DE69318710T2 - Antitussivum - Google Patents
AntitussivumInfo
- Publication number
- DE69318710T2 DE69318710T2 DE69318710T DE69318710T DE69318710T2 DE 69318710 T2 DE69318710 T2 DE 69318710T2 DE 69318710 T DE69318710 T DE 69318710T DE 69318710 T DE69318710 T DE 69318710T DE 69318710 T2 DE69318710 T2 DE 69318710T2
- Authority
- DE
- Germany
- Prior art keywords
- epoxy
- didehydro
- indolomorphinan
- methoxy
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 230000000954 anitussive effect Effects 0.000 claims abstract description 15
- 229940124584 antitussives Drugs 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000000857 delta opiate receptor antagonist Substances 0.000 claims abstract description 8
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 41
- -1 C4 -C5 transalkenyl Chemical group 0.000 claims description 28
- 150000002431 hydrogen Chemical group 0.000 claims description 28
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000002947 alkylene group Chemical group 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 239000011737 fluorine Substances 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 101100533877 Hypocrea jecorina (strain QM6a) sor8 gene Proteins 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000006699 (C1-C3) hydroxyalkyl group Chemical group 0.000 claims description 8
- XKNAGLMNQADBQE-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-(4-pyridin-4-yloxyphenyl)urea Chemical compound O1C(C(C)(C)C)=CC(NC(=O)NC=2C=CC(OC=3C=CN=CC=3)=CC=2)=N1 XKNAGLMNQADBQE-UHFFFAOYSA-N 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- CTGGEOLBUXCZPU-UHFFFAOYSA-N iodoimino(sulfanylidene)methane Chemical compound IN=C=S CTGGEOLBUXCZPU-UHFFFAOYSA-N 0.000 claims description 5
- 125000001810 isothiocyanato group Chemical group *N=C=S 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 101100422771 Caenorhabditis elegans sup-9 gene Proteins 0.000 claims 4
- 101100311330 Schizosaccharomyces pombe (strain 972 / ATCC 24843) uap56 gene Proteins 0.000 claims 3
- 125000001153 fluoro group Chemical group F* 0.000 claims 3
- 101150018444 sub2 gene Proteins 0.000 claims 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims 1
- 101100203602 Hypocrea jecorina (strain QM6a) sor7 gene Proteins 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 12
- 239000004480 active ingredient Substances 0.000 abstract description 5
- 230000001771 impaired effect Effects 0.000 abstract 1
- 230000003389 potentiating effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 44
- 206010011224 Cough Diseases 0.000 description 37
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 34
- 229960002504 capsaicin Drugs 0.000 description 17
- 235000017663 capsaicin Nutrition 0.000 description 17
- 241000700159 Rattus Species 0.000 description 12
- 229940125904 compound 1 Drugs 0.000 description 9
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical compound C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 9
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- WIYUZYBFCWCCQJ-IFKAHUTRSA-N Naltrindole Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC=2C3=CC=CC=C3NC=25)O)CC1)O)CC1CC1 WIYUZYBFCWCCQJ-IFKAHUTRSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000003434 antitussive agent Substances 0.000 description 8
- 230000029058 respiratory gaseous exchange Effects 0.000 description 8
- 230000001629 suppression Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 6
- 206010013663 drug dependence Diseases 0.000 description 6
- 208000011117 substance-related disease Diseases 0.000 description 6
- 206010063659 Aversion Diseases 0.000 description 5
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229960003086 naltrexone Drugs 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000009423 ventilation Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000003595 mist Substances 0.000 description 4
- 229960005181 morphine Drugs 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229960004126 codeine Drugs 0.000 description 3
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- DSMNGWOUQMYTJH-MBPVOVBZSA-N (4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)OC)CC1CC1 DSMNGWOUQMYTJH-MBPVOVBZSA-N 0.000 description 2
- WXOUFNFMPVMGFZ-BDQAUFNLSA-N 7-Benzylidenenaltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC(/C5=O)=C\C=2C=CC=CC=2)O)CC1)O)CC1CC1 WXOUFNFMPVMGFZ-BDQAUFNLSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 210000000038 chest Anatomy 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 108700023159 delta Opioid Receptors Proteins 0.000 description 2
- 102000048124 delta Opioid Receptors Human genes 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 150000003892 tartrate salts Chemical class 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical class O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical class C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- AJZDHLHTTJRNQJ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[2-(tetrazol-1-yl)ethyl]benzamide Chemical compound N1(N=NN=C1)CCNC(C1=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)=O AJZDHLHTTJRNQJ-UHFFFAOYSA-N 0.000 description 1
- UFWAWZMOTPGQJU-UHFFFAOYSA-N 5,6,7,8-tetrahydronaphthalen-1-ylhydrazine Chemical compound C1CCCC2=C1C=CC=C2NN UFWAWZMOTPGQJU-UHFFFAOYSA-N 0.000 description 1
- 229920002160 Celluloid Polymers 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000001944 accentuation Effects 0.000 description 1
- 150000001243 acetic acids Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical class OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- WHMJAIHVTRKDSF-UHFFFAOYSA-N isoquinolin-5-ylhydrazine Chemical compound N1=CC=C2C(NN)=CC=CC2=C1 WHMJAIHVTRKDSF-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 101150032584 oxy-4 gene Proteins 0.000 description 1
- 229960005118 oxymorphone Drugs 0.000 description 1
- 150000003021 phthalic acid derivatives Chemical class 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- YZKWEHGEHPCODG-UHFFFAOYSA-N quinolin-5-ylhydrazine Chemical compound C1=CC=C2C(NN)=CC=CC2=N1 YZKWEHGEHPCODG-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
- Linear Motors (AREA)
- Fats And Perfumes (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34194792 | 1992-12-22 | ||
| PCT/JP1993/001855 WO1994014445A1 (fr) | 1992-12-22 | 1993-12-22 | Antitussif |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69318710D1 DE69318710D1 (en) | 1998-06-25 |
| DE69318710T2 true DE69318710T2 (de) | 1998-09-10 |
Family
ID=18349997
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69318710T Expired - Fee Related DE69318710T2 (de) | 1992-12-22 | 1993-12-22 | Antitussivum |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5714483A (enExample) |
| EP (1) | EP0636371B1 (enExample) |
| KR (1) | KR950700065A (enExample) |
| CN (1) | CN1071117C (enExample) |
| AT (1) | ATE166229T1 (enExample) |
| AU (1) | AU674379B2 (enExample) |
| CA (1) | CA2130457A1 (enExample) |
| DE (1) | DE69318710T2 (enExample) |
| NO (1) | NO307496B1 (enExample) |
| TW (1) | TW366284B (enExample) |
| WO (1) | WO1994014445A1 (enExample) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU712012B2 (en) * | 1995-09-26 | 1999-10-28 | Toray Industries, Inc. | Indole derivatives and medical application thereof |
| EP0894799B1 (en) * | 1997-01-16 | 2004-04-07 | Toray Industries, Inc. | Indolomorphinane derivatives and remedies/preventives for cerebral disorders |
| EP0998928A4 (en) * | 1997-07-09 | 2002-10-24 | Toray Industries | Cough medium |
| KR20020012314A (ko) * | 1999-07-19 | 2002-02-15 | 히라이 가쯔히꼬 | 빈뇨 혹은 요실금의 치료 또는 예방제 |
| PL368612A1 (en) * | 2001-08-14 | 2005-04-04 | Biotie Therapies Corporation | Method of treating alcoholism or alcohol abuse |
| EP1522542A1 (en) * | 2002-07-11 | 2005-04-13 | Toray Industries, Inc. | Therapeutic or preventive agent for nausea/vomiting |
| TW200633721A (en) * | 2004-12-14 | 2006-10-01 | Shionogi & Co | A pharmaceutical composition for treating constipation |
| CN101355943A (zh) * | 2005-10-11 | 2009-01-28 | 东丽株式会社 | 呕气和/或呕吐治疗药 |
| JPWO2008001859A1 (ja) * | 2006-06-30 | 2009-11-26 | 学校法人北里研究所 | オピオイドδ受容体アゴニスト |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4613668A (en) * | 1983-12-22 | 1986-09-23 | The United States Of America As Represented By The Department Of Health And Human Services | Short total synthesis or morphinan compounds which uses cyclization of a cycloalkylcarbonyl compound selected from cyclopropylcarbonyl and cyclobutylcarbonyl |
| US4816586A (en) * | 1987-07-29 | 1989-03-28 | Regents Of The University Of Minnesota | Delta opioid receptor antagonists |
| PT95069B (pt) * | 1989-08-24 | 1997-10-31 | Searle & Co | Processo para a preparacao de (+)-isomeros de derivados de endoetano/endoetanoepoximofinano, uteis como agentes anti-tussicos |
| JP2906654B2 (ja) * | 1989-11-28 | 1999-06-21 | 東レ株式会社 | 免疫抑制剤及びその製造方法 |
| AU654275B2 (en) * | 1991-04-30 | 1994-11-03 | Ur Labs, Inc. | Method for reducing emesis and nausea induced by the administration of an emesis-causing agent |
| JPH04342529A (ja) * | 1991-05-21 | 1992-11-30 | Toray Ind Inc | 抗アレルギー剤 |
-
1993
- 1993-12-22 CA CA002130457A patent/CA2130457A1/en not_active Abandoned
- 1993-12-22 WO PCT/JP1993/001855 patent/WO1994014445A1/ja not_active Ceased
- 1993-12-22 AT AT94903039T patent/ATE166229T1/de not_active IP Right Cessation
- 1993-12-22 US US08/290,837 patent/US5714483A/en not_active Expired - Fee Related
- 1993-12-22 KR KR1019940702877A patent/KR950700065A/ko not_active Abandoned
- 1993-12-22 CN CN93119935A patent/CN1071117C/zh not_active Expired - Fee Related
- 1993-12-22 AU AU57156/94A patent/AU674379B2/en not_active Ceased
- 1993-12-22 DE DE69318710T patent/DE69318710T2/de not_active Expired - Fee Related
- 1993-12-22 EP EP94903039A patent/EP0636371B1/en not_active Expired - Lifetime
-
1994
- 1994-01-21 TW TW083100512A patent/TW366284B/zh active
- 1994-08-19 NO NO943070A patent/NO307496B1/no not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| US5714483A (en) | 1998-02-03 |
| EP0636371A1 (en) | 1995-02-01 |
| CA2130457A1 (en) | 1994-07-07 |
| KR950700065A (ko) | 1995-01-16 |
| EP0636371A4 (enExample) | 1995-03-01 |
| WO1994014445A1 (fr) | 1994-07-07 |
| NO943070L (no) | 1994-10-21 |
| CN1099617A (zh) | 1995-03-08 |
| DE69318710D1 (en) | 1998-06-25 |
| TW366284B (en) | 1999-08-11 |
| NO943070D0 (no) | 1994-08-19 |
| NO307496B1 (no) | 2000-04-17 |
| ATE166229T1 (de) | 1998-06-15 |
| AU5715694A (en) | 1994-07-19 |
| EP0636371B1 (en) | 1998-05-20 |
| CN1071117C (zh) | 2001-09-19 |
| AU674379B2 (en) | 1996-12-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8364 | No opposition during term of opposition | ||
| 8339 | Ceased/non-payment of the annual fee |