxing and stirring in ethanol for 10 minutes. The mixture was cooled to room temperature.
  • Example 4 ( ⁇ 4-methyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro- 2r/-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-(1Z)-ylidenemethyl]-1H-pyrrole-3-carbonyl ⁇ -amino)- acetic acid ethyl ester as a red-orange solid.
  • Example 5 1-[1-f3-methyl-4-(morpholine-4-carbonyl)-1f/-pyrrol-2-yl]-meth-(Z)-ylidene]-6,6-dioxo-3,6,8,9- tetrahydro-1rV-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one, was prepared using the general method of Example 2.
  • Acetic acid (24 mg, 0.40 mmol) was added and the refluxing continued for 10 minutes.
  • the reaction mixture was cooled to room temperature and the solids collected by vacuum filtration and washed with ethanol. The solids were slurry-washed by refluxing and stirring in ethanol for 10 minutes. The mixture was cooled to room temperature.
  • Example 5 1-[1-[3-methyl-4-(morpholine-4-carbonyl)-1r -pyrrol-2-yl]-meth-(Z)- ylidene]-6,6-dioxo-3,6,8,9-tetrahydro-1H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one as a red-orange solid.
  • Example 6 1 -[1 -[3-(3-Dimethylamino-propyl)-1 H-indol-2-yl]-meth-(Z)-ylidene]-6,6-dioxo-3,6,8,9- tetrahydro-1 H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one (70 mg, 45 % yield), was prepared by condensing 3-(3-dimethylamino-propyl)-1 W-indole-2-carbaldehyde with 6,6-dioxo-3,6,8,9- tetrahydro-1 H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one using the general method of Example 2.
  • Example 7 4-Methyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen- (1Z)-ylidenemethyl]-1 /--pyrrole-2-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide.
  • Example 8 4-methyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen- (1Z)-ylidenemethyl]-1 H-pyrrole-3-carboxylic acid ethyl ester (79 mg, 47 % yield), was prepared by condensing 5-formyl-4-methyl-1Hpyrrole-3-carboxylic acid ethyl ester with 6,6-dioxo-3,6,8,9- tetrahydro-1 H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one using the general method of Example 2.
  • Example 9 1 -[1 -[3-methyl-4-(piperidine-1 -carbonyl)-1 Hpyrrol-2-yl]-meth-(Z)-ylidene]-6,6-dioxo-3,6,8,9- tetra-hydro-1 V-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one (77 mg, 44 % yield), was prepared by condensing 3-methyl-4-(piperidine-1-carbonyl)-1/--pyrrole-2-carbaldehyde with 6,6- dioxo-3,6,8,9-tetra-hydro-1 /-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one using the general method of Example 2.
  • Example 10 6,6-Dioxo-1 -[1 -[3-phenyl-4-(piperidine-1 -carbonyl)-1 f/-pyrrol-2-yl]meth-(Z)-ylidene]-3,6,8,9- tetra-hydro-1H7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one (98 mg, 62 % yield), was prepared by condensing 3-phenyl-4-(piperidine-1-carbonyl)-1Hpyrrole-2-carbaldehyde with 6,6- dioxo-3,6,8,9-tetra-hydro-1 H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one using the general method of Example 2.
  • Example 11 1-[1-(3,5-Dimethyl-1 V-pyrrol-2-yl)-meth-(Z)-ylidene]-6,6-dioxo-3,6,8,9-tetrahydro-1 H-7-oxa- 6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one was prepared by condensing 3,5-dimethyl-1Hpyrrole-
  • Example 12 6,6-Dioxo-1 -[1 -(4,5,6,7-tetrahydro-1 f/-indol-2-yl)-meth-(Z)-ylidene]-3,6,8,9-tetrahydro-1 H-7- oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one was prepared by condensing 4,5,6,7-tetrahydro-
  • Example 13 3- ⁇ 2-[2,6,6-Trioxo-3,6,8,9-tetrahydro-2H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopentata]naphthalen-(1Z)- ylidenemethyl]-4,5,6,7-tetrahydro-1Hindol-3-yl ⁇ -propionic acid was prepared by condensing 3-(2- formyl-4,5,6,7-tetrahydro-1 H-indol-3-yl)-propionic acid with 6,6-dioxo-3,6,8,9-tetrahydro-1 H-7-oxa-
  • Example 14 1 -[1 -(1 H-lndol-2-yl)-meth-(Z)-ylidene]-6,6-dioxo-3,6,8,9-tetrahydro-1 H-7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-2-one was prepared by condensing 1 H-indole-2-carbaldehyde with 6,6- dioxo-3,6,8,9-tetrahydro-1 H7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one using the general method of Example 2. MS (m/z) 367 (M+1).
  • Example 15 1 -[1 -(4-Morpholin-4-yl-phenyl)-meth-(Z)-ylidene]-6,6-dioxo-3,6,8,9-tetrahydro-1 H7-oxa-6 ⁇ 6 - thia-3-aza-cyclopenta[a]naphthalen-2-one was prepared by condensing 4-morpholin-4-yl- benzaldehyde with 6,6-dioxo-3,6,8,9-tetrahydro-1W-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2- one using the general method of Example 2. MS (m/z) 413 (M+1).
  • Example 16 3- ⁇ 5-Methyl-2-[2,6,6-trioxo-3,6,8,9-tetrahydro-2H-7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-(1Z)-ylidenemethyl]-1 V-pyrrol-3-yl ⁇ -propionic acid was prepared by condensing 3-(2-formyl-5-methyl-1 Hpyrrol-3-yl)-propionic acid with 6,6-dioxo-3,6,8,9-tetrahydro-1 H-
  • Example 17 3- ⁇ 2,4-Dimethyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2rV-7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-(1Z)-ylidenemethyl]-1H-pyrrol-3-yl ⁇ -propionic acid was prepared by condensing 3-(5-formyl-2,4-dimethyl-1 Hpyrrol-3-yl)-propionic acid with 6,6-dioxo-3,6,8,9-tetrahydro- 1H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one using the general method of Example 2.
  • Example 19 2,4-Dimethyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2W-7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-(1 Z)-ylidenemethyl]-1 Hpyrrole-3-carboxylic acid (2-pyrrolidin-1 -yl-ethyl)- amide was prepared by condensing 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-pyrrolidin- 1 -yl-ethyl)-amide with 6,6-dioxo-3,6,8,9-tetrahydro-1 H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen- 2-one using the general method of Example 2.
  • Example 20 4-Methyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2H7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen- (1Z)-ylidenemethyl]-1 H-pyrrole-2-carboxylic acid was prepared by condensing 5-formyl-4-methyl-1 H- pyrrale-2-carboxylic acid with 6,6-dioxo-3,6,8,9-tetrahydro-1 H7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-2-one using the general method of Example 2.
  • Example 21 5-Methyl-2-[2,6,6-trioxo-3,6,8,9-tetrahydro-2H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen- , (1Z)-ylidenemethy ⁇ ]-1 Hpyrrole-3-carboxylic acid was prepared by condensing 2-formyl-5-methyl-1 H- pyrrole-3-carboxylic acid with 6,6-dioxo-3,6,8,9-tetrahydro-1 H7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-2-one using the general method of Example 2.
  • Example 23 4-(2-Carboxy-ethyl)-2-methyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2H7-oxa-6 ⁇ 6 : thia-3-aza- cyclopenta[a]naphthalen-(1Z)-ylidenemethyl]-1 H-pyrrole-3-carboxylic acid ethyl ester was prepared by condensing 4-(2-carboxy-ethyl)-5-formy!-2-methyl-1 H-pyrrole-3-carboxylic acid ethyl ester with 6,6- dioxo-3,6,8,9-tetrahydro-1 /-/-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[ajnaphthalen-2-one using the general method of Example 2.
  • Example 25 6,6-Dioxo-1 -[1 -(2,4,5,6-tetrahydro-cyclopenta[c]pyrrol-1 -yl)-meth-(Z)-ylidene]-3,6,8,9- tetrahydro-1 H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one was prepared by condensing
  • Example 26 4-(2-Hydroxy-ethyl)-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2/--7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-(1Z)-ylidenemethyl]-1r-/-pyrrole-3-carboxylic acid was prepared by condensing 5-formyl-4-(2-hydroxy-ethyl)-1H-pyrrole-3-carboxylic acid with "6,6-dioxo-3,6,8,9- tetrahydro-1H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one using the general method of
  • Example 27 4-(2-Carbamoyl-ethyl)-3-methyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2H7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-(1Z)-ylidenemethyl]-1H-pyrrole-2-carboxylic acid ethyl ester was prepared by condensing 4-(2-carbamoyl-ethyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester with
  • Example 28 1 -[1 -(5-Methyl-3-phenyl-1 Hpyrrol-2-yl)-meth-(Z)-ylidene]-6,6-dioxo-3,6,8,9-tetrahydro-1 H-7- oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one was prepared by condensing 5-methyl-3-phenyl-
  • Example 29 2-Methyl-4-phenyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2/V-7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-(1Z)-ylidenemethyl]-1 V-pyrrole-3-carboxylic acid ethyl ester was prepared by condensing 5-formyl-2-methyl-4-phenyl-1 f -pyrrole-3-carboxylic acid ethyl ester with 6,6-dioxo-
  • Example 32 4- ⁇ 2,4-Dimethyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2H7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-(1Z)-ylidenemethyl]-1H-pyrrol-3-yl ⁇ -benzoic acid was prepared by condensing 4-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-benzoic acid with 6,6-dioxo-3,6,8,9-tetrahydro-
  • Example 33 3- ⁇ 5-[2,6,6-Trioxo-3,6,8,9-tetrahydro-2H7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-(1Z)- ylidenemethyl]-1 H-pyrrol-2-yl ⁇ -propionic acid was prepared by condensing 3-(5-formyl-1 Hpyrrol-2-yl)- propionic acid with 6,6-dioxo-3,6,8,9-tetrahydro-1 H7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2- one using the general method of Example 2.
  • Example 35 ⁇ 2,4-Dimethyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2H-7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-(1Z)-ylidenemethyl]-1 /-/-pyrrol-3-yl ⁇ -acetic acid ethyl ester was prepared by condensing (5-formyl-2,4-dimethyl-1 Hpyrrol-3-yl)-acetic acid ethyl ester with 6,6-dioxo-3,6,8,9- tetrahydro-1 /--7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one using the general method of
  • Example 36 1 -[1 -(5-Ethyl-3-phenyl-1 H-pyrrol-2-yl)-meth-(Z)-ylidene]-6,6-dioxo-3,6,8,9-tetrahydro-1 H-7- oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one was prepared by condensing 5-ethyl-3-phenyl-1 H- pyrrole-2-carbaldehyde with 6,6-dioxo-3,6,8,9-tetrahydro-1 H7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-2-one using the general method of Example 2. MS (m/z) 421 (M+1 ).
  • Example 37 1 -[1 -[3-(4-Bromo-phenyl)-5-methyl-1 H-pyrrol-2-yl]-meth-(Z)-ylidene]-6,6-dioxo-3,6,8,9- tetrahydro-1H7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one was prepared by condensing 3-
  • Example 38 2-Methyl-4-phenyl-5-[2,6,6-trioxo-3,6,8,9-tetrahydro-2H-7-oxa-6 ⁇ 6 -thia-3-aza- cyclopenta[a]naphthalen-(1Z)-ylidenemethyl]-1 V-pyrrole-3-carboxylic acid was prepared by condensing 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid with 6,6-dioxo-3,6,8,9- tetrahydro-1 H-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one using the general method of
  • Example 40 1-[1-(3,5-Dimethyl-4-morpholin-4-ylmethyl-1 H-pyrrol-2-yl)-meth-(Z)-ylidene]-6,6-dioxo-3,6,8,9- tetrahydro-1 /7-7-oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one was prepared by condensing 3,5- dimethyl-4-morpholin-4-ylmethyl-1 H-pyrrole-2-carbaldehyde with 6,6-dioxo-3,6,8,9-tetrahydro-1 H-7- oxa-6 ⁇ 6 -thia-3-aza-cyclopenta[a]naphthalen-2-one using the general method of Example 2. MS (m/z)
  • Biotinylated peptide substrate (deb-tide). Peptide biotin-X-PKTPKKAKKL dissolved in dH 2 0 at a concentration of 5 mg/mL. Stored at -80 °C in 100 ⁇ L aliquots.
  • Titertek Multidrop Let sit on benchtop behind reactive shield for 1 hr.

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Abstract

L'invention concerne des composés dont la structure est représentée par la formule (I) ainsi que des procédés de synthèse et des méthodes d'utilisation de ces composés. Les composés préférés conviennent bien comme agents thérapeutiques, en particulier pour des maladies en rapport avec la protéine kinase tels que le cancer.
PCT/IB2005/001399 2004-05-20 2005-05-09 Cyclicsulfonate pyrrole indolinones en tant qu'inhibiteurs de kinase WO2005113561A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014808A1 (fr) * 1992-12-23 1994-07-07 Farmitalia Carlo Erba Srl Derives vinylene-azaindoliques et leur procede de preparation
WO1999021859A1 (fr) * 1997-10-10 1999-05-06 Glaxo Group Limited Azaoxindole, derives et applications
WO2001064681A2 (fr) * 2000-02-28 2001-09-07 Sugen, Inc. Composes de 3-(pyrolyllactone)-2-indolinone comme inhibiteurs des kinases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014808A1 (fr) * 1992-12-23 1994-07-07 Farmitalia Carlo Erba Srl Derives vinylene-azaindoliques et leur procede de preparation
WO1999021859A1 (fr) * 1997-10-10 1999-05-06 Glaxo Group Limited Azaoxindole, derives et applications
WO2001064681A2 (fr) * 2000-02-28 2001-09-07 Sugen, Inc. Composes de 3-(pyrolyllactone)-2-indolinone comme inhibiteurs des kinases

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