FI78103B - Foerfarande foer framstaellning av terapeutiskt anvaendbara 11-substituerade 5h,11h-pyrrolo/2,1-c//1,4/ bensoxazepiner. - Google Patents
Foerfarande foer framstaellning av terapeutiskt anvaendbara 11-substituerade 5h,11h-pyrrolo/2,1-c//1,4/ bensoxazepiner. Download PDFInfo
- Publication number
- FI78103B FI78103B FI844333A FI844333A FI78103B FI 78103 B FI78103 B FI 78103B FI 844333 A FI844333 A FI 844333A FI 844333 A FI844333 A FI 844333A FI 78103 B FI78103 B FI 78103B
- Authority
- FI
- Finland
- Prior art keywords
- formula
- compound
- pyrrolo
- piperidin
- benzoxazepine
- Prior art date
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- 230000001225 therapeutic effect Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 105
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 83
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 152
- -1 cyano, hydroxy, cyclopropyl Chemical group 0.000 claims description 86
- ZCXLTWVZYXBHJS-UHFFFAOYSA-N 1,2-benzoxazepine Chemical compound O1N=CC=CC2=CC=CC=C12 ZCXLTWVZYXBHJS-UHFFFAOYSA-N 0.000 claims description 81
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 63
- 239000000460 chlorine Substances 0.000 claims description 50
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 10
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 150000003751 zinc Chemical class 0.000 claims description 3
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 claims description 2
- XUUSYXJGMRQBKQ-UHFFFAOYSA-N 2h-2-benzazepine Chemical compound N1C=CC=C2C=CC=CC2=C1 XUUSYXJGMRQBKQ-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- WMJMABVHDMRMJA-UHFFFAOYSA-M [Cl-].[Mg+]C1CCCCC1 Chemical compound [Cl-].[Mg+]C1CCCCC1 WMJMABVHDMRMJA-UHFFFAOYSA-M 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000001266 acyl halides Chemical class 0.000 claims 1
- 150000001350 alkyl halides Chemical class 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 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 claims 1
- 230000000561 anti-psychotic effect Effects 0.000 abstract description 6
- 230000000202 analgesic effect Effects 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 2
- TYGBVOSJEFXEDH-UHFFFAOYSA-N 6,11-dihydropyrrolo[2,1-c][1,4]benzoxazepine Chemical class C1OC2=CC=CC=C2CN2C=CC=C12 TYGBVOSJEFXEDH-UHFFFAOYSA-N 0.000 abstract 1
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 261
- 239000000243 solution Substances 0.000 description 185
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 145
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 144
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- 239000000203 mixture Substances 0.000 description 109
- 239000007787 solid Substances 0.000 description 107
- 235000019439 ethyl acetate Nutrition 0.000 description 91
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 89
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 81
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 77
- 239000003921 oil Substances 0.000 description 77
- 235000019198 oils Nutrition 0.000 description 77
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 76
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 71
- 238000004458 analytical method Methods 0.000 description 62
- 239000002904 solvent Substances 0.000 description 38
- 238000004128 high performance liquid chromatography Methods 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 35
- 238000003756 stirring Methods 0.000 description 35
- 150000001412 amines Chemical class 0.000 description 29
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 26
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- 239000002244 precipitate Substances 0.000 description 24
- UWXIKAZQXAYFPT-UHFFFAOYSA-N 1,4-benzoxazepine Chemical compound O1C=CN=CC2=CC=CC=C12 UWXIKAZQXAYFPT-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 21
- 239000000047 product Substances 0.000 description 19
- 235000006408 oxalic acid Nutrition 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 15
- 239000000284 extract Substances 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- KDGZMBSTLZUZPE-UHFFFAOYSA-N 1,2-benzoxazepine;oxalic acid Chemical compound OC(=O)C(O)=O.O1N=CC=CC2=CC=CC=C12 KDGZMBSTLZUZPE-UHFFFAOYSA-N 0.000 description 13
- 150000001408 amides Chemical class 0.000 description 13
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000012280 lithium aluminium hydride Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 10
- 239000005457 ice water Substances 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 239000012265 solid product Substances 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 230000009194 climbing Effects 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- 229960004592 isopropanol Drugs 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 235000015320 potassium carbonate Nutrition 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 7
- 150000003891 oxalate salts Chemical class 0.000 description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
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- 229960004046 apomorphine Drugs 0.000 description 6
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 6
- 239000007818 Grignard reagent Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229910010082 LiAlH Inorganic materials 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 5
- 150000004795 grignard reagents Chemical class 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
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- 238000012360 testing method Methods 0.000 description 4
- BARLPBPUTCZWPM-WLHGVMLRSA-N 1,2-benzoxazepine;(e)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.O1N=CC=CC2=CC=CC=C12 BARLPBPUTCZWPM-WLHGVMLRSA-N 0.000 description 3
- 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 3
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- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 3
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- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
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- LQZLMHSGCZTWOG-UHFFFAOYSA-N oxepino[3,2-c]pyridine Chemical compound O1C=CC=CC2=CN=CC=C12 LQZLMHSGCZTWOG-UHFFFAOYSA-N 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
- 229940012189 methyl orange Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- MPBXMGDERLGNSJ-UHFFFAOYSA-N oxalic acid;6-[1-[[3-(trifluoromethyl)phenyl]methyl]piperidin-4-yl]-6,11-dihydropyrrolo[2,1-c][1,4]benzoxazepine Chemical compound OC(=O)C(O)=O.FC(F)(F)C1=CC=CC(CN2CCC(CC2)C2C3=CC=CN3CC3=CC=CC=C3O2)=C1 MPBXMGDERLGNSJ-UHFFFAOYSA-N 0.000 description 1
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical compound O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- INCIMLINXXICKS-UHFFFAOYSA-M pyronin Y Chemical compound [Cl-].C1=CC(=[N+](C)C)C=C2OC3=CC(N(C)C)=CC=C3C=C21 INCIMLINXXICKS-UHFFFAOYSA-M 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- General Health & Medical Sciences (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Claims (6)
1. Förfarande för framställning av terapeutiskt an-vändbara 11-substituerade 5H,llH-pyrrolo/S,l-o7bensoxaze-5 piner enligt formeln I och farmaceutiskt godtagbara syra-additionssalter därav, JL J-V —y χ^ιΓ
10 I 9 10 \ Q 15 r väri X är väte eller halogen, Y är väte, lägre alkyl eller halogen, och R är väte, cyan-, -C(NH2)NOH, 20 /-v -CO-NH , -CO-^ en osubstituerad lägre alkyl eller en substituerad lägre 25 alkyl med 1-3 substituenter, vilka valts bland cyan, hydroxi, cyklopropyl, cyklohexyl, furyl, tienyl, N—0 CH3 “Q. tai —°·Ό. (W)k ^ (W)k 78 78103 väri k är 1, 2 eller 3, varje W är självständigt väte, halogen, hydroxi, lägre alkyl, trifluormetyl, lägre alkoxi, nitro, amino, dilägre-alkylamino eller bensyloxi, ooh Z är väte eller 1-2 halogenatomer, kännetecknat 5 därav, att man a) cykliserar en förening med formeln II - I N
10. N If 15 ^ väri Rg är metyl eller bensyl och X och Y har sairaita bety-delse som ovan, i närvaro av en stark bas, för erhällande av en förening med formeln I, väri R är metyl eller bensyl, 20 b) eventuellt omsätter en sä erhällen förening med formeln I, väri R är metyl, med cyanbromid för erhällande av en förening med formeln I, väri R är cyan, c) eventuellt omsätter en sä erhällen förening med formeln I, väri R är cyan, med hydroxylaminhydroklorid för 25 erhällande av en förening med formeln I, väri R är gruppen -C(NH2)NOH, d) eventuellt utsätter en sä erhällen förening med formeln I, väri R är bensyl, för hydrogenolys för erhällan-de av en förening med formeln I, väri R är väte, 30 e) eventuellt omsätter en sä erhällen förening med formeln I, väri R är väte, med ett fenylisocyanat med formeln i 79 781 0 3 för erhällande av en förening med formeln I, väri R är gruppen -CO-NH-^ ^ eller med en alkylhalogenid med formeln R"-Hal eller med en metansulfonatförening med formeln O 10 m CH3-|-ORm o väri R" är en osubstituerad lägre alkyl eller en substi-tuerad lägre alkyl med 1-3 substituenter, vilka valts 15 bland cyan, hydroxi, cyklopropyl, cyklohexyl, furyl, tienyl, - N—0 zyl( tai 25 (W)k (w) k väri k och W har samma betydelse som ovan, för framställ-ning av en förening med formeln I, väri R har betydelsen 30 av R" sisom ovan angivits, eller f) eventuellt omsätter en förening med formlen I, väri R är väte, med en acylhalogenid med formeln R'"-CO-Hal, väri Hai är klor eller brom och R,M är en osubstituerad lägre alkyl eller en substituerad lägre alkyl med 1-3 35 substituenter, vilka valts bland cyan, hydroxi, cyklopropyl, cyklohexyl, furyl, tienyl, 8o 78103 $ ^-f N-O J*_n tai -°^w>3 ^(W)k 10 k väri k och W har samma betydelse som ovan, för framställ-ning av en förening med formeln XIII \ XIII o \ CO \ R ", 25 och sedan reducerar den erhällna föreningen tili en förening med formeln I, väri R är gruppen -CHjR'" , väri R'" har samma betydelse som ovan, eller g) eventuellt omsätter en förening med formeln I, 30 väri R är väte, med en förening med formeln Hal-CO —^ 35 (W)k 78103 81 väri Hai är halogen och W och k har samma betydelse som ovan, för erhällande av en förening med formeln I, väri R är gruppen (W)* h) eventuellt omsätter en förening med formeln I, väri R är väte, med en förening med formeln 10 I (CH3) ^-R.-CCH^ 15 väri Z har samma betydelse som ovan och R' är lägre alkyl, för erhällande av en förening med formeln 1, väri R är gruppen '•"O-, j) eventuellt omsätter en förening med formeln I, väri R är gruppen > ” med cyklohexylmagnesiumklorid eller -bromid och hydroly-serar den erhällna produkten för erhällande av en förening 30 med formeln I, väri R är gruppen -'rQ, OH 82 781 03 väri Z har samma betydelse som ovan och R' är lägre alkyl, k) eventuellt hydrogenolyserar en förening med forme In I, väri R är gruppen 5 -,h2>2^>o-ch2 för erhällande av en förening med formeln I, väri R är gruppen 10 /-\ -<ch2)2-^ Voh l) eventuellt omsätter en förening med formeln I, 15 väri R är metyl, med 2,2,2-trikloretyl-klorformat med formeln Cl-CO-C^-CCl^ för framställing av en förening med formeln I, väri R är gruppen O -C-OCH--CC1.J
20 J och därefter behandlar den erhällna föreningen med aktive-rad zink för erhällande av en förening med formeln I, väri R är väte, och m) eventuellt pä sedvanligt sätt framställer ett 25 farmaceutiskt godtagbart syraadditionssalt.
2. Förfarande enligt patentkravet 1, känne-t e c k n a t därav, att man framställer ll-{l->0- (1,3-dihyro-2-oxo-2H-bensimidazol-l-yl)propyl7-piperidin-4-ylJ -5H, llH-pyrrolo/T2,1-ς7 D-, 47bensoxazepin. 30
3. Förfarande enligt patentkravet 1, känne- tecknat därav, att man framställer ll-£l-/2-(4-me-toxifenyl) etyl7-piperidin-4-ylJ-5H, llH-pyrrolo^2, l-q7/l, 4^-bensoxazepin. I.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI885915A FI885915A (fi) | 1983-11-07 | 1988-12-21 | Mellanprodukter foer framstaellning av 11-substituerade 5h,11h-pyrrolo/2,1-c/ /1,4/ benzoxazepiner och foerfarande foer framstaellning av dessa mellanprodukter. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/549,098 US4608374A (en) | 1983-11-07 | 1983-11-07 | 11-substituted 5H,11H-pyrrolo[2,1-c][1,4]benzoxazepines as antipsychotic and analgesic agents |
| US54909883 | 1983-11-07 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI844333A0 FI844333A0 (fi) | 1984-11-05 |
| FI844333L FI844333L (fi) | 1985-05-08 |
| FI78103B true FI78103B (fi) | 1989-02-28 |
| FI78103C FI78103C (sv) | 1989-06-12 |
Family
ID=24191656
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI844333A FI78103C (sv) | 1983-11-07 | 1984-11-05 | Förfarande för framställning av terapeutiskt användbara 11-substituera de 5H,11H-pyrrolo/2,1-c//1,4/bensoxazepiner |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US4608374A (sv) |
| EP (2) | EP0258612A1 (sv) |
| JP (1) | JPS60115590A (sv) |
| KR (1) | KR850003893A (sv) |
| AT (1) | ATE47856T1 (sv) |
| AU (2) | AU582553B2 (sv) |
| CA (1) | CA1267893A (sv) |
| DE (1) | DE3480399D1 (sv) |
| DK (1) | DK527984A (sv) |
| ES (4) | ES8608524A1 (sv) |
| FI (1) | FI78103C (sv) |
| GR (1) | GR80839B (sv) |
| HU (1) | HU193233B (sv) |
| IL (1) | IL73434A0 (sv) |
| NO (1) | NO844423L (sv) |
| NZ (1) | NZ210100A (sv) |
| PH (1) | PH21257A (sv) |
| PT (1) | PT79457B (sv) |
| ZA (1) | ZA848655B (sv) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4758559A (en) * | 1986-01-21 | 1988-07-19 | Ciba-Geigy Corporation | Pyrrolo[1,2-a] [4,1]benzoxazepine derivatives useful as calmodulin and histamine inhibitors |
| US4794110A (en) * | 1987-07-20 | 1988-12-27 | Hoechst-Roussel Pharmaceuticals, Inc. | 5-Aryl-11-substituted-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepined as analgesic and hypotensive agents |
| US4865764A (en) * | 1987-07-20 | 1989-09-12 | Hoechst-Roussel Pharmaceuticals, Inc. | 5-aryl-11-substituted-5H,11H-pyrrolo[2,1-][1,4]benzoxazepines as hypotensive agents |
| US4812450A (en) * | 1987-07-30 | 1989-03-14 | Hoechst-Roussel Pharmaceuticals Inc. | Spiro((piperidine-pyrrolidine- or hexahydroazepinyl substituted) pyrrolo(2,1-C) (1,4)benzoxazepines) |
| US5015637A (en) * | 1990-05-25 | 1991-05-14 | Hoechst-Roussel Pharmaceutical Inc. | Pyrido[3,4-b]pyrrolo[1,2-e][1,4,5]oxadiazepines |
| GB9418326D0 (en) * | 1994-09-12 | 1994-11-02 | Lilly Industries Ltd | Pharmaceutical compounds |
| GB2308362A (en) * | 1995-12-19 | 1997-06-25 | Lilly Industries Ltd | Pharmaceutical indole derivatives |
| ATE445838T1 (de) | 2001-07-25 | 2009-10-15 | Raptor Pharmaceutical Inc | Zusammensetzungen und verfahren zur modulation des transports durch die blut-hirn-schranke |
| JP4400441B2 (ja) | 2004-12-14 | 2010-01-20 | 三菱電機株式会社 | 半導体装置 |
| DK1889198T3 (da) | 2005-04-28 | 2015-02-09 | Proteus Digital Health Inc | Farma-informatiksystem |
| WO2008036682A2 (en) | 2006-09-18 | 2008-03-27 | Raptor Pharmaceutical Inc. | Treatment of liver disorders by administration of receptor-associated protein (rap)-conjugates |
| GB0711776D0 (en) * | 2007-06-18 | 2007-07-25 | Syngenta Participations Ag | Substituted aromatic heterocyclic compounds as fungicides |
| ES2728225T3 (es) | 2009-02-20 | 2019-10-23 | 2 Bbb Medicines B V | Sistema de administración de fármacos a base de glutatión |
| US8445002B2 (en) | 2009-05-06 | 2013-05-21 | Laboratory Skin Care, Inc. | Dermal delivery compositions comprising active agent-calcium phosphate particle complexes and methods of using the same |
| US20120077778A1 (en) | 2010-09-29 | 2012-03-29 | Andrea Bourdelais | Ladder-Frame Polyether Conjugates |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4029672A (en) * | 1976-02-26 | 1977-06-14 | American Hoechst Corporation | Aminoalkylpyrrolobenzoxazalkanes |
| US4045448A (en) * | 1976-02-26 | 1977-08-30 | American Hoechst Corporation | Pyrrolo[2,1-c][1,4]benzoxazepine and benzoxazocine derivatives |
| US4053599A (en) * | 1976-02-26 | 1977-10-11 | American Hoechst Corporation | Piperazionalkylpyrrolobenzoxazalkanes |
| US4169094A (en) * | 1977-01-19 | 1979-09-25 | American Hoechst Corporation | Process for preparing aminoalkylpyrrolobenzoxazalkanes |
| US4169095A (en) * | 1977-01-19 | 1979-09-25 | American Hoechst Corporation | Process for preparing aminoalkylpyrrolobenzoxazalkanes |
| US4263438A (en) * | 1977-09-13 | 1981-04-21 | Pfizer Inc. | 3-[2,4-(Disubstituted)-phenyl]azacycloalkanones as analgesics |
| US4208417A (en) * | 1978-06-29 | 1980-06-17 | Pharmindustrie | Indole derivatives and their use as anxiolytics |
| GR73560B (sv) * | 1979-02-24 | 1984-03-15 | Pfizer | |
| CA1211437A (en) * | 1981-08-12 | 1986-09-16 | Rene Borer | Benzazepines |
-
1983
- 1983-11-07 US US06/549,098 patent/US4608374A/en not_active Expired - Fee Related
-
1984
- 1984-10-31 HU HU844037A patent/HU193233B/hu not_active IP Right Cessation
- 1984-11-02 EP EP87110724A patent/EP0258612A1/en not_active Withdrawn
- 1984-11-02 DE DE8484113181T patent/DE3480399D1/de not_active Expired
- 1984-11-02 AT AT84113181T patent/ATE47856T1/de not_active IP Right Cessation
- 1984-11-02 EP EP84113181A patent/EP0144729B1/en not_active Expired
- 1984-11-05 FI FI844333A patent/FI78103C/sv not_active IP Right Cessation
- 1984-11-05 AU AU35104/84A patent/AU582553B2/en not_active Ceased
- 1984-11-05 PH PH31405A patent/PH21257A/en unknown
- 1984-11-05 NZ NZ210100A patent/NZ210100A/xx unknown
- 1984-11-05 IL IL73434A patent/IL73434A0/xx unknown
- 1984-11-05 ES ES537369A patent/ES8608524A1/es not_active Expired
- 1984-11-05 GR GR80839A patent/GR80839B/el unknown
- 1984-11-06 DK DK527984A patent/DK527984A/da not_active Application Discontinuation
- 1984-11-06 ZA ZA848655A patent/ZA848655B/xx unknown
- 1984-11-06 NO NO844423A patent/NO844423L/no unknown
- 1984-11-06 CA CA000467151A patent/CA1267893A/en not_active Expired - Lifetime
- 1984-11-06 PT PT79457A patent/PT79457B/pt unknown
- 1984-11-06 JP JP59232553A patent/JPS60115590A/ja active Pending
- 1984-11-07 KR KR1019840006971A patent/KR850003893A/ko not_active Application Discontinuation
-
1985
- 1985-07-30 ES ES545728A patent/ES8707538A1/es not_active Expired
-
1986
- 1986-01-31 ES ES551522A patent/ES8704950A1/es not_active Expired
- 1986-03-01 ES ES552578A patent/ES8707953A1/es not_active Expired
-
1989
- 1989-01-18 AU AU28565/89A patent/AU2856589A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60115590A (ja) | 1985-06-22 |
| FI78103C (sv) | 1989-06-12 |
| IL73434A0 (en) | 1985-02-28 |
| EP0144729B1 (en) | 1989-11-08 |
| GR80839B (en) | 1985-02-26 |
| HU193233B (en) | 1987-08-28 |
| ES8608524A1 (es) | 1986-06-16 |
| AU3510484A (en) | 1985-05-16 |
| ES8707538A1 (es) | 1987-08-01 |
| ES552578A0 (es) | 1987-09-16 |
| US4608374A (en) | 1986-08-26 |
| HUT36127A (en) | 1985-08-28 |
| PH21257A (en) | 1987-08-31 |
| DK527984A (da) | 1985-05-08 |
| EP0258612A1 (en) | 1988-03-09 |
| FI844333L (fi) | 1985-05-08 |
| ES537369A0 (es) | 1986-06-16 |
| AU2856589A (en) | 1989-07-13 |
| AU582553B2 (en) | 1989-04-06 |
| CA1267893A (en) | 1990-04-17 |
| ES8704950A1 (es) | 1987-04-16 |
| ES8707953A1 (es) | 1987-09-16 |
| PT79457B (en) | 1986-11-14 |
| DK527984D0 (da) | 1984-11-06 |
| ES551522A0 (es) | 1987-04-16 |
| ATE47856T1 (de) | 1989-11-15 |
| PT79457A (en) | 1984-12-01 |
| ZA848655B (en) | 1985-06-26 |
| NZ210100A (en) | 1988-06-30 |
| NO844423L (no) | 1985-05-08 |
| EP0144729A1 (en) | 1985-06-19 |
| ES545728A0 (es) | 1987-08-01 |
| KR850003893A (ko) | 1985-06-29 |
| FI844333A0 (fi) | 1984-11-05 |
| DE3480399D1 (en) | 1989-12-14 |
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| MM | Patent lapsed |
Owner name: HOECHST-ROUSSEL PHARMACEUTICALS INCORPORATED |