SI20245A - Zmesi in metode za zmanjševanje dihalne depresije in spremljevalnih stranskih učinkov mi opioidnih spojin - Google Patents
Zmesi in metode za zmanjševanje dihalne depresije in spremljevalnih stranskih učinkov mi opioidnih spojin Download PDFInfo
- Publication number
- SI20245A SI20245A SI9720097A SI9720097A SI20245A SI 20245 A SI20245 A SI 20245A SI 9720097 A SI9720097 A SI 9720097A SI 9720097 A SI9720097 A SI 9720097A SI 20245 A SI20245 A SI 20245A
- Authority
- SI
- Slovenia
- Prior art keywords
- alkyl
- piperazinyl
- hydrogen
- dimethyl
- allyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 175
- 208000004756 Respiratory Insufficiency Diseases 0.000 title claims abstract description 117
- 206010038678 Respiratory depression Diseases 0.000 title claims abstract description 117
- 230000000694 effects Effects 0.000 title claims abstract description 67
- 239000000203 mixture Substances 0.000 title claims description 66
- 238000000034 method Methods 0.000 title abstract description 31
- 239000000841 delta opiate receptor agonist Substances 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 15
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 claims abstract description 11
- 206010028817 Nausea and vomiting symptoms Diseases 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 79
- 239000001257 hydrogen Substances 0.000 claims description 79
- -1 C 1 -C 3 alkoxy Chemical class 0.000 claims description 58
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 54
- 150000002431 hydrogen Chemical class 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 46
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 38
- 229910052757 nitrogen Inorganic materials 0.000 claims description 37
- 239000000556 agonist Substances 0.000 claims description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 28
- 150000002148 esters Chemical class 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 21
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 20
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 20
- 229940127240 opiate Drugs 0.000 claims description 19
- 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 claims description 18
- 230000000202 analgesic effect Effects 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 239000001301 oxygen Substances 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 239000000018 receptor agonist Substances 0.000 claims description 14
- 229940044601 receptor agonist Drugs 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 12
- 150000003857 carboxamides Chemical class 0.000 claims description 12
- 230000000975 bioactive effect Effects 0.000 claims description 11
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
- 229940124530 sulfonamide Drugs 0.000 claims description 10
- 150000003456 sulfonamides Chemical class 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 239000011593 sulfur Substances 0.000 claims description 10
- 229960005181 morphine Drugs 0.000 claims description 9
- 229960001391 alfentanil Drugs 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 150000001721 carbon Chemical group 0.000 claims description 7
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 150000003457 sulfones Chemical class 0.000 claims description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims description 6
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims description 6
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 6
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 230000000241 respiratory effect Effects 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 5
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 claims description 5
- 206010052904 Musculoskeletal stiffness Diseases 0.000 claims description 5
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 5
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 5
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 150000002825 nitriles Chemical class 0.000 claims description 5
- 239000000863 peptide conjugate Substances 0.000 claims description 5
- 125000006413 ring segment Chemical group 0.000 claims description 5
- 150000003462 sulfoxides Chemical class 0.000 claims description 5
- 150000003568 thioethers Chemical class 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 4
- 150000003573 thiols Chemical class 0.000 claims description 4
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 3
- 206010028813 Nausea Diseases 0.000 claims description 3
- 229960004126 codeine Drugs 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 230000008693 nausea Effects 0.000 claims description 3
- 229960000482 pethidine Drugs 0.000 claims description 3
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical group C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 claims description 3
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 claims 2
- 230000003387 muscular Effects 0.000 claims 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 claims 1
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 claims 1
- JAQUASYNZVUNQP-USXIJHARSA-N Levorphanol Chemical compound C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 JAQUASYNZVUNQP-USXIJHARSA-N 0.000 claims 1
- 239000008896 Opium Substances 0.000 claims 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 claims 1
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 claims 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 claims 1
- 229960001736 buprenorphine Drugs 0.000 claims 1
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 claims 1
- 229960001113 butorphanol Drugs 0.000 claims 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 claims 1
- 229960004193 dextropropoxyphene Drugs 0.000 claims 1
- 229960002069 diamorphine Drugs 0.000 claims 1
- 229960000920 dihydrocodeine Drugs 0.000 claims 1
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 claims 1
- 229960000240 hydrocodone Drugs 0.000 claims 1
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 claims 1
- 229960001410 hydromorphone Drugs 0.000 claims 1
- 229960003406 levorphanol Drugs 0.000 claims 1
- 229960001797 methadone Drugs 0.000 claims 1
- 239000003402 opiate agonist Substances 0.000 claims 1
- 229960001027 opium Drugs 0.000 claims 1
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 1
- 229960002085 oxycodone Drugs 0.000 claims 1
- 229960005118 oxymorphone Drugs 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 claims 1
- 230000036592 analgesia Effects 0.000 abstract description 30
- LBLDMHBSVIVJPM-YZIHRLCOSA-N 4-[(R)-[(2S,5R)-2,5-dimethyl-4-prop-2-enyl-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1[C@H](C=1C=C(O)C=CC=1)N1[C@@H](C)CN(CC=C)[C@H](C)C1 LBLDMHBSVIVJPM-YZIHRLCOSA-N 0.000 abstract description 9
- 241001465754 Metazoa Species 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 8
- 229940023861 alfenta Drugs 0.000 abstract description 3
- 239000002756 mu opiate receptor agonist Substances 0.000 abstract 2
- 208000002740 Muscle Rigidity Diseases 0.000 abstract 1
- 230000001404 mediated effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 104
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 96
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- 239000000243 solution Substances 0.000 description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 239000002904 solvent Substances 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 32
- 108700023159 delta Opioid Receptors Proteins 0.000 description 32
- 102000048124 delta Opioid Receptors Human genes 0.000 description 32
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 26
- 239000003921 oil Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 239000004480 active ingredient Substances 0.000 description 22
- 102000005962 receptors Human genes 0.000 description 22
- 108020003175 receptors Proteins 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 20
- 239000000730 antalgic agent Substances 0.000 description 19
- 239000000126 substance Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 229940035676 analgesics Drugs 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 241000700159 Rattus Species 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 230000027455 binding Effects 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 12
- 238000001819 mass spectrum Methods 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000004615 ingredient Substances 0.000 description 11
- 239000013543 active substance Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 125000006291 3-hydroxybenzyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 229960002428 fentanyl Drugs 0.000 description 9
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- 102000003840 Opioid Receptors Human genes 0.000 description 8
- 108090000137 Opioid Receptors Proteins 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000007789 gas Substances 0.000 description 8
- 238000001802 infusion Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 7
- 239000003193 general anesthetic agent Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 229940035674 anesthetics Drugs 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- YEKUWOWHPVKTCQ-UHFFFAOYSA-M tetraethylazanium;fluoride;hydrate Chemical compound O.[F-].CC[N+](CC)(CC)CC YEKUWOWHPVKTCQ-UHFFFAOYSA-M 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 101100108551 Mus musculus Akr1b7 gene Proteins 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229940125717 barbiturate Drugs 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 230000001747 exhibiting effect Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- GOUHYARYYWKXHS-UHFFFAOYSA-N 4-formylbenzoic acid Chemical compound OC(=O)C1=CC=C(C=O)C=C1 GOUHYARYYWKXHS-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 4
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 150000004885 piperazines Chemical class 0.000 description 4
- 150000003053 piperidines Chemical class 0.000 description 4
- 235000011056 potassium acetate Nutrition 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- NSMWYRLQHIXVAP-WDSKDSINSA-N (2s,5s)-2,5-dimethylpiperazine Chemical compound C[C@H]1CN[C@@H](C)CN1 NSMWYRLQHIXVAP-WDSKDSINSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000008484 agonism Effects 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000012867 bioactive agent Substances 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000013160 medical therapy Methods 0.000 description 3
- 230000004118 muscle contraction Effects 0.000 description 3
- 239000000014 opioid analgesic Substances 0.000 description 3
- 229940005483 opioid analgesics Drugs 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000010079 rubber tapping Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- HRTKQUHFGZFPPF-UHFFFAOYSA-M tetraethylazanium;fluoride;dihydrate Chemical compound O.O.[F-].CC[N+](CC)(CC)CC HRTKQUHFGZFPPF-UHFFFAOYSA-M 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- NSMWYRLQHIXVAP-PHDIDXHHSA-N (2r,5r)-2,5-dimethylpiperazine Chemical compound C[C@@H]1CN[C@H](C)CN1 NSMWYRLQHIXVAP-PHDIDXHHSA-N 0.000 description 2
- VKUXNUOPPQWDMV-BDAKNGLRSA-N (2s,5r)-2,5-dimethyl-1-prop-2-enylpiperazine Chemical compound C[C@@H]1CN(CC=C)[C@@H](C)CN1 VKUXNUOPPQWDMV-BDAKNGLRSA-N 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229940127450 Opioid Agonists Drugs 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- ZDVDCDLBOLSVGM-UHFFFAOYSA-N [chloro(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(Cl)C1=CC=CC=C1 ZDVDCDLBOLSVGM-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000012159 carrier gas Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- NWVNXDKZIQLBNM-UHFFFAOYSA-N diphenylmethylpiperazine Chemical compound C1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NWVNXDKZIQLBNM-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- VVZAIGZNZMZDFX-SFYZADRCSA-N ethyl (2s,5r)-2,5-dimethylpiperazine-1-carboxylate Chemical compound CCOC(=O)N1C[C@@H](C)NC[C@@H]1C VVZAIGZNZMZDFX-SFYZADRCSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- KEDPJWLRDLZEBC-UHFFFAOYSA-N n-ethyl-4-formyl-n-methylbenzamide Chemical compound CCN(C)C(=O)C1=CC=C(C=O)C=C1 KEDPJWLRDLZEBC-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 229960004739 sufentanil Drugs 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- QSUJAUYJBJRLKV-UHFFFAOYSA-M tetraethylazanium;fluoride Chemical compound [F-].CC[N+](CC)(CC)CC QSUJAUYJBJRLKV-UHFFFAOYSA-M 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- VGTVQDLTHRFXFF-MMALYQPHSA-N (2S)-2-[[(2S)-2-aminopropanoyl]amino]propanoic acid piperazine-2,3-dione Chemical compound O=C1NCCNC1=O.C[C@H](N)C(=O)N[C@@H](C)C(O)=O VGTVQDLTHRFXFF-MMALYQPHSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- ZHUJMSMQIPIPTF-IBURTVSXSA-N (2r)-2-[[(2s)-2-[[2-[[(2r)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoic acid Chemical compound C([C@@H](C(=O)N[C@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ZHUJMSMQIPIPTF-IBURTVSXSA-N 0.000 description 1
- NSMWYRLQHIXVAP-OLQVQODUSA-N (2r,5s)-2,5-dimethylpiperazine Chemical compound C[C@H]1CN[C@H](C)CN1 NSMWYRLQHIXVAP-OLQVQODUSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- PIPWSBOFSUJCCO-UHFFFAOYSA-N 2,2-dimethylpiperazine Chemical compound CC1(C)CNCCN1 PIPWSBOFSUJCCO-UHFFFAOYSA-N 0.000 description 1
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 description 1
- MNOJRWOWILAHAV-UHFFFAOYSA-N 3-bromophenol Chemical compound OC1=CC=CC(Br)=C1 MNOJRWOWILAHAV-UHFFFAOYSA-N 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- GEUFTNGXEFKADZ-UHFFFAOYSA-N 4-[[3-[tert-butyl(dimethyl)silyl]oxyphenyl]-hydroxymethyl]-n,n-diethylbenzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1C(O)C1=CC=CC(O[Si](C)(C)C(C)(C)C)=C1 GEUFTNGXEFKADZ-UHFFFAOYSA-N 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 101100243025 Arabidopsis thaliana PCO2 gene Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 101100493820 Caenorhabditis elegans best-1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229920001651 Cyanoacrylate Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 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 1
- 125000002061 L-isoleucyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](C([H])([H])[H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 241001351439 Oneida Species 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- YBMMFBUQHGOWMQ-UHFFFAOYSA-N [3-[(4-bromophenyl)-chloromethyl]phenoxy]-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC(C(Cl)C=2C=CC(Br)=CC=2)=C1 YBMMFBUQHGOWMQ-UHFFFAOYSA-N 0.000 description 1
- RSWGJHLUYNHPMX-ONCXSQPRSA-N abietic acid Chemical compound C([C@@H]12)CC(C(C)C)=CC1=CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(O)=O RSWGJHLUYNHPMX-ONCXSQPRSA-N 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 210000004381 amniotic fluid Anatomy 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003097 anti-respiratory effect Effects 0.000 description 1
- 230000000342 anti-suppressant effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- SNIABFMMCKVXSY-UHFFFAOYSA-N benzoylazanium;chloride Chemical compound Cl.NC(=O)C1=CC=CC=C1 SNIABFMMCKVXSY-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 230000008933 bodily movement Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000001914 calming effect Effects 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 239000000562 conjugate Substances 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000008640 diphenylmethylpiperazines Chemical class 0.000 description 1
- 230000009266 disease activity Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- JJJFUHOGVZWXNQ-UHFFFAOYSA-N enbucrilate Chemical compound CCCCOC(=O)C(=C)C#N JJJFUHOGVZWXNQ-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000002238 fumaric acids Chemical class 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 150000002485 inorganic esters Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000011981 lindlar catalyst Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- LDJNSLOKTFFLSL-UHFFFAOYSA-M lithium;benzoate Chemical compound [Li+].[O-]C(=O)C1=CC=CC=C1 LDJNSLOKTFFLSL-UHFFFAOYSA-M 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- OTGRTWQLBHAZFG-UHFFFAOYSA-N n,n-diethyl-4-formylbenzamide Chemical compound CCN(CC)C(=O)C1=CC=C(C=O)C=C1 OTGRTWQLBHAZFG-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
- YPHRECOHXALQKL-UHFFFAOYSA-N n-ethyl-n-methylbenzamide Chemical compound CCN(C)C(=O)C1=CC=CC=C1 YPHRECOHXALQKL-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- DKJCUVXSBOMWAV-PCWWUVHHSA-N naltrindole Chemical compound N1([C@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC2=C3[CH]C=CC=C3N=C25)O)CC1)O)CC1CC1 DKJCUVXSBOMWAV-PCWWUVHHSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 108010085082 sigma receptors Proteins 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000009974 thixotropic effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 210000001177 vas deferen Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 108020001588 κ-opioid receptors Proteins 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
- A61P11/16—Central respiratory analeptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pulmonology (AREA)
- Emergency Medicine (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/887,312 US5985880A (en) | 1996-06-05 | 1997-07-03 | Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds |
| PCT/US1997/017852 WO1999001033A1 (en) | 1997-07-03 | 1997-10-01 | Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SI20245A true SI20245A (sl) | 2000-12-31 |
Family
ID=25390891
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI9720097A SI20245A (sl) | 1997-07-03 | 1997-10-01 | Zmesi in metode za zmanjševanje dihalne depresije in spremljevalnih stranskih učinkov mi opioidnih spojin |
Country Status (23)
| Country | Link |
|---|---|
| US (5) | US5985880A (cs) |
| EP (1) | EP1003373B1 (cs) |
| JP (1) | JP2002502432A (cs) |
| KR (1) | KR20010014279A (cs) |
| CN (1) | CN1165308C (cs) |
| AT (1) | ATE259226T1 (cs) |
| AU (1) | AU756120B2 (cs) |
| BR (1) | BR9714739A (cs) |
| CA (1) | CA2294924C (cs) |
| CZ (1) | CZ9904694A3 (cs) |
| DE (1) | DE69727593D1 (cs) |
| HU (1) | HUP0003842A3 (cs) |
| IL (1) | IL133600A0 (cs) |
| IS (1) | IS5309A (cs) |
| NO (1) | NO996310L (cs) |
| NZ (1) | NZ501817A (cs) |
| PL (1) | PL337578A1 (cs) |
| RU (1) | RU2201231C2 (cs) |
| SI (1) | SI20245A (cs) |
| SK (1) | SK185399A3 (cs) |
| TR (1) | TR199903324T2 (cs) |
| TW (1) | TW513426B (cs) |
| WO (1) | WO1999001033A1 (cs) |
Families Citing this family (38)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5985880A (en) * | 1996-06-05 | 1999-11-16 | Delta Pharmaceuticals | Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds |
| US6011035A (en) * | 1998-06-30 | 2000-01-04 | Neuromed Technologies Inc. | Calcium channel blockers |
| CA2394077A1 (en) * | 1999-12-16 | 2001-06-21 | Trident Technologies, Llc | System and method for extended delivery of a therapeutic agent with its receptor loading dose |
| SE0001207D0 (sv) * | 2000-04-04 | 2000-04-04 | Astrazeneca Canada Inc | Novel compounds |
| AU2001264935A1 (en) | 2000-05-24 | 2001-12-03 | University Of Maryland Biotechnology Institute | Method for introducing and expressing genes in animal cells, and bacterial blebsfor use in same |
| PT1395567E (pt) | 2001-05-18 | 2009-03-26 | Astrazeneca Ab | Derivados de 4(fenil-piperazinil-metil)benzamida e sua utilização para o tratamento da ansiedade da dor ou de distúrbios gastrointestinais |
| NZ531875A (en) * | 2001-09-25 | 2006-10-27 | Ardent Pharmaceuticals Inc | An enantiomerically pure diarylmethylpiperazine and methods for use in the treatment for conditions such as drug addiction, mental disorders, arthritis and asthma |
| US7355042B2 (en) * | 2001-10-16 | 2008-04-08 | Hypnion, Inc. | Treatment of CNS disorders using CNS target modulators |
| CN1596113B (zh) * | 2001-10-29 | 2010-05-26 | 蒙特库克生物科学公司 | δ受体激动剂化合物在制备治疗抑郁症的药物中的应用 |
| EP1469850B1 (en) | 2002-01-02 | 2013-01-02 | Versi Group, LLC | Method of treating sexual dysfunctions with delta opioid receptor agonist compounds |
| US8476280B2 (en) * | 2002-05-09 | 2013-07-02 | Versi Group, Llc | Compositions and methods for combating lower urinary tract dysfunctions with delta opioid receptor agonists |
| SE0203302D0 (sv) * | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
| SE0203303D0 (sv) * | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
| EP2179987B1 (en) * | 2002-12-04 | 2013-02-13 | Virginia Commonwealth University | Use of heterocyclic carbaldehyde derivatives against sickle cell anemia |
| US7314880B2 (en) * | 2003-01-02 | 2008-01-01 | Mount Cook Biosciences, Inc. | Cardioprotective delta opioid receptor agonists and methods of using same |
| NZ527142A (en) * | 2003-07-23 | 2006-03-31 | Douglas Pharmaceuticals Ltd | A stable suspension formulation |
| US7119208B2 (en) * | 2003-12-03 | 2006-10-10 | Virginia Commonwealth University | Anti-sickling agents |
| KR101234421B1 (ko) | 2004-08-02 | 2013-02-18 | 아스트라제네카 아베 | 디아릴메틸 피페라진 유도체, 이의 제조 방법 및 용도 |
| ES2714198T3 (es) | 2005-03-07 | 2019-05-27 | Univ Chicago | Uso de antagonistas opioideos para atenuar la proliferación y la migración de células endoteliales |
| US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
| WO2006113468A2 (en) * | 2005-04-14 | 2006-10-26 | Mount Cook Biosciences, Inc. | Compositions of novel opioid compounds and method of use thereof |
| GB0606124D0 (en) * | 2006-03-28 | 2006-05-03 | Reckitt Benckiser Healthcare | Buprenorphine derivatives and uses thereof |
| JP2011500686A (ja) * | 2007-10-18 | 2011-01-06 | アイコ バイオテクノロジー | オピオイドと中性アンタゴニストを用いる組合せ鎮痛剤 |
| US8748448B2 (en) | 2007-10-18 | 2014-06-10 | Aiko Biotechnology | Combination analgesic employing opioid agonist and neutral antagonist |
| KR102082529B1 (ko) * | 2012-04-17 | 2020-02-27 | 퍼듀 퍼머 엘피 | 오피오이드-유도 유해 약역학 반응을 치료하기 위한 시스템 및 방법 |
| US9549909B2 (en) | 2013-05-03 | 2017-01-24 | The Katholieke Universiteit Leuven | Method for the treatment of dravet syndrome |
| ES3024232T3 (en) | 2015-12-22 | 2025-06-04 | Zogenix International Ltd | Fenfluramine compositions and methods of preparing the same |
| WO2017112701A1 (en) | 2015-12-22 | 2017-06-29 | Zogenix International Limited | Metabolism resistant fenfluramine analogs and methods of using the same |
| SG11201900975XA (en) | 2016-08-24 | 2019-03-28 | Zogenix International Ltd | Formulation for inhibiting formation of 5-ht 2b agonists and methods of using same |
| CA3061323C (en) * | 2017-04-30 | 2023-09-26 | Versi Group, Llc | An opioid for use to reduce and/or treat drug addiction |
| US10682317B2 (en) | 2017-09-26 | 2020-06-16 | Zogenix International Limited | Ketogenic diet compatible fenfluramine formulation |
| WO2019216919A1 (en) | 2018-05-11 | 2019-11-14 | Zogenix International Limited | Compositions and methods for treating seizure-induced sudden death |
| EP3806835A1 (en) * | 2018-06-14 | 2021-04-21 | Zogenix International Limited | Compositions and methods for treating respiratory depression with fenfluramine |
| EA202191079A1 (ru) | 2018-11-19 | 2021-09-20 | Зодженикс Интернэшнл Лимитед | Способы лечения синдрома ретта с применением фенфлурамина |
| US11612574B2 (en) | 2020-07-17 | 2023-03-28 | Zogenix International Limited | Method of treating patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) |
| US11977085B1 (en) | 2023-09-05 | 2024-05-07 | Elan Ehrlich | Date rape drug detection device and method of using same |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2630435A (en) * | 1948-09-09 | 1953-03-03 | Burroughs Wellcome Co | N-benzohydryl-n-methyl piperazines and process of preparing same |
| US4065573A (en) * | 1976-06-03 | 1977-12-27 | The Upjohn Company | 4-Amino-4-phenylcyclohexanone ketal compositions and process of use |
| US4167574A (en) * | 1978-03-13 | 1979-09-11 | Janssen Pharmaceutica, N.V. | N-phenyl-N-(4-piperidinyl)amides |
| US4518711A (en) * | 1983-05-16 | 1985-05-21 | Gibson-Stephens Institute | Conformationally constrained cyclic enkephalin analogs with delta receptor specificity |
| GB8320701D0 (en) * | 1983-08-01 | 1983-09-01 | Wellcome Found | Chemotherapeutic agent |
| DE3851081T2 (de) * | 1987-04-16 | 1995-02-16 | Lilly Co Eli | Piperidine als Opioid-Antagoniste. |
| US4816586A (en) * | 1987-07-29 | 1989-03-28 | Regents Of The University Of Minnesota | Delta opioid receptor antagonists |
| IL94768A (en) * | 1989-06-19 | 1995-08-31 | Wellcome Found | Use of aryl-substituted amine derivatives in the preparation of pharmaceutical compositions |
| DE415693T1 (de) * | 1989-08-28 | 1991-10-17 | Arizona Technology Development Corp., Tucson, Ariz. | Zusammensetzung und verfahren zur selektiven verstaerkung der opiat-wirkung und verminderung von opiat-toleranz und abhaengigkeit. |
| EP0458160A3 (en) * | 1990-05-25 | 1992-03-18 | Sociedad Espanola De Especialidades Farmaco-Terapeuticas, S.A. | Substituted diphenylmethane derivatives as analgesic or anti-inflammatory agents |
| US5159081A (en) * | 1991-03-29 | 1992-10-27 | Eli Lilly And Company | Intermediates of peripherally selective n-carbonyl-3,4,4-trisubstituted piperidine opioid antagonists |
| KR100243956B1 (ko) * | 1991-09-06 | 2000-03-02 | 랄프 알. 팔로 | 트라마돌 물질 및 아세트아미노펜을 포함하는 통증 치료용 약제학적 조성물 |
| IE914218A1 (en) * | 1991-09-11 | 1993-03-24 | Mcneilab Inc | Novel 4-arylpiperazines and 4-arylpiperidines |
| US5968551A (en) | 1991-12-24 | 1999-10-19 | Purdue Pharma L.P. | Orally administrable opioid formulations having extended duration of effect |
| US5807858A (en) | 1996-06-05 | 1998-09-15 | Delta Pharmaceutical, Inc. | Compositions and methods for reducing respiratory depression |
| GB9202238D0 (en) * | 1992-02-03 | 1992-03-18 | Wellcome Found | Compounds |
| US5681830A (en) | 1992-02-03 | 1997-10-28 | Delta Pharmaceuticals, Inc. | Opioid compounds |
| US5574159A (en) * | 1992-02-03 | 1996-11-12 | Delta Pharmaceuticals, Inc. | Opioid compounds and methods for making therefor |
| US5985880A (en) | 1996-06-05 | 1999-11-16 | Delta Pharmaceuticals | Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds |
| PT711289E (pt) * | 1993-07-30 | 2001-02-28 | Delta Pharmaceuticals Inc | Compostos piperazina utilizados em terapia |
| IT1270612B (it) * | 1994-07-14 | 1997-05-07 | Smithkline Beecham Farma | Derivati eterociclo-condensatori di morfinoidi |
| US5753516A (en) * | 1995-02-03 | 1998-05-19 | Heagy; Wyrta E. | Screening method for ligands of the EBI-1 receptor |
| IT1275433B (it) * | 1995-05-19 | 1997-08-07 | Smithkline Beecham Farma | Derivati di diarildiammine |
| IT1277597B1 (it) * | 1995-09-15 | 1997-11-11 | Smithkline Beecham Spa | Derivati di diarilalchenilammina |
| GB9709972D0 (en) | 1997-05-19 | 1997-07-09 | Pfizer Ltd | Tetrazoles |
| GB9804734D0 (en) | 1998-03-05 | 1998-04-29 | Pfizer Ltd | Compounds |
-
1997
- 1997-07-03 US US08/887,312 patent/US5985880A/en not_active Expired - Fee Related
- 1997-10-01 DE DE69727593T patent/DE69727593D1/de not_active Expired - Lifetime
- 1997-10-01 AT AT97910777T patent/ATE259226T1/de not_active IP Right Cessation
- 1997-10-01 KR KR1019997012402A patent/KR20010014279A/ko not_active Ceased
- 1997-10-01 EP EP97910777A patent/EP1003373B1/en not_active Expired - Lifetime
- 1997-10-01 CN CNB971822719A patent/CN1165308C/zh not_active Expired - Fee Related
- 1997-10-01 NZ NZ501817A patent/NZ501817A/en unknown
- 1997-10-01 WO PCT/US1997/017852 patent/WO1999001033A1/en not_active Ceased
- 1997-10-01 HU HU0003842A patent/HUP0003842A3/hu unknown
- 1997-10-01 SK SK1853-99A patent/SK185399A3/sk unknown
- 1997-10-01 CZ CZ19994694A patent/CZ9904694A3/cs unknown
- 1997-10-01 RU RU2000100816/14A patent/RU2201231C2/ru not_active IP Right Cessation
- 1997-10-01 TR TR1999/03324T patent/TR199903324T2/xx unknown
- 1997-10-01 AU AU48066/97A patent/AU756120B2/en not_active Ceased
- 1997-10-01 PL PL97337578A patent/PL337578A1/xx unknown
- 1997-10-01 SI SI9720097A patent/SI20245A/sl not_active IP Right Cessation
- 1997-10-01 BR BR9714739-7A patent/BR9714739A/pt not_active Application Discontinuation
- 1997-10-01 JP JP50859899A patent/JP2002502432A/ja active Pending
- 1997-10-01 CA CA2294924A patent/CA2294924C/en not_active Expired - Fee Related
- 1997-10-01 IL IL13360097A patent/IL133600A0/xx unknown
- 1997-10-24 TW TW086115899A patent/TW513426B/zh not_active IP Right Cessation
-
1999
- 1999-07-12 US US09/352,308 patent/US6300332B1/en not_active Expired - Fee Related
- 1999-12-17 IS IS5309A patent/IS5309A/is unknown
- 1999-12-17 NO NO996310A patent/NO996310L/no not_active Application Discontinuation
-
2001
- 2001-10-09 US US09/974,004 patent/US6919350B2/en not_active Expired - Fee Related
-
2005
- 2005-07-19 US US11/184,762 patent/US20050255151A1/en not_active Abandoned
-
2008
- 2008-04-07 US US12/098,899 patent/US20080193383A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| PL337578A1 (en) | 2000-08-28 |
| CZ9904694A3 (cs) | 2002-03-13 |
| JP2002502432A (ja) | 2002-01-22 |
| IL133600A0 (en) | 2001-04-30 |
| US20020111359A1 (en) | 2002-08-15 |
| TR199903324T2 (xx) | 2000-09-21 |
| BR9714739A (pt) | 2000-07-25 |
| US20080193383A1 (en) | 2008-08-14 |
| US5985880A (en) | 1999-11-16 |
| US6919350B2 (en) | 2005-07-19 |
| CN1165308C (zh) | 2004-09-08 |
| EP1003373A1 (en) | 2000-05-31 |
| HUP0003842A1 (hu) | 2001-04-28 |
| KR20010014279A (ko) | 2001-02-26 |
| HUP0003842A3 (en) | 2001-12-28 |
| IS5309A (is) | 1999-12-17 |
| NO996310L (no) | 2000-02-22 |
| CA2294924C (en) | 2010-12-21 |
| US20050255151A1 (en) | 2005-11-17 |
| SK185399A3 (en) | 2001-08-06 |
| EP1003373A4 (en) | 2000-09-20 |
| DE69727593D1 (de) | 2004-03-18 |
| NO996310D0 (no) | 1999-12-17 |
| TW513426B (en) | 2002-12-11 |
| NZ501817A (en) | 2002-02-01 |
| AU756120B2 (en) | 2003-01-02 |
| CN1262600A (zh) | 2000-08-09 |
| EP1003373B1 (en) | 2004-02-11 |
| RU2201231C2 (ru) | 2003-03-27 |
| CA2294924A1 (en) | 1999-01-14 |
| ATE259226T1 (de) | 2004-02-15 |
| AU4806697A (en) | 1999-01-25 |
| WO1999001033A1 (en) | 1999-01-14 |
| US6300332B1 (en) | 2001-10-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SI20245A (sl) | Zmesi in metode za zmanjševanje dihalne depresije in spremljevalnih stranskih učinkov mi opioidnih spojin | |
| EP0938317B1 (en) | Compositions for reducing respiratory depression | |
| US20020052007A1 (en) | Diarylmethylbenzylpiperazines and corresponding halobenzyl derivatives | |
| JP4892654B2 (ja) | デルタレセプターアゴニスト化合物によるうつ病の治療方法 | |
| US6924288B2 (en) | Enantiomerically pure opioid diarylmethylpiperzine and methods of using same | |
| AU2002341832A1 (en) | An enantiomerically pure diarylmethylpiperazine and methods of using same | |
| MXPA00000195A (en) | Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds | |
| AU2018340867A1 (en) | Metabolite inspired selective oxytocin receptor agonists | |
| US20140275060A1 (en) | Compounds for the treatment of neurologic disorders | |
| TW200404545A (en) | An enantiomerically pure opioid diarylmethylpiperzine and methods of using same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| IF | Valid on the event date | ||
| KO00 | Lapse of patent |
Effective date: 20050722 |