JP4352917B2 - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
- Publication number
- JP4352917B2 JP4352917B2 JP2004028958A JP2004028958A JP4352917B2 JP 4352917 B2 JP4352917 B2 JP 4352917B2 JP 2004028958 A JP2004028958 A JP 2004028958A JP 2004028958 A JP2004028958 A JP 2004028958A JP 4352917 B2 JP4352917 B2 JP 4352917B2
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- JP
- Japan
- Prior art keywords
- group
- formula
- ring
- lower alkyl
- pharmaceutical composition
- 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.)
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 108
- 150000003839 salts Chemical class 0.000 claims description 33
- 239000004480 active ingredient Substances 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 150000001555 benzenes Chemical group 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- -1 isopropyloxy group Chemical group 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 201000008482 osteoarthritis Diseases 0.000 claims description 5
- CCSONKKTCMHYFI-UHFFFAOYSA-N pyrido[3,4-f]quinoxaline Chemical class C1=NC=C2C3=NC=CN=C3C=CC2=C1 CCSONKKTCMHYFI-UHFFFAOYSA-N 0.000 claims description 5
- 229940124597 therapeutic agent Drugs 0.000 claims description 5
- 206010040070 Septic Shock Diseases 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 208000015100 cartilage disease Diseases 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 230000000069 prophylactic effect Effects 0.000 claims description 4
- XTRPORAHANZIBM-UHFFFAOYSA-N 6-(4-fluorophenyl)-8,9-dimethoxy-2,3,4,6,11,11a-hexahydro-1h-pyrazino[1,2-b]isoquinoline Chemical compound C1=2C=C(OC)C(OC)=CC=2CC2CNCCN2C1C1=CC=C(F)C=C1 XTRPORAHANZIBM-UHFFFAOYSA-N 0.000 claims description 3
- 208000010392 Bone Fractures Diseases 0.000 claims description 3
- 206010006482 Bronchospasm Diseases 0.000 claims description 3
- 206010017076 Fracture Diseases 0.000 claims description 3
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 208000026935 allergic disease Diseases 0.000 claims description 3
- 230000007885 bronchoconstriction Effects 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 230000035876 healing Effects 0.000 claims description 3
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 2
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 2
- 206010014950 Eosinophilia Diseases 0.000 claims description 2
- 206010018367 Glomerulonephritis chronic Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 206010063837 Reperfusion injury Diseases 0.000 claims description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 208000024780 Urticaria Diseases 0.000 claims description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 2
- 208000002205 allergic conjunctivitis Diseases 0.000 claims description 2
- 208000024998 atopic conjunctivitis Diseases 0.000 claims description 2
- 201000008937 atopic dermatitis Diseases 0.000 claims description 2
- 206010006451 bronchitis Diseases 0.000 claims description 2
- 208000007451 chronic bronchitis Diseases 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 230000036303 septic shock Effects 0.000 claims description 2
- 208000018464 vernal keratoconjunctivitis Diseases 0.000 claims description 2
- BXFCJJKIYIJYIW-UHFFFAOYSA-N 8,9-dimethoxy-6-(4-propan-2-yloxyphenyl)-2,3,4,6,11,11a-hexahydro-1h-pyrazino[1,2-b]isoquinoline Chemical compound C1=2C=C(OC)C(OC)=CC=2CC2CNCCN2C1C1=CC=C(OC(C)C)C=C1 BXFCJJKIYIJYIW-UHFFFAOYSA-N 0.000 claims 2
- 125000003282 alkyl amino group Chemical group 0.000 claims 2
- 206010039085 Rhinitis allergic Diseases 0.000 claims 1
- 201000010105 allergic rhinitis Diseases 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- 238000004519 manufacturing process Methods 0.000 description 28
- 230000002829 reductive effect Effects 0.000 description 28
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 102100024085 Alpha-aminoadipic semialdehyde dehydrogenase Human genes 0.000 description 17
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 235000019341 magnesium sulphate Nutrition 0.000 description 17
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 8
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012156 elution solvent Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- UQKZERJIZSURJA-UHFFFAOYSA-N 8,9-dimethoxy-6-phenyl-2,3,4,6,11,11a-hexahydro-1h-pyrazino[1,2-b]isoquinoline Chemical compound C1=2C=C(OC)C(OC)=CC=2CC2CNCCN2C1C1=CC=CC=C1 UQKZERJIZSURJA-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- 108010044467 Isoenzymes Proteins 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- YNRZBYNGFPHYNH-UHFFFAOYSA-N 8,9-dimethoxy-6-phenyl-2,3,4,6,11,11a-hexahydro-1h-pyrazino[1,2-b]isoquinoline;dihydrochloride Chemical compound Cl.Cl.C1=2C=C(OC)C(OC)=CC=2CC2CNCCN2C1C1=CC=CC=C1 YNRZBYNGFPHYNH-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N dopa Chemical compound OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000011533 pre-incubation Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- PTXXUIUFQFVJJI-UHFFFAOYSA-N (8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydropyrazino[1,2-b]isoquinolin-2-yl)-phenylmethanone Chemical compound C1=2C=C(OC)C(OC)=CC=2CC2CN(C(=O)C=3C=CC=CC=3)CCN2C1C1=CC=CC=C1 PTXXUIUFQFVJJI-UHFFFAOYSA-N 0.000 description 1
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Description
本発明は優れたＰＤＥ４阻害作用を有する新規ピラジノイソキノリン誘導体を有効成分としてなる医薬組成物に関する。 The present invention relates to a pharmaceutical composition comprising a novel pyrazinoisoquinoline derivative having an excellent PDE4 inhibitory action as an active ingredient.
細胞内セカンドメッセンジャーであるｃＡＭＰやｃＧＭＰは、ホスホジエステラーゼ（ＰＤＥ）により分解され不活性化する。ＰＤＥを阻害すると細胞内のｃＡＭＰやｃＧＭＰの濃度が上昇する。ＰＤＥはいくつかのアイソザイムに分類され、基質（ｃＡＭＰ、ｃＧＭＰ）特異性、体内分布等がアイソザイム毎に相違し、ＰＤＥアイソザイムのうち４型のＰＤＥ（ＰＤＥ４）は、ｃＡＭＰを特異的に分解することが知られている。 Intracellular second messengers cAMP and cGMP are degraded and inactivated by phosphodiesterase (PDE). When PDE is inhibited, the concentration of intracellular cAMP and cGMP increases. PDE is classified into several isozymes. Substrate (cAMP, cGMP) specificity, biodistribution, etc. are different for each isozyme. Among the PDE isozymes, type 4 PDE (PDE4) specifically degrades cAMP. It has been known.
また、ＰＤＥ４活性を阻害することにより、炎症性メディエーターの放出が阻害され得ること（例えば、非特許文献１参照）、ＰＤＥ４阻害剤が、免疫刺激に対する応答として単核食細胞により放出されるサイトカインであるＴＮＦ−αの産生を抑制し、ＴＮＦ−αが関与する各種炎症性疾患の治療に有用であることが知られている（例えば、特許文献１〜６参照）。 In addition, by inhibiting PDE4 activity, release of inflammatory mediators can be inhibited (see, for example, Non-Patent Document 1), and PDE4 inhibitors are cytokines released by mononuclear phagocytes in response to immune stimulation. It is known that the production of certain TNF-α is suppressed and useful for the treatment of various inflammatory diseases involving TNF-α (see, for example, Patent Documents 1 to 6).
代表的なＰＤＥ阻害剤であるテオフィリンは、従来から喘息の治療に用いられてきたが、そのＰＤＥ阻害作用が非特異的なため、気管支平滑筋弛緩作用以外に強心作用や中枢作用を有し、それ故常に副作用に留意せねばならない。このため、各種ＰＤＥアイソザイムの中でも、特に気管支平滑筋及び炎症細胞に多く存在するＰＤＥ４に対して特異的阻害作用を有する新規薬剤の開発が求められている。このような薬剤は優れた喘息の予防・治療剤（又は炎症性疾患の予防・治療剤等）になり得ると考えられる。 Theophylline, which is a typical PDE inhibitor, has been used for the treatment of asthma from the past, but its non-specific PDE inhibitory action has cardiotonic and central effects in addition to bronchial smooth muscle relaxing action, Therefore, always be aware of side effects. For this reason, among various PDE isozymes, development of a novel drug having a specific inhibitory action on PDE4, which is particularly abundant in bronchial smooth muscle and inflammatory cells, has been demanded. Such a drug is considered to be an excellent prophylactic / therapeutic agent for asthma (or a prophylactic / therapeutic agent for inflammatory diseases).
一方、本発明の有効成分である化合物ピラジノイソキノリン誘導体と構造上類似する化合物８，９−ジメトキシ−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリンに関し、該化合物が中枢抑制作用、血圧低下作用を有することが報告されている（例えば、非特許文献２参照）。しかしながら、該化合物がＰＤＥ４の阻害活性を有しているか否かについては、本報告では一切言及されていない。 On the other hand, the compound 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1, which is structurally similar to the compound pyrazinoisoquinoline derivative which is the active ingredient of the present invention. 2-b] With regard to isoquinoline, it has been reported that the compound has a central inhibitory action and a blood pressure lowering action (see, for example, Non-Patent Document 2). However, this report does not mention at all whether or not the compound has PDE4 inhibitory activity.
本発明は、ＰＤＥ４阻害剤として有用な新規ピラジノイソキノリン誘導体を有効成分としてなる医薬組成物を提供するものである。 The present invention provides a pharmaceutical composition comprising a novel pyrazinoisoquinoline derivative useful as a PDE4 inhibitor as an active ingredient.
本発明は、一般式［Ｉ］： The present invention relates to general formula [I]:
（式中、Ｒ１およびＲ２は同一または異なって水酸基または低級アルコキシ基、環Ａは置換もしくは非置換ベンゼン環または置換もしくは非置換芳香族複素環、Ｒ３は、
１）環Ａが置換ベンゼン環または置換もしくは非置換芳香族複素環のときは、水素原子、式：−（ＣＨ２）ｎ−Ｒ３１で示される基（但し、Ｒ３１は水素原子、アリール基、水酸基、アミノ基、カルボキシル基、低級アルコキシカルボニル基または低級アルキルチオ基、ｎは１〜６の整数を表す）、または式：−ＣＯ−Ｒ３２で示される基（但し、Ｒ３２はアリール基、低級アルキル基、ヒドロキシ低級アルキル基またはアミノ低級アルキル基を表す）を表し、
２）環Ａが非置換ベンゼン環のときは、式：−（ＣＨ２）ｎ−Ｒ３１で示される基（但し、Ｒ３１は水素原子、アリール基、水酸基、アミノ基、カルボキシル基、低級アルコキシカルボニル基または低級アルキルチオ基、ｎは１〜６の整数を表す）、または式：−ＣＯ−Ｒ３２で示される基（但し、Ｒ３２はアリール基、低級アルキル基、ヒドロキシ低級アルキル基またはアミノ低級アルキル基を表す）を表す。）
で示されるピラジノイソキノリン誘導体またはその薬理的に許容しうる塩を有効成分としてなる医薬組成物に関する。
(Wherein R 1 and R 2 are the same or different and are a hydroxyl group or a lower alkoxy group, ring A is a substituted or unsubstituted benzene ring or substituted or unsubstituted aromatic heterocyclic ring, and R 3 is
1) When ring A is a substituted benzene ring or a substituted or unsubstituted aromatic heterocyclic ring, a hydrogen atom, a group represented by the formula: — (CH 2 ) n —R 31 (where R 31 is a hydrogen atom, an aryl group) , A hydroxyl group, an amino group, a carboxyl group, a lower alkoxycarbonyl group or a lower alkylthio group, n represents an integer of 1 to 6, or a group represented by the formula: —CO—R 32 (wherein R 32 is an aryl group, Represents a lower alkyl group, a hydroxy lower alkyl group or an amino lower alkyl group),
2) When ring A is an unsubstituted benzene ring, a group represented by the formula: — (CH 2 ) n —R 31 (where R 31 is a hydrogen atom, aryl group, hydroxyl group, amino group, carboxyl group, lower alkoxy group) A carbonyl group or a lower alkylthio group, n represents an integer of 1 to 6, or a group represented by the formula: —CO—R 32 (wherein R 32 represents an aryl group, a lower alkyl group, a hydroxy lower alkyl group or an amino lower group). Represents an alkyl group). )
And a pharmacologically acceptable salt thereof as an active ingredient.
本発明の有効成分である化合物［Ｉ］またはその薬理的に許容しうる塩は、ＰＤＥ４に対して優れた阻害作用を有しており、ＰＤＥ４が関与する各種の疾患の予防・治療に有用である。 Compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof has an excellent inhibitory action on PDE4, and is useful for the prevention and treatment of various diseases involving PDE4. is there.
また、本発明の有効成分である化合物［Ｉ］またはその薬理的に許容しうる塩は、ＰＤＥ４を選択的に阻害することから、副作用も少ない。 In addition, since the compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof selectively inhibits PDE4, there are few side effects.
さらに、本発明の有効成分である化合物［Ｉ］またはその薬理的に許容しうる塩は低毒性であり、医薬として安全性が高いという特長をも有する。 Furthermore, the compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof has a feature of low toxicity and high safety as a medicine.
本発明の有効成分である化合物［Ｉ］がアリール基を有する場合において、当該アリール基としては、フェニル基、ナフチル基、アントリル基、フェナントリル基等の炭素数６〜１４個の単環式、二環式または三環式アリール基が挙げられる。このうち、フェニル基が好ましい。 In the case where the compound [I], which is an active ingredient of the present invention, has an aryl group, the aryl group may be a monocyclic group having 6 to 14 carbon atoms such as a phenyl group, a naphthyl group, an anthryl group, or a phenanthryl group. Examples include cyclic or tricyclic aryl groups. Of these, a phenyl group is preferred.
環Ａが置換または非置換芳香族複素環である場合、該芳香族複素環としては、１〜４個の窒素原子を含有する単環式、二環式または三環式芳香族複素環が挙げられ、このうち好ましい芳香族複素環としては、１〜３個の窒素原子を含有する単環式芳香族複素環（例えば、ピリジン環、ピリミジン環、ピラジン環、ピリダジン環等）、１〜３個の窒素原子を含有する二環式芳香族複素環（例えば、キノリン環、イソキノリン環、キナゾリン環、キノキサリン環、インドール環、ベンゾイミダゾール環、ピリドピリミジン環等）等が挙げられる。 When ring A is a substituted or unsubstituted aromatic heterocycle, the aromatic heterocycle includes monocyclic, bicyclic or tricyclic aromatic heterocycles containing 1 to 4 nitrogen atoms. Of these, preferred aromatic heterocycles include 1 to 3 monocyclic aromatic heterocycles containing 1 to 3 nitrogen atoms (for example, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, etc.), 1 to 3 And bicyclic aromatic heterocycles containing a nitrogen atom (for example, quinoline ring, isoquinoline ring, quinazoline ring, quinoxaline ring, indole ring, benzimidazole ring, pyridopyrimidine ring, etc.).
環Ａが置換ベンゼン環または置換芳香族複素環である場合、該ベンゼン環または該芳香族複素環上の置換基としては、低級アルキル基、低級アルコキシ基、水酸基およびハロゲン原子から選ばれる１〜３個の置換基が挙げられ、このうち好ましい置換基としては、低級アルコキシ基（例えば、メトキシ基、エトキシ基、イソプロピルオキシ基等）、水酸基およびハロゲン原子（例えば、塩素原子、フッ素原子、臭素原子等）から選ばれる１〜３個の置換基が挙げられる。 When ring A is a substituted benzene ring or a substituted aromatic heterocycle, the substituent on the benzene ring or aromatic heterocycle is 1 to 3 selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and a halogen atom. Among these, preferred substituents include lower alkoxy groups (for example, methoxy group, ethoxy group, isopropyloxy group, etc.), hydroxyl groups and halogen atoms (for example, chlorine atom, fluorine atom, bromine atom, etc.) 1 to 3 substituents selected from:
本発明の有効成分である化合物［Ｉ］のうち、好ましい化合物としては、Ｒ１およびＲ２が同一または異なって低級アルコキシ基、環Ａが低級アルコキシ基、水酸基およびハロゲン原子から選ばれる１〜３個の基で置換されたベンゼン環、Ｒ３が水素原子である化合物が挙げられ、より好ましい化合物としては、Ｒ１およびＲ２がメトキシ基またはエトキシ基、環Ａがイソプロピルオキシ基、水酸基およびハロゲン原子から選ばれる１〜３個の基で置換されたベンゼン環、Ｒ３が水素原子である化合物が挙げられる。この内、とりわけ好ましい化合物としては、６−［４−（イソプロピルオキシ）フェニル］−８，９−ジメトキシ−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン、６−（４−フルオロフェニル）−８，９−ジメトキシ−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン等があげられる。 Among the compounds [I] which are the active ingredients of the present invention, preferred compounds are those in which R 1 and R 2 are the same or different and a lower alkoxy group, ring A is selected from a lower alkoxy group, a hydroxyl group and a halogen atom. A benzene ring substituted with a group, a compound in which R 3 is a hydrogen atom, and more preferable compounds include R 1 and R 2 as methoxy group or ethoxy group, ring A as isopropyloxy group, hydroxyl group and halogen Examples thereof include a benzene ring substituted with 1 to 3 groups selected from atoms, and a compound wherein R 3 is a hydrogen atom. Among these, particularly preferable compounds include 6- [4- (isopropyloxy) phenyl] -8,9-dimethoxy-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b. ] Isoquinoline, 6- (4-fluorophenyl) -8,9-dimethoxy-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline and the like.
本発明の有効成分である化合物［Ｉ］は、Ｒ１、Ｒ２、Ｒ３上の置換基および／または環Ａ上の置換基ならびに１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン骨格上に不斉原子を有する場合、当該不斉原子に基づく複数の立体異性体（ジアステレオマー異性体、光学異性体）として存在しうるが、本発明の有効成分はこれらのうちのいずれか１個の立体異性体またはその混合物のいずれをも含むものである。 Compound [I] which is an active ingredient of the present invention includes a substituent on R 1 , R 2 , R 3 and / or a substituent on ring A and 1,3,4,6,11,11a-hexahydro-2H. -When having an asymmetric atom on the pyrazino [1,2-b] isoquinoline skeleton, it may exist as a plurality of stereoisomers (diastereoisomers, optical isomers) based on the asymmetric atom. These active ingredients include any one of these stereoisomers or a mixture thereof.
本発明の有効成分である化合物［Ｉ］またはその薬理的に許容しうる塩は、ＰＤＥ４に対して優れた阻害作用を有しており、ＰＤＥ４が関与する各種の疾患の予防・治療に有用である。かかる疾患としては、各種の炎症性疾患、アレルギー疾患が挙げられ、より具体的には、例えば、喘息、慢性閉塞性肺疾患（ＣＯＰＤ）、慢性気管支炎、アトピー性皮膚炎、蕁麻疹、アレルギー性鼻炎、アレルギー性結膜炎、春季カタル、好酸球増多症、乾癬、慢性関節リウマチ、敗血性ショック、潰瘍性大腸炎、クローン病、再灌流障害、慢性糸球体腎炎、エンドトキシンショック、成人呼吸窮迫症候群、骨関節炎などが挙げられる。 Compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof has an excellent inhibitory action on PDE4, and is useful for the prevention and treatment of various diseases involving PDE4. is there. Such diseases include various inflammatory diseases and allergic diseases. More specifically, for example, asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, atopic dermatitis, urticaria, allergic disease Rhinitis, allergic conjunctivitis, spring catarrh, hypereosinophilia, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome And osteoarthritis.
また、本発明の有効成分である化合物［Ｉ］またはその薬理的に許容しうる塩は、優れた気管支収縮抑制作用を有していることから、気管支収縮抑制剤として有用である。 In addition, compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof is useful as a bronchoconstriction inhibitor because it has an excellent bronchoconstriction inhibitory action.
なお、本件出願人は、ＰＤＥ４阻害作用を有する化合物が、骨折治癒の促進や軟骨疾患（例えば変形性関節症）の修復治療にも有用であることを見出して別途特許出願（特願２００１−１５４０６４および特願２００１−１５４０４８）している。当該知見から、本発明の有効成分である化合物［Ｉ］またはその薬理的に許容しうる塩は骨折治癒の促進や軟骨疾患（例えば変形性関節症）の修復治療にも有用である。 The present applicant has found that a compound having a PDE4 inhibitory action is useful for promoting fracture healing and repairing treatment of cartilage diseases (for example, osteoarthritis) (Japanese Patent Application No. 2001-154064). And Japanese Patent Application No. 2001-154048). Based on this finding, compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof is useful for promoting fracture healing and repairing treatment for cartilage diseases (for example, osteoarthritis).
本発明の有効成分である化合物［Ｉ］またはその薬理的に許容しうる塩は、ＰＤＥ４を選択的に阻害することから、副作用も少ない。さらに、本発明の有効成分である化合物［Ｉ］またはその薬理的に許容しうる塩は低毒性であり、医薬として安全性が高いという特長をも有する。 The compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof selectively inhibits PDE4 and therefore has few side effects. Furthermore, the compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof has a feature of low toxicity and high safety as a medicine.
本発明の有効成分である化合物［Ｉ］は、遊離の形でも、それらの薬理的に許容し得る塩の形でも医薬用途に使用することができる。薬理的に許容しうる塩としては、例えば、塩酸塩、硫酸塩、リン酸塩または臭化水素酸塩の如き無機酸塩、酢酸塩、フマル酸塩、シュウ酸塩、クエン酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、トシル酸塩またはマレイン酸塩の如き有機酸塩等が挙げられる。また、該化合物がその分子内にカルボキシル基を有する場合には、薬理的に許容し得る塩としては、塩基との塩（例えばナトリウム塩、カリウム塩等のアルカリ金属塩またはカルシウム塩の如きアルカリ土類金属塩）が挙げられる。 Compound [I], which is an active ingredient of the present invention, can be used for pharmaceutical use either in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salt include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, fumarate, oxalate, citrate, methanesulfone, and the like. And organic acid salts such as acid salts, benzenesulfonate, tosylate and maleate. In addition, when the compound has a carboxyl group in the molecule, the pharmacologically acceptable salt includes a salt with a base (for example, an alkali metal salt such as a sodium salt or a potassium salt, or an alkaline earth such as a calcium salt). Metal salts).
本発明の有効成分である化合物［Ｉ］またはその薬理的に許容しうる塩は、その分子内塩や付加物、それらの溶媒和物あるいは水和物等をいずれも含むものである。 Compound [I] or a pharmacologically acceptable salt thereof, which is an active ingredient of the present invention, includes any of its internal salts and adducts, solvates or hydrates thereof.
本発明の有効成分である化合物［Ｉ］またはその薬理的に許容しうる塩は経口的にも非経口的にも投与することができ、また、錠剤、顆粒剤、カプセル剤、散剤、注射剤、吸入剤等の慣用の医薬製剤として用いることができる。 Compound [I] or a pharmacologically acceptable salt thereof, which is an active ingredient of the present invention, can be administered orally or parenterally, and can also be used for tablets, granules, capsules, powders, injections. It can be used as a conventional pharmaceutical preparation such as an inhalant.
本発明の有効成分である化合物［Ｉ］またはその薬理的に許容し得る塩の投与量は、投与方法、患者の年令、体重、状態によっても異なるが、注射剤とすれば、通常、１日当り約０．０１〜１０ｍｇ／ｋｇ、とりわけ約０．０３〜３ｍｇ／ｋｇ程度、経口剤とすれば、通常、１日当り約０．１〜３０ｍｇ／ｋｇ、とりわけ約０．３〜１０ｍｇ／ｋｇ程度とするのが好ましい。 The dose of Compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, and condition. About 0.01 to 10 mg / kg per day, especially about 0.03 to 3 mg / kg, ordinarily about 0.1 to 30 mg / kg per day, especially about 0.3 to 10 mg / kg Is preferable.
＜ピラジノイソキノリン誘導体の製法＞
本発明の有効成分であるピラジノイソキノリン誘導体［Ｉ］は、下記により製造することができるが、これらに限定されるものではない。
<Production method of pyrazinoisoquinoline derivative>
The pyrazinoisoquinoline derivative [I], which is an active ingredient of the present invention, can be produced as follows, but is not limited thereto.
（式中、Ｒ４は低級アルキル基、Ｘ１はハロゲン原子を表し、他の記号は前記と同一意味を有する）
化合物［ＩＩ］から化合物［ＩＶ］を製造する反応は、慣用のエステル化反応（例えば、エタノール／塩化アセチル、エタノール／塩化チオニル、エタノール／塩化水素等の存在下）を用いて実施することができる。
(Wherein R 4 represents a lower alkyl group, X 1 represents a halogen atom, and other symbols have the same meaning as described above)
The reaction for producing compound [IV] from compound [II] can be carried out using a conventional esterification reaction (for example, in the presence of ethanol / acetyl chloride, ethanol / thionyl chloride, ethanol / hydrogen chloride, etc.). .
化合物［ＩＶ］と化合物［Ｖ］から化合物［ＶＩ］を製造する反応は、慣用の縮合剤（例えば、ジシクロヘキシルカルボジイミド、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド・塩酸塩／１−ヒドロキシベンゾトリアゾール・１水和物等）の存在下で実施することができる。 The reaction for producing compound [VI] from compound [IV] and compound [V] is carried out by using a conventional condensing agent (for example, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride / 1- In the presence of hydroxybenzotriazole monohydrate and the like.
化合物［ＶＩ］から化合物［ＶＩＩ］を製造する反応は、例えば、オキシ塩化リン、五塩化リン等を用いて縮合した後、慣用の還元剤（例えば、酸化白金／水素、パラジウム（炭素）／水素等）の存在下で実施することができる。 The reaction for producing the compound [VII] from the compound [VI] is carried out by, for example, condensing using phosphorus oxychloride, phosphorus pentachloride, etc., and then using a conventional reducing agent (for example, platinum oxide / hydrogen, palladium (carbon) / hydrogen). Etc.).
化合物［ＶＩＩ］と化合物［ＶＩＩＩ］から化合物［ＩＸ］を製造する反応は、慣用の縮合剤（例えば、カルボニルジイミダゾール等）の存在下で実施することができる。また、化合物［ＩＸ］は、化合物［ＶＩＩＩ］を活性化剤（例えば、クロロ炭酸イソブチル、クロロ炭酸エチル等）および塩基（例えば、トリエチルアミン、Ｎ−メチルモルホリン等）で処理して混合酸無水物に変換後、該混合酸無水物と化合物［ＶＩＩ］とを反応させて実施することもできる。 The reaction for producing compound [IX] from compound [VII] and compound [VIII] can be carried out in the presence of a conventional condensing agent (for example, carbonyldiimidazole and the like). Compound [IX] is prepared by treating compound [VIII] with an activator (eg, isobutyl chlorocarbonate, ethyl chlorocarbonate) and a base (eg, triethylamine, N-methylmorpholine, etc.) to form a mixed acid anhydride. After the conversion, the mixed acid anhydride can be reacted with compound [VII].
化合物［ＩＸ］を分子内閉環させて化合物［Ｘ］を製造する反応は、化合物［ＩＸ］を酸（例えば、トリフルオロ酢酸、塩酸等）処理後、加熱することにより実施することができる。 The reaction for producing compound [X] by intramolecular ring closure of compound [IX] can be carried out by heating compound [IX] after treatment with acid (eg, trifluoroacetic acid, hydrochloric acid, etc.).
化合物［Ｘ］を還元して化合物［ＸＩＩＩ］を製造する反応は、適当な還元剤（例えば、ボラン・ジメチルスルフィド錯体、リチウムアルミニウムハイドライド、ビス（２−メトキシエトキシ）アルミニウムハイドライド等）の存在下で実施することができる。 The reaction for producing compound [XIII] by reducing compound [X] is carried out in the presence of a suitable reducing agent (for example, borane / dimethylsulfide complex, lithium aluminum hydride, bis (2-methoxyethoxy) aluminum hydride, etc.). Can be implemented.
ここで、式［ＸＩＩＩ］の化合物のうち、環Ａが置換ベンゼン環または置換もしくは非置換芳香族複素環である化合物（化合物［Ｉ−ａ］）は、本発明の有効成分である化合物の範囲に包含される。 Here, among the compounds of the formula [XIII], the compound in which the ring A is a substituted benzene ring or a substituted or unsubstituted aromatic heterocyclic ring (compound [Ia]) is a range of compounds that are active ingredients of the present invention. Is included.
さらに、本発明の有効成分である化合物［Ｉ］のうち、Ｒ３が式：−（ＣＨ２）ｎ−Ｒ３１で示される基である化合物（化合物［Ｉ−ｂ］）は、化合物［ＸＩＩＩ］と化合物［ＸＩ］とを反応させることにより製造することができる。当該反応は、慣用の塩基（例えば、トリエチルアミン、炭酸カリウム等）の存在下で実施することができる。塩基の使用量は、化合物［ＸＩＩＩ］又は化合物［ＸＩ］に対して１当量〜３当量、好ましくは１．２当量〜１．５当量とすることができる。本反応は、−１０℃〜１００℃、好ましくは０℃〜３０℃で実施することができる。 Furthermore, among the compounds [I] which are the active ingredients of the present invention, the compound (compound [Ib]) in which R 3 is a group represented by the formula: — (CH 2 ) n —R 31 is represented by the compound [XIII ] And compound [XI] are allowed to react. The reaction can be carried out in the presence of a conventional base (for example, triethylamine, potassium carbonate, etc.). The amount of the base to be used can be 1 equivalent to 3 equivalents, preferably 1.2 equivalent to 1.5 equivalents, relative to compound [XIII] or compound [XI]. This reaction can be carried out at −10 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C.
さらに、本発明の有効成分である化合物［Ｉ］のうち、Ｒ３が式：−ＣＯ−Ｒ３２で示される基である化合物（化合物［Ｉ−ｃ］）は、化合物［ＸＩＩＩ］と化合物［ＸＩＩ］とを反応させることにより製造することができる。当該反応は、慣用の縮合剤（例えば、ジシクロヘキシルカルボジイミド、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド・塩酸塩／１−ヒドロキシベンゾトリアゾール・１水和物等）の存在下で実施することができる。縮合剤の使用量は、化合物［ＸＩＩＩ］又は化合物［ＸＩＩ］に対して１当量〜５当量、好ましくは１．１当量〜１．５当量とすることができる。本反応は−１０℃〜１００℃、好ましくは０℃〜３０℃で実施することができる。 Furthermore, among the compounds [I], which are the active ingredients of the present invention, the compound in which R 3 is a group represented by the formula: —CO—R 32 (compound [Ic]) is compound [XIII] and compound [X]. XII] can be reacted. The reaction is carried out in the presence of a conventional condensing agent (for example, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride / 1-hydroxybenzotriazole monohydrate, etc.). be able to. The amount of the condensing agent to be used can be 1 to 5 equivalents, preferably 1.1 to 1.5 equivalents, relative to compound [XIII] or compound [XII]. This reaction can be carried out at −10 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C.
また、化合物［Ｉ−ｃ］は、化合物［ＸＩＩ］をハロゲン化剤（例えば、塩化チオニル、塩化オキサリル等）で処理して対応酸ハライドに変換した後、塩基（例えば、トリエチルアミン）の存在下、当該酸ハライドと化合物［ＸＩＩＩ］とを反応させることにより製することもできる。ハロゲン化剤の使用量は、化合物［ＸＩＩ］に対して１当量〜３当量、好ましくは１．１当量〜１．５当量とすることができる。塩基の使用量は、上記酸ハライド又は化合物［ＸＩＩＩ］に対して１当量〜４当量、好ましくは１．１当量〜１．５当量とすることができる。本反応は−２０℃〜４０℃、とりわけ０℃〜３０℃で好適に進行する。 In addition, compound [Ic] is obtained by treating compound [XII] with a halogenating agent (eg, thionyl chloride, oxalyl chloride, etc.) to give the corresponding acid halide, and then in the presence of a base (eg, triethylamine). It can also be produced by reacting the acid halide with compound [XIII]. The amount of the halogenating agent to be used can be 1 equivalent to 3 equivalents, preferably 1.1 equivalent to 1.5 equivalents, relative to compound [XII]. The usage-amount of a base can be 1 equivalent-4 equivalent with respect to the said acid halide or compound [XIII], Preferably it can be 1.1 equivalent-1.5 equivalent. This reaction suitably proceeds at −20 ° C. to 40 ° C., particularly 0 ° C. to 30 ° C.
更にまた、化合物［Ｉ−ｃ］は、化合物［ＸＩＩ］を活性化剤（例えば、クロロ炭酸イソブチル、クロロ炭酸エチル等）および塩基（例えば、トリエチルアミン、Ｎ−メチルモルホリン、ジイソプロピルエチルアミン等）で処理して対応混合酸無水物変換した後、該混合酸無水物と化合物［ＸＩＩＩ］とを反応させることにより製することもできる。活性化剤の使用量は、化合物［ＸＩＩ］に対して、１当量〜４当量、好ましくは１．１当量〜１．５当量とすることができる。塩基の使用量は、化合物［ＸＩＩ］に対して１当量〜４当量、好ましくは１．１当量〜１．５当量とすることができる。本反応は−５０℃〜５０℃、とりわけ−２０℃〜３０℃で好適に進行する。 Furthermore, compound [Ic] is obtained by treating compound [XII] with an activator (eg, isobutyl chlorocarbonate, ethyl chlorocarbonate, etc.) and a base (eg, triethylamine, N-methylmorpholine, diisopropylethylamine, etc.). It can also be prepared by reacting the mixed acid anhydride with compound [XIII] after conversion to the corresponding mixed acid anhydride. The amount of the activator to be used can be 1 equivalent to 4 equivalents, preferably 1.1 equivalent to 1.5 equivalents, relative to compound [XII]. The amount of the base to be used can be 1 equivalent to 4 equivalents, preferably 1.1 equivalent to 1.5 equivalents, relative to compound [XII]. This reaction suitably proceeds at -50 ° C to 50 ° C, particularly -20 ° C to 30 ° C.
本発明の有効成分である化合物［Ｉ］は、上述のごとくして得られる化合物のＲ１、Ｒ２、Ｒ３上の置換基および／または環Ａ上の置換基を、さらに目的とする他の置換基へ変換することによっても製造することができる。このような置換基の変換方法は、目的とする置換基の種類に応じて適宜選択すればよい。例えば、一般式［Ｉ］におけるＲ１および／またはＲ２が低級アルコキシ基である化合物［Ｉ］は、Ｒ１および／またはＲ２が水酸基である対応化合物［Ｉ］と低級アルキル化剤（例えば、ジメチル硫酸、ハロゲン化メチル等）とを塩基（例えば、水酸化ナトリウム、水素化ナトリウム、炭酸カリウム、ナトリウムメトキシド等）の存在下、反応させることにより製造することもできる。低級アルキル化剤の使用量は、化合物［Ｉ］に対して１当量〜８当量、好ましくは１．２当量〜２．２当量とすることができる。本反応は０℃〜５０℃、とりわけ１０℃〜４０℃で好適に進行する。 The compound [I], which is an active ingredient of the present invention, is used for the purpose of the substituent on R 1 , R 2 , R 3 and / or the substituent on ring A of the compound obtained as described above. It can also be produced by converting to the above substituent. What is necessary is just to select suitably the conversion method of such a substituent according to the kind of target substituent. For example, the compound [I] in which R 1 and / or R 2 in the general formula [I] is a lower alkoxy group includes a corresponding compound [I] in which R 1 and / or R 2 is a hydroxyl group and a lower alkylating agent (for example, Dimethylsulfate, methyl halide, etc.) in the presence of a base (for example, sodium hydroxide, sodium hydride, potassium carbonate, sodium methoxide, etc.). The amount of the lower alkylating agent used can be 1 equivalent to 8 equivalents, preferably 1.2 equivalents to 2.2 equivalents, relative to compound [I]. This reaction suitably proceeds at 0 ° C to 50 ° C, particularly 10 ° C to 40 ° C.
上述の製法で得られる本発明の有効成分である化合物［Ｉ］は、所望により、薬理的に許容しうる塩に変換することもできる。薬理的に許容しうる塩への変換は、当業者に知られている方法に従って行なえばよい。 Compound [I], which is an active ingredient of the present invention obtained by the above-described production method, can be converted into a pharmacologically acceptable salt, if desired. Conversion to a pharmacologically acceptable salt may be carried out according to methods known to those skilled in the art.
本発明の有効成分である化合物［Ｉ］を製造するにあたり、各中間体化合物は、上記文中あるいは化学反応式に示しているものだけでなく、反応に悪影響を及ぼさなければ、それらの塩またはそれらの反応性誘導体も、適宜用いることができる。該塩としては、例えば、ナトリウム、カリウム、リチウム、カルシウム、マグネシウム等の金属との塩、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等の有機塩基との塩、塩酸、硫酸、硝酸、臭化水素酸、リン酸等の無機酸との塩、酢酸、シュウ酸、クエン酸、ベンゼンスルホン酸、安息香酸、マロン酸、クエン酸、ギ酸、フマル酸、マレイン酸、メタンスルホン酸、ｐ−トルエンスルホン酸、トリフルオロ酢酸等の有機酸との塩が挙げられる。 In the production of compound [I], which is an active ingredient of the present invention, each intermediate compound is not limited to those shown in the above sentence or in the chemical reaction formula. These reactive derivatives can also be used as appropriate. Examples of the salt include salts with metals such as sodium, potassium, lithium, calcium and magnesium, salts with organic bases such as pyridine, triethylamine and diisopropylethylamine, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and phosphoric acid. Salts with inorganic acids such as acetic acid, oxalic acid, citric acid, benzenesulfonic acid, benzoic acid, malonic acid, citric acid, formic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid And salts with organic acids such as
さらに、本発明の有効成分である化合物［Ｉ］および原料化合物の製造に際し、原料化合物ないし各中間体が官能基を有する場合、上記で示した以外にも合成化学の常法により各官能基に適切な保護基を導入し、また、必要が無くなればそれらの保護基を適宜除去してもよい。 In addition, when the compound [I], which is the active ingredient of the present invention, and the raw material compound are produced, when the raw material compound or each intermediate has a functional group, in addition to the above, each functional group is converted into a functional group by a conventional synthetic chemistry method. Appropriate protecting groups may be introduced, and those protecting groups may be removed as appropriate when they are no longer needed.
上記各反応は、必要に応じて、適当な溶媒中または無溶媒で実施することができる。当該溶媒としては、反応に悪影響を及ぼさない溶媒であれば特に限定されず、例えば、ジオキサン、エチレングリコールジメチルエーテル、ジメチルアセトアミド、ジメチルホルムアミド、ヘキサメチルホスホリックトリアミド（ＨＭＰＡ）、ヘキサメチルホスホラストリアミド（ＨＭＰＴ）、ベンゼン、テトラヒドロフラン、トルエン、キシレン、酢酸エチル、低級アルコール、塩化メチレン、クロロホルム、四塩化炭素、１，３−ジメチル−２−イミダゾリジノン、酢酸、ジエチルエーテル、ジイソプロピルエーテル、ジメトキシエタン、ジメチルスルホキシド、アセトン、メチルエチルケトン、アセトニトリル、水またはそれらの混合溶媒を適宜選択して用いることができる。 Each of the above reactions can be carried out in a suitable solvent or without a solvent as necessary. The solvent is not particularly limited as long as it does not adversely affect the reaction. For example, dioxane, ethylene glycol dimethyl ether, dimethylacetamide, dimethylformamide, hexamethylphosphoric triamide (HMPA), hexamethylphosphorous triamide ( HMPT), benzene, tetrahydrofuran, toluene, xylene, ethyl acetate, lower alcohol, methylene chloride, chloroform, carbon tetrachloride, 1,3-dimethyl-2-imidazolidinone, acetic acid, diethyl ether, diisopropyl ether, dimethoxyethane, dimethyl Sulfoxide, acetone, methyl ethyl ketone, acetonitrile, water or a mixed solvent thereof can be appropriately selected and used.
なお、本発明において、低級アルキルまたは低級アルコキシとは、炭素数１〜６の直鎖状または分岐鎖状のものが挙げられ、とりわけ炭素数１〜４のものが挙げられる。ハロゲン原子とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。 In the present invention, lower alkyl or lower alkoxy includes linear or branched ones having 1 to 6 carbon atoms, particularly those having 1 to 4 carbon atoms. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
実験例１〔ＰＤＥ４阻害作用〕
（ＰＤＥ４部分精製標品の調製）
ハートレイ（Ｈａｒｔｌｅｙ）系雄性モルモットより摘出した肺のホモジネートを遠心分離して得られた上清を陰イオン交換カラムクロマトグラフィーにて分画し、以下１．〜４．の条件を満たす画分を混合して、ホスホジエステラーゼ４の部分精製標品とした。
１．ｃＡＭＰを選択的に水解すること。
２．そのｃＡＭＰ水解活性がｃＧＭＰによる影響を受けないこと。
３．ＰＤＥ３選択的阻害薬であるＣＩ−９３０で阻害されないこと。
４．ＰＤＥ４選択的阻害薬であるロリプラム（Ｒｏｌｉｐｒａｍ）により強く阻害されること。
（ＰＤＥ４活性の測定）
トンプソンらの方法（アドバンシーズ・イン・サイクリック・ヌクレオチド・リサーチ〔Ａｄｖａｎｃｅｓ ｉｎ Ｃｙｃｌｉｃ Ｎｕｃｌｅｏｔｉｄｅ Ｒｅｓｅａｒｃｈ〕、１０巻、ラベン・プレス、ニューヨーク、６９〜９２頁、１９７９年）を一部改変して行った。すなわち、５０ｍＭ Ｔｒｉｓ−ＨＣｌ、ｐＨ８．０で全基質の約１０％を水解するように希釈したＰＤＥ４部分精製標品１００μｌをガラス製試験管に加えた。反応用緩衝溶液（５０ｍＭＴｒｉｓ−ＨＣｌ、ｐＨ ８．０、１２．５ｍＭ ＭｇＣｌ２、１０ｍＭ ２−メルカプトエタノール）を２００μｌ加えた後、ジメチルスルフォキサイドに溶解した検体化合物（１００倍濃度）を５μｌ加えた。３０℃で５分間プレインキュベートした後、２．５μＭ［３Ｈ］ｃＡＭＰ（３．７ｋＢｑ／２００μｌ）を２００μｌ加え、反応を開始した（終濃度５０ｍＭ Ｔｒｉｓ−ＨＣｌ、ｐＨ ８．０、５ｍＭ ＭｇＣｌ２、４ｍＭ ２−メルカプトエタノール、１μＭ ｃＡＭＰ）。３０℃で３０分間の反応後、試験管を沸騰水浴中に移し、反応を停止した。９０秒後、試験管を氷水浴中に移し、反応液の温度を下げた。３０℃、５分間のプレインキュベートの後、１ｍｇ／ｍｌヘビ毒水溶液１００μｌを添加し、３０℃で３０分間反応させた。メタノール５００μｌを添加することにより反応を停止させた後、ダウエックス樹脂（商品名：Ｄｏｗｅｘ １ｘ８、シグマ社製）２００μｌを予め加えておいたカラムに反応液１ｍｌを供した。続いてメタノール１ｍｌを加えることにより、ダウエックス樹脂を洗浄した。反応液のカラム通過液と洗浄液とを合し、その放射活性を測定した。酵素標品を加えずに緩衝溶液のみを加えたものをブランク、酵素標品を加えるが検体溶液の代わりにジメチルスルフォキシドのみを加えたものをコントロールとし、各検体のコントロールに対する阻害率を計算した。各検体のＩＣ５０値の計算は、３点以上の濃度における阻害率を求め、４−パラメータロジスティックエクエイション（４−ｐａｒａｍｅｔｅｒ ｌｏｇｉｓｔｉｃ ｅｑｕａｔｉｏｎ）法を用いて回帰することにより行った。
結果を第１表に示す。
Experimental Example 1 [PDE4 inhibitory action]
(Preparation of PDE4 partially purified preparation)
The supernatant obtained by centrifuging a lung homogenate excised from a Hartley male guinea pig was fractionated by anion exchange column chromatography. ~ 4. Fractions satisfying the above conditions were mixed to prepare a partially purified preparation of phosphodiesterase 4.
1. Selectively hydrolyze cAMP.
2. The cAMP hydrolysis activity is not affected by cGMP.
3. Not inhibited by CI-930, a PDE3 selective inhibitor.
4). Strong inhibition by Rolipram, a PDE4 selective inhibitor.
(Measurement of PDE4 activity)
The method of Thompson et al. (Advances in Cyclic Nucleotide Research, Vol. 10, Raven Press, New York, 69-92, 1979) was partially modified. That is, 100 μl of PDE4 partially purified preparation diluted with 50 mM Tris-HCl, pH 8.0 to hydrolyze about 10% of the total substrate was added to a glass test tube. After adding 200 μl of a reaction buffer solution (50 mM Tris-HCl, pH 8.0, 12.5 mM MgCl 2 , 10 mM 2-mercaptoethanol), 5 μl of a sample compound (100-fold concentration) dissolved in dimethyl sulfoxide is added. It was. After pre-incubation at 30 ° C. for 5 minutes, 200 μl of 2.5 μM [3H] cAMP (3.7 kBq / 200 μl) was added to initiate the reaction (final concentration 50 mM Tris-HCl, pH 8.0, 5 mM MgCl 2 , 4 mM). 2-mercaptoethanol, 1 μM cAMP). After the reaction at 30 ° C. for 30 minutes, the test tube was transferred into a boiling water bath to stop the reaction. After 90 seconds, the test tube was transferred into an ice water bath, and the temperature of the reaction solution was lowered. After pre-incubation at 30 ° C. for 5 minutes, 100 μl of 1 mg / ml snake venom aqueous solution was added and reacted at 30 ° C. for 30 minutes. After stopping the reaction by adding 500 μl of methanol, 1 ml of the reaction solution was applied to a column to which 200 μl of Dowex resin (trade name: Dowex 1 × 8, manufactured by Sigma) was previously added. Subsequently, the Dowex resin was washed by adding 1 ml of methanol. The reaction solution was passed through the column and the washing solution, and its radioactivity was measured. Calculate the inhibition rate of each sample with respect to the control by adding the buffer solution without adding the enzyme sample as blank and adding the enzyme sample but adding only dimethyl sulfoxide instead of the sample solution as the control. did. The calculation of the IC 50 value of each specimen was performed by obtaining the inhibition rate at three or more concentrations and performing regression using a 4-parameter logistic equation method.
The results are shown in Table 1.
前記例示の各方法で合成される本発明の有効成分である化合物［Ｉ］の具体例（製造例）を下記に示すが、これにより本発明が限定されるものではない。 Specific examples (production examples) of the compound [I], which is an active ingredient of the present invention synthesized by the above-described methods, are shown below, but the present invention is not limited thereto.
製造例１
（１）２−アミノ−３−（３，４−ジヒドロキシフェニル）プロパン酸９８．６ｇをギ酸９００ｍｌに溶解し、これに無水酢酸３００ｍｌを加え、室温で３時間攪拌する。反応溶液を減圧濃縮した後、残渣に蒸留水を加え、再び減圧濃縮する。残渣を蒸留水１５０ｍｌに溶解し、氷冷下で１０Ｍ水酸化ナトリウム水溶液１５０ｍｌ及びジメチル硫酸９５ｍｌを加える。更に、ジメチル硫酸２８５ｍｌを３０分毎３回に分けて加え、その間１０Ｍ水酸化ナトリウム水溶液２９０ｍｌを滴下し、反応温度を４０℃以下、ｐＨを５−９の間に保つ。室温で終夜攪拌した後、１０Ｍ水酸化ナトリウム水溶液５０ｍｌを加え室温で３０分攪拌する。硫酸でｐＨ２にした後、酢酸エチルを加え、有機層を硫酸マグネシウムで乾燥後、減圧濃縮する。残渣をエタノール１３００ｍｌに懸濁し、氷冷下アセチルクロリド２８０ｍｌを滴下して加え、室温で３日攪拌する。溶媒を減圧留去した後、残渣に塩化メチレンを加え、有機層を炭酸カリウム水溶液で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮し、２−アミノ−３−（３，４−ジメトキシフェニル）プロパン酸エチル１１１ｇを油状物として得る。ＭＳ（ｍ／ｚ）：２５３（Ｍ＋）。
（２）上記（１）で得られる化合物１１１ｇとトリエチルアミン７３．６ｍｌを塩化メチレン３００ｍｌに溶解し、氷冷下でベンゾイルクロリド５１．１ｍｌを滴下する。飽和炭酸水素ナトリウム水溶液を加え、有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。析出した結晶をジエチルエーテルで濾取して、３−（３，４−ジメトキシフェニル）−２−（フェニルカルボニルアミノ）プロパン酸エチル１４４ｇを得る。融点：８２−８３℃。ＭＳ（ｍ／ｚ）：３５７（Ｍ＋）。
（３）上記（２）で得られる化合物７１．５ｇをオキシ塩化リン２００ｍｌに溶解し、一晩加熱還流する。オキシ塩化リンを留去後、残渣を塩化メチレンで希釈する。炭酸カリウム水溶液で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。残渣をエタノールに溶解し、濃塩酸２０ｍｌを加え、減圧濃縮する。残渣をメタノール２００ｍｌに溶解し、二酸化白金１ｇを加え、水素加圧下（３気圧）、室温で４時間攪拌する。不溶物を濾去後、減圧濃縮する。残渣をクロロホルムに溶解し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。析出した結晶を濾取して、６，７−ジメトキシ−１−フェニル−３−エトキシカルボニル−１，２，３，４−テトラヒドロイソキノリン５４．４ｇを得る。融点：２１５−２１７℃（分解）。ＭＳ（ｍ／ｚ）：３４１（Ｍ＋）。
（４）２−［（ｔｅｒｔ−ブトキシ）カルボニルアミノ］酢酸２１．６ｇをテトラヒドロフラン７５ｍｌに溶解し、−２０℃でトリエチルアミン１８．７ｍｌ、クロロギ酸イソブチル１７．４ｍｌを滴下し、−１０℃で５分攪拌する。これに上記（３）で得られる化合物３８．２ｇをテトラヒドロフラン１１０ｍｌに懸濁したものを滴下し、室温で一晩攪拌する。反応液を減圧濃縮後、クロロホルムで抽出する。飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。ジエチルエーテルで結晶化後、濾取して、２−｛２−［（ｔｅｒｔ−ブトキシ）カルボニルアミノ］アセチル｝−６，７−ジメトキシ−１−フェニル−３−エトキシカルボニル−１，２，３，４−テトラヒドロイソキノリン３１．７ｇを得る。融点：１６６−１６７℃。ＭＳ（ｍ／ｚ）：４９８（Ｍ＋）。
（５）氷冷下、上記（４）で得られる化合物３１．７ｇにトリフルオロ酢酸６０ｍｌを加え、１時間攪拌する。反応液を減圧濃縮後、クロロホルムに溶解し、トリエチルアミンで中和する。飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。残渣をトルエン３５０ｍｌに溶解し、３時間加熱還流する。溶媒を留去後、析出物をジエチルエーテルで濾取して、８，９−ジメトキシ−６−フェニル−２，３，１１，１１ａ−テトラヒドロ−６Ｈ−ピラジノ［１，２−ｂ］イソキノリン−１，４−ジオン２０．６ｇを得る。融点：２６５−２６７℃。ＭＳ（ｍ／ｚ）：３５２（Ｍ＋）。
（６）窒素雰囲気下、ボラン・ジメチルスルフィド錯体２２．７ｍｌを氷冷し、これに上記（５）で得られる化合物２０ｇをテトラヒドロフラン５００ｍｌに溶解したものを滴下する。一晩加熱還流後、６Ｍ塩酸５０ｍｌを加え、溶媒を留去する。残渣をクロロホルムで希釈して、水酸化ナトリウム水溶液で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。得られた残渣をクロロホルム：メタノール（９：１）を溶出溶媒とするシリカゲルカラムクロマトグラフィーにて精製し、得られた結晶をクロロホルム−メタノールの混合溶媒に溶解する。これに４Ｍ塩酸／酢酸エチル溶液を加えた後、溶媒を留去する。析出物をエタノールで濾取して、８，９−ジメトキシ−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン・２塩酸塩７．６ｇを得る。融点：２２０−２２４℃（分解）。ＭＳ（ｍ／ｚ）：３２４（Ｍ＋）。
（７）８，９−ジメトキシ−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン・２塩酸塩（製造例１（６）で得られる化合物）２ｇをＮ，Ｎ−ジメチルホルムアミド１０ｍｌに溶解し、炭酸カリウム２．８ｇ、ベンジルブロミド０．７ｍｌを加え、室温で３時間攪拌する。反応液をクロロホルムで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。得られた析出物１．２ｇをクロロホルムに溶解し、これに４Ｍ塩酸／酢酸エチル溶液を加えた後、溶媒を留去する。エタノールで再結晶して、８，９−ジメトキシ−２−ベンジル−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン・２塩酸塩１．２ｇを得る。融点：１９８−２０３℃（分解）。ＭＳ（ｍ／ｚ）：４１４（Ｍ＋）。
Production Example 1
(1) 98.6 g of 2-amino-3- (3,4-dihydroxyphenyl) propanoic acid is dissolved in 900 ml of formic acid, 300 ml of acetic anhydride is added thereto, and the mixture is stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure, distilled water is added to the residue, and the mixture is concentrated again under reduced pressure. The residue is dissolved in 150 ml of distilled water, and 150 ml of 10M aqueous sodium hydroxide and 95 ml of dimethyl sulfate are added under ice cooling. Furthermore, 285 ml of dimethylsulfuric acid is added in 3 portions every 30 minutes, during which time 290 ml of 10M aqueous sodium hydroxide solution is added dropwise, keeping the reaction temperature below 40 ° C. and the pH between 5-9. After stirring overnight at room temperature, 50 ml of 10M aqueous sodium hydroxide solution is added and stirred at room temperature for 30 minutes. The pH is adjusted to 2 with sulfuric acid, ethyl acetate is added, and the organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue is suspended in 1300 ml of ethanol, 280 ml of acetyl chloride is added dropwise under ice cooling, and the mixture is stirred at room temperature for 3 days. After evaporating the solvent under reduced pressure, methylene chloride was added to the residue, and the organic layer was washed with an aqueous potassium carbonate solution, dried over magnesium sulfate, concentrated under reduced pressure, and 2-amino-3- (3,4-dimethoxyphenyl) propane. 111 g of ethyl acid are obtained as an oil. MS (m / z): 253 (M <+> ).
(2) 111 g of the compound obtained in the above (1) and 73.6 ml of triethylamine are dissolved in 300 ml of methylene chloride, and 51.1 ml of benzoyl chloride is added dropwise under ice cooling. Saturated aqueous sodium hydrogen carbonate solution is added, and the organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals are collected by filtration with diethyl ether to obtain 144 g of ethyl 3- (3,4-dimethoxyphenyl) -2- (phenylcarbonylamino) propanoate. Melting point: 82-83 ° C. MS (m / z): 357 (M <+> ).
(3) 71.5 g of the compound obtained in (2) above is dissolved in 200 ml of phosphorus oxychloride and heated to reflux overnight. After distilling off phosphorus oxychloride, the residue is diluted with methylene chloride. Wash with aqueous potassium carbonate, dry over magnesium sulfate, and concentrate under reduced pressure. Dissolve the residue in ethanol, add 20 ml of concentrated hydrochloric acid, and concentrate under reduced pressure. The residue is dissolved in 200 ml of methanol, 1 g of platinum dioxide is added, and the mixture is stirred at room temperature under hydrogen pressure (3 atm) for 4 hours. The insoluble material is removed by filtration and concentrated under reduced pressure. The residue is dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals are collected by filtration to obtain 54.4 g of 6,7-dimethoxy-1-phenyl-3-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline. Melting point: 215-217 ° C (decomposition). MS (m / z): 341 (M <+> ).
(4) 21.6 g of 2-[(tert-butoxy) carbonylamino] acetic acid was dissolved in 75 ml of tetrahydrofuran, 18.7 ml of triethylamine and 17.4 ml of isobutyl chloroformate were added dropwise at -20 ° C, and the mixture was stirred at -10 ° C for 5 minutes. Stir. A suspension of 38.2 g of the compound obtained in (3) above in 110 ml of tetrahydrofuran is added dropwise thereto and stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and extracted with chloroform. The extract is washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. After crystallization with diethyl ether, it was collected by filtration, and 2- {2-[(tert-butoxy) carbonylamino] acetyl} -6,7-dimethoxy-1-phenyl-3-ethoxycarbonyl-1,2,3. 31.7 g of 4-tetrahydroisoquinoline are obtained. Melting point: 166-167 ° C. MS (m / z): 498 (M <+> ).
(5) Under ice cooling, 60 ml of trifluoroacetic acid is added to 31.7 g of the compound obtained in the above (4), and the mixture is stirred for 1 hour. The reaction mixture is concentrated under reduced pressure, dissolved in chloroform, and neutralized with triethylamine. The extract is washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in 350 ml of toluene and heated to reflux for 3 hours. After the solvent was distilled off, the precipitate was collected by filtration with diethyl ether, and 8,9-dimethoxy-6-phenyl-2,3,11,11a-tetrahydro-6H-pyrazino [1,2-b] isoquinoline-1 , 4-dione (20.6 g) is obtained. Melting point: 265-267 [deg.] C. MS (m / z): 352 (M <+> ).
(6) Under a nitrogen atmosphere, 22.7 ml of borane-dimethylsulfide complex is ice-cooled, and 20 g of the compound obtained in (5) above is dissolved in 500 ml of tetrahydrofuran. After heating at reflux overnight, 50 ml of 6M hydrochloric acid is added and the solvent is distilled off. The residue is diluted with chloroform, washed with aqueous sodium hydroxide solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography using chloroform: methanol (9: 1) as an elution solvent, and the obtained crystals are dissolved in a mixed solvent of chloroform-methanol. 4M hydrochloric acid / ethyl acetate solution is added thereto, and then the solvent is distilled off. The precipitate was filtered with ethanol, and 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline dihydrochloride 7 .6 g is obtained. Melting point: 220-224 ° C. (decomposition). MS (m / z): 324 (M <+> ).
(7) 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline dihydrochloride (In Production Example 1 (6) 2 g of the compound obtained) is dissolved in 10 ml of N, N-dimethylformamide, 2.8 g of potassium carbonate and 0.7 ml of benzyl bromide are added, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. 1.2 g of the resulting precipitate is dissolved in chloroform, 4M hydrochloric acid / ethyl acetate solution is added thereto, and then the solvent is distilled off. Recrystallized with ethanol, 8,9-dimethoxy-2-benzyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline dihydrochloride 1.2 g is obtained. Melting point: 198-203 ° C. (decomposition). MS (m / z): 414 (M <+> ).
製造例２
（１）２−アミノ−３−（３，４−ジメトキシフェニル）プロパン酸エチル（製造例１（１）で得られる化合物）１５．２ｇ、４−イソプロピルオキシ安息香酸１０．８ｇ、１−ヒドロキシベンゾトリアゾール一水和物９．２ｇを塩化メチレン１２０ｍｌに溶解し、氷冷下で１，３−ジシクロヘキシルカルボジイミド１２．４ｇを加え、室温で一晩攪拌する。不溶物を濾去後、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。析出した結晶をジエチルエーテルで濾取して、３−（３，４−ジメトキシフェニル）−２−｛［４−（イソプロピルオキシ）フェニル］カルボニルアミノ｝プロパン酸エチル２４．２ｇを得る。融点：１２６−１２８℃。ＭＳ（ｍ／ｚ）：４１５（Ｍ＋）。
（２）上記（１）で得られる化合物を製造例１（３）〜（６）と同様に処理することにより、６−［４−（イソプロピルオキシ）フェニル］−８，９−ジメトキシ−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン・２塩酸塩１ｇを得る。融点：１８０−１８５℃（分解）。ＭＳ（ｍ／ｚ）：３８２（Ｍ＋）。
Production Example 2
(1) Ethyl 2-amino-3- (3,4-dimethoxyphenyl) propanoate (compound obtained in Production Example 1 (1)) 15.2 g, 10.8 g of 4-isopropyloxybenzoic acid, 1-hydroxybenzo 9.2 g of triazole monohydrate is dissolved in 120 ml of methylene chloride, 12.4 g of 1,3-dicyclohexylcarbodiimide is added under ice cooling, and the mixture is stirred overnight at room temperature. The insoluble material is removed by filtration, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals are collected by filtration with diethyl ether to obtain 24.2 g of ethyl 3- (3,4-dimethoxyphenyl) -2-{[4- (isopropyloxy) phenyl] carbonylamino} propanoate. Melting point: 126-128 ° C. MS (m / z): 415 (M <+> ).
(2) By treating the compound obtained in (1) above in the same manner as in Production Examples 1 (3) to (6), 6- [4- (isopropyloxy) phenyl] -8,9-dimethoxy-1, 1 g of 3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline dihydrochloride is obtained. Melting point: 180-185 ° C. (decomposition). MS (m / z): 382 (M +).
製造例３−８
対応原料化合物を製造例１（１）〜（６）あるいは製造例２と同様に処理することにより、第２表記載の化合物を得る。
Production Example 3-8
The corresponding starting material compounds are treated in the same manner as in Production Examples 1 (1) to (6) or Production Example 2 to obtain the compounds shown in Table 2.
製造例９−１１
対応原料化合物を製造例１と同様に処理することにより、第３表記載の化合物を得る。
Production Example 9-11
The corresponding raw material compounds are treated in the same manner as in Production Example 1 to obtain the compounds shown in Table 3.
製造例１２
８，９−ジメトキシ−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン（製造例１（６）で得られる化合物）３．２ｇを塩化メチレン２０ｍｌに溶解し、クロロメチルメチルスルフィド８．４ｍｌ、トリエチルアミン３．５ｍｌ、４−（ジメチルアミノ）ピリジン６１ｍｇを加え、室温で一晩攪拌する。反応液を飽和炭酸水素ナトリウム水溶液で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。得られた残渣をクロロホルム：酢酸エチル（９：１）を溶出溶媒とするシリカゲルカラムクロマトグラフィーにて精製し、得られた析出物１１５ｍｇをクロロホルムに溶解し、これに４Ｍ塩酸／酢酸エチル溶液を加えた後、溶媒を留去する。エタノールで再結晶して、８，９−ジメトキシ−２−（メチルチオメチル）−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン・２塩酸塩６０ｍｇを得る。融点：２１７−２２０℃（分解）。ＭＳ（ｍ／ｚ）：３８４（Ｍ＋）。
Production Example 12
8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline (compound obtained in Production Example 1 (6)) 3.2 g Is dissolved in 20 ml of methylene chloride, 8.4 ml of chloromethyl methyl sulfide, 3.5 ml of triethylamine and 61 mg of 4- (dimethylamino) pyridine are added, and the mixture is stirred overnight at room temperature. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform: ethyl acetate (9: 1) as an eluting solvent, and 115 mg of the resulting precipitate was dissolved in chloroform, and 4M hydrochloric acid / ethyl acetate solution was added thereto. After that, the solvent is distilled off. Recrystallized with ethanol, 8,9-dimethoxy-2- (methylthiomethyl) -6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline 60 mg of the dihydrochloride are obtained. Melting point: 217-220 ° C. (decomposition). MS (m / z): 384 (M <+> ).
製造例１３
（１）８，９−ジメトキシ−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン（製造例１（６）で得られる化合物）１．６ｇをＮ，Ｎ−ジメチルホルムアミド１０ｍｌに溶解し、炭酸カリウム０．８ｇ、ブロモ酢酸メチル０．５ｍｌを加え、室温で一晩攪拌する。反応液をクロロホルムで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。得られた残渣をクロロホルム：酢酸エチル（９：１）を溶出溶媒とするシリカゲルカラムクロマトグラフィーにて精製し、８，９−ジメトキシ−２−メトキシカルボニルメチル−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン９４０ｍｇを得る。融点：１１０−１１３℃。ＭＳ（ｍ／ｚ）：３９６（Ｍ＋）。
（２）上記（１）で得られる化合物９２０ｍｇをテトラヒドロフラン２０ｍｌに溶解し、２Ｍ水酸化ナトリウム水溶液１．３ｍｌを加え、室温で３時間攪拌する。２Ｍ塩酸で中和し、溶媒を留去する。残渣をクロロホルムで抽出し、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。得られた析出物６３９ｍｇをクロロホルムに溶解し、これに４Ｍ塩酸／酢酸エチル溶液を加えた後、溶媒を留去する。エタノールで再結晶して、８，９−ジメトキシ−２−カルボキシメチル−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン・２塩酸塩５５０ｍｇを得る。融点：２１４−２１７℃（分解）。ＭＳ（ｍ／ｚ）：３８２（Ｍ＋）。
Production Example 13
(1) 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline (compound obtained in Production Example 1 (6)) 1.6 g is dissolved in 10 ml of N, N-dimethylformamide, 0.8 g of potassium carbonate and 0.5 ml of methyl bromoacetate are added, and the mixture is stirred overnight at room temperature. The reaction mixture is diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform: ethyl acetate (9: 1) as an elution solvent, and 8,9-dimethoxy-2-methoxycarbonylmethyl-6-phenyl-1,3,4, 940 mg of 6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline is obtained. Melting point: 110-113 ° C. MS (m / z): 396 (M <+> ).
(2) 920 mg of the compound obtained in (1) above is dissolved in 20 ml of tetrahydrofuran, 1.3 ml of 2M aqueous sodium hydroxide solution is added, and the mixture is stirred at room temperature for 3 hours. Neutralize with 2M hydrochloric acid and remove the solvent. The residue is extracted with chloroform, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. 639 mg of the resulting precipitate is dissolved in chloroform, 4M hydrochloric acid / ethyl acetate solution is added thereto, and then the solvent is distilled off. Recrystallized with ethanol, 8,9-dimethoxy-2-carboxymethyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline / dihydrochloric acid 550 mg of salt are obtained. Melting point: 214-217 ° C (decomposition). MS (m / z): 382 (M <+> ).
製造例１４
８，９−ジメトキシ−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン（製造例１（６）で得られる化合物）１．６ｇを塩化メチレン１０ｍｌに溶解し、氷冷下、トリエチルアミン０．８ｍｌ、ベンゾイルクロリド０．６ｍｌを加え、３０分攪拌する。反応液を飽和炭酸水素ナトリウム水溶液で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。得られた残渣をクロロホルム：酢酸エチル（９：１）を溶出溶媒とするシリカゲルカラムクロマトグラフィーにて精製し、得られた残渣をクロロホルムに溶解し、これに４Ｍ塩酸／酢酸エチル溶液を加えた後、溶媒を留去する。酢酸エチルで結晶化、濾取して、８，９−ジメトキシ−２−ベンゾイル−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン・塩酸塩６５６ｍｇを得る。融点：２２９−２３３℃（分解）。ＭＳ（ｍ／ｚ）：４２８（Ｍ＋）。
Production Example 14
1.6 g of 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline (compound obtained in Production Example 1 (6)) Is dissolved in 10 ml of methylene chloride, and 0.8 ml of triethylamine and 0.6 ml of benzoyl chloride are added under ice cooling, followed by stirring for 30 minutes. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform: ethyl acetate (9: 1) as an elution solvent, the obtained residue was dissolved in chloroform, and 4M hydrochloric acid / ethyl acetate solution was added thereto. The solvent is distilled off. Crystallized with ethyl acetate and collected by filtration, 8,9-dimethoxy-2-benzoyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline Obtain 656 mg of hydrochloride. Melting point: 229-233 ° C. (decomposition). MS (m / z): 428 (M <+> ).
製造例１５
対応原料化合物を製造例１４と同様に処理することにより、第４表記載の化合物を得る。
Production Example 15
The corresponding starting material compounds are treated in the same manner as in Production Example 14 to obtain the compounds shown in Table 4.
製造例１６
（１）８，９−ジメトキシ−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン（製造例１（６）で得られる化合物）１．６ｇを塩化メチレン１０ｍｌに溶解し、氷冷下、トリエチルアミン０．８ｍｌ、ベンジルオキシアセチルクロリド０．８ｍｌを加え、３０分攪拌する。反応液を飽和炭酸水素ナトリウム水溶液で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。得られた残渣をクロロホルム：酢酸エチル（９：１）を溶出溶媒とするシリカゲルカラムクロマトグラフィーにて精製し、８，９−ジメトキシ−２−ベンジルオキシアセチル−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン１．１ｇを得る。融点：１００−１０３℃。ＭＳ（ｍ／ｚ）：４７２（Ｍ＋）。
（２）上記（１）で得られる化合物１．１ｇにチオアニソール２７４μｌ、トリフルオロ酢酸２０ｍｌを加え、室温で２時間攪拌する。反応液を減圧濃縮し、残渣をクロロホルムに溶解して、飽和炭酸水素ナトリウム水溶液で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。得られた残渣をクロロホルム：アセトン（９：１）を溶出溶媒とするシリカゲルカラムクロマトグラフィーにて精製し、得られた残渣４４７ｍｇをクロロホルムに溶解し、これに４Ｍ塩酸／酢酸エチル溶液を加えた後、溶媒を留去する。エタノールで再結晶して、８，９−ジメトキシ−２−ヒドロキシアセチル−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン・塩酸塩３０９ｍｇを得る。融点：２１０−２１４℃（分解）。ＭＳ（ｍ／ｚ）：３８２（Ｍ＋）。
Production Example 16
(1) 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline (compound obtained in Production Example 1 (6)) 1.6 g is dissolved in 10 ml of methylene chloride, and 0.8 ml of triethylamine and 0.8 ml of benzyloxyacetyl chloride are added under ice cooling and stirred for 30 minutes. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform: ethyl acetate (9: 1) as an elution solvent, and 8,9-dimethoxy-2-benzyloxyacetyl-6-phenyl-1,3,4, 1.1 g of 6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline are obtained. Melting point: 100-103 ° C. MS (m / z): 472 (M <+> ).
(2) To 1.1 g of the compound obtained in (1) above, 274 μl of thioanisole and 20 ml of trifluoroacetic acid are added and stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform: acetone (9: 1) as an elution solvent, 447 mg of the obtained residue was dissolved in chloroform, and 4M hydrochloric acid / ethyl acetate solution was added thereto. The solvent is distilled off. Recrystallized with ethanol, 8,9-dimethoxy-2-hydroxyacetyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline hydrochloride 309 mg is obtained. Melting point: 210-214 ° C. (decomposition). MS (m / z): 382 (M <+> ).
製造例１７
（１）２−［（ｔｅｒｔ−ブトキシ）カルボニルアミノ］酢酸１ｇをテトラヒドロフラン４ｍｌに溶解し、−２０℃でトリエチルアミン０．８ｍｌ、クロロギ酸イソブチル０．８ｍｌを滴下し、−１０℃で５分攪拌する。これに８，９−ジメトキシ−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン（製造例１（６）で得られる化合物）１．６ｇを塩化メチレン１５ｍｌに溶解したものを滴下し、室温で一晩攪拌する。反応液を減圧濃縮後、塩化メチレンで抽出する。飽和炭酸水素ナトリウム水溶液で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮する。得られた残渣をクロロホルム：酢酸エチル（４：１）を溶出溶媒とするシリカゲルカラムクロマトグラフィーにて精製し、８，９−ジメトキシ−２−（ｔｅｒｔ−ブトキシカルボニル）アミノアセチル−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン８７２ｍｇを得る。融点：８１−８４℃。ＭＳ（ｍ／ｚ）：４８１（Ｍ＋）。
（２）上記（１）で得られる化合物２４１ｍｇにトリフルオロ酢酸０．５ｍｌを加え、室温で１時間攪拌する。これに４Ｍ塩酸／酢酸エチル溶液を加え、反応液を減圧濃縮する。残渣にトルエンを加え、再び減圧濃縮する。得られた残渣をエタノール−酢酸エチルで再結晶し、８，９−ジメトキシ−２−アミノアセチル−６−フェニル−１，３，４，６，１１，１１ａ−ヘキサヒドロ−２Ｈ−ピラジノ［１，２−ｂ］イソキノリン・２塩酸塩１９０ｍｇを得る。融点：２２８−２３３℃（分解）。ＭＳ（ｍ／ｚ）：３８１（Ｍ＋）。
Production Example 17
(1) 1 g of 2-[(tert-butoxy) carbonylamino] acetic acid is dissolved in 4 ml of tetrahydrofuran, 0.8 ml of triethylamine and 0.8 ml of isobutyl chloroformate are added dropwise at −20 ° C., and the mixture is stirred at −10 ° C. for 5 minutes. . 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline (compound obtained in Production Example 1 (6)) 1 A solution of .6 g dissolved in 15 ml of methylene chloride is added dropwise and stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and extracted with methylene chloride. Wash with saturated aqueous sodium bicarbonate, dry over magnesium sulfate, and concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform: ethyl acetate (4: 1) as an elution solvent, and 8,9-dimethoxy-2- (tert-butoxycarbonyl) aminoacetyl-6-phenyl-1 was obtained. , 3,4,6,11,11a-872 mg of hexahydro-2H-pyrazino [1,2-b] isoquinoline. Melting point: 81-84 ° C. MS (m / z): 481 (M <+> ).
(2) To 241 mg of the compound obtained in (1) above, 0.5 ml of trifluoroacetic acid is added and stirred at room temperature for 1 hour. A 4M hydrochloric acid / ethyl acetate solution is added thereto, and the reaction solution is concentrated under reduced pressure. Toluene is added to the residue and concentrated again under reduced pressure. The obtained residue was recrystallized from ethanol-ethyl acetate, and 8,9-dimethoxy-2-aminoacetyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2 -B] 190 mg of isoquinoline dihydrochloride is obtained. Melting point: 228-233 ° C. (decomposition). MS (m / z): 381 (M <+> ).
Claims (16)
１）環Ａが低級アルキル基、低級アルコキシ基、水酸基およびハロゲン原子から選ばれる１〜３個の基で置換されたベンゼン環のときは、水素原子、式：−（ＣＨ２）ｎ−Ｒ３１で示される基（但し、Ｒ３１は水素原子、アリール基、水酸基、アミノ基、カルボキシル基、低級アルコキシカルボニル基または低級アルキルチオ基、ｎは１〜６の整数を表す）、または式：−ＣＯ−Ｒ３２で示される基（但し、Ｒ３２はアリール基、低級アルキル基、ヒドロキシ低級アルキル基またはアミノ低級アルキル基を表す）を表し、
２）環Ａが非置換ベンゼン環のときは、式：−（ＣＨ２）ｎ−Ｒ３１で示される基（但し、Ｒ３１は水素原子、アリール基、水酸基、アミノ基、カルボキシル基、低級アルコキシカルボニル基または低級アルキルチオ基、ｎは１〜６の整数を表す）、または式：−ＣＯ−Ｒ３２で示される基（但し、Ｒ３２はアリール基、低級アルキル基、ヒドロキシ低級アルキル基またはアミノ低級アルキル基を表す）を表す。）
で示されるピラジノイソキノリン誘導体またはその薬理的に許容しうる塩を有効成分としてなる医薬組成物。 Formula [I]:
1) When ring A is a benzene ring substituted with 1 to 3 groups selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and a halogen atom , a hydrogen atom, a formula: — (CH 2 ) n —R 31 (Wherein R 31 represents a hydrogen atom, an aryl group, a hydroxyl group, an amino group, a carboxyl group, a lower alkoxycarbonyl group or a lower alkylthio group, n represents an integer of 1 to 6), or a formula: —CO— groups represented by R 32 (where, R 32 represents an aryl group, a lower alkyl group, a hydroxy lower alkyl group or amino-lower alkyl group) represents,
2) When ring A is an unsubstituted benzene ring, a group represented by the formula: — (CH 2 ) n —R 31 (where R 31 is a hydrogen atom, aryl group, hydroxyl group, amino group, carboxyl group, lower alkoxy group) A carbonyl group or a lower alkylthio group, n represents an integer of 1 to 6, or a group represented by the formula: —CO—R 32 (wherein R 32 represents an aryl group, a lower alkyl group, a hydroxy lower alkyl group or an amino lower group). Represents an alkyl group). )
A pharmaceutical composition comprising a pyrazinoisoquinoline derivative represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient.
１）環Ａが低級アルキル基、低級アルコキシ基、水酸基およびハロゲン原子から選ばれる１〜３個の基で置換されたベンゼン環のときは、水素原子、式：−（ＣＨ２）ｎ−Ｒ３１で示される基（但し、Ｒ３１は水素原子、アリール基、水酸基、アミノ基、カルボキシル基、低級アルコキシカルボニル基または低級アルキルチオ基、ｎは１〜６の整数を表す）、または式：−ＣＯ−Ｒ３２で示される基（但し、Ｒ３２はアリール基、低級アルキル基、ヒドロキシ低級アルキル基またはアミノ低級アルキル基を表す）を表し、
２）環Ａが非置換ベンゼン環のときは、式：−（ＣＨ２）ｎ−Ｒ３１で示される基（但し、Ｒ３１は水素原子、アリール基、水酸基、アミノ基、カルボキシル基、低級アルコキシカルボニル基または低級アルキルチオ基、ｎは１〜６の整数を表す）、または式：−ＣＯ−Ｒ３２で示される基（但し、Ｒ３２はアリール基、低級アルキル基、ヒドロキシ低級アルキル基またはアミノ低級アルキル基を表す）を表す。）
で示されるピラジノイソキノリン誘導体またはその薬理的に許容しうる塩。 Formula [I]:
1) When ring A is a benzene ring substituted with 1 to 3 groups selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and a halogen atom , a hydrogen atom, a formula: — (CH 2 ) n —R 31 (Wherein R 31 represents a hydrogen atom, an aryl group, a hydroxyl group, an amino group, a carboxyl group, a lower alkoxycarbonyl group or a lower alkylthio group, n represents an integer of 1 to 6), or a formula: —CO— groups represented by R 32 (where, R 32 represents an aryl group, a lower alkyl group, a hydroxy lower alkyl group or amino-lower alkyl group) represents,
2) When ring A is an unsubstituted benzene ring, a group represented by the formula: — (CH 2 ) n —R 31 (where R 31 is a hydrogen atom, aryl group, hydroxyl group, amino group, carboxyl group, lower alkoxy group) A carbonyl group or a lower alkylthio group, n represents an integer of 1 to 6, or a group represented by the formula: —CO—R 32 (wherein R 32 represents an aryl group, a lower alkyl group, a hydroxy lower alkyl group or an amino lower group). Represents an alkyl group). )
Or a pharmacologically acceptable salt thereof.
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