JPH07267961A - Benzofuro (3,2-d)pyrimidine-4-one derivative - Google Patents
Benzofuro (3,2-d)pyrimidine-4-one derivativeInfo
- Publication number
- JPH07267961A JPH07267961A JP6084033A JP8403394A JPH07267961A JP H07267961 A JPH07267961 A JP H07267961A JP 6084033 A JP6084033 A JP 6084033A JP 8403394 A JP8403394 A JP 8403394A JP H07267961 A JPH07267961 A JP H07267961A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- pyrimidin
- compound
- benzofuro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- PCCWPSFTRGJXEF-UHFFFAOYSA-N 1h-[1]benzofuro[3,2-d]pyrimidin-4-one Chemical class C12=CC=CC=C2OC2=C1NC=NC2=O PCCWPSFTRGJXEF-UHFFFAOYSA-N 0.000 title claims description 15
- -1 phenoxy, morpholino Chemical group 0.000 claims abstract description 48
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000005843 halogen group Chemical group 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004149 thio group Chemical group *S* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 59
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 abstract description 11
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 abstract description 11
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 abstract description 10
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 abstract description 10
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 3
- 206010012438 Dermatitis atopic Diseases 0.000 abstract description 3
- 206010019280 Heart failures Diseases 0.000 abstract description 3
- 206010020772 Hypertension Diseases 0.000 abstract description 3
- 206010039085 Rhinitis allergic Diseases 0.000 abstract description 3
- 201000010105 allergic rhinitis Diseases 0.000 abstract description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 abstract description 3
- 208000006673 asthma Diseases 0.000 abstract description 3
- 201000008937 atopic dermatitis Diseases 0.000 abstract description 3
- 206010006451 bronchitis Diseases 0.000 abstract description 3
- DSGFTYZIGJFOAN-UHFFFAOYSA-N 2-(2-ethoxy-5-nitrophenyl)-1h-[1]benzofuro[3,2-d]pyrimidin-4-one Chemical compound CCOC1=CC=C([N+]([O-])=O)C=C1C(N1)=NC(=O)C2=C1C1=CC=CC=C1O2 DSGFTYZIGJFOAN-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract description 2
- DDKMFOUTRRODRE-UHFFFAOYSA-N chloromethanone Chemical compound Cl[C]=O DDKMFOUTRRODRE-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 206010061216 Infarction Diseases 0.000 abstract 1
- 230000000747 cardiac effect Effects 0.000 abstract 1
- 230000007574 infarction Effects 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- YAYOVHRLVOHYMW-UHFFFAOYSA-N 1h-pyrimidin-6-one;hydrochloride Chemical compound Cl.O=C1C=CN=CN1 YAYOVHRLVOHYMW-UHFFFAOYSA-N 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 230000008602 contraction Effects 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 3
- FXOYSSLDDDZIJN-UHFFFAOYSA-N 3-amino-1-benzofuran-2-carboxamide Chemical compound C1=CC=C2C(N)=C(C(=O)N)OC2=C1 FXOYSSLDDDZIJN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000001746 atrial effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229940014800 succinic anhydride Drugs 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- NFFGYPZZLADIOH-UHFFFAOYSA-N N-(2-cyanophenoxy)acetamide Chemical compound C(C)(=O)NOC1=C(C=CC=C1)C#N NFFGYPZZLADIOH-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
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- 230000001684 chronic effect Effects 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229950007919 egtazic acid Drugs 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
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- 230000002269 spontaneous effect Effects 0.000 description 2
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- QHKJIJXBJCOABP-UHFFFAOYSA-N 1-benzofuran-2-carboxamide Chemical compound C1=CC=C2OC(C(=O)N)=CC2=C1 QHKJIJXBJCOABP-UHFFFAOYSA-N 0.000 description 1
- BCMYXYHEMGPZJN-UHFFFAOYSA-N 1-chloro-2-isocyanatoethane Chemical compound ClCCN=C=O BCMYXYHEMGPZJN-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- XQGBYCCEKJFWLD-UHFFFAOYSA-N 2-ethoxy-5-nitrobenzoyl chloride Chemical compound CCOC1=CC=C([N+]([O-])=O)C=C1C(Cl)=O XQGBYCCEKJFWLD-UHFFFAOYSA-N 0.000 description 1
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- IPDVDSDZXBRDGY-UHFFFAOYSA-N 5-nitro-2-propoxybenzoyl chloride Chemical compound CCCOC1=CC=C([N+]([O-])=O)C=C1C(Cl)=O IPDVDSDZXBRDGY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- PMRYVIKBURPHAH-UHFFFAOYSA-N methimazole Chemical compound CN1C=CNC1=S PMRYVIKBURPHAH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical group OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、サイクリックＧＭＰ特
異的ホスホジエステラーゼ阻害作用を有するベンゾフロ
［３，２−ｄ］ピリミジン−４−オン誘導体に関する。TECHNICAL FIELD The present invention relates to a benzofuro [3,2-d] pyrimidin-4-one derivative having a cyclic GMP-specific phosphodiesterase inhibitory activity.
【０００２】[0002]
【従来の技術】従来、ピリミジノン骨格を有するサイク
リックＧＭＰ特異的ホスホジエステラーゼ阻害剤とし
て、特開平２−５６４８４号公報、同２−２９５９７８
号公報、欧州特許出願公開５２６００４号などの化合物
が知られているが、ベンゾフロ［３，２−ｄ］ピリミジ
ン−４−オン骨格を有するものは知られていない。Conventionally, as cyclic GMP-specific phosphodiesterase inhibitors having a pyrimidinone skeleton, JP-A-2-56484 and JP-A-2-295978 have been proposed.
Compounds such as Japanese Patent Publication No. EP-A-526004 and European Patent Application Publication No. 526004 are known, but those having a benzofuro [3,2-d] pyrimidin-4-one skeleton are not known.
【０００３】[0003]
【発明が解決しようとする課題】本発明の目的は、新し
いタイプのサイクリックＧＭＰ特異的ホスホジエステラ
ーゼ阻害作用を有する化合物を提供し、ひいては高血
圧、狭心症、心筋梗塞、心不全、動脈硬化、喘息、気管
支炎のごとき慢性可逆閉塞性肺炎、アトピー性皮膚炎お
よびアレルギー性鼻炎などの治療に役立てることにあ
る。The object of the present invention is to provide a compound having a novel type of cyclic GMP-specific phosphodiesterase inhibitory activity, and by extension, hypertension, angina, myocardial infarction, heart failure, arteriosclerosis, asthma, It is useful for treating chronic reversible obstructive pneumonia such as bronchitis, atopic dermatitis and allergic rhinitis.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、サイクリ
ックＧＭＰ特異的ホスホジエステラーゼ阻害作用を有す
る化合物を鋭意検討した結果、ある種のベンゾフロ
［３，２−ｄ］ピリミジン−４−オン骨格を有する化合
物が当該目的を満たすことを見いだし、更にその知見に
基づき本発明を完成した。Means for Solving the Problems As a result of diligent studies of compounds having a cyclic GMP-specific phosphodiesterase inhibitory action, the present inventors have found that a certain benzofuro [3,2-d] pyrimidin-4-one skeleton It was found that the compound possessed fulfills the object, and based on this finding, the present invention has been completed.
【０００５】すなわち本発明は、That is, the present invention is
【０００６】式（Ｉ） Formula (I)
【０００７】［式中、Ｒ1は炭素原子数１〜４個のアル
キル基を示し、ｎは０〜４を示し、Ｘはハロゲン原子、
カルボキシル基、フェノキシ基、（１−メチル−１Ｈ−
イミダゾール−２−イル）チオ基またはＲ2Ｒ3Ｎ基を示
す。[In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms, n represents 0 to 4, X represents a halogen atom,
Carboxyl group, phenoxy group, (1-methyl-1H-
Imidazol-2-yl) thio group or R 2 R 3 N group is shown.
【０００８】ここでＲ2、Ｒ3は同一もしくは異なってい
ても良く水素原子、炭素原子数１〜４個のハロゲン化ア
ルキル基、炭素原子数１〜４個のアルキル基または炭素
原子数１〜４個のヒドロキシアルキル基を示すか、Ｒ2
Ｒ3Ｎ基としてピペリジノ基、モルホリノ基、ピロリジ
ノ基、４−ヒドロキシピペリジノ基、４−（２−ヒドロ
キシエチル）ピペラジノ基、３−ヒドロキシピロリジノ
基または１，２，３，４−テトラヒドロイソキノリジノ
基を示す。］で表されるベンゾフロ［３，２−ｄ］ピリ
ミジン−４−オン誘導体およびその塩および式（ＩＩ）R 2 and R 3 may be the same or different and each may be a hydrogen atom, a halogenated alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms or 1 to 4 carbon atoms. Shows four hydroxyalkyl groups or R 2
As R 3 N group, piperidino group, morpholino group, pyrrolidino group, 4-hydroxypiperidino group, 4- (2-hydroxyethyl) piperazino group, 3-hydroxypyrrolidino group or 1,2,3,4-tetrahydroiso A quinolidino group is shown. ] The benzofuro [3,2-d] pyrimidin-4-one derivative represented by these, its salt, and Formula (II)
【０００９】 [0009]
【００１０】［式中、Ｒ1は炭素原子数１〜４個のアル
キル基を示し、Ｙはアミノ基またはニトロ基を示す。］
で表されるベンゾフロ［３，２−ｄ］ピリミジン−４−
オン誘導体およびその塩である。[In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms, and Y represents an amino group or a nitro group. ]
Benzofuro [3,2-d] pyrimidine-4-
One derivatives and salts thereof.
【００１１】本発明において、炭素原子数１〜４個のア
ルキル基とは、メチル基、エチル基、プロピル基、イソ
プロピル基などの直鎖状または分枝鎖状のアルキル基を
いう。炭素原子数１〜４個のハロゲン化アルキル基と
は、２−クロロエチル基、２−クロロプロピル基，３−
クロロプロピル基、３−ブロモプロピル基、２−クロロ
−１−メチルエチル基などの直鎖状または分枝鎖状のヒ
ドロキシアルキル基をいう。炭素原子数１〜４個のヒド
ロキシアルキル基とは、２−ヒドロキシエチル基、３−
ヒドロキシプロピル基、２−ヒドロキシ−１−メチルエ
チル基などの直鎖状または分枝鎖状のヒドロキシアルキ
ル基をいう。また、ハロゲン原子とは、フッ素原子、臭
素原子、塩素原子をいう。In the present invention, the alkyl group having 1 to 4 carbon atoms means a linear or branched alkyl group such as methyl group, ethyl group, propyl group and isopropyl group. The halogenated alkyl group having 1 to 4 carbon atoms means 2-chloroethyl group, 2-chloropropyl group, 3-
A linear or branched hydroxyalkyl group such as a chloropropyl group, a 3-bromopropyl group, and a 2-chloro-1-methylethyl group. The hydroxyalkyl group having 1 to 4 carbon atoms means a 2-hydroxyethyl group, 3-
A linear or branched hydroxyalkyl group such as a hydroxypropyl group and a 2-hydroxy-1-methylethyl group. Further, the halogen atom means a fluorine atom, a bromine atom or a chlorine atom.
【００１２】本発明の化合物は、例えば以下のような方
法により製造することができる。The compound of the present invention can be produced, for example, by the following method.
【００１３】出発原料である式（ＩＩＩ）The starting material of formula (III)
【００１４】 [0014]
【００１５】で表される化合物と式（ＩＶ）The compound represented by the formula (IV)
【００１６】 [0016]
【００１７】［式中、Ｒ1は前記と同意義である。］で
表される化合物を塩基存在下反応し、式（Ｖ）[In the formula, R 1 has the same meaning as described above. ] The compound represented by the formula (V)
【００１８】 [0018]
【００１９】［式中、Ｒ1は前記と同意義である。］で
表される化合物を得る。[In the formula, R 1 has the same meaning as described above. ] The compound represented by this is obtained.
【００２０】ここで、塩基としてはトリエチルアミン、
ピリジン等の有機塩基を用いることができ、反応溶媒と
してはＮ，Ｎ−ジメチルホルムアミド、テトラヒドロフ
ラン、アセトン等の溶媒を単独または混合して用いるこ
とができる。反応温度は０℃から還流温度である。Here, the base is triethylamine,
An organic base such as pyridine can be used, and a solvent such as N, N-dimethylformamide, tetrahydrofuran or acetone can be used alone or in combination as a reaction solvent. The reaction temperature is from 0 ° C to the reflux temperature.
【００２１】ついで、式（Ｖ）で表される化合物を塩基
で処理することにより、式（ＶＩ）Then, the compound of formula (V) is treated with a base to give a compound of formula (VI)
【００２２】 [0022]
【００２３】で表される化合物を得、更に式（ＶＩ）を
還元することにより、式（ＶＩＩ）The compound of formula (VII) is obtained by further reducing the compound of formula (VI).
【００２４】 [0024]
【００２５】［式中、Ｒ1は前記と同意義である。］で
表される化合物を得る。[In the formula, R 1 has the same meaning as described above. ] The compound represented by this is obtained.
【００２６】ここで用いる塩基としては水酸化カリウ
ム、水酸化ナトリウム等の無機塩基を用いることがで
き、溶媒としてはメタノール、エタノール等のアルコー
ル系溶媒を用いることができ、また、過酸化水素水を添
加することもできる。反応温度は、室温から還流温度で
ある。As the base used here, an inorganic base such as potassium hydroxide or sodium hydroxide can be used, and as the solvent, an alcohol solvent such as methanol or ethanol can be used. It can also be added. The reaction temperature is from room temperature to reflux temperature.
【００２７】また、還元剤としてはパラジウム炭素−水
素，塩化ニッケル−水素化ホウ素ナトリウム、鉄−酢酸
等の還元剤を用いることができ、反応溶媒としてはメタ
ノール、エタノール、テトラヒドロフラン、酢酸等の溶
媒を単独または混合して用いることができる。反応温度
は０℃から還流温度である。式（ＶＩＩ）で表される化
合物に塩基存在下式（ＶＩＩＩ） ＣｌＣＯ（ＣＨ2）nＺ （ＶＩＩＩ） ［式中、ｎは前記と同意義であり、Ｚはハロゲン原子、
フェノキシ基またはモルホリノ基を示す。］で表される
酸ハロゲン化物を反応させ、式（ＩＸ）As the reducing agent, palladium carbon-hydrogen, nickel chloride-sodium borohydride, iron-acetic acid or the like can be used, and the reaction solvent is a solvent such as methanol, ethanol, tetrahydrofuran or acetic acid. They can be used alone or as a mixture. The reaction temperature is from 0 ° C to the reflux temperature. Formula (VIII) ClCO (CH 2 ) n Z (VIII) in the presence of a base in the compound represented by formula (VII) [wherein n is as defined above, Z is a halogen atom,
A phenoxy group or a morpholino group is shown. ] By reacting with an acid halide represented by the formula (IX)
【００２８】 [0028]
【００２９】［式中、ｎ、Ｒ1、Ｚは前記と同意義であ
る］で表される化合物を得る。A compound represented by the formula: wherein n, R 1 and Z are as defined above is obtained.
【００３０】ここで用いる塩基としてはトリエチルアミ
ン、ピリジン等の有機塩基を用いることができ、溶媒と
してはＮ，Ｎ−ジメチルホルムアミド、テトラヒドロフ
ラン、アセトン等の溶媒を用いることができる。反応温
度は、室温から還流温度である。The base used here may be an organic base such as triethylamine or pyridine, and the solvent may be a solvent such as N, N-dimethylformamide, tetrahydrofuran or acetone. The reaction temperature is from room temperature to reflux temperature.
【００３１】ついで、式（ＩＸ）において、Ｚ＝Ｃｌで
ある化合物（Ｘ）Then, in the formula (IX), the compound (X) in which Z = Cl
【００３２】 [0032]
【００３３】［式中、ｎ、Ｒ1は前記と同意義である］
で表される化合物と１〜５当量の式（ＸＩ） Ｒ2Ｒ3ＮＨ （ＸＩ） ［式中、Ｒ2、Ｒ3は前記と同意義である。］で表される
アミンを反応させることにより式（ＸＩＩ）[In the formula, n and R 1 have the same meanings as described above]
1 to 5 equivalents of a compound represented by the formula (XI) R 2 R 3 NH (XI) [In the formula, R 2 and R 3 have the same meanings as described above. ] By reacting an amine represented by the formula (XII)
【００３４】 [0034]
【００３５】［式中、Ｒ1、Ｒ2、Ｒ3およびｎは前記と
同意義である。］で表される化合物を得ることができ
る。[In the formula, R 1 , R 2 , R 3 and n have the same meanings as described above. ] The compound represented by these can be obtained.
【００３６】ここで、反応溶媒としてはＮ，Ｎ−ジメチ
ルホルムアミド、テトラヒドロフラン、アセトン等の溶
媒を用いることができる。反応温度は０℃から還流温度
である。Here, a solvent such as N, N-dimethylformamide, tetrahydrofuran or acetone can be used as the reaction solvent. The reaction temperature is from 0 ° C to the reflux temperature.
【００３７】また、式（ＶＩＩ）の化合物と式（ＸＩＩ
Ｉ） Ｒ4ＮＣＯ （ＸＩＩＩ） ［式中、Ｒ4は炭素原子数１〜４個のアルキル基または
炭素原子数１〜４個のハロゲン化アルキル基を示す。］
で表される化合物を１〜３当量の反応させることにより
式（ＸＩＶ）Further, the compound of formula (VII) and the compound of formula (XII
I) R 4 NCO (XIII) [In the formula, R 4 represents an alkyl group having 1 to 4 carbon atoms or a halogenated alkyl group having 1 to 4 carbon atoms. ]
The compound represented by the formula (XIV)
【００３８】 [0038]
【００３９】［式中、Ｒ1、Ｒ4は前記と同意義である］
を得ることができる。[Wherein R 1 and R 4 have the same meanings as described above]
Can be obtained.
【００４０】また、式（ＶＩＩ）の化合物と式（ＸＶ）
で表される無水コハク酸Further, the compound of formula (VII) and the compound of formula (XV)
Succinic anhydride represented by
【００４１】 [0041]
【００４２】で表される化合物を反応させることによ
り、式（ＸＶＩ）By reacting the compound represented by the formula (XVI)
【００４３】 [0043]
【００４４】［式中、Ｒ1は前記と同意義である］で表
される化合物を得ることができる。A compound represented by the formula [wherein R 1 has the same meaning as defined above] can be obtained.
【００４５】ここで、反応溶媒としてはＮ，Ｎ−ジメチ
ルホルムアミド、テトラヒドロフラン、アセトン等の溶
媒を用いることができる。反応温度は０℃から還流温度
である。Here, a solvent such as N, N-dimethylformamide, tetrahydrofuran or acetone can be used as the reaction solvent. The reaction temperature is from 0 ° C to the reflux temperature.
【００４６】また、式（Ｘ）で表される化合物と式（Ｘ
ＶＩＩ）Further, the compound represented by the formula (X) and the compound represented by the formula (X
VII)
【００４７】 [0047]
【００４８】で表される２−メルカプト−１−メチル−
１Ｈ−イミダゾールを塩基存在下、反応させることによ
り式（ＸＶＩＩＩ）2-mercapto-1-methyl-represented by
By reacting 1H-imidazole in the presence of a base, the compound of formula (XVIII)
【００４９】 [0049]
【００５０】［式中、ｎ、Ｒ1は前記と同意義である］
で表される化合物を得ることができる。 ここで、反応
溶媒としてはＮ，Ｎ−ジメチルホルムアミド、メタノー
ル、アセトン等の溶媒を用いることができ、塩基として
は炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウ
ム、水酸化ナトリウム、水酸化カリウム等の無機塩基を
用いることができる。反応温度としては０℃から還流温
度である。[In the formula, n and R 1 have the same meanings as above]
A compound represented by can be obtained. Here, a solvent such as N, N-dimethylformamide, methanol or acetone can be used as a reaction solvent, and an inorganic base such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide can be used as a base. Can be used. The reaction temperature is 0 ° C to the reflux temperature.
【００５１】[0051]
【発明の効果】本発明の化合物は、優れたサイクリック
ＧＭＰ特異的ホスホジエステラーゼ阻害作用を有するの
で、高血圧、狭心症、心筋梗塞、心不全、動脈硬化、喘
息、気管支炎のごとき慢性可逆閉塞性肺炎、アトピー性
皮膚炎およびアレルギー性鼻炎などの治療に役立てるこ
とができる。The compound of the present invention has an excellent cyclic GMP-specific phosphodiesterase inhibitory action, and therefore, chronic reversible obstructive pneumonia such as hypertension, angina, myocardial infarction, heart failure, arteriosclerosis, asthma and bronchitis. , Can be used to treat atopic dermatitis and allergic rhinitis.
【００５２】[0052]
【実施例】以下、参考例、実施例および試験例を挙げて
本発明を更に詳細に説明する。EXAMPLES The present invention will be described in more detail below with reference to reference examples, examples and test examples.
【００５３】参考例３−アミノベンゾフラン−２−カルボキサミド 標記化合物はＪ．Ｐｒａｋｔ．Ｃｈｅｍ．、３１５巻、
７７９ページ（１９７３年、Ｋ．Ｇｅｗａｌｄら）に記
載された方法に準じて市販の２−シアニフェノールより
合成した。 （１）２−シアノフェノール２５．４２ｇのＮ，Ｎ−ジ
メチルホルムアミド３００ｍｌ溶液に、２−クロロアセ
タミド２１．９７ｇ（１．１当量）、ヨウ化カリウム３
９．０１ｇ（１．１当量）および炭酸カリウム５８．９
６ｇ（２．０当量）を加え、室温で６時間攪拌した。一
晩放置後、反応液を水にあけ、析出した結晶を濾取し、
乾燥して（２−シアノフェノキシ）アセタミド３０．５
３ｇを得た。このものは精製することなしに次の反応に
用いた。 （２）（２−シアノフェノキシ）アセタミド３０．５３
ｇのエタノール３００ｍｌ懸濁液に水酸化カリウム１
９．４３ｇ（２．０当量）を加え、７時間還流した。反
応溶液を水にあけ、析出した結晶を濾取、乾燥して標記
化合物２５．７０ｇを得た。このものは精製せずに次の
反応に用いた。Reference Example 3-Aminobenzofuran-2-carboxamide Prakt. Chem. Volume 315,
Synthesized from commercially available 2-caniphenol according to the method described on page 779 (1973, K. Gewald et al.). (1) 2-chloroacetamide 21.97 g (1.1 equivalent) and potassium iodide 3 were added to a solution of 2-cyanophenol 25.42 g and N, N-dimethylformamide 300 ml.
9.01 g (1.1 eq) and potassium carbonate 58.9
6 g (2.0 equivalent) was added, and the mixture was stirred at room temperature for 6 hours. After standing overnight, the reaction solution was poured into water, and the precipitated crystals were collected by filtration,
Dried (2-cyanophenoxy) acetamide 30.5
3 g was obtained. This product was used in the next reaction without purification. (2) (2-Cyanophenoxy) acetamide 30.53
g of ethanol 300ml suspension in potassium hydroxide 1
9.43 g (2.0 equivalents) was added and the mixture was refluxed for 7 hours. The reaction solution was poured into water, and the precipitated crystals were collected by filtration and dried to obtain 25.70 g of the title compound. This product was used in the next reaction without purification.
【００５４】実施例１３，４−ジヒドロ−２−（２−エトキシ−５−ニトロフ
ェニル）ベンゾフロ［３，２−ｄ］ピリミジン−４−オ
ン （１）３−アミノベンゾフラン−２−カルボキサミド
８．８０ｇとトリエチルアミン５．５６ｇ（１．１当
量）のアセトン１００ｍｌ溶液を氷冷し、２−エトキシ
−５−ニトロベンゾイルクロライド１１．４８ｇ（１．
１当量）を加え、５時間攪拌した。Example 1 3,4-Dihydro-2- (2-ethoxy-5-nitrof
Phenyl) benzofuro [3,2-d] pyrimidin-4-o
Switch (1) 3-amino-benzofuran-2-carboxamide 8.80g and acetone 100ml solution of triethylamine 5.56 g (1.1 eq) was ice-cooled, 2-ethoxy-5-nitrobenzoyl chloride 11.48 g (1.
1 equivalent) was added and stirred for 5 hours.
【００５５】一晩放置したのち、反応溶液を水にあけ、
３０分間攪拌した。析出した結晶を濾取し、乾燥して３
−（２−エトキシ−５−ニトロベンゾイルアミノ）ベン
ゾフラン−２−カルボキサミド１５．６３ｇを得た。こ
のものは精製することなしに次の反応に用いた。After standing overnight, the reaction solution was poured into water,
Stir for 30 minutes. The precipitated crystals are collected by filtration, dried and then 3
15.63 g of-(2-ethoxy-5-nitrobenzoylamino) benzofuran-2-carboxamide was obtained. This product was used in the next reaction without purification.
【００５６】（２）３−（２−エトキシ−５−ニトロベ
ンゾイルアミノ）ベンゾフラン−２−カルボキサミド１
３．９１ｇのメタノール２００ｍｌ溶液に水酸化カリウ
ム６．３３ｇ（３．０当量）、３０％過酸化水素水１３
ｍｌおよび水１００ｍｌを加え、４時間還流した。反応
液を室温まで冷却したのち、水にあけ、塩酸酸性にして
析出した結晶を濾取、乾燥して標記化合物５．１８ｇを
得た。(2) 3- (2-ethoxy-5-nitrobenzoylamino) benzofuran-2-carboxamide 1
A solution of 3.91 g of methanol in 200 ml of potassium hydroxide 6.33 g (3.0 equivalents), 30% hydrogen peroxide solution 13
ml and 100 ml of water were added and refluxed for 4 hours. The reaction solution was cooled to room temperature, poured into water, acidified with hydrochloric acid, and the precipitated crystals were collected by filtration and dried to obtain 5.18 g of the title compound.
【００５７】ｍ．ｐ．２８０〜２８２℃M. p. 280 to 282 ° C
【００５８】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
１．３６（３Ｈ，ｔ，Ｊ＝７Ｈｚ），４．２９（２Ｈ，
ｑ，Ｊ＝７Ｈｚ），７．４２（１Ｈ，ｄ，Ｊ＝８Ｈ
ｚ），７．５２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７１
（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．８８（１Ｈ，ｄ，Ｊ＝
８Ｈｚ），８．１２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．４
３（１Ｈ，ｄｄ，Ｊ＝２，８Ｈｚ），８．５５（１Ｈ，
ｄ，Ｊ＝２Ｈｚ），１２．９８（１Ｈ，ｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
1.36 (3H, t, J = 7Hz), 4.29 (2H,
q, J = 7Hz), 7.42 (1H, d, J = 8H
z), 7.52 (1H, t, J = 8Hz), 7.71
(1H, t, J = 8Hz), 7.88 (1H, d, J =
8 Hz), 8.12 (1H, d, J = 8 Hz), 8.4
3 (1H, dd, J = 2, 8Hz), 8.55 (1H,
d, J = 2 Hz), 12.98 (1H, s).
【００５９】実施例２３，４−ジヒドロ−２−（５−ニトロ−２−プロポキシ
フェニル）ベンゾフロ［３，２−ｄ］ピリミジン−４−
オン 実施例１と同様にして３−アミノベンゾフラン−２−カ
ルボキサミドと５−ニトロ−２−プロポキシベンゾイル
クロライドから標記化合物を得た。Example 2 3,4-dihydro-2- (5-nitro-2-propoxy
Phenyl) benzofuro [3,2-d] pyrimidine-4-
On In the same manner as in Example 1, the title compound was obtained from 3-aminobenzofuran-2-carboxamide and 5-nitro-2-propoxybenzoyl chloride.
【００６０】ｍ．ｐ．２３０〜２３２℃M. p. 230-232 ° C
【００６１】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
０．９４（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．７５（２Ｈ，
ｓｅｘｔ，Ｊ＝７Ｈｚ），４．１９（２Ｈ，ｔ，Ｊ＝７
Ｈｚ），７．４３（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．５３
（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７１（１Ｈ，ｔ，Ｊ＝
８Ｈｚ），７．８８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．１
２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．４３（１Ｈ，ｄｄ，
Ｊ＝２，８Ｈｚ），８．５５（１Ｈ，ｄ，Ｊ＝２Ｈ
ｚ），１２．９６（１Ｈ，ｂｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
0.94 (3H, t, J = 7Hz), 1.75 (2H,
sext, J = 7 Hz), 4.19 (2H, t, J = 7)
Hz), 7.43 (1H, d, J = 8 Hz), 7.53
(1H, t, J = 8Hz), 7.71 (1H, t, J =
8 Hz), 7.88 (1H, d, J = 8 Hz), 8.1
2 (1H, d, J = 8Hz), 8.43 (1H, dd,
J = 2,8 Hz), 8.55 (1H, d, J = 2H
z), 12.96 (1H, bs).
【００６２】実施例３２−（５−アミノ−２−エトキシフェニル）−３，４−
ジヒドロベンゾフロ［３，２−ｄ］ピリミジン−４−オ
ン塩酸塩 塩化ニッケル六水和物４．７４ｇ（２当量）のメタノー
ル７０ｍｌ溶液と２−（２−エトキシ−５−ニトロフェ
ニル）−３，４−ジヒドロベンゾフロ［３，２−ｄ］ピ
リミジン−４−オン３．５１ｇのテトラヒドロフラン３
５０ｍｌ溶液を混合した後、氷冷下で水素化ホウ素ナト
リウム１．４８ｇ（４当量）を少しずつ加えた。反応溶
液を３時間攪拌した後、溶媒を減圧留去した。Example 3 2- (5-amino-2-ethoxyphenyl) -3,4-
Dihydrobenzofuro [3,2-d] pyrimidin-4-o
Hydrochloride nickel chloride hexahydrate 4.74 g (2 equivalents) in 70 ml of methanol and 2- (2-ethoxy-5-nitrophenyl) -3,4-dihydrobenzofuro [3,2-d] pyrimidine- 4-one 3.51 g of tetrahydrofuran 3
After mixing the 50 ml solution, 1.48 g (4 equivalents) of sodium borohydride was added little by little under ice cooling. After the reaction solution was stirred for 3 hours, the solvent was distilled off under reduced pressure.
【００６３】残留にを２Ｎ塩酸２４０ｍｌを加え、１時
間攪拌した。析出した結晶を濾取、減圧乾燥して標記化
合物３．２８ｇを得た。このものは精製することなしに
次の反応に用いた。To the residue was added 240 ml of 2N hydrochloric acid, and the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (3.28 g). This product was used in the next reaction without purification.
【００６４】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
１．３５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），４．１７（２Ｈ，
ｑ，Ｊ＝７Ｈｚ），７．２９（１Ｈ，ｄ，Ｊ＝８Ｈ
ｚ），７．５０（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．５２
（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７１（１Ｈ，ｔ，Ｊ＝
８Ｈｚ），７．７４（１Ｈ，ｓ），７．８８（１Ｈ，
ｄ，Ｊ＝８Ｈｚ），８．０６（１Ｈ，ｄ，Ｊ＝８Ｈ
ｚ），１２．８０（１Ｈ，ｂｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
1.35 (3H, t, J = 7Hz), 4.17 (2H,
q, J = 7 Hz), 7.29 (1H, d, J = 8H
z), 7.50 (1H, d, J = 8 Hz), 7.52
(1H, t, J = 8Hz), 7.71 (1H, t, J =
8 Hz), 7.74 (1H, s), 7.88 (1H,
d, J = 8 Hz), 8.06 (1H, d, J = 8H
z), 12.80 (1H, bs).
【００６５】実施例４２−（５−アミノ−２−プロポキシフェニル）−３，４
−ジヒドロベンゾフロ［３，２−ｄ］ピリミジン−４−
オン塩酸塩 実施例３と同様にして３，４−ジヒドロ−２−（５−ニ
トロ−２−プロポキシフェニル）ベンゾフロ［３，２−
ｄ］ピリミジン−４−オンから標記化合物を得た。この
ものは精製することなしに次の反応に用いた。Example 4 2- (5-Amino-2-propoxyphenyl) -3,4
-Dihydrobenzofuro [3,2-d] pyrimidine-4-
O- hydrochloride 3,4-dihydro-2- (5-nitro-2-propoxyphenyl) benzofuro [3,2-similar to Example 3.
The title compound was obtained from d] pyrimidin-4-one. This product was used in the next reaction without purification.
【００６６】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
０．９５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．７４（２Ｈ，
ｓｅｘｔ，Ｊ＝７Ｈｚ），４．０８（２Ｈ，ｔ，Ｊ＝７
Ｈｚ），７．３２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．５２
（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．５７（１Ｈ，ｄｄ，Ｊ
＝２，８Ｈｚ），７．７１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
７．７９（１Ｈ，ｄ，Ｊ＝２Ｈｚ），７．８８（１Ｈ，
ｄ，Ｊ＝８Ｈｚ），８．０７（１Ｈ，ｄ，Ｊ＝８Ｈ
ｚ），１０．３３（３Ｈ，ｂｓ），１２．７８（１Ｈ，
ｂｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
0.95 (3H, t, J = 7Hz), 1.74 (2H,
sext, J = 7 Hz), 4.08 (2H, t, J = 7)
Hz), 7.32 (1H, d, J = 8 Hz), 7.52
(1H, t, J = 8Hz), 7.57 (1H, dd, J
= 2,8 Hz), 7.71 (1H, t, J = 8 Hz),
7.79 (1H, d, J = 2Hz), 7.88 (1H,
d, J = 8 Hz), 8.07 (1H, d, J = 8H
z), 10.33 (3H, bs), 12.78 (1H,
bs).
【００６７】実施例５２−（５−クロロアセタミド−２−エトキシフェニル）
−３，４−ジヒドロベンゾフロ［３，２−ｄ］ピリミジ
ン−４−オン ２−（５−アミノ−２−エトキシフェニル）−３，４−
ジヒドロベンゾフロ［３，２−ｄ］ピリミジン−４−オ
ン塩酸塩０．７０ｇとトリエチルアミン０．４４ｇ
（２．２当量）のＮ，Ｎ−ジメチルホルムアミド４０ｍ
ｌ溶液に氷冷下でクロロアセチルクロライド０．２７ｇ
（１．２当量）を滴加した。Example 5 2- (5-chloroacetamido-2-ethoxyphenyl)
-3,4-dihydrobenzofuro [3,2-d] pyrimidi
N-4-one 2- (5-amino-2-ethoxyphenyl) -3,4-
0.70 g of dihydrobenzofuro [3,2-d] pyrimidin-4-one hydrochloride and 0.44 g of triethylamine
(2.2 equivalents) of N, N-dimethylformamide 40 m
0.27 g of chloroacetyl chloride in 1 solution under ice cooling
(1.2 eq) was added dropwise.
【００６８】反応溶液を１時間攪拌したのち、水にあ
け、塩酸酸性にした。析出した結晶を濾取し、乾燥して
標記化合物０．６８ｇを得た。このものは精製すること
なしに次の反応に用いた。After the reaction solution was stirred for 1 hour, it was poured into water and acidified with hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain 0.68 g of the title compound. This product was used in the next reaction without purification.
【００６９】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
１．３４（３Ｈ，ｔ，Ｊ＝７Ｈｚ），４．１５（２Ｈ，
ｑ，Ｊ＝７Ｈｚ），４．２６（２Ｈ，ｓ），７．１９
（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．５２（１Ｈ，ｔ，Ｊ＝
８Ｈｚ），７．７０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７
８（１Ｈ，ｄｄ，Ｊ＝２，８Ｈｚ），７．８７（１Ｈ，
ｄ，Ｊ＝８Ｈｚ），８．０２（１Ｈ，ｄ，Ｊ＝２Ｈ
ｚ），８．０８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），１０．３９
（１Ｈ，ｓ），１２．６８（１Ｈ，ｂｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
1.34 (3H, t, J = 7Hz), 4.15 (2H,
q, J = 7 Hz), 4.26 (2H, s), 7.19
(1H, d, J = 8Hz), 7.52 (1H, t, J =
8Hz), 7.70 (1H, t, J = 8Hz), 7.7
8 (1H, dd, J = 2, 8Hz), 7.87 (1H,
d, J = 8 Hz), 8.02 (1H, d, J = 2H
z), 8.08 (1H, d, J = 8Hz), 10.39
(1H, s), 12.68 (1H, bs).
【００７０】実施例６２−（５−クロロアセタミド−２−プロポキシフェニ
ル）−３，４−ジヒドロベンゾフロ［３，２−ｄ］ピリ
ミジン−４−オン 実施例５と同様にして２−（５−アミノ−２−プロポキ
シフェニル）−３，４−ジヒドロベンゾフロ［３，２−
ｄ］ピリミジン−４−オン塩酸塩とクロロアセチルクロ
ライドから標記化合物を得た。このものは精製すること
なしに次の反応に用いた。Example 6 2- (5-chloroacetamide-2-propoxypheni
) -3,4-Dihydrobenzofuro [3,2-d] pyri
Midin-4-one 2- (5-amino-2-propoxyphenyl) -3,4-dihydrobenzofuro [3,2-similar to Example 5.
The title compound was obtained from d] pyrimidin-4-one hydrochloride and chloroacetyl chloride. This product was used in the next reaction without purification.
【００７１】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
０．９６（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．７４（２Ｈ，
ｓｅｘｔ，Ｊ＝７Ｈｚ），４．０５（２Ｈ，ｔ，Ｊ＝７
Ｈｚ），４．２４（２Ｈ，ｓ），７．２０（１Ｈ，ｄ，
Ｊ＝８Ｈｚ），７．５２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
７．７０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７８（１Ｈ，
ｄｄ，Ｊ＝２，８Ｈｚ），７．８６（１Ｈ，ｄ，Ｊ＝８
Ｈｚ），８．０３（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．０７
（１Ｈ，ｄ，Ｊ＝８Ｈｚ），１０．３８（１Ｈ，ｓ），
１２．６１（１Ｈ，ｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
0.96 (3H, t, J = 7Hz), 1.74 (2H,
sext, J = 7 Hz), 4.05 (2H, t, J = 7)
Hz), 4.24 (2H, s), 7.20 (1H, d,
J = 8Hz), 7.52 (1H, t, J = 8Hz),
7.70 (1H, t, J = 8Hz), 7.78 (1H,
dd, J = 2,8 Hz), 7.86 (1H, d, J = 8)
Hz), 8.03 (1H, d, J = 2 Hz), 8.07
(1H, d, J = 8Hz), 10.38 (1H, s),
12.61 (1H, s).
【００７２】実施例７２−［５−（４−クロロブチラミド）−２−エトキシフ
ェニル］−３，４−ジヒドロベンゾフロ［３，２−ｄ］
ピリミジン−４−オン 実施例５と同様にして２−（５−アミノ−２−エトキシ
フェニル）−３，４−ジヒドロベンゾフロ［３，２−
ｄ］ピリミジン−４−オン塩酸塩と４−クロロブチリル
クロライドから標記化合物を得た。Example 7 2- [5- (4-chlorobutyramide) -2-ethoxyphenol
Phenyl] -3,4-dihydrobenzofuro [3,2-d]
Pyrimidin-4-one 2- (5-amino-2-ethoxyphenyl) -3,4-dihydrobenzofuro [3,2-similar to Example 5.
The title compound was obtained from d] pyrimidin-4-one hydrochloride and 4-chlorobutyryl chloride.
【００７３】ｍ．ｐ．２２９〜２３１℃M. p. 229-231 ° C
【００７４】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
１．３４（３Ｈ，ｔ，Ｊ＝７Ｈｚ），２．０４（２Ｈ，
ｑｕｉｎｔ，Ｊ＝７Ｈｚ），２．４８（２Ｈ，ｔ，Ｊ＝
７Ｈｚ），３．７１（２Ｈ，ｔ，Ｊ＝７Ｈｚ），４．１
４（２Ｈ，ｑ，Ｊ＝７Ｈｚ），７．１５（１Ｈ，ｄ，Ｊ
＝８Ｈｚ），７．５２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．
７０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７６（１Ｈ，ｄ
ｄ，Ｊ＝２，８Ｈｚ），７．８７（１Ｈ，ｄ，Ｊ＝８Ｈ
ｚ），８．０３（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．０７
（１Ｈ，ｄ，Ｊ＝８Ｈｚ）１０．０５（１Ｈ，ｓ），１
２．６３（１Ｈ，ｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
1.34 (3H, t, J = 7Hz), 2.04 (2H,
quint, J = 7 Hz), 2.48 (2H, t, J =
7 Hz), 3.71 (2H, t, J = 7 Hz), 4.1
4 (2H, q, J = 7Hz), 7.15 (1H, d, J
= 8 Hz), 7.52 (1H, t, J = 8 Hz), 7.
70 (1H, t, J = 8Hz), 7.76 (1H, d
d, J = 2,8 Hz), 7.87 (1H, d, J = 8H
z), 8.03 (1H, d, J = 2Hz), 8.07
(1H, d, J = 8Hz) 10.05 (1H, s), 1
2.63 (1H, s).
【００７５】実施例８３，４−ジヒドロ−２−［５−（モルホリノカルボニル
アミノ）−２−プロポキシフェニル］ベンゾフロ［３，
２−ｄ］ピリミジン−４−オン ２−（５−アミノ−２−プロポキシフェニル）−３，４
−ジヒドロベンゾフロ［３，２−ｄ］ピリミジン−４−
オン塩酸塩７４３ｍｇとトリエチルアミン３０３ｍｇ
（１．５当量）のＮ，Ｎ−ジメチルホルムアミド２０ｍ
ｌ溶液にモルホリノカルボニルクロライド４１５ｍｇ
（１．４当量）を加え、５０℃で３時間攪拌した。Example 8 3,4-Dihydro-2- [5- (morpholinocarbonyl
Amino) -2-propoxyphenyl] benzofuro [3,
2-d] pyrimidin-4-one 2- (5-amino-2-propoxyphenyl) -3,4
-Dihydrobenzofuro [3,2-d] pyrimidine-4-
743 mg of on-hydrochloride and 303 mg of triethylamine
(1.5 eq) N, N-dimethylformamide 20 m
415 mg of morpholino carbonyl chloride in 1 solution
(1.4 eq) was added and stirred at 50 ° C. for 3 hours.
【００７６】反応溶液を水にあけ、酢酸エチルで抽出し
た。有機層を水で洗浄したのち、乾燥、溶媒を減圧留去
し、残留物をシリカゲルカラムクロマトグラフィー（溶
出溶媒；酢酸エチル）で精製して標記化合物３４０ｍｇ
を得た。The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate) to give 340 mg of the title compound.
Got
【００７７】ｍ．ｐ．２４３〜２４５℃M. p. 243-245 ° C
【００７８】1Ｈ−ＮＭＲ（ＣＤＣｌ3）δｐｐｍ；１．
１３（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．７３（２Ｈ，ｓｅ
ｘｔ，Ｊ＝７Ｈｚ），３．５６（４Ｈ，ｔ，Ｊ＝５Ｈ
ｚ），３．８０（４Ｈ，ｔ，Ｊ＝５Ｈｚ），４．１１
（２Ｈ，ｔ，Ｊ＝７Ｈｚ），６．７６（１Ｈ，ｓ），
６．９５（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．３５（１Ｈ，
ｔ，Ｊ＝８Ｈｚ），７．５５（１Ｈ，ｔ，Ｊ＝８Ｈ
ｚ），７．６３（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．８４
（１Ｈ，ｄｄ，Ｊ＝２，８Ｈｚ），８．００（１Ｈ，
ｄ，Ｊ＝８Ｈｚ），８．２４（１Ｈ，ｄ，Ｊ＝２Ｈ
ｚ）． 1 H-NMR (CDCl 3 ) δ ppm;
13 (3H, t, J = 7Hz), 1.73 (2H, se
xt, J = 7 Hz), 3.56 (4H, t, J = 5H
z), 3.80 (4H, t, J = 5Hz), 4.11.
(2H, t, J = 7Hz), 6.76 (1H, s),
6.95 (1H, d, J = 8Hz), 7.35 (1H,
t, J = 8 Hz), 7.55 (1H, t, J = 8H
z), 7.63 (1H, d, J = 8 Hz), 7.84
(1H, dd, J = 2, 8Hz), 8.00 (1H,
d, J = 8 Hz), 8.24 (1H, d, J = 2H
z).
【００７９】実施例９３，４−ジヒドロ−２−［２−エトキシ−５−（モルホ
リノカルボニルアミノ）フェニル］ベンゾフロ［３，２
−ｄ］ピリミジン−４−オン 実施例８と同様にして２−（５−アミノ−２−エトキシ
フェニル）−３，４−ジヒドロベンゾフロ［３，２−
ｄ］ピリミジン−４−オン塩酸塩とモルホリノカルボニ
ルクロライドから標記化合物を得た。Example 9 3,4-dihydro-2- [2-ethoxy-5- (morpho
Rinocarbonylamino) phenyl] benzofuro [3,2]
-D] Pyrimidin-4-one 2- (5-amino-2-ethoxyphenyl) -3,4-dihydrobenzofuro [3,2-similar to Example 8.
The title compound was obtained from d] pyrimidin-4-one hydrochloride and morpholinocarbonyl chloride.
【００８０】ｍ．ｐ．２１２〜２１４℃M. p. 212-214 ° C
【００８１】1Ｈ−ＮＭＲ（ＣＤＣｌ3）δｐｐｍ；１．
５７（３Ｈ，ｔ，Ｊ＝７Ｈｚ），３．５６（４Ｈ，ｔ，
Ｊ＝５Ｈｚ），３．８０（４Ｈ，ｔ，Ｊ＝５Ｈｚ），
４．２４（２Ｈ，ｑ，Ｊ＝７Ｈｚ），６．７６（１Ｈ，
ｓ），６．９５（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．３５
（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．５５（１Ｈ，ｔ，Ｊ＝
８Ｈｚ），７．６３（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．８
６（１Ｈ，ｄｄ，Ｊ＝２，８Ｈｚ），８．０１（１Ｈ，
ｄ，Ｊ＝８Ｈｚ），８．２５（１Ｈ，ｄ，Ｊ＝２Ｈ
ｚ）． 1 H-NMR (CDCl 3 ) δ ppm;
57 (3H, t, J = 7Hz), 3.56 (4H, t,
J = 5Hz), 3.80 (4H, t, J = 5Hz),
4.24 (2H, q, J = 7Hz), 6.76 (1H,
s), 6.95 (1H, d, J = 8Hz), 7.35
(1H, t, J = 8Hz), 7.55 (1H, t, J =
8 Hz), 7.63 (1H, d, J = 8 Hz), 7.8
6 (1H, dd, J = 2, 8Hz), 8.01 (1H,
d, J = 8 Hz), 8.25 (1H, d, J = 2H
z).
【００８２】実施例１０３，４−ジヒドロ−２−［５−（フェノキシアセタミ
ド）−２−プロポキシフェニル］ベンゾフロ［３，２−
ｄ］ピリミジン−４−オン ２−（５−アミノ−２−プロポキシフェニル）−３，４
−ジヒドロベンゾフロ［３，２−ｄ］ピリミジン−４−
オン塩酸塩４００ｍｇとトリエチルアミン２４０ｍｇ
（１．１当量）のＮ，Ｎ−ジメチルホルムアミド２０ｍ
ｌ溶液に氷冷下、フェノキシ酢酸クロライド２０２ｍｇ
（１．１当量）を加え、１時間攪拌した。反応溶液を水
にあけ、塩化メチレンで抽出した。有機層を水で洗浄し
たのち、乾燥、溶媒を減圧留去し、残留物をシリカゲル
カラムクロマトグラフィー（溶出溶媒；２０％酢酸エチ
ル−塩化メチレン）で精製して標記化合物４０６ｍｇを
得た。Example 10 3,4-dihydro-2- [5- (phenoxyacetamine
De) -2-propoxyphenyl] benzofuro [3,2-
d] pyrimidin-4-one 2- (5-amino-2-propoxyphenyl) -3,4
-Dihydrobenzofuro [3,2-d] pyrimidine-4-
On-hydrochloride 400 mg and triethylamine 240 mg
(1.1 eq) N, N-dimethylformamide 20 m
202 mg of phenoxyacetic acid chloride under ice cooling
(1.1 eq) was added and stirred for 1 hour. The reaction solution was poured into water and extracted with methylene chloride. The organic layer was washed with water, dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: 20% ethyl acetate-methylene chloride) to obtain 406 mg of the title compound.
【００８３】ｍ．ｐ．２０９〜２１１℃M. p. 209 to 211 ° C
【００８４】1Ｈ−ＮＭＲ（ＣＤＣｌ3）δｐｐｍ；１．
１７（３Ｈ，ｔ，Ｊ＝７Ｈｚ），２．０５（２Ｈ，ｓｅ
ｘｔ，Ｊ＝７Ｈｚ），４．２３（２Ｈ，ｑ，Ｊ＝７Ｈ
ｚ），４．６６（２Ｈ，ｓ），７．０−７．２（４Ｈ，
ｍ），７．３−７．５（３Ｈ，ｍ），７．６１（１Ｈ，
ｔ，Ｊ＝８Ｈｚ），７．６９（１Ｈ，ｄ，Ｊ＝８Ｈ
ｚ），８．１０（１Ｈ，ｄｄ，Ｊ＝２，８Ｈｚ），８．
２０（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．４６（１Ｈ，
ｓ），８．５８（１Ｈ，ｄ，Ｊ＝２Ｈｚ），１１．７５
（１Ｈ，ｂｓ）． 1 H-NMR (CDCl 3 ) δ ppm;
17 (3H, t, J = 7Hz), 2.05 (2H, se
xt, J = 7 Hz), 4.23 (2H, q, J = 7H)
z), 4.66 (2H, s), 7.0-7.2 (4H,
m), 7.3-7.5 (3H, m), 7.61 (1H,
t, J = 8 Hz), 7.69 (1H, d, J = 8H)
z), 8.10 (1H, dd, J = 2, 8 Hz), 8.
20 (1H, d, J = 8Hz), 8.46 (1H,
s), 8.58 (1H, d, J = 2Hz), 11.75
(1H, bs).
【００８５】実施例１１３，４−ジヒドロ−２−［２−エトキシ−５−（２−モ
ルホリノアセタミド）フェニル］ベンゾフロ［３，２−
ｄ］ピリミジン−４−オン ２−（５−クロロアセタミド−２−エトキシフェニル）
−３，４−ジヒドロベンゾフロ［３，２−ｄ］ピリミジ
ン−４−オン４００ｍｇとモルホリン２６３ｍｇ（３当
量）のＮ，Ｎ−ジメチルホルムアミド２０ｍｌ溶液を５
０℃で４時間攪拌した。反応溶液を水にあけ、酢酸エチ
ルで抽出したのち、水で洗浄して乾燥した。溶媒を減圧
留去し、残留物をシリカゲルカラムクロマトグラフィー
（溶出溶媒；酢酸エチル）で精製して標記化合物２２０
ｍｇを得た。Example 11 3,4-Dihydro-2- [2-ethoxy-5- (2-mo
Luforinoacetamido) phenyl] benzofuro [3,2-
d] Pyrimidin-4-one 2- (5-chloroacetamido-2-ethoxyphenyl)
A solution of 400 mg of -3,4-dihydrobenzofuro [3,2-d] pyrimidin-4-one and 263 mg (3 equivalents) of morpholine in 20 ml of N, N-dimethylformamide was added 5 times.
The mixture was stirred at 0 ° C for 4 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent; ethyl acetate) to give the title compound 220.
mg was obtained.
【００８６】ｍ．ｐ．２５６〜２５８℃M. p. 256-258 ° C
【００８７】1Ｈ−ＮＭＲ（ＣＤＣｌ3）δｐｐｍ；１．
６３（３Ｈ，ｔ，Ｊ＝７Ｈｚ），２．７１（４Ｈ，ｂ
ｓ），３．２３（２Ｈ，ｓ），３．８−３．９（４Ｈ，
ｍ）４．３４（２Ｈ，ｑ，Ｊ＝７Ｈｚ），７．０８（１
Ｈ，ｄ，Ｊ＝８Ｈｚ），７．４７（１Ｈ，ｔ，Ｊ＝８Ｈ
ｚ），７．６３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７０
（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０８（１Ｈ，ｄｄ，Ｊ
＝２，８Ｈｚ），８．１８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
８．５１（１Ｈ，ｄ，Ｊ＝２Ｈｚ），９．１９（１Ｈ，
ｂｓ），１１．７１（１Ｈ，ｓ）． 1 H-NMR (CDCl 3 ) δ ppm;
63 (3H, t, J = 7Hz), 2.71 (4H, b
s), 3.23 (2H, s), 3.8-3.9 (4H,
m) 4.34 (2H, q, J = 7Hz), 7.08 (1
H, d, J = 8Hz), 7.47 (1H, t, J = 8H)
z), 7.63 (1H, t, J = 8 Hz), 7.70
(1H, d, J = 8Hz), 8.08 (1H, dd, J
= 2,8Hz), 8.18 (1H, d, J = 8Hz),
8.51 (1H, d, J = 2Hz), 9.19 (1H,
bs), 11.71 (1H, s).
【００８８】実施例１２３，４−ジヒドロ−２−［２−エトキシ−５−（２−ピ
ペリジノアセタミド）フェニル］ベンゾフロ［３，２−
ｄ］ピリミジン−４−オン 実施例１１と同様にして２−（５−クロロアセタミド−
２−エトキシフェニル）−３，４−ジヒドロベンゾフロ
［３，２−ｄ］ピリミジン−４−オンとピペリジンから
標記化合物を得た。Example 12 3,4-dihydro-2- [2-ethoxy-5- (2-pi-
Peridinoacetamide) phenyl] benzofuro [3,2-
d] Pyrimidin-4-one 2- (5-chloroacetamide-
The title compound was obtained from 2-ethoxyphenyl) -3,4-dihydrobenzofuro [3,2-d] pyrimidin-4-one and piperidine.
【００８９】ｍ．ｐ．２２５〜２２７℃M. p. 225 to 227 ° C
【００９０】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
１．３３（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．４−１．７
（６Ｈ，ｍ），２．４−２．６（４Ｈ，ｍ），３．０６
（２Ｈ，ｓ），４．１３（２Ｈ，ｑ，Ｊ＝７Ｈｚ），
７．１６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．５２（１Ｈ，
ｔ，Ｊ＝８Ｈｚ），７．７０（１Ｈ，ｔ，Ｊ＝８Ｈ
ｚ），７．８０（１Ｈ，ｄｄ，Ｊ＝２，８Ｈｚ），７．
８６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０５（１Ｈ，ｄ，
Ｊ＝２Ｈｚ），８．０８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
９．７４（１Ｈ，ｓ），１２．６８（１Ｈ，ｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
1.33 (3H, t, J = 7Hz), 1.4-1.7
(6H, m), 2.4-2.6 (4H, m), 3.06
(2H, s), 4.13 (2H, q, J = 7Hz),
7.16 (1H, d, J = 8Hz), 7.52 (1H,
t, J = 8 Hz), 7.70 (1H, t, J = 8H)
z), 7.80 (1H, dd, J = 2, 8 Hz), 7.
86 (1H, d, J = 8Hz), 8.05 (1H, d,
J = 2 Hz), 8.08 (1H, d, J = 8 Hz),
9.74 (1H, s), 12.68 (1H, s).
【００９１】実施例１３３，４−ジヒドロ−２−［２−エトキシ−５−［（１，
２，３，４−テトラヒドロイソキノリン−２−イル）ア
セタミド］フェニル］ベンゾフロ［３，２−ｄ］ピリミ
ジン−４−オン 実施例１１と同様にして２−（５−クロロアセタミド−
２−エトキシフェニル）−３，４−ジヒドロベンゾフロ
［３，２−ｄ］ピリミジン−４−オンと１，２，３，４
−テトラヒドロイソキノリンから標記化合物を得た。Example 13 3,4-dihydro-2- [2-ethoxy-5-[(1,
2,3,4-tetrahydroisoquinolin-2-yl) a
Cetamide] phenyl] benzofuro [3,2-d] pyrimi
Zin-4-one 2- (5-chloroacetamide-
2-Ethoxyphenyl) -3,4-dihydrobenzofuro [3,2-d] pyrimidin-4-one and 1,2,3,4
The title compound was obtained from tetrahydroisoquinoline.
【００９２】ｍ．ｐ．２２８〜２３０℃M. p. 228 ~ 230 ℃
【００９３】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
１．３３（３Ｈ，ｔ，Ｊ＝７Ｈｚ），２．７−３．０
（６Ｈ，ｍ），３．７３（２Ｈ，ｓ），４．１３（２
Ｈ，ｑ，Ｊ＝７Ｈｚ），７．０−７．２（５Ｈ，ｍ），
７．５１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７０（１Ｈ，
ｔ，Ｊ＝８Ｈｚ），７．８３（１Ｈ，ｄｄ，Ｊ＝２，８
Ｈｚ），７．８６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０６
（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０８（１Ｈ，ｄ，Ｊ＝
２Ｈｚ），９．９０（１Ｈ，ｓ），１２．６８（１Ｈ，
ｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
1.33 (3H, t, J = 7Hz), 2.7-3.0
(6H, m), 3.73 (2H, s), 4.13 (2
H, q, J = 7 Hz), 7.0-7.2 (5H, m),
7.51 (1H, t, J = 8Hz), 7.70 (1H,
t, J = 8 Hz), 7.83 (1H, dd, J = 2, 8)
Hz), 7.86 (1H, d, J = 8Hz), 8.06
(1H, d, J = 8Hz), 8.08 (1H, d, J =
2Hz), 9.90 (1H, s), 12.68 (1H,
s).
【００９４】実施例１４３，４−ジヒドロ−２−［２−エトキシ−５−（２−ピ
ロリジノアセタミド）フェニル］ベンゾフロ［３，２−
ｄ］ピリミジン−４−オン 実施例１１と同様にして２−（５−クロロアセタミド−
２−エトキシフェニル）−３，４−ジヒドロベンゾフロ
［３，２−ｄ］ピリミジン−４−オンとピロリジンから
標記化合物を得た。Example 14 3,4-Dihydro-2- [2-ethoxy-5- (2-pi-
Loridinoacetamide) phenyl] benzofuro [3,2-
d] Pyrimidin-4-one 2- (5-chloroacetamide-
The title compound was obtained from 2-ethoxyphenyl) -3,4-dihydrobenzofuro [3,2-d] pyrimidin-4-one and pyrrolidine.
【００９５】ｍ．ｐ．２３６〜２３８℃M. p. 236 ~ 238 ℃
【００９６】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
１．３３（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．７−１．８
（４Ｈ，ｍ），２．５−２．７（４Ｈ，ｍ），３．２４
（２Ｈ，ｓ），４．１３（２Ｈ，ｑ，Ｊ＝７Ｈｚ），
７．１６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．５２（１Ｈ，
ｔ，Ｊ＝８Ｈｚ），７．７０（１Ｈ，ｔ，Ｊ＝８Ｈ
ｚ），７．８１（１Ｈ，ｄｄ，Ｊ＝２，８Ｈｚ），７．
８７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０８（１Ｈ，ｄ，
Ｊ＝２Ｈｚ），８．０９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
９．８０（１Ｈ，ｓ），１２．６７（１Ｈ，ｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
1.33 (3H, t, J = 7Hz), 1.7-1.8
(4H, m), 2.5-2.7 (4H, m), 3.24
(2H, s), 4.13 (2H, q, J = 7Hz),
7.16 (1H, d, J = 8Hz), 7.52 (1H,
t, J = 8 Hz), 7.70 (1H, t, J = 8H)
z), 7.81 (1H, dd, J = 2, 8 Hz), 7.
87 (1H, d, J = 8Hz), 8.08 (1H, d,
J = 2 Hz), 8.09 (1H, d, J = 8 Hz),
9.80 (1H, s), 12.67 (1H, s).
【００９７】実施例１５３，４−ジヒドロ−２−［２−エトキシ−５−［２−
（４−ヒドロキシピペリジノ）アセタミド］フェニル］
ベンゾフロ［３，２−ｄ］ピリミジン−４−オン 実施例１１と同様にして２−（５−クロロアセタミド−
２−エトキシフェニル）−３，４−ジヒドロベンゾフロ
［３，２−ｄ］ピリミジン−４−オンと４−ヒドロキシ
ピペリジンから標記化合物を得た。Example 15 3,4-Dihydro-2- [2-ethoxy-5- [2-
(4-Hydroxypiperidino) acetamide] phenyl]
Benzofuro [3,2-d] pyrimidin-4-one 2- (5-chloroacetamide-
The title compound was obtained from 2-ethoxyphenyl) -3,4-dihydrobenzofuro [3,2-d] pyrimidin-4-one and 4-hydroxypiperidine.
【００９８】ｍ．ｐ．２２１〜２２３℃M. p. 221 to 223 ° C
【００９９】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
１．３２（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．４−１．６
（２Ｈ，ｍ），１．６−１．８（２Ｈ，ｍ），２．２−
２．４（２Ｈ，ｍ），２．７−２．８（２Ｈ，ｍ），
３．０７（２Ｈ，ｓ），３．４−３．６（１Ｈ，ｍ），
４．１３（２Ｈ，ｑ，Ｊ＝７Ｈｚ），４．５７（１Ｈ，
ｄ，Ｊ＝４Ｈｚ），７．１６（１Ｈ，ｄ，Ｊ＝８Ｈ
ｚ），７．５２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７０
（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．８１（１Ｈ，ｄｄ，Ｊ
＝２，８Ｈｚ），７．８７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
８．０５（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．０９（１Ｈ，
ｄ，Ｊ＝８Ｈｚ），９．７６（１Ｈ，ｓ），１２．６７
（１Ｈ，ｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
1.32 (3H, t, J = 7Hz), 1.4-1.6
(2H, m), 1.6-1.8 (2H, m), 2.2-
2.4 (2H, m), 2.7-2.8 (2H, m),
3.07 (2H, s), 3.4-3.6 (1H, m),
4.13 (2H, q, J = 7Hz), 4.57 (1H,
d, J = 4Hz), 7.16 (1H, d, J = 8H
z), 7.52 (1H, t, J = 8 Hz), 7.70
(1H, t, J = 8Hz), 7.81 (1H, dd, J
= 2,8 Hz), 7.87 (1H, d, J = 8 Hz),
8.05 (1H, d, J = 2Hz), 8.09 (1H,
d, J = 8 Hz), 9.76 (1H, s), 12.67
(1H, s).
【０１００】実施例１６３，４−ジヒドロ−２−［５−［２−（４−ヒドロキシ
ピペリジノ）アセタミド］−２−プロポキシフェニル］
ベンゾフロ［３，２−ｄ］ピリミジン−４−オン 実施例１１と同様にして２−（５−クロロアセタミド−
２−プロポキシフェニル）−３，４−ジヒドロベンゾフ
ロ［３，２−ｄ］ピリミジン−４−オンと４−ヒドロキ
シピペリジンから標記化合物を得た。Example 16 3,4-dihydro-2- [5- [2- (4-hydroxy
Piperidino) acetamide] -2-propoxyphenyl]
Benzofuro [3,2-d] pyrimidin-4-one 2- (5-chloroacetamide-
The title compound was obtained from 2-propoxyphenyl) -3,4-dihydrobenzofuro [3,2-d] pyrimidin-4-one and 4-hydroxypiperidine.
【０１０１】ｍ．ｐ．２３４〜２３６℃M. p. 234-236 ° C
【０１０２】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
０．９４（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．４−１．８
（６Ｈ，ｍ），２．１−２．３（２Ｈ，ｍ），２．７−
２．８（２Ｈ，ｍ），３．０８（２Ｈ，ｓ），３．４−
３．６（１Ｈ，ｍ），４．０３（２Ｈ，ｔ，Ｊ＝７Ｈ
ｚ），４．５６（１Ｈ，ｄ，Ｊ＝５Ｈｚ），７．１７
（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．５２（１Ｈ，ｔ，Ｊ＝
８Ｈｚ），７．７０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．８
１（１Ｈ，ｄｄ，Ｊ＝２，８Ｈｚ），７．８７（１Ｈ，
ｄ，Ｊ＝８Ｈｚ），８．０５（１Ｈ，ｄ，Ｊ＝２Ｈ
ｚ），８．０８（１Ｈ，ｄ，Ｊ＝２Ｈｚ），９．７６
（１Ｈ，ｓ），１２．６６（１Ｈ，ｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
0.94 (3H, t, J = 7Hz), 1.4-1.8
(6H, m), 2.1-2.3 (2H, m), 2.7-
2.8 (2H, m), 3.08 (2H, s), 3.4-
3.6 (1H, m), 4.03 (2H, t, J = 7H
z), 4.56 (1H, d, J = 5Hz), 7.17
(1H, d, J = 8Hz), 7.52 (1H, t, J =
8 Hz), 7.70 (1 H, t, J = 8 Hz), 7.8
1 (1H, dd, J = 2, 8Hz), 7.87 (1H,
d, J = 8 Hz), 8.05 (1H, d, J = 2H
z), 8.08 (1H, d, J = 2 Hz), 9.76
(1H, s), 12.66 (1H, s).
【０１０３】実施例１７３，４−ジヒドロ−２−［５−（２−モルホリノアセタ
ミド）−２−プロポキシフェニル］ベンゾフロ［３，２
−ｄ］ピリミジン−４−オン 実施例１１と同様にして２−（５−クロロアセタミド−
２−プロポキシフェニル）−３，４−ジヒドロベンゾフ
ロ［３，２−ｄ］ピリミジン−４−オンとモルホリンか
ら標記化合物を得た。Example 17 3,4-Dihydro-2- [5- (2-morpholinoaceta
(Mido) -2-propoxyphenyl] benzofuro [3,2]
-D] pyrimidin-4-one 2- (5-chloroacetamide-
The title compound was obtained from 2-propoxyphenyl) -3,4-dihydrobenzofuro [3,2-d] pyrimidin-4-one and morpholine.
【０１０４】ｍ．ｐ．２０６〜２０８℃M. p. 206-208 ° C
【０１０５】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
０．９５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．７２（２Ｈ，
ｓｅｘｔ，Ｊ＝７Ｈｚ），２．４−２．６（４Ｈ，
ｍ），３．１３（２Ｈ，ｓ），３．６４（４Ｈ，ｔ，Ｊ
＝５Ｈｚ），４．０４（２Ｈ，ｔ，Ｊ＝７Ｈｚ），７．
１７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．５２（１Ｈ，ｔ，
Ｊ＝８Ｈｚ），７．７０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
７．８１（１Ｈ，ｄｄ，Ｊ＝２，８Ｈｚ），７．８７
（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０５（１Ｈ，ｄ，Ｊ＝
２Ｈｚ），８．０８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），９．８
３（１Ｈ，ｓ），１２．６５（１Ｈ，ｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
0.95 (3H, t, J = 7Hz), 1.72 (2H,
sext, J = 7 Hz), 2.4-2.6 (4H,
m), 3.13 (2H, s), 3.64 (4H, t, J
= 5 Hz), 4.04 (2H, t, J = 7 Hz), 7.
17 (1H, d, J = 8Hz), 7.52 (1H, t,
J = 8Hz), 7.70 (1H, t, J = 8Hz),
7.81 (1H, dd, J = 2, 8 Hz), 7.87
(1H, d, J = 8Hz), 8.05 (1H, d, J =
2 Hz), 8.08 (1H, d, J = 8 Hz), 9.8
3 (1H, s), 12.65 (1H, s).
【０１０６】実施例１８３，４−ジヒドロ−２−［５−［２−［４−（２−ヒド
ロキシエチル）ピペラジノ］アセタミド］−２−プロポ
キシフェニル］ベンゾフロ［３，２−ｄ］ピリミジン−
４−オン 実施例１１と同様にして２−（５−クロロアセタミド−
２−プロポキシフェニル）−３，４−ジヒドロベンゾフ
ロ［３，２−ｄ］ピリミジン−４−オンと２−ピペラジ
ノエタノールから標記化合物を得た。Example 18 3,4-Dihydro-2- [5- [2- [4- (2-hydr
Roxyethyl) piperazino] acetamide] -2-propo
Xyphenyl] benzofuro [3,2-d] pyrimidine-
4-one 2- (5-chloroacetamide-
The title compound was obtained from 2-propoxyphenyl) -3,4-dihydrobenzofuro [3,2-d] pyrimidin-4-one and 2-piperazinoethanol.
【０１０７】ｍ．ｐ．１８３〜１８５℃M. p. 183-185 ° C
【０１０８】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
０．９５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．７３（２Ｈ，
ｓｅｘｔ，Ｊ＝７Ｈｚ），２．３９（２Ｈ，ｔ，Ｊ＝６
Ｈｚ），２．４−２．６（８Ｈ，ｍ），３．１０（２
Ｈ，ｓ），３．４９（２Ｈ，ｑ，Ｊ＝６Ｈｚ），４．０
４（２Ｈ，ｔ，Ｊ＝７Ｈｚ），４．３７（１Ｈ，ｔ，Ｊ
＝６Ｈｚ），７．１７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．
５２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７０（１Ｈ，ｔ，
Ｊ＝８Ｈｚ），７．８１（１Ｈ，ｄｄ，Ｊ＝２，８Ｈ
ｚ），７．８７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０４
（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．０８（１Ｈ，ｄ，Ｊ＝
８Ｈｚ），９．７８（１Ｈ，ｓ），１２．６５（１Ｈ，
ｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
0.95 (3H, t, J = 7Hz), 1.73 (2H,
sext, J = 7 Hz), 2.39 (2H, t, J = 6)
Hz), 2.4-2.6 (8H, m), 3.10 (2
H, s), 3.49 (2H, q, J = 6Hz), 4.0
4 (2H, t, J = 7Hz), 4.37 (1H, t, J
= 6 Hz), 7.17 (1H, d, J = 8 Hz), 7.
52 (1H, t, J = 8Hz), 7.70 (1H, t,
J = 8Hz), 7.81 (1H, dd, J = 2,8H
z), 7.87 (1H, d, J = 8Hz), 8.04
(1H, d, J = 2Hz), 8.08 (1H, d, J =
8 Hz), 9.78 (1H, s), 12.65 (1H,
s).
【０１０９】実施例１９３，４−ジヒドロ−２−［５−［２−［Ｎ−（２−ヒド
ロキシエチル）−Ｎ−メチルアミノ］アセタミド］−２
−プロポキシフェニル］ベンゾフロ［３，２−ｄ］ピリ
ミジン−４−オン 実施例１１と同様にして２−（５−クロロアセタミド−
２−プロポキシフェニル）−３，４−ジヒドロベンゾフ
ロ［３，２−ｄ］ピリミジン−４−オンとＮ−メチルエ
タノールアミンから標記化合物を得た。Example 19 3,4-Dihydro-2- [5- [2- [N- (2-hydr
Roxyethyl) -N-methylamino] acetamide] -2
-Propoxyphenyl] benzofuro [3,2-d] pyri
Midin-4-one 2- (5-chloroacetamide-
The title compound was obtained from 2-propoxyphenyl) -3,4-dihydrobenzofuro [3,2-d] pyrimidin-4-one and N-methylethanolamine.
【０１１０】ｍ．ｐ．１５７〜１５９℃M. p. 157-159 ° C
【０１１１】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
０．９５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．７３（２Ｈ，
ｓｅｘｔ，Ｊ＝７Ｈｚ），２．３３（３Ｈ，ｓ），２．
５５（２Ｈ，ｔ，Ｊ＝６Ｈｚ），３．１９（２Ｈ，
ｓ），３．５３（２Ｈ，ｑ，Ｊ＝６Ｈｚ），４．０３
（２Ｈ，ｔ，Ｊ＝７Ｈｚ），４．７８（１Ｈ，ｔ，Ｊ＝
６Ｈｚ），７．１９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．５
３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７１（１Ｈ，ｔ，Ｊ
＝８Ｈｚ），７．８２（１Ｈ，ｄｄ，Ｊ＝２，８Ｈ
ｚ），７．８７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０６
（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．０８（１Ｈ，ｄ，Ｊ＝
８Ｈｚ），９．９１（１Ｈ，ｓ），１２．６６（１Ｈ，
ｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
0.95 (3H, t, J = 7Hz), 1.73 (2H,
sext, J = 7 Hz), 2.33 (3H, s), 2.
55 (2H, t, J = 6Hz), 3.19 (2H,
s), 3.53 (2H, q, J = 6Hz), 4.03
(2H, t, J = 7Hz), 4.78 (1H, t, J =
6 Hz), 7.19 (1H, d, J = 8 Hz), 7.5
3 (1H, t, J = 8Hz), 7.71 (1H, t, J
= 8 Hz), 7.82 (1H, dd, J = 2, 8H
z), 7.87 (1H, d, J = 8Hz), 8.06
(1H, d, J = 2Hz), 8.08 (1H, d, J =
8 Hz), 9.91 (1H, s), 12.66 (1H,
s).
【０１１２】実施例２０３，４−ジヒドロ−２−［５−［２−［Ｎ，Ｎ−ビス
（２−ヒドロキシエチル）アミノ］アセタミド］−２−
プロポキシフェニル］ベンゾフロ［３，２−ｄ］ピリミ
ジン−４−オン 実施例１１と同様にして２−（５−クロロアセタミド−
２−プロポキシフェニル）−３，４−ジヒドロベンゾフ
ロ［３，２−ｄ］ピリミジン−４−オンとジエタノール
アミンから標記化合物を得た。Example 20 3,4-Dihydro-2- [5- [2- [N, N-bis
(2-Hydroxyethyl) amino] acetamide] -2-
Propoxyphenyl] benzofuro [3,2-d] pyrimi
Zin-4-one 2- (5-chloroacetamide-
The title compound was obtained from 2-propoxyphenyl) -3,4-dihydrobenzofuro [3,2-d] pyrimidin-4-one and diethanolamine.
【０１１３】ｍ．ｐ．１５６〜１５８℃M. p. 156-158 ° C
【０１１４】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
０．９６（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．７３（２Ｈ，
ｓｅｘｔ，Ｊ＝７Ｈｚ），２．６−２．８（４Ｈ，
ｍ），３．３０（２Ｈ，ｓ），３．４−３．６（４Ｈ，
ｍ），４．０４（２Ｈ，ｔ，Ｊ＝７Ｈｚ），４．６−
４．８（２Ｈ，ｍ），７．１８（１Ｈ，ｄ，Ｊ＝８Ｈ
ｚ），７．５２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７０
（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７９（１Ｈ，ｄｄ，Ｊ
＝２，８Ｈｚ），７．８６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
８．０３（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．０９（１Ｈ，
ｄ，Ｊ＝８Ｈｚ），１０．０２（１Ｈ，ｓ），１２．６
６（１Ｈ，ｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
0.96 (3H, t, J = 7Hz), 1.73 (2H,
sext, J = 7 Hz), 2.6-2.8 (4H,
m), 3.30 (2H, s), 3.4-3.6 (4H,
m), 4.04 (2H, t, J = 7Hz), 4.6-
4.8 (2H, m), 7.18 (1H, d, J = 8H
z), 7.52 (1H, t, J = 8 Hz), 7.70
(1H, t, J = 8Hz), 7.79 (1H, dd, J
= 2,8 Hz), 7.86 (1H, d, J = 8 Hz),
8.03 (1H, d, J = 2Hz), 8.09 (1H,
d, J = 8 Hz), 10.02 (1H, s), 12.6
6 (1H, s).
【０１１５】実施例２１３，４−ジヒドロ−２−［５−［２−（３−ヒドロキシ
ピロリジノ）アセタミド］−２−プロポキシフェニル］
ベンゾフロ［３，２−ｄ］ピリミジン−４−オン 実施例１１と同様にして２−（５−クロロアセタミド−
２−プロポキシフェニル）−３，４−ジヒドロベンゾフ
ロ［３，２−ｄ］ピリミジン−４−オンと３−ピロリジ
ノールから標記化合物を得た。Example 21 3,4-Dihydro-2- [5- [2- (3-hydroxy
Pyrrolidino) acetamide] -2-propoxyphenyl]
Benzofuro [3,2-d] pyrimidin-4-one 2- (5-chloroacetamide-
The title compound was obtained from 2-propoxyphenyl) -3,4-dihydrobenzofuro [3,2-d] pyrimidin-4-one and 3-pyrrolidinol.
【０１１６】ｍ．ｐ．１９６〜１９９℃M. p. 196-199 ° C
【０１１７】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
０．９５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．５−１．８
（３Ｈ，ｍ），２．０−２．２（１Ｈ，ｍ），２．４−
２．６（２Ｈ，ｍ），２．７−２．８（２Ｈ，ｍ），
３．２３（２Ｈ，ｓ），４．０４（２Ｈ，ｔ，Ｊ＝７Ｈ
ｚ），４．１−４．３（１Ｈ，ｍ），４．８０（１Ｈ，
ｄ，Ｊ＝５Ｈｚ），７．１８（１Ｈ，ｄ，Ｊ＝８Ｈ
ｚ），７．５２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７０
（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．８３（１Ｈ，ｄｄ，Ｊ
＝２，８Ｈｚ），７．８７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
８．０５（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．０８（１Ｈ，
ｄ，Ｊ＝８Ｈｚ），９．７９（１Ｈ，ｓ），１２．６０
（１Ｈ，ｂｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
0.95 (3H, t, J = 7Hz), 1.5-1.8
(3H, m), 2.0-2.2 (1H, m), 2.4-
2.6 (2H, m), 2.7-2.8 (2H, m),
3.23 (2H, s), 4.04 (2H, t, J = 7H
z), 4.1-4.3 (1H, m), 4.80 (1H,
d, J = 5 Hz), 7.18 (1H, d, J = 8H
z), 7.52 (1H, t, J = 8 Hz), 7.70
(1H, t, J = 8Hz), 7.83 (1H, dd, J
= 2,8 Hz), 7.87 (1H, d, J = 8 Hz),
8.05 (1H, d, J = 2Hz), 8.08 (1H,
d, J = 8 Hz), 9.79 (1H, s), 12.60
(1H, bs).
【０１１８】実施例２２４−［４−エトキシ−３−（３，４−ジヒドロ−４−オ
キソベンゾフロ［３，２−ｄ］ピリミジン−２−イル）
フェニルアミノ］−４−オキソブタン酸一水和物 ２−（５−アミノ−２−エトキシフェニル）−３，４−
ジヒドロベンゾフロ［３，２−ｄ］ピリミジン−４−オ
ン塩酸塩３６０ｍｇとトリエチルアミン１５０ｍｇ
（１．５当量）のＮ，Ｎ−ジメチルホルムアミド１０ｍ
ｌ溶液に無水コハク酸１００ｍｇ（１当量）を加え、室
温で３時間攪拌したのち、さらに無水コハク酸２００ｍ
ｇ（２当量）を加え、５０℃で２時間攪拌した。Example 22 4- [4-ethoxy-3- (3,4-dihydro-4-o)
Xobenzofuro [3,2-d] pyrimidin-2-yl)
Phenylamino] -4-oxobutanoic acid monohydrate 2- (5-amino-2-ethoxyphenyl) -3,4-
Dihydrobenzofuro [3,2-d] pyrimidin-4-one hydrochloride 360 mg and triethylamine 150 mg
(1.5 equivalents) of N, N-dimethylformamide 10 m
100 mg (1 equivalent) of succinic anhydride was added to the solution l, and the mixture was stirred at room temperature for 3 hours, and then succinic anhydride 200 m
g (2 equivalents) was added, and the mixture was stirred at 50 ° C. for 2 hours.
【０１１９】反応溶液を水にあけ、塩酸酸性にして析出
した結晶を濾取し、減圧乾燥して標記化合物３９３ｍｇ
を得た。The reaction solution was poured into water, acidified with hydrochloric acid and the precipitated crystals were collected by filtration and dried under reduced pressure to give 393 mg of the title compound.
Got
【０１２０】ｍ．ｐ．２５４℃（分解）M. p. 254 ° C (decomposition)
【０１２１】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δｐｐｍ；
１．３３（３Ｈ，ｔ，Ｊ＝７Ｈｚ），２．５５（４Ｈ，
ｓ），４．１３（２Ｈ，ｑ，Ｊ＝７Ｈｚ），７．１６
（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．５２（１Ｈ，ｔ，Ｊ＝
８Ｈｚ），７．７１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７
６（１Ｈ，ｄｄ，Ｊ＝２，８Ｈｚ），７．８７（１Ｈ，
ｄ，Ｊ＝８Ｈｚ），８．０３（１Ｈ，ｄ，Ｊ＝２Ｈ
ｚ），８．０８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），１０．０３
（１Ｈ，ｓ），１２．１２（１Ｈ，ｂｓ），１２．６５
（１Ｈ，ｂｓ）． 1 H-NMR (DMSO-d 6 ) δ ppm;
1.33 (3H, t, J = 7Hz), 2.55 (4H,
s), 4.13 (2H, q, J = 7Hz), 7.16
(1H, d, J = 8Hz), 7.52 (1H, t, J =
8 Hz), 7.71 (1H, t, J = 8 Hz), 7.7
6 (1H, dd, J = 2, 8Hz), 7.87 (1H,
d, J = 8 Hz), 8.03 (1H, d, J = 2H
z), 8.08 (1H, d, J = 8Hz), 10.03
(1H, s), 12.12 (1H, bs), 12.65
(1H, bs).
【０１２２】実施例２３３，４−ジヒドロ−２−［５−［２−［（１−メチル−
１Ｈ−イミダゾール−２−イル）チオ］アセタミド］２
−プロポキシフェニル］ベンゾフロ［３，２−ｄ］ピリ
ミジン−４−オン ２−（５−クロロアセタミド−２−プロポキシフェニ
ル）−３，４−ジヒドロベンゾフロ［３，２−ｄ］ピリ
ミジン−４−オン６１７ｍｇと１−メチル−２−メルカ
プト−１Ｈ−イミダゾール２５７ｍｇ（１．５当量）の
Ｎ，Ｎ−ジメチルホルムアミド２０ｍｌ溶液に炭酸カリ
ウム３１１ｍｇ（１．５当量）を加え、６０℃で４時間
攪拌した。Example 23 3,4-dihydro-2- [5- [2-[(1-methyl-
1H-imidazol-2-yl) thio] acetamide] 2
-Propoxyphenyl] benzofuro [3,2-d] pyri
Midin-4-one 2- (5-chloroacetamido-2-propoxyphenyl) -3,4-dihydrobenzofuro [3,2-d] pyrimidin-4-one 617 mg and 1-methyl-2-mercapto-1H-imidazole To a solution of 257 mg (1.5 equivalents) of N, N-dimethylformamide in 20 ml was added potassium carbonate 311 mg (1.5 equivalents), and the mixture was stirred at 60 ° C. for 4 hours.
【０１２３】一晩放置後、反応溶液を水にあけ、酢酸エ
チルで抽出したのち、水で洗浄して乾燥した。溶媒を減
圧留去し、残留物をヘキサン−酢酸エチルで結晶化させ
て標記化合物４２２ｍｇを得た。After standing overnight, the reaction solution was poured into water, extracted with ethyl acetate, washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was crystallized from hexane-ethyl acetate to obtain 422 mg of the title compound.
【０１２４】ｍ．ｐ．２３６〜２３８℃M. p. 236 ~ 238 ℃
【０１２５】1Ｈ−ＮＭＲ（ＣＤＣｌ3）δｐｐｍ；０．
９５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．７３（２Ｈ，ｓｅ
ｘｔ，Ｊ＝７Ｈｚ），３．６１（３Ｈ，ｓ），３．８７
（２Ｈ，ｓ），４．０４（２Ｈ，ｔ，Ｊ＝７Ｈｚ），
６．９７（１Ｈ，ｓ），７．１８（１Ｈ，ｄ，Ｊ＝８Ｈ
ｚ），７．２６（１Ｈ，ｓ），７．５２（１Ｈ，ｔ，Ｊ
＝８Ｈｚ），７．７０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．
７２（１Ｈ，ｄｄ，Ｊ＝２，８Ｈｚ），７．８７（１
Ｈ，ｄ，Ｊ＝８Ｈｚ），７．９９（１Ｈ，ｄ，Ｊ＝２Ｈ
ｚ），８．０８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），１０．４１
（１Ｈ，ｓ），１２．６３（１Ｈ，ｂｓ）． 1 H-NMR (CDCl 3 ) δ ppm;
95 (3H, t, J = 7Hz), 1.73 (2H, se
xt, J = 7 Hz), 3.61 (3H, s), 3.87
(2H, s), 4.04 (2H, t, J = 7Hz),
6.97 (1H, s), 7.18 (1H, d, J = 8H
z), 7.26 (1H, s), 7.52 (1H, t, J
= 8 Hz), 7.70 (1H, t, J = 8 Hz), 7.
72 (1H, dd, J = 2, 8Hz), 7.87 (1
H, d, J = 8 Hz, 7.99 (1H, d, J = 2H)
z), 8.08 (1H, d, J = 8Hz), 10.41
(1H, s), 12.63 (1H, bs).
【０１２６】実施例２４３，４−ジヒドロ−２−［５−［（メチルアミノ）カル
ボニルアミノ］２−プロポキシフェニル］ベンゾフロ
［３，２−ｄ］ピリミジン−４−オン ２−（５−アミノ−２−プロポキシフェニル）−３，４
−ジヒドロベンゾフロ［３，２−ｄ］ピリミジン−４−
オン塩酸塩４００ｍｇとトリエチルアミン２４０ｍｇ
（１．１当量）のＮ，Ｎ−ジメチルホルムアミド２０ｍ
ｌ溶液にメチルイソシアネート１８５ｍｇ（３当量）を
加え、室温で４時間攪拌した。酢酸エチル８０ｍｌを加
え、３０分間攪拌して析出した結晶を濾取した。得られ
た結晶をメタノールで洗浄して標記化合物２８１ｍｇを
得た。Example 24 3,4-Dihydro-2- [5-[(methylamino) calcal
Bonylamino] 2-propoxyphenyl] benzofuro
[3,2-d] pyrimidin-4-one 2- (5-amino-2-propoxyphenyl) -3,4
-Dihydrobenzofuro [3,2-d] pyrimidine-4-
On-hydrochloride 400 mg and triethylamine 240 mg
(1.1 eq) N, N-dimethylformamide 20 m
185 mg (3 equivalents) of methyl isocyanate was added to the 1-solution, and the mixture was stirred at room temperature for 4 hours. 80 ml of ethyl acetate was added, the mixture was stirred for 30 minutes, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol to obtain 281 mg of the title compound.
【０１２７】ｍ．ｐ．＞３００℃M. p. > 300 ° C
【０１２８】1Ｈ−ＮＭＲ（ＣＤＣｌ3）δｐｐｍ；０．
９６（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．７３（２Ｈ，ｓｅ
ｘｔ，Ｊ＝７Ｈｚ），２．６５（３Ｈ，ｄ，Ｊ＝５Ｈ
ｚ），４．０２（２Ｈ，ｔ，Ｊ＝７Ｈｚ），５．９６
（１Ｈ，ｑ，Ｊ＝５Ｈｚ），７．１０（１Ｈ，ｄ，Ｊ＝
８Ｈｚ），７．５２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．５
９（１Ｈ，ｄｄ，Ｊ＝２，８Ｈｚ），７．７０（１Ｈ，
ｔ，Ｊ＝８Ｈｚ），７．８６（１Ｈ，ｄ，Ｊ＝２Ｈ
ｚ），７．８７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０８
（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．５７（１Ｈ，ｓ），１
２．５６（１Ｈ，ｂｓ）． 1 H-NMR (CDCl 3 ) δ ppm;
96 (3H, t, J = 7Hz), 1.73 (2H, se
xt, J = 7 Hz), 2.65 (3H, d, J = 5H)
z), 4.02 (2H, t, J = 7Hz), 5.96.
(1H, q, J = 5Hz), 7.10 (1H, d, J =
8 Hz), 7.52 (1 H, t, J = 8 Hz), 7.5
9 (1H, dd, J = 2, 8Hz), 7.70 (1H,
t, J = 8 Hz), 7.86 (1H, d, J = 2H)
z), 7.87 (1H, d, J = 8Hz), 8.08
(1H, d, J = 8Hz), 8.57 (1H, s), 1
2.56 (1H, bs).
【０１２９】実施例２５３，４−ジヒドロ−２−［５−［（２−クロロエチルア
ミノ）カルボニルアミノ］２−プロポキシフェニル］ベ
ンゾフロ［３，２−ｄ］ピリミジン−４−オン 実施例２４と同様にして２−（５−アミノ−２−プロポ
キシフェニル）−３，４−ジヒドロベンゾフロ［３，２
−ｄ］ピリミジン−４−オン塩酸塩と２−クロロエチル
イソシアネートから標記化合物を得た。Example 25 3,4-dihydro-2- [5-[(2-chloroethyl
Mino) carbonylamino] 2-propoxyphenyl] beta
Nzofuro [3,2-d] pyrimidin-4-one 2- (5-amino -2-propoxyphenyl ) -3,4-dihydrobenzofuro [3,2 was prepared in the same manner as in Example 24.
The title compound was obtained from -d] pyrimidin-4-one hydrochloride and 2-chloroethylisocyanate.
【０１３０】ｍ．ｐ．２２３〜２２５℃M. p. 223-225 ° C
【０１３１】1Ｈ−ＮＭＲ（ＣＤＣｌ3）δｐｐｍ；０．
９５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），１．７３（２Ｈ，ｓｅ
ｘｔ，Ｊ＝７Ｈｚ），３．４２（２Ｈ，ｑ，Ｊ＝７Ｈ
ｚ），３．６６（２Ｈ，ｔ，Ｊ＝７Ｈｚ），４．０３
（２Ｈ，ｔ，Ｊ＝７Ｈｚ），６．３７（１Ｈ，ｔ，Ｊ＝
７Ｈｚ），７．１１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．５
２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．５６（１Ｈ，ｄｄ，
Ｊ＝２，８Ｈｚ），７．７０（１Ｈ，ｔ，Ｊ＝８Ｈ
ｚ），７．８６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．８８
（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．０８（１Ｈ，ｄ，Ｊ＝
８Ｈｚ），８．７３（１Ｈ，ｓ），１２．５８（１Ｈ，
ｂｓ）． 1 H-NMR (CDCl 3 ) δ ppm;
95 (3H, t, J = 7Hz), 1.73 (2H, se
xt, J = 7 Hz), 3.42 (2H, q, J = 7H)
z), 3.66 (2H, t, J = 7Hz), 4.03.
(2H, t, J = 7Hz), 6.37 (1H, t, J =
7 Hz), 7.11 (1H, d, J = 8 Hz), 7.5
2 (1H, t, J = 8Hz), 7.56 (1H, dd,
J = 2,8 Hz), 7.70 (1H, t, J = 8H
z), 7.86 (1H, d, J = 8 Hz), 7.88
(1H, d, J = 2Hz), 8.08 (1H, d, J =
8 Hz), 8.73 (1 H, s), 12.58 (1 H,
bs).
【０１３２】以下、試験例により本発明の効果を具体的
に説明する。The effects of the present invention will be specifically described below with reference to test examples.
【０１３３】試験例１．サイクリックＧＭＰ特異的ホス
ホジエステラーゼ阻害作用 ホスホジエステラーゼアイソザイムは、犬大動脈可溶画
分よりＭｏｎｏＱＨＲ５／５カラムを用いたＦＰＬＣシ
ステムにて精製した。すなわち、摘出組織を２５ｍＭト
リス塩酸緩衝液、２５０ｍＭスクロース、２ｍＭ塩化マ
グネシウム、１ｍＭエチレングリコールビス（β−アミ
ノエチルエーテル）Ｎ，Ｎ，Ｎ’，Ｎ’−四酢酸、１ｍ
Ｍジチオスレイトールおよび各種プロテアーゼインヒビ
ターの存在下にてホモジナイズした後、遠心分離にて上
清を得、ＭｏｎｏＱカラムに添加した。Test Example 1. Cyclic GMP-specific phosphodiesterase inhibitory action The phosphodiesterase isozyme was purified from the soluble fraction of dog aorta by the FPLC system using MonoQHR5 / 5 column. That is, the extracted tissue was treated with 25 mM Tris-HCl buffer, 250 mM sucrose, 2 mM magnesium chloride, 1 mM ethylene glycol bis (β-aminoethyl ether) N, N, N ′, N′-tetraacetic acid, 1 m.
After homogenizing in the presence of M dithiothreitol and various protease inhibitors, the supernatant was obtained by centrifugation and added to the MonoQ column.
【０１３４】十分量洗浄後、塩勾配により蛋白質画分の
溶出を行ない、各画分のホスホジエステラーゼ活性を測
定することによりカルシウム・カルモジュリン依存性ホ
スホジエステラーゼとサイクリックＧＭＰ特異的ホスホ
ジエステラーゼの混合画分を得た。さらにカルモジュリ
ンアフィニティークロマトグラフィーにより両者を分離
精製した。After washing with a sufficient amount, the protein fraction was eluted with a salt gradient, and the phosphodiesterase activity of each fraction was measured to obtain a mixed fraction of calcium / calmodulin-dependent phosphodiesterase and cyclic GMP-specific phosphodiesterase. . Further, both were separated and purified by calmodulin affinity chromatography.
【０１３５】ホスホジエステラーゼ活性の測定はＢｉｏ
ｃｈｅｍ．Ｂｉｏｐｈｙｓ．Ｒｅｓ．Ｃｏｍｍｕｎ．、
第１４８巻、第１４６８頁（１９８７年、Ｓ．Ｍａｔｓ
ｕｓｈｉｍａら）に記載された方法に従い、犬大動脈サ
イクリックＧＭＰ特異的ホスホジエステラーゼについて
は活性化因子として０．２ｍＭエチレングリコールビス
（β−アミノエチルエーテル）Ｎ，Ｎ，Ｎ’，Ｎ’−四
酢酸存在下に０．４μＭ［３Ｈ］サイクリックＧＭＰを
基質として測定した。Phosphodiesterase activity is measured by Bio
chem. Biophys. Res. Commun. ,
Vol. 148, p. 1468 (1987, S. Mats
Ushima et al.), the presence of 0.2 mM ethylene glycol bis (β-aminoethyl ether) N, N, N ′, N′-tetraacetic acid as an activator for canine aortic cyclic GMP-specific phosphodiesterase. Below, 0.4 μM [3H] cyclic GMP was measured as a substrate.
【０１３６】被検薬物は１００％ジメチルスルホキシド
に溶解後、１０％ジメチルスルホキシド溶液として用い
た。反応液中の最終濃度は１％ジメチルスルホキシドと
した。結果は表１に示す。The test drug was dissolved in 100% dimethyl sulfoxide and then used as a 10% dimethyl sulfoxide solution. The final concentration in the reaction solution was 1% dimethyl sulfoxide. The results are shown in Table 1.
【０１３７】[0137]
【表１】 [Table 1]
【０１３８】試験例２．血管拡張作用 血管拡張作用はＡｍ．Ｊ．Ｐｈｙｓｉｏｌ．２６２（Ｈ
ｅａｒｔ Ｃｉｒｃ．Ｐｈｙｓｉｏｌ．３１）：Ｈ１１
０４（１９９２年、Ｎ．Ｍｉｙａｔａら）に記載された
方法に従い測定した。Test Example 2. Vasodilatory action The vasodilatory action is Am. J. Physiol. 262 (H
early Circ. Physiol. 31): H11
04 (1992, N. Miyata et al.).
【０１３９】Ｗｉｓｔａｒ系雄性ラット（体重２５０〜
３００ｇ）より胸部大動脈を摘出し、余分な結合組織を
除去した後、幅５ｍｍのリング状標本を作製した。血管
の張力は、通常の平滑筋測定用マグヌス装置にて、等尺
性張力を測定した。Wistar male rats (body weight 250-
The thoracic aorta was excised from 300 g), excess connective tissue was removed, and a ring-shaped specimen with a width of 5 mm was prepared. The blood vessel tension was measured as isometric tension with a normal smooth muscle measuring Magnus apparatus.
【０１４０】なお、血管内皮細胞は、温存した状態で実
験を行なった。６０〜９０分のインキュベーションの
後、１０-7Ｍノルエピネフリンで血管を収縮させ、収縮
が安定したところで、被検薬物を１０-10〜１０-5Ｍの
濃度で累積投与し、弛緩反応を検討した。The experiment was carried out while the vascular endothelial cells were preserved. After incubation for 60 to 90 minutes, the blood vessels were contracted with 10 -7 M norepinephrine, and when the contraction was stable, the test drug was cumulatively administered at a concentration of 10 -10 to 10 -5 M to examine the relaxation reaction. .
【０１４１】また、実験結果（ＩＣ50値）は、１０-7Ｍ
ノルエピネフリン収縮を１００％としたときに、その収
縮を５０％拡張させる被検薬物の濃度として示した。な
お、被検薬物はすべて１００％ジメチルスルホキシドに
溶解して実験に用いた。The experimental result (IC 50 value) was 10 −7 M
When the norepinephrine contraction was set to 100%, it was shown as the concentration of the test drug that expanded the contraction by 50%. All test drugs were dissolved in 100% dimethyl sulfoxide and used in the experiment.
【０１４２】結果は表２に示す。The results are shown in Table 2.
【０１４３】[0143]
【表２】 [Table 2]
【０１４４】試験例３．降圧作用 降圧作用はＪ．Ｃａｒｄｉｏｖａｓｃ．Ｐｈａｒｍａｃ
ｏｌ．１８：８５５（１９９１年、Ｔ．Ｔａｋａｄａ
ら）に記載された方法に従い測定した。Test Example 3. Antihypertensive effect Antihypertensive effect is described in J. Cardiovasc. Pharmac
ol. 18: 855 (1991, T. Takada.
Et al.).
【０１４５】８〜１２週齢のＷｉｓｔａｒ系雄性ラット
をウレタン麻酔し、動脈圧測定のため右総頸動脈にカニ
ューレを挿入し、さらに被検薬物投与のため大腿動脈に
カニューレを挿入した。被検薬物は０．０５Ｎ水酸化ナ
トリウム水溶液もしくは５０％ジメチルスルホキシドに
溶解して静脈内投与した。Wistar male rats aged 8 to 12 weeks were anesthetized with urethane, a right common carotid artery was cannulated for measuring arterial blood pressure, and a femoral artery was cannulated for administration of a test drug. The test drug was dissolved in 0.05N aqueous sodium hydroxide solution or 50% dimethyl sulfoxide and intravenously administered.
【０１４６】実験結果は各被検薬物の用量反応曲線を求
めた後、線形回帰法により１５ｍｍＨｇ平均血圧を下降
させる用量（μｇ／ｋｇ）として示した。The experimental results were shown as the dose (μg / kg) that lowers the mean blood pressure of 15 mmHg by the linear regression method after determining the dose-response curve of each test drug.
【０１４７】結果は表３に示す。The results are shown in Table 3.
【０１４８】[0148]
【表３】 [Table 3]
【０１４９】試験例４．心収縮増加作用 心収縮増加作用はＡｒｚｎｅｉｍ．−Ｆｏｒｓｃｈ．／
Ｄｒｕｇ Ｒｅｓ．４０（１９９０年、Ｋ．Ｎｉｓｈｉ
ｍｕｒａら）に記載された方法に従い測定した。Test Example 4. Increased systolic effect Increased systolic effect is described in Arzneim. -Forsch. /
Drug Res. 40 (1990, K. Nishi
Mura et al.).
【０１５０】体重２００〜５００ｇのＨａｒｔｌｅｙ系
雄性モルモットを頭部撲殺し放血致死させ、速やかに心
臓を摘出し、混合ガス（９５％酸素、５％二酸化炭素）
で飽和した３０℃のＫｒｅｂｓ−Ｈｅｎｓｅｌｅｉｔ溶
液（組成；１１８ｍＭ塩化ナトリウム、４．７ｍＭ塩化
カリウム、３．０ｍＭ塩化カルシウム、１．２ｍＭリン
酸二水素ナトリウム、２５．０ｍＭ炭酸水素ナトリウ
ム、１１．０ｍＭグルコース）中で心房標本を作製し
た。右心房端を金属ホルダーに固定し、１０ｍｌの混合
ガス飽和Ｋｒｅｂｓ−Ｈｅｎｓｅｌｅｉｔ溶液を入れた
マグヌス槽に標本を入れた後、左心房端を等尺性張力ト
ランスデュサーに直接結び、標本を懸垂した。静止張力
はほぼ最大発生張力が得られるまで負荷した。A Hartley male guinea pig weighing 200 to 500 g was killed by bruising the head and lethal to exsanguination, and the heart was rapidly removed and mixed gas (95% oxygen, 5% carbon dioxide).
30 ° C. Krebs-Henseleit solution (composition; 118 mM sodium chloride, 4.7 mM potassium chloride, 3.0 mM calcium chloride, 1.2 mM sodium dihydrogen phosphate, 25.0 mM sodium hydrogen carbonate, 11.0 mM glucose) Atrial specimens were prepared in it. The right atrial end was fixed to a metal holder, the sample was placed in a Magnus tank containing 10 ml of a mixed gas saturated Krebs-Henseleit solution, and then the left atrial end was directly connected to an isometric tension transducer to suspend the sample. . Resting tension was applied until the maximum generated tension was obtained.
【０１５１】その状態で溶液は約１５分間隔で置換しな
がら最低１時間以上インキュベーションし、自発性収縮
力および心拍数が一定であることを確認後、実験を開始
した。 発生した自発性収縮は歪圧力用アンプを用い
て、また、心拍数は収縮の出力を瞬時心拍計ユニットに
入力して計測し、ポリグラフレコーダーにそれぞれ記録
した。実験結果は各被検薬物を１０-7〜１０-4Ｍまで累
積的に投与して用量反応曲線を求め、収縮力を２０％増
加させるために必要な薬物濃度（ＥＣ20値）として示し
た。In this state, the solution was replaced at intervals of about 15 minutes and incubated for at least 1 hour or longer, and after confirming that the spontaneous contractile force and the heart rate were constant, the experiment was started. The spontaneous contractions that occurred were measured using a strain pressure amplifier, and the heart rate was measured by inputting the contraction output to an instantaneous heart rate unit and recorded on a polygraph recorder. The experimental results were shown as the drug concentration (EC 20 value) required to increase the contractile force by 20% by cumulatively administering each test drug up to 10 -7 to 10 -4 M to obtain a dose-response curve. .
【０１５２】また、被検薬物は１００％ジメチルスルホ
キシドに溶解して用いた。The test drug was used by dissolving it in 100% dimethyl sulfoxide.
【０１５３】結果を表４に示す。The results are shown in Table 4.
【０１５４】[0154]
【表４】 [Table 4]
【０１５５】* ：被検薬物の濃度が１００μＭのときの
収縮力の変化率を示す。 * : Shows the rate of change in contractile force when the concentration of the test drug is 100 μM.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/505 ＡＢＵ ＡＢＸ ＡＣＤ ＡＤＡ ＡＥＤ ─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 6 Identification code Internal reference number FI Technical display area A61K 31/505 ABU ABX ACD ADA AED
Claims (2)
し、ｎは０〜４を示し、Ｘはハロゲン原子、カルボキシ
ル基、フェノキシ基、（１−メチル−１Ｈ−イミダゾー
ル−２−イル）チオ基またはＲ2Ｒ3Ｎ基を示す。ここで
Ｒ2、Ｒ3は同一もしくは異なっていても良く水素原子、
炭素原子数１〜４個のハロゲン化アルキル基、炭素原子
数１〜４個のアルキル基または炭素原子数１〜４個のヒ
ドロキシアルキル基を示すか、Ｒ2Ｒ3Ｎ基としてピペリ
ジノ基、モルホリノ基、ピロリジノ基、４−ヒドロキシ
ピペリジノ基、４−（２−ヒドロキシエチル）ピペラジ
ノ基、３−ヒドロキシピロリジノ基または１，２，３，
４−テトラヒドロイソキノリジノ基を示す。］で表され
るベンゾフロ［３，２−ｄ］ピリミジン−４−オン誘導
体およびその塩。1. A formula [In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms, n represents 0 to 4, X represents a halogen atom, a carboxyl group, a phenoxy group, (1-methyl-1H-imidazole-2- Il) thio group or R 2 R 3 N group. Here, R 2 and R 3 may be the same or different, and a hydrogen atom,
A halogenated alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms or a hydroxyalkyl group having 1 to 4 carbon atoms, or a piperidino group or morpholino group as R 2 R 3 N group Group, pyrrolidino group, 4-hydroxypiperidino group, 4- (2-hydroxyethyl) piperazino group, 3-hydroxypyrrolidino group or 1,2,3,3
A 4-tetrahydroisoquinolidino group is shown. ] The benzofuro [3,2-d] pyrimidin-4-one derivative represented by these, and its salt.
し、Ｙはアミノ基またはニトロ基を示す。］で表される
ベンゾフロ［３，２−ｄ］ピリミジン−４−オン誘導体
およびその塩。2. A formula [In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms, and Y represents an amino group or a nitro group. ] The benzofuro [3,2-d] pyrimidin-4-one derivative represented by these, and its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6084033A JPH07267961A (en) | 1994-03-30 | 1994-03-30 | Benzofuro (3,2-d)pyrimidine-4-one derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6084033A JPH07267961A (en) | 1994-03-30 | 1994-03-30 | Benzofuro (3,2-d)pyrimidine-4-one derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH07267961A true JPH07267961A (en) | 1995-10-17 |
Family
ID=13819227
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6084033A Pending JPH07267961A (en) | 1994-03-30 | 1994-03-30 | Benzofuro (3,2-d)pyrimidine-4-one derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07267961A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09202785A (en) * | 1995-12-11 | 1997-08-05 | Bayer Ag | Benzofuranylureas substituted by heterocyclic carbonyl |
| WO2001068609A1 (en) * | 2000-03-14 | 2001-09-20 | Actelion Pharmaceuticals Ltd. | 1,2,3,4-tetrahydroisoquinoline derivatives |
| WO2003000697A1 (en) * | 2001-06-22 | 2003-01-03 | Takeda Chemical Industries, Ltd. | Furoisoquinoline derivative, process for producing the same, and use |
| JP2003526601A (en) * | 1998-06-08 | 2003-09-09 | ダーウィン・ディスカバリー・リミテッド | Furopyridine derivatives and their therapeutic use |
| US7763638B2 (en) | 2004-03-01 | 2010-07-27 | Actelion Pharmaceuticals Ltd. | Substituted 1,2,3,4-tetrahydroisoquinoline derivatives |
| US8247560B2 (en) | 2007-12-28 | 2012-08-21 | Actelion Pharmaceuticals Ltd. | Trisubstituted 3,4-dihydro-1H-isoquinolin compound, process for its preparation, and its use |
-
1994
- 1994-03-30 JP JP6084033A patent/JPH07267961A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09202785A (en) * | 1995-12-11 | 1997-08-05 | Bayer Ag | Benzofuranylureas substituted by heterocyclic carbonyl |
| JP2003526601A (en) * | 1998-06-08 | 2003-09-09 | ダーウィン・ディスカバリー・リミテッド | Furopyridine derivatives and their therapeutic use |
| WO2001068609A1 (en) * | 2000-03-14 | 2001-09-20 | Actelion Pharmaceuticals Ltd. | 1,2,3,4-tetrahydroisoquinoline derivatives |
| US6703392B2 (en) | 2000-03-14 | 2004-03-09 | Actelion Pharmaceuticals Ltd. | 1,2,3,4-tetrahydroisoquinoline derivatives |
| CN100393703C (en) * | 2000-03-14 | 2008-06-11 | 埃科特莱茵药品有限公司 | 1,2,3,4-tetrahydroisoquinoline derivatives |
| WO2003000697A1 (en) * | 2001-06-22 | 2003-01-03 | Takeda Chemical Industries, Ltd. | Furoisoquinoline derivative, process for producing the same, and use |
| US7763638B2 (en) | 2004-03-01 | 2010-07-27 | Actelion Pharmaceuticals Ltd. | Substituted 1,2,3,4-tetrahydroisoquinoline derivatives |
| US8247560B2 (en) | 2007-12-28 | 2012-08-21 | Actelion Pharmaceuticals Ltd. | Trisubstituted 3,4-dihydro-1H-isoquinolin compound, process for its preparation, and its use |
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