JPH0446157A - New isoquinoline derivative - Google Patents
New isoquinoline derivativeInfo
- Publication number
- JPH0446157A JPH0446157A JP2150483A JP15048390A JPH0446157A JP H0446157 A JPH0446157 A JP H0446157A JP 2150483 A JP2150483 A JP 2150483A JP 15048390 A JP15048390 A JP 15048390A JP H0446157 A JPH0446157 A JP H0446157A
- Authority
- JP
- Japan
- Prior art keywords
- hydroxy
- acid
- compound
- acid addition
- addition salt
- 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.)
- Granted
Links
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 150000002537 isoquinolines Chemical class 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- HMDGBVSVHZEFGU-UHFFFAOYSA-N propyl 5-hydroxyisoquinoline-1-carboxylate Chemical compound C1=CC=C2C(C(=O)OCCC)=NC=CC2=C1O HMDGBVSVHZEFGU-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- AFPZXOKRIKFYFD-UHFFFAOYSA-N [2-(dimethylamino)-2-oxoethyl] 5-hydroxyisoquinoline-1-carboxylate Chemical compound C1=CC=C2C(C(=O)OCC(=O)N(C)C)=NC=CC2=C1O AFPZXOKRIKFYFD-UHFFFAOYSA-N 0.000 claims 1
- BTAYOMMGZIAQRX-UHFFFAOYSA-N benzyl 5-hydroxyisoquinoline-1-carboxylate Chemical compound N1=CC=C2C(O)=CC=CC2=C1C(=O)OCC1=CC=CC=C1 BTAYOMMGZIAQRX-UHFFFAOYSA-N 0.000 claims 1
- LPVOPSBEOVMADD-UHFFFAOYSA-N butyl 5-hydroxyisoquinoline-1-carboxylate Chemical compound C1=CC=C2C(C(=O)OCCCC)=NC=CC2=C1O LPVOPSBEOVMADD-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- FTAXWLGHYFTOME-UHFFFAOYSA-N propan-2-yl 5-hydroxyisoquinoline-1-carboxylate Chemical compound C1=CC=C2C(C(=O)OC(C)C)=NC=CC2=C1O FTAXWLGHYFTOME-UHFFFAOYSA-N 0.000 claims 1
- 150000002440 hydroxy compounds Chemical class 0.000 abstract description 9
- GYWACVVCOABXJM-UHFFFAOYSA-N 5-hydroxyisoquinoline-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=NC=CC2=C1O GYWACVVCOABXJM-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- SXTSBZBQQRIYCU-UHFFFAOYSA-N 4-guanidinobenzoic acid Chemical compound NC(=N)NC1=CC=C(C(O)=O)C=C1 SXTSBZBQQRIYCU-UHFFFAOYSA-N 0.000 abstract description 4
- 108091005804 Peptidases Proteins 0.000 abstract description 3
- -1 Propyl 5-hydroxy-1-isoquinolinecarboxylate Chemical compound 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 102000035195 Peptidases Human genes 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 235000019833 protease Nutrition 0.000 abstract 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- AZYTZQYCOBXDGY-UHFFFAOYSA-N 2-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=CC=N1 AZYTZQYCOBXDGY-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- FCEQRBOTYXIORK-UHFFFAOYSA-N 2-(diaminomethylideneamino)benzoic acid Chemical compound NC(=N)NC1=CC=CC=C1C(O)=O FCEQRBOTYXIORK-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 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
- 229910015900 BF3 Inorganic materials 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- XJTQJERLRPWUGL-UHFFFAOYSA-N iodomethylbenzene Chemical compound ICC1=CC=CC=C1 XJTQJERLRPWUGL-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- CATWEXRJGNBIJD-UHFFFAOYSA-N n-tert-butyl-2-methylpropan-2-amine Chemical compound CC(C)(C)NC(C)(C)C CATWEXRJGNBIJD-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は新規なイソキノリン誘導体およびその酸付加塩
に関する。本発明の化合物は、医薬中間体として有用で
ある。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel isoquinoline derivatives and acid addition salts thereof. Compounds of the invention are useful as pharmaceutical intermediates.
〔従来技術および解決しようとする課題〕従来、種々の
イソキノリン誘導体が見出されているが、５−ヒドロキ
シ−１−インキノリンカルボン酸エステルに関しては僅
かにエチルエステル（Ｊ、 Ｏｒｇ、 Ｃｈｅｗ、 ２
７．４５７１． （１９６２））が報告されているのみ
である。[Prior Art and Problems to be Solved] Various isoquinoline derivatives have been found in the past, but only ethyl ester (J, Org, Chew, 2
7.4571. (1962)) has only been reported.
本発明者は、新規な蛋白分解酵素阻害剤の研究開発中、
−船蔵（１）で表される一連のイソキノリン誘導体を見
出した。そしてこの化合物を合成中間体として新規イン
キノリン誘導体を製造すると、この化合物を効率よく製
造することができ、しかも得られる化合物が優れた蛋白
分解酵素阻害効果を有することを見出し、本発明を完成
するに至った。すなわち、本発明は、−船蔵（１）〔式
中、
Ｒは炭素数３または４の直鎖または分枝鎖アルキル基、
フェニル基、ベンジル基、ＣＨ，Ｃ０ＮＲ’Ｒ２基（Ｒ
’、 Ｒ”は水素または炭素数１〜４までの直鎖または
分枝鎖アルキル基で同一または異なっていてもよい）よ
りなる群から選択される基を表す］
で示されるイソキノリン誘導体またはその薬理学的に許
容できる酸付加塩に関する。The present inventor is currently researching and developing a new protease inhibitor.
- We have discovered a series of isoquinoline derivatives represented by (1). The inventors have discovered that when a new inquinoline derivative is produced using this compound as a synthetic intermediate, this compound can be produced efficiently, and that the resulting compound has an excellent protease inhibitory effect, thus completing the present invention. reached. That is, the present invention provides - Funazura (1) [wherein R is a straight or branched alkyl group having 3 or 4 carbon atoms,
Phenyl group, benzyl group, CH, C0NR'R2 group (R
', R'' represents a group selected from the group consisting of hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, which may be the same or different] or a drug thereof Concerning physically acceptable acid addition salts.
本発明化合物（Ｉ）は、次式（Ｕ）
Ｈ
で表される５−ヒドロキシ−１−イソキノリンカルボン
酸またはその反応性誘導体と次式（ＩＩＩ）ＲＯＭ
（［［［）
〔式中、Ｒは炭素数３または４の直鎖または分枝鎖アル
キル基、フェニル基、ベンジル基、Ｃｌ ｚｃＯＮＲ’
Ｒ’基（Ｒ１，ＲＺは水素または炭素数１〜４までの
直鎖または分枝鎖アルキル基で同一または異なっていて
もよい）よりなる群から選択される基を表す〕
で示されるヒドロキシ化合物またはその反応性誘導体を
反応させることにより得ることができる。The compound (I) of the present invention is a combination of 5-hydroxy-1-isoquinolinecarboxylic acid represented by the following formula (U) H or a reactive derivative thereof and the following formula (III) ROM
([[[) [wherein R is a straight or branched alkyl group having 3 or 4 carbon atoms, a phenyl group, a benzyl group, Cl zcONR'
R' group (R1 and RZ are hydrogen or a straight chain or branched alkyl group having 1 to 4 carbon atoms and may be the same or different) A hydroxy compound represented by Alternatively, it can be obtained by reacting a reactive derivative thereof.
また、５−ヒドロキシ−１−イソキノリンカルボン酸（
Ｉ［）とヒドロキシ化合物（ＤＩ）との反応は、一般の
脱水反応を適用することができる。例えば、（ａ）触媒
、縮合剤等の存在下に遊離のカルボン酸（ＩＩ）または
その酸付加塩とヒドロキシ化合物（Ｉｌｌ）またはその
酸付加塩を反応させる方法、（ｂ）カルボン酸（Ｉｔ）
とヒドロキシ化合物（Ｉ［［）の反応性誘導体を反応さ
せる方法などを適用できる。In addition, 5-hydroxy-1-isoquinolinecarboxylic acid (
A general dehydration reaction can be applied to the reaction between I[) and the hydroxy compound (DI). For example, (a) a method of reacting free carboxylic acid (II) or an acid addition salt thereof with a hydroxy compound (Ill) or an acid addition salt thereof in the presence of a catalyst, a condensing agent, etc.; (b) a method of reacting a free carboxylic acid (II) or an acid addition salt thereof with a hydroxy compound (Ill);
A method of reacting a reactive derivative of a hydroxy compound (I[[) with a reactive derivative of the hydroxy compound (I[[)], etc. can be applied.
方法（ａ）における触媒としては、例えば硫酸、塩酸、
ｐ−）ルエンスルホン酸、オキシ塩化リン、ポリリン酸
、三フン化ホウ素等の酸触媒が挙げられる。縮合剤とし
ては、例えばジフェニルホスホリルアジド、ジシクロへ
キシルカルボジイミド、Ｎ、Ｎ’ −カルボジイミダゾ
ール、Ｎ、Ｎ’ −ジスクシンイミジ力ルバメート、１
−（３−ジメチルアミンプロピル）−３−エチルカルボ
ジイミド、ジメチルホルムアミドジエチルアセクール、
ＮＮ’ジメチルホスホルアミジンクジクロライド、ジク
ロルリン酸フェニル等を利用できる。この時、ジメチル
アミノピリジン、ピロリジノピリジン等の塩基触媒を併
用することもできる。Examples of the catalyst in method (a) include sulfuric acid, hydrochloric acid,
p-) Acid catalysts such as luenesulfonic acid, phosphorus oxychloride, polyphosphoric acid, and boron trifluoride can be mentioned. Examples of the condensing agent include diphenylphosphoryl azide, dicyclohexylcarbodiimide, N,N'-carbodiimidazole, N,N'-disuccinimidylrubamate, 1
-(3-dimethylaminepropyl)-3-ethylcarbodiimide, dimethylformamide diethyl acecool,
NN'dimethylphosphoramidine dichloride, phenyl dichlorophosphate, etc. can be used. At this time, a base catalyst such as dimethylaminopyridine or pyrrolidinopyridine can also be used in combination.
反応条件は、用いる触媒または縮合剤によって異なるが
、例えば縮合剤であるジシクロへキシルカルボジイミド
を用いる場合には、溶媒中でカルボン酸（ＩＩ）とジシ
クロへキシルカルボジイミドとを反応させ、これに化合
物（ｎ［）の溶液を加えて塩基の存在下または不存在下
に一３０〜１００℃で、数時間ないし数日間撹拌するこ
とによって反応終了する。このとき用いられる溶媒とし
ては、一般の有機溶媒、例えばピリジン、ジメチルホル
ムアミド、クロロホルム、ジクロロメタン、四塩化炭素
、ベンゼン、トルエン、キシレン、ジエチルエーテル、
ジオキサン、テトラヒドロフラン、アセトニトリル、酢
酸エチル、ジメチルスルホキシドの他、水が挙げられる
。また、塩基としては、ピリジン、トリエチルアミン、
ジイソプロピルエチルアミン、ジ−ｔ−ブチルアミン、
ジメチルアミノピリジン、ピロリジノピリジン、Ｎ−メ
チルモルホリン、１，８−ジアザビシクロ（５，４，０
）７−ウンデセン等が挙げられる。Reaction conditions vary depending on the catalyst or condensing agent used, but for example, when using dicyclohexylcarbodiimide as a condensing agent, carboxylic acid (II) and dicyclohexylcarbodiimide are reacted in a solvent, and the compound ( The reaction is completed by adding a solution of n[) and stirring at -30 to 100° C. for several hours to several days in the presence or absence of a base. Solvents used at this time include common organic solvents such as pyridine, dimethylformamide, chloroform, dichloromethane, carbon tetrachloride, benzene, toluene, xylene, diethyl ether,
Examples include dioxane, tetrahydrofuran, acetonitrile, ethyl acetate, dimethyl sulfoxide, and water. In addition, as a base, pyridine, triethylamine,
diisopropylethylamine, di-t-butylamine,
Dimethylaminopyridine, pyrrolidinopyridine, N-methylmorpholine, 1,8-diazabicyclo(5,4,0
) 7-undecene and the like.
方法（ｂ）における化合物（ＩＩＩ）の反応性誘導体と
しては、例えば（■）
ＲＸ （ＩＶ）
（式中、Ｒは前記と同じ基を、Ｘはクロロ、ブロモ、ヨ
ードを表す）
で表されるアルキルハライド、トリフロロ酢酸エステル
、あるいは（Ｖ）
↑
Ｒ−０−３−０−Ｒ（Ｖ）
（式中、Ｒは前記と同じ基を表す）
で表される化合物等が利用できる。The reactive derivative of compound (III) in method (b) is, for example, represented by (■) RX (IV) (wherein R is the same group as above, and X represents chloro, bromo, or iodo). Alkyl halides, trifluoroacetic esters, or compounds represented by (V) ↑ R-0-3-0-R(V) (wherein R represents the same group as above) can be used.
反応条件は用いる反応性誘導体によって異なるが、例え
ばアルキルハライドを用いる場合には、溶媒中でカルボ
ン酸（Ｉｔ）のアルカリ金属塩とアルキルハライドを一
３０〜１００°Ｃで、数時間ないし数日間撹拌すること
によって反応は終了する。The reaction conditions vary depending on the reactive derivative used, but for example, when using an alkyl halide, the alkali metal salt of carboxylic acid (It) and the alkyl halide are stirred in a solvent at -30 to 100°C for several hours to several days. The reaction is then terminated.
また、反応液から本発明化合物（１）を単離精製するに
は、抽出、濃縮、結晶化、濾過、再結晶、各種クロマト
グラフィー等、通常の単離精製に用いられる化学操作を
適用して行うことができる。In addition, to isolate and purify the compound (1) of the present invention from the reaction solution, chemical operations commonly used for isolation and purification such as extraction, concentration, crystallization, filtration, recrystallization, and various chromatography may be applied. It can be carried out.
以上のごとくして得られる本発明化合物（１）は、必要
に応し、常法により酸付加塩とすることができる。酸と
しては、硫酸、塩酸、硝酸、リン酸、臭化水素酸、炭酸
等の無機酸、また、酢酸、乳酸、コハク酸、酒石酸、リ
ンゴ酸、クエン酸、メタンスルホン酸、トルエンスルホ
ン酸、ベンゼンスルホン酸等の有機酸が利用できる。The compound (1) of the present invention obtained as described above can be converted into an acid addition salt by a conventional method, if necessary. Examples of acids include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, and carbonic acid, as well as acetic acid, lactic acid, succinic acid, tartaric acid, malic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, and benzene. Organic acids such as sulfonic acid can be used.
次に本発明を実施例を挙げて説明するが、これは本発明
を具体的により、理解し易くするためのもので、本発明
化合物の製造がこれにより制限されるものではない。Next, the present invention will be explained with reference to Examples, but these are intended to make the present invention more concrete and easier to understand, and the production of the compounds of the present invention is not limited thereto.
実施例１
プロピル ５−ヒ ロキシー１−イソキノ１ンカルボキ
シーート
５−ヒドロキシ−１−イソキノリンカルボン酸３、ＯＯ
ｇを塩化水素ガス飽和の１−プロパツール５０ｄに懸濁
し、２５時間加熱還流した。Example 1 Propyl 5-hydroxy 1-isoquinolinecarboxylate 5-hydroxy-1-isoquinolinecarboxylic acid 3,OO
g was suspended in 1-propatol 50d saturated with hydrogen chloride gas, and heated under reflux for 25 hours.
溶媒を減圧留去し、残渣に飽和炭酸水素ナトリウム水溶
液５０〆を加え、酢酸エチル１００ｄで３回抽出した。The solvent was distilled off under reduced pressure, 50 g of saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with 100 g of ethyl acetate.
抽出液を減圧濃縮し、残渣を含水エタノールから再結晶
して次の融点をもつ標題化合物１．４８ｇ （収率４
０，３％）を得た。The extract was concentrated under reduced pressure, and the residue was recrystallized from aqueous ethanol to obtain 1.48 g of the title compound having the following melting point (yield: 4
0.3%) was obtained.
融点：１４８〜１５０℃
ＦＡＢ−ＭＳ：２３２（Ｍ＋Ｈ） ”
ＩＲ： ｙ ”’ ｃ−Ｉｍ−’ ：
３４３０ 、２９７０．１７２０．１５８５．１４６０
．１２６５．１１７０．１１２０．８２０゜元素分析値
’ Ｃ＋Ｊ＋Ｊ（ｈとして計算Ｃ（％） Ｈ（％）
Ｎ（％）
理論値 ６７．５２ ５゜６７ ６．０６実測値
６７．４２ ５．７７ ６．１１実施例２
イソプロピル ５−ヒ′ロキシー１−イソキノ５−ヒド
ロキシ−１−イソキノリンカルボン酸２．５１ｇをエタ
ノール２０ｄに懸濁、水酸化カリウム０．８８ｇを溶か
したエタノール溶液２０ｄを加え、減圧留去した。残渣
をジメチルホルムアミド（ＤＭＦ）２０ｄに懸濁、２−
ヨードプロパン２．２６ｇを加え、水冷下１時間、室温
下２７時間撹拌した。Melting point: 148-150°C FAB-MS: 232 (M+H) "IR: y"'c-Im-': 3430, 2970.1720.1585.1460
．． 1265.1170.1120.820゜Elemental analysis value' C + J + J (calculated as h C (%) H (%)
N (%) Theoretical value 67.52 5゜67 6.06 Actual value
67.42 5.77 6.11 Example 2 2.51 g of isopropyl 5-hydroxy-1-isoquino-5-hydroxy-1-isoquinolinecarboxylic acid was suspended in 20 d of ethanol, and 0.88 g of potassium hydroxide was dissolved in ethanol. 20 d of solution was added and evaporated under reduced pressure. The residue was suspended in 20 d of dimethylformamide (DMF), 2-
2.26 g of iodopropane was added, and the mixture was stirred for 1 hour under water cooling and for 27 hours at room temperature.
反応液を５％千オ硫酸ナトリウム水溶液２００蔽にあけ
、酢酸エチル１００Ｍ１で３回抽出した。The reaction solution was poured into 200ml of 5% aqueous sodium sulfate solution and extracted three times with 100Ml of ethyl acetate.
抽出液を減圧濃縮し、残渣を含水２−プロパツールから
再結晶して、次の融点をもつ標題化合物１．３６ｇ
（収率４４．２％）を得た。The extract was concentrated under reduced pressure, and the residue was recrystallized from aqueous 2-propanol to obtain 1.36 g of the title compound having the following melting point:
(yield 44.2%).
融点：１８２〜１８３°Ｃ
Ｅｌ〜ＭＳ： ２３１ Ｍ”
ＩＲニジに’Ｃｌ１１−’：
３４５０、２９８０．１７２５．１５８５．１４６０．
２３７０．１２７０１１７０１１０５．９３０，８２０
，７４０
元素分析値：Ｃ＋Ｊ＋ＪＯ３として計算Ｃ（％）
■（％）
Ｎ（％）
理論値 ６７．５２ ５．６７ ６．０６実測値
６７．３２ ５．６２ ５．９６実施例３
５−ヒドロキシ−１−イソキノリンカルボン酸３．０Ｏ
ｇと水酸化カリウム１．０５ｇ 、ヨウ化ベンジル４．
１６ｇを用い、実施例２記載の方法に従って反応精製を
行い、次の融点をもつ標題化合物１．１４ｇ（収率２５
．７％）を得た。Melting point: 182-183°C El~MS: 231 M" IR 'Cl11-': 3450, 2980.1725.1585.1460.
2370.127011701105.930,820
,740 Elemental analysis value: Calculated as C + J + JO3 C (%) ■ (%) N (%) Theoretical value 67.52 5.67 6.06 Actual value
67.32 5.62 5.96 Example 3 5-hydroxy-1-isoquinolinecarboxylic acid 3.0O
g, potassium hydroxide 1.05 g, benzyl iodide 4.
Using 16g, reaction purification was carried out according to the method described in Example 2 to obtain 1.14g of the title compound (yield 25%) having the following melting point.
．． 7%).
融点： １６４．５〜１６６℃
Ｅｌ−ＭＳ： ２７９ Ｍ”
ＩＲニジＫＩｌｒＣ１１″′：
３４３０．３０４０，２９５０，１７２０．１５８０，
１４６０，１３７０．１２６０１１７０、１１２０．９
５０，８２０，７５０，６９５，５６５元素分析値：Ｃ
＋Ｊ＋ＪＯ３として計算Ｃ（％）Ｈ（％）Ｎ（％）
理論値 ７３．１１ ４．６９ ５−０２実測値
７３．００
実施例４
４．７８
５．０７
５−ヒドロキシ−１−イソキノリンカルボン酸３．００
ｇと水酸化カリウム１．０５ｇ 、α−ブロモ−ＮＮ−
ジメチルアセトアミド３．ＯＯｇを用い、実施例２記載
の方法に従って反応、精製を行い次の融点をもつ標題化
合物２．２０ｇ（収率５０．６％）を得た。Melting point: 164.5-166°C El-MS: 279 M" IR Niji KIlrC11"': 3430.3040, 2950, 1720.1580,
1460, 1370.12601170, 1120.9
50,820,750,695,565 elemental analysis value: C
Calculated as +J+JO3 C (%) H (%) N (%) Theoretical value 73.11 4.69 5-02 Actual value
73.00 Example 4 4.78 5.07 5-Hydroxy-1-isoquinolinecarboxylic acid 3.00
g and potassium hydroxide 1.05 g, α-bromo-NN-
Dimethylacetamide 3. Using OOg, reaction and purification were carried out according to the method described in Example 2 to obtain 2.20 g (yield 50.6%) of the title compound having the following melting point.
融点＝２０５〜２０８℃
Ｅｌ−阿Ｓ： ２７４ Ｍ’
ＩＲ： Ｖ ”’ ＣＩ−’ ：
３１５０、１７２０．１６５０．１２６０．１１６０．
１１２０．８１５元素分析値： Ｃ＋Ｊ＋４ＮｚＯ４と
して計算Ｃ（％） Ｈ（％） Ｎ（％）
理論値 ６１．３１ ５．１４ １０．２１実測値
６１．１１ ５．３４ １０．１１実施例５
ブ ル ５−ヒ′ロキシー −イソキノン力
ルボキシーート
５−ヒドロキシ−１−イソキノリンカルボン酸３、 ｏ
ｏｇと水酸化カリウム１．０５ｇ、１−ヨードブタンＩ
１．６ｇを用い、実施例２記載の方法に従って反応、精
製を行い次の融点をもつ標題化合物０．５４ｇ（収率１
３．９％）を得た。Melting point = 205-208°C El-A S: 274 M' IR: V"'CI-': 3150, 1720.1650.1260.1160.
1120.815 Elemental analysis value: Calculated as C+J+4NzO4 C (%) H (%) N (%) Theoretical value 61.31 5.14 10.21 Actual value 61.11 5.34 10.11 Example 5 Bull 5 -hydroxyl -isoquinone carboxylate 5-hydroxy-1-isoquinolinecarboxylic acid 3, o
og and potassium hydroxide 1.05g, 1-iodobutane I
Using 1.6 g, reaction and purification were performed according to the method described in Example 2 to obtain 0.54 g of the title compound (yield: 1
3.9%).
融点：１４８〜１５０°Ｃ
Ｅｌ−ＭＳ： ２４５ Ｍ”
【Ｒニジ”’ Ｃ１１−’ ：
２９５０．２５７０，１７２０．１５８０．１４５０．
１２５５．１１７０１１２０．８２５，７５０，５７０
元素分析値： Ｃｌ４８Ｉ５ＮＯ３として計算Ｃ（％）
Ｈ（％） Ｎ（％）
理論値 ６８．８４ ５．７８ ５．７３実測値
６８．７９ ６．１９ ５．６８本発明の新規イソ
キノリン誘導体（１）は、次の式で示される４−グアニ
ジノ安息香酸（Ｖｌ）またはその反応性誘導体と反応さ
せるこｋによって最終製品である次式で示されるイソキ
ノリン誘導体（■）
を効率良く得ることができる。Melting point: 148-150°C El-MS: 245 M" [R Niji"'C11-': 2950.2570, 1720.1580.1450.
1255.11701120.825,750,570 Elemental analysis value: Calculated as Cl48I5NO3 C (%)
H (%) N (%) Theoretical value 68.84 5.78 5.73 Actual value
68.79 6.19 5.68 The novel isoquinoline derivative (1) of the present invention can be reacted with 4-guanidinobenzoic acid (Vl) or a reactive derivative thereof represented by the following formula to produce the final product: The isoquinoline derivative (■) represented by the formula can be obtained efficiently.
Ｈ 反応と同様の方法を適用することができる。H A similar method to the reaction can be applied.
参考例として、本発明の新規イソキノリン誘導体（１）
から最終製品のイソキノリン誘導体（■）を得る方法の
具体例を参考例として示す。As a reference example, the novel isoquinoline derivative (1) of the present invention
A specific example of the method for obtaining the final product, the isoquinoline derivative (■), is shown as a reference example.
参考例
４−グアニジノ安息香酸１．０８ｇをピリジン２０ｍに
溶解し、ジシクロへキシルカルボジイミド１．０３ｇを
加え水冷下１時間撹拌した。ピリジン−〇ＭＦ混液に溶
解したプロピル ５−ヒドロキシ−１−イソキノリンカ
ルボキシラード（実施例１記載の方法に従って製造）
１．１６ｇを滴下し、水冷下１時間さらに室温で１６時
間撹拌した。反応液を濾過した後、濾液にエーテル５０
＋ｄを加え生成する沈澱を濾取した。沈澱を水２０１ｄ
に懸濁、飽和炭酸水素ナトリウム水溶液３０Ｗ１を加え
混合濾過し、沈澱を水およびアセトンで洗浄し炭酸塩１
．７１ｇを得た。Reference Example 4 - 1.08 g of guanidinobenzoic acid was dissolved in 20 m of pyridine, 1.03 g of dicyclohexylcarbodiimide was added, and the mixture was stirred for 1 hour under water cooling. Propyl 5-hydroxy-1-isoquinoline carboxylate dissolved in pyridine-〇MF mixture (prepared according to the method described in Example 1)
1.16 g was added dropwise, and the mixture was stirred for 1 hour under water cooling and further stirred at room temperature for 16 hours. After filtering the reaction solution, add 50% ether to the filtrate.
+d was added and the resulting precipitate was collected by filtration. Precipitate with water 201d
Add 30W1 of a saturated aqueous sodium bicarbonate solution, mix and filtrate, and wash the precipitate with water and acetone to obtain 1 carbonate.
．． 71 g was obtained.
炭酸塩をメタノールＩＣ１ｄに懸濁し、メタンスルボン
酸０．８７ｇを加えると発泡しながら溶けて澄明溶液と
なった。溶液にエーテル５０＋ｄを加え、デカントして
上清を除き、油状物を得た。油状物をシリカゲルクロマ
トグラフィー（ＣＨＣｌｉ：ＣＨｚＯＨ＋Ｃ）１．Ｃ０
０１（・１０：１：１で溶出）で精製した。溶出液を減
圧濃縮、濃縮液にエーテル１００Ｈ１を加えデカントし
て上清を除き、油状物を得た。油状物を２−プロパツー
ルから再結晶して次の物性を有する１′〜プロポキシ−
５′−イソキノリル ４−グアニジノベンゾアート・３
７２メタンスルホン酸塩０．８４ｇ（収率３１．３％）
を得た。When the carbonate was suspended in methanol IC1d and 0.87 g of methanesulfonic acid was added, it dissolved while bubbling to become a clear solution. Ether 50+d was added to the solution and the supernatant was removed by decanting to obtain an oil. The oil was subjected to silica gel chromatography (CHCli:CHzOH+C)1. C0
01 (eluted with 10:1:1). The eluate was concentrated under reduced pressure, ether 100H1 was added to the concentrate, and the mixture was decanted and the supernatant was removed to obtain an oil. The oil is recrystallized from 2-propanol to obtain 1'~propoxy-, which has the following physical properties.
5'-isoquinolyl 4-guanidinobenzoate 3
72 methanesulfonate 0.84g (yield 31.3%)
I got it.
融点７１７０〜１７４℃
ＦＡＢ−ＭＳ ３９３（Ｍ＋）ｌ）”
ＩＲニジＫＩ Ｃ１１−’：
３３００．３２５０．３＋２０．１７４０．１６９０．
１６１０．１５８０．１２７０゜１２３０、１１．７０
．１０４０，８２０，７７５，５５５．５３５元素分析
値： Ｃ，、Ｈ２゜Ｎ４０４・３７２ＣＨ，ＳＯ，Ｈと
して計算Ｃ（％） Ｈ（％） Ｎ（％）
ｓ（％）理論値 ５０．３７ ４．８８ １０．４
４ ８．９６実測値 ５０．３２ ４．９９ １０
．３６ ８．８４この化合物のイン・ビトロでのトリプ
シン阻害作用（５０％阻害濃度）を打粉らの方法〔ザ・
ジャーナル・オプ・ビオケミストリイ（↑ｈｅ Ｊｏｕ
ｒｎａｌ ｏｆＢｉｏｃｈｅｍｉｓｔｒｙ）、５８．２
１４（１９６５）参照〕に準して測定すると次の如くで
あった。Melting point 7170-174°C FAB-MS 393(M+)l)" IR Niji KI C11-': 3300.3250.3+20.1740.1690.
1610.1580.1270゜1230, 11.70
．． 1040,820,775,555.535 Elemental analysis value: Calculated as C,, H2°N404・372CH,SO,H C (%) H (%) N (%)
s (%) Theoretical value 50.37 4.88 10.4
4 8.96 Actual value 50.32 4.99 10
．． 36 8.84 The in vitro trypsin inhibitory effect (50% inhibitory concentration) of this compound was determined by the method of Tako et al.
Journal of Biochemistry (↑he Jou
RNA of Biochemistry), 58.2
14 (1965)], the results were as follows.
基質がｐ−４ジルアルギニンメチルエステルのとき５．
７ Ｘｌ０−”Ｍ、カゼインのとき１．５ Ｘｌ０−’
Ｍ。When the substrate is p-4 dylarginine methyl ester5.
7 Xl0-"M, casein 1.5 Xl0-'
M.
本発明のイソキノリン誘導体は、新規化合物であって、
この化合物と４−グアニジノ安息香酸とを反応させる蛋
白分解酵素阻害作用を有するイソキノリン誘導体を効率
良く得ることができる。The isoquinoline derivative of the present invention is a novel compound, comprising:
An isoquinoline derivative having a protease inhibitory effect can be efficiently obtained by reacting this compound with 4-guanidinobenzoic acid.
従って本発明のイソキノリン誘導体は、医薬中間体とし
て有用である。Therefore, the isoquinoline derivatives of the present invention are useful as pharmaceutical intermediates.
Claims (6)
キル基、フェニル基、ベンジル基、−ＣＨ＿２ＣＯＮＲ
＾１Ｒ＾２基（Ｒ＾１、Ｒ＾２は水素または炭素数１〜
４までの直鎖または分枝鎖アルキル基で同一または異な
っていてもよい）よりなる群から選択される基を表す〕 で示されるイソキノリン誘導体またはその薬理学的に許
容できる酸付加塩(1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R is a straight or branched alkyl group with 3 or 4 carbon atoms, phenyl group, benzyl group, -CH_2CONR
^1R^2 groups (R^1 and R^2 are hydrogen or carbon number 1~
up to 4 straight-chain or branched alkyl groups, which may be the same or different; isoquinoline derivatives or pharmacologically acceptable acid addition salts thereof;
ボキシラートまたはその薬理学的に許容できる酸付加塩
である請求項（１）記載の化合物(2) The compound according to claim (1), which is propyl 5-hydroxy-1-isoquinolinecarboxylate or a pharmacologically acceptable acid addition salt thereof.
カルボキシラートまたはその薬理学的に許容できる酸付
加塩である請求項（１）記載の化合物(3) The compound according to claim (1), which is isopropyl 5-hydroxy-1-isoquinoline carboxylate or a pharmacologically acceptable acid addition salt thereof.
ボキシラートまたはその薬理学的に許容できる酸付加塩
である請求項（１）記載の化合物(4) The compound according to claim (1), which is benzyl 5-hydroxy-1-isoquinolinecarboxylate or a pharmacologically acceptable acid addition salt thereof.
キシ−１−イソキノリンカルボキシラートまたはその薬
理学的に許容できる酸付加塩である請求項（１）記載の
化合物(5) The compound according to claim (1), which is N,N-dimethylcarbamoylmethyl 5-hydroxy-1-isoquinolinecarboxylate or a pharmacologically acceptable acid addition salt thereof.
キシラートまたはその薬理学的に許容できる酸付加塩で
ある請求項（１）記載の化合物(6) The compound according to claim (1), which is butyl 5-hydroxy-1-isoquinoline carboxylate or a pharmacologically acceptable acid addition salt thereof.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15048390A JP2654847B2 (en) | 1990-06-08 | 1990-06-08 | New isoquinoline derivatives |
| US07/630,064 US5116985A (en) | 1989-12-28 | 1990-12-19 | Isoquinoline derivatives and salts thereof |
| EP90125396A EP0435235B1 (en) | 1989-12-28 | 1990-12-24 | Isoquinoline derivatives and salts thereof as protease inhibitors. |
| ES90125396T ES2073502T3 (en) | 1989-12-28 | 1990-12-24 | ISOQUINOLINE DERIVATIVES AND THEIR SALTS AS PROTEASE INHIBITORS. |
| AT90125396T ATE119523T1 (en) | 1989-12-28 | 1990-12-24 | ISOQUINOLINE DERIVATIVES AND THEIR SALTS AS PROTEASE INHIBITORS. |
| DK90125396.3T DK0435235T3 (en) | 1989-12-28 | 1990-12-24 | New isoquinoline derivatives and salts thereof |
| DE69017627T DE69017627T2 (en) | 1989-12-28 | 1990-12-24 | Isoquinoline derivatives and their salts as protease inhibitors. |
| CA002033374A CA2033374A1 (en) | 1989-12-28 | 1990-12-28 | Isoquinoline derivatives and salts thereof |
| KR1019900022103A KR920012041A (en) | 1990-06-08 | 1990-12-28 | Novel isoquinoline derivatives and salts thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15048390A JP2654847B2 (en) | 1990-06-08 | 1990-06-08 | New isoquinoline derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0446157A true JPH0446157A (en) | 1992-02-17 |
| JP2654847B2 JP2654847B2 (en) | 1997-09-17 |
Family
ID=15497866
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15048390A Expired - Lifetime JP2654847B2 (en) | 1989-12-28 | 1990-06-08 | New isoquinoline derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2654847B2 (en) |
-
1990
- 1990-06-08 JP JP15048390A patent/JP2654847B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2654847B2 (en) | 1997-09-17 |
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