IE49630B1 - Benzazepine derivatives - Google Patents
Benzazepine derivativesInfo
- Publication number
- IE49630B1 IE49630B1 IE227/80A IE22780A IE49630B1 IE 49630 B1 IE49630 B1 IE 49630B1 IE 227/80 A IE227/80 A IE 227/80A IE 22780 A IE22780 A IE 22780A IE 49630 B1 IE49630 B1 IE 49630B1
- Authority
- IE
- Ireland
- Prior art keywords
- hydrogen
- group
- lower alkyl
- compound
- chloro
- Prior art date
Links
- 150000008038 benzoazepines Chemical class 0.000 title 1
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 63
- 239000001257 hydrogen Substances 0.000 claims abstract description 63
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 56
- 239000002253 acid Substances 0.000 claims abstract description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 23
- 239000000460 chlorine Substances 0.000 claims abstract description 22
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 22
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 20
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 19
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 18
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 17
- 150000002367 halogens Chemical group 0.000 claims abstract description 17
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 9
- 125000003396 thiol group Chemical class [H]S* 0.000 claims abstract description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 9
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 8
- 239000002249 anxiolytic agent Substances 0.000 claims abstract description 7
- 239000000932 sedative agent Substances 0.000 claims abstract description 7
- 230000000949 anxiolytic effect Effects 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 229940125723 sedative agent Drugs 0.000 claims abstract description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 5
- SYYWEHJLUMPGIZ-UHFFFAOYSA-N C1=CC=NC=C2C3=CNC=NC3=CC=C21 Chemical class C1=CC=NC=C2C3=CNC=NC3=CC=C21 SYYWEHJLUMPGIZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940005530 anxiolytics Drugs 0.000 claims abstract description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract 23
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims abstract 4
- 150000001875 compounds Chemical class 0.000 claims description 109
- -1 alkyl amide Chemical class 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 35
- 238000002360 preparation method Methods 0.000 claims description 18
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- CLYXKIKVKJZIOF-UHFFFAOYSA-N 9-chloro-7-(2-chlorophenyl)-5h-pyrimido[5,4-d][2]benzazepine Chemical compound C=1C(Cl)=CC=C(C2=NC=NC=C2CN=2)C=1C=2C1=CC=CC=C1Cl CLYXKIKVKJZIOF-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 229910052731 fluorine Chemical group 0.000 claims description 3
- 239000011737 fluorine Chemical group 0.000 claims description 3
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 230000003635 deoxygenating effect Effects 0.000 claims description 2
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 230000001624 sedative effect Effects 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 4
- 208000019901 Anxiety disease Diseases 0.000 claims 2
- 239000013543 active substance Substances 0.000 claims 2
- 230000036506 anxiety Effects 0.000 claims 2
- 230000005284 excitation Effects 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- GJPUTKWVQJEZPE-UHFFFAOYSA-N 1h-azepin-2-amine Chemical compound NC1=CC=CC=CN1 GJPUTKWVQJEZPE-UHFFFAOYSA-N 0.000 claims 1
- 125000005122 aminoalkylamino group Chemical group 0.000 claims 1
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 510
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 211
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 177
- 239000000203 mixture Substances 0.000 description 114
- 239000000243 solution Substances 0.000 description 94
- 238000006243 chemical reaction Methods 0.000 description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 64
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 47
- 239000003921 oil Substances 0.000 description 41
- 235000019198 oils Nutrition 0.000 description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 38
- 239000000047 product Substances 0.000 description 32
- 238000001953 recrystallisation Methods 0.000 description 32
- 239000007787 solid Substances 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- 239000013078 crystal Substances 0.000 description 21
- 239000007795 chemical reaction product Substances 0.000 description 19
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 17
- 239000000908 ammonium hydroxide Substances 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 16
- 235000011152 sodium sulphate Nutrition 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 229960000583 acetic acid Drugs 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 239000003826 tablet Substances 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 239000003480 eluent Substances 0.000 description 11
- WCQOBLXWLRDEQA-UHFFFAOYSA-N ethanimidamide;hydrochloride Chemical compound Cl.CC(N)=N WCQOBLXWLRDEQA-UHFFFAOYSA-N 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- STIAPHVBRDNOAJ-UHFFFAOYSA-N carbamimidoylazanium;carbonate Chemical compound NC(N)=N.NC(N)=N.OC(O)=O STIAPHVBRDNOAJ-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- XUUSYXJGMRQBKQ-UHFFFAOYSA-N 2h-2-benzazepine Chemical compound N1C=CC=C2C=CC=CC2=C1 XUUSYXJGMRQBKQ-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001409 amidines Chemical class 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 238000005903 acid hydrolysis reaction Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 150000008064 anhydrides Chemical class 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 150000002357 guanidines Chemical class 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 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 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000000538 analytical sample Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 3
- 229910052727 yttrium Inorganic materials 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- TUCYWBVWKLKPMG-UHFFFAOYSA-N 1h-1-benzazepin-2-ol Chemical compound N1C(O)=CC=CC2=CC=CC=C21 TUCYWBVWKLKPMG-UHFFFAOYSA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- ZEGKMPUYDXONKA-UHFFFAOYSA-N 2,9-dichloro-7-(2-fluorophenyl)-5h-pyrimido[5,4-d][2]benzazepine Chemical compound FC1=CC=CC=C1C1=NCC2=CN=C(Cl)N=C2C2=CC=C(Cl)C=C12 ZEGKMPUYDXONKA-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- 229940105325 3-dimethylaminopropylamine Drugs 0.000 description 2
- IMUKFZCUTKPIIS-UHFFFAOYSA-N 4-(dimethylaminomethylidene)-3h-2-benzazepin-5-one Chemical compound O=C1C(=CN(C)C)CN=CC2=CC=CC=C21 IMUKFZCUTKPIIS-UHFFFAOYSA-N 0.000 description 2
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- XYULIKIBJYNXPC-UHFFFAOYSA-N ethyl 2-[9-chloro-7-(2-fluorophenyl)-5h-pyrimido[5,4-d][2]benzazepin-2-yl]acetate Chemical compound C12=CC(Cl)=CC=C2C2=NC(CC(=O)OCC)=NC=C2CN=C1C1=CC=CC=C1F XYULIKIBJYNXPC-UHFFFAOYSA-N 0.000 description 1
- 239000002038 ethyl acetate fraction Substances 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- WQYQQUWRQLYQOC-UHFFFAOYSA-N methyl 4-chloro-2-(2-fluorobenzoyl)benzoate Chemical compound COC(=O)C1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1F WQYQQUWRQLYQOC-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- XVIAPHVAGFEFFN-UHFFFAOYSA-N pyrimidine-5-carbonitrile Chemical compound N#CC1=CN=CN=C1 XVIAPHVAGFEFFN-UHFFFAOYSA-N 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- LXEXBJXDGVGRAR-UHFFFAOYSA-N trichloro(trichlorosilyl)silane Chemical compound Cl[Si](Cl)(Cl)[Si](Cl)(Cl)Cl LXEXBJXDGVGRAR-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
- C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
- C07C291/04—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds containing amino-oxide bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
- C07C65/34—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups polycyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Pyrimido-2-benzazepines of the formula <IMAGE> wherein A is one of the groups <IMAGE> R<1> is hydrogen, chlorine, bromine, lower alkyl, the group NR<4>R<5>, the group -CH2-CO-R<7>, the group -NH(CH2)mNR<8>R<9>, hydroxy, lower alkoxy, mercapto or lower alkyl mercapto, R<2> is hydrogen, amino or di-lower alkyl amino, R<3> is hydrogen, lower acyloxy or hydroxy, X is hydrogen, halogen, trifluoromethyl, ethyl alpha -hydroxy ethyl or acetyl, Y is hydrogen or halogen, R<4> and R<5> each are hydrogen or lower alkyl or, together complete a five to seven membered heterocyclic ring, R<7> is hydroxy, lower alkoxy or NR<8>R<9>, R<8> and R<9> each are hydrogen or lower alkyl, n is 0 or 1 and m is 1 to 7, with certain provisos, and pharmaceutically acceptable acid addition salts thereof, exhibit pharmacological utility as anxiolytics and sedatives.
Description
The present invention relates to pyrimido-2-benzazepines of the general formula R is hydrogen, chlorine, bromine, lower alkyl, the group NR%5, the group -Clk-CO-R?, the group HQ -NH(CHO)„NR R , hydroxy, lower alkoxy, mercapto or lower alkyl mercapto, R is hydrogen, lower acyloxy or hydroxy, X is hydrogen, halogen, trifluoromethyl, ethyl, α-hydroxy ethyl or acetyl, Y is hydrogen or halogen, R4 and R9 each are hydrogen or lower alkyl or, together with the co-bonded nitrogen atom, represent a five to seven membered heterocycle which may contain an oxygen or sulphur atom or the group ^N-lower alkyl, R? is hydroxy, lower 5 Q Q Q alkoxy or NR R , R and RJ each are hydrogen or lower alkyl, n is 0 or 1 and m is 1 to 7, with the proviso that (i ) when R3 is lower acyloxy or hydroxy, A is group (a), or acetyl and, -NH(CH-) NR8R9 2 m are lower alkyl; X is hydrogen, halogen, trifluoromethyl, ethyl 1 if R represents the group 8 <3 then R and R each (ii ) when A is group (d) and R1 represents the group ~ 8 q then R and R’ each -NH(CH2)mNR8R9, are lower alkyl; and (iii) when n is 1, R1 is hydrogen, lower alkyl, lower alkoxy, chlorine, bromine or the group -CH2-C0-R‘ (wherein R? is as above) and A is group (a) or (b); and pharmaceutically acceptable acid addition salts thereof. These compounds exhibit pharmacological activity as anxiolytics and sedatives.
As used herein, the term lower alkyl means straight or branched hydrocarbon groups having from 1 to 7 carbon atoms, prefereably 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl and the like.
The term halogen represents all four forms thereof, i.e., fluorine, chlorine, iodine and bromine unless expressly indicated otherwise.
The terms lower alkoxy and lower alkyl mercapto denote a moiety of the formula -0-lower alkyl and -S-lower alkyl, respectively, wherein lower alkyl is as above.
Where the term heteroatom or carbon atom nucleo10 philes is utilized there are meant moieties as described in Belgian Patent No. 833,249 which disclosure is incorporated by reference herein.
The expression pharmaceutically acceptable salts 15 is used to include salts with both inorganic and organic pharmaceutically acceptable strong acids, such as, sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and p-toluene sulfonic acid. Such salts can be formed quite readily by those skilled in the art 20 with the prior art and the nature of the compound to be placed in salt form in view.
Among the compounds of formula I, above, those wherein A is group (a), above, and n is o are preferred.
Particularly preferred compounds of formula I are those wherein A is group (a), above, n is o and R3 is hydrogen and R^ is hydrogen, lower alkyl, the group NR^R^ (wherein R^ and r5 each are hydrogen or lower alkyl), hydroxy, 30 chlorine, bromine, the group -NH-(CHO)_NR®R^ (wherein Q Q " R and R’ each are lower alkyl) or the group -CH^-CO-R? (wherein R? is as above), with hydrogen, amino and lower alkyl being especially preferred; or ’5 _ R3 is hydroxy and is hydrogen, lower alkyl or the group NR^R^ (wherein R2* and R^ each are hydrogen or lower alkyl) - 49630 Furthermore, those among the compounds of formula I are preferred wherein X is halogen, with chlorine being particularly preferred, and/or wherein Y is hydrogen, chlorine or fluorine.
A particularly preferred compound of the invention is 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2 Ibenzazepine.
Further examples of preferred compounds of the invention are -9-chloro-7-(2-fluorophenyl)-5H-pyr imi do[5,4-d][2]benzazepine; -9-chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4-d][2Ibenzazepine; -9-chloro-7-(2-fluorophenyl)-5H-pyrimido/5,4-d//2/15 benzazepin-2-ol; and -9-chloro-N,N-dimethyl-7-(2-fluorophenyl)-5H-pyrimido/J,4-d7/27benzazepin-2-amine.
In accordance with the present invention, compounds of formula I and pharmaceutically acceptable acid addi20 tion salts thereof can be prepared by a) cydizing a compound of the general formula wherein X and ϊ are as above and R1 is hydrogen, Bq 8 Q lower alkyl or NR R wherein R and R are as above, or b) dehydrogenating a compound of the general formula or c) reacting a compound of the general formula iv wherein X and ϊ are as above, p is 0 or 1 and R represents di-lower alkyl amino, with a compound of the general formula NH NHn wherein R is hydrogen, mercapto, lower alkyl fig 8 9 mercapto, lower alkyl or NR R wherein R and R are as above, or d) reducing a compound of the general formula la . 49630 wherein X, Υ and R are as above, or e) lower-alkylating a compound of the general formula or f) oxidizing a compound of the general formula wherein X and Y are as above and R^ represents 51 hydrogen, lower alkyl, hydroxy, lower alkoxy, NR R (wherein R2*1 and R^1 each are hydrogen or lower alkyl or, together with the oo-bonded nitrogen atom, represent a 5 to 7 membered heterocycle which may contain an oxygen atom), chlorine, bromine or the group -CH2-C0-r7 (wherein R? is as above), or - 49630 g) lower alkylating a compound of the general formula wherein X, Y and p are as above and R represents mercapto or hydroxy, or h) converting a compound of the general formula into the corresponding 2-hydroxy compound, or i) converting a compound of the general formula wherein X and Y are as above, into a corresponding 2-chloro or bromo compound, or k) treating a compound of the general formula wherein X, Y and p are as above and R represents chlorine or bromine, with hydrogen sulfide, with a lower alkylmercaptan, with 4 5 a lower alkanol, with a compound of formula HNR R wherein ll c R and R are as above, with a compound of formula g q g q HgN-CCH2)mNR R wherein R , R’ and m are as above or with the carbanion of a compound of the formula π ^CORTl ch2 OOR71 or COR71 6h2 \oR21 21 wherein R‘ is lower alkoxy and R is as above, or l) converting a compound of the general formula wherein r7\ X, Y and p are as above, into the corresponding free acid or into a corresponding amide, lower alkyl amide or di-lower alkyl amide, or m) reacting a compound of the general formula chlorine, bromine, lower alkyl, the group NR^R^, 6 30 the group -CI^-CO-R', the group -NH(CH2)mNR8lR^1, hydroxy, loweralkoxy, mercapto or lower alkylmercapto, X1 is hydrogen, halogen, trifluoromethyl, ethyl or acetyl, R 1 and ο 1 4 5 7 R each are lower alkyl and R , R and R1 are as above, with a lower acylating agent or n) hydrolyzing a compound of the general formula Ik 31 wherein X1, Y and R are as above and RJ is lower acyloxy, or o) deoxygenating a compound of the general formula II wherein X and Y are as above, R is hydrogen, lower alkyl, the group NR^R^, the group -CHg-CO-R?, Q the group NH-(CH,) -NR R , hydroxy, lower alkoxy, mercapto or lower alkylmercapto and R , R , R7, R8 and R9 are as above, or p) removing the elements of H-Z from a compound of the 1.8 wherein X and Y are as above, R is hydrogen, lower alkyl, lower alkoxy, chlorine, bromine or the group -CH^-CO-R7 (wherein R7 is as above) and Z represents hydrogen or an easily cleavable acyl group, or ql converting a compound of formula I into a pharma15 ceutically acceptable acid addition salt.
It will be appreciated and readily apparent to those skilled in the art that when the compound to be subjected to any of the aforementioned reactions contains, in addition to the group(s) involved in the reaction, groups which may be vulnerable under the conditions of such reaction, then either a method for performing such reaction has to be utilized which does not affect such vulnerable group, if such method is available, or such vulnerable group has to be protected before carrying out the reao14 6 30 tion and thereafter the protecting group has to be removed.
Process embodiments a) and b), above, and the prepara tion of the starting materials therefor are, by way of example, illustrated by the following Reaction Scheme I wherein X, Y and R11 are as above: Reaction Scheme I 4-9 630 The compounds VI, VII and VIII are generically known in the art. A method to produce them is included for completeness of disclosure.
VI -} VII The compound of formula VI which is a well-known prior art compound is reacted with cuprous cyanide after being previously treated with sulfuric acid, sodium nitrite and optionally sodium tetrafluorborate in seriatium. Thereafter the mixture is hydrolysed with an alio kali metal hydroxide, e.g., sodium or potassium hydroxide at reflux temperatures.
VII -> VIII The compound of formula VIII is formed by the reaction of the carboxylic acid of formula VII which metha15 nol in the presence of an acid catalyst, such as, sulfuric acid at about the reflux temperature of methanol for about 3 to 18 hours.
VIII -> IX The compound of formula VIII is thereafter reacted with 1-chloro-2,3-epoxy propane or other suitable epoxide ketalizing reagents such as ethylene oxide and 1,2epoxypropane in the presence of a Lewis acid, such as, aluminum chloride or boron trifluoride or preferably stannic chloride in an inert organic solvent, such as, tolu25 ene, carbon tetrachloride, or benzene. Suitable reaction temperatures range from about 20°C to 110°C with about 25°C being preferred.
Thereafter the compound of formula XX is reacted with acetonitrile (CH^CN) in the presence of an alkali metal amide, such as, sodium or potassium amide, in liquid ammonia in the presence of an inert organic solvent, such as, diethyl ether, tetrahydrofuran or dioxane. Reaction temperature may vary from about the reflux temperature of liquid ammonia to room temperature.
The compound of formula X is thereafter reacted with a dialkoxy acetal of dimethylformamide, such as, dimethylformamide dimethylacetal. Suitable reaction temperatures range from about 25°C to 120°C with the reflux temperature of the dimethylacetal as preferred.
XX-> XII The conversion of the compounds of formula XI into the compounds of formula XII involves two steps, viz. reaction with a suitable acid addition salt of an amidine or guanidine of the formula Va nh2 11 wherein R is as above, and acid hydrolysis of the ketal function. Where X and Y both are hydrogen, the acid hydrolysis of the ketal function is preferably effected before the reaction with the amidine or guanidine salt whilst where X and/or Y is/are other than hydrogen, the acid hydrolysis of the ketal function is preferably effected after the reaction with the amidine or guanidine salt. By-products formed have to be removed from the reaction mixture before proceeding further.
The reaction with a suitable acid additional salt of an amidine or guanidine of the formula Va, such as, formamidine acetate, acetamidine hydrochloride, guanidine carbonate or a substituted guanidine carbonate is expediently effected in an aprotic polar organic solvent, such as, dimethylsulfoxide at a temperature range of from about 25°C to 125°C with a preferred range of about 90° to 95°C.
The ketai function is hydrolysed by means of an aqueous inorganic acid, such as, sulfuric, phosphoric or preferably a hydrohalic acid, such as, hydrochloric acid in the presence of a lower alkyl organic alcohol solvent, preferably, ethanol. The reaction is run at about room temperature.
XII-> II The compound of formula II is formed by the hydrogenation of the compound of formula XII in the presence of a metal catalyst such as platinum, palladium or Raney nickel and cyclizes spontaneously to give compound In.
The hydrogenation may be carried out in a suitable organic solvent such as lower alkyl organic alcohols or lower alkyl carboxylic acids, i.e., acetic acid. Depending on the conditions used in the aforementioned hydrogenation, a dihydro pyrimido compound of formula III may be formed in addition to, or instead of, the compound of formula In. This dihydropyrimido compound may be converted into the compound of formula In by treatment with a mild oxidizing agent, such as, manganese dioxide, air and the like.
Process embodiment c), above, involves the reaction of a compound of formula IV with an amidine of guanidine salt or with thiourea or an S-lower alkyl isothiourea.
For the reaction with the amidine or guanidine salt, any inert organic solvent such as dioxane, tetrahydrofuran or dimethylformamide may be utilized with a reaction temperature ranging from about room temperature to reflux temperature of the solvent with about room temperature as preferred. The reaction with thiourea or with an S-lower alkyl isothiourea can be effected in the presence of an alcoholic e.g., methanolic, solution of an alkali metal alkoxide, e.g. sodium methoxide. The reaction may be carried out at from about O°C to 65°C with about room temperature as preferred.
Process embodiments d) and e, are, by way of example, illustrated by the following Reaction Scheme III, wherein R is as above: Reaction Scheme III XIII x49630 In Io and In or lo XIII The compound of formula In (see Reaction Scheme I) is treated with a reducing agent such as zinc in acetic acid at a reaction temperature of about -40°C to 20°C to give Io. The solvent utilized may be a halogenated hydrocarbon suoh as methylene chloride.
The compound of formula In or Io* is reacted with hydrogen in the presence of platinum oxide or prehydrogenated platinum oxide and as a solvent acetic acid to give XIII. The reaction is normally run at about room temperature.
Other useful reducing agents for process embodiment d) include sodium cyanoborohydride, sodium borohydride and the like.
In many instances, mixtures of the 6,7-dihydro and the 4,5,6,7-tetrahydro compounds are obtained. The said 4,5,6,7-tetrahydro compounds also exhibit useful CNS properties.
Io' The compound of formula Io* is reacted with formaldehyde in formic acid with heating, e.g. about reflux temperature to methylate the dihydro compound. Methylation can also be accomplished with e.g. methyl iodide, dimethylsulfate or the like.
Lower alkyl substituents other then methyl may be produced by utilizing the appropriate alkyl halides, sulfates, alkylsulfonates, tosylates or the like in a solvent, such as, dimethylformamide, tetrahydrofuran, glyme and diglyme, or etherial solvents or by utilizing the appropriate aldehydes under reducing reaction conditions.
Process embodiment f) is, by way of example, illus trated by the following Reaction Scheme IV wherein R11 is as above: Reaction Scheme IV 9 6 3 0 The compound of formula In is reacted with a suitable oxidizing agent such as metachloroperbenzoic acid in an inert organic solvent, such as, methylene chloride. The reaction may be run at between about 0°C to room temperature with about room temperature as preferred.
The reaction time may be varied depending on whether the N-oxide or di-N-oxide product is desired. The N-oxide Iq is produced predominantly where the reaction time is varied between about 2 and 25 hours whereas the di-N10 oxide Ir is produced In predominance where the reaction time is between about 40 and 60 hours.
According to process embodiment g), above, a mercapto or hydroxy group is lower alkylated according to methods known per se. The alkylation of the mercapto group is expediently effected by means of an appropriate alkyl halide in the presence of a mixture of an alkali metal hydroxide, such as, sodium hydroxide and a C1 to alcohol, such as, ethanol. The reaction may be carried out preferably at about room temperature.
The alkylation of the hydroxy group is expediently effected with a dialkyl sulfate such as, dimethyl or diethyl sulfate in the presence of basic conditions, e.g., 25 with sodium hydroxide present. The reaction may be run at from about 0°C to 65°C with about room temperature as preferred.
The conversion of a 2-amino compound into the corres30 ponding 2-hydroxy compound according to process embodiment h), above, can be effected by means of an acid, such as, sulphuric acid. The reaction temperature may be varied from about 25°C to 125°C with about 100°C as the preferred temperature.
Other methods which may be used for this conversion include alkaline hydrolysis and displacement of diazo• 49630 nium salts.
The conversion of a 2-hydroxy compound into the corresponding 2-chloro or bromo compound according to process embodiment i), above, can be effected; respectively, with a suitable chlorinating agent, such as, phosphorus trichloride at reflux temperature of the mixture, and with a suitable brominating agent, such as, phosphoryl bromide or phosphorus pentabromide at from about room temperature to reflux.
According to process embodiment k), above, the chlorine or bromine atom In position 2 of the compound of formula Ig can be displaced by nucleophilic substitution with a number of heteroatom and carbon atom nucleophiles suoh as methanol, 3-dimethylaminopropylamine, methylamine, dimethylamine, N-methylpiperazine, the oarbanion of diethylmalonate and the like, in an inert polar organic solvent, such as, dimethylformamide at from O°C to reflux temperature of the solvent, preferably at room temperature.
The conversion of a compound of formula Ih into the corresponding free acid according to process embodiment 1), above, is expediently effected by hydrolysis under alkaline conditions, e.g. by means of an alkali or earth alkali metal hydroxyde, such as, sodium or potassium hydroxide or the like, in the presence of a suitable solvent such as a lower alkanol, e.g. ethanol.
The conversion of a compound of formula Ih into a corresponding amide according to process embodiment 1), above, ean be effected either by treatment with ammonia or an appropriate mono- or di-lower alkylamine at room temperature or at an elevated temperature (suitably about 5O-13O°C), in the presence of an inert organic solvent such as a lower alkanol, e.g. ethanol, or by hydrolysis to the corresponding free acid, conversion of the free acid into a reactive derivative, such as an acid chloride or a mixed anhydride, and subsequent treatment of this reactive derivative with ammonia or an appropriate mono- or di-lower alkylamine.
Process embodiments m) and n) are by way of example illustrated by the following Reaction Scheme V wherein X', Y, R11 and R91 are as above: 4S63U Reaction Scheme V The compound of formula Is can be reacted with an acid anhydride of a suitable carboxylic acid such as acetic- or trifluoroaoetic-anhydride. The reaction is preferably done at about the reflux temperature of the anhydride chosen. Instead of an acid anhydride, also an acid chloride can be utilized.
Iu The compound of formula It can be reacted with an alkali metal carbonate, such as, sodium or potassium carbonate in a C1 to alcohol, such as, methanol at a temperature range of about 0°C to 65°C with about room temperature as preferred. Other reaction conditions suitable for this step include the use of alkali metal hydroxides, e.g., sodium or potassium hydroxide, and a to alcohol in the presence of water or, in the alternative, an acid hydrolysis utilizing an aqueous mine ral acid such as hydrochloric or sulfuric acid with a solvent such as THF or dioxane with a reaction temperature from about 0°C to room temperature with 0°C as preferred.
The deoxygenation according to process embodiment o), above, can be effected by methods known per se, e.g. by means of reagents such as phosphorus trichloride, trilower alkyl phosphites (e.g. triethyl phosphite), hexachlorodisilane, Raney-nickel and the like.
Process embodiment p), above, and the preparation of the starting materials therefor are, by way of example, illustrated by the following Reaction Scheme VI, wherein X, Y and R are as above and Z' represents an easily cleavable acyl group: - 49630 ,Υ 630 This conversion involves an acylation utilizing a suitable acylating agent to yield the easily cleavable acyl group Z*, such as trifluoroacetylchloride, p-toluenesulfonylchloride, methanesulfonylchloride, the mixed anhydride of formic acid and acetic acid, ethyl chloroformate, benzyloxycarbonylchloride and the like. The conditions for carrying out an acylation of this kind will be readily apparent to .those skilled in the art.
XIV —->XV The compound of formula XIV is reacted with a suitable oxidizing agent such as metachloroperbenzoic acid in an inert organic solvent, such as, methylene chloride. The reaction may be run at between about 0°C to about room temperature with about room temperature as preferred. The reaction time is between about 40 to 60 hours.
XV ·... > XVI The acyl group Z' is split off by methods known per se which are readily apparent to those skilled in the art. The choice of the method to be utilized depends of course, from the nature of the acyl group Z'. Thus, for example, the tri fluoroacetyl or ethoxycarbonyl groups can be removed by alkaline hydrolysis, the formyl group by acid hydrolysis and the benzyloxycarbonyl group by means of hydrogen bromide etc.
XVI or XV-> Iw The conversion of XVI into Iw involves a dehydrogenation which can be effected by methods known per se, e.g. by means of diethylazodlcarboxylate or by N-halogenation (preferably N-bromination) followed by a dehy31 drohalogenation under alkaline conditions, e.g. by means of a tertiary amine such as triethylamine.
When Z' in formula XV is a group such as tosyl or mesyl, there can be carried out an elimination of H-Z' under alkaline conditions, e.g. by means of an alkali metal alkoxide in the corresponding alkanol, such as, methanolic sodium methoxide.
Any 7H-isomer of the compound of formula Iw formed can be isomerised to the compound of formula Iw by treat10 ment with a suitable base, e.g. methanolic sodium methoxide.
For the sake of oompletness, the preparation of those among the intermediates of formula IV wherein p is 1 is, by way of example, illustrated by the following Reaction Scheme VII wherein X and Ϊ are as above: Reaction Scheme Til XVIII The compound of formula XVII can be reacted with a peracid such as, metachloroperbenzoic acid in an inert organic solvent such as a halogenated hydrocarbon, e.g. methylene chloride, or an ether. The reaction may be carried out from about 0°C to 40°C with room temperature as preferred. The mixture of products may thereafter be separated from one another by fractional crystallization. Analysis by thin-layer chromatography indicates the presence of both products.
The compound of formula XVIII can be reacted with dimethylformamide dimethylacetal in an inert solvent, such as, a halogenated hydrocarbon, e.g. methylene chloride, or dimethylformamide or high boiling ethers. The reaction temperature may range from about 0°C to 100°C with room temperature as preferred.
The pyrimido-2-benzazepines of formula I, above, and their pharmaceutically acceptable acid addition salts, are useful as pharmaceuticals and are characterized by activity as sedative and anxiolytic agents. These compounds can be used in the form of conventional pharmaceutical preparations; for example, the aforesaid compounds can be mixed with conventional organic or inorganic, inert pharmaceutical carriers suitable for parenteral or enteral administration such as for example, water gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gums, polyalkylene glycols, Vaseline or the like. They can be administered in conventional pharmaceutical forms, e.g., solid forms, for example, tablets, dragees, capsules, suppositories or the like, or in liquid forms, for example, solutions, suspensions or emulsions. Moreover, the pharmaceutical compositions containing compounds of this invention can be subjected to conventional pharmaceutical expedients such as sterilization, and can contain conventional pharmaceutical excipients such as preservations, stabilizing agents, wetting agents, emul49630 sifying agents, salts for the adjustment of osmotic pressure, or buffers. The compositions can also contain other therapeutically active materials.
The following table shows the results obtained when 5 the following compounds were subjected to certain wellknown tests such as the inclined screen test, the foot shock test, the unanesthetized cat test and the antipentamethylenetetrazole test (metrazol test) as well as indi cations as to their toxicity: A: 9-Chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4-d][2]benzazepine B: 9-Chloro-7-(2-chlorophenyl)-5H-pyrimi do[5,4-d][2]benzazepine D: 9-Chloro-7- (2-chlorophenyl)-6,7-dihydro-2-methyl15 5H-pyrimido/5,4-d//Vbenzazepine dihydrochloride F: 9-Chloro-7-(2-chlorophenyl)-6,7-dihydro-2,5-dimethyl5H-pyrimido/5,4-d//2/benzazepine methanesulfonic acid salt (1:2) G: 9-Chloro-7-(2-fluorophenyl)-5H-pyrimido/5,4-d//2y20 benzazepin-2-ol H: 9-Chloro-7-(2-fluorophenyl)-5H-pyrimido/5,4-3//2/benzazepine I: 9-Chloro-7-(2-fluorophenyl)-2-methoxy-5H-pyrimido[5,4-d][2]benzazepine K: 9-Chloro-7-(2-fluorophenyl)-M,N-dimethyl-5H-pyrimido-[5,4-d][2]benzazepin-2-amine A suitable pharmaceutical dosage unit can contain from about 1 to about 500 mg of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof with a dosage range of from about 1 mg to about 100 mg being the preferred oral administration and a dosage range of from about 1 mg to about 50 mg being preferred for parenteral administration. However, for any particular subject, the specific dosage regimen should be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compounds. It is to be understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of this invention.
The term dosage unit as employed throughout this specification refers to pharmaceutically discrete units suitable as unitary dosages for mammalian subjects each containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle.
The following examples are illustrative, but not 25 limitative of this invention. All temperatures given are in degrees centigrade, unless indicated otherwise.
Example 1 2-Amino-9-chloro-7-phenyl-5H-pyrimido[5,4-d] [2] benzazepine A stirred suspension of 10 g (0.032 mol) of 8-chloro-3,4-dihydro-4(dimethylaminomethylene)-l-phenyl-5H-2-benzazepin-5-one and 8.5 g (0.047 mol) of guanidine carbonate in 250 ml of methanol was treated at room temperature, under argon, with 5.1 g (0.094 mol) of sodium methylate in one portion. Methylene chloride (150 ml) was added after 10 min and stirring was continued. The same quantities of sodium methylate and guanidine carbonate were added two more times at 2 hr intervals and stirring was continued overnight. After diluting with 250 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Crystallization of the residue from ethanol gave light tan crystals: mp 209-210° C. Recrystallization of a sample from methylene chloride/ethyl acetate gave off-white prisms: mp 210-211° C.
Example 2 2-Amino-9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d] [2] benzazepine A stirred suspension of 16 g (0.047 mol) of 8-ehloro-l-(2-fluorophenyl)3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one and 12.5 g (0.07 mol) of guanidine carbonate in 460 ml of methanol was treated at room temperature, under argon, with 7.5 g (0.14 mol) of sodium methylate in one portion. Methylene chloride (290 ml) was added after 10 min. and stirring was continued. The same quantities of sodium methylate and guanidine carbonate were added two more times at 2 hr intervals and stirring was continued overnight. After diluting with 460 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Recrystallization of the residue from ethanol/methylene chloride solution gave off-white crystals: mp 245-248° C.
Dihydrochloride salt A warm solution of the above end product in 100 ml of 1:1 methanol/methylene chloride was filtered and concentrated on a steam bath to 1/2 volume. The filtrate was treated with 5 ml of 5.7 N ethanolic hydrogen chloride solution and kept at room temperature for 2 hr. The pale yellow crystals were filtered, washed with ethanol and air dried to yield the dihydrochloride salt: mp 232-237° C Example 3 9-Chloro-2-methyl-7-phenyl-5H-pyrimido[5,4-d] [2] benzazepine A suspension of L6 g (0.005 mol) of 8-ehloro-3,4-dihydro-4-(dimethylaminomethylene)-l-phenyl-5H-2-benzazepin-5-one and 0.7 g (0.0075 mol) of acetamidine hydrochloride in 50 ml of methanol was stirred at room temperature, under argon, and treated with 0.8 g (0.015 mol) of sodium methylate in one portion. After stirring for 10 min, 30 ml of methylene chloride was added and stirring was continued. Another 0.8 g (0.015 mol) of sodium methylate and 0.7 g (0.0075 mol) of acetamidine hydrochloride were added after 2 hrs. The addition of 0.015 mol of sodium methylate and 0.0075 mol of acetamidine hydrochloride was repeated after another 2 hr and stirring at room temperature was continued overnight. After diluting with 50 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Crystallization occurred when the residue was dissolved in 20 ml of warm hexane and cooled. Evaporation of the solvent gave a second crop oi product. Recrystallization from hexane (charcoal) gave offwhite crystals: mp 120-122° C.
Example 4 9-Chloro-7-(2-fluorophenyl)-2-methyl-5H-pyrimido[5,4-dl [21 benzazepine A suspension of 5.1 g (0.015 mol) of 8-chloro-l(2-fluorophenyl)-3,4-dihydro-4-/"(dimethylamino)methylenq7-5H2-benzazepin-5-one and 2.1 g (0.0225 mol) of acetamidine hydrochloride in 150 ml of methanol was stirred at room temp5 erature under argon, and treated with 2.4 g (0.045 mol) of sodium methylate in one portion. After stirring for 10 min, ml of methylene chloride was added and stirring was continued Another 2.4 g (0.045 mol) of sodium methylate and 2.1 g (0.0225 mol) of acetamidine hydrochloride were added after 2 hrs. The addition of 0.045 mol of sodium methylate and 0.0225 mol of acetamidine hydrochloride was repeated after another 2 hr interval and stirring at room temperature was continued overnight. After diluting with 150 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Recrystallization of the residue from hexane (charcoal) gave white crystals: mp 104107°C.
Example 6 2-(2-Fluorobenzoyl)-4-chlorobenzoic acid, methyl ester A solution of 2.0 g (7.19 mmoles) of /2-(2-fluorobenzoyl)-4-chlorobenzoic acid7, in 40 ml of methanol and 0.3 ml of sulfuric acid was refluxed for 10 hrs and then evaporated.
The residue was partitioned between 50 ml of dichloromethane and 30 ml of dilute ammonium hydroxide, and the organic layer was dried and evaporated. The resulting oil was dissolved in 20 ml of dichloromethane, filtered through 25 g of Florisil and eluted with dichloromethane. The solvent was evaporated and the oil was crystallized from ether and recrystallized from dichloromethane/ether/petrol to give white rods: mp 115-116°C.
Example 7 4-Chloro-2-/4-(chloromethyl)-2-(2-fluorophenyl)-1,3-dioxolan2-yl7benzoic acid methyl ester To a solution of 47 g (0.16 mol) of the end product of Example 6 in 350 ml of dry toluene was added 21.4 ml (0.18 mol) of stannic chloride, and after 5 hrs a solution of 24 ml (0.308 mol) of l-chloro-2,3-epoxypropane in 25 ml of toluene was added with stirring over a 30 min period. After 18 hrs an additional 12 ml (0.154 mol) of l-chloro-2,3-epoxypropane was added over a 15 min period.
After 4 hrs the reaction was cooled in an ice bath and made basic with concentrated ammonium hydroxide. The reaction was filtered through celite, and the celite was washed with toluene. The combined filtrates were washed with 200 ml of water, dried over sodium sulfate, and evaporated. The resulting oil was dissolved in 100 ml of dichloromethane and chromatographed through 500 g of alumina. The column was eluted with 4 1 of dichloromethane/petrol (2/1) to give an oil, which was about 90-95% pure by TLC. A sample was crystallized and recrystallized from ether/petrol to give white prisms, mp 117-122° C.
Example 8 2-[4-Chloromethyl-2-(2-fluorophenyl)-l,3-dioxolan-2-yl] - o< [(di-methylamino)15 methylene] -z? -oxo-(4-chlorophenyl)propanenitrile To 800 ml of liquid ammonia was added a small piece of sodium and a few crystals of ferric nitrate. A total of 8.7 g (0.378 mol) of sodium was added with stirring over a 30 min period, and after 15 mins a solution of 20.1 ml (0.378 mol) of acetonitrile in 70 ml of ether was added over a 15 min period. After 10 mins a solution of 56 g (0.145 mol) of the end product of Example 7 in 250 ml of ether was added over a 10 min period. The reaction was stirred for 2 hrs, and then 700 ml of ether was added. After allowing the ammonia to evaporate overnight, ice was added and the reaction was acidified with acetic acid. It was neutralized with a saturated sodium bicarbonate solution, and the water was separated and extracted again with 500 ml of ether. The combined ether layers were washed with brine (200 ml), dried over sodium sulfate and evaporated to dryness. The crude oil was dissolved in 150 ml of dichloromethane and filtered through 400 g of FlorisiL The column was eluted with L5 1 of dichloromethane to give an oil, which was about 90-95% pure by TLC.
The 48 g of the oil was refluxed and stirred for 90 mins with Ν,Νdimethylformamide dimethylacetal and the mixture was then evaporated to dryness. The residue was triturated with 300 ml of ice water, which was then decanted. The remaining oil was dissolved in 300 ml of dichloromethane, washed with 200 ml of water, and then dried over sodium sulfate. The solution was evaporated and the residue was crystallized from diehloromethane/ether to give end product. The filtrates were evaporated, dissolved in 100 ml of dichlorctnethane and filtered through 300 g of Florisil. Elution with dichlorcxnethane (400 ml) and ether (1.5 1) gave upon evaporation and then crystal 11 zation fran dichloromethane/ether end product. The filtrates contained end product as an oil which was about 85% pure hy TLC. An analytical sample was recrystallized fran the same solvents to give off-white prisms, irp 143-147°C.
Example 9 2-Amino-4-[2-[4-(chloromethyU-2-(2-fluorophenyl)-l,3-dioxolan-2-yl]-4-chlorophenyl] pyrimidine-5-carbonitrile To a solution of LO g (0.00223 mol) of the end product of Example 8 in 8 ml of dry dimethylsulfoxide was added 4 g of molecular sieves (type 5A) and 0.7 g (0.00389 mol) of guanidine carbonate. The reaction was stirred at 90-95° C for 5 hrs, cooled and 50 ml of dichloromethane was added. The solution was decanted and the solids were washed with dichloromethane and water several times. The combined solutions were separated, and the organic layer was washed with dilute brine (2x), and then dried over sodium sulfate and concentrated to a small volume. This solution was developed on 4 silica gel thick layer plates in dichloromethane/ethyl acetate (3/1). The band at Rf 0.4 was removed and crystallized and recrystallized from methanol to give offwhite prisms, mp 184-191" C.
Example 10 2-Amino-4-[2-(2-fluorobenzoyl)-4-chlorophenyl]-pyrimidine-5-cart>onitrile A solution of 0.2 g (0.448 mmoles) of the end product of Example 9 in 20 ml of methanol and 10 ml of 3N hydrochloric acid was refluxed for 20 mins and the solvent was evaporated. The residue was partitioned between 50 ml of dichloromethane and 30 ml of dilute ammonium hydroxide, and the organic layer was dried, concentrated and filtered through 15 g of Florisil. The column was eluted with 200 ml of ether which was concentrated, filtered and recrystallized from dichloromethane/ether/petrol to give white prisms, mp 153-157° C.
Example 11 2-Amino-9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-dl [2] benzazepine A solution of 50 mg (0.142 mmoles) of the end product of Example 10 in 10 ml of acetic acid was treated with 1/4 spatula of Raney nickel, and hydrogenated for 2.5 hrs. The reaction was filtered through celite, evaporated, and partitioned between 30 ml of dichloromethane and 15 ml of dilute ammonium hydroxide. The organic layer was dried with sodium sulfate, evaporated and the residue was refluxed in ethanol for 1 hr, and then evaporated to dryness. The solid was dissolved in dichloromethane and developed on a thick layer of silica gel plate in ethyl aeetate/ethanol (20/1). The band of Rf 0.3 was removed and crystallized from ether to give white prisms, mp 243-248° C, and a mixed mp of 244-248° C with authentic material obtained as in Example 2.
Example 12 2-(4-( Chloromethyl)-2-phenyl-l,3-dioxolan-2-yl] benzoic acid, methyl ester To a solution of 33 g (0.138 mol) of 2-benzoyl benzoic acid methyl ester in 200 ml of dry carbon tetrachloride was added 10.1 ml (0.13 mol) of 1-chloro3,4-epoxypropane. The reaction mixture was cooled in an ice bath and a solution of 1.5 ml (0.013 mol) of stannic chloride in 10 ml of carbon tetrachloride was added with stirring over a 20 min period. The reaction was allowed to stand over the weekend, and then the same-iquantities of l-chloro-2,3-epoxy-propane and stannic chloride were added. After 18 hours the reaction was cooled in an ice bath, and neutralized with concentrated ammonium hydroxide. The precipitate was filtered off and washed with dichloromethane and the combined filtrates were washed with 150 ml of water, dried with sodium sulfate and evaporated.
The resulting oil was dissolved in 100 ml of dichloromethane and chromatographed through 500 g of neutral alumina. Elution with 3 1 of dichloromethane gave the end product as an oil which was about 95% pure by TLC. Crystallization and recrystailization of a small sample from ether/petrol gave white rods, mp 90-91° C.
Example 13 2-[4-(Chloromethyl)-2-phenyl-l,3-dioxolan-2-yl]-o<-[(dimethylamino)methylene] -^axobenzenepropanenitrile To a stirring solution of 75 ml of liquid ammonia was added a small piece of sodium and a few crystals oi ferric nitrate. A total of L15 g (0.0502 mol) of sodium was added over a 20 min period, and after 5 mins a solution of 2.9 ml (0.050 mol) of acetonitrile in 10 ml of ether was added dropwise. A solution of 6.3 g (0.0198 mol) of the end product of Example 12 in 40 ml of ether was added dropwise, and after 2 hrs 100 ml of ether was added and the ammonia was allowed to evaporate. About 100 g of ice was added to the reaction, which was then acidified with acetic acid, followed by neutralization with a saturated solution of sodium bicarbonate. The water layer was separated and extracted once more with ether. The combined ether layers were washed with 100 ml of water, dried over sodium sulfate and evaporated. The oil was dissolved in 15 ml of dichloromethane and filtered through 100 g of Florisil. Elution with dichloromethane, and evaporation gave 2-[4-{chloromethyl)-2-phenyl-l,3-dioxo5 ian-2-yl] -/iaco-benzenepropanenitrile which was used without further purification.
A solution of 20 g (0.0585 mol) of the above propanenitrile in 75 ml of Ν,Ν-dimethylformamide dimethylacetal was refluxed and stirred for 90 mins, and evaporated to dryness. The oil was triturated with ice water which was decanted, and the residue was partitioned between 150 ml of dichloromethane and 150 ml of water. The organic layer was dried with sodium sulfate, concentrated, and filtered through 150 g of Florisil. The column was eluted with ether which was evaporated, and the resulting oil was crystallized from ethanol to give end product. A sample was recrystallized from dichloromethane/ether to give white prisms, mp 107-110" C.
Example 14 2-amino-4-(2-benzoylphenyl)pyrimidine-5-carbonitrile and Ι-οχο-3-phenyl-lHindene-2-carbonitrile To a solution of 2.0 g (0.00504 mol) of the end product of Example 13 in ml of dichloromethane was added 10 ml of methanol and 2 ml (0.0192 mol) of 9.6 N ethanolic hydrogen chloride. After 90 mins the solvent was evaporated and the oil was partitioned between 50 ml of dichloromethane and 30 ml of a saturated sodium bicarbonate solution. The organic layer was dried with sodium sulfate and evaporated. The 1.5 g of oil obtained was dissolved in 30 ml of methanol, and 1.5 g (0.00833 mol) of guanidine carbonate was added. The solution was stirred for 90 minutes and then refluxed for 2 hours. The reaction was evaporated and then partitioned between 50 ml of dichloromethane and 30 ml of dilute ammonium hydroxide. The organic layer was dried with sodium sulfate and filtered through 50 g of Florisil. The column was eluted with dichloromethane (200 ml) and then ether (300 ml). The dichloromethane fraction was evaporated, crystallized and then recrystallized from dichloromethane/petrol to give the indene as yellow rods, mp 173-175° C.
The ether fraction was evaporated and crystallized from dichlorome20 thane/petrol to give the pyrimidine mp 195-199° C. An analytical sample was recrystallized from methanol to give off-white prisms, mp 197-200° C.
Example 15 7-phenyl-5H-pyrimido[5,4-d] [2] benzazepin-2-amine A solution of 3.1 g (0.0103 mol) of the pyrimidine compound of Example in 60 ml of glacial acetic acid was treated with 1 teaspoon of Raney nickel and then hydrogenated for 8.5 hours. The reaction was filtered through celite, and evaporated. The filtrate was partitioned between 50 ml of dichloromethane and 30 ml of dilute ammonium hydroxide, and the organic layer was dried with sodium sulfate and evaporated. The resulting oil was refluxed in 75 ml of methanol for 15 minutes, evaporated and dissolved in 100 ml of dichloromethane. This was treated with 3 g of activated manganese dioxide, and then refluxed and stirred for 30 mins. The reaction was filtered, concentrated and chromatographed over 100 g of Florisil. The column was eluted with 300 ml of dichloromethane, 500 ml of ether and 1.5 1 of ethyl acetate. The ethyl acetate fraction was evaporated, and the oil was crystallized from ether and recrystallized from dichloromethane/ether to give white rods, mp 239-242" C. The filtrates and the ether fraction from the column were evaporated and developed on silica gel thick layer plates in ethyl acetate/methanol (20/1) to give additional product. An analytical sample was recrystallized from ether to give white prisms, mp 201-205’ C which reset to form rods, mp 240-243’ C.
Example 16 9-chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4-dl [2] benzazepine In five equal portions 5.5 g (58 mmole) of acetamidine hydrochloride and 15 ml (62 mmole) of a 4.12 M methanol solution of sodium methoxide was added over 3 hr. to a solution of 3.5 g (10 mmole) of 8-ehloro-l-(2-ehlorophenyl)-3,4dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one in 140 ml of methanol and 140 ml of methylene chloride. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water dried with anhydrous sodium sulfate, and concentrated at reduced pressure to give an amber oil. The amber oil was dissolved in 10 ml (10 mmole) of a 1 M methanol solution of methanesulfonic acid and the resulting salt was precipitated by the addition of ether to give yellow prisms, mp 193-197° C. Recrystallization from a mixture of methanol and ether gave yellow prisms, mp 197-198° C.
Example 17 9-ehloro-7-(2-ehlorophenyl)-5H-pyrimido[5,4-d] (2] benzazepine In five equal portions 21 g (200 mmole) of formamidine acetate and 32.5 ml (135 mmole) of a 4.12 M methanol solution of sodium methoxide was added over 3 hr to a solution of 7.2 g (20 mmole) of 8-chloro-l-(2-ehlorophenyl)-3,4dihydro-[(dimethylamino)methylene]-5H-2-benzazepin-5-one in 270 ml of methanol and 270 ml of methylene chloride. The solution was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give an amber oil. Purification by column chromatography (100 g silica gel; eluent 1:1 methylene chloride and ethyl acetate) gave end poduct mp 122-124° C. Recrystallization from ether gave pale yellow prisms, mp 122-125°C.
Example 18 9-chloro-7-(2-chlorophenyl)3-isopropyl-5H-pyrimido[5,4-d] [21 benzazepine A mixture of 3.5 g (10 mmole) of S-chloro-l-(2-chlorophenyl)-3,4-dihydro-4 [(dimethylamino)methylene]-5H-2-benzazepin-5-one, 4.8 g (40 mmole) of isobutyramidine hydrochloride, 10 ml (41 mmole) ot a 4.12 M methanol solution of sodium methoxide and 100 ml of methanol was stirred at room temperature for 2 hr. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. Crystalliza10 tion of the oil with ether gave a light yellow solid, mp 127-129° C. Recrystallization from a mixture of ether and petroleum ether gave colorless rods, mp 127-129* C.
Examples 19 2-amino-9-chloro-7-(2-chlorophenyl)-5H-pyrlmido[5,4-d][2]benzazepine In two equal portions 14.4 g (80 mmole) of guanidine carbonate and 20 ml (82 mmole) of 4.12 M methanol solution of sodium methoxide was added over 90 min to a solution of 3.6 g (10 mmole) of 8-chloro-l-(2-chlorophenyl)3,4-dihydro-4-[(dlmethylamino)methylene] -5H-2-benzazepin-5-one in 100 ml of 2c methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. Crystallization of the oil with methylene chloride gave a white solid, mp 240-241° C. Recrystallization from a mixture of ethr and methylene chloride gave colorless needles, mp 240-241° C.
Example 20 7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4-d] [2] benzazepine methanesulfonate In four equal portions 7.2 g (76 mmole) of acetamidine hydrochloride and 18 ml (80 mmole) of a 4.46 M methanol solution of sodium methoxide was added over a 3 hr period to a solution of 4.5 g (14 mmole) of l-(2-chlorophenyl)3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one in 180 ml of methanol and 180 of methylene chloride. The mixture was diluted with water, and extracted with methylene chloride. The methylene chloride solution was washed with water, dried with anhydrous sodium sulfate, and concentrated at reduced pressure to give an amber oil. The amber oil was dissolved in a mixture of 15 ml of isopropanol and 1.3 g (14 mmole) of methanesulfonic acid, and the isopropanol was removed at reduced pressure. The residue was crystallized from a mixture of ether and methylene chloride to give a ligh yellow solid, mp 147-151° C. Recrystallization from a mixture of ether and methylene chloride gave yellow prisms as the half hydrate, mp 159-160° C.
Example 21 2-methyl-7-phenyl-5H-pyrimidoI5,4-d] [2] benzazepine dihydrochloride In five equal portions 9.0 g (95 mmole) of acetamidine hydrochloride and 22.5 ml (0.1 mole) of a 4.46 M methanol solution of sodium methoxide was added over 3 hr to a solution of 4.5 g (15 mmole) of l-phenyl-3,4-dihydro-4Kdimethylamino)methylene] -5H-2-benzazepin-5-one in 180 ml of methanol and 180 ml of methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give an oil. The oil was dissolved in an excess of 6% methanolic hydrogen chloride and the solvent was removed at reduced pressure to dryness. The residue was crystallized from a mixture of ether and methylene chloride to give a white solid mp 211-221’C. Recrystallization from a mixture of methanol and ether gave white flakes, mp 217-227’ C.
Example 22 9-chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4-d1 [2] benzazepine-6oxide A solution of 2.0 g (5.6 mmole) of 9-chloro-7-(2-clilorophenyl)-2-methyl5H-pyrimido[5,4-d] [2] benzazepine and 2.2 g (10.8 mmole) of 85% meta-chloro20 perbenzoie acid in 100 ml of methylene chloride was stirred at room temperature for 21 hr. The methylene chloride solution was washed with cold dilute aqueous sodium hydroxide, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to dryness. Purification by plug filtration (silica gel, 25 g; eluent 1000 ml 1:1 ether methylene chloride) gave a colorless solid, mp 215-216’C.
Example 23 9-chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4-d]l2] benzazepine-3,6dioxide A solution of 3.8 g (10.7 mmole) of 9-chloro-7-(2-chlorophenyl)-25 methyl-5H-pyrimido[5,4-d] [2] benzazepine and 9.6 g (47 mmole) of 85% metachloroperbenzoic acid in 400 ml of methylene chloride was stirred at room temperature for 55 hr. The methylene chloride solution was washed with cold dilute aqueous sodium hydroxide, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to dryness. Purification by plug filtration (silica gel, 25 g; eluents 400 ml 1:1 ether, methylene chloride followed by 200 ml 9:1 methylene chloride, methanol) gave colorless solid, mp 241-243° C.
Example 24 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-2-methyl-5H-pyrimido[5,4-d][2]benza15 zepine dihydrochloride A mixture of 3.7 g (10.5 mmole) of 9-chloro-7-(2-chlorophenyl)-2methyl-5H-pyrimido[5,4-d] [2] benzazepine, 1.3 g of zinc dust, and 40 ml of acetic acid in 90 ml of methylene chloride was stirred at -15° C to -20° C for 30 min. The mixture was filtered over hyflo, and the filtrate was basified with cold dilute aqueous sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. The yellow oil was crystallized from an excess of 6% methanolic hydrogen chloride to give the title compound as a white solid, mp 272-274° C. Recrystallization from methanol gave colorless rods, mp 272-274° C. • 49630 A sample of the above material was partitioned between dilute aqueous sodium hydroxide and methylene chloride.
The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue crystallized from ether to give the free base as cream o colored prisms, mp 176-177 C.
Example 25 8-chloro-l- (2-chlorqghenyl)-3,4-dihydro-4-/~(dimethylamino) methylene7-5H-2-benzazepln-5-one A mixture of 18.6 g (61 mmole) of 8-chloro-3,4dihydro-1-(2-chlorophenyl)-5H-2-benzazepin-5-one and 149 ml of dimethylformamide dimethyl acetal was gently heated (ca 50°) for 12 hr. The mixture was concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of ether and methylene chloride to give the end product as a yellow solid, mp 17O-171°C. Recrystallization from ether gave yellow prisms, mp 17O-171°C. t 49630 Example 26 l-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one A mixture of 3.4 g (12.5 mmole) of l-(2-chlorophenyl)-3,4-dihydro-5H-25 benzazepin-5-one and 28 ml of dimethylformamide dimethyl acetal was refluxed for 2 hr. The mixture was concentrated at reduced pressure and the resulting solid was triturated with ether to give a tan solid, mp 155-157° C. Recrystallization from a mixture of methylene chloride and ether gave yellow prisms, mp 158-159 °C.
Example 27 - 3,4-Dihydro-l-phenyl-4-[(dimethylamino)methylenel-5H-2-benzazepin-5-one A mixture of 5.2 g (22 mmole) of 3,4-dihydro-l-phenyl-5H-2-benzazepin5-one and 43 ml of dimethylformamide dimethyl acetal was refluxed for 4 hr.
The mixture was concentrated at reduced pressure to dryness. The residue was crystallized with ether to give a yellow solid, mp 131-133° C. Recrystallization from ether gave yellow prisms, mp 131-132° C. • 49630 Example 28 9-chloro-7-(2-chlorophenyl)-2-(methylthio)-5H-pyrimido[5,4-d] [2] benzazepine A mixture of Ll g (3.0 mmole) of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2] benzazepin-2-thiol, 1.0 ml (10 mmole) of dimethyl sulfate, 20 ml of IN sodium hydroxide and 10 ml of ethanol was stirred at room temperature for 15 min. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give an oiL Crystallization from ether gave colorless prisms, mp 187-188" C.
Example 29 9-chloro-7-(2-chlorophenyl)-2-(methylthio)-5H-pyrimido[5,4- The methanesulfonate salt of 9-chloro-7-{2-chlorophenyl)-2-(methyl15 thio)-5H-pyrimido(5,4-d] [2] benzazepine was prepared by the addition of equimolar amounts of the above compound and methanesulfonic acid to methanol and by precipitating the resulting salt by the addition of ether. Recrystailization from ethanol gave cream colored needles, mp 105-166" C. . 49θ30 Example 30 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d3 [2] benzazepine-2-thiol A mixture of 2.8 g (7.8 mmole) of 8-chloro-l-(2-chlorophenyl)-3,4dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5~one, 2.8 g (37 5 mmole) of thiourea, and 8.0 ml (32 mmole) of a 4.0 M methanol solution of sodium methoxide in 80 ml of methanol was stirred at room temperature for 18 hr. The mixture was diluted with water and extracted with ether. The aqueous layer was neutralized with acetic acid and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow solid, mp 238239° C. Recrystallization from tetrahydrofuran gave yellow crystals, mp 232234° C.
Example 31 Preparation of 9-chloro-7-(2-fluorophenyl)-5H-pyrimiclo[5,4-tl] [2] benzazepin2-ol A solution of 1.2 g (0.00354 mol) of 9-ehloro-7-(2-fluorophenyl)-2-amino-5H5 pyrimido[5,4-d] [2] benzazepine in 20 ml of concentrated sulfuric acid and 20 ml of water was refluxed for 12 hr, and then cooled. After the addition of ice, the reaction mixture was basified with ammonium hydroxide and extracted with 100 ml of dichloromethane. The solids were collected by filtration and recyrstallized from dichloromethane/methanol to give the end product as white prisms, mp 297-299° dec. The dichloromethane extract was dried, evaporated and the residue crystallized from dichloromethane/methanol to give additional product.
Example 32 Preparation of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrlmido[5,4-d] [21 benzaze15 pine A solution of 1.0 g (0.00294 mol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d] [2] benzazepin-2-ol in 5 ml of phosphorous oxychloride was heated on the steam bath for 4 hr, and evaporated to dryness. The solid was crystallized from dichloromethane/ether, and the precipitate was partitioned between 50 ml of dichloromethane and 40 ml of saturated solution of sodium bicarbonate. The organic layer was dried, evaporated and crystallized from ether. Recrystallization from dichloromethane/ether gave the end product as offwhite prisms, mp 157-160*. . 49630 Example 33 Preparation of 9-chloro-N-methyl-7-(2-fluorophenyl)-5H-pyrimido[5,4-d] [2] benzazepine-2-amine A solution of 1 g (0.00279 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H5 pyrimido[5,4-d] [2] benzazepine in 4 ml of Ν,Ν-dimethylformamide was cooled in an ice bath and saturated with methylamine. After 64 hr at room temperature, 50 ml of ice water was added and the reaction was filtered. The precipitate was partitioned between 50 ml of dichloromethane and 50 ml of water, and the organic layer was washed with 25 ml of brine solution, dried and evaporated to dryness. The oil was crystallized from ether and then reerystallized from diehloromethane/ether and then from methanol to give the end product as white prisms, mp 172-179°.
Example 34 Preparation of 9-chloro-N,N-dimethyl-7-(2-fluorophenyl)-5H-pyrimido[5,4-d] 15 [2] benzazepin-2-amine A solution of 4.0 g (0.0112 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5Hpyrimido[5,4-d] [2] benzazepine in 15 ml of Ν,Ν-dimethylformamide was cooled in an ice bath and saturated with dim ethylamine. After 18 hr at room temperature, 80 ml of ice water was added and the precipitate was collected by filtration and reerystallized twice from methanol to give the end produet as white rods, mp 175-179°.
Example 35 Preparation of 9-chIoro-7-(2-fIuorophenyl)-N-(3-N,N-dimethylaminopropyl)5H-pyrimido[5,4-d] [2] benzazepin-2-amine To 3.5 g (0.00978 mol) of 2,9-diehloro-7-(2-fluorophenyl)-5H-pyrimido[5,45 d] [2] benzazepine in 7 ml of Ν,Ν-dimethylformamide was added 2.7 ml (0.0215 mol) of 3-dimethylaminopropylamine while cooling the reaction in an ice bath. After 66 hr at room temperature 50 ml of ice water was added and the reaction was filtered. The precipitate was dissolved in 50 ml of dichloromethane, washed with 40 ml of water, and evaporated. The oil was dissolved in dilute hydrochloric acid and brought to pH 2 with ammonium hydroxide. The acidic solution was extracted with dichloromethane (2x50 ml), and the acid layer was then made basic with ammonium hydroxide and extracted with 75 ml of dichloromethane which was dried and and evaporated. The residue was crystallized and recrystallized from ether/petrol to give white needles, mp 9015 101°.
Example 36 Preparation of 9-chloro-2-methoxy-7-(2-fluorophenyl)-5H-pyrimido[5>4-d] [2] benzazepine To 25 ml of methanol was added 1.0 g (0.00279 mol) of 2,9-dichloro-7-{220 fluorophenyl)-5H-pyrimido[5,4-d] [2] benzazepine and 0.18 g (0.00335 mol) of sodium methoxide. The reaction was stirred for 18 hr, and evaporated to dryness. The solid was dissolved in 50 ml of dichloromethane and washed with 40 ml of water, dried and evaporated to dryness. The oil was crystallized and recrystallized from ether/petrol and then from ether to give the end product as white prisms, mp 137-141°.
Example 37 9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d] [2] benzazepine A mixture of 34.2 g (0.1 mole) of 8-chloro-3,4-dihydro-l-(2-fluorophenyl)4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one, 62.4 g (0.6 mole) of formamidine acetate, and 35 g (0.63 mole) of sodium methoxide in 700 ml of methanol was stirred at room temperature for 3 hr, while bubbling nitrogen through the solution. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a red oil. The oil was suspended in boiling hexane and the hexane solution decanted. Upon cooling the end product was collected by filtration. Recrystallization from cyclohexane gave off-white crystals, mp 123-125° C.
Example 38 9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-dl [2] -benzazepine-6-oxide A solution of 3.2 g (10 mmoles) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido~ [5,4-d] [2] benzazepine, 3 g (15 mmoles) of 85% m-chloroperbenzoic acid in 100 ml of methylene chloride was stirred at room temperature for 4 hours. The reaction mixture was washed with an excess of ice cold dilute sodium hydroxide, dried over anhydrous sodium sulfate and filtered over hyflo. The filtrate was concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of methylene chloride and ether to give the crude product, m.p. 185-186° C. Recrystallization from a mixture of methylene chloride and ether gave the pure product, m.p. 187-188° C.
Example 39 9-Chloro-7-(2-fluorophenyl)-5H-pyrlmido/5,4-37/27 benzazepin5-ol acetate A mixture of 2.5 g (7.4 mmoles) of 9-chloro-7-(25 fluorophenyl)-5H-pyrimido-/5,4-d7/2ybenzazepine-6-oxide and 50 ml of acetic anhydride was heated on the steambath for 24 hours. The reaction mixture was concentrated at reduced pressure to dryness and the residue was crystallized from a mixture of methylene chloride and ether to give the crude product, m.p. 197-198°C. Recrystailization from a mixture of methylene chloride and ether gave the pure product as cream colored prisms, m.p. 2OO-2O1°C.
Example 41 2-Amino-9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d] [2] benzazepine-6oxide In two equal portions 28 g (150 mmole) of guanidine carbonate and 38 ml (150 mmole) of a 4.09 M methanol solution of sodium methoxide was added over a 2 hr period to a solution of 7.0 g (20 mmole) of 8-ehloro-l-(2-fluorophenyl)3,4-dihydro-4-[(dimethylamino)methylene] -5H-2-benzazepin-5-one-2-oxide in 210 ml of methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a red solid. Recrystallization from a mixture of methanol and ethyl acetate gave the product as fine yellow needles, m.p. 320-323° C.
Example 42 9-Chloro-7-(2-chlorophenyl)-6,7-dihydro-2,6-dimethyl-5H-pyrimido[5,4-d]15 [2] benzazepine A mixture of 4 g (11 mmole) of 9-chloro-7-(2-ehlorophenyl)-6,7-dihydro-2methyl-5H-pyrimido[5,4-d] [2] benzazepine 2 ml of 88% formic acid and 2 ml of 37.5% formaldehyde solution was heated on the steambath for 3 hours. The reaction mixture was poured into an excess of dilute ice cold sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give the crude product, m.p. 155-156° C. Recrystallization from ether gave the pure product as colorless prisms, m.p. 156-157’ C. 9 6 3 Ο Example 43 8-Chloro-l-(2-fluoropheny 1)-3,4-dihydro-4-[(diniethyIamino)methylene] -5 H2-benzazepin-5-one Method A. A mixture of 7.2 g (25 mmole) of 8-chloro-l-(25 fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one and 50 ml of dimethylformamide dimethyl acetal was refluxed for 1 hr. The mixture was concentrated at reduced pressure to give tan crystals. Recrystallization from ether gave yellow prisms, mp 228-233° C.
Method B. A mixture of 10 g (35 mmole) of crude 8-chloro-3,4-dihydro10 l-(2-fluorophenyl)-5H-2-benzazepin-5-one and 10 g (84 mmole) of dimethylformamide dimethyl acetal in 10 ml of dimethylformamide was stirred at room temperature for 12 hr. The resulting precipitate was collected by filtration, and washed successively with ethanol and ether to give tan crystals which were identical in every respect to an authentic sample.
Example 44 8-Chloro-l-phenyl-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin5-one The preparation of 8-chIoro-I-phenyl-3,4-dihydro-4-[(dimethylamino)methylenel-5H-2-benzazepin-5-one was conducted in the same manner as the preparation of 8-chloro-l-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene] -5H-2-benzazepin-5-one (Method A) to give yellow prisms, mp 180— 183’C.
Example 45 8-C hloro-l-(2-fIuoropheny 1)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide A mixture of 6.4 g (22 mmole) of 8-chloro-I-(2-fIuorophenyI)-3,4dihydro-5H-2-benzazepin-5-one and 6.4 g (34 mmole) of m-ehloroperbenzoic acid in 350 ml of methylene chloride v/as stirred at room temperature for 2 hr. The methylene chloride solution was washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. The oil was crystallized from a mixture of ether and petroleum ether to give off-white prisms, mp 166-168° C.
Recrystallization from a mixture of ether and methylene chloride gave colorless prisms, mp 168-170’C.
Example 46 8-Chloro-l-(2-chlorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide The preparation of 8-chloro-l-(2-chlorophenyl)-3,4-dihydro-5H-2-benza15 zepin-5-one-2-oxide was conducted in the same manner as the preparation of 8chloro-l-(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide to give yellow prisms, mp 184-187° C.
Example 47 8-Chloro-l-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H20 2-benzazepin-5-one-2-oxide A mixture of 3.4 g (11 mmole) of 8-chloro-l-(2-fluorophenyl)-3,4-dihydro5H-2-benzazepin-5-one-2-oxide and 26 ml of dimethylformamide dimethyl acetal was stirred at room temperature for 12 hr. The mixture was diluted with ether and the precipitate collected to give a yellow solid, mp 175-178° C.
Recrystallization from a mixture of ether and ethyl acetate gave yellow needles, mp 193-194° C.
Example 48 8-Chloro-l-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H2-benzazepin-5-one-2-oxide The preparation of 8-ehloro-l-(2-chlorophenyl)-3,4-dihydro-4-Kdimethyl5 amino)methylene]-5H-2-benzazepin-5-one-2-oxide was prepared in the same manner as the preparation of 8-chloro-l-{2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene] -5H-2-benzazepin-5-one-2-oxide to give yellow prisms, mp 196-198° C.
Example 49 9-Chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4d][2]-benzazeplne-6-oxlde A mixture of 1 g (2.8 mmole) of 8-chloro-1-(2-chlorophenyl )-4-[(dimethylamino)methylene]-3,4-dihydro-5H2-benzazepine-5-one-2-oxide, 1.0 g (11 mmole) of acetamidine hydrochloride and 2.0 ml (9.9 mmole) of a 4.46M methanol sulution of sodium methoxide in a mixture of 20 ml of methanol and 20 ml of methylene chloride was stirred at room temperature for 2 hr. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Recrystailization of the residue from a mixture of ether and methylene chloride gave a colorless solid, mp 215-216°C.
Example 50 9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-5-ol A solution of 3.7 g (9-7 mmole) of 9-chloro-7-(2fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-5-ol, acetate in a mixture of 25 ml of tetrahydrofuran, 50 ml of methanol and 2 ml of 3N sodium hydroxide was stirred at room temperature for 0.5 hr. The reaction mixture was poured into ice water and extracted with methylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue crystallized from a mixture of methylene chloride and ether to give a crude product melting at 186-188°C. Recrystailization from a mixture of ether and methylene chloride gave the product as cream colored prisms, mp 196-198°C. 9 6 3 0 Example 51 9-Chloro-7-(2-ohlorophenyl)-5H-pyrimido[5,4-d][2]benzazeplne-6-oxide A solution of 6.8 g (20 mmole) of 9-chloro-7-(25 chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine, 6 g (30 mmole) of 85% m-chloroperbenzoic acid in 200 ml of methylene chloride was stirred at room temperature for 4 hrs. The mixture was washed with an excess of ice cold dilute sodium hydroxide, dried over ahydrous sodium sulfate and filtered over hyflo. The filtrate was concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of methylene chloride and ether to give a crude product, mp 228-229°C. Recrystallization from a mixture of methylene chloride and ether gave the product, mp 216-217°C.
Example 52 9-Chloro-7-(2-chlorophenyl)-5H-pyrlmido[5,4-d][2]benzazepln-5-ol acetate A mixture of 3 g (8 mmole) of 9-chloro-7-(2-chloro20 phenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide and 50 ml of aoetio anhydride was heated on the steam bath for 22 hrs. The reaction mixture was concentrated at reduced pressure to dryness and the residue was crystallized from a mixture of methylene chloride and ether to give a pro25 duct of mp 211-212°C. Recrystallization from a mixture of methylene chloride and ether gave the pure product as colorless prisms, mp 211-212°C.
Example 53 9-Chloro-7-(2-chlorophenyl)-5H-pyrimldo[5,4-d][2]benzazepln-5-ol A solution of 4.8 g (12 mmole) of 8-ohloro-7-(25 chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-5-ol acetate in a mixture of 50 ml of tetrahydrofuran, 50 ml of methanol and 4 ml of 3N sodium hydroxide was stirred at room temperature for 30 min. The reaction mixture was poured into ice water and extracted with methylene chlo10 ride. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of methylene chloride and ether to give a product of mp 105-117°C. Recrystallization from a mixture of methylene chloride and acetone gave the pure product as colorless prisms, mp 174-175°C.
Example 54 9-Chloro-7-(2-fluorophenyl)-2-(4-methyl-1-plperazinyl)5H-pyrimido[5,4-d][2]benzazepine hydrochloride 2o To a solution of 3.0 g (0.00838 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2Ibenzazepine in 8 ml of Ν,Ν-dimethylformamide was added 2 g (0.02 mol) of N-methylpiperazine. After 20 hr ice water (40 ml) was added to the reaction which was then filtered. The so25 lid was partitioned between 50 ml of dichloromethane and 50 ml of 1N hydrochloric acid, and the pH was adjusted to 1-2 with ammonium hydroxide. The resulting precipitate was filtered and recrystallized twice from methanol to give white prisms, mp 187-194°C. The acid layer was made basic with ammonium hydroxide, and extracted with 100 ml of dichloromethane which was dried and evaporated. The oil was acidified with 1N hydrochloric acid, adjusted to pH 1-2 with ammonium hydroxide, cooled and filtered. The precipitate wae recrystallized from methanol to give a further crop of the product.
Example 55 9-Chloro-2-methoxy-7-(2-fluorophenyl)-5H-pyrlmldo[5,4di [2 Ibenzazeplne To 25 ml of methanol was added 1.0 g (0.00279 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimidot5,4-d ] [2]benzazepine and 0.18 g (0.00335 mol) of sodium methoxide. The reaction was stirred for 18 hr, and evaporated to dryness. The solid was dissolved in 50 ml of dichloromethane and washed with 40 ml of water, dried and evaporated to dryness. The oil was crystallized and recrystallized from ether/petrol and then from ether to give white prisms, mp 137-141°C.
Example 56 9-Chloro-7-(2-fluorophenyl)-5H-pyr imido[5,4-d][2]benzazepine-2-aoetlc acid ethyl ester To 20 ml of diethylmalonate was added 1.9 g (16.8 mmol) of potassium tertiary butoxide with stirring under nitrogen, and after 15 min, 2.0 g (5.59 mmol) of 2,9dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine was added. The reaction was kept at 110°C for 2 hr and 14O°C for 4 hr. Ice was added to the reaction mixture which was then acidified with concentrated hydrochloric acid, and extracted with 100 ml of ether. The ether layer was extracted with 25 ml of 3N hydrochloric acid, and the combined acid layers were made basic with ammonium hydroxide and extracted with ether (2x100 ml). The solution was dried, ehareoal filtered and concentrated to a small volume. Petroleum ether was added and the product was filtered and reerystallized from the same solvents to give white rods, mp 98-103°C.
Example 57 9-Chloro-7-(2-fluorophenyl)-5H-pyrImido[5,4-d1C 2]benza5 zepine-2-aoetio acid A solution of 4.0 g (9.76 mmol) of 9-chloro-7-(2fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-aeetic acid ethyl ester in 30 ml of ethanol and 25 ml of 1N sodium hydroxide was heated on the steam bath for 3 hr.
The mixture was partitioned between 75 ml of water and 75 ml of ether. The basic layer was acidified with acetic acid and extracted with dichloromethane (2x100 ml), which was dried and evaporated. The resulting oil was crystallized from methanol and reerystallized from di15 chloromethane/ether/petroleum ether to give off-white prisms, mp 138-14O°C.
Example 58 9-Chloro-7-(2-fluorophenyl)-N-methyl-5H-pyrimldot 5.4d][2]benzazepine-2-acetamide Methylamine was bubbled into a solution of 2.6 g (6.34 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4 d][2]benzazepine-2-acetic acid ethylester in 60 ml of ethanol for 10 min. After standing for 18 hr, the reaction was evaporated and the residue was partitioned bet25 ween 75 ml of dichloromethane and 50 ml of water. The organic layer was dried and evaporated. The residue was crystallized and then reerystallized from dichloromethane/ether to give white rods, mp 175-177°C.
Example 59 9-Chloro-7-(2-ohlorophenyl)-5H-pyrimido-[ 5,4-d][2]benzazepine A mixture of 90.5 g (0.25 mol) of 8-chloro-1-(25 chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]5H-2-benzazepine-5-one, 100 g (0.96 mol) of formamidine acetate and 1.0 L of formamide was heated on a steam bath for 16 hr. The mixture was cooled to 0° and the resulting precipitate collected by filtration. The precipi10 tate was washed with water and dried to constant weight to give off-white crystals, mp 120-121 °C.
Example 60 9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2Ibenzazeplne-6-oxlde A mixture of 0.4 g (1.1 mmol) of 8-chloro-1-(2-fluorophenyl)-3,4-d ihydro-4-[(dimethylamino)methylene]-5H2-benzazepin-5-cne-2-axider 1.0 g (9.6 nmol) of foxtnamicline acetate and 20 ml of formamide was heated on a steam bath for 6 hr. The mixture was poured over ice and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue crystallized with the addition of a mixture of ether and methylene chloride to give off-white crystals, mp 186-188°C.
Example 61 9-Chloro-7-(2-chlorophenyl)-5H-pyrimido[5l4-d][2]benzazeplne-6-oxide A mixture of 0.4 g (1.1 mmol) of 8-chloro-1-(2-chloro5 phenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2benzazepin-5-one-2-oxi<3e and'HO g (9.6 nmol) of fomamidine acetate in 20 ml of formamide was heated on a steam bath for 7 hr. The mixture was poured over ice and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was triturated with ether to give an off-white solid, mp 215-217°C.
Example 62 9-Chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]-benzazepine A mixture of 0.5 g (1.3 mmol) of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide and 1.0 ml (10 mmol) of phosphorous trichloride in 20 ml of methylene chloride was refluxed for 3 hr. The mixture was cooled, poured over ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pres25 sure. The residue crystallized upon the addition of ether to give colorless prisms, mp 121-123°C.
Example 63 9-Chloro-7-(2-fluorophenyl)-5H-pyrlmldo[5,4-dK23benzazepine A mixture of 0.5 g (1.5 mmol) of 9-chloro-7-(2-fluo5 rophenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide, and 1.0 ml (10 mmol) of phosphorous trichloride in 20 ml of methylene chloride was heated at reflux for 2 hr. The mixture was poured over ioe, basified with ammonium hydroxide and extracted with methylene chloride. The methy10 lene chloride solution was dried over anhydrous sodium sulfate and eoneentrated at reduced pressure to dryness. The residue was crystallized from ether to give off-white crystals, mp 122-124°C.
Example 64 9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][23benzazeplne-2-thiol-6-oxide A mixture of 1.5 g (4 mmol) of 8-chloro-1-(2-fluorophenyl )-3,4-dihydro-4-[(dimethylaminoJmethylene]—5H— 2-benzazepin-5-one-2-oxide, 1.5 g (20 mmol) of thiourea and 5 ml of a 4M methanol solution of sodium methoxide in 30 ml of methanol was stirred at room temperature for 5 hr. The mixture was poured into water and extracted with ether. The aqueous solution was acidified with acetic acid and extracted with methylene chloride. The methy25 lene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was triturated with methylene chloride to give an orange solid. Recrystallization from methylene chloride gave the product as orange crystals, mp 323-325°C (dec.).
Example 65 9-Chloro-7-(2-ohlorophenyl)-6,7-dlhydro-5H-pyrimido[5,4d][2]benzazepine A mixture of 68 g (0.2 mol) of 9-chloro-7-(2-chloro5 phenyl)-5H-pyrimido[5,4-d][2]benzazepine, 27 g of zinc dust and 250 ml of acetic acid in 600 ml of methylene chloride was stirred at -30°C for 2 hr. The mixture was filtered over hyflo into a stirred mixture of 600 ml of concentrated ammonium hydroxide and 500 ml of ice. The 10 methylene chloride solution was separated, dried over anhydrous sodium sulfate and concentrated at reduced pres sure. The residue crystallized from a mixture of methy.· lene chloride and ether to give the product as a colorless solid. Recrystallization from a mixture of ether and methylene chloride gave the product as colorless need les, mp 169-17O°C.
Example 66 9-Chloro-7-(2-chlorophenyl)-6,7-dihydro-6-[(4-methylphenyl ) sulfonyl]-5H-pyrimido[5.4-d][2Ibenzazeplne A solution of 14.5 g (42 mmole) of 9-chloro-7-(2chloropheny1)-6,7-d ihydro-5H-pyr imido[5,4-d][2]benzazepine, 14.5 g (76 mmols) of p-toluene-sulfonyl chloride, ml of pyridine and 0.3 g of 4-dimethylaminopyridine in 300 ml of methylene chloride was stirred at room tempe rature for 24 hr. The mixture was washed with an excess of dilute ice cold hydrochloric acid and dilute aqueous sodium hydroxide. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue crystallized from a mixture of methylene chloride and ether to give the product as a white solid, mp 200-201 °C. Recrystallization from a mixture of ether and methylene chloride gave the pure product as colorless prisms, mp 200-201°C.
Example 67 9-Chloro-7-(2-chlorophenyl)-6,7-dlhydro-6-(trifluoroacetyl)-5H-pyrimido[5,4-d][2Ibenzazepine Dropwise 5.0 ml (35 mmol) of trifluoroacetic anhydride was added to a solution of 6.4 g (19 mmol) of 9chlor0-7-(2-chlorophenyl)-6,7-dihydro-5H-pyrimido[5,4d)[2]benzazepine and 10 ml (12.8 mmol) of pyridine in 75 ml of methylene chloride which was cooled to 0°C. After stirring for 1 hr, the mixture was poured into ice cold dilute hydrochloric acid. The methylene chloride solution was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was crystallized from ether to give the product as pink crystals, mp 178-179°C. Recrystailization from ether gave the product as off-white crystals, mp 179-18O°C.
Example 68 9-Chloro-7-(2-chlorophenyl)-6,7-dihydro-6-[(4-methylphenyl) sulfonyl ]-5H-pyrimldo[5,4-d][2]benzazeplne-3-oxide A solution of 7.6 g (15 mmol) of 9-chloro-7-(2-chlorophenyl )-6,7-dihydro-6-[(4-methylphenyl) sulfonyl]-5Hpyrimido[5,4-d][2]benzazepine and 4.0 g (20 mmol) of mchloroperbenzoic acid in 300 ml of methylene chloride was stirred at room temperature for 48 hr. The mixture was washed with cold dilute sodium hydroxide and saturated aqueous sodium chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue (8.2 g) was purified by column chromatography (silica gel, 20 g; eluents, methylene chloride then ethyl ace76 tate) the methylene chloride eluent gave 2.0 g of the starting material as a colorless solid. The ethyl acetate eluent gave 2.1 g of the product as an off-white solid, mp, 242-243°C, Recrystallization from a mixture of ether and methylene chloride gave the product as colorless crystals, mp 243-244°C.
Example 69 9-Chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-3-oxide Method A. A mixture of 2.0 g (3.9 mmol) of 9-chloro7-(2-chlorophenyl)-6,7-dihydro-6-[(4-methylphenyl)sulfo15 nyl]-5H-pyrimido[5,4-d][2]benzazepine-3-oxide and 8 ml of a 4M methanol solution of sodium methoxide in a mixture of 130 ml of tetrahydrofuran and 180 ml of methanol was stirred at room temperature for 19 hr. The mixture was poured into an ice oold sodium chloride solu20 tion and extracted with methylene chloride. The methylene chloride solution was washed with aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was purified by column chromatography (silica gel, 20 g; eluents 20? ether in methylene chloride then 10? methanol in methylene chloride) to give the product in the 10? methanol in methylene chloride eluent as a white solid. Recrystallization from a mixture of methylene chloride and ether gave the product as long colorless prisms, mp 189-19O°C.
Method B. A mixture of 1.5 g (4.3 mmol) of 9-chloro7-(2-chlorophenyl)-6,7-dihydro-5H-pyrimido[5,4-d][2]benza zepine-3-oxide, and 6 ml of a 5? methylene chloride solution of bromine in 600 ml of methylene chloride was stir35 red at room temperature for 30 min. The mixture was basified with the addition of 4.5 ml (32 mmol) of triethylamine and stirred for 10 min. The mixture was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was purified by column chromatography (silica gel, 50 g; eluents methylene chloride then ethyl acetate then 30Ϊ tetrahydrofuran in methylene chloride). The ethyl acetate eluent contained a colorless solid, mp 242-244°C which was identified as a compound isomeric about the imine bond with the product. The 30< tetrahydrofuran in methylene chloride eluent contained the product as co10 lorless prisms, mp 189-190%.
Example 70 9-Chloro-7-(2-chlorophenyl)-6.7-dihydro-6-(trifluoroaoe15 tyl)-5H-pyrimido[5.4-d H 2lbenzazeplne-3-oxtde The preparation of 9-ohloro-7-(2-chlorophenyl)-6,7dihydro-6-(trifluoroaoetyl)-5H-pyrimido[5,4-d][2Jbenzazepine-3-oxide was conducted in the same manner as the preparation of 9-chloro-7-(2-chlorophenyl-6,7-dihydro6- [ (4-methylphenyl)sulfonyl]-5H-pyrimido[5,4-d][2]benzazepine-3-oxide to give the product as colorless crystals, mp 209-211 °C.
Example 71 9-Chloro-7-(2-chlorophenyl)-6,7-dihydro-5H-pyrlmidot5,4d][2]benzazeplne-3-oxlde A mixture of 4.9 g (11 mmol) of 9-ohloro-7-(2-chlorophenyl)-6,7-d ihydro-6-(tri fluoroaoetyl)-5H-pyrimi do[5,4d][2]benzazepine-3-oxide, 50 ml of 3N aqueous sodium hydroxide, 100 ml of ethanol and 100 ml of tetrahydrofuran was stirred at room temperature for 30 min. The mixture was concentrated at reduced pressure to a small volume.
The resulting precipitate was collected by filtration to give a colorless solid, mp 259-26O°C. Recrystallization from tetrahydrofuran gave the product as eolorless crystals, sp 263"264°6i gxaapl.e^A TABLET FORMULATION (Wot granulation) Item Ingredients. sig/tablet aig/tablet ag/b,ablsb ag/tablst 1. 2-arnine-9chloro-7‘-(2fluorophenyl)5H=pyriaido[g, 4» io d)[2jbenzazepine or g 10 §5 7-phenyi-gH-pyriaidoi g,4-djbenaazepin-2-afflifie 1’ 2. Laetese 201 3· Modified Stareh 25 4. Pregeiatinlaed 20 Stareh g. Distilled - ?o water cjiS. 6. Magnesium Stearate 250 ag Weight of tablet 232 251 230 35 45 55 25 30 35 a B „4 --5 300 ag 350 mg 400 Procedure: 1. Mix Items 1-4 in a suitable mixer. 2. Granulate with sufficient distilled water to proper consistency. Mill. 3. Dry in a suitable oven. 4. Mill and mix with magnesium stearate for 3 minutes.
. Compress on a suitable press equipped with appropriate punches.
Example B io TABLET FORMULATION (Direct compression) Item Ingredients mg/tablet mg/tablet mg/tablet mg/tablet 1. 2-amino-9- chloro-7-(2fluorophenyl)5H-pyrimido[5,4d][2]benzazepine 1 or 7-phenyl-5H-pyri- mido[5,4-dIbenzazepine-2-amine 2. Lactose 221 3. Avicel 45 4. Direct Compression Starch 30 5. Magnesium Stearate _2 25 217 212 181 45 45 55 30 30 35 4 Weight of tablet 300 mg 300 mg 300 mg 300 mg 630 Procedure: 1. Mix Item 1 with an equal amount of lactose. Mix well. 2. Mix with items 3, and 4, and the remaining amount of Item 2. Mix well. 3. Add magnesium stearate and mix for 3 minutes. 4. Compress on a suitable press equipped with appropriate punches.
Example C CAPSULE FORMULATION Item Ingredients mg/tablet mg/tablet mg/tablet mg/tablet 1. 2-amino-9- 1 chloro-7-(2fluorophenyl)5H-pyrimido[5,415 d][2]benzazepine or 7-phenyl-5H-pyrimido[5,4-d]benzazepine-2-amine 2. Lactose 203 3- Starch 30 4. Talc 15 5. Aerosol OT 1 Capsule fill weight 250 10 25 293.5 328- 372.5 35 40 30 15 20 20 1.5 2 2.5 350 mg 400 mg 450 mg * 49630 Procedure; 1. Mill Items 1, 2, 3, and 5 in a suitable mixer. Mill. 2. Add talc and mix well. 3. Encapsulate on suitable equipment.
Claims (10)
1. Pyrimido-2-benzazepines of the general formula wherein A is one of the groups R^ is hydrogen, chlorine, bromine, lower alkyl,
2. Compounds as claimed in Claim 1 wherein A is group (b), R 1 is amino, n is 0, X is hydrogen, halogen having an atomic number not greater than 35 or trifluoromethyl and Y is hydrogen or halogen having an atomic number
3. Compounds as claimed in Claim 1 wherein R^ is hydrogen, chlorine, bromine, lower alkyl, the group Nr8r9 (wherein R® and R^ each are hydrogen or lower alkyl), 7 7 the group -CH 2 -C0-R (wherein R' is lower alkoxy), dialkyl10 aminoalkylamino, hydroxy, lower alkoxy, mercapto or lower alkyl mercapto, with the proviso that (i) when A is group (b), (c) or (d) or when o A is group (a) and R J is lower acyloxy or hydroxy, then R^ is hydrogen, lower alkyl 8 9 15 or NR°R , (ii) when nisi, then A is group (b); and (iii) when A is group (b), R 1 is amino and Y is hydrogen or halogen having an atomic number not greater than 35, then X is other than 20 hydrogen, halogen having an atomic number not greater than 35 or trifluoromethyl 4. 9 6 3 0 wherein X and- Y are as defined in Claim 1, T ft R 1 is hydrogen, lower alkyl, lower alkoxy, chlorine, bromine or the group -CHg-CO-R (wherein R? is as defined in Claim 1) and 4 5 ' mercapto or lower alkyl mercapto and R , R , 7 8 Q R , R and R are as defined in Claim 1, or (p) removing the elements of H-Z from a compound of the general formula 4 5 7 alkyl and S , R and R are as defined in Claim 1, with a lower acylating agent or (n) hydrolyzing a compound of the general formula wherein Y is as defined in Claim 1, 4 9 6 3 0 wherein X and Y are as defined in Claim 1, p is as above and R represents chlorine or bromine, with hydrogen sulfide, with a lower alkylmercaptan, with 4 5 (wherein R and R each are hydrogen or lower alkyl). 4 5
4. Compounds as claimed in Claim 1 wherein A is group (a) and n is 0. 4 5 7 the group NR R , the group -Ci^-CO-R , 5. 12 to 15. 24. A medicament containing 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine or a pharmaceutically acceptable acid addition salt thereof. 25. An anxiolytic and sedative agent containing 10 9-ohloro-7-(2-chlorophenyl)-5H-pyrimldo[5,4-d][2]benzazepine or a pharmaceutically acceptable acid addition salt thereof. 100 26. The use of compounds as claimed in any one of Claims 1 to 10 and 12 to 15 in the control or prevention of illnesses in a non-human animal. 27. The use of compounds as claimed in any one 5 of Claims 1 to 10 and 12 to 15 in the control or prevention of anxiety and excitation in a non-human animal 28. The use of 9-chloro-7-(2-chlorophenyl)-5Hpyrimido[5,4—d][2]benzazepine or of pharmaceutically acceptable acid addition salts thereof in the control 10 or prevention of illnesses in a non-human animal. 29. The use of 9-ohloro-7-(2-chlorophenyl)-5Hpyrimidof5,4-d][2]benzazepine or of pharmaceutically acceptable acid addition salts thereof in the control or prevention of anxiety and excitation in a non-human animal. 101 30. Compounds as claimed in any one of Claims 1 to 10 and 12 to 15, whenever prepared according to the process claimed in Claim 20 or by an obvious chemical equivalent thereof. 5 31. 9-Chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine, whenever prepared according to the process claimed in Claim 21 or by an obvious chemical equivalent thereof. 32. Compounds of the general formula I given in 5 Z represents hydrogen or an easily cleavable acyl group, or (q) converting a compound of formula I as defined 10 in Claim 1 into a pharmaceutically acceptable acid addition salt. 21. A process as claimed in Claim 20 wherein 9-chlor0-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2 J benzazepine is prepared. 22. A medicament containing a compound as claimed in any one of Claims 1 to 10 and 12 to 15. 23. An anxiolytic and sedative agent containing a compound as claimed in any one of Claims 1 to 10 and 5 or (nt) reacting a compound of the general formula r 16 wherein Y is as defined in Claim 1, R^6 is hydrogen, chlorine, bromine, lower alkyl, U 5 γ 10 the group NR R , the group -CHg-CO-R , the group -NH(CH2) m NR®'''R^^, hydroxy, lower alkoxy, mercapto or lower alkylmercapto, X' is hydrogen, halogen, trifluoromethyl, ethyl or acetyl, R® 1 and R^ 1 each are lower 5 a lower alkanol, with a compound of formula HNR^R^ wherein 4 5 R and R are as defined in Claim l,with a compound of Q q Q Q formula H 2 N-(CH 2 ) m NR R y wherein R , R’ and m are as defined in Claim 1 or with the carbanion of a compound of the formula COR 71 COR 71 CH, or CH- 10 ''COR 71 \ ?1 COR^ 1 71 wherein R is 21 lower alkoxy and R is ί or (1) converting a compound of the general formula X· > 48830 wherein X and Y are as defined in Claim 1 and 71 R and p are as above, into the corresponding free acid or into a corresponding amide, lower alkyl amide or di-lower alkyl amide, 5 (i) converting a compound of the general formula wherein X and Y are as defined in Claim 1, into a corresponding 2-chloro or bromo compound, or 10 (kJ treating a compound of the general formula 5 p is as above and R represents mercapto or hydroxy, or (h) converting a compound of the general formula • 49630 wherein X and Y are as defined in Claim 1 and p is as above, into the corresponding 2-hydroxy compound, or 5 wherein X and Y are as defined in Claim 1, p is 0 or 1 and R represents di-lower alkyl amino, with a compound of the general formula wherein R is hydrogen, mercapto, lower alkyl 8 9 8 mercapto, lower alkyl or NR R’ wherein R and ar e as defined in Claim 1, (d) reducing a compound of the general formula or wherein X, Y and R^ are as defined in Claim 1, (e) lower-alkylating a compound of the general formula • 49630 wherein X, Y and R 1 are as defined in Claim 1, (f) oxidizing a compound of the general formula wherein X and Y are as defined in Claim 1 and R 1 ^ represents hydrogen, lower alkyl, hydroxy, lower alkoxy, NR^R 8 ^ (wherein R 1 * 1 51 ‘ and R each are hydrogen or lower alkyl or, 10 together with the co-bonded nitrogen atom, represent a 5 to 7 membered heterocycle which may contain an oxygen atom), chlorine, bromine 7 7 or the group -CH 2 -CO-R (wherein R is as defined in Claim l) y (g) lower alkylating a compound of the general formula wherein X and Y are as defined in Claim 1, 5 wherein X and Y are as defined in Claim 1 and R 11 is hydrogen, lower alkyl or NR®R^ wherein 8 Q R and R are as defined in Claim 1 or (b) dehydrogenating a compound of the general formula 496 30 wherein X and Y are a3 defined in Claim 1 and R 3,1 is as above, (c) reacting a compound of the general formula 5 (wherein R and R each are hydrogen or lower alkyl), hydroxy, 8 9 8 chlorine, bromine, the group -NH(CH 2 ) m NR R (wherein R and
5. Compounds as claimed in Claim 4 wherein R is 5 not greater than 35· 5 the group ΞΝ—lower alkyl,
6. Compounds as claimed in Claim 5 wherein R 1 is hydrogen, amino or lower alkyl. 10
7. Compounds as claimed in Claim 4 wherein R is 7 8 9 R is hydroxy, lower alkoxy or NR R ,
8. Compounds as claimed in any one of Claims 4 to 7 wherein X is halogen. 8 q R and R ? each are hydrogen or lower alkyl, n is 0 or 1 and m is 1 to 7, with the proviso that (i) when R is lower acyloxy or hydroxy, A is group (a), X is hydrogen, halogen, trifluoromethyl, ethyl or acetyl and, if R^ represents the group -NH(CH 2 ) m NR 8 R 9 , then R 8 and R 9 each are lower alkyl; (ii) when A is group (d) and R A represents the group -NH(CH 2 ) m NR 8 R 9 , then R 8 and Q R each are lower alkyl; and (iii) when n is 1, R 1 is hydrogen, lower alkyl, lower alkoxy, chlorine, bromine or the 7 7 group -CH 2 -C0-R (wherein R is as above) and A is group (a) or (b); and pharmaceutically acceptable acid addition salts thereof. 8 9 the group -NH(CH 2 ) n NR R , hydroxy, lower alkoxy, mercapto or lower alkyl mercapto, 10 is hydrogen, lower acyloxy or hydroxy, X is nydrogen, halogen, trifluoromethyl, ethyl, α-hydroxy ethyl or acetyl, Y is hydrogen or halogen, η κ R and R each are hydrogen or lower alkyl or, together with the co-bonded nitrogen atom, represent a five to seven membered heterocycle which may contain an oxygen or sulphur atom or
9. Compounds as claimed in Claim 8 wherein X is chlorine. 10. Compounds as claimed in any one of Claims 4 to 9 wherein Y is hydrogen, chlorine or fluorine. 5 11. 9-Chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine. 12. 9-Chloro-7-(2~fluorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine. 13. 9-Chloro-7-(2-chlorophenyl)-2-methyl-5H10 pyrimido]5,4-d][2]benzazepine. 14. 9-Chloro-7-(2-fluorophenyl)-5H-pyrimido/ij ,4-d7 /2/benzazepin-2-ol. 15. 9-Chloro-N,N-dimethyl-7-(2-fluorophenyl)-5Hpyrimido/5,4-d7/27benz azepin-2-amine. 16. Compounds as claimed In any one of Claims 1 to 10 and 12 to 15 as pharmaceutically active substances. 17. Compounds as claimed in any one of Claims 1 to 10 and 12 to 15 as anxiolytics and sedatives. 5 18. 9-Chloro-7-(2-chlorophenyl)-5H-pyrimidoZ5,4-d//2/benzazepine as pharmaceutically active substance. 19. 9-Chloro-7-(2-chlorophenyl)-5H-pyrlmido/5,4-d7~ /2/benzazepine as anxiolytics and seda tives. as claimed (a) A process in any one cyclizing for the preparation of compounds of Claims 1 to 15 which comprises a compound of the general formula 9 7 R each are lower alkyl) or the group -CHj-CO-R .
10. Claim 1, substantially as hereinbefore described.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1011879A | 1979-02-07 | 1979-02-07 | |
US1670979A | 1979-03-01 | 1979-03-01 | |
CH51080 | 1980-01-22 |
Publications (2)
Publication Number | Publication Date |
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IE800227L IE800227L (en) | 1980-08-07 |
IE49630B1 true IE49630B1 (en) | 1985-11-13 |
Family
ID=27172162
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE227/80A IE49630B1 (en) | 1979-02-07 | 1980-02-06 | Benzazepine derivatives |
Country Status (26)
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EP (1) | EP0014470B1 (en) |
AT (1) | ATE14225T1 (en) |
AU (1) | AU535233B2 (en) |
CA (1) | CA1138863A (en) |
DD (1) | DD149066A5 (en) |
DE (2) | DE3004381A1 (en) |
ES (1) | ES8101590A1 (en) |
FI (1) | FI68832C (en) |
FR (1) | FR2450833A1 (en) |
GB (1) | GB2043636B (en) |
HU (1) | HU182662B (en) |
IE (1) | IE49630B1 (en) |
IL (1) | IL59316A (en) |
IN (1) | IN151574B (en) |
IT (1) | IT1140535B (en) |
LU (1) | LU82143A1 (en) |
MC (1) | MC1314A1 (en) |
MT (1) | MTP864B (en) |
NL (1) | NL8000715A (en) |
NO (1) | NO153138C (en) |
NZ (1) | NZ192803A (en) |
PT (1) | PT70794B (en) |
RO (1) | RO79168A (en) |
SE (1) | SE8000964L (en) |
SU (1) | SU1181547A3 (en) |
YU (1) | YU32380A (en) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK347781A (en) * | 1980-08-05 | 1982-02-06 | Hoffmann La Roche | PROCEDURE FOR PREPARING PYRIMIDO- (4,5-D) (2) -BENZEZEPINS OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF |
EP0273697A3 (en) * | 1986-12-30 | 1989-11-29 | Merck & Co. Inc. | 2-benzazepines with 5- and 6- membered heterocyclic rings |
US5013333A (en) * | 1990-04-13 | 1991-05-07 | Tennant Company | Unattended air cleaning system for surface maintenance machine |
JP5097539B2 (en) | 2004-05-07 | 2012-12-12 | アムジエン・インコーポレーテツド | Protein kinase modulators and methods of use |
ATE381566T1 (en) | 2004-05-14 | 2008-01-15 | Millennium Pharm Inc | COMPOUNDS AND METHODS FOR INHIBITING MITOTIC PROGRESSION BY INHIBITING AURORAKINASE |
US7718648B2 (en) | 2006-08-09 | 2010-05-18 | Millennium Pharmaceuticals, Inc. | Pyridobenzazepine compounds and methods for inhibiting mitotic progression |
CL2007003244A1 (en) | 2006-11-16 | 2008-04-04 | Millennium Pharm Inc | COMPOUNDS DERIVED FROM PIRIMIDO [5,4-D] [2] BENZAZEPINA; PHARMACEUTICAL COMPOSITION THAT INCLUDES SUCH COMPOUND; AND USE OF THE COMPOUND FOR THE TREATMENT OF CANCER. |
CN102264368B (en) | 2008-12-22 | 2014-09-10 | 米伦纽姆医药公司 | Combination of aurora kinase inhibitors and anti-CD20 antibodies |
JO3635B1 (en) | 2009-05-18 | 2020-08-27 | Millennium Pharm Inc | Solid pharmaceutical compositions and processes for their production |
JP2013520424A (en) | 2010-02-19 | 2013-06-06 | ミレニアム ファーマシューティカルズ, インコーポレイテッド | Sodium 4-{[9-chloro-7- (2-fluoro-6-methoxyphenyl) -5H-pyrimido [5,4-d] [2] benzoazepin-2-yl] amino} -2-methoxybenzoate Crystal form |
US20130303519A1 (en) | 2012-03-20 | 2013-11-14 | Millennium Pharmaceuticals, Inc. | Methods of treating cancer using aurora kinase inhibitors |
JP6360881B2 (en) | 2013-03-22 | 2018-07-18 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | Combination of catalytic MTORC1 / 2 inhibitor and selective inhibitor of Aurora A kinase |
EP3324976A4 (en) | 2015-07-21 | 2019-03-27 | Millennium Pharmaceuticals, Inc. | Administration of aurora kinase inhibitor and chemotherapeutic agents |
Family Cites Families (1)
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US3947585A (en) * | 1974-06-03 | 1976-03-30 | Ciba-Geigy Corporation | Pyrazolobenzazepines |
-
1980
- 1980-02-05 NL NL8000715A patent/NL8000715A/en not_active Application Discontinuation
- 1980-02-05 FR FR8002469A patent/FR2450833A1/en active Granted
- 1980-02-05 SU SU802879255A patent/SU1181547A3/en active
- 1980-02-05 IL IL59316A patent/IL59316A/en unknown
- 1980-02-05 NZ NZ192803A patent/NZ192803A/en unknown
- 1980-02-05 CA CA000345062A patent/CA1138863A/en not_active Expired
- 1980-02-06 DD DD80218921A patent/DD149066A5/en unknown
- 1980-02-06 GB GB8003910A patent/GB2043636B/en not_active Expired
- 1980-02-06 MC MC801426A patent/MC1314A1/en unknown
- 1980-02-06 HU HU80271A patent/HU182662B/en unknown
- 1980-02-06 MT MT864A patent/MTP864B/en unknown
- 1980-02-06 IE IE227/80A patent/IE49630B1/en unknown
- 1980-02-06 IT IT19740/80A patent/IT1140535B/en active
- 1980-02-06 AU AU55296/80A patent/AU535233B2/en not_active Ceased
- 1980-02-06 PT PT70794A patent/PT70794B/en unknown
- 1980-02-06 DE DE19803004381 patent/DE3004381A1/en not_active Withdrawn
- 1980-02-06 AT AT80100610T patent/ATE14225T1/en not_active IP Right Cessation
- 1980-02-06 ES ES488311A patent/ES8101590A1/en not_active Expired
- 1980-02-06 EP EP80100610A patent/EP0014470B1/en not_active Expired
- 1980-02-06 FI FI800367A patent/FI68832C/en not_active IP Right Cessation
- 1980-02-06 LU LU82143A patent/LU82143A1/en unknown
- 1980-02-06 DE DE8080100610T patent/DE3070847D1/en not_active Expired
- 1980-02-06 NO NO800316A patent/NO153138C/en unknown
- 1980-02-06 SE SE8000964A patent/SE8000964L/en not_active Application Discontinuation
- 1980-02-06 IN IN138/CAL/80A patent/IN151574B/en unknown
- 1980-02-07 RO RO80100118A patent/RO79168A/en unknown
- 1980-02-07 YU YU00323/80A patent/YU32380A/en unknown
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