WO2003006060A1 - Inhibiteurs de la liaison au domaine sh3 - Google Patents

Inhibiteurs de la liaison au domaine sh3 Download PDF

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Publication number
WO2003006060A1
WO2003006060A1 PCT/JP2002/003932 JP0203932W WO03006060A1 WO 2003006060 A1 WO2003006060 A1 WO 2003006060A1 JP 0203932 W JP0203932 W JP 0203932W WO 03006060 A1 WO03006060 A1 WO 03006060A1
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Prior art keywords
substituted
compound
acceptable salt
pharmacologically acceptable
domain binding
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PCT/JP2002/003932
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English (en)
Japanese (ja)
Inventor
Sreenath V. Sharma
Chitose Oneyama
Hirofumi Nakano
Tsutomu Agatsuma
Yutaka Kanda
Noriko Tsumagari
Katsuhiko Ando
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Kyowa Hakko Kogyo Co., Ltd.
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Priority to JP2003511866A priority Critical patent/JPWO2003006060A1/ja
Priority to US10/483,439 priority patent/US20050069999A1/en
Publication of WO2003006060A1 publication Critical patent/WO2003006060A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an SH3 domain binding inhibitor containing a non-peptide compound or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention also relates to compounds useful as SH3 domain binding inhibitors.
  • Various receptors exist on the cell membrane and are activated in response to extracellular stimuli to transmit their signals into cells.
  • Various signal molecules gather on the cytoplasmic side of the receptor to form a complex. Depending on the type of stimulus, each signal molecule elicits a different physiological effect.
  • the domain structure plays an important role in the formation of signal molecule complexes.
  • the Src homology domain 3 was discovered as a region of high homology between the Src family — a domain consisting of approximately 60 amino acids, located in various proteins, and containing a proline-containing sequence (proline-rich).
  • proline-rich a proline-containing sequence
  • Known proteins having a proline-rich sequence include HIV-1Nef, p22-phox, p47-phox, Sam68, Sosl, Zol, Dynamic c-Cbl and the like [for example, EMBO J., 14 vol.
  • Proteins having an SH3 domain have been found in, for example, all eukaryotes, viruses such as HIV, and the like, and are considered to have universal functions.
  • Frc which is a Src family kinase, Ras-GAP, PLC, PI3K, Abl, Btk, Lyn, Hck, Fgr, Proteins with enzyme activity such as Yes, adapter proteins without enzyme activity such as Grb2, Neks Vav, etc., p40-phox, p47-phox, p67-phox, etc. which are components of the NADPH oxidase complex [Proceding Prop. Natl. Acad. Sci. USA, Vol. 91, p. 10650 (1994) It is known that Txk, Tec, Tsk, Crk, Cortactin and the like have an SH3 domain. It is thought that protein-protein binding via the SH3 domain plays a role in forming a protein complex through an interaction with an appropriate affinity.
  • SH3 domain binding inhibitors Protein-protein binding via the SH3 domain exists between signal molecules that are thought to be a cause in various diseases such as cancer, AIDS (acquired immune deficiency syndrome), allergy, etc. [Biopolymer. 383 pages (1997)]. This suggests that SH3 domain binding inhibitors that inhibit protein-protein binding via the SH3 domain (SH3 domain binding inhibitory activity) are considered to be effective as therapeutic agents for these diseases, such as in vivo carcinogenesis. It can be used for many applications including the regulation of disease-causing proteins that involve E. coli.
  • the SH3 domain binding inhibitors reported so far have been peptides or peptide compounds based on hydrophobic amino acids such as proline with a molecular weight of 750 or more.
  • Peptides or peptidic compounds, for example generally have poor blood stability, poor oral absorption, high molecular weight and are not easily incorporated into cells, and are easy to manufacture due to their complex structure However, it is costly, and it has many difficulties to use it as a therapeutic agent for diseases associated with SH3 domain binding.
  • UCS15A (Luminacin C2 / SP4228A) is published in The Journal of Antibiotics, 53, 579 (2000), No. 58-116686, and No. 63-22583. No. 61-293920, No. 62-294619, No. 63-48213, No. 8-268888, Bone resorption inhibitory action, bactericidal action, immunosuppressive action, anti-trichophyton action, anti-tumor It is described as an active compound.
  • Cytochalasins cytochalasin
  • oral sericaracin Rossellichalasiii
  • epoxy cytochalasin epoxycytochalasii ⁇ , force etoglobosin, chanoglobosin, penochalasin, and blood vessels such as aspochalasin
  • Biological activities such as an inhibitory effect on renewal (WO98 / 41205) are known.
  • the present invention relates to the following [1] to [ 51 ].
  • An SH3 domain binding inhibitor comprising, as an active ingredient, a non-peptide compound having SH3 domain binding inhibitory activity or a pharmacologically acceptable salt thereof.
  • R 3 ⁇ R 3b and R 4 are the same or different, and each represents a hydrogen atom, hydroxy, carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, or substituted or unsubstituted lower alkoxy.
  • R 3a and R 3b together represent an oxygen atom;
  • R 23 and R 2b are the same or different and are a hydrogen atom, substituted or unsubstituted lower alkyl or substituted or unsubstituted
  • R 5a and R 5a are the same or different and are independently a hydrogen atom, hydroxy, carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkenyl, substituted or Unsubstituted lower alkanoyloxy, substituted or unsubstituted lower alkenyloxy or substituted Or an unsubstituted lower arylaminocarbonylcarbonyl, or R 5a is taken together to represent an oxygen atom, and X represents an oxygen atom or —CH 2 —.
  • R 6 represents a hydrogen atom, substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkenyl
  • R 7 and R 9 are the same or different and represent a hydrogen atom, formyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower Al Kanoiru or substituted or unsubstituted Ararukiru
  • R 11 are the same One or different, a hydrogen atom, a halogen, a hydroxy Doxy, a carboxy, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkoxy, a substituted or unsubstituted lower alkanol, formyl, cyano, nitro, amino, mono- or di-lower Arukiruamino, a compound represented by the representative) a substituted or unsubstituted lower aralkyl force Noiruamino or substitution or
  • a non-peptidic compound having SH3 domain binding inhibitory activity is represented by the general formula (Ilia)
  • R 12a represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl
  • Q 1 represents a single bond or an oxygen atom
  • represents a single bond.
  • Q 2 represents —C (OH) (CH 3 ) — when the two represent a single bond.
  • X is an oxygen atom
  • RR 4 and 1 ⁇ ⁇ are hydrogen atoms
  • R 1 and R 3b are the same or different, and are hydroxy, carboxy, substituted or unsubstituted lower alkoxy or substituted or unsubstituted A lower alkanoyloxy
  • R 2b is a substituted or unsubstituted lower alkyl
  • R 5a is a group represented by the general formula (IV)
  • R 5 represents substituted or unsubstituted lower alkyl
  • R 5d and R 5 are the same or different and represent a hydrogen atom, hydroxy or substituted or unsubstituted lower alkoxy, or R 5 5d and R 5e represents together a connexion oxygen atom
  • Nini represents a single bond or a double bond
  • R 3A and R 3B are the same or different and each represent a hydrogen atom, hydroxy, hydroxyl, substituted or unsubstituted lower alkoxy or substituted or unsubstituted lower alkanoyloxy, or R 3A And R 3B together represent an oxygen atom, represents a substituted or unsubstituted lower alkyl, and R 5e , R 5d , R 5e , R 5f , RR 5i and R 5j are as defined above.
  • R 5G is formyl and R 3A or R 3A
  • R 3B is a hydrogen atom
  • the other of R 3A or R 3B is not hydroxy] or a pharmacologically acceptable salt thereof.
  • a medicament comprising the compound of the above-mentioned [9] or [10] or a pharmacologically acceptable salt thereof as an active ingredient.
  • a medicament comprising the compound of the above-mentioned [11] or a pharmacologically acceptable salt thereof as an active ingredient.
  • An SH3 domain binding inhibitor comprising, as an active ingredient, the compound according to the above [9] or [10] or a pharmacologically acceptable salt thereof.
  • An SH3 domain binding inhibitor comprising the compound of the above-mentioned [11] or a pharmacologically acceptable salt thereof as an active ingredient.
  • virus-derived protein is a protein derived from a retrovirus, a hepatitis virus or a virus.
  • Proteins having an SH3 domain are Src, Yes, Fg Hck, Lck ⁇ Abl, Fyn, Lyn, Blks Yrk, Ras-GAP, PLC 7 s PI3K :, Tec, Txk / Rlk ⁇ Tsk / Emt / Itk, Btk, Crk, Grb2, Neks Vav, STAT, Cortactin, p40-phox, p67-phox, p47-phox ⁇
  • TCR signal molecule TCRsm
  • SH3 domain binding inhibitor The TCR signal molecule (TCRsm) or the ⁇ 2R? SH3 domain binding inhibitor.
  • the binding of the protein having the SH3 domain to the protein having the proline rich sequence is Grb2 and Sosl, Fyn and Sam68, Src and Sam68, PLC and Sam68, Grb2 and Sam68, Lyn and HIV-lNef ⁇ Hck and HIV -lNef ⁇ TCRsm and HIV-lNef ⁇ p47-phox and p22-phox ⁇ 67-phox and p47-phox, Lyn and Dynamii Cortactin and Z01, Lyn and c-Cbl, IL-2R /?
  • the binding between the protein having the SH3 domain and the protein having the proline-rich sequence is Grb2 and Sosl, Fyn and Sam68, Src and Sam68, PLC and Sam68, Grb2 and Sam68, Lyn and HIV-lNef or Cortactin and ZOl.
  • ⁇ dUZd ⁇ used in the production of the compound according to [9] or [10] above, is a filamentous fungus (jylariaks filamentous fungus) MPC1005 (Accession number: FERM BP-7980), Aspergillus species ( A microorganism selected from the group consisting of MPC1006 (Accession number: FERM BP-7899) and Aspergillus sp. ( ⁇ "s sp.) MPC1009 (Accession number: FERM BP-7900).
  • MPC1005 jylariaks filamentous fungus
  • Aspergillus species A microorganism selected from the group consisting of MPC1006 (Accession number: FERM BP-7899) and Aspergillus sp. ( ⁇ "s sp.) MPC1009 (Accession number: FERM BP-7900).
  • An antitumor agent comprising the compound of the above-mentioned [9] or [10] or a pharmacologically acceptable salt thereof as an active ingredient.
  • An antitumor agent comprising the compound of the above-mentioned [11] or a pharmacologically acceptable salt thereof as an active ingredient.
  • a therapeutic agent for allergic diseases comprising as an active ingredient the compound according to the above [9] or [10] or a pharmacologically acceptable salt thereof.
  • a therapeutic agent for allergic diseases comprising the compound of the above-mentioned [11] or a pharmacologically acceptable salt thereof as an active ingredient.
  • a therapeutic agent for a viral disease comprising as an active ingredient the compound according to [ 9 ] or [10] or a pharmacologically acceptable salt thereof.
  • a therapeutic agent for a viral disease comprising the compound of the above-mentioned [11] or a pharmacologically acceptable salt thereof as an active ingredient.
  • An AIDS therapeutic agent comprising the compound of the above-mentioned [9] or [10] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • An AIDS therapeutic agent comprising the compound of the above-mentioned [11] or a pharmacologically acceptable salt thereof as an active ingredient.
  • [42] treatment of various diseases involving SH3 domain binding characterized by administering an effective amount of the compound according to [9] or [10] or a pharmacologically acceptable salt thereof, or Z or Prevention methods.
  • a method for treating and / or preventing or treating various diseases involving SH3 domain binding which comprises administering an effective amount of the compound according to the above [11] or a pharmacologically acceptable salt thereof.
  • a method for treating a malignant tumor which comprises administering an effective amount of the compound of the above-mentioned [9] or [10] or a pharmacologically acceptable salt thereof.
  • a method for treating a malignant tumor which comprises administering an effective amount of the compound of the above-mentioned [11] or a pharmacologically acceptable salt thereof.
  • a method for treating and preventing or preventing allergic diseases which comprises administering an effective amount of the compound according to [11] or a pharmacologically acceptable salt thereof.
  • a method for treating a viral disease which comprises administering an effective amount of the compound according to the above [9] or [10] or a physiologically acceptable salt thereof.
  • a method for treating a viral disease which comprises administering an effective amount of the compound of the above-mentioned [11] or a pharmacologically acceptable salt thereof.
  • a method for treating AIDS which comprises administering an effective amount of the compound of the above-mentioned [9] or [10] or a pharmacologically acceptable salt thereof.
  • a method for treating AIDS which comprises administering an effective amount of the compound of the above-mentioned [11] or a pharmacologically acceptable salt thereof.
  • a method for treating AIDS which comprises administering an effective amount of a compound having SH3 domain binding inhibitory activity or a pharmacologically acceptable salt thereof.
  • a method for treating a viral disease which comprises administering an effective amount of a compound having SH3 domain binding inhibitory activity or a pharmacologically acceptable salt thereof.
  • An AIDS therapeutic agent comprising a compound having SH3 domain binding inhibitory activity or a pharmacologically acceptable salt thereof as an active ingredient.
  • a therapeutic agent for a viral disease comprising as an active ingredient a compound having SH3 domain binding inhibitory activity or a pharmacologically acceptable salt thereof.
  • Lower alkyl, and lower alkyl of lower alkoxy, lower alkoxycarbonyl, lower alkoxymethyl, lower alkylamino and mono- or di-lower alkylamino include, for example, straight-chain or branched alkyl having 1 to 8 carbon atoms, Specifically, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and the like, or a cyclic alkyl having 3 to 8 carbon atoms, Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • the lower alkenyl includes, for example, a straight-chain or branched alkenyl having 2 to 8 carbon atoms, specifically, vinyl, aryl, 1-propenyl, methacrylyl, crotyl,
  • 1,3-butene genil, 1,3-pentene genil, 2,4-pentene genil, 1,5-dimethyl-1,4-hexagenyl, 1,3,5-hexatrienyl, etc. can give.
  • the lower alkanoyl, and the lower alkanoyloxy, lower alkanoyloxymethyl, lower alkanoylmethyl, lower alkanoylamino and lower alkanoylaminocarbonyl portions of the lower alkanoyl moiety include, for example, linear or branched Examples include branched alkanols having 2 to 8 carbon atoms, specifically, acetyl, propionyl, butyryl, isoptyryl, valeryl, isoparryl, piperoyl, hexanoyl, heptanoyl, and oxylnoyl.
  • aryl, arylaryl, arylsulfonylamino and aryloxy aryl include, for example, aryl having 6 to 14 carbon atoms, specifically, phenyl, naphthyl, anthryl and the like.
  • the aralkyl and the aralkyl moiety of the aralkyloxy include, for example, aralkyl having 7 to 15 carbon atoms, specifically, benzyl, phenethyl, and benzhydr. Lil, naphthylmethyl and the like.
  • the heteroaryl includes, for example, a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or a nitrogen atom
  • a bicyclic or tricyclic condensed aromatic heterocyclic group containing at least one heteroatom selected from the group consisting of an oxygen atom and a sulfur atom and having a fused 3- to 8-membered ring.
  • Halogen represents each atom of fluorine, chlorine, bromine and iodine.
  • the lower alkenyl part of the lower alkenyloxy has the same meaning as the lower alkenyl (2).
  • the substituents in the substituted aryl, the substituted aryloxy, the substituted arylamino, the substituted arylsulfonylamino, the substituted aralkyl and the substituted aralkyloxy are the same or different, for example, the number of substitutions:! To 5, hydroxy, halogen, formyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, lower alkanol and the like.
  • the substitution position is not particularly limited.
  • the lower alkyl moiety and the lower alkanoyl of the halogen, lower alkyl and lower alkoxy shown herein are respectively the same as the halogen (7) 7the lower alkyl (1) and the lower alkanoyl (3), and are substituted lower alkyl.
  • the substituent of the lower alkoxy includes, for example, hydroxy or lower alkoxy having 1 to 3 substituents [the lower alkyl portion of the lower alkoxy is the same as the lower alkyl (1)], a halogen [the halogen is the halogen It is the same as (7)].
  • the substitution position is not particularly limited.
  • the lower alkanol portion of the lower alkanol and lower alkenyl group, the lower alkyl portion of the lower alkyl and lower alkoxy group, and the aryl portion of the aryl and alkyl groups described herein are respectively the lower alkyl group. It is synonymous with the power nozzle (3), the lower alkyl (1), and the aryl (4).
  • the substituents on the substituted aryl and the substituted aryl have the same meanings as the substituents on the substituted aryl (9), and the substituents on the substituted lower alkanoyl and the substituted lower alkanol include the number of substituents 1 Examples of the above include hydroxy, lower alkoxy [the lower alkyl part of the lower alkoxy is the same as the lower alkyl (1)], halogen [the halogen is the same as the halogen (7)], and the like.
  • cytochalasins for example, cytochalasin (cytochalasin), oral serichalasin (Rosdlichalasit ⁇ , epoxycytochalasin), force etoglobosin (chaetoglobosin), penocalasin, and aspochalasin. can give.
  • SH3 domain binding inhibition refers to inhibition of protein-protein binding via the SH3 domain.
  • SH3 domain binding may be, for example, any binding between a protein having an SH3 domain and a protein having a proline-rich sequence, for example, SH3 domain. And a protein having a proline rich sequence and / or a protein derived from a virus.
  • proteins derived from the virus include proteins derived from retroviruses such as human immunodeficiency virus-1 (HIV-1) and human T lymphocyte virus-1 (HTLV-1), and Derberian hepatitis virus (HDV).
  • HIV-1 human immunodeficiency virus-1
  • HTLV-1 human T lymphocyte virus-1
  • HDV Derberian hepatitis virus
  • NDV Newcastle disease virus
  • HBV-2 simple herpes virus 1-2
  • EBV EB virus
  • H. mori herpes virus H. saimiri
  • Atererher's virus H. fltefe
  • proteins derived from a herpes virus include Src, a non-receptor tyrosine kinase Src family protein, and Yes ⁇ Fgr ⁇ Hck ⁇ Lck ⁇ Abl ⁇ Fyn.
  • Ras-GAP ras-GTPase-activating
  • enzymatic activity such as (fgr / yes-related novel eene Lyn (lgr / yes-related novel gene, Blk (B-cell lymphocyte kinase) s Yrk, es-related kinase)) protein
  • PLC PLC
  • Tec Txk / Rlk, Tsk / Emt / Itks Btk, a protein of the Tec family of non-receptor-type oral synkinases such as (phospholipase C-gamma) ⁇ PI3K (phosphatidylinositol 3-kinase)
  • a transcription factor such as Crk (CT-10bregulated), Grb2 (growth factor receptor -bound protein 2), Nck, and Vav, which are adapter proteins such as (Bruton's tyrosine kinase)
  • T cell receptor such as p40-phox, p67-phox, p47-phox, etc.
  • TCRsm [Current 'Biology-(Curr. Biol.), Vol. 11, p. 1294 (2001)], etc., the IL-2R (interleukin-2 receptor) chain or chain [Journal of Biology (J. Virol.), Vol. 74, p. 9828
  • Proteins having a proline-rich sequence include, for example, p22 which is a component of HIV-lNe, a NefT 'involved in virus infection and / or proliferation, and replication of HIV-1 and a complex of NADPH-oxynase. -Phox, p47-phox, etc.
  • cytoskeleton such as Sosl (son of sevenless) which is an adapter protein, Dynamic c-Cbl (casitas B-lineage lymphoma) HTLV-1 pX ORF I (open reading frame I of the pX regione) related to the persistence of virus infection, etc.
  • Sosl son of sevenless
  • Dynamic c-Cbl casitas B-lineage lymphoma
  • HTLV-1 pX ORF I open reading frame I of the pX regione
  • Examples of the binding between a protein having an SH3 domain and a protein having a proline rich sequence include, for example, Fyn and Sam68 [Journal of Biologic 'Chemistry (J. Biol. Chem.), 272, 6214 (1997). ], Src and Sam68 [Molecular Cell Biology (Mol. Cell Biol.), Vol. 15, 186 (1995)], Grb2 and Sosl [Nature, 363, 83 (1993) )], PLC J and Sam68 [Oncogene, 18 volumes, 4647 pages (1999)], Grb2 and Sam68 [Molecular and Cellular Biology (Mol. Cell. Biol), 15, 186 ( 1995)], Lyn and HIV-lNef or Hck and HIV-lNef [EMBO. J., 14, 484 (1995), Virology, 262, 55 (1999)], TCRsm and HIV-lNef [Curr. Biol., Vol. 11, 1294 (2001)], p47-phox and p22-pho
  • Non-peptide compounds include, for example, pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Pharmaceutically acceptable acid addition salts of non-peptide compounds include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, maleate, fumarate, and citrate
  • examples of the pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, and the like.
  • Aluminum salts, zinc salts, etc. are listed.
  • Pharmacologically acceptable ammonium salts include ammonium and tetramethylammonium.
  • Pharmacologically acceptable organic amine addition salts include morpholine, piperidine and the like; pharmacologically acceptable amino acid addition salts include Addition salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid and the like can be mentioned.
  • the non-peptide compound used in the present invention can be produced, for example, by a series of reactions shown below.
  • compound (VI) can be produced by the following series of reaction steps.
  • the compound (Via) wherein R 5G is hydroxymethyl can be produced from the compound (VII) by the following reaction steps.
  • R, R 3A , R 3B , R 5e , R 5d , R 5e , R 5f , R, R 5i and R 5j have the same meanings as described above, respectively.
  • Compound (Via) can be obtained by treating compound (VII) with a reducing agent in an inert solvent.
  • Examples of the reducing agent include sodium borohydride, lithium aluminum hydride, diisobutyl aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and the like. 1 to: 10 equivalents are used.
  • inert solvent examples include methanol, ethanol, chloroform, dichloromethane, tetrahydrofuran (THF), dimethyl ether, toluene, and dimethylformamide (DMF).
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, and is usually completed in 1 minute to 24 hours.
  • the compound (VIb) in which R 5G is a substituted or unsubstituted lower alkoxymethyl or a substituted or unsubstituted lower alkanoyloxymethyl is obtained from the compound (Via) obtained in Step 1 It can be produced by the following reaction steps.
  • R, R 3A , R 3B , R 5cs R 5d , R 5es R 5f , R, R 5i and R 5j each have the same meaning as described above, and R is a substituted or unsubstituted lower.
  • Alkyl [wherein the lower alkyl has the same meaning as the lower alkyl (1), and the substituent of the substituted lower alkyl has the same meaning as the substituent (10) of the substituted lower alkyl] or a substituted or unsubstituted lower alkyl
  • Canoyl [the lower alkanoyl has the same meaning as the lower alkanoyl (3), and the substituent of the substituted lower alkenyl has the same meaning as the substituent (10) of the substituted lower alkenyl].
  • the compound (VIb) is the same as the compound (Via) obtained in the step 1:! To 20 equivalents of R—Z (wherein R is as defined above, and Z represents each atom of chlorine, bromine, or iodine) ) In an inert solvent in the presence of a base.
  • R—Z wherein R is as defined above, and Z represents each atom of chlorine, bromine, or iodine
  • R—Z represents each atom of chlorine, bromine, or iodine
  • Examples of the base include pyridine, triethylamine, potassium carbonate, cesium carbonate, sodium hydride and the like, and the base is used in an amount of 1 to 50 equivalents to compound (Via) or as a solvent.
  • inert solvent examples include chloroform, dichloromethane, acetone, dimethyl ether, acetonitrile, and THF ⁇ DMF ⁇ ⁇ ⁇ .
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, and is usually completed in 5 minutes to 24 hours.
  • Examples of the base include pyridine, triethylamine and the like, and the base is used in an amount of 1 to 20 equivalents based on compound (VII).
  • Inert solvents include, for example, chloroform, dichloromethane, acetone, methyl ether, acetonitrile, THF, DMF ⁇ .
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, and is usually completed in 5 minutes to 24 hours.
  • the starting material (VII) in this production method 1 is, for example, the Journal of Antibiotics, Vol. 53, p. 579 (2000), or It can be obtained according to the method described in Japanese Unexamined Utility Model Publication No. 58-116686, or according to them.
  • Manufacturing method 2 is, for example, the Journal of Antibiotics, Vol. 53, p. 579 (2000), or It can be obtained according to the method described in Japanese Unexamined Utility Model Publication No. 58-116686, or according to them.
  • Compound (II) can be produced, for example, from compound (VIII) by the following method.
  • the acid examples include organic acids such as formic acid, acetic acid, and trifluoroacetic acid; inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; and Lewis acids such as titanium tetrachloride and boron trifluoride etherate. Among them, boron trifluoride etherate is more preferably used.
  • the acid is used in an amount of 1 to 100 equivalents based on compound (VIII) or as a solvent.
  • Inert solvents include, for example, chloroform, dichloromethane, THF, DMF ⁇ .
  • the reaction is carried out at a temperature between -30 ° C and the boiling point of the solvent used, and is usually completed in 1 minute to 24 hours.
  • the starting compound (VIII) can be used as a commercially available product or as described in the journal “Ob” American Chemical Chemical Society (J. Am. Chem. Soc.), Vol. 122, p. 3071 (2000). Or it can be obtained according to it.
  • Compound (lib) is prepared by treating compound (Ila) obtained in Step 1 of Production Method 2 with 1 to 20 equivalents of RZ (R and Z are as defined above) in an inert solvent in the presence of a base. It can be obtained by reacting.
  • Examples of the base include pyridine, triethylamine, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydride and the like, and the base is used in an amount of 1 to 5 equivalents to compound (Ila).
  • inert solvent examples include chloroform, dichloromethane, acetone, methyl ether, acetonitrile, and THF ⁇ DMF ⁇ .
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, and is usually completed in 5 minutes to 24 hours.
  • Compound (I) can be prepared, for example, according to the method described in the above-mentioned Production method 1, Journal of America, Chemical Society (Am. Chem. Soc.), Vol. 107, page 256 (1985), Vol. 2549 (1972), etc., The Journal of Antibiotics, 53, 579 (2000), JP-A-58-116686, etc. Method or according to them.
  • compound (Va) and compound (Vb) cytochalasin derivative
  • Production method 5 Production method 5:
  • the cytochalasin derivative is produced by culturing a microorganism having a cytochalasin derivative-producing ability in a medium, producing and accumulating the cytochalasin derivative in the culture, and collecting the cytochalasin derivative from the culture.
  • any strain can be used as long as it is a strain having a cytochalasin derivative-producing ability.
  • Mutants obtained by mutating these strains by an artificial mutation method for example, ultraviolet irradiation, 'X-ray irradiation, treatment with a mutagen, etc. Any of these can be used in the present invention.
  • an ordinary method for culturing a filamentous fungus is applied.
  • the medium any of a synthetic medium and a natural medium can be used as long as the medium contains a carbon source, a nitrogen source, an inorganic substance, etc. which can be assimilated by microorganisms.
  • -Carbon sources include glucose, starch, dextrin, mannose, fructo Sucrose, lactose, xylose, arabinose, mannitol, molasses and the like are used alone or in combination.
  • hydrocarbons, alcohols, organic acids, etc. are used depending on the assimilation ability of the bacteria.
  • ammonium chloride, ammonium nitrate, ammonium sulfate, sodium nitrate, urea, peptone, meat extract, yeast extract, dried yeast, corn-steep liquor, soybean powder, casamino acid, etc. are used alone or in combination.
  • Inorganic salts can also be added.
  • trace components that promote the growth of the bacteria used and the production of cytochalasin derivatives can be appropriately added.
  • a liquid culture method particularly a submerged stirring culture method, is suitable.
  • the cultivation is carried out at a temperature of 16 to 37 ° C, preferably 25 to 32 ° C, at pH 4 to 10, preferably at pH 6 to 8.
  • aqueous ammonia or ammonium carbonate solution or the like is used. Used. Culture is usually completed in 1 to 10 days, but it is preferable to stop the culture when the cytochalasin derivative is produced and accumulated in the culture solution and in the cells, and the amount of production in the culture reaches the maximum.
  • Isolation and purification of the cytochalasin derivative accumulated in the culture from the culture are performed according to a method commonly used for isolating and purifying ordinary microbial metabolites from the culture.
  • the culture is separated into a culture filtrate and cells by filtration, and the cell components are extracted from the cells with a solvent such as black form, acetone, and methanol.
  • the extract and the culture filtrate are combined and passed through a polystyrene-based adsorbent, for example, Diaion HP-20 (manufactured by Ryishi Chemical Co., Ltd.), to adsorb the active components, and then, methanol, acetone, or the like is used. Elute.
  • cytolasin derivative is obtained by column chromatography using octyl decyl group-bonded silica gel (ODS), high-performance liquid chromatography, column chromatography using silica gel, or the like.
  • ODS octyl decyl group-bonded silica gel
  • the detection of cytochalasin derivatives during the culturing, isolation, and purification procedures was performed by thin-layer chromatography. It can be carried out by using an Eod reagent.
  • the present inventors have proposed that as a strain having cytochalasin derivative-producing ability, MPC1006 and MPC1009, newly isolated from soil and belonging to Aspergillus sp. 'C43 ⁇ 4erg Zi «sp.), Have cytochalasin having SH3 binding inhibitory action. Found to produce derivatives.
  • the representative strain MPC1006 producing the compound of the present invention was isolated from soil and has the following bacteriological properties.
  • the diameter of the colonies reaches 38-39 mm on day 7 of culture and 65-68 mm on day 11 of culture.
  • the center of the surface of the colony on day 11 of culture has a very pale reddish yellow color, and the outside has a very pale yellow color.
  • the center of the back of the settlement is light red-yellow at the center and extremely light yellow at the outside.
  • the diameter of the colonies reaches 38 to 40 mm on day 7 of culture and 46 to 48 mm on day 11 of culture.
  • the center of the surface of the colony is light grayish yellow, and the outside is very pale yellow. It is white in some places.
  • the center of the back of the settlement has a dull yellow color, and the outside has a pale yellow color.
  • the growth temperature range of this fungus is 11.5-34 ° C, and it grows best around 28.5 ° C.
  • the growth pH ranges from 3.5 to 11.5 and grows best around pH 7.5.
  • the following shows the results of observation of this bacterium with a light microscope when cultured on a malt extract agar medium at 25 ° C for 7 days.
  • Hyphae have partitions, 1.0-3.0 m wide, smooth, colorless, and well-branched.
  • the conidiophore has no bulkhead, 3.5-5.0 m wide, 420-700 ⁇ ⁇ , smooth, colorless and does not branch.
  • the tip of the conidiophore bulges round and forms a cap. Its diameter is 12. 5 25.0 Zm, the entire surface metulae are formed, the length of metulae is 5.5 ⁇ 8.0 ⁇ M.
  • a thin, thick-eared phialide conidia-forming cell
  • conidium is formed from fiaraid into endogenous budding type and fibular type and linked.
  • the filamentous conidium is unicellular, pale yellowish green, spherical to subspherical in shape, and its surface is smooth and 1.5 to 3.0 m in diameter. In this strain, only the anamorph described above is observed, and no teleomorph is observed.
  • strain MPC-1009 producing the compound of the present invention was also isolated from the soil, and has the following bacteriological properties.
  • the diameter of colonies reaches 18 to 25 mm on day 4 of culture and 37 to 48 mm on day 11 of culture.
  • the center of the surface of the colony has a very pale yellow color, and the outside has a yellowish white color.
  • the back of the settlement is light grayish yellow.
  • the diameter of colonies reaches 17-18 mm on the fourth day of culture and 27-31 mm on the 11th day of culture.
  • the center of the colony on the 11th day of culture has a bright gray-yellow surface and a yellowish white outside.
  • the center of the back of the settlement has a light grayish yellow at the center and a very pale yellow outside.
  • the growth temperature range of this fungus is 13.0-34.5 ° C, and it grows best around 27.5 ° C. Growth
  • the pH ranges from 3.5 to 11.2 and grows best around pH 7.3.
  • the following shows the observation results of this bacterium with an optical microscope when cultured at 25 ° C for 2 weeks on a malt extract agar medium.
  • Hyphae have septum, width of 1.5-2.5 m, smooth, colorless and well-branched.
  • the conidiophore has no partition, 3.0-5.0 / m wide, 300-350 ⁇ m long, smooth, colorless, and does not branch.
  • the tip of the conidiophore bulges round and forms a cap. Its diameter is from 15.0 to 17.5 m, and thin, thick-eared phialides (conidiogenesis cells) are formed on the entire surface.
  • the length of the phiaride is 10.0-11.5 / m. No metres are formed, and the conidia are formed from phialides in an endogenous budding type and a phial type and linked.
  • This Firo-type conidium is unicellular, light green, spherical or subspherical in shape, its surface is smooth, and its diameter is 2.0 to 3.0 m. In this strain, only the anamorph described above is observed, and teleomorph is not observed.
  • the taxonomic position of the bacterium was determined by The Genera of Fungi Sporulating in Pure Culture, 2nd ed. 2nd ed., Cramer, Vanduz, JA von Arx, 197)), and it was revealed that the thick bacilli eventually belonged to ⁇ ) a filamentous infectious bacterium, Aspergillus sp. Was.
  • the present inventors have named these strains as “Aspergillus sp. MPC1006” and “Aspergillus sp.
  • strain MPC1005 producing the compound of the present invention was also isolated from soil, and its bacteriological properties are as follows.
  • the growth temperature range of this fungus is 13.3-38.6 ° C, and it grows best around 33.0 ° C. Growth The pH ranges from 3.7 to 9.4 and grows best around pH 7.2.
  • Hyphae have septum, width 0.5-3.0 m, smooth, colorless, sometimes colored and well-branched.
  • the cells were cultured at 25 ° C for 2 months or more. In this generation, neither anamorph nor teleomorph was observed.
  • the partial nucleotide sequence (1228 bp) of the 18S ribosomal DNA (18S rDNA) of this bacterium had the nucleotide sequence represented by SEQ ID NO: 1.
  • this bacterium Black-spotted mushroom, Nippon-yaki orchid MPC1005 (Xylariales filamentous fungus MPC1005)”, and received the accession number FERM BP-7980 (Original deposit date: March 2002) 26th) Deposited at the National Institute of Advanced Industrial Science and Technology (AIST) Patent Depositary Center (1-1 Tsukuba East, Ibaraki Prefecture, Japan, 1 Chuo No. 6)
  • the intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographies, etc. can do.
  • the intermediate can be subjected to the next reaction without particular purification.
  • Compound (I), (II), (Ilia), (Illb), (Va), (Vb) or (VI) may have stereoisomers such as geometric isomers and optical isomers However, all the possible isomers and mixtures thereof, including these, are also included in these compounds, and the non-peptidic conjugates used in the present invention, compounds (1), (11), (Ilia ), (IIIb), (Va), (Vb) or (VI), the non-peptidic compound used in the present invention, compound (I), ( ⁇ ), (Ilia), When (Illb), (Va), (Vb) or (VI) is obtained in the form of a salt, it may be purified as it is, and when it is obtained in the free form, the non-peptide compound used in the present invention may be used.
  • (Illb), (Va), (Vb) or (VI) may be dissolved or suspended in an appropriate solvent, and then isolated or purified by adding an acid or a base.
  • non-peptide compound used in the present invention compound (I), (II), (Ilia), (Illb), (Va), (Vb) or (VI) and its pharmacologically acceptable
  • the salt may be present in the form of an adduct with water or various solvents, and these adducts are also included in the above-mentioned conjugate or a pharmaceutically acceptable salt thereof.
  • the compounds shown in the above Tables 1 to 3 are also used, and specific examples of the compounds used in the present invention include compounds (I), ( ⁇ ), (Ilia) and (Ilia). Illb) is shown in Tables 4-7.
  • Test example 1 SH3 domain binding inhibition test 1
  • Sam68AC Human recombinant Sam68
  • RSB mmol / L Tris monohydrochloride, pH7
  • BSA bovine serum albumiii
  • FV bovine blood albumin
  • Nacalai Tesque, Inc. Nacalai Tesque, Inc.
  • the compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mmol / L DMSO solution.
  • DMSO dimethyl sulfoxide
  • the DMSO solution was added to the above Sam68 ⁇ C solution such that the final concentrations were 20 and 100 Hmol / L, respectively.
  • the amount of DMSO added was the same.
  • the Sam68A C solution containing the compound was incubated at 37 ° C for 6 hours while gently rotating in a rotary incubator to remove the compound.
  • Fyn-SH3 protein-agarose beads (hereinafter referred to as Fyn-SH3 beads) in which the mouse recombinant SH3 domain of protein SH3 having SH3 domain is bound to agarose beads are added to the Sam68AC solution reacted with the compound in (1) above. 85-139) AC; manufactured by Santa Crutz '].
  • the protein-protein binding reaction between Sam68 ⁇ C after the compound reaction and Fyn-SH3 beads containing the SH3 domain was carried out at 4 ° C for 16 hours while gently rotating in a rotary culture machine.
  • the complex of Sam68 ⁇ C and Fyn-SH3 beads was precipitated by a rotary centrifuge at 4 ° C and 50 ppm for 3 minutes, and then a TritonX / Np40 extraction buffer solution containing a surfactant [50 mmol / L Tris-1 Hydrochloric acid pH 7.4, 150 mmol / L NaCl lmmol / L ethylenediaminetetraacetate (EDTA), 1% Triton X-100 (TritonX-100), 0.5% nonidet P-40 (NP-40)] Add ImL and add 4 ° Rotation at C for 10 minutes After gentle rotation in the incubator, the same precipitation and washing was performed twice.
  • a TritonX / Np40 extraction buffer solution containing a surfactant [50 mmol / L Tris-1 Hydrochloric acid pH 7.4, 150 mmol / L NaCl lmmol / L ethylenediaminetetraacetate (EDTA), 1% Triton
  • Human colon cancer-derived cell line HCT116 (ATCC No. CCL-247) was used at 37 ° C. using a modified McCoy's medium [McCoy's 5A modified medium; Gibco (GIBCO)] containing 10% ⁇ , fetal serum. in 5% C0 2 under the conditions of CC T Nkyube Isseki one were cultured in 100mm diameter Didzushi Interview for cell culture. Then, compound 1 was added to two dishes of HCT116 cells on the second day so that the final concentrations were 0.5, 1, 2, 2.5, 5, 10, 20, and 30 mol / L, respectively. . Compound 1 to be added was previously diluted with DMSO so that the amount of DMSO added was the same.
  • HCT116 cell tissue with Compound 1 was added at 37 ° C! , And incubated 5% C0 2 under the conditions of the C0 2 incubator base Isseki one 2 hours, allowed to act compound. Collect two dishes of HCT116 cells with compound 1 and react with the medium. After mixing well, the mixture was stirred at 4 ° C for 45 minutes while gently rotating in a rotary culture machine to extract cytoplasmic proteins. The cell extract was centrifuged at 15,000 rpm at 4 ° C for 30 minutes, and the supernatant was collected.
  • the cell extract obtained after the addition of the compound obtained in the above (1) was added with 3 g of anti-Src antibody [manufactured by Santa Crutz] and anti-PLC antibody [Santa Crutz] 3 ⁇ g, anti-Grb2 antibody [from Sanyo Cruz (5 && 1 ⁇ )] 3 ⁇ , or anti-Cortactin antibody [from Sanyo Cruz (Santa Cmtz)] 3 ⁇ g
  • the reaction was carried out at 4 ° C for 16 hours with gentle rotation.
  • Protein A / G-conjugated agarose beads 30 were added to each SH3 domain-binding protein complex after the antibody reaction, and reacted at 4 ° C for 1 hour while gently rotating in a rotary culture machine.
  • a protein containing a proline-rich sequence in each SH3 domain-binding protein complex in the supernatant was detected by Western blotting as follows. First, the protein in the gel after the electrophoresis described in (2) above was plotted on a 0.45 ⁇ m nitrocellulose membrane [Protran; Produced by Schleicher and SchuelO], and PBS was applied to the membrane. Non-specific binding was blocked by loading -TG. Eg anti-Sam68 antibody for detection of Sam68, Eg anti-Sosl antibody for detection of Sos, and detection of Z01 for Z01. ⁇ A heron anti-ZOl antibody was diluted 1: 1000 with PBS-TG and reacted for 2 hours.
  • Nef derived from HIV-1 having a proline-rich sequence [Nef (3-190); manufactured by Cortex Corporation] 0.3 ⁇ g and purified Lyn derived from sea bream [Lyn; manufactured by Upstate Biotechnology] 1 Zg was added to 1 mL of RSB (10 mmol / L Tris-HCl pH7.6, 10 mmol / L NaCi .5 mmol / L MgCl 2 ), a hypotonic buffer containing 0.1% BSA (bovine serum albumin), and Nef And a mixed solution of Lyn was prepared. The compound was dissolved in DMSO to prepare a DMSO solution having a concentration of 10 mmol / L.
  • RSB 10 mmol / L Tris-HCl pH7.6, 10 mmol / L NaCi .5 mmol / L MgCl 2
  • BSA bovine serum albumin
  • the DMSO solution was added to the above-mentioned mixed solution of Nef and Lyn such that the final concentrations were 1, 2, 5, and 10 mol / L, respectively.
  • the compound to be added was diluted in advance with DMSO so that the amount of DMSO added was the same.
  • the mixed solution of Nef and Lyn to which the compound had been added was stirred at 4 ° C for 16 hours while gently rotating in a rotary culture machine to react the compound with Nef and Lyn proteins.
  • the Nef protein containing a proline-rich sequence in the Nef / Lyn SH3 domain-binding protein complex in the above supernatant was detected by Western blotting as follows. First, the protein in the gel after the electrophoresis in the above (2) was plated on a 0.45 ⁇ m nitrocellulose membrane [Protran; Produced by Schleicher aixi Schuell], and then applied to the membrane. Non-specific binding was blocked with PBS-TG. Since galactosidase was fused to the recombinant Nef protein used, Nef was detected using an anti-galactosidase antibody (anti- ⁇ -gal antibody).
  • a heron anti-galactosidase antibody was diluted 1: 1000 with PBS-TG and reacted for 2 hours. After washing with PBS-T, an HRP-conjugated anti-Egret antibody [manufactured by Amersham] diluted 1: 4000 with PBS-TG was reacted for 1 hour. After washing with PBS-T, detection was performed by chemiluminescence using an ECL reagent (Amersham Pharmacia Biotech).
  • Test example Calculation of the SH3 domain binding inhibition rate of a compound Based on the results plotted according to the method of Test Example 1, the SH3 domain binding inhibition rate of the compound was calculated as follows.
  • the band intensity of Fyn-1 SH3 and Sam 68 AC developed on the film by chemiluminescence was measured using a gel scanner-1 (manufactured by TOYOBO).
  • the band intensity of Sam68AC was divided by the band intensity of Fyn-SH3 to calculate the band intensity of Sam68AC with respect to the band intensity of Fyn-SH3.
  • the ratio of the band intensity of Sam68AC to the band intensity of Fyn-SH3 when no compound was added was defined as 100%, and the ratio of decrease in the band intensity of Sam68AC after the compound was added was defined as the inhibition ratio of SH3 domain binding of the compound. The results are shown in Table 8.
  • MT2 cells (T cell line) were transformed using RPMI1640 medium [Gibco (GIBCO) No. 26140-076] containing 10% fetal bovine serum [GIBCO (No. 26 140-079)]. The volume was adjusted to 10 5 cells / mL, and 1 mL was dispensed per well into a 24-well plate [24 well plate: No.3526, manufactured by Coster Corporation].
  • culture supernatants of 50 / L were collected at 3, 5, 7, and 9, respectively, and stored at -80 ° C until measurement.
  • the virus which infected the virus and did not add the drug was defined as positive control, and the virus which did not infect the virus and did not add the drug was defined as negative control.
  • the test was performed three times with the same contents.
  • the quantification of HIV-1 was determined by the RT assay method (Reverse) with a slight modification to the method described in Journal Off, J. Virol., Vol. 38, p. 239 (1981). Transcriptase assay).
  • RT cocktail 50 mmol / L Tris pH 7.5, 50 mmol / L EDTA ⁇ 75 mmol / L KC1, 5 mmol / L MgC, 5 jLL g / mL Poly (A ) [Pharmacia (Pharmacia) No.27-4110-01], 1.6 ⁇ g / mL oligo (dT) 12-18 [Pharmacia No.27-7858-01] ⁇ 5mmol / L DTT (dithiolate), 0.05% NP-40, 10 / Ci / mL [ shed - 32 P] dTTP ⁇ was added 25 ⁇ L and incubated for 2 hours at 37 ° C.
  • reaction solution 6 ⁇ L of their DEAE filtermat [Perkin Elmer one (PerMn Elmer) Co., Nanba1450-522] spotted, after removing the shed one 32 P] dTTP unreacted Infiltrate MeltiLex-A [Perkin Elmer, No. 1450-441], and measure the amount of HIV-1 as RT activity count (cpm / L) in MICROBETA The measurement was performed using a PLUS liquid scintillation counter [Perkin Elmer Co.].
  • MT2 cells T cell line
  • RPMI1640 medium manufactured by Gibco (GIBCO), No. 26140-076] containing 10% fetal bovine serum [GIBCO (No. 26140-079)]. It was adjusted to 10 5 cells / mL, 96 Werupureto [96 well plate: Costar (Coster) Co.] was dispensed at 100 L per minute Kakuu Ell. After adding the compound to each cell and culturing, observe the state of the cells on the third day, collect the cells, stain the cells with 0.4% trypan blue [SIGMA], ⁇ -8154]. The number of surviving cells was counted. As a result, even when the compound 1 was added at a concentration of 10 mol / L, no decrease in the number of viable cells was observed.
  • a drug containing a compound having an excellent SH3 domain binding inhibitory activity as an active ingredient can be used for various diseases involving protein-protein binding via SH3 domain (e.g., AIDS, malignant tumor, allergy) It is suggested to be effective for sexual diseases, viral diseases, etc. [Biopolymer, vol. 43, p. 383 (1997)].
  • Compound (I), (II), (Ilia), (Illb), (Va), (Vb) or (VI) or a pharmacologically acceptable salt thereof can be administered alone as it is. However, it is usually desirable to provide them as various pharmaceutical preparations. The pharmaceutical preparations are used for animals and humans.
  • the pharmaceutical preparation according to the present invention comprises a compound (1), (11), (Ilia), (IIIb), (Va), (Vb) or (VI) as an active ingredient or a pharmacologically acceptable salt thereof.
  • a compound (1) (11), (Ilia), (IIIb), (Va), (Vb) or (VI) as an active ingredient or a pharmacologically acceptable salt thereof.
  • such pharmaceutical preparations are produced by mixing the active ingredient with one or more pharmacologically acceptable carriers and by any method well known in the technical field of pharmaceuticals.
  • Examples of the administration form include tablets, powders, granules, syrups, and injections.
  • Liquid preparations suitable for oral administration, such as syrups include, for example, water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil, and soybean oil.
  • Preservatives such as p-hydroxybenzoic acid esters, flavors such as strawberry flavor and peppermint
  • Tablets, powders, granules and the like include excipients such as lactose, pudose, sucrose and mannitol, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate, talc, poly It can be produced using a binder such as vinyl alcohol, hydroxypropylcellulose, and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin.
  • Formulations suitable for parenteral administration comprise a sterile aqueous preparation containing the active compound which is preferably isotonic with the blood of the recipient.
  • a solution for injection is prepared using, for example, a carrier comprising a salt solution, a glucose solution or a mixture of a salt solution and a butudose solution.
  • the diluents, preservatives, and flavoring agents exemplified for the oral preparations are used.
  • One or more auxiliary ingredients selected from bars, excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like can also be added.
  • the dose and frequency of compound (I), (II), (Ilia), (Illb), (Va), (Vb) or (VI), or a pharmaceutically acceptable salt thereof It depends on the form of administration, the age and weight of the patient, the nature or severity of the condition to be treated, etc., but in the case of oral administration, usually 0.01 mg to lg per adult, preferably 0.05 to 50 mg once or more per day Dosing once. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg , preferably 0.01 to 10 mg , per adult is administered once to several times a day. However, the dose and the number of administrations vary depending on the various conditions described above.
  • FIG. 1 shows the results of an assay for inhibiting the binding of Sam68 C and Fyn-SH3 at the in-vitro mouth when compounds (I) and (VI) were added at different concentrations.
  • the numbers at the top of each lane indicate the compound number and the concentration (Lmol / L) of each compound added to the Sam68AC solution.
  • the description on the left shows the name of each plot.
  • FIG. 2 shows the results of inhibition of binding between Sam68AC and Fyn-SH3 at the in-vitro mouth when compound 1 and compound (Ilia) were added at different concentrations.
  • the numbers at the top of each lane indicate the compound number and the concentration ( ⁇ mol / L) of each compound added to the Sam68 ⁇ C solution.
  • the description on the left shows the name of each plot.
  • FIG. 3 shows the in vitro results of the inhibition of the binding of Sam68AC and Fyn-SH3 when the compounds (II) and (Ilia) were added at different concentrations.
  • the numbers above each lane indicate the compound number and the concentration ( ⁇ mol / L) of each compound added to the Sam68AC solution.
  • the description on the left shows the name of each plot.
  • FIG. 4 shows the results of a binding inhibition assay between Src and Sam68 in cells when Compound 1 was added at different concentrations.
  • the numbers at the top of each lane indicate the concentration (/ mol / L) of compound 1 added to HCT116 cells.
  • the description on the left shows the name of the broth.
  • FIG. 5 shows the results of the binding inhibition assay between the intracellular PLC and Sam68 when compound 1 was added at different concentrations.
  • the numbers at the top of each lane are for HCT116 cells. Shows the concentration (md / L) of Compound 1 added.
  • the description on the left shows the name of the plot.
  • FIG. 6 shows the results of assays for inhibiting the binding of Grb2 to Sosl in cells when compound 1 was added at different concentrations.
  • the numbers at the top of each lane indicate the concentration (Zmol / L) of compound 1 added to HCT116 cells.
  • the description on the left shows the name of the broth.
  • FIG. 7 shows the results of the assay for inhibiting the binding of intracellular Cortactin and ZOl when the compound 1 was added at a different concentration.
  • the numbers above each lane indicate the concentration (mol / L) of compound 1 added to HCT116 cells.
  • the description on the left shows the name of the plot.
  • FIG. 8 shows the results of in vitro binding inhibition assay of Nef and Lyn when compounds 1 and 3 were added at different concentrations.
  • the numbers at the top of each lane indicate the compound number and the concentration ( ⁇ mol / L) of the compound added to the mixed solution of Nef and Lyn.
  • the description on the left shows the name of the plot.
  • Figures 9 to L1 show the results of the HIV-1 proliferation inhibition test (RT Assay) when compound 1 was added at different concentrations. The results were obtained by performing three tests under the same conditions. is there.
  • the left side of the vertical axis of the graph shows the amount of HIV-1 as the count of RT activity (cpmA L), and the lower side of the horizontal axis of the graph shows the number of days elapsed since HIV-1 infection (days). Is shown.
  • the meaning of each plot on the graph is as follows.
  • Figs. 12 to 14 show the results of the HIV-1 growth inhibition test (RT Assay) when PP2 was added at different concentrations, and the results of three tests performed under the same conditions. is there.
  • the amount of HIV-1 is shown as RT activity count (cpm / ⁇ L).
  • the number of days elapsed since HIV-1 infection was plotted. (Day). The meaning of each plot on the graph is as follows.
  • a tablet having the following composition is prepared by a conventional method.
  • Compound 2 40 g
  • lactose (286.8 g) and potato starch 60 g
  • a 10% aqueous solution of hydroxypropyl cellulose 120 g
  • This mixture is kneaded by a conventional method, granulated, dried, and then sized to obtain granules for tableting.
  • Maguneshiumu stearate 1.2 g
  • a tableting machine having a pestle of diameter 8mm in performing tableting Karlikusui, RT-15
  • tablets per tablet active ingredient 2 Omg Containing
  • a capsule having the following composition is prepared by a conventional method.
  • Compound 12 (200 g), Avicel (995 g) and magnesium stearate (5 g) are mixed by a conventional method.
  • This mixture is filled into Hard Capsule No. 4 (capacity of 120 mg per capsule) with a capsule filling machine (LZ-64 type, manufactured by Zanasi) to obtain a capsule (containing 20 mg of active ingredient per capsule). .
  • An injection having the following composition is prepared by a conventional method.
  • Purify Compound 10 (lg) Dissolve in soybean oil and add purified egg yolk lecithin (12 g) and glycerin for injection (25 g). This mixture is kneaded and emulsified with distilled water for injection to 100 mL in a conventional manner. The resulting dispersion is aseptically filtered using a 0.2 / m disposable membrane filter, and then aseptically filled into glass vials in 2 mL increments. Injection (containing 2 mg of active ingredient per vial) Get.
  • Example 5 Compound 3 Compound 2 (10 mg; 0.021 mmol) obtained in Example 4 was dissolved in pyridine (0.5 mL), acetic anhydride (0.5 mL) was added, and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction solution, the obtained residue was crystallized from a mixed solvent of IPE and n-hexane to obtain 4.6 mg of Compound 3 (yield: 32%).
  • each platinum loop was filled with 50 mL of seed medium (3% mash, 3% glucose, 10% glucose, 0.5% yeast extract, pH 6.5). And inoculated on a rotary stirrer at 28 ° C. for 5 days to obtain a seed culture.
  • Production medium of seed culture 2.5mL of this 50 mL (2% glucose, mashed 2%, Bae script down 0.5%, H 2 PO 4 0.5 %, Mg 3 (O 4) 2 '8H 2 O0.05%, pH6 .0) containing 300mL ⁇ Scos (40) were inoculated and cultured on a rotary shaker at 25 ° C for 5 days.
  • the culture solution (2 L) was separated into bacterial cells and supernatant by suction filtration, and the culture supernatant was subjected to column chromatography using Diaion HP-20 (30 mL) previously filled with 20% methanol. After washing stepwise with 40, 50, and 60% methanol, elution was performed with 90 and 100% methanol.
  • the eluate (150 mL) was concentrated, extracted with ethyl acetate, and the extract was separated and purified by high-performance liquid chromatography (Develosil HG-5 20x250 mm; 40-; eluted stepwise with L00% aqueous acetonitrile). 2.2 mg of compound 20 was obtained.
  • 75 mL of this primary seed culture is mixed with 2.5 L of a secondary seed medium (glucose 2%, marsh potato 1%, peptone 0.5%, KH 2 PO 4 0.5%, Mg PO 4 ) 2 '8H 2 O 0.05%, ⁇ 6. ⁇ ) Was inoculated into a 5 L section of the yeast overnight, followed by aeration and agitation culture at 25 ° C for 24 hours.
  • a secondary seed medium (glucose 2%, marsh potato 1%, peptone 0.5%, KH 2 PO 4 0.5%, Mg PO 4 ) 2 '8H 2 O 0.05%, ⁇ 6. ⁇ )
  • the resulting secondary-seed culture 450mL of 15L of production medium (2% glucose, mashed 2%, Bae script down 0.5%, KH 2 PO 4 0.5 % s Mg PO 4) 2 '8H 2 O0.05%, pH6 .0) was inoculated into 2 jars of jar fermenter having a capacity of 30 L and aerated and stirred at 25 ° C for 5 days. After cultivation, The culture solution (30 L) was separated into cells and supernatant by suction filtration, and 20 L of methanol was added to the cells, followed by extraction by stirring.
  • the extract was subjected to column chromatography with Dyaion HP-20 (1.5 L) previously filled with a 30% aqueous methanol solution, washed with a 50% aqueous methanol solution, and eluted with 100% methanol. The eluate was concentrated, extracted with ethyl acetate, and concentrated to dryness to obtain 23.7 g of bacterial cell extract.
  • the obtained bacterial cell extract was subjected to silica gel column chromatography (a mixed solvent of black form and methanol), and a fraction containing compound 21 was collected and concentrated to dryness. The resulting residue was partitioned between a 90% aqueous methanol solution and n-hexane to remove fatty acid components.
  • the extract (5.44 g) in a 90% aqueous methanol solution was subjected to silica gel column chromatography (a mixed solvent of n-hexane and ethyl acetate), and the fraction containing compound 21 was collected and concentrated.
  • the obtained residue (1.24 g) was dissolved in a small amount of ether, and powdered by adding n-hexane to obtain compound 21 (343 mg).
  • a loop of each platinum loop was filled with four 50 mL seed culture media (3% matsushpotato, 10% glucose, 0.5% yeast extract, pH 6.5) in a 300 mL triangle.
  • the flask was inoculated and cultured on a rotary stirrer at 28 ° C. for 5 days to obtain a seed culture.
  • 2.5 mL of this seed culture was added to 50 5 OmL production media (3% sucrose, 2% soluble starch, Inoculate a 300 mL Erlenmeyer flask containing dried yeast 0.5%, malt extract 1%, corn steep liquor (CSL) 0.5%, vegetable juice 20%, CaCO 3 0.5%, pH 6.0 C.
  • the culture was performed on a rotary shaker for 5 days.
  • the culture solution (2.5 L) was separated into cells and supernatant by suction filtration, 6 L of methanol was added to the cells, and the mixture was stirred and extracted.
  • the extract was concentrated under reduced pressure until the volume became about 3 L.
  • the culture supernatant and the concentrated cell extract were combined, subjected to column chromatography on Diane HP-20 (150 mL) packed with 50% methanol, washed with 50% methanol, and then washed with 100% methanol. It was eluted at the medium.
  • the eluate was concentrated under reduced pressure to about 200 mL, extracted with ethyl acetate (250 mL ⁇ 2), washed with saturated saline, and dried over anhydrous sodium sulfate.
  • Reference Example 1 Compound 1 (UCS15A / Luminacin C2 / SP4228A) Compound 1 was produced by the method described in The Journal of Antibiotics, vol. 53, p. 579 (2000) and JP-A-58-116686. It was obtained by culturing actinomycetes belonging to the genus Streptoy and isolating and purifying it from the culture broth.
  • Compound 5 can be obtained according to the method described in JP-A-62-294619, but can also be obtained by the following method.
  • Reference Example 1 Compound obtained in 1; dissolved (Llmg 0.023 mmol) in a mixed solvent of THF (LML) and water (0.5 mL) and methanol Ichiru (1 drop), sulfate methylhydrazine (3 0 mg, 0. 2 lmmol) and stirred at room temperature for 4 hours.
  • the reaction mixture was diluted with ethyl acetate (lOmL) and extracted, and the organic layer was washed with water and an aqueous solution of lmol / L ⁇ acid.
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated, and the obtained residue was crystallized from a mixed solvent of IPE and n-hexane to obtain 5.9 mg of Compound 5 (yield 50%).
  • Resorcinol 600 mg; 5.45 mmol
  • sorbic acid 600 mg; 5.36 mmol
  • boron trifluoride etherate 10 mL
  • a small amount of water was added to the reaction solution while cooling with ice, and the mixture was extracted with ethyl acetate (50 mL x 2).
  • the residue was dissolved in a mixed solvent of THF (50 mL) and water (50 mL), and the mixture was heated under reflux for 30 minutes.
  • Compound 10 can be obtained by the method described in Tetrahedron, vol. 31, p. 1593 (1975), but can also be obtained by methylation of compound 7.
  • Compound 7 (424 mg; 2.08 mmol) obtained in Reference Example 3 was dissolved in 30 mL of acetone, and calcium carbonate (650 mg; 4.70 mmol) and methyl iodide (0.260 mL; 4.18 mmol) were added, followed by heating under reflux for 1 hour. .
  • the reaction solution was allowed to cool at room temperature, diluted with ethyl acetate (50 mL), and extracted with lmol / L aqueous acid solution.
  • the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Compound 12 can be obtained according to the method described in JP-A-10-114776.
  • Compound 26 (Aspochalasin C), Compound 27 (Aspochalasin D) and Compound 28 (Aspochalasin E) should be cultured and isolated and purified from MPC1009 filamentous fungi by the method described in Example 13. Was obtained. Also, Helvetica Chim. Acta, Vol. 62, p. 1501 (1979), Journal of Antibiotics (J. Antibiot.), Vol. 46, p. 679 ( 1993), and the like, by culturing a filamentous fungus capable of producing the compound and isolating and purifying the same from a culture solution.
  • the compound 2 5 (Aspochalasin B) is Herube Chika-Himika ' ⁇ click evening (Helv. Chim. Acta), 6 2 Certificates, according to the method described in 1501 pages (197, 1997), the production of the compound It can also be obtained by culturing a functional filamentous fungus and isolating and purifying it from a culture solution. .
  • compound 24 is a filamentous fungus capable of producing the compound according to the method described in Helvetica Chimica Acta, Vol. 62, p. 1501 (1979). It can also be obtained by culturing and isolating and purifying from a culture solution.
  • the present invention provides an SH3 domain binding inhibitor comprising a non-peptidic compound or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention also provides a compound useful as an SH3 domain binding inhibitor or a pharmacologically acceptable salt thereof.

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Abstract

L'invention concerne des inhibiteurs de la liaison au domaine SH3 contenant comme ingrédient actif des composés non peptidiques présentant une activité d'inhibition de la liaison au domaine SH3, des composés de faible poids moléculaire présentant une activité d'inhibition de la liaison au domaine SH3 et un poids moléculaire inférieur à 750, en particulier des composés représentés par les formules générales (I) et (II), des cytochalasines ou leurs sels acceptables d'un point de vue pharmacologique, et des composés représentés par les formules générales (Va), (Vb) et (VI) et leurs sels acceptables d'un point de vue pharmacologique.
PCT/JP2002/003932 2001-07-09 2002-04-19 Inhibiteurs de la liaison au domaine sh3 WO2003006060A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007037333A1 (fr) * 2005-09-29 2007-04-05 Osaka Bioscience Institute Inhibiteur de liaison à une séquence riche en proline non typique
CN1830960B (zh) * 2005-07-01 2010-08-18 中国海洋大学 10-苯基氢化异吲哚酮类化合物及其制备方法和用途
CN102260271A (zh) * 2011-06-01 2011-11-30 中国海洋大学 细胞松弛素类化合物及其制备方法和用途
CN103787953A (zh) * 2014-01-17 2014-05-14 杭州维康科技有限公司 化合物Aspochalasin V及其制备方法和应用
CN105085538A (zh) * 2015-08-21 2015-11-25 华中科技大学 具有肿瘤细胞g1期阻滞作用的化合物及其制备和应用

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1830960B (zh) * 2005-07-01 2010-08-18 中国海洋大学 10-苯基氢化异吲哚酮类化合物及其制备方法和用途
WO2007037333A1 (fr) * 2005-09-29 2007-04-05 Osaka Bioscience Institute Inhibiteur de liaison à une séquence riche en proline non typique
CN102260271A (zh) * 2011-06-01 2011-11-30 中国海洋大学 细胞松弛素类化合物及其制备方法和用途
CN102260271B (zh) * 2011-06-01 2013-10-30 中国海洋大学 细胞松弛素类化合物及其制备方法和用途
CN103787953A (zh) * 2014-01-17 2014-05-14 杭州维康科技有限公司 化合物Aspochalasin V及其制备方法和应用
CN103787953B (zh) * 2014-01-17 2015-12-02 杭州维康科技有限公司 化合物Aspochalasin V及其制备方法和应用
CN105085538A (zh) * 2015-08-21 2015-11-25 华中科技大学 具有肿瘤细胞g1期阻滞作用的化合物及其制备和应用

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