CN1374865A - 用于治疗咳嗽的nociceptin受体ORL-1激动剂 - Google Patents
用于治疗咳嗽的nociceptin受体ORL-1激动剂 Download PDFInfo
- Publication number
- CN1374865A CN1374865A CN00813077A CN00813077A CN1374865A CN 1374865 A CN1374865 A CN 1374865A CN 00813077 A CN00813077 A CN 00813077A CN 00813077 A CN00813077 A CN 00813077A CN 1374865 A CN1374865 A CN 1374865A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- aryl
- hydrogen
- low
- cycloalkyl
- 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.)
- Pending
Links
- 206010011224 Cough Diseases 0.000 title claims abstract description 26
- 108010020615 nociceptin receptor Proteins 0.000 title claims abstract description 14
- 102100028646 Nociceptin receptor Human genes 0.000 title claims description 9
- 239000000556 agonist Substances 0.000 title abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 115
- 239000001257 hydrogen Substances 0.000 claims abstract description 71
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 71
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 125000003118 aryl group Chemical group 0.000 claims abstract description 34
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 32
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 206010020751 Hypersensitivity Diseases 0.000 claims abstract description 7
- 208000026935 allergic disease Diseases 0.000 claims abstract description 7
- 230000007815 allergy Effects 0.000 claims abstract description 7
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 5
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 4
- 239000012453 solvate Substances 0.000 claims abstract description 3
- 208000024891 symptom Diseases 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 93
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 68
- -1 methylene-dioxy Chemical group 0.000 claims description 65
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 62
- 239000000203 mixture Substances 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- 150000002367 halogens Chemical class 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 239000012190 activator Substances 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 239000003112 inhibitor Substances 0.000 claims description 13
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 230000000954 anitussive effect Effects 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 230000001387 anti-histamine Effects 0.000 claims description 8
- 239000000739 antihistaminic agent Substances 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 239000003172 expectorant agent Substances 0.000 claims description 8
- 230000003419 expectorant effect Effects 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 102000003820 Lipoxygenases Human genes 0.000 claims description 7
- 108090000128 Lipoxygenases Proteins 0.000 claims description 7
- 229940124584 antitussives Drugs 0.000 claims description 7
- 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 description 7
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 claims description 6
- 102000004436 G-Protein-Coupled Receptor Kinase 2 Human genes 0.000 claims description 6
- 108010056715 G-Protein-Coupled Receptor Kinase 2 Proteins 0.000 claims description 6
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000695 adrenergic alpha-agonist Substances 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 6
- 239000000850 decongestant Substances 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 210000003630 histaminocyte Anatomy 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 6
- 239000003381 stabilizer Substances 0.000 claims description 6
- 239000002462 tachykinin receptor antagonist Substances 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 230000004927 fusion Effects 0.000 claims description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 4
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 4
- 239000002269 analeptic agent Substances 0.000 claims description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
- QEMCALPQWWKCTR-UHFFFAOYSA-N azidourea Chemical group NC(=O)NN=[N+]=[N-] QEMCALPQWWKCTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 4
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 2
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 4
- 208000006673 asthma Diseases 0.000 abstract description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 abstract description 3
- 239000000018 receptor agonist Substances 0.000 abstract 1
- 229940044601 receptor agonist Drugs 0.000 abstract 1
- 125000003003 spiro group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 53
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- 239000000243 solution Substances 0.000 description 29
- 238000000034 method Methods 0.000 description 27
- 108090000622 Nociceptin Proteins 0.000 description 26
- 102000048266 Nociceptin Human genes 0.000 description 26
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- PULGYDLMFSFVBL-SMFNREODSA-N nociceptin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 PULGYDLMFSFVBL-SMFNREODSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 26
- 239000000376 reactant Substances 0.000 description 26
- 239000002585 base Substances 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 150000001721 carbon Chemical group 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000000460 chlorine Chemical group 0.000 description 14
- 239000012141 concentrate Substances 0.000 description 14
- 238000005406 washing Methods 0.000 description 13
- 239000000370 acceptor Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 150000003053 piperidines Chemical class 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000003513 alkali Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 229940126062 Compound A Drugs 0.000 description 7
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- CWRYPZZKDGJXCA-UHFFFAOYSA-N acenaphthene Chemical compound C1=CC(CC2)=C3C2=CC=CC3=C1 CWRYPZZKDGJXCA-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 229960000794 baclofen Drugs 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 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 6
- 238000012545 processing Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 5
- 229960002504 capsaicin Drugs 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 230000036387 respiratory rate Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 229910052681 coesite Inorganic materials 0.000 description 4
- 229910052906 cristobalite Inorganic materials 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052682 stishovite Inorganic materials 0.000 description 4
- 229910052905 tridymite Inorganic materials 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- KQKFQBTWXOGINC-UHFFFAOYSA-N 4-phenylpiperidin-4-ol Chemical class C=1C=CC=CC=1C1(O)CCNCC1 KQKFQBTWXOGINC-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
- 229920002261 Corn starch Polymers 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 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 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 108090000137 Opioid Receptors Proteins 0.000 description 3
- 102000003840 Opioid Receptors Human genes 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- HXGDTGSAIMULJN-UHFFFAOYSA-N acetnaphthylene Natural products C1=CC(C=C2)=C3C2=CC=CC3=C1 HXGDTGSAIMULJN-UHFFFAOYSA-N 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 239000002249 anxiolytic agent Substances 0.000 description 3
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 3
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- 229910052593 corundum Inorganic materials 0.000 description 3
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 230000000945 opiatelike Effects 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000004224 protection Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229910001845 yogo sapphire Inorganic materials 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 description 2
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical class OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108010001478 Bacitracin Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 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 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- ZZHLYYDVIOPZBE-UHFFFAOYSA-N Trimeprazine Chemical compound C1=CC=C2N(CC(CN(C)C)C)C3=CC=CC=C3SC2=C1 ZZHLYYDVIOPZBE-UHFFFAOYSA-N 0.000 description 2
- HUCJFAOMUPXHDK-UHFFFAOYSA-N Xylometazoline Chemical compound CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCCN1 HUCJFAOMUPXHDK-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 229960003071 bacitracin Drugs 0.000 description 2
- 229930184125 bacitracin Natural products 0.000 description 2
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000012888 bovine serum Substances 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 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 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 229960001271 desloratadine Drugs 0.000 description 2
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical class C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000011597 hartley guinea pig Methods 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229910052740 iodine Chemical group 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 150000002617 leukotrienes Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000002762 nociceptin receptor agonist Substances 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- WYWIFABBXFUGLM-UHFFFAOYSA-N oxymetazoline Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 WYWIFABBXFUGLM-UHFFFAOYSA-N 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 2
- 229960000395 phenylpropanolamine Drugs 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 2
- 229960003908 pseudoephedrine Drugs 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- BYJAVTDNIXVSPW-UHFFFAOYSA-N tetryzoline Chemical compound N1CCN=C1C1C2=CC=CC=C2CCC1 BYJAVTDNIXVSPW-UHFFFAOYSA-N 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical group O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- OBSLWIKITOYASJ-AZEWMMITSA-N (2r,3s,4s,5r,6s)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical compound CN[C@@H]1[C@H](O)O[C@@H](CO)[C@H](O)[C@H]1O OBSLWIKITOYASJ-AZEWMMITSA-N 0.000 description 1
- DTQNEFOKTXXQKV-HKUYNNGSSA-N (2s,3s)-n-[(2-methoxyphenyl)methyl]-2-phenylpiperidin-3-amine Chemical compound COC1=CC=CC=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)NCCC1 DTQNEFOKTXXQKV-HKUYNNGSSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- MMSNEKOTSJRTRI-LLVKDONJSA-N 1-[(2r)-4-[5-[(4-fluorophenyl)methyl]thiophen-2-yl]but-3-yn-2-yl]-1-hydroxyurea Chemical compound S1C(C#C[C@@H](C)N(O)C(N)=O)=CC=C1CC1=CC=C(F)C=C1 MMSNEKOTSJRTRI-LLVKDONJSA-N 0.000 description 1
- SFOVDSLXFUGAIV-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]-n-piperidin-4-ylbenzimidazol-2-amine Chemical compound C1=CC(F)=CC=C1CN1C2=CC=CC=C2N=C1NC1CCNCC1 SFOVDSLXFUGAIV-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- BGSRSMTXDSZDMZ-UHFFFAOYSA-N 2-[2-(1h-imidazol-5-yl)ethylsulfanyl]-5-nitropyridine Chemical compound N1=CC([N+](=O)[O-])=CC=C1SCCC1=CNC=N1 BGSRSMTXDSZDMZ-UHFFFAOYSA-N 0.000 description 1
- BAWMMJAUVBLLEE-UHFFFAOYSA-N 2-[2-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 BAWMMJAUVBLLEE-UHFFFAOYSA-N 0.000 description 1
- VKPJPAPCRZIUMA-UHFFFAOYSA-N 2-[3-(1h-imidazol-5-yl)propyl]guanidine Chemical compound NC(N)=NCCCC1=CN=CN1 VKPJPAPCRZIUMA-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- JUYQSMXGDBGGSX-UHFFFAOYSA-N 2-piperidin-1-yl-1h-benzimidazole Chemical class C1CCCCN1C1=NC2=CC=CC=C2N1 JUYQSMXGDBGGSX-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- CPOUJACQGWJJQB-UHFFFAOYSA-N 3-[(4-chlorophenyl)methyl]-5-[2-(1h-imidazol-5-yl)ethyl]-1,2,4-oxadiazole Chemical compound C1=CC(Cl)=CC=C1CC1=NOC(CCC=2N=CNC=2)=N1 CPOUJACQGWJJQB-UHFFFAOYSA-N 0.000 description 1
- VNIOQSAWKLOGLY-UHFFFAOYSA-N 3-[(5-methylfuran-2-yl)methyl]-n-piperidin-4-ylimidazo[4,5-b]pyridin-2-amine Chemical compound O1C(C)=CC=C1CN1C2=NC=CC=C2N=C1NC1CCNCC1 VNIOQSAWKLOGLY-UHFFFAOYSA-N 0.000 description 1
- XCMISAPCWHTVNG-UHFFFAOYSA-N 3-bromothiophene Chemical class BrC=1C=CSC=1 XCMISAPCWHTVNG-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000003836 4-phenylbutoxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical class O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 1
- CZIIGGQJILPHEU-HCHVXQBBSA-N 5-[(4r,5r)-5-hydroxy-4-[(e,3s)-3-hydroxyoct-1-enyl]-1-phenyl-5,6-dihydro-4h-cyclopenta[b]pyrrol-2-yl]pentanoic acid Chemical compound C([C@@H](O)[C@@H]1/C=C/[C@@H](O)CCCCC)C2=C1C=C(CCCCC(O)=O)N2C1=CC=CC=C1 CZIIGGQJILPHEU-HCHVXQBBSA-N 0.000 description 1
- YTCGNPGLMAECND-UHFFFAOYSA-N 5-cyclohexyl-1-[4-(1h-imidazol-5-yl)piperidin-1-yl]pentan-1-one Chemical compound C1CC(C=2N=CNC=2)CCN1C(=O)CCCCC1CCCCC1 YTCGNPGLMAECND-UHFFFAOYSA-N 0.000 description 1
- PMZBHPUNQNKBOA-UHFFFAOYSA-N 5-methylbenzene-1,3-dicarboxylic acid Chemical class CC1=CC(C(O)=O)=CC(C(O)=O)=C1 PMZBHPUNQNKBOA-UHFFFAOYSA-N 0.000 description 1
- USCSJAIWXWYTEH-UHFFFAOYSA-N 7-[3-[4-[(4-chlorophenyl)methyl]piperazin-1-yl]propoxy]-3,4-dimethylchromen-2-one Chemical compound C1=CC=2C(C)=C(C)C(=O)OC=2C=C1OCCCN(CC1)CCN1CC1=CC=C(Cl)C=C1 USCSJAIWXWYTEH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZXSCBTQRDWPUMB-UHFFFAOYSA-N COC1=CC=CC=C1[Mg] Chemical compound COC1=CC=CC=C1[Mg] ZXSCBTQRDWPUMB-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- HUYWAWARQUIQLE-UHFFFAOYSA-N Isoetharine Chemical compound CC(C)NC(CC)C(O)C1=CC=C(O)C(O)=C1 HUYWAWARQUIQLE-UHFFFAOYSA-N 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 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
- 241001124569 Lycaenidae Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 description 1
- UEQUQVLFIPOEMF-UHFFFAOYSA-N Mianserin Chemical compound C1C2=CC=CC=C2N2CCN(C)CC2C2=CC=CC=C21 UEQUQVLFIPOEMF-UHFFFAOYSA-N 0.000 description 1
- PVLJETXTTWAYEW-UHFFFAOYSA-N Mizolastine Chemical compound N=1C=CC(=O)NC=1N(C)C(CC1)CCN1C1=NC2=CC=CC=C2N1CC1=CC=C(F)C=C1 PVLJETXTTWAYEW-UHFFFAOYSA-N 0.000 description 1
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 1
- 101000822667 Mus musculus Something about silencing protein 10 Proteins 0.000 description 1
- QKDDJDBFONZGBW-UHFFFAOYSA-N N-Cyclohexy-4-(imidazol-4-yl)-1-piperidinecarbothioamide Chemical compound C1CC(C=2NC=NC=2)CCN1C(=S)NC1CCCCC1 QKDDJDBFONZGBW-UHFFFAOYSA-N 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 102100022364 Polyunsaturated fatty acid 5-lipoxygenase Human genes 0.000 description 1
- 101710156627 Polyunsaturated fatty acid 5-lipoxygenase Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 1
- 102000003141 Tachykinin Human genes 0.000 description 1
- OGEAASSLWZDQBM-UHFFFAOYSA-N Temelastine Chemical compound C1=NC(C)=CC=C1CC(C(N1)=O)=CN=C1NCCCCC1=NC=C(Br)C=C1C OGEAASSLWZDQBM-UHFFFAOYSA-N 0.000 description 1
- UFLGIAIHIAPJJC-UHFFFAOYSA-N Tripelennamine Chemical compound C=1C=CC=NC=1N(CCN(C)C)CC1=CC=CC=C1 UFLGIAIHIAPJJC-UHFFFAOYSA-N 0.000 description 1
- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 description 1
- FCMVFAXBBGSVRG-UHFFFAOYSA-N [2-(2-chlorophenyl)phenyl]methanol Chemical class OCC1=CC=CC=C1C1=CC=CC=C1Cl FCMVFAXBBGSVRG-UHFFFAOYSA-N 0.000 description 1
- SRJDFSRXQHFSBO-UHFFFAOYSA-N acetic acid;methylcyclopropane Chemical compound CC1CC1.CC(O)=O SRJDFSRXQHFSBO-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229960003792 acrivastine Drugs 0.000 description 1
- PWACSDKDOHSSQD-IUTFFREVSA-N acrivastine Chemical compound C1=CC(C)=CC=C1C(\C=1N=C(\C=C\C(O)=O)C=CC=1)=C/CN1CCCC1 PWACSDKDOHSSQD-IUTFFREVSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 229960003790 alimemazine Drugs 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000006295 amino methylene group Chemical group [H]N(*)C([H])([H])* 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 150000003975 aryl alkyl amines Chemical class 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229960000383 azatadine Drugs 0.000 description 1
- SEBMTIQKRHYNIT-UHFFFAOYSA-N azatadine Chemical compound C1CN(C)CCC1=C1C2=NC=CC=C2CCC2=CC=CC=C21 SEBMTIQKRHYNIT-UHFFFAOYSA-N 0.000 description 1
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N benzocyclopentane Natural products C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- MAFMQEKGGFWBAB-UHFFFAOYSA-N benzonatate Chemical compound CCCCNC1=CC=C(C(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCOC)C=C1 MAFMQEKGGFWBAB-UHFFFAOYSA-N 0.000 description 1
- 229960003789 benzonatate Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- FZGVEKPRDOIXJY-UHFFFAOYSA-N bitolterol Chemical compound C1=CC(C)=CC=C1C(=O)OC1=CC=C(C(O)CNC(C)(C)C)C=C1OC(=O)C1=CC=C(C)C=C1 FZGVEKPRDOIXJY-UHFFFAOYSA-N 0.000 description 1
- 229960004620 bitolterol Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229960000725 brompheniramine Drugs 0.000 description 1
- ZDIGNSYAACHWNL-UHFFFAOYSA-N brompheniramine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Br)C=C1 ZDIGNSYAACHWNL-UHFFFAOYSA-N 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- RIMGDBZXWSGBQN-UHFFFAOYSA-N burimamide Chemical compound CNC(=S)NCCCCC1=CN=C[N]1 RIMGDBZXWSGBQN-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229960000428 carbinoxamine Drugs 0.000 description 1
- OJFSXZCBGQGRNV-UHFFFAOYSA-N carbinoxamine Chemical compound C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 OJFSXZCBGQGRNV-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- XGHOVGYJHWQGCC-UHFFFAOYSA-N carebastine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 XGHOVGYJHWQGCC-UHFFFAOYSA-N 0.000 description 1
- 229950010123 carebastine Drugs 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 229960002881 clemastine Drugs 0.000 description 1
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 1
- UCAIEVHKDLMIFL-UHFFFAOYSA-N clobenpropit Chemical compound C1=CC(Cl)=CC=C1CNC(=N)SCCCC1=CNC=N1 UCAIEVHKDLMIFL-UHFFFAOYSA-N 0.000 description 1
- WRCHFMBCVFFYEQ-UHFFFAOYSA-N clofedanol Chemical compound C=1C=CC=C(Cl)C=1C(O)(CCN(C)C)C1=CC=CC=C1 WRCHFMBCVFFYEQ-UHFFFAOYSA-N 0.000 description 1
- 229960004472 clofedanol Drugs 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- 229960004170 clozapine Drugs 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960003564 cyclizine Drugs 0.000 description 1
- UVKZSORBKUEBAZ-UHFFFAOYSA-N cyclizine Chemical compound C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 UVKZSORBKUEBAZ-UHFFFAOYSA-N 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 229960001140 cyproheptadine Drugs 0.000 description 1
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- 229960001992 dimetindene Drugs 0.000 description 1
- MVMQESMQSYOVGV-UHFFFAOYSA-N dimetindene Chemical compound CN(C)CCC=1CC2=CC=CC=C2C=1C(C)C1=CC=CC=N1 MVMQESMQSYOVGV-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- WDEABJKSGGRCQA-UHFFFAOYSA-N docebenone Chemical compound CC1=C(C)C(=O)C(CCCCC#CCCCC#CCO)=C(C)C1=O WDEABJKSGGRCQA-UHFFFAOYSA-N 0.000 description 1
- 229950003667 docebenone Drugs 0.000 description 1
- 229960005178 doxylamine Drugs 0.000 description 1
- HCFDWZZGGLSKEP-UHFFFAOYSA-N doxylamine Chemical compound C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 HCFDWZZGGLSKEP-UHFFFAOYSA-N 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 229960001971 ebastine Drugs 0.000 description 1
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 description 1
- 229950003420 efletirizine Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 229960003449 epinastine Drugs 0.000 description 1
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 230000008717 functional decline Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 208000006278 hypochromic anemia Diseases 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- MZCJWLAXZRFUPI-UHFFFAOYSA-N impentamine Chemical compound NCCCCCC1=CN=CN1 MZCJWLAXZRFUPI-UHFFFAOYSA-N 0.000 description 1
- MURRAGMMNAYLNA-UHFFFAOYSA-N impromidine Chemical compound N1C=NC(CSCCNC(N)=NCCCC=2NC=NC=2)=C1C MURRAGMMNAYLNA-UHFFFAOYSA-N 0.000 description 1
- 229950005073 impromidine Drugs 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 229960001268 isoetarine Drugs 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- ZCGOMHNNNFPNMX-KYTRFIICSA-N levocabastine Chemical compound C1([C@@]2(C(O)=O)CCN(C[C@H]2C)[C@@H]2CC[C@@](CC2)(C#N)C=2C=CC(F)=CC=2)=CC=CC=C1 ZCGOMHNNNFPNMX-KYTRFIICSA-N 0.000 description 1
- 229960001120 levocabastine Drugs 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 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
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- NNICRUQPODTGRU-UHFFFAOYSA-N mandelonitrile Chemical compound N#CC(O)C1=CC=CC=C1 NNICRUQPODTGRU-UHFFFAOYSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229960001474 meclozine Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960003955 mianserin Drugs 0.000 description 1
- 229950008866 mifentidine Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960001144 mizolastine Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- GOZUADYOHPCXLE-UHFFFAOYSA-N n-[4-(1h-imidazol-5-yl)phenyl]-n'-propan-2-ylmethanimidamide Chemical compound C1=CC(NC=NC(C)C)=CC=C1C1=CN=CN1 GOZUADYOHPCXLE-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960005016 naphazoline Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 229960004398 nedocromil Drugs 0.000 description 1
- RQTOOFIXOKYGAN-UHFFFAOYSA-N nedocromil Chemical compound CCN1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1OC(C(O)=O)=CC(=O)C1=C2 RQTOOFIXOKYGAN-UHFFFAOYSA-N 0.000 description 1
- 229940105623 neo-synephrine Drugs 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229960005419 nitrogen Drugs 0.000 description 1
- 229950009470 noberastine Drugs 0.000 description 1
- 230000001129 nonadrenergic effect Effects 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical group O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 229960001528 oxymetazoline Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 229950010674 picumast Drugs 0.000 description 1
- GJQNVZVOTKFLIU-UHFFFAOYSA-N piperidin-1-ium-4-one;chloride Chemical class Cl.O=C1CCNCC1 GJQNVZVOTKFLIU-UHFFFAOYSA-N 0.000 description 1
- 229950000204 piriprost Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960004583 pranlukast Drugs 0.000 description 1
- UAJUXJSXCLUTNU-UHFFFAOYSA-N pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC(C=1)=CC=C(C(C=2)=O)C=1OC=2C=1N=NNN=1 UAJUXJSXCLUTNU-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- JCRIVQIOJSSCQD-UHFFFAOYSA-N propylhexedrine Chemical compound CNC(C)CC1CCCCC1 JCRIVQIOJSSCQD-UHFFFAOYSA-N 0.000 description 1
- 229960000786 propylhexedrine Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- PGKXDIMONUAMFR-AREMUKBSSA-N saredutant Chemical compound C([C@H](CN(C)C(=O)C=1C=CC=CC=1)C=1C=C(Cl)C(Cl)=CC=1)CN(CC1)CCC1(NC(C)=O)C1=CC=CC=C1 PGKXDIMONUAMFR-AREMUKBSSA-N 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 201000006152 substance dependence Diseases 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229950005829 temelastine Drugs 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 229960000337 tetryzoline Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 229960003223 tripelennamine Drugs 0.000 description 1
- 229960001128 triprolidine Drugs 0.000 description 1
- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229960000833 xylometazoline Drugs 0.000 description 1
- 229960004764 zafirlukast Drugs 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- 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
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- 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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61P11/06—Antiasthmatics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及单独的ORL-1受体激动剂或与一种或更多种治疗咳嗽、变态反应或哮喘症状的药物联合以便治疗咳嗽的用途,特别是涉及式(I)的ORL-1激动剂或其药学上可接受的盐或溶剂化物的用途,其中:虚线代表任选的双键;X1是任选取代的烷基、环烷基、芳基、杂芳基或杂环烷基;X2是-CHO、CN、任选取代的氨基、烷基或芳基;或X1是任选取代的苯并稠合的杂环基和X2是氢;或X1和X2一起形成任选苯并稠合的螺杂环基团,R1、R2、R3和R4独立是H和烷基,或(R1和R4)或(R2和R3)或(R1和R3)或(R2和R4)一起可以形成具有1-3个碳原子的亚烷基桥;Z1是任选取代的烷基、芳基、杂芳基、环烷基或杂环烷基或-CO2(烷基或取代的氨基)或CN;Z2是H或Z1;Z3是H或烷基。或Z1、Z2和Z3与其所连接的碳原子一起形成双环饱和或不饱和的环。
Description
背景技术
已经证明在动物模型中nociceptin受体ORL-1涉及疼痛的调节。ORL-1(nociceptin受体)被发现为“孤独阿片样物质受体”即其配体不明的受体。nociceptin受体是G蛋白偶联的受体。尽管它与三种典型的阿片样物质受体即对于传统阿片样物质镇痛药的靶目标在结构上高度相关,但是它不被内源性阿片样物质激活。内源性阿片样物质同样不能激活nociceptin受体。像典型的阿片样物质受体一样,nociceptin受体在中枢神经系统中具有广泛的分布。
在1995年末,发现了nociceptin,也称为Orphanin FQ(OFQ)并认为是激活nociceptin受体的内源性肽配体。在早期出版物中的资料认为nociceptin和它的受体是涉及痛觉刺激的感受的新发现的途径的一部分。随后一些实验室的工作证明当经脊柱内给予啮齿动物nociceptin时,它是一种镇痛药。nociceptin的功效与内源性阿片样物质肽的功效相似。最近的资料证明当直接将nociceptin给予啮齿动物脑部时,它起抗焦虑药的作用。当在标准的焦虑动物模型中试验时,nociceptin的功效与典型的苯并二氮杂类抗焦虑药的功效相似。这些资料认为nociceptin受体的小分子激动剂可能具有明显的镇痛或抗焦虑活性。
另外的新的资料(Rizzi等,Life Sci.,64,(1999),第157-163页)已证明激活离体豚鼠支气管中nociceptin受体抑制速激肽能的(tachykinergic)、非-肾上腺素能的、非-胆碱能的收缩作用,显示nociceptin受体激动剂在治疗哮喘中是有效的。也有报道(Ciccocioppo等,Physchopharmacology,141(1999),第220-224页)nociceptin降低了偏爱msP酒精大鼠的乙醇的奖赏特性,指出nociceptin介入在酒精滥用的治疗中有效。在EP 856,514中公开了用于许多疾病包括抑郁症的治疗的、作为orphanin FQ(即nociceptin)的激动剂和/或拮抗剂的8-取代的1,3,8-三氮杂螺[4,5]癸烷-4-酮衍生物;在WO 98/54168中公开的2-氧代咪唑衍生物具有相似的效用。较早时,在U.S 3,318,900中公开了具有镇痛活性的苯并咪唑基哌啶化合物。
有效的镇痛药例如传统的阿片样物质如吗啡本身带有明显的付作用。临床上相关的付作用包括耐受性、物质依赖性、呼吸抑制、镇静作用和胃肠动力功能下降。对于许多病人,特别是那些长期接受阿片样物质治疗的病人即癌症病人而言,这些付作用限止了可以服用的阿片样物质的剂量。临床资料表明超过三分之一的癌症病人具有现有的药物难以控制的疼痛。使用nociceptin获得的资料表明其潜在优势超过阿片样物质。与吗啡相比,长期给予啮齿类动物nociceptin不出现成瘾倾向。另外,长期吗啡治疗不导致对nociceptin的“交叉耐受性”,提示这些药物通过不同的途径起作用。
出人意料地发现ORL-1受体激动剂在治疗咳嗽中有效。
本发明概述
本发明涉及ORL-1受体激动剂在治疗咳嗽中的用途。提出任何具有ORL-1激动剂活性化合物的用途,但以以下非限定的化合物作为ORL-1激动剂的实例:a)一种由以下结构式代表的化合物:或其药学上可接受的盐或溶剂化物,其中:虚线代表任选的双键;X1是R5-(C1-C12)烷基、R6-(C3-C12)环烷基、R7-芳基、R8-杂芳基或R10-(C3-C7)杂环烷基;X2是-CHO、-CN、-NHC(=N-R26)NHR26、-CH(=NOR26)、-NHOR26、R7-芳基、R7-芳基(C1-C6)烷基、R7-芳基(C1-C6)链烯基、R7-芳基(C1-C6)-炔基、-(CH2)vOR13、-(CH2)vCOOR27、-(CH2)vCONR14R15、-(CH2)vNR21R22或-(CH2)vNHC(O)R21,其中v是0、1、2或3和其中q是1-3和a是1或2;或X1是和X2是氢;或X1和X2一起形成下式的螺环基团m是1或2;n是1、2或3,条件是当n是1时,R16和R17之一是-C(O)R28;p是0或1;Q是-CH2-、-O-、-S-、-SO-、-SO2-或-NR17-;R1、R2、R3和R4独立选自氢和(C1-C6)烷基,或(R1和R4)或(R2和R3)或(R1和R3)或(R2和R4)可以一起形成1-3个碳原子的亚烷基桥;R5是1-3个独立选自H、R7-芳基、R6-(C3-C12)环烷基、R8-杂芳基、R10-(C3-C7)杂环烷基、-NR19R20、-OR13和-S(O)0-2R13的取代基;R6是1-3个独立选自H、(C1-C6)烷基、R7-芳基、-NR19R20、-OR13和-SR13的取代基;R7是1-3个独立选自氢、卤素、(C1-C6)烷基、R25-芳基、(C3-C12)环烷基、-CN、-CF3、-OR19、-(C1-C6)烷基-OR19、-OCF3、-NR19R20、-(C1-C6)烷基-NR19R20、-NHSO2R19、-SO2N(R26)2、-SO2R19、-SOR19、-SR19、-NO2、-CONR19R20、-NR20COR19、-COR19、-COCF3、-OCOR19、-OCO2R19、-COOR19、-(C1-C6)烷基-NHCOOC(CH3)3、-(C1-C6)烷基-NHCOCF3、-(C1-C6)烷基-NHSO2-(C1-C6)烷基、-(C1-C6)烷基-NHCONH-(C1-C6)-烷基或的取代基,其中f是0-6;或在相邻环碳原子上的R7取代基可一起形成亚甲二氧基或亚乙二氧基环;R8是1-3个独立选自氢、卤素、(C1-C6)烷基、R25-芳基、(C3-C12)环烷基、-CN、-CF3、-OR19、-(C1-C6)烷基-OR19、-OCF3、-NR19R20、-(C1-C6)烷基-NR19R20、-NHSO2R19、-SO2N(R26)2、-NO2、-CONR19R20、-NR20COR19、-COR19、-OCOR19、-OCO2R19和-COOR19的取代基;R9是氢、(C1-C6)烷基、卤素、-OR19、-NR19R20、-NHCN、-SR19或-(C1-C6)烷基-NR19R20;R10是H、(C1-C6)烷基、-OR19、-(C1-C6)烷基-OR19、-NR19R20或-(C1-C6)烷基-NR19R20;R11独立选自H、R5-(C1-C6)烷基、R6-(C3-C12)环烷基、-(C1-C6)烷基(C3-C12)环烷基、-(C1-C6)烷基-OR19、-(C1-C6)烷基-NR19R20和,其中q和a如上所定义;R12是H、(C1-C6)烷基、卤素、-NO2、-CF3、-OCF3、-OR19、-(C1-C6)烷基-OR19、-NR19R20或-(C1-C6)烷基-NR19R20;R13是H、(C1-C6)烷基、R7-芳基、-(C1-C6)烷基-OR19、-(C1-C6)烷基-NR19R20、-(C1-C6)烷基-SR19或芳基(C1-C6)烷基;R14和R15独立选自氢、R5-(C1-C6)烷基、R7-芳基和,其中q和a如上所定义;R16和R17独立选自氢、R5-(C1-C6)烷基、R7-芳基、(C3-C12)环烷基、R8-杂芳基、R8-杂芳基(C1-C6)烷基、-C(O)R28、-(C1-C6)烷基(C3-C7)-杂环烷基、-(C1-C6)烷基-OR19和-(C1-C6)烷基-SR19;R19和R20独立选自氢、(C1-C6)烷基、(C3-C12)环烷基、芳基和芳基(C1-C6)烷基;R21和R22独立选自氢、(C1-C6)烷基、(C3-C12)环烷基、(C3-C12)环烷基(C1-C6)烷基、(C3-C7)杂环烷基、-(C1-C6)烷基(C3-C7)杂环烷基、R7-芳基、R7-芳基(C1-C6)烷基、R8-杂芳基(C1-C12)烷基、-(C1-C6)烷基-OR19、-(C1-C6)烷基-NR19R20、-(C1-C6)烷基-SR19、-(C1-C6)烷基-NR18-(C1-C6)烷基-O-(C1-C6)烷基和-(C1-C6)烷基-NR18-(C1-C6)烷基-NR18-(C1-C6)烷基;R18是氢或(C1-C6)烷基;Z1是R5-(C1-C12)烷基、R7-芳基、R8-杂芳基、R6-(C3-C12)环烷基、R10-(C3-C7)杂环烷基、-CO2(C1-C6)烷基、CN或-C(O)NR19R20;Z2是氢或Z1;Z3是氢或(C1-C6)烷基;或Z1、Z2和Z3与它们所连接的碳一起形成以下基团,其中r是0-3;w和u各是0-3,条件是w和u的总数是1-3;c和d独立是1或2;s是1-5;和环A是稠合的R7-苯基或R8-杂芳基环;R23是1-3个独立选自H、(C1-C6)烷基、-OR19、-(C1-C6)烷基-OR19、-NR19R20和-(C1-C6)烷基-NR19R20的取代基;R24是1-3个独立选自R23、-CF3、-OCF3、NO2或卤素的取代基,或相邻环碳原子上的R24取代基可以一起形成亚甲二氧基或亚乙二氧基环;R25是1-3个独立选自H、(C1-C6)烷基、(C1-C6)烷氧基和卤素的取代基;R26独立选自H、(C1-C6)烷基和R25-C6H4-CH2-;R27是H、(C1-C6)烷基、R7-芳基(C1-C6)烷基或(C3-C12)环烷基;和R28是(C1-C6)烷基、-(C1-C6)烷基(C3-C12)环烷基、R7-芳基、R7-芳基-(C1-C6)烷基、R8-杂芳基、-(C1-C6)烷基-NR19R20、-(C1-C6)烷基-OR19或-(C1-C6)烷基-SR19。
式I的优选化合物是那些其中Z1和Z2各是R7-芳基,特别是R7-苯基的化合物。优选的R7取代基是(C1-C6)烷基和卤素,更优选邻位取代。
优选其中R1、R2、R3和R4各是氢的式I的化合物,以及其中R1和R3各是氢和R2和R4是2或3个碳原子的亚烷基桥的化合物。
优选其中X1是R7-芳基,例如R7-苯基和X2是OH(即X2是-(CH2)vOR13,其中v是0和R13是H)或-NC(O)R28的式I化合物,优选其中X1是,其中R12是氢和R11是(C1-C6)烷基、-(C1-C6)烷基(C3-C12)环烷基、-(C1-C6)烷基-OR19或-(C1-C6)烷基-NR19R20的化合物;和优选其中X1和X2一起形成螺环基团,其中m是1,R17是苯基和R11是-(C1-C6)烷基-OR19或-(C1-C6)烷基-NR19R20,或的化合物。
也优选其中X1和X2形成螺环基团、Z1是R7-芳基,特别是R7-苯基和Z2是C4-12烷基的式I的化合物。b)一种在EP 856,514中公开的、以下结构式II代表的化合物:其中R1a和R2a彼此独立是氢、低级烷基、低级烷氧基或卤素;R3a是苯基,任选由低级烷基、CF3、低级烷氧基或卤素取代;和R4a是氢、低级烷基、低级链烯基、-C(O)-低级烷基、-C(O)-苯基、低级烷基-C(O)-苯基、低级亚烷基(alkylen)-C(O)-低级烷基、低级烷三基-二-C(O)O-低级烷基、羟基-低级烷基、低级烷基-O-低级烷基、低级烷基-CH(OH)CF3、苯基或苄基;R5a和R6a彼此独立是氢、苯基、低级烷基或二-低级烷基或可以一起形成苯环,和R5a和R1a或R2a之一可以一起形成饱和或不饱和6元环;Aa是4-7元饱和环,该环可以含有杂原子如O或S,或其药学上可接受的酸加成盐。
优选的式II化合物包括:(-)-8-(5,8-二氯代-1,2,3,4-四氢-萘基-2)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;8-(8-氯代-1,2,3,4-四氢-萘基-2)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;1-苯基-8-(1,2,3,4-四氢-萘基-1)-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;8-茚满-2-基-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;(RS)-8-(二氢苊-1-基)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;(RS)-8-(二氢苊-1-基)-3-甲基-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;(RS)-8-(2,3-二氢-1H-phenalen-1-基)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;(R)-8-(二氢苊-1-基)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;8-(2,3,3a,4,5,6-六氢-1H-phenalen-1-基)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;和(RS)-8-(5-甲基-1,2,3,4-四氢-萘-1-基)-1,3,8-三氮杂-螺[4.5]癸烷-4-酮。c)一种在EP 921,125中公开的、以下结构式III代表的化合物其中R1b是氢、低级烷基、卤素、低级烷氧基、CF3、低级烷基-苯基或(C5-7)-环烷基;R2b是氢、低级烷基、苯基或低级烷基-苯基;R3b是氢、低级烷基、苄基、低级烷基-苯基、低级烷基-二苯基、三嗪基、氰基甲基、低级烷基-哌啶基、低级烷基-萘基、(C5-7)-环烷基、低级烷基-(C5-7)-环烷基、低级烷基-吡啶基、低级烷基-吗啉基、低级烷基二氧戊环基、低级烷基、噁唑基或低级烷基-2-氧代-噁唑烷基并且其中的环系统可以由其它的低级烷基、低级烷氧基、CF3或苯基取代,或-(CH2)nC(O)O-低级烷基、-(CH2)nC(O)NH2-、-(CH2)nC(O)N(低级烷基)2、-(CH2)nOH或-(CH2)nC(O)NHCH2C6H6;R4b是氢、低级烷基或次氮基;Ab是由(a)(C5-15)-环烷基组成的环系统,除R4b外它可以任选由低级烷基、CF3、苯基、(C5-7)-环烷基、螺-十一烷-烷基或由2-降冰片基(norbornyl)取代,或是以下基团之一:、十二氢-苊-1-基(e),双环[6.2.0]癸-9-基(f)和双环壬烷-9-基(g);和其中R5b和R6b是氢、低级烷基或与其所连接的碳原子一起形成苯环;R7b是氢或低级烷基;虚线代表任选的双键和n是1-4;或其药学上可接受的酸加成盐。
优选的式III化合物包括:8-(十氢-萘-2-基)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;8-(十氢-萘-2-基)-3-甲基-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;(2RS,4aRS,8aSR)-和(2RS,4aRS,8aSR)-8-(十氢-萘-2-基)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮的混合物;(2RS,4aSR,8aRS)-8-(十氢-萘-2-基)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;顺式-8-(4-甲基-环己基)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;8-环癸基-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;8-环壬基-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;顺式-8-(4-异丙基-环己基)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;(R,S)-8-环癸基-1-(3-甲基-苯基)-2-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;8-环癸基-4-氧代-1-苯基-1,3,8-三氮杂-螺[4.5]癸-3-基)-乙腈;8-(顺式-八氢-茚-2-基)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮;和8-(顺式-双环[6.2.0]癸-9-基)-1-苯基-1,3,8-三氮杂-螺[4.5]癸烷-4-酮。d)一种在WO 99/36421中公开的、以下结构式IV代表的化合物:或其药学上可接受的盐,其中R1c和R2c独立是C1-C4烷基;或R1c和R2c与它们所连接的碳原子一起形成具有6-13个碳原子的单-、双-、三-或螺-环基团,其中所述环基团由独立选自以下的1-5个取代基任选取代:C1-C4烷基、C2-C4亚烷基、C1-C4烷氧基、羟基、氧代、=CH2和=CH-C1-C4烷基;R3c是C1-C7烷基、C2-C5链烯基、C2-C5炔基、苯基-C1-C5烷基、由1-3个独立选自以下基团的取代基任选取代的苯基:氟、C1-C3烷基和C1-C3烷氧基,或选自呋喃基、噻吩基(theinyl)、吡咯基和吡啶基的杂芳基,其中所述杂芳基由1-3个独立选自卤素、C1-C3烷基和C1-C3烷氧基的取代基任选取代,条件是当R1c和R2c都是C1-C4烷基时,则R3c不是C1-C7烷基、C2-C5链烯基和C2-C5炔基;R4c选自1)氢;2)任选取代的一-或二-取代的C1-C8烷基、C3-C7环烷基、C2-C8链烯基、C2-C8炔基、C1-C6烷基-Zc、C1-C6烷基-Zc-(C1-C6)烷基、C3-C7环烷基-Zc-(C1-C6)烷基、C2-C6链烯基-Zc-(C1-C6)烷基或C2-C6炔基-Zc-(C1-C6)烷基,其中Zc选自O、S、SO、SO2、CO、CO2、OCO、NRc、CONRc和NRcCO,其中Rc是氢或C1-C6烷基,并且连接烷基、链烯基、炔基或环烷基部分的取代基独立选自卤素、羟基、羧基、氨基、一-或二-(C1-C4烷基)氨基、肼基、叠氮基、脲基、脒基和胍基;或3)任选一-或二-取代的芳基、杂环、芳基(C1-C5)烷基、杂环(C1-C5)烷基、杂环-杂环(C1-C5)烷基、芳基-杂环(C1-C5)烷基、杂环-Zc-(C1-C5)烷基、芳基-Zc-(C1-C5)烷基、芳基(C1-C5)烷基-Zc-(C1-C5)烷基或杂环(C1-C5)烷基-Zc-(C1-C5)烷基,其中Zc选自O、S、SO、SO2、CO、CO2、OCO、NRc、CONRc和NRcCO,其中Rc是氢或C1-C6烷基,并且连接芳基或杂环部分的取代基独立选自卤素、羟基、羧基、C1-C4烷基、C1-C4烷氧基、C1-C4烷基-CO-、氨基(C1-C4)烷基-CO-、苯基、苄基、氨基、一-或二-(C1-C4烷基)氨基、肼基、叠氮基、脲基、脒基和胍基;R5c独立选自卤素、C1-C3烷基、C1-C3烷氧基、C1-C3烷基磺酰基、CF3、羧基、羟基、氨基、烷基氨基、酰氨基、芳基羰基、烷基羰基和羟基烷基;和n是0、1、2、3或4。
优选的式IV化合物包括:1-{1-[1-甲基-1-(2-噻吩基)乙基]-4-哌啶基}1,3-二氢-2H-1,3-苯并咪唑-2-酮;1-[1-(1-苯基环庚基)-4-哌啶基]-1,3-二氢-2H-1,3-苯并咪唑-2-酮;1-[4-哌啶基-1-(1-丙基环壬基)]-1,3-二氢-2H-1,3-苯并咪唑-2-酮;1-[1-(1-苯基环辛基)-4-哌啶基]-1,3-二氢-2H-1,3-苯并咪唑-2-酮;1-[1-(1-苯基环壬基)-4-哌啶基]-1,3-二氢-2H-1,3-苯并咪唑-2-酮;1-{1-[1-(4-氟代苯基)环庚基]-4-哌啶基}-1,3-二氢-2H-1,3-苯并咪唑-2-酮;1-[1-(1-甲基环壬基)-4-哌啶基]-1,3-二氢-2H-1,3-苯并咪唑-2-酮;1-[1-(1-乙基环壬基)-4-哌啶基]-1,3-二氢-2H-1,3-苯并咪唑-2-酮;1-[1-(1-甲基环辛基)-4-哌啶基]-1,3-二氢-2H-1,3-苯并咪唑-2-酮;1-[1-(1-苯基环庚-4-烯基)-4-哌啶基]-1,3-二氢-2H-1,3-苯并咪唑-2-酮;1-(6-氨基己基)-3-[1-(1-苯基环庚基)-4-哌啶基]-1,3-二氢-2H-1,3-苯并咪唑-2-酮;1-(2-氨基乙基)-3-[1-(1-苯基环庚-4-烯基)-4-哌啶基]-1,3-二氢-2H-1,3-苯并咪唑-2-酮;和1-[1-(1-苯基环庚基)-4-哌啶基]-3-(2-哌啶基乙基)-1,3-二氢-2H-1,3-苯并咪唑-2-酮。e)一种在WO 98/54 168中公开的、以下结构式V代表的化合物或其盐或酯,其中Ar1d是任选取代的芳族碳环或杂环,其中所述任选的取代基独立选自卤素、烷基、氨基、烷基氨基、二烷基氨基、羟基、烷氧基和羧基;是任选取代的单-或双-环C3-14脂族含氮杂环;Cyd是任选取代的单-、双-或三-环C3-20脂族碳环;R1d是氢、低级链烯基、低级炔基、低级环烷基、氨基、低级烷基氨基、二(低级烷基)氨基、羟基、低级烷氧基、羧基、低级烷氧基羰基、氨基甲酰基、低级烷基氨基甲酰基、二(低级烷基)氨基甲酰基或任选取代的低级烷基;和R2d是氢或低级烷基。f)一种在WO 99/48492中公开的、以下结构式VI代表的化合物或其药学上可接受的盐,其中Ae是芳基或杂环的环;Be是苯基、噻吩基、呋喃基、吡咯基、吡咯烷基、噁唑基或环己烯基;R1e和R2e独立是氢、烷基、羟基烷基、氨基、烷基氨基或二-烷基氨基;R3e和R4e独立是氢、卤素或烷基;Xe是氢、卤素、烷基、烷氧基烷基、链烯基、氨基、CN或-(CH2)me-Ee(CH2)ne-Ge;Ee是键、-CH=CR6e、O、S、NR7e、CO、SO2或NHCO;Ge是芳基、杂环基、环烷基或稠合的芳基,全部由1-5个R5e基团任选取代;R5e独立选自卤素、OH、烷基、由烷氧基、烷氧基烷氧基、卤素、OH或链烷酰基氧基任选取代的烷基、烷氧基、烷氧基烷氧基、氨基、烷基氨基、二-烷基氨基、NO2、CN、链烷酰基、链烷酰基氧基、羧基、烷氧基羰基、烷基磺酰基和苯基;R6e是氢或芳基;R7e是氢、烷基或烷氧基羰基;me是0-8;和ne是1-4。
一种优选的式VI化合物是:N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙基苯氧基)甲基]苯甲酰胺。
将EP 856,514、EP 921,125、WO 99/36421、WO 98/54168和WO99/48492中公开的内容结合在本文中作为参考。式I化合物详细叙述如下。
本发明也涉及ORL-1激动剂在制备用于治疗咳嗽的药物中的用途。特别是,本发明涉及式I-VI中任一个的化合物在制备用于治疗咳嗽的药物中的用途。
本发明也涉及包括给予需要此治疗的哺乳动物有效量的ORL-1激动剂治疗咳嗽的方法。特别是,本发明涉及包括给予需要此治疗的哺乳动物有效量的式I-VI中任一个的化合物治疗咳嗽的方法。
另一方面,本发明涉及包括给予需要此治疗的哺乳动物以下药物治疗咳嗽的方法:(a)有效量的nociceptin受体CRL-1激动剂;和(b)有效量的选自以下的一种或更多种治疗咳嗽、变态反应或哮喘症状的药物,包括抗组胺药、5-脂氧合酶抑制剂、白三烯抑制剂、H3抑制剂、β-肾上腺素能受体激动剂、黄嘌呤衍生物、α-肾上腺素能受体激动剂、肥大细胞稳定剂、镇咳药、祛痰药、减充血剂、NK1、NK2和NK3速激肽受体拮抗剂和GABAB激动剂。
另外一方面,本发明涉及药用组合物,该组合物包含nociceptin受体ORL-1激动剂和一种或更多种选自以下的药物:抗组胺药、5-脂氧合酶抑制剂、白三烯抑制剂、H3抑制剂、β-肾上腺素能受体激动剂、黄嘌呤衍生物、α-肾上腺素能受体激动剂、肥大细胞稳定剂、镇咳药、祛痰药、减充血剂、NK1、NK2和NK3速激肽受体拮抗剂和GABAB激动剂。
联合使用并以联合的药用组合物使用的优选的ORL-1激动剂是那些式I-VI所代表的化合物。
附图的简要说明
图1说明在豚鼠体内化合物A和B(参见实施例12)与巴氯芬相比对由辣椒素引起的咳嗽的影响。
图2A和2B表明给予化合物A或巴氯芬后潮气量的变化,图2C表明给予化合物A或巴氯芬后呼吸频率的变化。
本发明详述
如在式I中所使用的,除非另外说明,以下术语定义如下:
M+代表在质谱中分子的分子离子和MH+代表在质谱中分子的分子离子加氢;
Bu是丁基;Et是乙基;Me是甲基;和Ph是苯基;
烷基(包括烷氧基、烷基氨基和二烷基氨基的烷基部分)代表含有1-12个碳原子或1-6个碳原子的直和支碳链;例如甲基、乙基、丙基、异-丙基、正-丁基、叔-丁基、正-戊基、异戊基、己基等;
链烯基代表在所述链中含有一个或两个双键的2-6个碳原子的烷基链,例如乙烯基、丙烯基或丁烯基;
炔基代表在所述链中含有一个三键的2-6个碳原子的烷基链,例如乙炔基或丙炔基;
烷氧基代表烷基部分通过氧原子共价结合到相邻的结构元素上,例如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等;
芳基(包括芳基烷基的芳基部分)代表含有6-15个碳原子和具有至少一个芳族环的碳环基(例如芳基是苯基),其中所述芳基任选可以与芳基、(C3-C7)环烷基、杂芳基或杂(C3-C7)环烷基环稠合;其中R7-芳基指在所述芳基和/或所述稠环中的任何适合取代的碳原子和氮原子任选并独立被取代,其中芳环由1-3个R7基团取代。芳基的实例是苯基、萘基和蒽基;
芳基烷基代表如上所定义的烷基,其中所述烷基部分的一个或更多个氢原子已由1-3个芳基取代;其中芳基如上所定义;
芳氧基代表如上所定义的芳基,其中所述芳基通过氧原子共价结合到相邻的结构元素上,如苯氧基;
环烷基代表3-12个碳原子、优选3-7个碳原子的饱和碳环;其中R6-环烷基指在所述环烷基中的任何适合取代的碳原子任选并独立被取代,其中所述环烷基环由1-3个R6基团取代;
环烷基烷基代表如上所定义的烷基,其中所述烷基部分的一个或更多个氢原子已由1-3个环烷基取代,其中环烷基如上所定义;
卤素代表氟、氯、溴和碘;
杂芳基代表具有1-3个选自O、S和N的杂原子的环基团,所述杂原子间断碳环结构并具有足够数目的非定域的π电子以便提供芳香性,芳杂环基含有5-14个碳原子,其中所述杂芳基可以任选与一个或更多个芳基、环烷基、杂芳基或杂环烷基环稠合;其中在所述杂芳基和/或所述稠环中的任何适合取代的碳或氮原子可以任选并独立被取代,其中所述杂芳环可以由1-3个R8基团取代;代表性的杂芳基可以包括例如呋喃基、噻吩基、咪唑基、嘧啶基、三唑基、2-、3-或4-吡啶基或2-、3-或4-吡啶基N-氧化物,其中吡啶基N-氧化物可以由下式代表:
杂芳基烷基代表如上所述的烷基,其中一个或更多个氢原子已由一个或更多个如上所述的杂芳基置换;
杂环烷基代表含有3-7个碳原子、优选4-6个碳原子,由1-3个选自-O-、-S-和-NR21的杂原子间断的饱和环,其中R21如上所定义,其中所述环可以任选含有一个或两个不饱和键,该键不赋予所述环芳香性;其中在所述环中任何适合取代的碳原子可以取代,其中所述杂环烷基的环可以由1-3个R10基团取代;代表性的杂环烷基包括2-或3-四氢呋喃基、2-或3-四氢噻吩基、1-、2-、3-或4-哌啶基、2-或3-吡咯烷基、1-、2-或3-哌嗪基、2-或4-二噁烷基、吗啉基、,其中R17如上所定义和t是0、1或2。
当在式I的哌啶基环中存在任选的双键时,X1和X2之一与3-位的碳形成键并且剩下的X1或X2不是氢。
当式I中的X1和X2形成如上所定义的螺环基团时,在定义中所示结构中的波纹线表示连接到哌啶基环4-位碳的连接点,例如形成下式的化合物:
一些式I的化合物可以存在不同的立体异构型(例如对映异构体、非对映异构体和阻转异构体)。本发明包括了所有这类纯的形式和混合物形式的立体异构体,包括外消旋混合物。
某些在本发明中使用的化合物在性质上是酸性的,例如那些具有羧基或酚羟基的化合物。这些化合物可以形成药学上可接受的盐。这类盐的实例可以包括钠、钾、钙、铝、金和银盐。也包括与药学上可接受的胺如氨、烷基胺、羟基烷基胺、N-甲基葡糖胺等形成的盐。
某些碱性化合物也形成药学上可接受的盐,例如酸加成盐。例如吡啶-氮原子可以与强酸形成盐,而那些具有碱性取代基如氨基的化合物也可与弱酸形成盐。用于形成盐的合适酸的实例是盐酸、硫酸、磷酸、乙酸、柠檬酸、草酸、丙二酸、水杨酸、苹果酸、富马酸、琥珀酸、抗坏血酸、马来酸、甲磺酸和那些本领域技术人员熟知的其它无机酸和羧酸。用常规方法,通过使游离碱形式与足够量的产生盐所需要的酸接触制备所述盐。所述游离碱形式可以通过用合适的稀碱水溶液如稀的NaOH、碳酸钾、氨和碳酸氢钠水溶液处理所述盐再生。游离碱形式与它们各自的盐形式在某些物理特性例如在极性溶剂中的溶解度方面多少有点不同,但是对于本发明的目的来说,所述酸和碱的盐在其它方面与它们各自的游离碱形式相同。
所有这类酸和碱的盐均打算作为在本发明范围内的药学上可接受的盐并且认为对于本发明的目的来说,所有酸和碱的盐与相应化合物的游离形式相当。
式I的化合物可以通过已知方法、由本领域已知的原料制备或通过本领域已知的方法制备。以下给出一般方法和特定制备的实例。
一般而言,X1,X2-取代的哌啶在过量的碱如K2CO3和Et3N存在下,在溶剂如DMF、THF或CH3CN中,在室温或在升高的温度下,用Z1,Z2,Z3-取代的卤代甲烷烷基化。
X1,X2-取代的哌啶可购买得到或通过已知方法制备。例如根据以下反应方案,可将4-羟基-4-苯基-哌啶转变为4-tBoc-氨基-4-苯基哌啶,其中Bn是苄基、Ph是苯基和tBoc是叔-丁氧基羰基:
将购买得到的4-苯基-4-哌啶醇用苄基保护,然后将得到的中间体用Me3SiCN处理。将得到的酰胺用HCl的CH3OH水溶液水解产生4-氨基化合物。将氨基用tBoc保护并通过氢解除去N-苄基产生所需的4-氨基-哌啶衍生物。
然后,可以使4-(保护的)氨基-哌啶与Z1,Z2,Z3-卤代甲烷反应并除去保护基。可以使胺(即X2是-NH2)经历各种标准转化以便得到胺衍生物。例如,可以使式I的胺与R22-甲醛在温和的还原剂如Na(OAc)3BH存在下反应或与式R22-L的化合物,其中L是离去基团如Cl或Br,在碱如Et3N存在下反应。
制备其中X1是R7-芳基和X2是OH的式I化合物的另一种方法涉及用Z1,Z2,Z3-卤代甲烷将4-哌啶酮盐酸盐烷基化,然后使该酮与合适取代的R7-苯基溴化镁或与式X1-L1的化合物,其中L1是Br或I和叔-丁基锂反应。
通过在X1和/或X2取代基上进行本领域已知的反应,可以将X1,X2-取代的式I化合物转变为其它的式I化合物。例如,可以将甲醛取代的哌啶(即X2是-CHO)转变为取代的哌啶,其中X2是R13-O-CH2-,如在以下用于式I化合物的方法中所示,其中X1是苯基,Z1和Z2分别是苯基和R1、R2、R3和R4,以及Z3是H:
可以将氰基取代的哌啶(即X2是-CN)转变为取代的哌啶,其中X2是R21R22N-CH2或X2是R28C(O)NH-CH2-,如在以下用于式I化合物的方法中所示,其中X1是苯基,R21、R1、R2、R3和R4,以及Z3是H,L是离去基团如Cl或Br:
通过其中R11是氢的相应的化合物与式R11L(R11不是H和L如上所定义)的化合物反应制备式I的化合物,其中X1是苯并稠合的含有氮的杂环,该杂环所具有的R11取代基不是氢。
另外,通过如前类似的方法与Z1,Z2,Z3-取代的卤代甲烷反应,可以将X1,X2-取代的哌啶原料转变为X1,X2-取代的哌啶。
对于式I化合物而言,其中R1、R2、R3和R4分别形成亚烷基桥,将购买得到的N-保护的4-哌啶酮用苯基锂处理并将得到的中间体脱保护以便产生所需的化合物,例如:其中Pr是N-保护基团,Ph是苯基和z是1-2。
Z1,Z2,Z3-卤代甲基衍生物,其中Z1和Z2是R7-苯基,可以购买得到或可以用以下反应方案中所示的方法制备:
可以使用类似的或本领域已知的其它方法制备其中Z取代基不是苯基的化合物。
通过以下实施例说明式I的化合物和其制备的原料,该实施例不能认为是对于所公开内容范围的限制。
本文中所提到的以下溶剂和试剂以缩写表示:四氢呋喃(THF);乙醇(EtOH);甲醇(MeOH);乙酸(HOAc或AcOH);乙酸乙酯(EtOAc);N,N-二甲基甲酰胺(DMF)和乙醚(Et2O)。室温缩写为rt。
在室温下搅拌4-羟基-4-苯基哌啶(1.5g,8.47mmol)和K2CO3(3.0g,21.73mmol)的CH3CN混合物。向该混合物中加入α-溴代-二苯基甲烷(2.5g,10.12mmol)并将反应物搅拌过夜。将该反应混合物浓缩,重新溶于CH2Cl2中,用水洗涤,干燥(MgSO4)并浓缩。层析(SiO2,9∶1己烷/EtOAc)得到标题化合物(2.6g,90%)。1H NMR(CDCl3):δ1.80(m,2H),2.25(m,2H),2.42(m,2H),2.90(m,2H),4.40(s,1H),7.2-7.6(m,15H)。
步骤1:用在实施例1中所述的方法,将4-哌啶酮一水合物盐酸盐(5g,32.6mmol)的CH3CN溶液烷基化。将残余物在硅胶上层析(95∶5己烷/EtOAc)得到所需的化合物。
步骤2:在0℃下,将溴化4-甲基苯基镁(0.5M,溶于THF中,1.75ml,0.87mmol)滴加入到步骤1产物(191mg,0.72mmol)的THF溶液中。在0℃下将该溶液搅拌2小时,用冰-水猝灭,用EtOAc萃取,用水和盐水洗涤,干燥并浓缩。将残余物在硅胶上层析(95∶5己烷/EtOAc,93∶7己烷/EtOAc)得到标题化合物(0.091g,30%)。1H NMR(CDCl3):δ7.5(m,6H,ArH),7.3(t,4H,ArH),7.2(t,4H,ArH),4.35(s,1H),2.8(d,2H),2.4(m,5H),2.2(td,2H),1.75(d,2H);MS(CI)358(M+1);C25H27NO.1.2H2O的元素分析:计算值:C 79.2,H 7.82,N 3.69;实测值:C 78.90,H 8.02,N 3.85。
实施例3
在-70℃下,将n-BuLi(2.5M,0.38ml,0.95mmol)滴加入到3-溴代噻吩(0.15g,0.95mmol)的Et2O溶液中并搅拌2小时。将实施例2步骤1的产物(230mg,0.87mmol)的Et2O(4ml)溶液加入到该反应混合物中,经3小时缓慢加热至室温,用冰冷的NH4Cl(水溶液)猝灭,用Et2O萃取,用H2O和盐水洗涤,干燥并浓缩。将残余物层析(95∶5己烷/EtOAc)得到标题化合物(90mg)。1H NMR(CDCl3):δ7.5(d,2H),7.35(bt,4H),7.25(m,3H),7.2(m,2H),4.4(s,1H),2.8(d,2H),2.5(t,2H),2.3(dt,2H),2.0(d,2H);MS(CI)350(M+1);对于C22H22NOS.1.1HCl.0.9H2O的元素分析:计算值:C 65.11,H 6.43,N 3.54,S 7.8,Cl 9.61;实测值:C65.27,H 6.54,N 3.45,S 7.30,Cl 9.43。
步骤1:用实施例1、步骤1的方法,将4-苯基-4-哌啶甲醛(1.0g,5.29mM)烷基化得到所需产物(1.69g,90%)。1H NMR(CDCl3):δ2.40(m,4H),2.50(m,2H),2.85(m,2H),4.25(s,1H),7.20-7.50(m,15H),9.42(s,1H)。
步骤2:将步骤1的产物(3.0g,8.45mmol)的溶液冷却至0℃并用NaBH4(1.0g,26.32mmol)处理。0.5小时后,将反应混合物用1N HCl处理并浓缩。将残余物用CH2Cl2萃取,干燥(MgSO4)并蒸发。将残余物柱层析(4∶1己烷/EtOAc)得到所需的伯醇。1H NMR(CDCl3):δ2.00(m,2H),2.25(m,4H),2.65(m,2H),3.65(d,2H),4.20(s,1H),4.25(d,1H),7.2-7.6(m,15H)。
步骤3:在0℃下,将步骤2的产物用NaH的DMF溶液处理0.5小时。加入CH3I并将反应物加热至室温。搅拌过夜后,将该反应混合物倒在冰上,用Et2O萃取,干燥(MgSO4)并蒸发。将残余物柱层析得到标题化合物。1H NMR(CDCl3):δ2.10(m,4H),2.40(m,2H),2.78(m,2H),2.90(m,2H),3.00(s,3H),4.38(s,1H),7.21-7.52(m,15H)。
实施例5
步骤1:将4-氰基-4-苯基哌啶盐酸盐(5.0g,22.4mM)的DMF(30ml)溶液用Et3N(7.20ml,47mM)和溴代二苯基甲烷(6.38g,25.80mM)处理并在室温、氮气氛下搅拌20小时。将该反应混合物在真空中浓缩并分配在EtOAc和H2O之间。将有机层用水洗涤两次,然后用盐水洗涤并干燥(MgSO4),过滤并浓缩。层析(SiO2,19∶1己烷/EtOAc),得到6.0g(76%)所需产物。1H NMR(CDCl3):δ2.21(m,4H),2.49(t,J=12.3Hz,2H),3.11(d,J=12.5Hz,2H),4.46(s,1H),7.45(m,15H)。
步骤2:将步骤1产物(6.0g,17mM)的Et2O(40ml)溶液冷却至0℃并在氮气氛下经0.5小时滴加1M LAH溶液(34.10ml,34mM)处理。将该反应混合物加热至室温,然后回流4小时。将反应混合物冷却至0℃并用水(8当量)处理。将反应混合物加热至室温并搅拌1小时。滤出得到的固体并用Et2O漂洗,将滤液浓缩得到5.45g(90%)所需产物。1H NMR(CD3OD):δ1.84(m,2H),2.16(m,4H),2.56(m,2H),2.68(m,2H),4.07(s,1H),7.25(m,15H)。
步骤3:在室温、氮气氛下,将步骤2产物(0.2g,0.56mM)的CH2Cl2溶液(3ml)用苯甲酰氯(0.078ml,0.673mM)和吡啶(0.045g,0.568mM)处理18小时。将该反应混合物浓缩,然后分配在H2O和CH2Cl2之间。用水(2x)和盐水洗涤有机层,然后干燥(MgSO4),过滤并浓缩。层析(SiO2,3∶1己烷/EtOAc)得到0.2g(77%)所需产物。1H NMR(CD3OD):δ2.13(m,6H),2.66(m,4H),3.50(s,2H),4.07(s,1H),7.11-7.65(m,20H)。
步骤4:将步骤3产物(0.075g,0.16mM)的THF(3ml)溶液搅拌着冷却至0℃。在氮气氛下加入LAH(固体,0.025g,0.65mM)并继续搅拌0.25小时。然后,将该反应混合物回流5小时,然后在室温下搅拌18小时。将反应混合物冷却至0℃并用水(8当量)猝灭。将反应混合物加热至室温并搅拌1小时。滤出得到的固体并用Et2O漂洗,将滤液干燥(MgSO4)并浓缩。层析(中性Al2O3,CH2Cl2,然后3∶1 CH2Cl2∶EtOAc),得到0.014g(20%)标题化合物。1H NMR(CD3OD):δ1.90(m,2H),2.15(m,4H),2.48(m,2H),2.68(s,2H),3.53(s,2H),4.05(s,1H),7.01-7.38(m,20H)。
将实施例5、步骤2的产物(0.2g,0.561mM)、乙酐(3ml)和Et3N(0.096ml,0.67mM)混合并在室温下搅拌18小时。将该反应混合物浓缩并分配在H2O和CH2Cl2之间。将有机层用水(2x)、盐水洗涤,然后干燥(MgSO4),过滤并浓缩得到0.214g(95%)标题化合物。1H NMR(CD3OD):δ1.87(m,5H),2.16(m,4H),2.61(m,2H),3.31(s,2H),4.07(s,1H),7.12-7.40(m,20H)。
实施例7
步骤1:将4-苯基-4-羟基哌啶(10.0g,56.4mM)的DMF(60ml)溶液用Et3N(8.28ml,59.2mM)和苄基溴(7.37ml,62.10mM)处理并在室温、氮气氛下搅拌20小时。将该反应混合物在真空中浓缩,用饱和NaHCO3碱化至pH为8并分配在EtOAc和H2O之间。将有机层用水洗涤两次,然后用盐水洗涤,干燥(MgSO4),过滤并浓缩。层析(中性Al2O3,己烷,然后1∶1己烷∶EtOAc),得到11.95g(80%)所需的产物。
步骤2:在氮气氛下,向在乙二醇/CO2浴中冷却至-15℃的步骤1产物(30.0g,0.112mol)和(CH3)3SiCN(59.94ml,0.448mol)的混合物中滴加入冰AcOH(47ml),同时保持内部温度为-15℃。滴加入浓H2SO4(47ml,0.34M),伴随剧烈搅拌,同时保持内部温度为-15℃。然后将冷却浴移去并将反应混合物在室温下搅拌18小时。将该反应混合物倒在冰上并用50% NaOH溶液将pH调至7,同时保持温度为25℃。然后,将反应混合物用CH2Cl2萃取并将有机层用水(2x)、然后用盐水洗涤。干燥(MgSO4),过滤并浓缩。用EtOAc/己烷(1∶10)重结晶,得到22.35g(68%)所需的化合物。1H NMR(CD3OD):δ2.10(m,2H),2.40(m,4H),2.82(d,J=11.50Hz,2H),3.57(s,2H),7.20-7.43(m,10H),8.05(s,1H)。
步骤3:将步骤2的产物(20g,67.9mM)和5%(w/w)浓HCl(水溶液)/CH3OH(350ml)在氮气氛下搅拌48小时。将该混合物浓缩得到泡沫状物,将其悬浮在Et2O中并浓缩以除去过量的HCl。将得到的固体重新悬浮在Et2O中,经真空过滤收集,用Et2O洗涤并在真空中干燥,得到所需产物(23g,100%)。二-HCl盐的1H NMR(CD3OD):δ2.59(t,J=13.3Hz,2H),2.93(t,J=13.3Hz,2H),3.07(d,J=13.50Hz,2H),3.58(d,J=13Hz,2H),4.26(s,2H),7.56(m,10H)。
步骤4:将步骤3的产物(24.10g,71mM)、CH2Cl2(300ml)、(tBoc)2O(17.0g,78.1mM)和Et3N(14.37g,0.142M)混合并在氮气氛、室温下搅拌18小时。将该反应混合物分配在CH2Cl2和H2O之间,将含水层用CH2Cl2萃取。将合并的有机层用水(2x)、然后用盐水洗涤并干燥(MgSO4),过滤并浓缩。将得到的固体悬浮在Et2O中并声处理,过滤并干燥得到所需化合物(21.98g,90%)。1H NMR(CD3OD):δ1.09(bs,2H),1.39(s,1H),2.05(m,2H),2.34(m,4H),2.65(d,J=11.8Hz,2H),3.56(s,2H),7.18-7.40(m,10H)。
步骤5:将步骤4的产物(5.22g,14.2mM)、CH3OH(430ml)、Pd(OH)2/C(3.0g)和NH4COOH(18.86g,0.298M)混合并在氮气氛下回流8小时。将该反应混合物用硅藻土过滤,用CH3OH洗涤。将合并的滤液浓缩得到所需产物(3.90g,97%)。1H NMR(CD3OD):δ1.10(bs,2H),1.39(s,7H),1.90(m,2H),2.26(m,4H),2.92(m,4H),7.17-7.41(m,5H)。
步骤6:将步骤5的产物(2.74g,9.91mM)、CH3CN(85ml)、Et3N(1.75ml,12.40mM)和溴代二苯基甲烷(2.70g,10.9mM)混合并在室温、氮气氛下搅拌18小时。将该混合物浓缩并将得到的残余物分配在H2O和EtOAc之间。用水(2x)、盐水洗涤EtOAc层,然后干燥(MgSO4),过滤并浓缩。层析(中性Al2O3,己烷,然后4∶1己烷∶EtOAc),得到2.85g(65%)所需产物。1H NMR(CD3OD):δ1.07(bs,2H),1.37(s,7H),2.23(m,2H),2.24(m,4H),2.74(d,J=12.1Hz,2H),4.27(s,1H),7.10-7.47(m,15H)。
步骤7:将步骤6的产物(4.6g,10mM)、1,4-二噁烷(38ml)和4MHCl的1,4-二噁烷(25ml,101mM)混合并在室温、氮气氛下搅拌4小时。将该混合物浓缩并将残余物悬浮在Et2O中并重新浓缩。将得到的固体重新悬浮在Et2O中,声处理并通过真空过滤收集产物并干燥,得到3.27g(80%)所需产物。二-HCl盐的1H NMR(CD3OD):δ2.91(m,8H),5.34(s,1H),7.37-7.77(m,15H)。
步骤8:在氮气氛、室温下,向步骤7产物(0.3g,0.722mM)的CH2Cl2(3ml)悬浮液中加入2-噻吩甲醛(0.133ml,1.44mM)。用Et3N将反应物的pH调节至6并将该混合物搅拌0.5小时。然后加入Na(OAc)3BH(0.230g,1.08mM)并将反应混合物在室温、氮气氛下搅拌3小时。将反应物用饱和NaHCO3(水溶液)猝灭并分配在Et2O和H2O之间。用水(2x)、盐水洗涤有机层,干燥(MgSO4),过滤并浓缩。层析(SiO2,甲苯,然后1∶19 EtOAc∶甲苯),得到0.158g(50%)所需产物。1H NMR(CD3OD):δ1.96(m,2H),2.17(m,2H),2.52(m,4H),3.45(s,2H),4.24(s,1H),6.76(d,J=3.5Hz,1H),6.85(dd,J=3.6Hz,1H),7.13-7.50(m,16H)。
实施例8
步骤1:用实施例1步骤1所述的方法,将4-(2-氧代-1-苯并咪唑基)-哌啶的CH3CN溶液烷基化得到所需化合物。
步骤2:向3-[1-(二苯基甲基)-4-哌啶基]-1,3-二氢-2H-苯并咪唑-1-酮(2.5g,6.6mmol)的DMF(25ml)溶液中加入NaH并在室温下搅拌1小时。在室温下向该混合物中加入正-丁基碘并搅拌过夜。用冰-水猝灭,用EtOAc萃取,用水和盐水洗涤,干燥(MgSO4)并浓缩。将残余物在硅胶上层析(1∶9 EtOAc/己烷),得到标题化合物(2.35g)。将标题化合物溶于Et2O中,加入HCl的Et2O溶液(8ml,1M),搅拌1小时并过滤得到HCl盐。1H NMR(CDCl3):δ7.55(m,4H,ArH),7.35(m,5H,ArH),7.25(m,2H,ArH),7.15(m,2H,ArH),7.1(m,1H,ArH),4.4(m,2H),3.95(t,2H),3.15(d,2H),2.6(dq,2H),2.1(t,2H,1.8,m,4H),1.5(m,2H),1.0(t,3H);ESI-MS 440(M+1);C29H33N3O.HCl.H2O的元素分析:计算值:C 70.5,H 7.3,N 8.5,Cl 7.18;实测值:C 70.48,H 7.28,N 8.49,Cl 7.49。
在室温下,向2-(氯代-苯基)苯基甲醇(300mg,1.38mmol)的CH2Cl2溶液中加入SOCl2(247mg,2.07mmol),在室温下搅拌5小时并浓缩。将残余物溶于CH3CN中,加入K2CO3、4-羟基-4-苯基哌啶和NaI。将该溶液在回流下搅拌过夜,过滤并浓缩。将残余物在硅胶上层析(9∶1己烷/EtOAc),得到标题化合物。1H NMR(CDCl3):δ7.91(d,1H),7.58(d,2H),7.54(d,2H),7.42(t,2H),7.32(m,5H),7.26(t,3H),7.16(t,3H),5.0(s,1H),2.8(dd,2H),2.5(dq,2H),2.2(dt,2H),1.75(d,2H)。将标题化合物溶于乙醚中,加入HCl/Et2O(1M),得到HCl盐。MS(CI)378(M+1);C24H24NOCl.HCl.0.2H2O的元素分析:计算值:C 68.97,H 6.13,N 3.35,Cl 16.96;实测值:C 68.87,H 6.04,N 3.35,Cl 17.00。
实施例10
步骤1:用在实施例9中所述的方法,用扁桃腈(1g,7.51mmol)将4-哌啶酮一水合物盐酸盐(880mg,5mmol)的CH3CN溶液烷基化。将残余物在硅胶上层析,随后重结晶(EtOAc),得到所需化合物(630mg)。
步骤2:在0℃下,向步骤1产物(330mg,1.185mmol)的THF溶液中加入溴化2-甲氧基苯基镁的THF溶液(24ml,0.5M,11.85mmol)。除去冰浴并将该反应混合物在回流下搅拌6小时。将反应物用NH4Cl(水溶液)猝灭,用EtOAc萃取,用盐水洗涤,干燥并浓缩。将残余物层析(95∶5,9∶1己烷/EtOAc),得到标题化合物(330mg)。1H NMR(CDCl3):δ7.76(d,1H),7.62(d,1H),7.55(d,1H),7.45(t,1H),7.34(m,3H),7.24(m,2H),7.03(t,1H),6.90(d,2H),4.88(s,1H),3.89(s,3H),2.94(d,1H),2.82(d,1H),2.45(td,2H),2.26(t,2H),1.78(d,2H)。将标题化合物溶于Et2O中,加入HCl的Et2O溶液,搅拌1小时并过滤得到HCl盐。MS FAB 374.1(M+1);对于C25H27NO2.HCl.0.15H2O的元素分析:计算值:C 72.77,H 6.91,N 3.39,Cl 8.59;实测值:C 72.76,H7.02,N 3.59,Cl 8.83。
步骤1:用在实施例1的步骤1中所述的方法,将1-苯基-1,3,8-三氮杂螺[4,5]癸烷-4-酮(0.5g)的CH3CN溶液烷基化,得到所需化合物。
步骤2:通过实施例1的步骤2中所述的方法,用CH3I将步骤1的产物1-苯基-8-(二苯基甲基)-1,3,8-三氮杂螺[4,5]癸烷-4-酮(0.4g)烷基化,得到标题化合物(0.25g)。1H NMR(CDCl3):δ1.70(d,2H),2.85(m,6H),3.05(s,3H),4.50(s,1H),4.72(s,2H),6.95(t,1H),7.05(d,2H),7.20-7.60(m,12H)。
用实施例1-11的方法,使用合适的原料,制备以下表中所示的化合物。
表7
根据引用的专利说明书中公开的方法可以制备式II-VI的化合物。测定nociceptin结合测定
将表达ORL-1受体的CHO细胞膜制品(2mg)与在含有50mMHEPES(pH7.4)、10mM NaCl、1mM MgCl2、2.5mM CaCl2、1mg/ml牛血清清蛋白和0.025%杆菌肽的缓冲液中的各种浓度的[125I][Tyr14]nociceptin(3-500pM)一起温育。在一些研究中,在50mM tris-HCl(pH7.4)、1mg/ml牛血清清蛋白和0.025%杆菌肽的缓冲液中进行测定。将样品在室温(22℃)下温育1小时。用Brandell细胞收获器,通过在0.1%聚乙烯亚胺中预浸过的GF/B滤膜收获结合到细胞膜上的放射性标记的配体并用5ml冷蒸馏水洗涤5次。通过在1μM nociceptin存在下进行的类似测定,平行测定非特异性结合。在总的和非特异性结合的所有测定点进行重复试验。
用本领域熟知的方法进行Ki的计算。
实施例12咳嗽研究
化合物A 化合物B
根据Bolser等British Journal of Pharmacology(1995)114,735-738的方法,评估在由辣椒素引起咳嗽的豚鼠体内nociceptin激动剂化合物A(0.3-10mg/kg,口服)和化合物B(10mg/kg,口服)的效应。该模型为评估潜在镇咳药的活性的广泛使用的方法。将禁食过夜的雄性Hartley豚鼠(350-450g,Charles River,Bloomington,MA,USA)放置在12”×14”的透明小室内。将该动物暴露在由喷射喷雾器(Puritan Bennett,Lenexa,KS,USA)产生的雾化辣椒素(300μM,4分钟)中以诱发咳嗽反射。将每只豚鼠只暴露在辣椒素中一次。通过放置在小室中的扩音器检查咳嗽的次数并由训练有素的观察员验证。将来自扩音器的信号传送到描记器,描记器提供咳嗽次数的记录。在给予雾化辣椒素以前2小时,给予溶媒(甲基纤维素1ml/kg,口服)或化合物A或化合物B。将巴氯芬(3mg/kg,口服)作为阳性对照也测试其镇咳活性。该结果以条状图形式归结在图1中。
实施例13呼吸测定
对体重为450-550g的雄性Hartley豚鼠进行研究。将所述动物禁食过夜但无限止地给予饮水。将该豚鼠全身在内、头在外放置在体积描记器中并将橡皮圈置于动物的头部以便在豚鼠和体积描记器之间形成密封。测定作为金属丝网筛两侧压差的气流,所述金属丝网筛覆盖在体积描记器壁的1-英寸孔上。用前置放大器电路和肺功能计算机(Buxco Electronics,Sharon,CT,型号XA)将气流信号集成为与体积成正比的信号。将脑室连接到体积描记器上并通过脑室计算来自压缩气源(21% O2,其余为N2)的气流以便连续研究。在豚鼠呼吸所述循环气体的同时,进行全部呼吸测量。
将来自每只动物的体积信号传送到数据收集/分析系统(BuxcoElectronics,型号XA)中,该系统计算不间断呼吸的潮气量和呼吸频率。这些信号被可视性地显示在监测器上。以每分平均值记录潮气量和呼吸频率。
将豚鼠在体积描记器中平衡30分钟。在30分钟末得到基础测定值。然后,将豚鼠从体积描记器中移出并口服给予来自实施例12的化合物A(10mg/kg,口服)、巴氯芬(3mg/kg,口服)或甲基纤维素溶媒空白对照剂(2ml/kg,口服)。给药或溶媒后立即将豚鼠放入体积描记器中,将脑室与循环气体重新连接并在治疗后30、60、90和120分测定呼吸变量。在ACUC方案#960103条件下进行此研究。数据分析
测定基础条件和给药或溶媒后每一时间点的潮气量(VT)、呼吸频率(f)和分钟量(MV=VT×f)。将结果表示为均值±SEM。该结果显示在图2A、2B和2C中。图2A表示潮气量的变化,图2B表示潮气量的变化和图2C表示呼吸频率的变化。
我们惊奇地发现,nociceptin受体ORL-1激动剂显示出镇咳活性,它们在哺乳动物体内可以有效地抑制咳嗽。ORL-1激动剂降低了咳嗽的严重程度和频率。咳嗽可以是慢性、顽固的或由短暂的医疗或环境条件引起。引起咳嗽的非限定实例为刺激物、炎性疾病、感冒、哮喘和上呼吸道疾病。
对于治疗咳嗽的哺乳动物,nociceptin受体ORL-1激动剂可以与选自以下的一种或更多种其它的治疗咳嗽、变态反应或哮喘症状的药物一起给药:抗组胺药、5-脂氧合酶抑制剂、白三烯抑制剂、H3抑制剂、β-肾上腺素能受体激动剂、黄嘌呤衍生物、α-肾上腺素能受体激动剂、肥大细胞稳定剂、镇咳药、祛痰药、减充血剂、NK1、NK2和NK3速激肽受体拮抗剂和GABAB激动剂。例如,ORL-1激动剂可以与祛痰药或抗组胺药联合给药,或与祛痰药和抗组胺药联合给药。所述联合优选包括2-4种活性剂。
抗组胺药的非限定性实例包括:阿斯咪唑、阿扎他定、氮斯汀、阿伐斯汀、溴苯那敏、西替利嗪、氯苯那敏、氯马斯汀、赛克力嗪、卡瑞斯汀、赛庚啶、卡比沙明、descarboethoxyloratadine(也称为SCH-34117)、多西拉敏、二甲茚定、依巴斯汀、依匹斯汀、efletirizine、fexofenadine、羟嗪、酮替芬、氯雷他定、左卡巴斯汀、咪唑斯汀、equitazine、米安色林、诺柏斯汀、美克洛嗪、norastemizole、哌香豆司特、美吡拉敏、异丙嗪、特非那定、曲吡那敏、替美斯汀、阿利马嗪和曲普利啶。
非限定性组胺H3受体拮抗剂的实例包括:thioperamide、英普咪定、布立马胺、clobenpropit、impentamine、咪芬替丁、S-索普咪定、R-索普咪定、SKF-91486、GR-175737、GT-2016、UCL-1199和氯氮平。通过已知方法包括豚鼠脑膜测定和豚鼠神经元(neuronal)回肠收缩测定,可以容易地评估确定H3受体活性的其它化合物,所述两种方法在美国专利5,352,707中被介绍。另一种有用的测定可以利用大鼠脑膜并由West等在“Identification of Two-H3-组胺受体亚型”,MolecularPharmacology,第38卷,第610-613页(1990)中介绍。
术语“白三烯抑制剂”包括任何抑制、限定、阻滞白三烯的作用或活性或者反之与白三烯的作用或活性相配合的药物或化合物。白三烯抑制剂的非限定性实例包括在EP 0 480 717中介绍的montelukast[R-(E)]-1[[[1-[3-[2-(7-氯代-2-喹啉基)-乙烯基]苯基]-3[2-(1-羟基-1-甲基乙基)苯基]丙基]硫代]甲基]环丙烷乙酸和它的钠盐;在WO97/28797和美国专利5,270,324中介绍的1-(((R)-(3-(2-(6,7-二氟代-2-喹啉基)乙烯基)苯基)-3-(2-(2-羟基-2-丙基)苯基)硫代)甲基环丙烷乙酸和它的钠盐;在WO 97/28797和美国专利5,472,964中介绍的1-(((1(R)-3(3-(2-(2,3-二氯代噻吩并[3,2-b]吡啶-5-基)-(E)-乙烯基)苯基)-3-(2-(1-羟基-1-甲基乙基)苯基)丙基)硫代)甲基)环丙烷乙酸和它的钠盐;在WO97/28797和EP 173,516中介绍的普仑司特(N-[4-氧代-2-(1H-四唑-5-基)-4H-1-苯并吡喃-8-基]-对-(4-苯基丁氧基)苯甲酰胺);在WO97/28797和EP 199,543中介绍的zafirlukast(3-[2-甲氧基-4-[(邻-甲苯磺酰基)氨基甲酰基]苄基]-1-甲基吲哚-5-氨基甲酸环戊酯);和在美国专利5,296,495和日本专利JP 08325265A中介绍的[2-[[2-(4-叔丁基-2-噻唑基)-5-苯并呋喃基]氧代甲基]苯基]乙酸。
术语”5-脂氧合酶抑制剂”或5-LO抑制剂”包括任何抑制、限定、阻滞5-脂氧合酶的酶作用或反之与5-脂氧合酶的酶作用相配合的药物或化合物。5-脂氧合酶抑制剂的非-限定性实例包括齐留通、多西苯醌、吡前列素、ICI-D2318和ABT 761。
β-肾上腺素能受体激动剂的非限定性实例包括:沙丁胺醇、比托特罗、异他林、mataproterenol、perbuterol、沙美特罗、特布他林、异丙肾上腺素、麻黄碱和肾上腺素。
黄嘌呤衍生物的非限定性实例是茶碱。
α-肾上腺素能受体激动剂的非限定性实例包括芳基烷基胺类(例如苯丙醇胺和伪麻黄碱)、咪唑类(例如萘甲唑林、羟甲唑啉、四氢唑啉和赛洛唑啉)和环烷基胺类(例如丙己君)。
肥大细胞稳定剂的非限定性实例是奈多罗米钠。
镇咳药的非限定性实例包括可待因、右美沙芬、苯佐那酯、氯苯达诺和那可丁。
祛痰药的非限定性实例是愈创甘油醚。
减充血剂的非限定性实例是伪麻黄碱、苯丙醇胺和去氧肾上腺素。
NK1、NK2和NK3速激肽受体拮抗剂的非限定性实例包括CP-99,994和SR 48968。
GABAB激动剂的非限定性实例包括巴氯芬和3-氨基丙基-次膦酸。
对于由本发明公开的化合物制备药用组合物而言,惰性、药学上可接受的载体可以是固体或液体。固体形式制剂包括散剂、片剂、分散颗粒剂、胶囊剂、扁形胶囊剂和栓剂。散剂和片剂可以含有大约5-70%的活性成分。合适的固体载体是本领域已知的,例如碳酸镁、硬脂酸镁、滑石、糖、乳糖。片剂、散剂、扁形胶囊剂和胶囊可以作为适合口服的固体剂型使用。
对于制备栓剂而言,首先将低熔点的蜡如脂肪酸甘油酯或可可油的混合物熔化,随着搅拌其活性成分均匀地分散。然后将熔化的均匀混合物倒入合适尺寸的模具中,冷却,从而凝固。
液体形式的制剂包括溶液、悬浮液和乳液。可以提及的实例是用于肠胃外注射的水或水-丙二醇的溶液。
液体形式制剂也可以包括用于鼻内给药的溶液。
适合吸入的气雾剂可以包括溶液和粉末形式的固体,它们可以与药学上可接受的载体如惰性压缩气体混合。
也包括固体形式制剂,该制剂为可以在使用前的短时间内转变为液体形式制剂以便口服或肠胃外给药。这样的液体形式包括溶液、悬浮液和乳液。
本发明的化合物也可以经皮使用。经皮的组合物可以是乳膏、洗液、气雾剂和/或乳剂的形式并可以包括在基质型或贮库型(如本领域用于此目地的传统类型)的经皮贴剂中。
优选所述化合物口服给药。
优选药用制剂为单位剂量形式。在此形式中,所述制剂可以再分为含有合适量如达到所需目的的有效量的活性成分。
所实际使用的剂量可以根据病人的需要和所治疗疾病的严重度而变化。对于特定情况的合适剂量的确定方法是本领域技术人员已知的。通常,治疗从较小的剂量(其小于所述化合物的最佳剂量)开始。然后,将剂量少量递增直到在所述情况下达到最佳的效果。为方便起见,如果需要可将总的日剂量分成等分并在一天内分次给药。
给予本发明的化合物和其药学上可接受的盐的量和次数将根据临床医师考虑如病人的年令、状态和身高体重以及所治疗疾病的严重程度的判断调整。
用于治疗咳嗽而言,单位剂量的nociceptin受体ORL-1激动剂的用量优选大约0.1mg-1000mg,更优选大约1mg-300mg。常用建议剂量为口服1mg-2000mg/天,优选1-1000mg/天,分为2-4个分剂量。在此剂量范围内给药,所述化合物是无毒性的。
当nociceptin受体ORL-1激动剂与一种或更多种其它药物一起给药时,它们优选以复合剂型(例如单一片剂)给药,尽管它们可以分别给药。以有效提供缓解咳嗽、变态反应或哮喘症状的量给予所述的其它药物,优选每单位剂量大约0.1mg-1000mg,更优选大约1mg-300mg。通常推荐的所述其它药物的剂量为1mg-2000mg/天,优选1-1000mg/天,以2-4个分剂量。
以下是含有本发明化合物的药用剂型的实施例。所提供的实施例不是对本发明药用组合物范围的限制。
药用剂型实施例
实施例A-片剂
编号 | 成分 | mg/片 | mg/片 |
1 | 活性化合物 | 100 | 500 |
2 | 乳糖USP | 122 | 113 |
3 | 玉米淀粉,食用级,为溶于纯化水中的10%糊 | 30 | 40 |
4 | 玉米淀粉,食用级 | 45 | 40 |
5 | 硬脂酸镁 | 3 | 7 |
总计 | 300 | 700 |
制备方法
在合适的混合器中将第1和2项混合10-15分钟。用第3项将所述混合物制粒。如果需要将湿颗粒通过粗孔筛(如1/4”,0.63cm)。将湿颗粒干燥。如果需要,将干颗粒过筛并与第4项混合并混合10-15分钟。加入第5项并混合1-3分钟。在合适的压片机上将混合物压成合适的大小和重量。
实施例B-胶囊剂
编号 | 成分 | mg/胶囊 | mg/胶囊 |
1 | 活性化合物 | 100 | 500 |
2 | 乳糖USP | 106 | 123 |
3 | 玉米淀粉,食用级 | 40 | 70 |
4 | 硬脂酸镁NF | 7 | 7 |
总计 | 253 | 700 |
制备方法
在合适的掺合器中将第1、2和3项混合10-15分钟。加入第4项并混合1-3分钟。在合适的胶囊包封机上将所述混合物填入合适的两节的硬明胶胶囊中。
尽管结合以上所述特定的实施方案已经介绍了本发明,其许多替代、改进和变体对本领域普通技术人员而言是显而易见的。所有这些替代、改进和变体都在本发明的精神和范围之内。
Claims (12)
1.单独的ORL-1受体激动剂或与一种或更多种治疗咳嗽、变态反应或哮喘症状的药物联合以便治疗咳嗽的用途。
2.权利要求1的用途,其中所述ORL-1激动剂选自:a)一种由下式代表的化合物或其药学上可接受的盐或溶剂化物,其中:虚线代表任选的双键;X1是R5-(C1-C12)烷基、R6-(C3-C12)环烷基、R7-芳基、R8-杂芳基或R10-(C3-C7)杂环烷基;X2是-CHO、-CN、-NHC(=NR26)NHR26、-CH(=NOR26)、-NHOR26、R7-芳基、R7-芳基(C1-C6)烷基、R7-芳基(C1-C6)链烯基、R7-芳基(C1-C6)-炔基、-(CH2)vOR13、-(CH2)vCOOR27、-(CH2)vCONR14R15、-(CH2)vNR21R22或-(CH2)vNHC(O)R21,其中v是0、1、2或3和其中q是1-3和a是1或2;或X1是和X2是氢;或X1和X2一起形成下式的螺环基团m是1或2;n是1、2或3,条件是当n是1时,R16和R17之一是-C(O)R28;p是0或1;Q是-CH2-、-O-、-S-、-SO-、-SO2-或-NR17-;R1、R2、R3和R4独立选自氢和(C1-C6)烷基,或(R1和R4)或(R2和R3)或(R1和R3)或(R2和R4)可以一起形成1-3个碳原子的亚烷基桥;R5是1-3个独立选自以下基团的取代基:H、R7-芳基、R6-(C3-C12)环烷基、R8-杂芳基、R10-(C3-C7)杂环烷基、-NR19R20、-OR13和-S(O)0-2R13;R6是1-3个独立选自以下基团的取代基:H、(C1-C6)烷基、R7-芳基、-NR19R20、-OR13和-SR13;R7是1-3个独立选自以下基团的取代基:氢、卤素、(C1-C6)烷基、R25-芳基、(C3-C12)环烷基、-CN、-CF3、-OR19、-(C1-C6)烷基-OR19、-OCF3、-NR19R20、-(C1-C6)烷基-NR19R20、-NHSO2R19、-SO2N(R26)2、-SO2R19、-SOR19、-SR19、-NO2、-CONR19R20、-NR20COR19、-COR19、COCF3、-OCOR19、-OCO2R19、-COOR19、-(C1-C6)烷基-NHCOOC(CH3)3、-(C1-C6)烷基-NHCOCF3、-(C1-C6)烷基-NHSO2-(C1-C6)烷基、-(C1-C6)烷基-NHCONH-(C1-C6)-烷基或,其中f是0-6;或在相邻环碳原子上的R7取代基可一起形成亚甲二氧基或亚乙二氧基环;R8是1-3个独立选自以下基团的取代基:氢、卤素、(C1-C6)烷基、R25-芳基、(C3-C12)环烷基、-CN、-CF3、-OR19、-(C1-C6)烷基-OR19、-OCF3、-NR19R20、-(C1-C6)烷基-NR19R20、-NHSO2R19、-SO2N(R26)2、-NO2、-CONR19R20、-NR20COR19、-COR19、-OCOR19、-OCO2R19和-COOR19;R9是氢、(C1-C6)烷基、卤素、-OR19、-NR19R20、-NHCN、-SR19或-(C1-C6)烷基-NR19R20;R10是H、(C1-C6)烷基、-OR19、-(C1-C6)烷基-OR19、-NR19R20或-(C1-C6)烷基-NR19R20;R11独立选自H、R5-(C1-C6)烷基、R6-(C3-C12)环烷基、-(C1-C6)烷基(C3-C12)环烷基、-(C1-C6)烷基-OR19、-(C1-C6)烷基-NR19R20和,其中q和a如上所定义;R12是H、(C1-C6)烷基、卤素、-NO2、-CF3、-OCF3、-OR19、-(C1-C6)烷基-OR19、-NR19R20或-(C1-C6)烷基-NR19R20;R13是H、(C1-C6)烷基、R7-芳基、-(C1-C6)烷基-OR19、-(C1-C6)烷基-NR19R20或-(C1-C6)烷基-SR19;R14和R15独立选自氢、R5-(C1-C6)烷基、R7-芳基和,其中q和a如上所定义;R16和R17独立选自氢、R5-(C1-C6)烷基、R7-芳基、(C3-C12)环烷基、R8-杂芳基、R8-杂芳基(C1-C6)烷基、-C(O)R28、-(C1-C6)烷基(C3-C7)-杂环烷基、-(C1-C6)烷基-OR19和-(C1-C6)烷基-SR19;R19和R20独立选自氢、(C1-C6)烷基、(C3-C12)环烷基、芳基和芳基(C1-C6)烷基;R21和R22独立选自氢、(C1-C6)烷基、(C3-C12)环烷基、(C3-C12)环烷基(C1-C6)烷基、(C3-C7)杂环烷基、-(C1-C6)烷基(C3-C7)杂环烷基、R7-芳基、R7-芳基(C1-C6)烷基、R8-杂芳基(C1-C12)烷基、-(C1-C6)烷基-OR19、-(C1-C6)烷基-NR19R20、-(C1-C6)烷基-SR19、-(C1-C6)烷基-NR18-(C1-C6)烷基-O-(C1-C6)烷基和-(C1-C6)烷基-NR18-(C1-C6)烷基-NR18-(C1-C6)烷基;R18是氢或(C1-C6)烷基;Z1是R5-(C1-C12)烷基、R7-芳基、R8-杂芳基、R6-(C3-C12)环烷基、R10-(C3-C7)杂环烷基、-CO2(C1-C6)烷基、CN或-C(O)NR19R20;Z2是氢或Z1;Z3是氢或(C1-C6)烷基;或Z1、Z2和Z3与它们所连接的碳原子一起形成以下基团,其中r是0-3;w和u各是0-3,条件是w和u的总数是1-3;c和d独立是1或2;s是1-5;和环A是稠合的R7-苯基或R8-杂芳基环;R23是1-3个独立选自H、(C1-C6)烷基、-OR19、-(C1-C6)烷基-OR19、-NR19R20和-(C1-C6)烷基-NR19R20的取代基;R24是1-3个独立选自R23、-CF3、-OCF3、NO2或卤素的取代基,或在相邻环碳原子上的R24取代基可以一起形成亚甲二氧基或亚乙二氧基环;R25是1-3个独立选自H、(C1-C6)烷基、(C1-C6)烷氧基和卤素的取代基;R26独立选自H、(C1-C6)烷基和R25-C6H4-CH2-;R27是H、(C1-C6)烷基、R7-芳基(C1-C6)烷基或(C3-C12)环烷基;和R28是(C1-C6)烷基、-(C1-C6)烷基(C3-C12)环烷基、R7-芳基、R7-芳基-(C1-C6)烷基、R8-杂芳基、-(C1-C6)烷基-NR19R20、-(C1-C6)烷基-OR19或-(C1-C6)烷基-SR19;b)一种由式II代表的化合物其中R1a和R2a彼此独立是氢、低级烷基、低级烷氧基或卤素;R3a是苯基,任选由低级烷基、CF3、低级烷氧基或卤素取代;和R4a是氢、低级烷基、低级链烯基、-C(O)-低级烷基、-C(O)-苯基、低级烷基-C(O)-苯基、低级亚烷基-C(O)-低级烷基、低级烷三基-二-C(O)O-低级烷基、羟基-低级烷基、低级烷基-O-低级烷基、低级烷基-CH(OH)CF3、苯基或苄基;R5a和R6a彼此独立是氢、苯基、低级烷基或二-低级烷基或可以一起形成苯环,和R5a与R1a或R2a之一可以一起形成饱和或不饱和6元环;Aa是4-7元饱和环,该环可以含有杂原子如O或S,或其药学上可接受的酸加成盐;c)一种结构式III代表的化合物其中R1b是氢、低级烷基、卤素、低级烷氧基、CF3、低级烷基-苯基或(C5-7)-环烷基;R2b是氢、低级烷基、苯基或低级烷基-苯基;R3b是氢、低级烷基、苄基、低级烷基-苯基、低级烷基-二苯基、三嗪基、氰基甲基、低级烷基-哌啶基、低级烷基-萘基、(C5-7)-环烷基、低级烷基-(C5-7)-环烷基、低级烷基-吡啶基、低级烷基-吗啉基、低级烷基二氧戊环基、低级烷基、噁唑基或低级烷基-2-氧代-噁唑烷基并且其中的环系统可以由另外的低级烷基、低级烷氧基、CF3或苯基取代,或-(CH2)nC(O)O-低级烷基、-(CH2)nC(O)NH2-、-(CH2)nC(O)N(低级烷基)2、-(CH2)nOH或-(CH2)nC(O)NHCH2C6H6;R4b是氢、低级烷基或次氮基;Ab是由(a)(C5-15)-环烷基组成的环系统,除R4b外它可以任选由低级烷基、CF3、苯基、(C5-7)-环烷基、螺-十一烷-烷基或由2-降冰片基取代,或是以下基团之一:十二氢-苊-1-基(e)、双环[6.2.0]癸-9-基(f)和双环壬烷-9-基(g);和其中R5b和R6b是氢、低级烷基或与其所连接的碳原子一起形成苯环;R7b是氢或低级烷基;虚线代表任选的双键和n是1-4;或其药学上可接受的酸加成盐;d)一种由结构式IV代表的化合物或其药学上可接受的盐,其中R1c和R2c独立是C1-C4烷基;或R1c和R2c与它们所连接的碳原子一起形成具有6-13个碳原子的单-、双-、三-或螺-环基团,其中所述环基团由独立选自以下的1-5个取代基任选取代:C1-C4烷基、C2-C4亚烷基、C1-C4烷氧基、羟基、氧代、=CH2和=CH-C1-C4烷基;R3c是C1-C7烷基、C2-C5链烯基、C2-C5炔基、苯基-C1-C5烷基、由1-3个独立选自以下基团的取代基任选取代的苯基:氟、C1-C3烷基和C1-C3烷氧基,或选自呋喃基、噻吩基(theinyl)、吡咯基和吡啶基的杂芳基,其中所述杂芳基由1-3个独立选自卤素、C1-C3烷基和C1-C3烷氧基的取代基任选取代,条件是当R1c和R2c都是C1-C4烷基时,则R3c不是C1-C7烷基、C2-C5链烯基和C2-C5炔基;R4c选自1)氢;2)任选取代的一-或二-取代的C1-C8烷基、C3-C7环烷基、C2-C8链烯基、C2-C8炔基、C1-C6烷基-Zc、C1-C6烷基-Zc-(C1-C6)烷基、C3-C7环烷基-Zc-(C1-C6)烷基、C2-C6链烯基-Zc-(C1-C6)烷基或C2-C6炔基-Zc-(C1-C6)烷基,其中Zc选自O、S、SO、SO2、CO、CO2、OCO、NRc、CONRc和NRcCO,其中Rc是氢或C1-C6烷基,并且连接烷基、链烯基、炔基或环烷基部分的取代基独立选自卤素、羟基、羧基、氨基、一-或二-(C1-C4烷基)氨基、肼基、叠氮基、脲基、脒基和胍基;或3)任选一-或二-取代的芳基、杂环、芳基(C1-C5)烷基、杂环(C1-C5)烷基、杂环-杂环(C1-C5)烷基、芳基-杂环(C1-C5)烷基、杂环-Zc-(C1-C5)烷基、芳基-Zc-(C1-C5)烷基、芳基(C1-C5)烷基-Zc-(C1-C5)烷基或杂环(C1-C5)烷基-Zc-(C1-C5)烷基,其中Zc选自O、S、SO、SO2、CO、CO2、OCO、NRc、CONRc和NRcCO,其中Rc是氢或C1-C6烷基,连接芳基或杂环部分的取代基独立选自卤素、羟基、羧基、C1-C4烷基、C1-C4烷氧基、C1-C4烷基-CO-、氨基(C1-C4)烷基-CO-、苯基、苄基、氨基、一-或二-(C1-C4烷基)氨基、肼基、叠氮基、脲基、脒基和胍基;R5c独立选自卤素、C1-C3烷基、C1-C3烷氧基、C1-C3烷基磺酰基、CF3、羧基、羟基、氨基、烷基氨基、酰氨基、芳基羰基、烷基羰基和羟基烷基;和n是0、1、2、3或4;e)一种由结构式V代表的化合物或其盐或酯,其中Ar1d是任选取代的芳族碳环或杂环,其中所述任选的取代基独立选自卤素、烷基、氨基、烷基氨基、二烷基氨基、羟基、烷氧基和羧基;是任选取代的单-或双-环C3-14脂族含氮杂环;Cyd是任选取代的单-、双-或三-环C3-20脂族碳环;R1d是氢、低级链烯基、低级炔基、低级环烷基、氨基、低级烷基氨基、二(低级烷基)氨基、羟基、低级烷氧基、羧基、低级烷氧基羰基、氨基甲酰基、低级烷基氨基甲酰基、二(低级烷基)氨基甲酰基或任选取代的低级烷基;和R2d是氢或低级烷基;和f)一种由结构式VI代表的化合物或其药学上可接受的盐,其中Ae是芳基或杂环的环;Be是苯基、噻吩基、呋喃基、吡咯基、吡咯烷基、噁唑基或环己烯基;R1e和R2e独立是氢、烷基、羟基烷基、氨基、烷基氨基或二-烷基氨基;R3e和R4e独立是氢、卤素或烷基;Xe是氢、卤素、烷基、烷氧基烷基、链烯基、氨基、CN或-(CH2)me-Ee-(CH2)ne-Ge;Ee是键、-CH=CR6e、O、S、NR7e、CO、SO2或NHCO;Ge是芳基、杂环基、环烷基或稠合的芳基,全部由1-5个R5e基团任选取代;R5e独立选自卤素、OH、烷基、由烷氧基、烷氧基烷氧基、卤素、OH或链烷酰基氧基任选取代的烷基、烷氧基、烷氧基烷氧基、氨基、烷基氨基、二-烷基氨基、NO2、CN、链烷酰基、链烷酰基氧基、羧基、烷氧基羰基、烷基磺酰基和苯基;R6e是氢或芳基;R7e是氢、烷基或烷氧基羰基;me是0-8;和ne是1-4。
3.权利要求2的用途,其中所述化合物由结构式I代表。
4.权利要求3的用途,其中在式I的化合物中Z1和Z2各是R7-芳基。
5.权利要求4的用途,其中R7选自(C1-C6)烷基和卤素。
10.权利要求1的用途,其中所述治疗咳嗽、变态反应或喘哮症状的药物选自:抗组胺药、5-脂氧合酶抑制剂、白三烯抑制剂、H3抑制剂、β-肾上腺素能受体激动剂、黄嘌呤衍生物、α-肾上腺素能受体激动剂、肥大细胞稳定剂、镇咳药、祛痰药、减充血剂、NK1、NK2和NK3速激肽受体拮抗剂和GABAB激动剂。
11.单独的一种ORL-1受体激动剂或与一种或更多种治疗咳嗽、变态反应或喘哮症状的药物联合在制备治疗咳嗽的药物中的用途。
12.一种药用组合物,它包含:治疗有效量的nociceptin受体ORL-1激动剂;治疗有效量的一种或更多种选自以下的药物:抗组胺药、5-脂氧合酶抑制剂、白三烯抑制剂、H3抑制剂、β-肾上腺素能受体激动剂、黄嘌呤衍生物、α-肾上腺素能受体激动剂、肥大细胞稳定剂、镇咳药、祛痰药、减充血剂、NK1、NK2和NK3速激肽受体拮抗剂和GABAB激动剂;和药学上可接受的载体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/359771 | 1999-07-26 | ||
US09/359,771 US6262066B1 (en) | 1998-07-27 | 1999-07-26 | High affinity ligands for nociceptin receptor ORL-1 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1374865A true CN1374865A (zh) | 2002-10-16 |
Family
ID=23415204
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN00813077A Pending CN1374865A (zh) | 1999-07-26 | 2000-01-26 | 用于治疗咳嗽的nociceptin受体ORL-1激动剂 |
Country Status (13)
Country | Link |
---|---|
US (4) | US6262066B1 (zh) |
EP (1) | EP1200087A1 (zh) |
JP (1) | JP2003505420A (zh) |
CN (1) | CN1374865A (zh) |
AU (1) | AU2629800A (zh) |
BR (1) | BR0012801A (zh) |
CA (1) | CA2379398A1 (zh) |
HK (1) | HK1042236A1 (zh) |
HU (1) | HUP0203458A3 (zh) |
MX (1) | MXPA02001033A (zh) |
NO (1) | NO20020392L (zh) |
WO (1) | WO2001007050A1 (zh) |
ZA (1) | ZA200200275B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104302623A (zh) * | 2012-05-01 | 2015-01-21 | 住友化学株式会社 | 哌啶化合物及其有害生物防除用途 |
Families Citing this family (84)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040067950A1 (en) * | 1998-07-27 | 2004-04-08 | Schering-Plough Corporation | High affinity ligands for nociceptin receptor ORL-1 |
US7485650B2 (en) * | 1998-07-27 | 2009-02-03 | Schering Corporation | High affinity ligands for nociceptin receptor ORL-1 |
JP3989247B2 (ja) * | 1999-12-06 | 2007-10-10 | ユーロ−セルティーク エス.エイ. | ノシセプチン受容体親和性を有するトリアゾスピロ化合物 |
US7456198B2 (en) * | 1999-12-06 | 2008-11-25 | Purdue Pharma L.P. | Benzimidazole compounds having nociceptin receptor affinity |
DE20005049U1 (de) * | 2000-03-20 | 2000-05-18 | Dewert Antriebs Systemtech | Elektromotorische Antriebseinheit |
WO2002083673A1 (en) * | 2001-04-10 | 2002-10-24 | Ortho-Mcneil Pharmaceutical, Inc. | 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of orl-1 receptor mediated disorders |
MXPA03009353A (es) * | 2001-04-12 | 2004-02-12 | Pharmacopeia Inc | Aril y biaril piperidinas utilizadas como antagonistas de mch. |
HUP0402510A3 (en) | 2001-04-18 | 2012-08-28 | Euro Celtique Sa | Nociceptin analogs and pharmaceutical compositions containing them |
CA2443938C (en) * | 2001-04-18 | 2010-06-22 | R. Richard Goehring | Spiroindene and spiroindane compounds as opioid ligands useful for treating pain |
EP1598340B1 (en) | 2001-04-18 | 2009-03-04 | Euro-Celtique S.A. | 1-(4-piperidinyl)-1,3-dihydro-2h-benzoxazole-2-one derivatives and related compounds as nociceptin analogs and orl1 ligands for the treatment of pain |
AU2002338424B2 (en) | 2001-04-18 | 2005-04-21 | Euro-Celtique S.A. | Benzimidazolone compounds |
ATE403429T1 (de) | 2001-04-18 | 2008-08-15 | Euro Celtique Sa | Spiropyrazol-verbindungen |
WO2002088089A1 (fr) * | 2001-04-19 | 2002-11-07 | Banyu Pharmaceutical Co., Ltd. | Derives de spiropiperidine, antagonistes du recepteur de nociceptine les contenant en tant qu'ingredient actif et compositions medicinales |
WO2002100861A1 (en) * | 2001-06-13 | 2002-12-19 | Akzo Nobel N.V. | 1-(3-phenyloxypropyl)piperidine derivatives |
US20030040479A1 (en) * | 2001-07-02 | 2003-02-27 | Omeros Corporation | Rotational intrathecal analgesia method and device |
CA2490386A1 (en) * | 2001-07-02 | 2003-01-16 | Omeros Corporation | Method for producing analgesia comprising administration of an opioid receptor agonist in rotation with an opioid receptor like-1 receptor agonist |
FR2827281B1 (fr) * | 2001-07-16 | 2003-12-19 | Sanofi Synthelabo | Procede pour la preparation de la 4-methylamino-4-phenylpiperidine |
FR2827282B1 (fr) * | 2001-07-16 | 2004-08-13 | Sanofi Synthelabo | Procede pour la preparation de 4-amino-4-phenylpiperidines |
AU2002343489A1 (en) | 2001-10-09 | 2003-04-22 | Synvax, Inc. | Nociceptin-based analgesics |
TWI317360B (en) * | 2001-11-07 | 2009-11-21 | Schering Corp | Heteroaryl derivatives as superior ligands for nociceptin receptor orl-1 |
AR037364A1 (es) | 2001-11-16 | 2004-11-03 | Schering Corp | Azetidinil diaminas utiles como ligandos del receptor de nociceptina orl-1 |
US20040033986A1 (en) | 2002-05-17 | 2004-02-19 | Protopopova Marina Nikolaevna | Anti tubercular drug: compositions and methods |
US7652039B2 (en) | 2002-05-17 | 2010-01-26 | Sequella, Inc. | Methods of use and compositions for the diagnosis and treatment of infectious disease |
US6995168B2 (en) | 2002-05-31 | 2006-02-07 | Euro-Celtique S.A. | Triazaspiro compounds useful for treating or preventing pain |
PT1534313E (pt) * | 2002-07-30 | 2013-01-25 | Omeros Corp | Soluções e método de irrigação oftalmológica |
US20060241142A1 (en) * | 2002-08-29 | 2006-10-26 | Aleatel Wireless, Inc. | Naphthamide derivatives and their use |
AU2003268512A1 (en) * | 2002-09-09 | 2004-03-29 | Janssen Pharmaceutica N.V. | Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders |
US7045527B2 (en) | 2002-09-24 | 2006-05-16 | Amgen Inc. | Piperidine derivatives |
TWI299664B (en) | 2003-01-06 | 2008-08-11 | Osi Pharm Inc | (2-carboxamido)(3-amino)thiophene compounds |
US7696225B2 (en) | 2003-01-06 | 2010-04-13 | Osi Pharmaceuticals, Inc. | (2-carboxamido)(3-Amino) thiophene compounds |
PE20050250A1 (es) * | 2003-07-17 | 2005-04-08 | Glaxo Group Ltd | Antagonistas de los receptores muscarinicos de la acetilcolina |
UY28417A1 (es) * | 2003-07-17 | 2005-02-28 | Glaxo Group Ltd | Antagonistas de los receptores muscarinicos de la acetilcolina |
US8067603B2 (en) * | 2003-09-25 | 2011-11-29 | Solvay Pharmaceuticals B.V. | Benzimidazolone and quinazolinone derivatives as agonists on human ORL1 receptors |
AP2007004239A0 (en) * | 2003-10-14 | 2007-12-31 | Glaxo Group Ltd | Muscarinic acetycholine receptor antagonists |
EP1677796A4 (en) * | 2003-10-17 | 2006-12-27 | Glaxo Group Ltd | MUSCARIN ACETYLCHOLIN RECEPTOR ANTAGONISTS |
WO2005037269A1 (ja) * | 2003-10-21 | 2005-04-28 | Dainippon Sumitomo Pharma Co., Ltd. | 新規ピペリジン誘導体 |
PE20050489A1 (es) * | 2003-11-04 | 2005-09-02 | Glaxo Group Ltd | Antagonistas de receptores de acetilcolina muscarinicos |
AR046756A1 (es) | 2003-12-12 | 2005-12-21 | Solvay Pharm Gmbh | Derivados de hidronopol como agonistas de receptores orl-1 humanos. |
WO2005060947A2 (en) * | 2003-12-19 | 2005-07-07 | Sri International | Agonist and antagonist ligands of the nociceptin receptor |
WO2005087236A1 (en) * | 2004-03-11 | 2005-09-22 | Glaxo Group Limited | Novel m3 muscarinic acetylcholine receptor antagonists |
JP2007529513A (ja) | 2004-03-17 | 2007-10-25 | グラクソ グループ リミテッド | M3ムスカリン性アセチルコリン受容体アンタゴニスト |
US8007827B2 (en) * | 2004-04-02 | 2011-08-30 | Impax Laboratories, Inc. | Pharmaceutical dosage forms having immediate release and/or controlled release properties |
PE20060259A1 (es) | 2004-04-27 | 2006-03-25 | Glaxo Group Ltd | Compuestos de quinuclidina como antagonistas del receptor de acetilcolina muscarinico |
JP2007537261A (ja) * | 2004-05-13 | 2007-12-20 | グラクソ グループ リミテッド | ムスカリン性アセチルコリン受容体アンタゴニスト |
US20060178390A1 (en) * | 2004-08-02 | 2006-08-10 | Alfonzo Jordan | 1,3,8-Triazaspiro[4,5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders |
EP1791838A2 (en) * | 2004-09-15 | 2007-06-06 | Schering-Plough Ltd. | Process for preparing substituted 8-azabicyclo[3.2.1] octan-3-ols |
MY179032A (en) | 2004-10-25 | 2020-10-26 | Cancer Research Tech Ltd | Ortho-condensed pyridine and pyrimidine derivatives (e.g.purines) as protein kinase inhibitors |
AU2006252781A1 (en) * | 2005-06-02 | 2006-12-07 | Janssen Pharmaceutica, N.V. | Novel 3-spirocyclic indolyl derivatives useful as ORL-1 receptor modulators |
WO2007011810A1 (en) | 2005-07-18 | 2007-01-25 | Merck & Co., Inc. | Spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease |
US20080234315A1 (en) * | 2005-08-02 | 2008-09-25 | Jakob Busch-Petersen | M3 Muscarinic Acetylcholine Receptor Antagonists |
US20080275079A1 (en) * | 2005-08-02 | 2008-11-06 | Glaxo Group Limited | M3 Muscarinic Acetylcholine Receptor Antagonists |
WO2007022351A2 (en) * | 2005-08-18 | 2007-02-22 | Glaxo Group Limited | Muscarinic acetylcholine receptor antagonists |
JP2009507800A (ja) * | 2005-09-09 | 2009-02-26 | ユーロ−セルティーク エス.エイ. | 縮合およびスピロ環化合物ならびにその使用 |
CA2621310C (en) | 2005-09-27 | 2014-08-12 | Shionogi & Co., Ltd. | Sulfonamide derivative having pgd2 receptor antagonistic activity |
PE20071159A1 (es) * | 2005-10-31 | 2007-11-30 | Schering Corp | Derivados de tropano 3-monosustituido como ligandos de receptores de nociceptina |
JP2009525269A (ja) * | 2006-01-30 | 2009-07-09 | ユーロ−セルティーク エス.エイ. | カルシウムチャネルブロッカーとしての環状尿素化合物 |
EP1847542A1 (en) * | 2006-04-21 | 2007-10-24 | Laboratorios del Dr. Esteve S.A. | Spiro[benzopyran] or spiro[benzofuran] derivatives which inhibit the sigma receptor |
WO2007125321A2 (en) | 2006-04-25 | 2007-11-08 | Astex Therapeutics Limited | Purine and deazapurine derivatives as pharmaceutical compounds |
CA2654262A1 (en) * | 2006-06-20 | 2007-12-27 | Wyeth | Kv1.5 potassium channel inhibitors |
JP2010502705A (ja) * | 2006-09-07 | 2010-01-28 | メルク エンド カムパニー インコーポレーテッド | アルツハイマー病の治療用としてのスピロピペリジンベータセクレターゼ阻害剤 |
CA2670858C (en) * | 2006-11-28 | 2015-01-13 | Janssen Pharmaceutica N.V. | Salts of 3-(3-amino-2-(r)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one |
PT2076506E (pt) * | 2007-01-16 | 2010-12-10 | Purdue Pharma Lp | Compostos de piperidina substituídos nos grupos heterocíclicos como ligandos orl-1 |
AU2008219980B2 (en) * | 2007-03-01 | 2012-01-12 | Mitsubishi Tanabe Pharma Corporation | Benzimidazole compound and pharmaceutical use thereof |
EP2150552B1 (en) * | 2007-04-09 | 2013-01-02 | Janssen Pharmaceutica NV | 1,3,8-trisubstituted-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as ligands of the orl-i receptor for the treatment of anxiety and depression |
EP2433935A1 (en) * | 2007-08-31 | 2012-03-28 | Purdue Pharma LP | Substituted-quinoxaline-type-piperidine compounds and the uses thereof |
EP2201012B1 (en) | 2007-10-11 | 2014-06-25 | AstraZeneca AB | Pyrrolo[2,3-d]pyrimidin derivatives as protein kinase b inhibitors |
EP2537844A1 (en) | 2008-07-21 | 2012-12-26 | Purdue Pharma L.P. | Substituted-quinoxaline-type bridged-piperidine compounds and the uses thereof |
PE20110777A1 (es) * | 2008-11-23 | 2011-10-29 | Pfizer | Nuevas lactamas como inhibidores de beta secretasa |
ITNA20090026A1 (it) * | 2009-05-14 | 2010-11-15 | Agostino Bruno D | Agonisti del recettore nop e loro usi terapeutici |
JP5863650B2 (ja) * | 2009-07-27 | 2016-02-16 | ノシセプタ エルエルシー | 疼痛を処置するための方法 |
WO2011099980A1 (en) | 2010-02-12 | 2011-08-18 | The Johns Hopkins University | Use of the lactosylceramide synthase isoform b1, 4galt-v as a biomarker for cancer |
BR112013025410A2 (pt) | 2011-04-01 | 2016-12-20 | Astrazeneca Ab | tratamento terapêutico |
WO2013079964A1 (en) | 2011-11-30 | 2013-06-06 | Astrazeneca Ab | Combination treatment of cancer |
EP2797912B1 (en) | 2011-12-01 | 2016-05-25 | Purdue Pharma L.P. | Azetidine-substituted quinoxaline-type piperidine compounds and uses thereof |
AU2013204533B2 (en) | 2012-04-17 | 2017-02-02 | Astrazeneca Ab | Crystalline forms |
AU2013201465B2 (en) | 2012-10-24 | 2016-03-03 | Rayner Surgical (Ireland) Limited | Stable preservative-free mydriatic and anti-inflammatory solutions for injection |
US9040533B2 (en) * | 2012-12-27 | 2015-05-26 | Purdue Pharma L.P. | Oxime-substituted-quinoxaline-type piperidine compounds as ORL-1 modulators |
AU2013369649B2 (en) * | 2012-12-31 | 2018-07-26 | Sunovion Pharmaceuticals Inc. | Heterocyclic compounds and methods of use thereof |
TWI705812B (zh) | 2014-12-01 | 2020-10-01 | 奥默羅斯公司 | 用於抑制術後眼睛炎性病況的抗炎和散瞳前房溶液 |
CA2972975A1 (en) | 2015-01-07 | 2016-07-14 | Trigemina, Inc. | Magnesium-containing oxytocin formulations and methods of use |
WO2017161017A1 (en) * | 2016-03-15 | 2017-09-21 | The Scripps Research Institute | Signaling-biased mu opioid receptor agonists |
GB201706162D0 (en) | 2017-04-19 | 2017-05-31 | Nat Univ Singapore | Compounds |
KR20240022630A (ko) | 2021-07-14 | 2024-02-20 | 이창 휴먼웰 파마슈티칼 코포레이션, 리미티드 | 피페리딘 유도체 및 그 약물 조성물, 제조 방법과 용도 |
IT202200011057A1 (it) * | 2022-05-26 | 2023-11-26 | Univ Degli Studi Della Campania Luigi Vanvitelli | Carriers nanotecnologici degli agonisti del recettore nop |
Family Cites Families (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE633914A (zh) * | 1962-06-22 | |||
GB1052302A (zh) * | 1963-04-22 | |||
US3318900A (en) | 1964-05-06 | 1967-05-09 | Janssen Pharmaceutica Nv | Derivatives of benzimidazolinyl piperidine |
US3311264A (en) | 1964-12-14 | 1967-03-28 | Arthur W Cayer | Measuring and dispensing device |
US4526896A (en) * | 1978-12-26 | 1985-07-02 | Riker Laboratories, Inc. | Tetrazol-5-yl 2-nitro-3-phenylbenzofurans and antimicrobial use thereof |
US4521537A (en) | 1982-08-20 | 1985-06-04 | Hoechst-Roussel Pharmaceuticals Incorporated | Spiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine and -3'-pyrrolidine] compounds and their use as antihypertensive agents |
DK139684A (da) | 1983-04-11 | 1984-10-12 | Janssen Pharmaceutica Nv | N-aryl-alpha-amino-carboxamider |
CA1261835A (en) | 1984-08-20 | 1989-09-26 | Masaaki Toda | (fused) benz(thio)amides |
FR2579596B1 (fr) | 1985-03-26 | 1987-11-20 | Inst Nat Sante Rech Med | (imidazolyl-4) piperidines, leur preparation et leur application en therapeutique |
JPS61225167A (ja) | 1985-03-28 | 1986-10-06 | Yoshitomi Pharmaceut Ind Ltd | ベンゾ〔g〕キノリン誘導体 |
GB8607294D0 (en) | 1985-04-17 | 1986-04-30 | Ici America Inc | Heterocyclic amide derivatives |
EP0480717B1 (en) | 1990-10-12 | 1998-04-15 | Merck Frosst Canada Inc. | Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists |
GB9100505D0 (en) | 1991-01-10 | 1991-02-20 | Shell Int Research | Piperidine derivatives |
JP2600644B2 (ja) | 1991-08-16 | 1997-04-16 | 藤沢薬品工業株式会社 | チアゾリルベンゾフラン誘導体 |
US5583000A (en) | 1991-09-03 | 1996-12-10 | The Regents Of The University Of California | Protease-binding compounds and methods of use |
GB9202238D0 (en) | 1992-02-03 | 1992-03-18 | Wellcome Found | Compounds |
US5352707A (en) | 1992-03-26 | 1994-10-04 | Harbor Branch Oceanographic Institution, Inc. | Method for treating airway congestion |
US5270324A (en) | 1992-04-10 | 1993-12-14 | Merck Frosst Canada, Inc. | Fluorinated hydroxyalkylquinoline acids as leukotriene antagonists |
US5436255A (en) | 1992-07-23 | 1995-07-25 | Pfizer Inc. | Method of treating diseases susceptable to treatment by blocking NMDA-receptors |
US5472964A (en) | 1992-12-22 | 1995-12-05 | Merck Frosst Canada, Inc. | Diaryl 5,6-fused heterocyclic acids as leukotriene antagonists |
CA2166975C (en) * | 1993-07-16 | 2005-04-05 | Mark G. Bock | Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin receptor antagonists |
US5495052A (en) * | 1994-09-29 | 1996-02-27 | Arco Chemical Technology, L.P. | Process for producing enantiomerically enriched guaifenesin |
EP0709375B1 (en) | 1994-10-25 | 2005-05-18 | AstraZeneca AB | Therapeutic heterocycles |
IL117149A0 (en) | 1995-02-23 | 1996-06-18 | Schering Corp | Muscarinic antagonists |
DE19519245C2 (de) | 1995-04-14 | 2003-04-30 | Boehringer Ingelheim Kg | Neue Arylglycinamidderivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen |
EP0742208A1 (en) | 1995-05-05 | 1996-11-13 | Grelan Pharmaceutical Co., Ltd. | 2-Ureido-benzamide derivatives |
FR2734265B1 (fr) | 1995-05-17 | 1997-06-13 | Adir | Nouveaux composes spiro heterocycliques, leur procede de preparation et les compositions pharmaceutiques les contenant |
US5654316A (en) | 1995-06-06 | 1997-08-05 | Schering Corporation | Piperidine derivatives as neurokinin antagonists |
CA2245162A1 (en) | 1996-02-08 | 1997-08-14 | Merck & Co., Inc. | Method of treatment and pharmaceutical composition |
CA2226058C (en) | 1997-01-30 | 2008-01-29 | F. Hoffmann-La Roche Ag | 8-substituted-1,3,8-triaza-spiro[4.5]decan-4-one derivatives |
AU7916798A (en) | 1997-05-22 | 1998-12-11 | Boots Company Plc, The | Pharmaceutical compositions of flurbiprofen and burn-masking agent for treating sore throat |
EP0921125B1 (en) | 1997-12-05 | 2002-01-30 | F. Hoffmann-La Roche Ag | 1,3,8-Triazaspiro[4,5]decan-4-on derivatives |
JP3342478B2 (ja) | 1998-01-19 | 2002-11-11 | ファイザー製薬株式会社 | Orl1−レセプターアゴニストとしての4−(2−ケト−1−ベンズイミダゾリニル)ピペリジン化合物 |
US6277991B1 (en) * | 1998-05-18 | 2001-08-21 | Novo Nordisk A/S | 1,3,8-triazaspiro[4.5]decanones with high affinity for opioid receptor subtypes |
ID29137A (id) * | 1998-07-27 | 2001-08-02 | Schering Corp | Ligan-ligan afinitas tinggi untuk reseptor nosiseptin orl-1 |
EP0997464B1 (en) * | 1998-10-23 | 2005-02-16 | Pfizer Inc. | 1,3,8-Triazaspiro[4,5] decanone compounds as orl1-receptor agonists |
TWI317360B (en) * | 2001-11-07 | 2009-11-21 | Schering Corp | Heteroaryl derivatives as superior ligands for nociceptin receptor orl-1 |
-
1999
- 1999-07-26 US US09/359,771 patent/US6262066B1/en not_active Expired - Lifetime
-
2000
- 2000-01-26 CA CA002379398A patent/CA2379398A1/en not_active Abandoned
- 2000-01-26 EP EP00904560A patent/EP1200087A1/en not_active Withdrawn
- 2000-01-26 BR BR0012801-5A patent/BR0012801A/pt not_active IP Right Cessation
- 2000-01-26 MX MXPA02001033A patent/MXPA02001033A/es unknown
- 2000-01-26 JP JP2001511934A patent/JP2003505420A/ja active Pending
- 2000-01-26 CN CN00813077A patent/CN1374865A/zh active Pending
- 2000-01-26 AU AU26298/00A patent/AU2629800A/en not_active Abandoned
- 2000-01-26 WO PCT/US2000/001853 patent/WO2001007050A1/en not_active Application Discontinuation
- 2000-01-26 HU HU0203458A patent/HUP0203458A3/hu unknown
-
2001
- 2001-01-25 US US09/769,824 patent/US6455527B2/en not_active Expired - Lifetime
-
2002
- 2002-01-11 ZA ZA200200275A patent/ZA200200275B/xx unknown
- 2002-01-25 NO NO20020392A patent/NO20020392L/no not_active Application Discontinuation
- 2002-05-08 HK HK02103499.8A patent/HK1042236A1/zh unknown
- 2002-05-23 US US10/155,277 patent/US6716846B2/en not_active Expired - Fee Related
-
2004
- 2004-01-21 US US10/761,977 patent/US7094784B2/en not_active Expired - Fee Related
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104302623A (zh) * | 2012-05-01 | 2015-01-21 | 住友化学株式会社 | 哌啶化合物及其有害生物防除用途 |
Also Published As
Publication number | Publication date |
---|---|
US6455527B2 (en) | 2002-09-24 |
US6716846B2 (en) | 2004-04-06 |
CA2379398A1 (en) | 2001-02-01 |
AU2629800A (en) | 2001-02-13 |
NO20020392L (no) | 2002-03-25 |
US6262066B1 (en) | 2001-07-17 |
US20030073690A1 (en) | 2003-04-17 |
US20010011092A1 (en) | 2001-08-02 |
ZA200200275B (en) | 2003-06-25 |
HUP0203458A2 (hu) | 2003-02-28 |
MXPA02001033A (es) | 2002-08-20 |
BR0012801A (pt) | 2002-05-07 |
EP1200087A1 (en) | 2002-05-02 |
JP2003505420A (ja) | 2003-02-12 |
US20040152707A1 (en) | 2004-08-05 |
HUP0203458A3 (en) | 2004-01-28 |
HK1042236A1 (zh) | 2002-08-09 |
US7094784B2 (en) | 2006-08-22 |
WO2001007050A1 (en) | 2001-02-01 |
NO20020392D0 (no) | 2002-01-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1374865A (zh) | 用于治疗咳嗽的nociceptin受体ORL-1激动剂 | |
CN1311777A (zh) | 伤害感受蛋白受体orl-1的高亲合性配体 | |
US6340681B1 (en) | 2-benzimidazolylamine compounds as ORL-1-receptor agonists | |
CN1195736C (zh) | 3-或4-取代的4-(氨基甲基)-哌啶衍生物,其制备方法及其药物用途 | |
WO2001025228A1 (fr) | Derives d'amines | |
CN1214634A (zh) | 止痒药物 | |
EP1951721B1 (en) | 3 -monosubstituted tropane derivative as nociceptin receptor ligand | |
CN1386503A (zh) | 治疗酒精中毒和酒精瘾的联合治疗 | |
CN1097053C (zh) | 1,2,3,4-四氢-苯并呋喃并[3,2,-c]吡啶衍生物,其制备方法和用途 | |
CN1198820C (zh) | N-取代的氮杂环化合物 | |
EP1444200B1 (en) | Azetidinyl diamines useful as ligands of the nociceptin receptor orl-1 | |
TW201118070A (en) | Prodrugs of a piperidinyl derivative as modulators of chemokine receptor activity | |
US20040067950A1 (en) | High affinity ligands for nociceptin receptor ORL-1 | |
JP2002088079A (ja) | アミン誘導体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |