WO1997032847A1 - Pyrrolidone derivatives - Google Patents
Pyrrolidone derivatives Download PDFInfo
- Publication number
- WO1997032847A1 WO1997032847A1 PCT/JP1997/000627 JP9700627W WO9732847A1 WO 1997032847 A1 WO1997032847 A1 WO 1997032847A1 JP 9700627 W JP9700627 W JP 9700627W WO 9732847 A1 WO9732847 A1 WO 9732847A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- protein phosphatase
- formula
- acid
- protein
- Prior art date
Links
- 150000004040 pyrrolidinones Chemical class 0.000 title claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 claims description 14
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229940116193 Protein phosphatase inhibitor Drugs 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000003934 phosphoprotein phosphatase inhibitor Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 239000003018 immunosuppressive agent Substances 0.000 abstract description 3
- 108090000623 proteins and genes Proteins 0.000 abstract description 3
- 102000004169 proteins and genes Human genes 0.000 abstract description 3
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 229940125721 immunosuppressive agent Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 230000030609 dephosphorylation Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- -1 3-cyano 5-hydroxy-4,5-dimethyl-2-pyrrolidone Chemical compound 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- BWCBVSHEZSMRCU-UHFFFAOYSA-N CCCCCCCCCCCCCCCC[NH+]([CH-]C(C(C)=O)=C1C)C1=C=C Chemical compound CCCCCCCCCCCCCCCC[NH+]([CH-]C(C(C)=O)=C1C)C1=C=C BWCBVSHEZSMRCU-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000011609 ammonium molybdate Substances 0.000 description 1
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 1
- 235000018660 ammonium molybdate Nutrition 0.000 description 1
- 229940010552 ammonium molybdate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- VLAPMBHFAWRUQP-UHFFFAOYSA-L molybdic acid Chemical compound O[Mo](O)(=O)=O VLAPMBHFAWRUQP-UHFFFAOYSA-L 0.000 description 1
- NDSQLYUWCXRSCB-UHFFFAOYSA-N n-hexadecyl-3-oxobutanamide Chemical compound CCCCCCCCCCCCCCCCNC(=O)CC(C)=O NDSQLYUWCXRSCB-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
Definitions
- the present invention relates to a pyridone derivative, and more particularly to a pyrrolidone derivative having a protein phosphatase inhibitory action.
- Phosphorylation and dephosphorylation of proteins are one of the basic regulatory mechanisms of biological functions. Among them, many agents that inhibit protein kinases have been reported as antitumor agents. However, little has been reported on inhibitors of protein phosphatase, which also plays an essential role in cell growth. Protein dephosphorylation, like phosphorylation, plays a so-called “switch” role in protein activity, and it has recently been clearly shown that protein dephosphorylation controls the activity and inactivity of proteins in vivo. It is becoming.
- the present invention provides a compound represented by the formula (I):
- R 1 represents a hydrogen atom or an alkyl group having 1 to 20 carbon atoms
- R 2 represents a cyano group or an acetyl group
- an alkyl group having 1 to 20 carbon atoms is a linear or branched alkyl group having 1 to 20 carbon atoms, such as a methyl group, an ethyl group, and a propyl group. And isopropyl, butyl, hexyl, hexadecyl, and octadecyl.
- the compound of the present invention represented by the formula (I) can be synthesized by the following method. That is, according to the method described in Journal of the American's Chemical Society [J. Am. Chem. Soc. Vol. 81, p. 4355 (1959)], 2,3-dioxobutane And expression
- the compound can be synthesized by treating a compound obtained by condensing the compound represented by the formula with an acid.
- the acid used at this time include mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid, and sulfonic acids such as 10-camphorsulfonic acid, p-toluenesulfonic acid, and methanesulfonic acid. it can.
- the acid treatment may be performed in a solvent, and a solvent such as dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, acetone, toluene, benzene and the like can be used as the solvent.
- a solvent such as dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, acetone, toluene, benzene and the like can be used as the solvent.
- tablets, pills, capsules, granules, solutions, emulsions, and suspensions can be prepared by using the compound as it is or by formulating it according to a conventional method. It can be prepared as an injection or the like and administered orally or parenterally.
- Dosage should be administered to adult patients in the range of l to 1000 mg for oral administration and 0.01 to 10 Omg for parenteral administration once to several times a day. Can be. This dosage can be appropriately increased or decreased depending on the type of the disease, the age, weight, and symptoms of the patient.
- the compound was prepared by dissolving in dimethyl sulfoxide.
- Human cell-derived protein phosphatase was prepared using Escherichia coli transfected with VHR gene.
- the protein tyrosine phosphatase CD45 was prepared from the cell membrane of the cultured cell Ba11-1.
- the compound of the present invention inhibits protein phosphatase Since it has an action, it is useful as a therapeutic agent for diseases caused by protein phosphatase, such as an antitumor agent, an immunosuppressant, and a therapeutic agent for diabetes.
Abstract
Pyrrolidone derivatives represented by general formula (I), wherein R1 represents hydrogen or C¿1-20? alkyl and R?2¿ represents cyano or acetyl. They are effective as remedies for diseases caused by protein dephosphorylase, for example, as an antitumor agent, an immunosuppressive agent, and a diabetes remedy.
Description
明細書 Specification
ピロリ ドン誘導体 Pyrrolidone derivative
技術分野 Technical field
本発明はピ口リ ドン誘導体に関し、 さらに詳しくはタンパク質脱リン酸化酵素 阻害作用を有するピロリ ドン誘導体に関する。 背景技術 The present invention relates to a pyridone derivative, and more particularly to a pyrrolidone derivative having a protein phosphatase inhibitory action. Background art
タンパク質のリン酸化、 脱リン酸化は生体機能の基本的な調節機構の一つであ る。 このうち、 タンパク質のリン酸化酵素を阻害する薬剤は抗腫瘍剤として数多 く報告されている。 しかし、 同じく細胞増殖にとって必須な役割をはたしている タンパク質脱リン酸化酵素に対する阻害物質については、 ほとんどその報告がな されていない。 タンパク質の脱リン酸化は、 リン酸化と同様に、 タンパク質の働 きの、 いわゆる 「スィッチ」 の役割をしており、 生体内でのタンパク質の活性、 不活性を制御していることが近年明らかになりつつある。 従って、 タンパク質の 脱リン酸化酵素の阻害は抗腫瘍剤、 免疫抑制剤などの研究分野において、 新しい 作用機序であり、 さらに特異性、 有効性に優れたタンパク質脱リン酸化酵素の阻 害剤の開発が望まれている。 発明の開示 Phosphorylation and dephosphorylation of proteins are one of the basic regulatory mechanisms of biological functions. Among them, many agents that inhibit protein kinases have been reported as antitumor agents. However, little has been reported on inhibitors of protein phosphatase, which also plays an essential role in cell growth. Protein dephosphorylation, like phosphorylation, plays a so-called “switch” role in protein activity, and it has recently been clearly shown that protein dephosphorylation controls the activity and inactivity of proteins in vivo. It is becoming. Therefore, inhibition of protein phosphatase is a new mechanism of action in research fields such as antitumor agents and immunosuppressants, and it has been reported that inhibitors of protein phosphatase with excellent specificity and efficacy are Development is desired. Disclosure of the invention
本発明者らは種々検討した結果、 ある種のピロリ ドン誘導体が優れたタンパク 質脱リン酸化酵素阻害剤となることを見出し本発明を完成した。 As a result of various studies, the present inventors have found that a certain pyrrolidone derivative is an excellent protein phosphatase inhibitor, and have completed the present invention.
すなわち本発明は、 式 （ I ) That is, the present invention provides a compound represented by the formula (I):
(式中 R 1は水素原子または炭素数 1〜 2 0のアルキル基を示し、 R 2はシァノ基 またはァセチル基を示す） で表わされるピロリ ドン誘導体である。 (Wherein R 1 represents a hydrogen atom or an alkyl group having 1 to 20 carbon atoms, and R 2 represents a cyano group or an acetyl group).
本発明において、 炭素数 1〜 2 0のアルキル基とは炭素原子数 1〜 2 0個の直 鎖状または分枝鎖状のアルキル基であり、 たとえばメチル基、 ェチル基、 プロピ
ル基、 イソプロピル基、 ブチル基、 へキシル基、 へキサデシル基、 ォク夕デシル 基などである。 In the present invention, an alkyl group having 1 to 20 carbon atoms is a linear or branched alkyl group having 1 to 20 carbon atoms, such as a methyl group, an ethyl group, and a propyl group. And isopropyl, butyl, hexyl, hexadecyl, and octadecyl.
式 （ I ) に示される本発明化合物は以下に示すような方法で合成することがで きる。 すなわち、 ジャーナル · ォブ · ジ · アメリカン ' ケミカル · ソサイァティ [J. Am. Chem. Soc.第 8 1巻、 第 4355頁 （ 1 959年） ] に記載の方法に準じ て、 2， 3—ジォキソブタンと式 The compound of the present invention represented by the formula (I) can be synthesized by the following method. That is, according to the method described in Journal of the American's Chemical Society [J. Am. Chem. Soc. Vol. 81, p. 4355 (1959)], 2,3-dioxobutane And expression
R2CH2CONHR 1 R 2 CH2CONHR 1
(式中 R1及び R2は前述と同義である。 ） で示される化合物を縮合させて得られ る化合物を、 酸で処理することによって合成することができる。 このときに用い る酸としては例えば塩酸、 臭化水素酸、 硝酸、 硫酸などの鉱酸類、 10— カン フルスルホン酸、 p—トルエンスルホン酸、 メタンスルホン酸などのスルホン酸 類などを用いることができる。 酸処理は溶媒中で行っても良く、 そのときの溶媒 としてはジォキサン、 テトラヒドロフラン、 ジメチルホルムアミ ド、 ジメチルス ルホキシド、 塩化メチレン、 クロ口ホルム、 アセトン、 トルエン、 ベンゼンなど の溶媒を用いることができる。 (Wherein R 1 and R 2 have the same meanings as described above). The compound can be synthesized by treating a compound obtained by condensing the compound represented by the formula with an acid. Examples of the acid used at this time include mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid, and sulfonic acids such as 10-camphorsulfonic acid, p-toluenesulfonic acid, and methanesulfonic acid. it can. The acid treatment may be performed in a solvent, and a solvent such as dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, acetone, toluene, benzene and the like can be used as the solvent.
本発明化合物をタンパク質脱りン酸化酵素の阻害剤として用いるには、 化合物 をそのまま、 または常法に従い製剤化することにより、 錠剤、 丸剤、 カプセル剤、 顆粒剤、 液剤、 乳剤、 懸濁剤、 注射剤などに調製し、 経口的または非経口的に投 与することができる。 In order to use the compound of the present invention as an inhibitor of protein oxidase, tablets, pills, capsules, granules, solutions, emulsions, and suspensions can be prepared by using the compound as it is or by formulating it according to a conventional method. It can be prepared as an injection or the like and administered orally or parenterally.
投与量は、 成人の患者に対して、 通常経口投与の場合、 l〜 1 000mg、 非 経口投与の場合、 0. 0 1〜 1 0 Omgを 1日 1回〜数回に分けて投与すること ができる。 この投与量は疾病の種類、 患者の年齢、 体重、 症状などにより適宜増 減することができる。 発明を実施するための最良の形態 Dosage should be administered to adult patients in the range of l to 1000 mg for oral administration and 0.01 to 10 Omg for parenteral administration once to several times a day. Can be. This dosage can be appropriately increased or decreased depending on the type of the disease, the age, weight, and symptoms of the patient. BEST MODE FOR CARRYING OUT THE INVENTION
本発明を、 実施例および試験例からさらに詳細に説明する。 The present invention will be described in more detail with reference to Examples and Test Examples.
実施例 1 Example 1
3—シァノ— 4—メチル一 5—ビニリデンー 2―ピロリ ドン (化合物 1 ) 3-cyano 4-methyl-1-5-vinylidene-2-pyrrolidone (Compound 1)
(1) 2， 3—ジォキソブタン （25. 6 g) および、 シァノアセ卜アミ ド （2 5 g) を水 （ 37. 5m l ) に溶解し 1 0 %水酸化ナトリゥム液 （0. 45m l )
を加え、 室温で 1. 5時間撹拌した。 析出した結晶を濾取して 3—シァノー 5— ヒドロキシー 4， 5 _ジメチルー 2—ピロリ ドン （融点 1 45〜 1 49 °C) を得 た。 (1) Dissolve 2,3-dioxobutane (25.6 g) and cyanoacetamide (25 g) in water (37.5 ml) and add 10% sodium hydroxide solution (0.45 ml). Was added and stirred at room temperature for 1.5 hours. The precipitated crystals were collected by filtration to obtain 3-cyano 5-hydroxy-4,5-dimethyl-2-pyrrolidone (melting point: 145 to 149 ° C).
(2) ( 1 ) の化合物 （0. 76 g) および 1 0—カンフルスルホン酸 （0. 0 7 g) を塩化メチレン （ 1 0m l ) に溶解し、 室温で 1 6時間撹拌した。 反応 混合物に水を加え、 分離した塩化メチレン層を飽和炭酸水素ナトリウム液、 続い て飽和食塩水で洗浄後、 無水硫酸ナトリウムで乾燥した後減圧留去した。 残渣を シリカゲルカラムクロマトグラフィー （クロ口ホルム ： メタノール = 9 5 ： 5) に付して化合物 1を得た。 (2) The compound of (1) (0.76 g) and 10-camphorsulfonic acid (0.07 g) were dissolved in methylene chloride (10 ml) and stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the separated methylene chloride layer was washed with a saturated sodium hydrogen carbonate solution and subsequently with a saturated saline solution, dried over anhydrous sodium sulfate, and distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 95: 5) to give compound 1.
nip. 2 00 以上 （分解） nip. 200 or more (disassembly)
'H-NMR(CDC13) δ :2.4ppm(s.3H)、 5.3ppm(dd, 2H)、 8.4ppm(bs, 1H) 'H-NMR (CDC13) δ: 2.4 ppm (s.3H), 5.3 ppm (dd, 2H), 8.4 ppm (bs, 1H)
MS(EI)m/z:134 MS (EI) m / z: 134
IR(KBr)cm— ' :3176、 2231、 1703, 1642、 1362, 1167, 895, 771, 689, 652 実施例 2 IR (KBr) cm— ': 3176, 2231, 1703, 1642, 1362, 1167, 895, 771, 689, 652 Example 2
3—ァセチルー 1—へキサデシル— 4—メチルー 5—ビニリデンー 2一ピロリ ド 3-acetyl-1 hexadecyl 4-methyl-5-vinylidene 2-pyrrolide
、 ,
(1) 2， 3—ジォキソブタン （4. 3 g) 、 N—へキサデシルァセトァセトァ ミド （ 1 6. 2 g) 、 水 （6m l ) 、 エタノール （5 0m l ) およびクロロホル ム （1 0m l ) の混合物に 1 0 %水酸化ナ卜リゥム液 （0. 2 5m l ) を加え、 1. 5時間撹拌した。 反応混合物に飽和食塩水を加えクロ口ホルムで抽出した。 クロ口ホルム層を 1 0 %水酸化ナトリウム液、 飽和食塩水で順次洗浄後、 無水硫 酸ナ卜リゥムで乾燥し溶媒を減圧留去した。 残渣をシリカゲルカラムクロマトグ ラフィ一 （展開液： クロ口ホルム） に付した後エーテルから再結晶して 3—ァセ チルー 1一へキサデシルー 5—ヒドロキシ— 4, 5一ジメチルー 2—ピロリ ドン(1) 2,3-Dioxobutane (4.3 g), N-hexadecylacetoacetamide (16.2 g), water (6 ml), ethanol (50 ml) and chloroform (10 ml) 10% sodium hydroxide solution (0.25 ml) was added to the mixture in l), and the mixture was stirred for 1.5 hours. A saturated saline solution was added to the reaction mixture, and the mixture was extracted with chloroform. The port-form layer was washed successively with a 10% sodium hydroxide solution and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (developing solution: black form), and recrystallized from ether to give 3-acetyl-11-hexadecyl-5-hydroxy-4,51-dimethyl-2-pyrrolidone.
(融点 8 3. 5〜 8 5 :) を得た。 (Melting point: 83.5 to 85 :) was obtained.
(2 ) ( 1 ) で得た化合物 （1. 0 g) および 1 0—カンフルスルホン酸 （0. 0 7 g) を塩化メチレン （ 1 0m l ) に溶解し室温で 1 6時間撹拌した。 反応混 合物に水を加え分離した塩化メチレン層を飽和炭酸水素ナトリゥム液、 続いて飽 和食塩水で洗浄後無水硫酸ナ卜リウムで乾燥した後減圧留去した。 残渣をシリカ
ゲルカラムクロマトグラフィー （展開液クロ口ホルム ： メタノール =9 5 ： 5) に付して 3—ァセチルー 1一へキサデシルー 4ーメチル— 5 -ビニリデンー 2一 ピロリ ドン （融点 66〜 6 7 °C) を得た。 試験例 (2) The compound (1.0 g) obtained in (1) and 10-camphorsulfonic acid (0.07 g) were dissolved in methylene chloride (10 ml) and stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the separated methylene chloride layer was washed with a saturated sodium hydrogen carbonate solution, subsequently with a saturated saline solution, dried over anhydrous sodium sulfate, and then distilled off under reduced pressure. Silica residue Gel column chromatography (form of developing solution: methanol = 95: 5) yielded 3-acetyl-11-hexadecyl-4-methyl-5-vinylidene-21-pyrrolidone (melting point 66-67 ° C). Was. Test example
化合物はジメチルスルホキシドに溶解して調製した。 The compound was prepared by dissolving in dimethyl sulfoxide.
試験例 1 [人細胞由来タンパク質脱リン酸化酵素阻害作用] Test Example 1 [Human cell-derived protein phosphatase inhibitory effect]
人細胞由来タンパク質脱リン酸化酵素は VHR遺伝子を導入した大腸菌により 調製した。 Human cell-derived protein phosphatase was prepared using Escherichia coli transfected with VHR gene.
試験は、 タンパク質脱リン酸化酵素に一連の希釈倍率の測定対象物を加え、 基 質としてパラニトロフエニルホスフェート （シグマ社製） を用い、 3 7 で 30 分間反応させた。 反応後 1 Nの水酸化ナトリウムを加え、 生成したパラニトロフ エノ一ルの吸光度を E I Aリーダー （モデル 2 5 5 0 :バイオラッ ド社製） で測 定して、 その数値を本発明化合物の活性の有無の判定の指標とした。 In the test, a series of dilution factors were added to the protein phosphatase, and the reaction was carried out at 37 for 30 minutes using paranitrophenyl phosphate (manufactured by Sigma) as a substrate. After the reaction, 1 N sodium hydroxide was added, and the absorbance of the generated paranitrophenol was measured with an EIA reader (Model 250: manufactured by BioRad), and the value was used to determine the presence or absence of the activity of the compound of the present invention. Was used as an index for determination.
薬剤無添加時のタンパク質脱リン酸化酵素活性を 1 00 %としたときの、 化合 物 1の添加における 5 0 %阻害活性濃度は 2 6 びであった。 試験例 2 [タンパク質脱リン酸化酵素 CD 4 5阻害作用] When the protein phosphatase activity when no drug was added was 100%, the concentration of 50% inhibitory activity in the addition of Compound 1 was 26. Test Example 2 [protein phosphatase CD45 inhibitory effect]
タンパク質チロシン脱リン酸化酵素 CD 4 5は培養細胞 B a 1 1 - 1の細胞膜 より調整した。 The protein tyrosine phosphatase CD45 was prepared from the cell membrane of the cultured cell Ba11-1.
試験は、 タンパク質脱リン酸化酵素に一連の希釈倍率の測定対象物を加え、 基 質としてホスホチロシン （シグマ社製） を用い、 3 7でで 30分間反応後 2 5 % トリクロ口酢酸で反応停止させた。 反応液と assay buffer (6N硫酸： 1 0 %ァ スコルビン酸： 2. 5 %モリブデン酸アンモニゥム：水 = 1 ： 1 ： 1 ： 2) を 3 7でで 2時間インキュべ一卜し、 生成したリンモリブデン酸の吸光度を E I Aリ —ダ一 （モデル 2 5 5 0 ：バイオラッド社製） で測定して、 これを本発明化合物 の活性の有無の判定の指標とした。 In the test, a series of dilution factors were added to the protein phosphatase, and phosphotyrosine (manufactured by Sigma) was used as a substrate. The reaction was performed at 37 for 30 minutes, and the reaction was stopped with 25% trichloroacetic acid. Was. The reaction solution and assay buffer (6N sulfuric acid: 10% ascorbic acid: 2.5% ammonium molybdate: water = 1: 1: 1: 2) were incubated at 37 for 2 hours, and the phosphorus produced The absorbance of molybdic acid was measured using an EIA lidar (Model 250: manufactured by Bio-Rad), and this was used as an index for determining the presence or absence of the activity of the compound of the present invention.
薬剤無添加時のタンパク質脱リン酸化酵素活性を 1 00 %としたときの、 化合 物 1添加における 50 %阻害活性濃度は 5 2 であった。 産業上の利用の可能性 Assuming that the protein phosphatase activity when no drug was added was 100%, the 50% inhibitory activity concentration when Compound 1 was added was 52. Industrial applicability
本発明の化合物は、 試験例から明らかなようにタンパク質脱リン酸化酵素阻害
作用を有するので、 タンパク質脱リン酸化酵素に起因する疾病治療剤、 例えば抗 腫瘍剤、 免疫抑制剤、 糖尿病治療薬などとして有用である。
As is clear from the test examples, the compound of the present invention inhibits protein phosphatase Since it has an action, it is useful as a therapeutic agent for diseases caused by protein phosphatase, such as an antitumor agent, an immunosuppressant, and a therapeutic agent for diabetes.
Claims
請求の範囲 The scope of the claims
式 （ I )
Equation (I)
(式中 R1は水素原子または炭素数 1〜20のアルキル基を示し、 R2はシァノ基 またはァセチル基を示す。 ） で示されるピロリ ドン誘導体。 (In the formula, R 1 represents a hydrogen atom or an alkyl group having 1 to 20 carbon atoms, and R 2 represents a cyano group or an acetyl group.) A pyrrolidone derivative represented by the formula:
2. 式 （ I ) で示されるピロリ ドン誘導体のタンパク質脱リン酸化酵素阻害剤 としての使用。 2. Use of a pyrrolidone derivative represented by the formula (I) as a protein phosphatase inhibitor.
3. 式 （ I ) で示されるピロリ ドン誘導体による、 タンパク質脱リン酸化酵素 に起因する疾病の治療。 3. Treatment of diseases caused by protein phosphatase with a pyrrolidone derivative represented by the formula (I).
4. 式 （ I ) で示される化合物を含む医薬組成物。
4. A pharmaceutical composition comprising the compound represented by the formula (I).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU18128/97A AU1812897A (en) | 1996-03-04 | 1997-03-03 | Pyrrolidone derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4526296 | 1996-03-04 | ||
| JP8/45262 | 1996-03-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997032847A1 true WO1997032847A1 (en) | 1997-09-12 |
Family
ID=12714386
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1997/000627 WO1997032847A1 (en) | 1996-03-04 | 1997-03-03 | Pyrrolidone derivatives |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU1812897A (en) |
| WO (1) | WO1997032847A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2583678A2 (en) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0317057A (en) * | 1989-06-15 | 1991-01-25 | Fujisawa Pharmaceut Co Ltd | New 5-membered ring heterocyclic compound |
-
1997
- 1997-03-03 AU AU18128/97A patent/AU1812897A/en not_active Abandoned
- 1997-03-03 WO PCT/JP1997/000627 patent/WO1997032847A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0317057A (en) * | 1989-06-15 | 1991-01-25 | Fujisawa Pharmaceut Co Ltd | New 5-membered ring heterocyclic compound |
Non-Patent Citations (1)
| Title |
|---|
| CHEM. BER., Vol. 108, No. 10, (1975), ROEBER, HUBERT et al., "Kondensation von 1,2-Diketonen mit 2-Cyanacetamid", p. 3262-3270. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2583678A2 (en) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
Also Published As
| Publication number | Publication date |
|---|---|
| AU1812897A (en) | 1997-09-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2150162C (en) | New n-pyridyl carboxamides and derivatives thereof, preparation processes thereof and pharmaceutical compositions containing thereof | |
| JPH072770A (en) | New substituted indole, its production and pharmaceutical composition containing said indole | |
| JP2023545784A (en) | Small molecule compounds and their uses as JAK kinase inhibitors | |
| FR2472561A1 (en) | 4-GUANIDINOMETHYLCYCLOHEXANE CARBOXYLIC ACID DERIVATIVES, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC APPLICATION | |
| JPH064616B2 (en) | 2- (piperazinyl) -2-oxoethylene-substituted flavonoid derivative, process for its production and pharmaceutical composition containing the same | |
| JP3990477B2 (en) | Neural differentiation inducer | |
| EP1911760A1 (en) | Xanthine oxidase inhibitor | |
| ZA200106198B (en) | Polycyclic 2-amino-thiazole systems, method for the production thereof and medicament containing said compounds. | |
| JPH08269062A (en) | Pyripyropene derivative | |
| WO1997032847A1 (en) | Pyrrolidone derivatives | |
| JPS625970A (en) | Pyrazine derivative and platelet coagulation inhibitor containing same | |
| JP3688337B2 (en) | Pyripyropene derivative | |
| CN102617478B (en) | Synthesis of benzimidazole, oxazole and thiazole derivatives and application thereof | |
| FR2669633A1 (en) | NOVEL BENZOSELENAZOLINONE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. | |
| JPH08269064A (en) | Pyrypropene derivative | |
| EP2650292A1 (en) | Thiazolamine derivative and use thereof as anti-picornaviral infection medicament | |
| US3755589A (en) | Compositions and methods for treating gout | |
| JPH09295968A (en) | Pyrrolidone derivative | |
| JPH01308227A (en) | Protease inhibitor | |
| US11608320B2 (en) | Oxazolidinone hydroxamic acid derivatives | |
| JPH09241160A (en) | Inhibitor of protein dephosphorylase | |
| EP0395526A1 (en) | Benzothiazolinone derivatives, process for their preparation and pharmaceutical compositions containing them | |
| EP0098204A1 (en) | Therapeutical compositions containing N-substituted hydrazones, and N-substituted hydrazones | |
| JPS63201186A (en) | Novel isoxazole derivative, manufacture and pharmacological preparation | |
| JP3491711B2 (en) | Purine derivatives and inhibitors of inflammatory diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA CN KR US |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| NENP | Non-entry into the national phase |
Ref country code: CA |
|
| 122 | Ep: pct application non-entry in european phase |