IL104582A - Opioid compounds Pharmacological preparations containing them and the process for making certain such compounds - Google Patents
Opioid compounds Pharmacological preparations containing them and the process for making certain such compoundsInfo
- Publication number
- IL104582A IL104582A IL10458293A IL10458293A IL104582A IL 104582 A IL104582 A IL 104582A IL 10458293 A IL10458293 A IL 10458293A IL 10458293 A IL10458293 A IL 10458293A IL 104582 A IL104582 A IL 104582A
- Authority
- IL
- Israel
- Prior art keywords
- formula
- compound
- piperazinyl
- alkyl
- hydrogen
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 323
- 238000000034 method Methods 0.000 title claims description 91
- 238000002360 preparation method Methods 0.000 title claims description 10
- 230000008569 process Effects 0.000 title claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 9
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 claims abstract description 41
- 108700023159 delta Opioid Receptors Proteins 0.000 claims abstract description 41
- 102000048124 delta Opioid Receptors Human genes 0.000 claims abstract description 41
- 241000894007 species Species 0.000 claims abstract description 41
- 230000036592 analgesia Effects 0.000 claims abstract description 34
- 102000051367 mu Opioid Receptors Human genes 0.000 claims abstract description 30
- 108020001612 μ-opioid receptors Proteins 0.000 claims abstract description 30
- 230000027455 binding Effects 0.000 claims abstract description 23
- 102000005962 receptors Human genes 0.000 claims abstract description 22
- 108020003175 receptors Proteins 0.000 claims abstract description 22
- 241000282414 Homo sapiens Species 0.000 claims abstract description 8
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 8
- 206010013663 drug dependence Diseases 0.000 claims abstract description 7
- 208000007848 Alcoholism Diseases 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 331
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 185
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 118
- 229910052739 hydrogen Inorganic materials 0.000 claims description 106
- 239000001257 hydrogen Substances 0.000 claims description 102
- 150000003839 salts Chemical class 0.000 claims description 97
- 125000000217 alkyl group Chemical group 0.000 claims description 78
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 76
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 68
- 229910052757 nitrogen Inorganic materials 0.000 claims description 68
- 238000006243 chemical reaction Methods 0.000 claims description 65
- 150000002148 esters Chemical class 0.000 claims description 64
- -1 C3-C cycloalkyi Chemical group 0.000 claims description 61
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 56
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 50
- 150000003857 carboxamides Chemical class 0.000 claims description 42
- 230000000694 effects Effects 0.000 claims description 42
- 150000002431 hydrogen Chemical class 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 125000001424 substituent group Chemical group 0.000 claims description 39
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
- 150000001412 amines Chemical class 0.000 claims description 37
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 31
- 229940124530 sulfonamide Drugs 0.000 claims description 28
- 150000003456 sulfonamides Chemical class 0.000 claims description 28
- 239000000556 agonist Substances 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 26
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
- 239000000543 intermediate Substances 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 23
- 239000003446 ligand Substances 0.000 claims description 23
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 125000004429 atom Chemical group 0.000 claims description 22
- 230000015572 biosynthetic process Effects 0.000 claims description 22
- 239000005557 antagonist Substances 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 229910052731 fluorine Chemical group 0.000 claims description 18
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 238000003786 synthesis reaction Methods 0.000 claims description 17
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 16
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 16
- 239000011737 fluorine Chemical group 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 150000002825 nitriles Chemical class 0.000 claims description 13
- 239000000863 peptide conjugate Substances 0.000 claims description 13
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 12
- 239000002168 alkylating agent Substances 0.000 claims description 12
- 229940100198 alkylating agent Drugs 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 12
- 239000002184 metal Substances 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 150000001721 carbon Chemical group 0.000 claims description 11
- 125000002524 organometallic group Chemical group 0.000 claims description 11
- 230000001747 exhibiting effect Effects 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 241001465754 Metazoa Species 0.000 claims description 9
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 9
- 150000003457 sulfones Chemical class 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 125000002837 carbocyclic group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000001569 carbon dioxide Substances 0.000 claims description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 8
- 108010016626 Dipeptides Proteins 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 239000002552 dosage form Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 239000004721 Polyphenylene oxide Chemical group 0.000 claims description 6
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
- 230000029936 alkylation Effects 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 239000002858 neurotransmitter agent Substances 0.000 claims description 6
- 150000004885 piperazines Chemical class 0.000 claims description 6
- 229920000570 polyether Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 150000003462 sulfoxides Chemical class 0.000 claims description 6
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 5
- 101100533877 Hypocrea jecorina (strain QM6a) sor8 gene Proteins 0.000 claims description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 230000001413 cellular effect Effects 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 230000006870 function Effects 0.000 claims description 5
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 230000001939 inductive effect Effects 0.000 claims description 5
- 108010085082 sigma receptors Proteins 0.000 claims description 5
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- 206010011224 Cough Diseases 0.000 claims description 4
- 206010012735 Diarrhoea Diseases 0.000 claims description 4
- 206010037423 Pulmonary oedema Diseases 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- 206010046543 Urinary incontinence Diseases 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 208000010877 cognitive disease Diseases 0.000 claims description 4
- 239000000562 conjugate Substances 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 208000020016 psychiatric disease Diseases 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 3
- 208000002193 Pain Diseases 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 230000002255 enzymatic effect Effects 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229940043257 glycylglycine Drugs 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 238000007913 intrathecal administration Methods 0.000 claims description 3
- 102000048260 kappa Opioid Receptors Human genes 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- 230000003340 mental effect Effects 0.000 claims description 3
- 230000036407 pain Effects 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 3
- 150000003568 thioethers Chemical class 0.000 claims description 3
- 230000009466 transformation Effects 0.000 claims description 3
- 108020001588 κ-opioid receptors Proteins 0.000 claims description 3
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 claims description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 2
- 238000006969 Curtius rearrangement reaction Methods 0.000 claims description 2
- 206010014561 Emphysema Diseases 0.000 claims description 2
- 108010008488 Glycylglycine Proteins 0.000 claims description 2
- 206010001584 alcohol abuse Diseases 0.000 claims description 2
- 208000025746 alcohol use disease Diseases 0.000 claims description 2
- 125000004694 alkoxyaminocarbonyl group Chemical group 0.000 claims description 2
- 208000008784 apnea Diseases 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000002996 emotional effect Effects 0.000 claims description 2
- 238000003821 enantio-separation Methods 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 125000000962 organic group Chemical group 0.000 claims description 2
- 208000023504 respiratory system disease Diseases 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 229910052723 transition metal Inorganic materials 0.000 claims description 2
- 150000003624 transition metals Chemical class 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 3
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims 1
- 206010013654 Drug abuse Diseases 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims 1
- 208000010643 digestive system disease Diseases 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 208000018685 gastrointestinal system disease Diseases 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 claims 1
- 229930192474 thiophene Natural products 0.000 claims 1
- 208000003870 Drug Overdose Diseases 0.000 abstract description 3
- 206010033296 Overdoses Diseases 0.000 abstract description 3
- 231100000725 drug overdose Toxicity 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 510
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 240
- 239000000243 solution Substances 0.000 description 158
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 154
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- 229910001868 water Inorganic materials 0.000 description 123
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 121
- 235000019441 ethanol Nutrition 0.000 description 113
- 239000002904 solvent Substances 0.000 description 112
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 105
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 99
- 239000000203 mixture Substances 0.000 description 99
- 239000007787 solid Substances 0.000 description 99
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 97
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 96
- 239000000741 silica gel Substances 0.000 description 94
- 229910002027 silica gel Inorganic materials 0.000 description 94
- 238000004587 chromatography analysis Methods 0.000 description 89
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 84
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 81
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 80
- 239000003921 oil Substances 0.000 description 71
- 235000019198 oils Nutrition 0.000 description 71
- 238000005481 NMR spectroscopy Methods 0.000 description 70
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
- 239000000047 product Substances 0.000 description 65
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 58
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 56
- 229910052938 sodium sulfate Inorganic materials 0.000 description 55
- 235000011152 sodium sulphate Nutrition 0.000 description 55
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 54
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 34
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 28
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 27
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 27
- YEKUWOWHPVKTCQ-UHFFFAOYSA-M tetraethylazanium;fluoride;hydrate Chemical compound O.[F-].CC[N+](CC)(CC)CC YEKUWOWHPVKTCQ-UHFFFAOYSA-M 0.000 description 27
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 26
- 238000001819 mass spectrum Methods 0.000 description 26
- 238000001704 evaporation Methods 0.000 description 23
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- 238000009472 formulation Methods 0.000 description 23
- 238000010992 reflux Methods 0.000 description 23
- 238000004448 titration Methods 0.000 description 21
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 19
- 239000011521 glass Substances 0.000 description 19
- 239000010410 layer Substances 0.000 description 19
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 18
- 238000001556 precipitation Methods 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 239000003643 water by type Substances 0.000 description 16
- 239000006260 foam Substances 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- 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 14
- 239000013543 active substance Substances 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 12
- 239000000908 ammonium hydroxide Substances 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 239000005711 Benzoic acid Substances 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- 229940127240 opiate Drugs 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 10
- 239000005695 Ammonium acetate Substances 0.000 description 10
- 229920000858 Cyclodextrin Polymers 0.000 description 10
- 239000001116 FEMA 4028 Substances 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 235000019257 ammonium acetate Nutrition 0.000 description 10
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 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
- 229960004793 sucrose Drugs 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
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- RFUWRXIYTQGFGA-QRPNPIFTSA-N tert-butyl (2s)-2-amino-4-methylpentanoate;hydron;chloride Chemical compound Cl.CC(C)C[C@H](N)C(=O)OC(C)(C)C RFUWRXIYTQGFGA-QRPNPIFTSA-N 0.000 description 1
- VJEYRLMJNBJAHS-UHFFFAOYSA-N tert-butyl 2-[(2-aminoacetyl)amino]acetate Chemical compound CC(C)(C)OC(=O)CNC(=O)CN VJEYRLMJNBJAHS-UHFFFAOYSA-N 0.000 description 1
- AHTXZZQCPYRJGR-UHFFFAOYSA-N tert-butyl 2-[[2-(phenylmethoxycarbonylamino)acetyl]amino]acetate Chemical compound CC(C)(C)OC(=O)CNC(=O)CNC(=O)OCC1=CC=CC=C1 AHTXZZQCPYRJGR-UHFFFAOYSA-N 0.000 description 1
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
- OGMILNSTKFCXJT-UHFFFAOYSA-N tert-butyl-(2,6-difluorophenoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=C(F)C=CC=C1F OGMILNSTKFCXJT-UHFFFAOYSA-N 0.000 description 1
- XYCONJXQTVOVQQ-UHFFFAOYSA-N tert-butyl-(2-fluorophenoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC=C1F XYCONJXQTVOVQQ-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
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- 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
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- C07D295/027—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929202238A GB9202238D0 (en) | 1992-02-03 | 1992-02-03 | Compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL104582A0 IL104582A0 (en) | 1993-06-10 |
| IL104582A true IL104582A (en) | 1998-10-30 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL10458293A IL104582A (en) | 1992-02-03 | 1993-02-02 | Opioid compounds Pharmacological preparations containing them and the process for making certain such compounds |
Country Status (17)
| Country | Link |
|---|---|
| US (2) | US5658908A (fr) |
| EP (1) | EP0649414B1 (fr) |
| JP (1) | JP3109832B2 (fr) |
| KR (1) | KR100287749B1 (fr) |
| AT (1) | ATE237597T1 (fr) |
| AU (1) | AU675928B2 (fr) |
| CA (1) | CA2129046C (fr) |
| DE (1) | DE69332882T2 (fr) |
| DK (1) | DK0649414T3 (fr) |
| ES (1) | ES2197152T3 (fr) |
| GB (1) | GB9202238D0 (fr) |
| IL (1) | IL104582A (fr) |
| NZ (1) | NZ246916A (fr) |
| PT (1) | PT649414E (fr) |
| TW (1) | TW327634B (fr) |
| WO (1) | WO1993015062A1 (fr) |
| ZA (1) | ZA93717B (fr) |
Families Citing this family (96)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5807858A (en) * | 1996-06-05 | 1998-09-15 | Delta Pharmaceutical, Inc. | Compositions and methods for reducing respiratory depression |
| 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 |
| US5681830A (en) * | 1992-02-03 | 1997-10-28 | Delta Pharmaceuticals, Inc. | Opioid compounds |
| GB9202238D0 (en) * | 1992-02-03 | 1992-03-18 | Wellcome Found | Compounds |
| PT711289E (pt) | 1993-07-30 | 2001-02-28 | Delta Pharmaceuticals Inc | Compostos piperazina utilizados em terapia |
| US5849760A (en) * | 1993-12-09 | 1998-12-15 | Institut De Recherche Jouveinal | 2-(arylalkenyl)azacycloalkane derivatives as ligands for sigma receptors |
| US6410537B1 (en) * | 1994-09-09 | 2002-06-25 | The United States Of America As Represented By The Secretary Of The Army | Compositions having neuroprotective and analgesic activity |
| US6046200A (en) * | 1994-09-09 | 2000-04-04 | The United States Of America As Represented By The Secretary Of The Army | Compositions having neuroprotective and analgesic activity |
| IL117149A0 (en) * | 1995-02-23 | 1996-06-18 | Schering Corp | Muscarinic antagonists |
| IT1275433B (it) * | 1995-05-19 | 1997-08-07 | Smithkline Beecham Farma | Derivati di diarildiammine |
| SE9504662D0 (sv) * | 1995-12-22 | 1995-12-22 | Astra Pharma Inc | New compounds |
| SE9504661D0 (sv) * | 1995-12-22 | 1995-12-22 | Astra Pharma Inc | New compounds |
| TW548271B (en) | 1996-12-20 | 2003-08-21 | Astra Pharma Inc | Novel piperidine derivatives having an exocyclic double bond with analgesic effects |
| SE9604786D0 (sv) * | 1996-12-20 | 1996-12-20 | Astra Pharma Inc | New compounds |
| AU6747698A (en) * | 1997-04-11 | 1998-11-11 | Nippon Shinyaku Co. Ltd. | Remedies for frequent urination and urinary incontinence |
| US6723719B1 (en) | 1997-04-25 | 2004-04-20 | Pfizer Inc | Pyrazolopyrimidinones which inhibit type 5 cyclic guanosine 3′,5′—monophosphate phosphodiesterase (cGMP PDE5) for the treatment of sexual dysfunction |
| GB9709972D0 (en) * | 1997-05-19 | 1997-07-09 | Pfizer Ltd | Tetrazoles |
| IT1293804B1 (it) * | 1997-08-01 | 1999-03-10 | Recordati Chem Pharm | Diarilalchilpiperazine attive sulle basse vie urinarie |
| EP1049676B1 (fr) * | 1997-12-24 | 2005-10-12 | Ortho-Mcneil Pharmaceutical, Inc. | (4)-aryl(piperidine-4-yl) aminobenzamides se liant au recepteur opioide delta |
| GB9804734D0 (en) * | 1998-03-05 | 1998-04-29 | Pfizer Ltd | Compounds |
| US6900228B1 (en) | 1998-03-10 | 2005-05-31 | Research Triangle Institute | Opiate compounds, methods of making and methods of use |
| RS50011B (sr) | 1998-04-20 | 2008-09-29 | Pfizer Inc., | Derivati piridin-3-karboksilne kiseline i njihova upotreba kao intermedijera |
| US6359111B1 (en) | 1998-05-28 | 2002-03-19 | Neorx Corporation | Opioid receptor targeting |
| WO1999065932A1 (fr) | 1998-06-18 | 1999-12-23 | Sepracor, Inc. | Tetrapeptides, analogues, et peptidomimetiques qui se fixent selectivement aux recepteurs mammiferes opioides |
| US6011035A (en) * | 1998-06-30 | 2000-01-04 | Neuromed Technologies Inc. | Calcium channel blockers |
| US6262066B1 (en) * | 1998-07-27 | 2001-07-17 | Schering Corporation | High affinity ligands for nociceptin receptor ORL-1 |
| GB9823102D0 (en) | 1998-10-23 | 1998-12-16 | Pfizer Ltd | Pharmaceutically active compounds |
| US6436959B1 (en) | 1998-12-23 | 2002-08-20 | Ortho-Mcneil Pharmaceutical, Inc. | 4-[aryl(piperidin-4-yl)]aminobenzamides |
| US6420560B1 (en) * | 1999-06-07 | 2002-07-16 | Theravance, Inc. | H1—histamine receptor antagonists |
| PE20010623A1 (es) | 1999-10-05 | 2001-07-07 | Gruenenthal Chemie | Uso de (+)-tramadol y/o o-demetiltramadol para tratamiento de urgencia urinaria incrementada y/o incontinencia urinaria |
| DE19947747A1 (de) * | 1999-10-05 | 2001-04-12 | Gruenenthal Gmbh | Verwendung von (+)-Tramadol, O-Demethyltramadol bzw. (+)-O-Demethyltramadol zur Therapie der Harninkontinenz |
| TWI265925B (en) | 1999-10-11 | 2006-11-11 | Pfizer | Pyrazolo[4,3-d]pyrimidin-7-ones useful in inhibiting type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterases(cGMP PDE5), process and intermediates for their preparation, their uses and composition comprising them |
| HK1049834A1 (zh) | 1999-10-11 | 2003-05-30 | 辉瑞大药厂 | 用作磷酸二酯酶抑制剂的5-(2-取代的-5-杂环基磺酰基吡啶-3-基)-二氢吡唑并[4,3-d]嘧啶-7-酮类化合物 |
| SE9904673D0 (sv) | 1999-12-20 | 1999-12-20 | Astra Pharma Inc | Novel compounds |
| SE9904674D0 (sv) | 1999-12-20 | 1999-12-20 | Astra Pharma Inc | Novel compounds |
| EP1242421A1 (fr) | 1999-12-22 | 2002-09-25 | Ortho-McNeil Pharmaceutical, Inc. | Derives d'acide aminobenzoique 4- aryl(8-azabicyclo 3.2.1]octane-3-yl) |
| US6916822B2 (en) | 2000-02-18 | 2005-07-12 | Meiji Seika Kaisha, Ltd. | Phenoxyalkylamine derivatives useful as opioid δ receptor agonists |
| IL151550A0 (en) | 2000-03-03 | 2003-04-10 | Ortho Mcneil Pharm Inc | 3-(diarylmethylene)-8-azabicyclo [3.2.1] octane derivatives |
| DE60119696T2 (de) | 2000-03-15 | 2007-01-25 | Wolfgang Ross Sadee | Naloxon- und naltrexon-analoga in der behandlung bei drogenmissbrauch |
| US7115664B2 (en) * | 2000-03-16 | 2006-10-03 | Sepracor Inc. | Peptidomimetic ligands for cellular receptors and ion channels |
| CA2404280A1 (fr) * | 2000-03-24 | 2002-09-23 | Meiji Seika Kaisha, Ltd. | Derives de la diphenylalkylamine utiles comme agonistes du recepteur de l'opioide .delta. |
| SE0001208D0 (sv) | 2000-04-04 | 2000-04-04 | Astrazeneca Canada Inc | Novel compounds |
| SE0001207D0 (sv) | 2000-04-04 | 2000-04-04 | Astrazeneca Canada Inc | Novel compounds |
| SE0001209D0 (sv) | 2000-04-04 | 2000-04-04 | Astrazeneca Canada Inc | Novel compounds |
| WO2002022579A2 (fr) * | 2000-09-11 | 2002-03-21 | Sepracor, Inc. | Heterocycles sulfonamides antipsychotiques et leurs methodes d'utilisation |
| JPWO2002030896A1 (ja) * | 2000-10-12 | 2004-02-19 | エスエス製薬株式会社 | 2,2−ジフェニルブタンアミド誘導体及びこれを含有する医薬 |
| DE10059411A1 (de) * | 2000-11-30 | 2002-06-13 | Gruenenthal Gmbh | Verwendung von 6-Dimethylaminomethyl-1-phenyl-cyclohexanverbindungen zur Therapie der Harninkontinenz |
| DE10059413A1 (de) * | 2000-11-30 | 2002-06-20 | Gruenenthal Gmbh | Verwendung von substituierten 6-Dimethylaminomethyl-1-phenyl-cyclohexanverbindungen zur Therapie der Harninkontinenz |
| DE10059415A1 (de) | 2000-11-30 | 2002-06-06 | Gruenenthal Gmbh | Verwendung von schwachen Opioiden und gemischten Opioidagonisten/-antagonisten zur Therapie der Harninkontinenz |
| WO2002048122A2 (fr) * | 2000-12-14 | 2002-06-20 | Ortho-Mcneil Pharmaceutical, Inc. | Derives de la benzamidine |
| SE0100764D0 (sv) | 2001-03-07 | 2001-03-07 | Astrazeneca Ab | New assymetric process |
| SE0101765D0 (sv) | 2001-05-18 | 2001-05-18 | Astrazeneca Ab | Novel compounds |
| 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 |
| SE0101768D0 (sv) | 2001-05-18 | 2001-05-18 | Astrazeneca Ab | Novel compounds |
| SE0101766D0 (sv) | 2001-05-18 | 2001-05-18 | Astrazeneca Ab | Novel compounds |
| US7189725B2 (en) | 2001-09-25 | 2007-03-13 | Mount Cook Biosciences, Inc. | Enantiomerically pure opioid diarylmethylpiperazine as a cardioprotection agent |
| 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 |
| SE0103313D0 (sv) | 2001-10-03 | 2001-10-03 | Astrazeneca Ab | Novel compounds |
| EA006507B1 (ru) | 2001-10-15 | 2005-12-29 | Янссен Фармацевтика Н.В. | Новые замещенные 4-фенил-4-[1h-имидазол-2-ил] пиперидиновые производные и их применение в качестве селективных непептидных агонистов дельта-опиоидов |
| 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 (fr) | 2002-01-02 | 2013-01-02 | Versi Group, LLC | Methode de traitement de dysfonctions sexuelles au moyen de composes d'agoniste du recepteur delta opioide |
| 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 |
| DE10224107A1 (de) * | 2002-05-29 | 2003-12-11 | Gruenenthal Gmbh | Kombination ausgewählter Opioide mit anderen Wirkstoffen zur Therapie der Harninkontinenz |
| CN1288158C (zh) * | 2002-07-11 | 2006-12-06 | 东丽株式会社 | 用于预防恶心和呕吐的治疗剂或预防剂 |
| SE0203301D0 (sv) * | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
| SE0203302D0 (sv) * | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
| SE0203300D0 (sv) | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
| SE0203303D0 (sv) | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
| US7314880B2 (en) * | 2003-01-02 | 2008-01-01 | Mount Cook Biosciences, Inc. | Cardioprotective delta opioid receptor agonists and methods of using same |
| CN100435796C (zh) * | 2003-01-02 | 2008-11-26 | 蒙特库克生物科学公司 | 保护心脏的δ类阿片受体激动剂和该激动剂在制备药物中的应用 |
| SE0300104D0 (sv) * | 2003-01-16 | 2003-01-16 | Astrazeneca Ab | Diarylmethylidene piperidine derivatives, preparations thereof and uses thereof |
| NZ546834A (en) | 2003-10-01 | 2010-03-26 | Adolor Corp | Spirocyclic heterocyclic derivatives and methods of their use |
| TWI317286B (en) | 2003-12-31 | 2009-11-21 | Targeting delivery system | |
| SE0400027D0 (sv) * | 2004-01-09 | 2004-01-09 | Astrazeneca Ab | Diarylmethyl piperazine derivatives, preparations thereof and uses thereof |
| US7435822B2 (en) | 2004-02-03 | 2008-10-14 | Janssen Pharmaceutica N.V. | 3-(diheteroarylmethylene)-8-azabicyclo[3.2.1]octane and 3-((aryl)(heteroaryl)methylene)-8-azabicyclo[3.2.1]octane derivatives |
| KR101234421B1 (ko) * | 2004-08-02 | 2013-02-18 | 아스트라제네카 아베 | 디아릴메틸 피페라진 유도체, 이의 제조 방법 및 용도 |
| SE0401968D0 (sv) * | 2004-08-02 | 2004-08-02 | Astrazeneca Ab | Diarylmethyl piperazine derivatives, preparations thereof and uses thereof |
| JP2008514612A (ja) * | 2004-09-23 | 2008-05-08 | ミシャロウ、アレクサンダー | 対抗適応を誘発することにより神経伝達物質系を調節する方法 |
| SE0402485D0 (sv) | 2004-10-13 | 2004-10-13 | Astrazeneca Ab | Polymorph of N,N-Diethyl-4-(3-Fluorophenyl-Piperidin-4-Ylidene-Methyl)-Benzamide Hydrochloride salt |
| US7598261B2 (en) | 2005-03-31 | 2009-10-06 | Adolor Corporation | Spirocyclic heterocyclic derivatives and methods of their use |
| WO2006113468A2 (fr) * | 2005-04-14 | 2006-10-26 | Mount Cook Biosciences, Inc. | Compositions de nouveaux composes opioides et methode d'utilisation associee |
| EP2317316A3 (fr) | 2005-07-08 | 2011-06-15 | Braincells, Inc. | Procédés permettant d'identifier l'agent et les conditions qui modulent la neurogénèse |
| US20070197786A1 (en) * | 2005-07-22 | 2007-08-23 | Kwen-Jen Chang | Enantiomerically pure opioid diarylmethylpiperazine |
| TW200803856A (en) * | 2005-09-02 | 2008-01-16 | Mount Cook Biosciences Inc | Method of treating parkinson's disease with diarylmethylpiperazine compounds exhibiting delta receptor agonist activity |
| US7576207B2 (en) | 2006-04-06 | 2009-08-18 | Adolor Corporation | Spirocyclic heterocyclic derivatives and methods of their use |
| AU2007265467C1 (en) | 2006-06-28 | 2013-11-07 | Amgen Inc. | Glycine transporter-1 inhibitors |
| WO2008033299A2 (fr) | 2006-09-12 | 2008-03-20 | Adolor Corporation | Méthodes d'amélioration de la fonction cognitive |
| CA2663857C (fr) * | 2006-09-20 | 2017-10-31 | The Board Of Regents Of The University Of Texas System | Procede pour administrer des anesthesiants volatils pour une anesthesie locale et/ou le soulagement de la douleur |
| PL2244737T3 (pl) | 2008-01-22 | 2020-05-18 | The Board Of Regents Of The University Of Texas System | Kompozycje lotnego środka znieczulającego zawierające rozpuszczalniki ekstrakcyjne do znieczulania miejscowego i / albo zwalczania bólu |
| US8685979B2 (en) | 2008-01-25 | 2014-04-01 | Nektar Therapeutics | Oligomer-diarylpiperazine conjugates |
| US20090291966A1 (en) * | 2008-05-20 | 2009-11-26 | Astrazeneca Ab | Method Of Treating Anxious Major Depressive Disorder |
| EP2539706B1 (fr) * | 2010-02-24 | 2015-03-04 | Research Triangle Institute | Antagonistes arylpipérazine de récepteur opioïde |
| CN103467460A (zh) * | 2013-09-23 | 2013-12-25 | 昆明理工大学 | 一类含噻吩环和苄基的二芳基甲基哌嗪化合物及其应用 |
| CA2967857A1 (fr) * | 2014-11-21 | 2016-05-26 | Laboratorios Del Dr. Esteve, S.A. | Composes de 1,9-diazaspiro-undecane a activite multimodale contre la douleur |
| CA3061323C (fr) | 2017-04-30 | 2023-09-26 | Versi Group, Llc | Opioide destine a etre utilise pour reduire et/ou traiter la pharmacodependance |
Family Cites Families (10)
| 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 |
| 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 |
| 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 |
| GB9202238D0 (en) * | 1992-02-03 | 1992-03-18 | Wellcome Found | Compounds |
| US5574159A (en) * | 1992-02-03 | 1996-11-12 | Delta Pharmaceuticals, Inc. | Opioid compounds and methods for making therefor |
-
1992
- 1992-02-03 GB GB929202238A patent/GB9202238D0/en active Pending
-
1993
- 1993-02-02 ES ES93914513T patent/ES2197152T3/es not_active Expired - Lifetime
- 1993-02-02 US US08/284,445 patent/US5658908A/en not_active Expired - Lifetime
- 1993-02-02 DE DE69332882T patent/DE69332882T2/de not_active Expired - Fee Related
- 1993-02-02 PT PT93914513T patent/PT649414E/pt unknown
- 1993-02-02 JP JP05513072A patent/JP3109832B2/ja not_active Expired - Fee Related
- 1993-02-02 NZ NZ246916A patent/NZ246916A/en not_active IP Right Cessation
- 1993-02-02 ZA ZA93717A patent/ZA93717B/xx unknown
- 1993-02-02 DK DK93914513T patent/DK0649414T3/da active
- 1993-02-02 WO PCT/GB1993/000216 patent/WO1993015062A1/fr not_active Ceased
- 1993-02-02 AU AU34573/93A patent/AU675928B2/en not_active Ceased
- 1993-02-02 TW TW082100667A patent/TW327634B/zh not_active IP Right Cessation
- 1993-02-02 IL IL10458293A patent/IL104582A/en not_active IP Right Cessation
- 1993-02-02 CA CA002129046A patent/CA2129046C/fr not_active Expired - Fee Related
- 1993-02-02 AT AT93914513T patent/ATE237597T1/de not_active IP Right Cessation
- 1993-02-02 KR KR1019940702666A patent/KR100287749B1/ko not_active Expired - Fee Related
- 1993-02-02 EP EP93914513A patent/EP0649414B1/fr not_active Expired - Lifetime
-
1997
- 1997-05-28 US US08/864,667 patent/US5854249A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2129046A1 (fr) | 1993-08-05 |
| DE69332882T2 (de) | 2004-02-26 |
| ATE237597T1 (de) | 2003-05-15 |
| DK0649414T3 (da) | 2003-08-11 |
| JP3109832B2 (ja) | 2000-11-20 |
| AU3457393A (en) | 1993-09-01 |
| KR950700262A (ko) | 1995-01-16 |
| AU675928B2 (en) | 1997-02-27 |
| ZA93717B (en) | 1994-08-02 |
| EP0649414B1 (fr) | 2003-04-16 |
| NZ246916A (en) | 1996-08-27 |
| TW327634B (en) | 1998-03-01 |
| CA2129046C (fr) | 2008-06-10 |
| JPH07503247A (ja) | 1995-04-06 |
| IL104582A0 (en) | 1993-06-10 |
| PT649414E (pt) | 2003-09-30 |
| GB9202238D0 (en) | 1992-03-18 |
| ES2197152T3 (es) | 2004-01-01 |
| KR100287749B1 (ko) | 2001-04-16 |
| US5658908A (en) | 1997-08-19 |
| DE69332882D1 (de) | 2003-05-22 |
| EP0649414A1 (fr) | 1995-04-26 |
| WO1993015062A1 (fr) | 1993-08-05 |
| US5854249A (en) | 1998-12-29 |
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