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WO2012047017A2 - Dérivé 2,3-dihydro-isoindol-1-one et composition le comprenant - Google Patents

Dérivé 2,3-dihydro-isoindol-1-one et composition le comprenant Download PDF

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WO2012047017A2
WO2012047017A2 PCT/KR2011/007370 KR2011007370W WO2012047017A2 WO 2012047017 A2 WO2012047017 A2 WO 2012047017A2 KR 2011007370 W KR2011007370 W KR 2011007370W WO 2012047017 A2 WO2012047017 A2 WO 2012047017A2
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substituted
fluoro
phenyl
dihydro
nmr
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WO2012047017A3 (fr
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홍용래
이미정
김정미
홍장원
장호진
박수봉
이휘성
최종류
노성구
조중명
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크리스탈지노믹스(주)
한국보건산업진흥원
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Publication of WO2012047017A2 publication Critical patent/WO2012047017A2/fr
Publication of WO2012047017A3 publication Critical patent/WO2012047017A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a 2,3-dihydro-isoindol-1-one derivative and a composition comprising the same, wherein the compounds and compositions of the present invention are for treating diseases or conditions associated with abnormal or deregulated kinase activity. It can be useful for mitigation or prevention.
  • Protein kinases have been important therapeutic targets because they phosphorylate specific amino acids of proteins and are closely associated with various signal transduction and disease mechanisms in cells. These protein kinases represent a large group of proteins that play a pivotal role in regulating various cellular processes in maintaining cellular function and are classified according to their phosphorylation substrate. The kinases are classified into the following groups: protein-tyrosine, protein-serine / threonine, protein-histidine, and the like.
  • Protein-tyrosine kinases include Abl, Irk, IGFR-1, Zap-70, BLK, Bmx, Btk, Csk homologous kinase (CHK), C-terminal Skin kinase (CSK), Itk-1, Src (c-Src, Lyn, yn, Lck, Syk, Hck, Yes, Blk, Fgr, Frk), Tec, Txk / Rlk, Abl, EGFR (EGFR-1 / ErbB-2, ErbB-2 / NEU / HER-2, ErbB-3 , ErbB-4), FAK, FGF1R (FGFR1 or FGR-1), FGF2R (FGR-2), MET (Met-1 or c-Met), PDGFR- ⁇ , PDGFR- ⁇ , Tie-1, Tie-2 (Tek-1 or Tek-2), VEGFR1 (FLT-1), VEGFR2 (KDR), FLT-3, FLT-4,
  • Protein serine / threonine kinases include Aurora, Ark, AMT (1--1). 3), CamK (I ⁇ IV), CamKK, Chk1 and 2, CKI, CK2, IKK-I, IKK-2, IlK, Jnk91-3), LimK (1 and 2), MLK3Raf (AC), CDK (1 -10), PKC, Plk (1-3), NIK, Pak (1-3), PDK1, PKR, RhoK, RIP, RIP-2, GSK3 (A and B), PKA, P38, Erk (1-3) ), PKB, IRAK1, FRK, SGK, TAK1, Tpl-2 (COT), and the like.
  • protein kinases involved in this process include Abl, Aurora, CDK, EGFR, EMT, Erk, FGF, FAK, Flk-1, Flt, JAK, KDR, HER-2, IGF-1R, IR, LCK, MAP, MEK, c-MET, PDGFR, PI3, RAF, Src. And m-Tor et al. (Traxler, P.M. protein Tyrosine Kinase Inhibitors in Cancer Treatment.Exp. Opin. Ther. Patents (1997) 7: 571-588).
  • non-selective kinase inhibitors such as Pfizer, Sprycel (BMS) and the like have been released and used.
  • BMS Sprycel
  • these drugs appear to be more effective than selective kinase inhibitors in some solid cancers, their range of use is quite limited due to off-target toxicity due to lack of selectivity.
  • the present invention provides a compound represented by the following formula (1).
  • R0 to R3 are as defined below.
  • the present invention is a pharmaceutical for the treatment, alleviation or prevention of diseases associated with abnormal or deregulated kinase activity, including the compound represented by Formula 1 and a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof To provide a composition.
  • the present invention provides a compound represented by the following formula (1).
  • R0 is or ego
  • R1 to R3 are each independently hydrogen, halogen, hydroxy, carboxy, cyano, nitro, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, cycloalkoxy, thioester, amide, amino , Substituted amino, aminoacyl, acyl, acyloxy, aryl, aryloxy, substituted aryl, urea, substituted urea, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle,
  • R 4 is selected from the group consisting of hydrogen, hydroxy, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle,
  • R 10 and R 11 are each independently hydrogen, alkyl, substituted alkyl, ethylhydroxy, amino, substituted amino, aryl, substituted aryl, urea, substituted urea, heteroaryl, substituted heteroaryl, heterocyclic or substituted Selected from the group consisting of heterocycles, when Y is N, R 10 and R 11 are not introduced, and
  • X and Y are each independently selected from elements consisting of C, N, O and S.
  • R0 is Phosphorus provides a compound represented by the following formula (2):
  • R1 to R4 are as defined in the formula (1).
  • specific examples of the compound wherein R1 is aryl or substituted aryl include a compound represented by the following formula (3).
  • R2 to R4 are as defined in Formula 1
  • R5 to R9 are each independently hydrogen, halogen, hydroxy, carboxy, cyano, nitro, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Alkoxy, substituted alkoxy, cycloalkoxy, thioester, amide, amino, substituted amino, aminoacyl, acyl, acyloxy, aryl, aryloxy, substituted aryl, urea, substituted urea, heteroaryl, substituted heteroaryl , Heterocyclic ring or substituted heterocyclic ring.
  • R9 is preferably selected from the following functional groups.
  • R12 may be selected from the group consisting of hydrogen, hydroxy, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero ring or substituted hetero ring, but is not limited thereto. no.
  • R0 is Phosphorus provides a compound represented by the following formula (4):
  • R1 to R3, R10, R11, X and Y are as defined in the formula (1).
  • specific examples of the compound wherein R1 is aryl or substituted aryl include a compound represented by the following formula (5).
  • R2, R3, R10, R11, X and Y are as defined in Formula 1
  • R5 to R9 is as defined in Formula 3.
  • R9 is preferably selected from the following functional groups.
  • R12 is as defined in formula (3).
  • the compounds of the present invention may contain one or more chiral centers.
  • such compounds may be prepared or separated as pure stereoisomers, ie as individual enantiomers or diastereomers, or as stereoisomer-diastereomers. All such stereoisomers (and diastereomers) are also included within the scope of the compounds of the present invention.
  • the present invention is a pharmaceutical for the treatment, alleviation or prevention of diseases associated with abnormal or deregulated kinase activity, including the compound represented by Formula 1 and a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof To provide a composition.
  • Diseases associated with abnormal or deregulated kinase activity subject to the application of the pharmaceutical composition of the present invention include cancer, asthma, allergies, atopic dermatitis, psoriasis, rheumatoid arthritis, etc.
  • the disease is preferably cancer.
  • the cancer may include gastric cancer, thyroid cancer, colon cancer, liver cancer, kidney cancer, brain cancer, uterine cancer, menstrual cancer, non-small cell lung cancer, pancreatic cancer, breast cancer, blood cancer, bladder cancer, colorectal cancer, glioblastoma, and the like.
  • composition of the present invention may further include at least one or more of an agent such as an antibiotic, an alkylating agent, an anti-metabolic agent, a hormonal agent, an immunological agent, an interferon agent or another anticancer agent.
  • an agent such as an antibiotic, an alkylating agent, an anti-metabolic agent, a hormonal agent, an immunological agent, an interferon agent or another anticancer agent.
  • the composition of the present invention is ultimately aimed at inhibiting the growth of cancer cells and inhibiting metastasis or necrosis of cancer cells.
  • Compounds represented by Formula 1 of the present invention act as selective combinations of single or multiple targets against protein kinases, in particular kinases that play an important role in the differentiation, growth, invasion and / or metastasis of cancer cells, thereby enhancing their activity. By regulating, the effect which is superior to a conventional anticancer agent and a protein kinase modulator can be exhibited.
  • protein kinases include Abl, Aurora, AXL, BLK, BMX, Aurora, c-KIT, c-MET, CDK, FER, FGFR, FGR, FLT, FRK, FYN, HCK, IRR, ITK, JAK, KDR , KIT, LCK, LYN, MAPK, MER, MEK, MUSK, PDGFR, PLK, RET, RON, SRC, SRM, TIE2, TNK1, TRKA, TNIK, VEGFR and the like, but are not limited thereto.
  • the types of representative kinases that play important roles in the differentiation, growth, invasion and / or metastasis of cancer cells and their roles are summarized as follows:
  • c-Met is a receptor tyrosine kinase (RTK) that has a high affinity for hepatocyte growth factor (HGF) / scatter factor (SF) .
  • RTK receptor tyrosine kinase
  • HGF hepatocyte growth factor
  • SF scatter factor
  • the signal activation process involves trans phosphorylation when HGF binds to form a dimer. The tyrosine residues are then phosphorylated to form docking sites. Subsequently, signal molecules in the down stream are induced to transmit signals into the cell.
  • HGF / c-Met signaling pathways also correlate with pathways related to cell proliferation and differentiation through MAPK activation, cell survival via PI3K-Akt signaling pathways, apoptosis, and PKC réelle pathways. It is also known to be involved in transformation and tubulogenesis through signaling pathways. It is known that dysregulation between HGF and c-Met and overexpression of c-Met play an important role in the progression of metastatic cancer, and thus c-Met is an important target for chemotherapy. Livio T., Andrea B. , Paolo M .; MET signaling: principles and function in development, organ regeneration and cancer, Nat. Rev. Mol. Cell Biol. 11 (12), (2010), 834-848).
  • the c-Met inhibitors are particularly angiogenesis-dependent, including diabetic retinopathy, macular degeneration and inflammatory diseases such as rheumatoid arthritis. It can also be effective in disease.
  • Aurora is a type of conserved serine / threonine kinase, which is divided into three types of aurora kinases (A, B and C), and these aurora families perform essential functions in cell differentiation.
  • the three mammalian paralogues have very similar sequences, but their positions, functions, substrates and regulatory partners are very different from each other.
  • Aurora A is primarily associated with spindles during mitosis, which is required for centrosome separation and maturation (Sausville EA. Nat. Med., 10, (2004), 234-235). Aurora A also performs its function in the meiosis process by promoting oocyte maturation, polar release, spindle localization and termination of mid-term I.
  • Aurora B is a chromosome-passenger protein with multiple functions in mitosis. This is necessary for phosphorylation of histone H3, target condensation and compaction of normal chromosomes. It has also recently been shown to be essential for chromosome biorientation, isotope-microtubule interactions and spindle-assembly checkpoints, and plays an essential role in the completion of cytoplasmic division.
  • aurora C kinase Little is known about aurora C kinase except that it appears to be preferentially expressed in meiotic cells, and aurora c kinase appears to provide additional levels of adjustment that may be essential for the construction of meiosis.
  • Aurora kinases are overexpressed in certain types of cancers, including colorectal cancer, breast cancer, pancreatic cancer, ovarian cancer and other solid cancers. Genes encoding Aurora A and B kinases tend to be amplified in certain types of cancers, while genes encoding Aurora C kinases are present in regions of the chromosome that are rearranged and deleted. Aurora A is associated with various malignancies including primary colon cancer, colon cancer, breast cancer, gastric cancer, ovarian cancer, prostate cancer and cervical cancer, neuroblastoma, and other solid-tumor cancers (Warner et al .; Molecular Cancer Therapeutics 2 , (2003), 589-595).
  • Aurora A and B kinases are frequently increased or overexpressed in human cancers, they may be interesting targets for effective cancer treatment (Mountzios et al., Cancer Treatment Reviews, 34, (2008), 175-182; Gautschi et al. , Clin., Cancer Res. 14 (6), (2008), 1639-1648; Mortlock et al., Current Topics in Medicinal Chemistry, 5, (2005), 807-821).
  • VEGF Vascular endothelial growth factor
  • VEGF Vascular endothelial growth factor
  • PDGF platelet-derived growth factor
  • VEGF is a dimeric glycoprotein associated with platelet-derived growth factor (PDGF), produced by normal and tumor cell lines, and exhibits angiogenic activity in in vivo test systems (e.g. rabbit cornea) Induces plasminogen activators associated with proteolysis of extracellular matrix during capillary formation in cells.
  • Many isoforms [VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3], which show comparable biological activity to VEGF but differ in cell morphology and heparin-binding capacity.
  • VEGFR-1 Flt-1
  • VEGFR-2 KDR
  • VEGFR-3 VEGFR-3
  • VEGF vascular endothelial growth
  • VEGF vascular endothelial growth
  • VEGF vascular endothelial growth factor
  • the compound represented by the formula (I) of the present invention is further understood by reference to the following embodiments for the purpose of pure illustration, but the present invention is not limited by the illustrated embodiment, and the compound of the present invention is any functionally equivalent method. It can be prepared by.
  • the introduction of a protecting group for any functional group is not limited to the illustrated embodiment, and may be extended to a method of introducing a protecting group or a deprotecting group generally known.
  • Reagent supply sources include, but are not limited to, companies such as Aldrich, Sigma, TCI, Wako, Kanto, Fluorchem, Acros, Abocado, Alfa, Fluka, and the like.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and / or deprotecting specific functional groups are well known in the art. For example, numerous protectors can be found in T.W. Greene and G.M. Wuts, Protecting Groups in Organic Synthesis, Second edition, Wiley, New York, 1991, and references cited therein.
  • the compounds of the present invention may contain one or more chiral centers.
  • such compounds may be prepared or separated as pure stereoisomers, ie as individual enantiomers or diastereomers, or as stereoisomer-diastereomers.
  • Pure stereoisomers (and diastereomers) can be prepared, for example, using optically active starting materials or stereoselective reagents known in the art.
  • racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral degradants and the like.
  • the compound represented by the formula (2) of the present invention can be synthesized by the reaction according to Scheme 1, but is not limited thereto.
  • the compound represented by Chemical Formula 3 of the present invention may be synthesized by a reaction according to Scheme 2, but is not limited thereto.
  • the compound represented by Formula 4 of the present invention may be synthesized by the reaction according to the following Scheme 3 or Scheme 4, but is not limited thereto.
  • the compound represented by Chemical Formula 5 of the present invention may be synthesized by a reaction according to Scheme 5 or Scheme 6, but is not limited thereto.
  • Z 1 , Z 2 , Z 3 and Z 4 are each independently hydrogen, halogen, hydroxy, carboxy, cyano, nitro, alkyl, substituted alkyl, cycloalkyl, Substituted cycloalkyl, alkoxy, substituted alkoxy, cycloalkoxy, thioester, amide, amino, substituted amino, aminoacyl, acyl, acyloxy, aryl, aryloxy, substituted aryl, urea, substituted urea, heteroaryl , Substituted heteroaryl, hetero ring or substituted hetero ring can be selected from the group consisting of.
  • compositions of the present invention can be delivered in a pharmaceutical composition either directly or with a suitable carrier or excipient well known in the art.
  • the pharmaceutical compositions of the invention may be administered in an amount effective to a subject having or at risk of anemia due to, for example, chronic renal failure, diabetes, cancer, AIDS, radiation therapy, chemotherapy, kidney dialysis, or surgery.
  • the subject is a mammalian subject, more preferably a human subject.
  • the effective amount of the composition of the present invention can be easily determined by routine experimentation to be the most effective and convenient route and the most suitable formulation.
  • Suitable routes of administration of the compositions of the invention include intramuscular, subcutaneous, intramedullary injections as well as intradural, direct intraventricular, intravenous, intraperitoneal, nasal, or intraocular injections, eg, oral, rectal And, via mucosal, nasal or intestinal administration and parenteral delivery.
  • the agent or composition thereof may be administered topically rather than systemically.
  • suitable agents can be delivered via injection or into a targeted drug delivery system such as a storage or sustained release formulation.
  • compositions of the present invention may be prepared without limitation by any of the well known methods, such as conventional mixing, dissolving, granulating, dragee-making, flouring, emulsifying, encapsulating, encapsulating, or lyophilizing processes.
  • the compositions of the present invention may include one or more physiologically acceptable carriers such as excipients and adjuvants.
  • compositions of the present invention may be formulated with physiologically compatible buffers such as aqueous solutions, preferably Hanks' solutions, Ringer's solutions, or saline buffers.
  • physiologically compatible buffers such as aqueous solutions, preferably Hanks' solutions, Ringer's solutions, or saline buffers.
  • penetrants suitable for penetration into the barrier are used in the formulation. Such penetrants are generally well known in the art.
  • the compounds of the invention are prepared in a formulation for oral administration.
  • the compounds of the present invention can be readily formulated by combining with pharmaceutically acceptable carriers known in the art.
  • Such carriers allow the compounds of the invention to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject.
  • the compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas containing, for example, conventional suppository bases such as cocoa butter or other glycerides.
  • Formulations for oral use can be obtained as solid excipients by adding suitable auxiliaries to obtain tablets or dragee cores as needed, followed by optionally grinding the resulting mixture and processing the particulate mixture.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; Cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth rubber, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP) to be.
  • fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol
  • Cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth rubber, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidon
  • disintegrants such as cross-linked polyvinyl pyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate can be added.
  • wetting agents such as sodium dodecyl sulfate, may be included.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions can be used, which optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. It may contain.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize other combinations of active compound doses.
  • Formulations for oral administration include soft, sealed capsules made of gelatin and push-fit capsules made of gelatin as well as plasticizers such as glycerol or sorbitol.
  • Push-fit capsules may contain the active ingredient in admixture with fillers such as lactose, binders such as starch 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 compounds of the present invention can be administered transdermally, or topically, such as through a skin patch.
  • transdermal or topical formulations of the invention may additionally include one or multiple infiltration enhancers or other effectors comprising agents that enhance the transport of the delivered compound. Transdermal or topical administration may be preferred, for example, in situations where location specific delivery is desired.
  • the compounds for use according to the invention may be formulated with a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or any other suitable gas.
  • a suitable propellant for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or any other suitable gas.
  • a suitable dosage unit can be determined by providing a valve for delivering a metered amount.
  • capsules and cartridges of gelatin for use in an inhaler or blower can be formulated. These typically contain a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions prepared for parenteral administration by injection may be presented in unit dose form, eg, in ampoules or in multi-dose containers, with an added preservative.
  • the composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain chemicals such as suspending, stabilizing and / or dispersing agents.
  • Formulations for parenteral administration include aqueous solutions or other compositions in water-soluble form.
  • suspensions of the active compounds can be prepared as appropriate oily injection suspensions.
  • suitable lipophilic solvents or vehicles include fatty oils such as sesame oil and 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 contain suitable stabilizers or agents that increase the solubility of the compounds to enable the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, for example sterile water free of pyrogen.
  • compositions of the present invention may also be formulated as a storage formulation.
  • Such long acting formulations may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be suitable polymers or hydrophobic materials (e.g. as emulsions in acceptable oils) or ion exchange resins, or as very soluble derivatives, for example very soluble salts. It can be prepared as.
  • the effective dose for treatment can be estimated initially using various techniques well known in the art.
  • dosages can be formulated to achieve a circulating concentration range comprising an IC 50 as determined in cell culture in an animal model.
  • Dosage ranges suitable for human subjects can be determined, for example, using data obtained from cell culture assays and other animal studies.
  • An effective dosage for the treatment of a medicament means an amount of a medicament that results in alleviation of symptoms or prolongation of survival in the subject.
  • the toxicity and therapeutic efficacy of such molecules can be determined in standard pharmaceutical procedures by determining, for example, LD 50 (fatal dose up to 50% of the subject) and ED 50 (dose effective at 50% of the subject) in cell culture or experimental animals. Can be determined by.
  • the dose ratio of toxicity to treatment is the therapeutic index, which can be expressed as the ratio of LD 50 / ED 50 . Agents that exhibit high therapeutic indices are preferred.
  • the dose is preferably in the range of circulating concentrations comprising ED 50 which is little or no toxic.
  • the dosage may vary within this range depending upon the type of dosage employed and the route of administration utilized.
  • the exact formulation, route of administration, and dose should be selected according to methods known in the art in view of the nature of the subject's condition.
  • the dosage of the medicament or composition can vary depending on various factors, including the sex, age, weight, severity of pain, mode of administration, and the judgment of the prescribing physician of the subject being treated.
  • Compounds of the present invention or pharmaceutical compositions containing the same can be usefully used for the treatment, alleviation or prevention of diseases associated with abnormal or deregulated kinase activity by inhibiting the activity of various kinds of protein kinases.
  • Flask Compound A-6 (5 g, 21.1 mmol) and 3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl)
  • phenylamide (8.1 g, 42.2 mmol)
  • Pd (PPh 3 ) 4 (1.6 g, 1.69 mmol)
  • LiCl (2 g, 59.1 mmol)
  • 100 ml of ethanol 100 ml of toluene and 1 N Na 2 CO 3 (40 mL) was added and stirred at 90 ° C. for 10 hours. Termination of the reaction was confirmed by TLC.
  • Flask Compound A-13 (2.56 g, 8.53 mmol), 1- (4-fluoro-phenylcarbamoyl) -cyclopropanecarboxylic acid (2.44 g, 11.09 mmol), EDC (2.45 g, 12.80 mol), HOBT (1.5 g, 11.09 mmol) was added and dissolved in 1 L of DMF, followed by stirring at room temperature for 3 hours.
  • c-Met, Aurora and KDR were expressed in insect cells in the following manner, and then purified by chromatography.
  • the eluate was received fractionally while eluting the protein using buffer A containing 500 mM imidazole. Samples were collected from these fractions, and the fractions for the next step were collected after confirming the location of the target protein through SDS-PAGE.
  • the next step was performed gel filtration chromatography (GE healthcare, HiLoad 16/600 Superdex 200 pg) using buffer B (25mM Tris-HCl, 200mM NaCl, 5% glycerol, 2mM DTT, 10mM EDTA, pH 7.5). Samples were collected from each fraction and the fractions were collected after confirming the location of the target protein through SDS-PAGE.
  • buffer B 25mM Tris-HCl, 200mM NaCl, 5% glycerol, 2mM DTT, 10mM EDTA, pH 7.5.
  • Next step was performed ion chromatography (GE healthcare, Resource Q) using buffer C (25mM Tris-HCl, 5% glycerol, 2mM DTT, 1mM EDTA, pH 7.5). At this time, the target protein was eluted without adhering to the ionic resin, and thus the flowthrough was collected. The solution was concentrated to 10 mg / ml and stored at -70 ° C.
  • the buffer was used 50 mM Tris-HCl (pH 7.5), 100 mM NaCl, 2 mM DTT. Samples were collected from each fraction to confirm the location of the target protein through SDS-PAGE, and the fractions were collected to complete purification. After purification, 4 mM ATP and 26 mM MgCl 2 were added at 4 ° C. for autophosphorylation. After the reaction, dialysis was performed with 50 mM Tris-HCl (pH 7.5), 100 mM NaCl, and 2 mM DTT buffer. The solution was concentrated to 1 mg / ml and stored at -70 ° C.
  • the eluate was received fractionally while eluting the protein using buffer A containing 500 mM imidazole. Samples were collected from these fractions, and the fractions for the next step were collected after confirming the location of the target protein through SDS-PAGE.
  • the next step was performed gel filtration chromatography (GE healthcare, HiLoad 26/600 Superdex 200 pg) using buffer B (50mM Tris-HCl, 25mM NaCl, 5% glycerol, 1mM DTT, pH 8.0). Samples were collected from each fraction and the fractions were collected after confirming the location of the target protein through SDS-PAGE. The final 4 mM ATP, 26 mM MgCl 2 was added to this fraction and the autophosphorylation reaction proceeded at 4 ° C. overnight.
  • buffer B 50mM Tris-HCl, 25mM NaCl, 5% glycerol, 1mM DTT, pH 8.0.
  • Phosphorylated samples were dialyzed for 2 to 3 hours using 2 L of buffer C (10 mM HEPES, 10 mM NaCl, 10 mM DTT, pH7.5). This was repeated three times, concentrated to 6.0 mg / ml and stored at -70 ° C.
  • the c-Met protein was overexpressed by gene recombination, followed by enzymatic reaction using purified c-Met enzyme. Specifically, 250 nM biotin-Axl substrate peptide serving as a substrate with 20 nM c-Met enzyme was added to the reaction buffer (15 mM Tris-HCl (pH 7.5), 10 mM MgCl 2 , 5 mM MnCl 2 , 0.01% Tween-). 20, 2 mM DTT) enzyme reaction was carried out. Compounds of the concentration to be tested were treated and reacted at 30 ° C. for 1 hour.
  • the activity was measured using the ELISA method.
  • the absorbance value of the sample that was not treated with the compound was a 100% control group, and the activity of the c-Met inhibitor was evaluated as% of the residual activity of the c-Met enzyme in the sample treated with the compound of the concentration to be tested.
  • the concentration of the compound at which 50% c-Met enzyme activity inhibition occurs compared to the control group was determined as the IC 50 value of the c-Met inhibitor.
  • Aurora A purified after overexpression by gene recombination was used.
  • the compound was used dissolved in 100% DMSO.
  • kinase-glo mix Promega
  • Luminescence was measured using a Fusion-FP (Packard) device.
  • Enzyme inhibitory activity was expressed as a percentage of the measured value in the presence of the sample compound to the measured value in the absence of the test compound, the concentration of the compound inhibiting 50% of the enzyme activity was determined as IC 50 ( ⁇ M) value.
  • E4Y peptide acts as a substrate for the 2.5 nM KDR enzyme in reaction buffer (50 mM Tris-HCl, pH 7.5), 15 mM MgCl 2 , 1 mM MnCl 2 , 0.01% Tween-20, 2 mM DTT Enzymatic reaction was carried out. Compounds of the concentration to be tested were treated and reacted at 30 ° C. for 1 hour. After the enzymatic reaction, the kinase glo mix was added and reacted for 10 minutes at room temperature, and then the luminescence was measured using a Fusion-FP (Packard) instrument. The data was analyzed with the measured RLU values to verify the activity of the KDR inhibitors.
  • reaction buffer 50 mM Tris-HCl, pH 7.5
  • 15 mM MgCl 2 15 mM MgCl 2
  • 1 mM MnCl 2 0.01% Tween-20
  • 2 mM DTT Enzymatic reaction was carried out. Compounds of
  • the RLU value of the sample that was not treated with the compound was a 100% control, and the activity of the KDR inhibitor was evaluated as the percentage of the residual activity of the KDR enzyme in the sample that was treated with the concentration of the compound to be tested. After measuring the KDR enzyme activity remaining at various concentrations of compound treatment, the concentration of the compound at which 50% KDR enzyme activity inhibition occurs compared to the control group was determined as the IC 50 value of the KDR inhibitor.
  • MTS analysis was performed to determine whether the compound prepared above had cancer cell proliferation inhibitory effect through inhibition of extracellular signal-regulated kinase activity (Barltrop, JA et al., (1991) 5- (3-carboxymethoxyphenyl) -2- (4,5-dimethylthiazoly) -3- (4-sulfophenyl) tetrazolium, inner salt (MTS) and related analog of 3- (4,5-dimethylthiazolyl) -2,5, -diphenyltetrazolium bromide (MTT) reducing to purple water soluble formazans as cell-viability indicators.Bioorg.Med.Chem.Lett. 1, 611-4; Cory, AH et al (1991) Use of an aqueous soluble tertrazolium / formazan assay for cell growth assays in culture. Comm. 3, 207-12.).
  • MKN45 cell line and colon cancer cell line HCT-116 cell line were dispensed at concentrations of 5,000 cells / well in 96-well plates containing RPMI-1640 medium (GIBCO, Invitrogen) containing 10% FBS, respectively, at 5% CO 2 and 37 ° C. Incubated for 24 hours at. Thereafter, each well was treated with the compounds prepared in Example 3 at concentrations of 0.2, 1, 5, 25 and 100 ⁇ M, respectively, and 0.08% by weight of the same dimethylsulfoxide (DMSO) as the control group. Treated at a concentration of Each cell was then incubated for 48 hours.
  • DMSO dimethylsulfoxide
  • A ⁇ 50 nM
  • B 50 nM to 200 nM
  • C 200 nM to 1 ⁇ M
  • D > 1 ⁇ M
  • E ⁇ 0.5 ⁇ M
  • F 0.5 ⁇ M to 1 ⁇ M
  • G 1 ⁇ M to 5 ⁇
  • H > 5 ⁇ .
  • the compounds of the present invention exhibit excellent kinase inhibitory activity not only against kinase enzymes such as c-Met, VEGFR-2 and Aurora A, but also against gastric and colorectal cancer cell lines. It has been found that it can be usefully used for the treatment, alleviation or prevention of diseases or symptoms associated with modulated kinase activity, such as various types of cancer.

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Abstract

La présente invention concerne une composition pharmaceutique pour le traitement, le soulagement ou la prévention de maladies associées à une activité kinase anormale ou déréglée, la composition comprenant un composé représenté par la formule chimique 1 et son sel, hydrate, promédicament ou solvat pharmaceutiquement acceptable. Le composé et la composition de la présente invention inhibent divers types d'activité de protéines kinases, et peuvent donc être utilisés de façon avantageuse dans le traitement, le soulagement ou la prévention de maladies associées à une activité kinase anormale ou déréglée.
PCT/KR2011/007370 2010-10-05 2011-10-05 Dérivé 2,3-dihydro-isoindol-1-one et composition le comprenant WO2012047017A2 (fr)

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