WO2007102368A1 - Nouveau dérivé de 3-(1-aminoalkylidène)furann-2,4(3h,5h)-dione, sa méthode de production et une composition pharmaceutique l'incluant au titre de principe actif - Google Patents

Nouveau dérivé de 3-(1-aminoalkylidène)furann-2,4(3h,5h)-dione, sa méthode de production et une composition pharmaceutique l'incluant au titre de principe actif Download PDF

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WO2007102368A1
WO2007102368A1 PCT/JP2007/053763 JP2007053763W WO2007102368A1 WO 2007102368 A1 WO2007102368 A1 WO 2007102368A1 JP 2007053763 W JP2007053763 W JP 2007053763W WO 2007102368 A1 WO2007102368 A1 WO 2007102368A1
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group
formula
chemical
compound
substituent
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Japanese (ja)
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Mikiko Sodeoka
Go Hirai
Yuko Otani
Kosuke Dodo
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RIKEN
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RIKEN
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/60—Two oxygen atoms, e.g. succinic anhydride
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel 3_ (1-aminoalkylidene) furan-2,4 (3H, 5H) -dione derivative, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient.
  • RK-682 which is known as an inhibitor of the bispecific protein phosphatase, has been reported to inhibit the growth of cancer cells. However, since RK-682 has low cell membrane permeability, its effect at the cellular level was low.
  • RK-682 (Patent Document 1), which is known as an inhibitor of protein phosphatase, is a known compound and has been reported to be isolated from cells or chemically synthesized. (Patent Document 2 etc.). It is also known as a bispecific protein phosphatase mainly as an inhibitory substance against VHR (Patent Document 1). In addition, various derivatives have also been synthesized as optically active substances, and as effective bispecific protein phosphatase inhibitors, inhibition of VHR and Cdc25B, and protein tyrosine phosphatase inhibitors such as CD45 and PTP-S2 Substances have been reported (Non-Patent Document 1).
  • both compounds have a 3-acyltetronic acid skeleton as a chemical structure and are acidic substances. Therefore, it is an amphiphilic compound because it has a negative charge in an aqueous solution near neutrality and also has structural characteristics derived from fatty acids. This chemical property is similar to that of a surfactant, and it was thought that there was a problem with cell membrane permeability, mainly when applied to tumor cells. As data showing this, the growth inhibitory activity in P388 cells was significantly reduced compared to the inhibitory activity of protein dephosphorylation enzymes (Non-patent Document 1).
  • Prior art documents related to the present invention include the following.
  • Patent Document 5 There are reports on the synthesis of RK-682, synthesis of 3_ (1-aminoalkylidene) furan-2,4 (3H, 5H) -dione derivatives and evaluation of herbicidal activity.
  • Patent Document 1 Japanese Patent No. 2856379
  • Patent Document 2 Japanese Patent No. 3156006
  • Patent Document 3 Japanese Patent Laid-Open No. 10-45740
  • Patent Document 4 JP-A-10-212284
  • Patent Document 5 GB2237569
  • Non-Patent Document 1 Synthesis of tetronic acid derivatives and phosphatase inhibitory activity, P388 cell growth inhibitory activity: Journal of Synthetic Organic Chemistry, Japan, page 1095, Mikiko Sodeoka (1 other)
  • Non-Patent Document 2 Synthesis and antitumor activity of 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) _dione derivatives: Pharmaceutical Journal, 1976, 96-536, Hideki Yuki et al. (Other 6 Name)
  • An object of the present invention is to provide a compound that can be used as an active ingredient of an antitumor agent or a protein phosphatase inhibitor.
  • the compound group of the present invention is a novel compound group not reported in any literature.
  • the antitumor activity of the compounds of the present invention is determined by the growth inhibition test of human leukemia cells HL60 cells. And evaluated. RK-682, which was the base, did not show HL60 cell growth inhibitory activity in this test system. On the other hand, the 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) _dione derivative of the present invention showed remarkable HL60 cell growth inhibitory activity. This activity showed a higher growth inhibitory ability than the ability of RK-682 itself to inhibit protein phosphatase.
  • the compounds of the present invention have also been found to exhibit inhibitory activity against VHR, which is a bispecific protein phosphatase. Cell growth inhibitory activity and VHR inhibition do not necessarily correlate directly, but this fact may inhibit other protein phosphatases to produce cytostatic effects. Conceivable.
  • the present invention includes the following inventions.
  • R and R are, independently of one another, hydrogen; a hetero selected from the group consisting of N, 0 and S
  • a linear, branched or cyclic saturated or unsaturated hydrocarbon radical which may be more substituted; or may contain a heteroatom selected from the group consisting of N, 0 and S
  • R and R, or R and R are united with the atom to which they are bonded, and R and R are bonded.
  • N may contain a heteroatom selected from the group consisting of N, 0 and S.
  • a saturated or unsaturated aliphatic ring optionally substituted by a substituent Or may form an aromatic ring;
  • the bond represented by [0012] may be a single bond or a double bond; when the bond is a double bond, R is hydrogen; when the bond is a single bond R is a halogen
  • R and R is H and the other is
  • R is * One (CH 2 ) 14 CH 3 *-(CH 2 ) i 0 CH 3 * — (CH 2 ) 6 CH 3
  • the compound or a salt or solvate thereof according to (1) which is a group selected from the group consisting of
  • R is H
  • the compound or a salt or solvate thereof according to (1) which is a group selected from the group consisting of
  • a pharmaceutical composition comprising the compound described in (1) to (4) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • the compound represented by the formula (I) has two tautomers in an equilibrium state.
  • the present invention provides a group of compounds that can be used as an active ingredient of an antitumor agent or a protein phosphatase inhibitor.
  • FIG. 1 is a diagram showing the results of an HL60 cell growth inhibitory activity test.
  • FIG. 2 is a diagram showing the results of an HL60 cell growth inhibitory activity test.
  • R and R are, independently of one another, a hydrogen selected from the group consisting of hydrogen; N, 0 and S
  • R is a heteroatom selected from the group consisting of N, 0 and S (e.g.
  • R represents a heteroatom selected from the group consisting of N, 0 and S (eg, _0_, -S-, -NH
  • the aryl group or aralkyl group having 5 to 20 carbon atoms is preferred.
  • R and R, or R and R are united with the atom to which they are bonded, and R and R are bonded.
  • a saturated or unsaturated aliphatic ring or aromatic ring preferably having 4 to 7 carbon atoms may be formed.
  • the bond represented by may be a single bond or a double bond.
  • R is hydrogen when the bond is a double bond.
  • R is halogen (chlorine,
  • —X— is preferably —O—.
  • [0048] is an asymmetric carbon when is a single bond.
  • the compounds of the present invention may be optically active or racemic.
  • a racemic body is obtained as a result of synthesis, the two optical isomers may be separated or may be used as a racemate without being separated.
  • an optically pure compound is used as a starting material in the synthesis, it is possible to obtain an optically pure compound of the present invention without performing resolution.
  • halogen chlorine, fluorine, bromine or iodine
  • R, R, R, R, R and R are independently of each other,
  • the aryl group or aralkyl group of formula 5 to 20 can be used, but is not limited thereto. These substituents may be further substituted with the same substituent.
  • R 3 is a straight-chain saturated hydrocarbon group, an azido group as a substituent, 6- (4,4 difunoleo port-1, 3-dimethyl-5- (4- Methoxyphenyl) -4-bora-3a, 4a-diaza-s_indacene-2-propionylamino) hexanoylamino groups may be present.
  • one of R and R is H and the other is
  • R is [Chemical 24]
  • R and R are combined to form an alkylene chain (for example,
  • R and R are combined to form an alkylene chain (for example,
  • R is preferably H.
  • the names are for convenience and do not limit the invention.
  • Compounds containing asymmetric carbon may be optically active or racemic.
  • the compounds of the present invention can form salts.
  • an alkali or alkaline earth metal salt such as lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt; ammonium salt, methylammonium salt, dimethylammonium salt, trimethyl Ammonium salts such as ammonium salts can be formed.
  • mineral salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; acetate, propionate, tartrate, fumarate, maleate
  • Organic acids such as malate, citrate, methanesulfonate, and P-toluenesulfonate can be formed.
  • the compound of the present invention or a salt thereof can also exist as a solvate.
  • Solvates include those formed by absorbing moisture in the air in addition to solvates to which the solvent used for crystal crystallization is added.
  • the solvent include lower alcohols such as methanol and ethanol, acetone, acetonitrile, and water.
  • a preferred synthesis method of the compound of the present invention will be outlined, but the synthesis method of the present invention is not limited to the following method.
  • intermediate 1 is first prepared from 4-hydroxyfuran-2 (5H) _one according to the procedure shown in the example (Scheme 1):
  • This group can be converted to a hydroxymethyl group (-CH OH, the terminal hydroxyl group corresponds to R) by removing the protecting group.
  • R ' Can be further converted to other R-containing groups in one or more stages.
  • the conversion of the partial structure to be included is performed after the preparation of intermediate 3 described later.
  • intermediate 1 is condensed with a carboxylic acid R COOH having a desired group R (
  • Intermediate 2 can also be synthesized according to the method of Sodeoka, M. et al. J. Med. Chem. 2001, 44, 3216-3222.
  • the compound of the present invention is useful as an antitumor agent because of its excellent antitumor activity, and can be used as a human and veterinary drug, a pharmaceutical raw material, and the like.
  • the antitumor agent of the present invention comprises a compound represented by the formula (I) as an active ingredient.
  • the antitumor agent of the present invention may further contain other antitumor agents and / or additives. Any other antitumor agents and additives can be used as long as they do not reduce the antitumor activity of the compound of the present invention. Examples thereof include adriamycin, cisplatin, taxol, herceptin and the like. Can be mentioned.
  • the antitumor agent of the present invention is used for the purpose of prevention or treatment of tumors, prevention or treatment
  • the target of is not particularly limited.
  • the antitumor agent of the present invention can be used for the prevention or treatment of at least one kind of tumor such as cancer, sarcoma, benign tumor and the like. These illnesses can be targeted, whether they are single, concomitant, or other illnesses other than those mentioned above.
  • cancer types are not particularly limited: brain tumor, nasopharyngeal cancer, tongue cancer, esophageal cancer, stomach cancer, pancreas cancer, liver cancer, rectal cancer, colon cancer, uterine cancer, ovarian cancer, testicular cancer, bone And at least one selected from the group consisting of sarcoma and leukemia. Further, not only a single cancer but also a plurality of cancers may be combined.
  • the present invention also provides an effective amount of a compound represented by formula (I) or a salt or solvate thereof for prevention or treatment of a tumor to a subject animal in need of prevention or treatment of the tumor.
  • the present invention relates to a method for preventing or treating a tumor, comprising a step of administering.
  • the present invention also relates to the use of a compound represented by formula (I) or a salt or solvate thereof in the manufacture of a medicament for preventing or treating a tumor.
  • the subject to which the antitumor agent of the present invention is administered is not limited, but mammals such as humans, domestic animals (such as horses and horses), pets (such as Inu and cats), It can be a laboratory animal (mouse, rat, hamster, etc.).
  • the antitumor agent of the present invention can be administered to a mammal as a pharmaceutical composition containing a pharmaceutically acceptable carrier or additive.
  • a pharmaceutically acceptable carrier or additive examples include water, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxybule polymer, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, Kuching, xanthan gum, gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sonolebitol, ratatoose, acceptable as a pharmaceutical additive
  • artificial cell structures such as ribosomes can be mentioned.
  • the additive to be used is appropriately or in combination selected from the above depending on the dosage form of the pharmaceutical composition.
  • the antitumor agent of the present invention is administered orally, the antitumor agent of the present invention is produced as a solid preparation such as a tablet, granule, powder, or pill, or a liquid preparation such as a liquid or syrup. It can be formulated. In particular, granules and powders can be made into unit dosage forms as capsules, and in the case of liquid preparations, they may be dried products that are redissolved when used.
  • the solid preparation may contain additives such as a binder, an excipient, a lubricant, a disintegrant, and a wetting agent that are generally used in the preparation.
  • Liquid preparations can contain additives such as stabilizers, buffering agents, flavoring agents, preservatives, fragrances, and coloring agents that are commonly used in preparations.
  • injections are prepared by dissolving or suspending polyalkoxyflavonoids in solutions, suspensions, emulsions, etc., and are usually provided in the form of unit dose ampoules or multi-dose containers.
  • the injection may be a powder that is redissolved in an appropriate carrier, for example, sterile pyrogen-free water when used.
  • an appropriate carrier for example, sterile pyrogen-free water when used.
  • the injection technique include intravenous drip injection, intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, and intradermal injection.
  • These parenteral dosage forms usually contain additives such as emulsifying agents and suspending agents that are generally used pharmaceutically in their compositions.
  • the amount of the compound of the present invention in the above-mentioned antitumor agent varies depending on the use, dosage form, administration route and the like, based on the total weight:! To 5 wt%, preferably 2 to 3 wt%.
  • the effective amount of the compound of the present invention varies depending on the age of the administration subject, the administration route, and the number of administrations, and can vary widely.
  • the daily dose is 0.1 to 0.1 mg / kg body weight, and several times a day can be administered at intervals of several weeks.
  • the compound of the present invention can also be used as an active ingredient of a protein phosphatase inhibitor.
  • the protein phosphatase inhibitor of the present invention can also be formulated in the same manner as the antitumor agent.
  • the compound of the present invention has inhibitory activity against a bispecific protein phosphatase represented by VHR (vaccinia virus-encoded phosphatase VHl-related phosphatase). To do.
  • VHR vaccinia virus-encoded phosphatase VHl-related phosphatase
  • the compounds of the present invention are also effective for these enzymes.
  • the compounds of the present invention are considered to have inhibitory activity against other protein phosphatases. Therefore, the compounds of the present invention can be used for the prevention or treatment of diseases involving protein phosphatases. For example
  • PTP1B protein tyrosine phosphatase IB
  • PTP1B protein tyrosine phosphatase IB
  • the compounds of the present invention may be used as therapeutic agents for type 2 diabetes .
  • the compound of the present invention can be used as a biological research reagent for elucidation of intracellular signal transduction involving protein dephosphorylating enzyme.
  • the present invention also requires that the compound represented by the formula (I) or a salt or solvate thereof in an amount effective to inhibit protein phosphatase is used to inhibit protein phosphatase.
  • a method for inhibiting protein dephosphorylation enzyme comprising a step of administering to a target animal.
  • the present invention also relates to the use of a compound represented by the formula (I) or a salt or solvate thereof in the production of a protein phosphatase inhibitor.
  • composition comprising a compound represented by formula (I) or a salt or solvate thereof is marketed as a protein phosphatase inhibitor
  • Packaging or instructions indicating the use can be attached.
  • the present invention also provides an amount of a compound represented by the formula (I) or a salt or solvate thereof effective for preventing or treating a disease involving protein dephosphorylation enzyme.
  • the present invention relates to a method for preventing or treating a disease involving protein dephosphorylating enzyme, comprising a step of administering to a subject animal in need of prevention or treatment of a disease involving an enzyme.
  • the present invention also relates to the use of a compound represented by formula (I) or a salt or solvate thereof in the manufacture of a medicament for preventing or treating a disease involving protein dephosphorylating enzyme.
  • a pharmaceutical composition comprising a compound represented by formula (I) or a salt or solvate thereof is When it is marketed as a prophylactic or therapeutic agent for a disease involving protein dephosphorylating enzyme, a package or instructions that indicate that it is used for the prevention or treatment of the disease involving protein dephosphorylating enzyme It can be attached.
  • ' ⁇ NMR and 13 C NMR spectra are JEOL AL400 and AL300 manufactured by JASCO Corporation.
  • Tetramethylsilane was used as the internal standard substance when black mouth form was used as the measurement solvent. Chemical shift values are expressed in ppm. Mass spectrum (FAB-MS (Pos.))
  • a compound having an asymmetric carbon means a racemic mixture unless otherwise specified.
  • Compound 5 is a common intermediate for compounds with different R substituents.
  • Compound 8 can be used as a common intermediate for compounds having different R4 substituents.
  • Compound 15 is a secondary amine derivative.
  • Carbon tetrabromide (39.5 mg, 0.12 mmol) and triphenylphosphine (18.5 mg, 0.073 mmol) were added to a methylene chloride solution (1.5 mL) of compound 8 (29.3 mg, 0.064 mmol), and the mixture was stirred at room temperature for 22 hours. .
  • Carbon tetrabromide (20.0 mg, 0.060 mmol) and triphenylphosphine (10.0 mg, 0.039 mmol) were added, and the mixture was further stirred at room temperature for 1 hour. Water was added to the reaction solution, and extracted three times with ethyl acetate.
  • N, N-diisopropylethylamine (16 ML , 0.092 mmol) was added to a methylene chloride solution (0.5 mL) of compound 8 (20.0 mg, 0.044 mmol).
  • the growth inhibitory activity of the compounds against human leukemia cells HL60 was evaluated using alamarBlue TM.
  • Growth inhibitory activity (%) 100-(Fluorescence fluctuation value when compound is added) Fluorescence fluctuation value of Z compound-free group) X 100
  • HL60 cells cultured in RPMI1640 medium containing 5% fetal calf serum (FCS) are suspended in new medium to 4xl0 4 cells / ml, then seeded at 99.5 ⁇ l each in a 96-well plate and cultured for 2 hours did.
  • FCS fetal calf serum
  • DMSO no compound added group
  • DMSO solution of each compound was added at 0.5 ⁇ each, and further cultured for 3 days.
  • 10 ⁇ l of a lamarBlue TM (Biosource) as a viable cell number indicator to each well, immediately after addition and at 37 ° C with 5% CO ink.
  • Growth inhibitory activity (%) 100-(fluorescence fluctuation value when compound is added / fluorescence fluctuation value in group without compound) X 100
  • RK-682 shows almost no cytostatic activity even at a high concentration of 30 ⁇ , whereas the compound developed in the present invention shows activity at 10 / M or less. From this, it was clarified that it was converted into a skeleton that can be applied to cells. Among them, compound 39 was remarkably suppressed in cell proliferation even at a very low concentration of 0.3, and was shown to have strong anticancer activity.
  • bispecific compounds against bispecific protein phosphatase VHR vaccinia virus-encoded phosphatase VH1-related phosphatase
  • pNPP p-nitrophenyl phosphate
  • Inhibition rate by test compound (%) 100- (absorption fluctuation value when compound is added / absorption fluctuation value when compound is not added) xl OO
  • VHR expressed in E. coli and diluted with enzyme reaction buffer 50 mM succinate, 1 mM EDTA, 150 mM NaCI, pH 6.0
  • enzyme reaction buffer 50 mM succinate, 1 mM EDTA, 150 mM NaCI, pH 6.0
  • the compound-free group) or DMSO solution of each compound was added in two increments and left at 30 ° C for 30 minutes. Thereafter, 120 / iL of pNPP (5.0 mM) was added at a time, and left at 30 ° C for 15 minutes.
  • Inhibition rate by test compound (%) 100- (absorption fluctuation value when compound is added Z light absorption fluctuation value when Z compound is not added) xlOO

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Abstract

La présente invention concerne un composé qui peut être employé en tant que principe actif dans un agent antitumoral ou un inhibiteur de protéine phosphatase. La présente invention concerne spécifiquement un composé de formule (I) ci-dessous, un sel dudit composé ou un solvate dudit composé ou de son sel. La présente invention concerne en outre spécifiquement une composition pharmaceutique contenant un tel composé, et présentant une activité antitumorale ou une activité inhibitrice de protéine phosphatase.
PCT/JP2007/053763 2006-02-28 2007-02-28 Nouveau dérivé de 3-(1-aminoalkylidène)furann-2,4(3h,5h)-dione, sa méthode de production et une composition pharmaceutique l'incluant au titre de principe actif Ceased WO2007102368A1 (fr)

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CN104530018A (zh) * 2014-12-12 2015-04-22 郑州大学 含α-亚甲基-γ-丁内酯结构的吲哚类化合物、制备方法及其应用

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