IL110512A - History of diarylmethyl piperazine, their preparation and pharmaceutical preparations containing them - Google Patents
History of diarylmethyl piperazine, their preparation and pharmaceutical preparations containing themInfo
- Publication number
- IL110512A IL110512A IL11051294A IL11051294A IL110512A IL 110512 A IL110512 A IL 110512A IL 11051294 A IL11051294 A IL 11051294A IL 11051294 A IL11051294 A IL 11051294A IL 110512 A IL110512 A IL 110512A
- Authority
- IL
- Israel
- Prior art keywords
- allyl
- dimethyl
- piperazinyl
- hydroxybenzyl
- compound
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
- 150000004885 piperazines Chemical class 0.000 title abstract description 16
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 256
- 230000036592 analgesia Effects 0.000 claims abstract description 25
- 238000011282 treatment Methods 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 14
- 206010013663 drug dependence Diseases 0.000 claims abstract description 10
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 10
- 208000007848 Alcoholism Diseases 0.000 claims abstract description 8
- 208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 8
- 206010037423 Pulmonary oedema Diseases 0.000 claims abstract description 8
- 208000020016 psychiatric disease Diseases 0.000 claims abstract description 8
- 206010011224 Cough Diseases 0.000 claims abstract description 7
- 206010012735 Diarrhoea Diseases 0.000 claims abstract description 7
- 206010046543 Urinary incontinence Diseases 0.000 claims abstract description 7
- 208000010877 cognitive disease Diseases 0.000 claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 114
- 238000000034 method Methods 0.000 claims description 67
- 150000003839 salts Chemical class 0.000 claims description 51
- -1 N-methylcarbamoyl Chemical group 0.000 claims description 38
- 150000002148 esters Chemical class 0.000 claims description 35
- 230000015572 biosynthetic process Effects 0.000 claims description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 150000001412 amines Chemical class 0.000 claims description 21
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 21
- 238000003786 synthesis reaction Methods 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- 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 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 150000008064 anhydrides Chemical class 0.000 claims description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 229910000765 intermetallic Inorganic materials 0.000 claims description 10
- 239000002168 alkylating agent Substances 0.000 claims description 9
- 229940100198 alkylating agent Drugs 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 241000282414 Homo sapiens Species 0.000 claims description 7
- 239000001569 carbon dioxide Substances 0.000 claims description 7
- 238000006268 reductive amination reaction Methods 0.000 claims description 7
- 208000002193 Pain Diseases 0.000 claims description 6
- 230000029936 alkylation Effects 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 230000036407 pain Effects 0.000 claims description 6
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 5
- 208000003870 Drug Overdose Diseases 0.000 claims description 5
- 206010033296 Overdoses Diseases 0.000 claims description 5
- 231100000725 drug overdose Toxicity 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 230000002152 alkylating effect Effects 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 208000023504 respiratory system disease Diseases 0.000 claims description 4
- 229910052723 transition metal Inorganic materials 0.000 claims description 4
- 150000003624 transition metals Chemical class 0.000 claims description 4
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 claims description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 230000001149 cognitive effect Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 125000002346 iodo group Chemical group I* 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 230000000241 respiratory effect Effects 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- YAIUKXOVFBOUER-UHFFFAOYSA-N n-ethyl-n-(4-fluorophenyl)benzamide Chemical compound C=1C=C(F)C=CC=1N(CC)C(=O)C1=CC=CC=C1 YAIUKXOVFBOUER-UHFFFAOYSA-N 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 230000007704 transition Effects 0.000 claims 1
- 102000005962 receptors Human genes 0.000 abstract description 27
- 108020003175 receptors Proteins 0.000 abstract description 27
- 239000000556 agonist Substances 0.000 abstract description 20
- 239000005557 antagonist Substances 0.000 abstract description 19
- 238000003556 assay Methods 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 9
- 239000002858 neurotransmitter agent Substances 0.000 abstract description 8
- 230000001225 therapeutic effect Effects 0.000 abstract description 7
- 208000004756 Respiratory Insufficiency Diseases 0.000 abstract description 5
- 206010038678 Respiratory depression Diseases 0.000 abstract description 5
- 102000048260 kappa Opioid Receptors Human genes 0.000 abstract description 4
- 108020001588 κ-opioid receptors Proteins 0.000 abstract description 4
- 206010014561 Emphysema Diseases 0.000 abstract description 3
- 208000008784 apnea Diseases 0.000 abstract description 3
- 208000006673 asthma Diseases 0.000 abstract description 3
- 206010047700 Vomiting Diseases 0.000 abstract description 2
- 238000012544 monitoring process Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 147
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 118
- 239000000243 solution Substances 0.000 description 110
- 239000000203 mixture Substances 0.000 description 104
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
- 238000009472 formulation Methods 0.000 description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- 238000005481 NMR spectroscopy Methods 0.000 description 51
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 229910001868 water Inorganic materials 0.000 description 45
- 239000002904 solvent Substances 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 37
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 35
- 108700023159 delta Opioid Receptors Proteins 0.000 description 35
- 102000048124 delta Opioid Receptors Human genes 0.000 description 35
- 239000007787 solid Substances 0.000 description 35
- 239000004480 active ingredient Substances 0.000 description 33
- 230000000694 effects Effects 0.000 description 32
- 239000000843 powder Substances 0.000 description 30
- 102000051367 mu Opioid Receptors Human genes 0.000 description 28
- 108020001612 μ-opioid receptors Proteins 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 229910052757 nitrogen Inorganic materials 0.000 description 24
- 238000001819 mass spectrum Methods 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
- 241000894007 species Species 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- 235000019198 oils Nutrition 0.000 description 20
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- 238000010992 reflux Methods 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 16
- 239000004615 ingredient Substances 0.000 description 16
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 16
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- 239000013543 active substance Substances 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- 239000002775 capsule Substances 0.000 description 11
- 238000001556 precipitation Methods 0.000 description 11
- 239000003039 volatile agent Substances 0.000 description 11
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- 239000008101 lactose Substances 0.000 description 10
- 235000019359 magnesium stearate Nutrition 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 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 10
- 239000003208 petroleum Substances 0.000 description 10
- VKUXNUOPPQWDMV-DTWKUNHWSA-N (2r,5s)-2,5-dimethyl-1-prop-2-enylpiperazine Chemical compound C[C@H]1CN(CC=C)[C@H](C)CN1 VKUXNUOPPQWDMV-DTWKUNHWSA-N 0.000 description 9
- 239000005711 Benzoic acid Substances 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 9
- 239000012964 benzotriazole Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 238000004821 distillation Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 101100108551 Mus musculus Akr1b7 gene Proteins 0.000 description 8
- 102000003840 Opioid Receptors Human genes 0.000 description 8
- 108090000137 Opioid Receptors Proteins 0.000 description 8
- 235000010233 benzoic acid Nutrition 0.000 description 8
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 8
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 229940127240 opiate Drugs 0.000 description 8
- 235000011056 potassium acetate Nutrition 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 210000003405 ileum Anatomy 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 229940069328 povidone Drugs 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000018 receptor agonist Substances 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 241000700199 Cavia porcellus Species 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 239000007903 gelatin capsule Substances 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 229940044601 receptor agonist Drugs 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 239000008215 water for injection Substances 0.000 description 6
- 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 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229960001797 methadone Drugs 0.000 description 5
- 229960005181 morphine Drugs 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000007911 parenteral administration Methods 0.000 description 5
- 230000036515 potency Effects 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 108010085082 sigma receptors Proteins 0.000 description 5
- CMIBUZBMZCBCAT-HOTGVXAUSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 description 4
- QZVQQUVWFIZUBQ-UHFFFAOYSA-N 3-fluoroaniline Chemical compound NC1=CC=CC(F)=C1 QZVQQUVWFIZUBQ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- 108010092674 Enkephalins Proteins 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000000730 antalgic agent Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 150000008640 diphenylmethylpiperazines Chemical class 0.000 description 4
- 239000012259 ether extract Substances 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 229940080313 sodium starch Drugs 0.000 description 4
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 3
- FHYDHJXZZQCXOX-UHFFFAOYSA-N 3-fluoro-n-methylaniline Chemical compound CNC1=CC=CC(F)=C1 FHYDHJXZZQCXOX-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 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 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 3
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical class 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 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 230000008484 agonism Effects 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000010533 azeotropic distillation Methods 0.000 description 3
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 3
- 239000012965 benzophenone Substances 0.000 description 3
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000007963 capsule composition Substances 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000000841 delta opiate receptor agonist Substances 0.000 description 3
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000006196 drop Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- ZBEMVEQFSWCODH-UHFFFAOYSA-N n-(3-fluorophenyl)-3-formyl-n-methylbenzamide Chemical compound C=1C=CC(F)=CC=1N(C)C(=O)C1=CC=CC(C=O)=C1 ZBEMVEQFSWCODH-UHFFFAOYSA-N 0.000 description 3
- 238000002663 nebulization Methods 0.000 description 3
- 229940124636 opioid drug Drugs 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- YEKUWOWHPVKTCQ-UHFFFAOYSA-M tetraethylazanium;fluoride;hydrate Chemical compound O.[F-].CC[N+](CC)(CC)CC YEKUWOWHPVKTCQ-UHFFFAOYSA-M 0.000 description 3
- BFRHMVJJJGUHDI-UHFFFAOYSA-N (3-bromophenoxy)-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC(Br)=C1 BFRHMVJJJGUHDI-UHFFFAOYSA-N 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- PLDWAJLZAAHOGG-UHFFFAOYSA-N 1-bromo-3-methoxybenzene Chemical compound COC1=CC=CC(Br)=C1 PLDWAJLZAAHOGG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- LYUPJHVGLFETDG-UHFFFAOYSA-N 1-phenylbutan-2-ol Chemical compound CCC(O)CC1=CC=CC=C1 LYUPJHVGLFETDG-UHFFFAOYSA-N 0.000 description 2
- SAPQIENQEZURNZ-UHFFFAOYSA-N 2,2,2-trifluoro-n-phenylacetamide Chemical compound FC(F)(F)C(=O)NC1=CC=CC=C1 SAPQIENQEZURNZ-UHFFFAOYSA-N 0.000 description 2
- AAEJMRFPMLLTIX-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxybenzaldehyde Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC(C=O)=C1 AAEJMRFPMLLTIX-UHFFFAOYSA-N 0.000 description 2
- MNOJRWOWILAHAV-UHFFFAOYSA-N 3-bromophenol Chemical compound OC1=CC=CC(Br)=C1 MNOJRWOWILAHAV-UHFFFAOYSA-N 0.000 description 2
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 2
- VLWRKVBQUANIGI-UHFFFAOYSA-N 4-fluoro-n-methylaniline Chemical compound CNC1=CC=C(F)C=C1 VLWRKVBQUANIGI-UHFFFAOYSA-N 0.000 description 2
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 2
- 108010049140 Endorphins Proteins 0.000 description 2
- 102000009025 Endorphins Human genes 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 2
- 208000002740 Muscle Rigidity Diseases 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
- OJGMBLNIHDZDGS-UHFFFAOYSA-N N-Ethylaniline Chemical compound CCNC1=CC=CC=C1 OJGMBLNIHDZDGS-UHFFFAOYSA-N 0.000 description 2
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 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
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical group [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 239000012062 aqueous buffer Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical class 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 150000003935 benzaldehydes Chemical class 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 239000012159 carrier gas Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000007907 direct compression Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000001038 ionspray mass spectrometry Methods 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- JGZKUKYUQJUUNE-UHFFFAOYSA-L magnesium;ethoxyethane;dibromide Chemical compound [Mg+2].[Br-].[Br-].CCOCC JGZKUKYUQJUUNE-UHFFFAOYSA-L 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000003340 mental effect Effects 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- PRPPANIATVQNFY-UHFFFAOYSA-N n,n-diethyl-3-iodobenzamide Chemical compound CCN(CC)C(=O)C1=CC=CC(I)=C1 PRPPANIATVQNFY-UHFFFAOYSA-N 0.000 description 2
- LQFLWKPCQITJIH-UHFFFAOYSA-N n-allyl-aniline Chemical compound C=CCNC1=CC=CC=C1 LQFLWKPCQITJIH-UHFFFAOYSA-N 0.000 description 2
- AOTWIFLKURJQGE-UHFFFAOYSA-N n-cyclopropylaniline Chemical compound C1CC1NC1=CC=CC=C1 AOTWIFLKURJQGE-UHFFFAOYSA-N 0.000 description 2
- BKFMLVNSBPSOJX-UHFFFAOYSA-N n-ethyl-n-(4-fluorophenyl)-3-formylbenzamide Chemical compound C=1C=C(F)C=CC=1N(CC)C(=O)C1=CC=CC(C=O)=C1 BKFMLVNSBPSOJX-UHFFFAOYSA-N 0.000 description 2
- FRCFWPVMFJMNDP-UHFFFAOYSA-N n-propan-2-ylaniline Chemical compound CC(C)NC1=CC=CC=C1 FRCFWPVMFJMNDP-UHFFFAOYSA-N 0.000 description 2
- 230000003533 narcotic effect Effects 0.000 description 2
- 239000007923 nasal drop Substances 0.000 description 2
- 229940100662 nasal drops Drugs 0.000 description 2
- 229940097496 nasal spray Drugs 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 230000003040 nociceptive effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 229960000482 pethidine Drugs 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 239000012048 reactive intermediate Substances 0.000 description 2
- 238000001525 receptor binding assay Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- HRTKQUHFGZFPPF-UHFFFAOYSA-M tetraethylazanium;fluoride;dihydrate Chemical compound O.O.[F-].CC[N+](CC)(CC)CC HRTKQUHFGZFPPF-UHFFFAOYSA-M 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000026683 transduction Effects 0.000 description 2
- 238000010361 transduction Methods 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 1
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 1
- QHXFGOIOVYTMHQ-UHFFFAOYSA-N 2,4,6-trichloro-n-methylaniline Chemical compound CNC1=C(Cl)C=C(Cl)C=C1Cl QHXFGOIOVYTMHQ-UHFFFAOYSA-N 0.000 description 1
- NATVSFWWYVJTAZ-UHFFFAOYSA-N 2,4,6-trichloroaniline Chemical compound NC1=C(Cl)C=C(Cl)C=C1Cl NATVSFWWYVJTAZ-UHFFFAOYSA-N 0.000 description 1
- VBLXCTYLWZJBKA-UHFFFAOYSA-N 2-(trifluoromethyl)aniline Chemical compound NC1=CC=CC=C1C(F)(F)F VBLXCTYLWZJBKA-UHFFFAOYSA-N 0.000 description 1
- LDVAIJZDACHGML-UHFFFAOYSA-N 2-fluoro-n-methylaniline Chemical compound CNC1=CC=CC=C1F LDVAIJZDACHGML-UHFFFAOYSA-N 0.000 description 1
- ADMJICSNKXQZOS-UHFFFAOYSA-N 2-fluoro-n-propylaniline Chemical compound CCCNC1=CC=CC=C1F ADMJICSNKXQZOS-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- GTKIGDZXPDCIKR-UHFFFAOYSA-N 2-phenylbenzamide Chemical compound NC(=O)C1=CC=CC=C1C1=CC=CC=C1 GTKIGDZXPDCIKR-UHFFFAOYSA-N 0.000 description 1
- YHEKBXQMXRLCCX-UHFFFAOYSA-N 2h-benzotriazol-4-ylmethanol Chemical compound OCC1=CC=CC2=C1N=NN2 YHEKBXQMXRLCCX-UHFFFAOYSA-N 0.000 description 1
- UHDNUPHSDMOGCR-UHFFFAOYSA-N 3-Formylbenzoic acid Chemical compound OC(=O)C1=CC=CC(C=O)=C1 UHDNUPHSDMOGCR-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
- 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
- HQSCPPCMBMFJJN-UHFFFAOYSA-N 4-bromobenzonitrile Chemical compound BrC1=CC=C(C#N)C=C1 HQSCPPCMBMFJJN-UHFFFAOYSA-N 0.000 description 1
- XCEYKKJMLOFDSS-UHFFFAOYSA-N 4-chloro-n-methylaniline Chemical compound CNC1=CC=C(Cl)C=C1 XCEYKKJMLOFDSS-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- JFXDIXYFXDOZIT-UHFFFAOYSA-N 4-methoxy-n-methylaniline Chemical compound CNC1=CC=C(OC)C=C1 JFXDIXYFXDOZIT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000144730 Amygdalus persica Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 208000027534 Emotional disease Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241000282412 Homo Species 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229920003094 Methocel™ K4M Polymers 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028347 Muscle twitching Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 241001351439 Oneida Species 0.000 description 1
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 102000016979 Other receptors Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 208000020339 Spinal injury 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
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- ZYVFZFLDCKMQQJ-UHFFFAOYSA-K [Cl-].[Cl-].[Cl-].O=[Ti+3] Chemical compound [Cl-].[Cl-].[Cl-].O=[Ti+3] ZYVFZFLDCKMQQJ-UHFFFAOYSA-K 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 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
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000003502 anti-nociceptive effect Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- MXJIHEXYGRXHGP-UHFFFAOYSA-N benzotriazol-1-ylmethanol Chemical compound C1=CC=C2N(CO)N=NC2=C1 MXJIHEXYGRXHGP-UHFFFAOYSA-N 0.000 description 1
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 238000003965 capillary gas chromatography Methods 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 208000015114 central nervous system disease Diseases 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
- 239000012707 chemical precursor Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007958 cherry flavor Substances 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 231100000867 compulsive behavior Toxicity 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 229940076286 cupric acetate Drugs 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000000857 delta opiate receptor antagonist Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000012631 diagnostic technique Methods 0.000 description 1
- 150000001990 dicarboxylic acid derivatives Chemical class 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 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
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 1
- NWVNXDKZIQLBNM-UHFFFAOYSA-N diphenylmethylpiperazine Chemical class C1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NWVNXDKZIQLBNM-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000007904 elastic gelatin capsule Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 230000010491 emotional process Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- 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 1
- 239000012467 final product Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000002238 fumaric acids Chemical class 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 229940116364 hard fat Drugs 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
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000006289 hydroxybenzyl group Chemical group 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 150000002485 inorganic esters Chemical class 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 230000003924 mental process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 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
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002756 mu opiate receptor agonist Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- YLZSPAGUOILDCE-UHFFFAOYSA-N n-(benzotriazol-1-ylmethyl)-3-fluoroaniline Chemical compound FC1=CC=CC(NCN2C3=CC=CC=C3N=N2)=C1 YLZSPAGUOILDCE-UHFFFAOYSA-N 0.000 description 1
- UYFBSIJFMJLIAZ-UHFFFAOYSA-N n-(cyclopropylmethyl)aniline Chemical compound C1CC1CNC1=CC=CC=C1 UYFBSIJFMJLIAZ-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
- QNSZDXLOSMUCPQ-UHFFFAOYSA-N n-ethyl-2-fluoroaniline Chemical compound CCNC1=CC=CC=C1F QNSZDXLOSMUCPQ-UHFFFAOYSA-N 0.000 description 1
- SBNPVCZGSKLRSJ-UHFFFAOYSA-N n-ethyl-3-fluoroaniline Chemical compound CCNC1=CC=CC(F)=C1 SBNPVCZGSKLRSJ-UHFFFAOYSA-N 0.000 description 1
- RNRDHZGWBBEZBK-UHFFFAOYSA-N n-methyl-2-(trifluoromethyl)aniline Chemical compound CNC1=CC=CC=C1C(F)(F)F RNRDHZGWBBEZBK-UHFFFAOYSA-N 0.000 description 1
- NCCHARWOCKOHIH-UHFFFAOYSA-N n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1 NCCHARWOCKOHIH-UHFFFAOYSA-N 0.000 description 1
- CDZOGLJOFWFVOZ-UHFFFAOYSA-N n-propylaniline Chemical compound CCCNC1=CC=CC=C1 CDZOGLJOFWFVOZ-UHFFFAOYSA-N 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000003880 negative regulation of appetite Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical class 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000216 proconvulsive effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 208000012788 shakes Diseases 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000003579 shift reagent Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000002731 stomach secretion inhibitor Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 201000009032 substance abuse Diseases 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
- 229960004016 sucrose syrup 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
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000007916 tablet composition Substances 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
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000009974 thixotropic effect Effects 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- ZHXAZZQXWJJBHA-UHFFFAOYSA-N triphenylbismuthane Chemical compound C1=CC=CC=C1[Bi](C=1C=CC=CC=1)C1=CC=CC=C1 ZHXAZZQXWJJBHA-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- 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
- C07D295/14—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Addiction (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
- Water Treatment By Sorption (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9833393A | 1993-07-30 | 1993-07-30 | |
| US16987993A | 1993-12-17 | 1993-12-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL110512A0 IL110512A0 (en) | 1994-10-21 |
| IL110512A true IL110512A (en) | 1998-10-30 |
Family
ID=26794651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL11051294A IL110512A (en) | 1993-07-30 | 1994-07-29 | History of diarylmethyl piperazine, their preparation and pharmaceutical preparations containing them |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5552404A (fr) |
| EP (1) | EP0711289B1 (fr) |
| JP (1) | JPH09501156A (fr) |
| CN (1) | CN1054850C (fr) |
| AT (1) | ATE195733T1 (fr) |
| AU (1) | AU692788B2 (fr) |
| CA (1) | CA2168432C (fr) |
| DE (1) | DE69425662T2 (fr) |
| DK (1) | DK0711289T3 (fr) |
| ES (1) | ES2149881T3 (fr) |
| GR (1) | GR3034695T3 (fr) |
| HU (1) | HU221726B1 (fr) |
| IL (1) | IL110512A (fr) |
| MY (1) | MY111348A (fr) |
| PT (1) | PT711289E (fr) |
| RU (1) | RU2133744C1 (fr) |
| TW (1) | TW386081B (fr) |
| WO (1) | WO1995004051A1 (fr) |
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 |
| US5807858A (en) * | 1996-06-05 | 1998-09-15 | Delta Pharmaceutical, Inc. | Compositions and methods for reducing respiratory depression |
| US5681830A (en) * | 1992-02-03 | 1997-10-28 | Delta Pharmaceuticals, Inc. | Opioid compounds |
| 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 |
| SE9504661D0 (sv) * | 1995-12-22 | 1995-12-22 | Astra Pharma Inc | New compounds |
| SE9504662D0 (sv) * | 1995-12-22 | 1995-12-22 | Astra Pharma Inc | New compounds |
| GB9709972D0 (en) * | 1997-05-19 | 1997-07-09 | Pfizer Ltd | Tetrazoles |
| GB9804734D0 (en) * | 1998-03-05 | 1998-04-29 | Pfizer Ltd | Compounds |
| 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 |
| 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 |
| AU2001239896A1 (en) * | 2000-03-16 | 2001-10-03 | Sepracor, Inc. | Peptidomimetic ligands for cellular receptors and ion channels |
| SE0001209D0 (sv) | 2000-04-04 | 2000-04-04 | Astrazeneca Canada Inc | Novel compounds |
| SE0100764D0 (sv) * | 2001-03-07 | 2001-03-07 | Astrazeneca Ab | New assymetric process |
| WO2002080918A1 (fr) * | 2001-04-02 | 2002-10-17 | Toray Industries, Inc. | Agent therapeutique ou prophylactique en cas de miction frequente ou d'incontinence urinaire |
| CA2446326C (fr) | 2001-05-18 | 2010-12-07 | Astrazeneca Ab | Derives de 4(phenyl-piperazine-methyle) benzamide et utilisation de ces derives pour le traitement de la douleur, de l'anxiete ou des troubles gastro-intestinaux |
| US7030124B2 (en) * | 2001-10-29 | 2006-04-18 | Ardent Pharmaceuticals, Inc. | Method of treating depression with delta receptor agonist compounds |
| AU2003214800A1 (en) | 2002-01-02 | 2003-07-24 | Ardent Pharmaceuticals, Inc. | Method of treating sexual dysfunctions with delta opioid receptor agonist compounds |
| US6881829B2 (en) * | 2002-04-26 | 2005-04-19 | Chimeracom, L.L.C. | Chimeric hybrid analgesics |
| 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 |
| ES2298522T3 (es) * | 2002-05-16 | 2008-05-16 | N.V. Organon | Combinacion sinergica de un analgesico opioide y un aine. |
| CN1202843C (zh) * | 2002-06-21 | 2005-05-25 | 天大药业(深圳)有限公司 | 一种戒毒药物组合物及其制备方法和应用 |
| CA2492694A1 (fr) * | 2002-07-11 | 2004-01-22 | Toray Industries, Inc. | Agent therapeutique ou preventif pour la nausee/le vomissement |
| US20050241431A1 (en) * | 2002-09-27 | 2005-11-03 | Continental Teves Ag & Co. Ohg | Adjustable pedal device |
| SE0203303D0 (sv) | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
| SE0203300D0 (sv) | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
| SE0203302D0 (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 |
| US20050026879A1 (en) * | 2003-07-31 | 2005-02-03 | Robinson Cynthia B. | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a tyrosine kinase inhibitor, delta opioid receptor antagonist, neurokinin receptor antagonist, or VCAM inhibitor for treatment of asthma or chronic obstructive pulmonary disease |
| US20090297611A1 (en) * | 2003-07-31 | 2009-12-03 | Robinson Cynthia B | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a tyrosine kinase inhibitor, delta opioid receptor antagonist, neurokinin receptor antagonist, or vcam inhibitor for treatment of asthma or chronic obstructive pulmonary disease |
| TWI317286B (en) | 2003-12-31 | 2009-11-21 | Targeting delivery system | |
| MX2007001240A (es) | 2004-08-02 | 2007-03-23 | Astrazeneca Ab | Derivados de diarilmetil-piperazina, preparaciones y usos de las mismas. |
| US7683168B2 (en) * | 2005-04-14 | 2010-03-23 | Mount Cook Bio Sciences, Inc. | Compositions of novel opioid compounds and method of use thereof |
| DK2081562T3 (en) | 2006-09-20 | 2016-05-30 | Univ Texas | Method of administering volatile anesthetics for regional anesthesia and / or pain relief |
| EP2244737B1 (fr) | 2008-01-22 | 2019-04-10 | The Board of Regents of The University of Texas System | Compositions anesthésiques volatiles comprenant des solvants d'extraction pour une anesthésie régionale et/ou un soulagement de la douleur |
| CA2724955A1 (fr) * | 2008-05-20 | 2009-11-26 | Astrazeneca Ab | Procede de traitement d'un trouble depressif majeur anxieux |
Family Cites Families (12)
| 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 |
| IN163948B (fr) | 1986-01-17 | 1988-12-10 | Robins Co Inc A H | |
| PH24752A (en) * | 1987-04-16 | 1990-10-01 | Lilly Co Eli | Piperidine opioid antagonists |
| US4816586A (en) | 1987-07-29 | 1989-03-28 | Regents Of The University Of Minnesota | Delta opioid receptor antagonists |
| JPH04506072A (ja) * | 1989-06-19 | 1992-10-22 | ザ・ウエルカム・ファウンデーション・リミテッド | 癌治療に有用であり、かつ抗ヒスタミン特性を有する医薬 |
| 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 |
| SE467304B (sv) * | 1990-10-31 | 1992-06-29 | Kamewa Ab | Styr- och reverseringsanordning foer ett marint straaldriftsaggregat |
| 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 |
| NZ240863A (en) * | 1991-09-11 | 1995-04-27 | Mcneilab Inc | Substituted 4-aryl piperidine and 4-aryl piperazine derivatives, preparation and pharmaceutical compositions thereof |
| GB9202238D0 (en) | 1992-02-03 | 1992-03-18 | Wellcome Found | Compounds |
-
1994
- 1994-07-29 RU RU96104351/04A patent/RU2133744C1/ru not_active IP Right Cessation
- 1994-07-29 IL IL11051294A patent/IL110512A/en not_active IP Right Cessation
- 1994-07-29 AU AU72351/94A patent/AU692788B2/en not_active Ceased
- 1994-07-29 PT PT94921756T patent/PT711289E/pt unknown
- 1994-07-29 MY MYPI94001988A patent/MY111348A/en unknown
- 1994-07-29 AT AT94921756T patent/ATE195733T1/de not_active IP Right Cessation
- 1994-07-29 ES ES94921756T patent/ES2149881T3/es not_active Expired - Lifetime
- 1994-07-29 DE DE69425662T patent/DE69425662T2/de not_active Expired - Fee Related
- 1994-07-29 HU HU9501982A patent/HU221726B1/hu not_active IP Right Cessation
- 1994-07-29 EP EP94921756A patent/EP0711289B1/fr not_active Expired - Lifetime
- 1994-07-29 JP JP7505665A patent/JPH09501156A/ja not_active Ceased
- 1994-07-29 CN CN94192949A patent/CN1054850C/zh not_active Expired - Fee Related
- 1994-07-29 CA CA002168432A patent/CA2168432C/fr not_active Expired - Fee Related
- 1994-07-29 WO PCT/GB1994/001641 patent/WO1995004051A1/fr active IP Right Grant
- 1994-07-29 DK DK94921756T patent/DK0711289T3/da active
- 1994-08-02 TW TW083107072A patent/TW386081B/zh not_active IP Right Cessation
-
1995
- 1995-04-28 US US08/431,377 patent/US5552404A/en not_active Expired - Lifetime
-
2000
- 2000-10-27 GR GR20000402382T patent/GR3034695T3/el not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU692788B2 (en) | 1998-06-18 |
| AU7235194A (en) | 1995-02-28 |
| HUT72893A (en) | 1996-06-28 |
| MY111348A (en) | 1999-11-30 |
| HU9501982D0 (en) | 1995-09-28 |
| TW386081B (en) | 2000-04-01 |
| ATE195733T1 (de) | 2000-09-15 |
| EP0711289A1 (fr) | 1996-05-15 |
| DE69425662T2 (de) | 2001-04-12 |
| HU221726B1 (hu) | 2002-12-28 |
| WO1995004051A1 (fr) | 1995-02-09 |
| IL110512A0 (en) | 1994-10-21 |
| PT711289E (pt) | 2001-02-28 |
| CN1133593A (zh) | 1996-10-16 |
| RU2133744C1 (ru) | 1999-07-27 |
| DK0711289T3 (da) | 2000-11-06 |
| CA2168432C (fr) | 2004-03-23 |
| JPH09501156A (ja) | 1997-02-04 |
| DE69425662D1 (de) | 2000-09-28 |
| GR3034695T3 (en) | 2001-01-31 |
| EP0711289B1 (fr) | 2000-08-23 |
| ES2149881T3 (es) | 2000-11-16 |
| CA2168432A1 (fr) | 1995-02-09 |
| US5552404A (en) | 1996-09-03 |
| CN1054850C (zh) | 2000-07-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0711289B1 (fr) | Composes a base de piperazine, a usage therapeutique | |
| US5574159A (en) | Opioid compounds and methods for making therefor | |
| US5681830A (en) | Opioid compounds | |
| US5854249A (en) | Opioid diarylmethylpiperazines and piperidines | |
| US5985880A (en) | Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds | |
| EP0938317B1 (fr) | Compositions pour la reduction de la depression respiratoire | |
| JP2006510716A (ja) | 置換アミド類 | |
| JP2002511836A (ja) | 化合物および方法 | |
| US20020052007A1 (en) | Diarylmethylbenzylpiperazines and corresponding halobenzyl derivatives | |
| HUP0300295A2 (hu) | Helyettesített benzamidszármazékok, ezeket tartalmazó gyógyszerkészítmények és alkalmazásuk | |
| CA2595400C (fr) | Derives de methylphenidate et leurs utilisations pour le traitement de conditions et de maladies angiogeniques | |
| TWI335312B (en) | Formamide derivatives for the treatment of diseases | |
| WO2012033435A1 (fr) | Procédé, composé, composition pharmaceutique et médicament destinés à la récupération de la mémoire (à l'état normal ou pathologique) | |
| CN101677546A (zh) | 具有中枢神经系统活性的取代的吡咯烷化合物 | |
| PL179341B1 (pl) | Związki difenylometylopiperazyny |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FF | Patent granted | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| HC | Change of name of proprietor(s) | ||
| MM9K | Patent not in force due to non-payment of renewal fees |