IL90560A - History of phenothiazine, method of preparation and pharmaceutical preparations containing them - Google Patents
History of phenothiazine, method of preparation and pharmaceutical preparations containing themInfo
- Publication number
- IL90560A IL90560A IL9056089A IL9056089A IL90560A IL 90560 A IL90560 A IL 90560A IL 9056089 A IL9056089 A IL 9056089A IL 9056089 A IL9056089 A IL 9056089A IL 90560 A IL90560 A IL 90560A
- Authority
- IL
- Israel
- Prior art keywords
- kpa
- propyl
- under reduced
- reduced pressure
- mixture
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims description 28
- 229940066767 systemic antihistamines phenothiazine derivative Drugs 0.000 title abstract description 14
- 125000001484 phenothiazinyl group Chemical class C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 title abstract 2
- 239000000203 mixture Substances 0.000 claims abstract description 319
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 107
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 99
- 239000002253 acid Substances 0.000 claims abstract description 55
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 40
- 239000001257 hydrogen Substances 0.000 claims abstract description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 38
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000001301 oxygen Substances 0.000 claims abstract description 21
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 21
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000005864 Sulphur Chemical group 0.000 claims abstract description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 16
- 125000004429 atom Chemical group 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
- 150000002367 halogens Chemical group 0.000 claims abstract description 13
- 229910052736 halogen Chemical group 0.000 claims abstract description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 10
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 9
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 7
- 125000002636 imidazolinyl group Chemical group 0.000 claims abstract description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 186
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 79
- -1 hydroxy, methyl Chemical group 0.000 claims description 59
- 229950000688 phenothiazine Drugs 0.000 claims description 34
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 27
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 16
- 150000001408 amides Chemical class 0.000 claims description 15
- 150000002825 nitriles Chemical class 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 7
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 150000004985 diamines Chemical class 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 150000003556 thioamides Chemical class 0.000 claims description 4
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 230000002411 adverse Effects 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims 1
- 150000007513 acids Chemical class 0.000 abstract description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 abstract 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract 1
- 229940035676 analgesics Drugs 0.000 abstract 1
- 239000000730 antalgic agent Substances 0.000 abstract 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 abstract 1
- 239000002934 diuretic Substances 0.000 abstract 1
- 229940030606 diuretics Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 740
- 230000002829 reductive effect Effects 0.000 description 437
- 239000000243 solution Substances 0.000 description 376
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 313
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 234
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 218
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 211
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 209
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 183
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 175
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 170
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 137
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 126
- 238000004587 chromatography analysis Methods 0.000 description 120
- 239000012153 distilled water Substances 0.000 description 120
- 239000000047 product Substances 0.000 description 120
- 239000000741 silica gel Substances 0.000 description 113
- 229910002027 silica gel Inorganic materials 0.000 description 113
- 238000003756 stirring Methods 0.000 description 113
- 239000007787 solid Substances 0.000 description 110
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 109
- 235000019341 magnesium sulphate Nutrition 0.000 description 109
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 107
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 97
- 238000001816 cooling Methods 0.000 description 95
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 94
- 239000012074 organic phase Substances 0.000 description 90
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 89
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 89
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 88
- 239000003921 oil Substances 0.000 description 88
- 235000019198 oils Nutrition 0.000 description 88
- 229940073584 methylene chloride Drugs 0.000 description 76
- 238000002329 infrared spectrum Methods 0.000 description 73
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 70
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 69
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 65
- 239000011541 reaction mixture Substances 0.000 description 65
- 125000003118 aryl group Chemical group 0.000 description 64
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 62
- 235000019502 Orange oil Nutrition 0.000 description 55
- 239000010502 orange oil Substances 0.000 description 55
- 239000013078 crystal Substances 0.000 description 52
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 49
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- 239000000725 suspension Substances 0.000 description 48
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 46
- 239000011780 sodium chloride Substances 0.000 description 46
- 238000010992 reflux Methods 0.000 description 44
- 239000002244 precipitate Substances 0.000 description 41
- 239000000706 filtrate Substances 0.000 description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 235000011121 sodium hydroxide Nutrition 0.000 description 30
- 239000000155 melt Substances 0.000 description 29
- 229940086542 triethylamine Drugs 0.000 description 29
- 239000001530 fumaric acid Substances 0.000 description 26
- 229960001701 chloroform Drugs 0.000 description 24
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 21
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 21
- 230000005587 bubbling Effects 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- 150000002990 phenothiazines Chemical class 0.000 description 19
- 238000002425 crystallisation Methods 0.000 description 18
- 230000008025 crystallization Effects 0.000 description 18
- 238000009835 boiling Methods 0.000 description 17
- 238000001914 filtration Methods 0.000 description 16
- YAPQVCXMMMPTRU-UHFFFAOYSA-N 10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbothioamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(N)=S)C=C2N1C(C)CN1CCCC1 YAPQVCXMMMPTRU-UHFFFAOYSA-N 0.000 description 15
- LPPPABVBCXZTRD-UHFFFAOYSA-N 2-(2-cyanophenothiazin-10-yl)propyl methanesulfonate Chemical compound C1=C(C#N)C=C2N(C(COS(C)(=O)=O)C)C3=CC=CC=C3SC2=C1 LPPPABVBCXZTRD-UHFFFAOYSA-N 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 14
- 239000011521 glass Substances 0.000 description 14
- 230000007935 neutral effect Effects 0.000 description 13
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 13
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- AHNIZOFGMRUXHD-UHFFFAOYSA-N 10-[1-(diethylamino)propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C1=C(C(N)=S)C=C2N(C(C)CN(CC)CC)C3=CC=CC=C3SC2=C1 AHNIZOFGMRUXHD-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 11
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 10
- WVZBOLUWBWGONJ-UHFFFAOYSA-N 10-[1-(dimethylamino)propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C1=C(C(N)=S)C=C2N(C(CN(C)C)C)C3=CC=CC=C3SC2=C1 WVZBOLUWBWGONJ-UHFFFAOYSA-N 0.000 description 10
- BYORHHDOZQYRKQ-UHFFFAOYSA-N 10-[1-(ethylamino)propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(C)CNCC)C3=CC=CC=C3SC2=C1 BYORHHDOZQYRKQ-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000006748 scratching Methods 0.000 description 10
- 230000002393 scratching effect Effects 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- XZYJRLIBPLYWMK-UHFFFAOYSA-N 10-[1-(diethylamino)propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(C)CN(CC)CC)C3=CC=CC=C3SC2=C1 XZYJRLIBPLYWMK-UHFFFAOYSA-N 0.000 description 9
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 9
- 239000003610 charcoal Substances 0.000 description 9
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 9
- BRMYZIKAHFEUFJ-UHFFFAOYSA-L mercury diacetate Chemical compound CC(=O)O[Hg]OC(C)=O BRMYZIKAHFEUFJ-UHFFFAOYSA-L 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- QQMAOOUIVDZAKO-UHFFFAOYSA-N 2,3,3a,4,5,6-hexahydro-1h-benzimidazole Chemical compound C1CCC=C2NCNC21 QQMAOOUIVDZAKO-UHFFFAOYSA-N 0.000 description 8
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- FCGDEHGBHMUDIB-UHFFFAOYSA-N 10-[1-[ethyl(methyl)amino]propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C1=C(C(N)=S)C=C2N(C(C)CN(C)CC)C3=CC=CC=C3SC2=C1 FCGDEHGBHMUDIB-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- RSWGJHLUYNHPMX-ONCXSQPRSA-N abietic acid Chemical class C([C@@H]12)CC(C(C)C)=CC1=CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(O)=O RSWGJHLUYNHPMX-ONCXSQPRSA-N 0.000 description 6
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- QOQPYUSHDDPJQO-UHFFFAOYSA-N 10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboxylic acid;hydrochloride Chemical compound Cl.C12=CC=CC=C2SC2=CC=C(C(O)=O)C=C2N1C(C)CN1CCCC1 QOQPYUSHDDPJQO-UHFFFAOYSA-N 0.000 description 5
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 101150041968 CDC13 gene Proteins 0.000 description 5
- OPFTUNCRGUEPRZ-QLFBSQMISA-N Cyclohexane Natural products CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- WYKWIDKHJCQELF-UHFFFAOYSA-N 10-(1-hydroxypropan-2-yl)phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(CO)C)C3=CC=CC=C3SC2=C1 WYKWIDKHJCQELF-UHFFFAOYSA-N 0.000 description 4
- XZSIGWOVDPSPMG-UHFFFAOYSA-N 10h-phenothiazine-2-carbonitrile Chemical compound C1=CC=C2NC3=CC(C#N)=CC=C3SC2=C1 XZSIGWOVDPSPMG-UHFFFAOYSA-N 0.000 description 4
- JZUHFVDWSRZVEI-UHFFFAOYSA-N 2-(7-chloro-2-cyanophenothiazin-10-yl)propyl methanesulfonate Chemical compound C1=C(C#N)C=C2N(C(COS(C)(=O)=O)C)C3=CC=C(Cl)C=C3SC2=C1 JZUHFVDWSRZVEI-UHFFFAOYSA-N 0.000 description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 4
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-GUEYOVJQSA-N acetic acid-d4 Chemical compound [2H]OC(=O)C([2H])([2H])[2H] QTBSBXVTEAMEQO-GUEYOVJQSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 4
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 4
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 4
- 108020001588 κ-opioid receptors Proteins 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- JLBNRUBOQHLQNU-UHFFFAOYSA-N 10-[1-(3-methylpiperidin-1-yl)propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(N)=S)C=C2N1C(C)CN1CCCC(C)C1 JLBNRUBOQHLQNU-UHFFFAOYSA-N 0.000 description 3
- OJMFSTAZIMHRCD-UHFFFAOYSA-N 10-[1-(azepan-1-yl)propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C12=CC=CC=C2SC2=CC=C(C#N)C=C2N1C(C)CN1CCCCCC1 OJMFSTAZIMHRCD-UHFFFAOYSA-N 0.000 description 3
- GPZICUOYBMMEAX-UHFFFAOYSA-N 10-[1-(azepan-1-yl)propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(N)=S)C=C2N1C(C)CN1CCCCCC1 GPZICUOYBMMEAX-UHFFFAOYSA-N 0.000 description 3
- KYGUFSCCEUPYDV-OMOCHNIRSA-N 10-[1-[(2r)-2-(hydroxymethyl)pyrrolidin-1-yl]propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C12=CC=CC=C2SC2=CC=C(C#N)C=C2N1C(C)CN1CCC[C@@H]1CO KYGUFSCCEUPYDV-OMOCHNIRSA-N 0.000 description 3
- FBULWHBHTGRLSB-UHFFFAOYSA-N 10-[1-[methyl(propan-2-yl)amino]propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(C)CN(C)C(C)C)C3=CC=CC=C3SC2=C1 FBULWHBHTGRLSB-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- XCTBCYQTRQJJMT-UHFFFAOYSA-N 7-chloro-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbothioamide Chemical compound C12=CC=C(Cl)C=C2SC2=CC=C(C(N)=S)C=C2N1C(C)CN1CCCC1 XCTBCYQTRQJJMT-UHFFFAOYSA-N 0.000 description 3
- NXNSXSCGVADGDF-UHFFFAOYSA-N 7-chloro-10h-phenothiazine-2-carbonitrile Chemical compound N#CC1=CC=C2SC3=CC(Cl)=CC=C3NC2=C1 NXNSXSCGVADGDF-UHFFFAOYSA-N 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 3
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 3
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 150000001409 amidines Chemical class 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 3
- UVWNIHBFEQHULA-UHFFFAOYSA-N ethyl 2-(7-chloro-2-cyanophenothiazin-10-yl)propanoate Chemical compound C1=C(C#N)C=C2N(C(C)C(=O)OCC)C3=CC=C(Cl)C=C3SC2=C1 UVWNIHBFEQHULA-UHFFFAOYSA-N 0.000 description 3
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000003208 petroleum Substances 0.000 description 3
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- LRFWYBZWRQWZIM-UHFFFAOYSA-N (2-fluorophenyl)methanamine Chemical compound NCC1=CC=CC=C1F LRFWYBZWRQWZIM-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 2
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 2
- MALFDKVGFWWZHA-UHFFFAOYSA-N 10-(1-hydroxypropan-2-yl)phenothiazine-1-carbonitrile Chemical compound C1=CC(C#N)=C2N(C(CO)C)C3=CC=CC=C3SC2=C1 MALFDKVGFWWZHA-UHFFFAOYSA-N 0.000 description 2
- ATCUCVRYXYRJRY-UHFFFAOYSA-N 10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbonitrile Chemical compound C12=CC=CC=C2SC2=CC=C(C#N)C=C2N1C(C)CN1CCCC1 ATCUCVRYXYRJRY-UHFFFAOYSA-N 0.000 description 2
- UPOGZXUPGLXYIF-UHFFFAOYSA-N 10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbonyl chloride;hydrochloride Chemical compound Cl.C12=CC=CC=C2SC2=CC=C(C(Cl)=O)C=C2N1C(C)CN1CCCC1 UPOGZXUPGLXYIF-UHFFFAOYSA-N 0.000 description 2
- GPVUUTWFAFKJLF-UHFFFAOYSA-N 10-[1-(2,5-dimethylpyrrolidin-1-yl)propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C12=CC=CC=C2SC2=CC=C(C#N)C=C2N1C(C)CN1C(C)CCC1C GPVUUTWFAFKJLF-UHFFFAOYSA-N 0.000 description 2
- XEVCYLKAXVWQJB-UHFFFAOYSA-N 10-[1-(diethylamino)propan-2-yl]-n-(3-methylbutyl)phenothiazine-2-carbothioamide Chemical compound C1=C(C(=S)NCCC(C)C)C=C2N(C(C)CN(CC)CC)C3=CC=CC=C3SC2=C1 XEVCYLKAXVWQJB-UHFFFAOYSA-N 0.000 description 2
- SYFWMFDFJSPNRY-UHFFFAOYSA-N 10-[1-(diethylamino)propan-2-yl]-n-propylphenothiazine-2-carbothioamide Chemical compound C1=CC=C2N(C(C)CN(CC)CC)C3=CC(C(=S)NCCC)=CC=C3SC2=C1 SYFWMFDFJSPNRY-UHFFFAOYSA-N 0.000 description 2
- PMOWUMMDIIENQA-UHFFFAOYSA-N 10-[1-(dimethylamino)propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(CN(C)C)C)C3=CC=CC=C3SC2=C1 PMOWUMMDIIENQA-UHFFFAOYSA-N 0.000 description 2
- ISLPHQKMRQUJSR-UHFFFAOYSA-N 10-[1-(methylamino)propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(C)CNC)C3=CC=CC=C3SC2=C1 ISLPHQKMRQUJSR-UHFFFAOYSA-N 0.000 description 2
- GGNDUSCXIGWSTI-UHFFFAOYSA-N 10-[1-[2-hydroxyethyl(methyl)amino]propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(CN(C)CCO)C)C3=CC=CC=C3SC2=C1 GGNDUSCXIGWSTI-UHFFFAOYSA-N 0.000 description 2
- PESGNCRLOGZUBU-UHFFFAOYSA-N 10-[1-[2-hydroxyethyl(methyl)amino]propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C1=C(C(N)=S)C=C2N(C(CN(C)CCO)C)C3=CC=CC=C3SC2=C1 PESGNCRLOGZUBU-UHFFFAOYSA-N 0.000 description 2
- GUTFZWOWHYJANC-UHFFFAOYSA-N 10-[1-[ethyl(2-hydroxyethyl)amino]propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(C)CN(CCO)CC)C3=CC=CC=C3SC2=C1 GUTFZWOWHYJANC-UHFFFAOYSA-N 0.000 description 2
- NLHZFZGOACRCBF-UHFFFAOYSA-N 10-[1-[ethyl(methyl)amino]propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(C)CN(C)CC)C3=CC=CC=C3SC2=C1 NLHZFZGOACRCBF-UHFFFAOYSA-N 0.000 description 2
- OVKQLVHKJOKKMS-UHFFFAOYSA-N 10-[1-[ethyl(propan-2-yl)amino]propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(C)CN(CC)C(C)C)C3=CC=CC=C3SC2=C1 OVKQLVHKJOKKMS-UHFFFAOYSA-N 0.000 description 2
- COLNZXKWGHJZFY-UHFFFAOYSA-N 10-[1-[ethyl(propan-2-yl)amino]propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C1=C(C(N)=S)C=C2N(C(C)CN(CC)C(C)C)C3=CC=CC=C3SC2=C1 COLNZXKWGHJZFY-UHFFFAOYSA-N 0.000 description 2
- VFMJTAJLXSXBPT-UHFFFAOYSA-N 10-[1-[methyl(propan-2-yl)amino]propan-2-yl]phenothiazine-2-carbothioamide;hydrochloride Chemical compound Cl.C1=C(C(N)=S)C=C2N(C(C)CN(C)C(C)C)C3=CC=CC=C3SC2=C1 VFMJTAJLXSXBPT-UHFFFAOYSA-N 0.000 description 2
- SNCDMVFOCSYKRG-UHFFFAOYSA-N 10-[1-[methyl(propyl)amino]propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(C)CN(C)CCC)C3=CC=CC=C3SC2=C1 SNCDMVFOCSYKRG-UHFFFAOYSA-N 0.000 description 2
- FXGFBSKVVNGWKL-UHFFFAOYSA-N 10-[1-[methyl(propyl)amino]propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C1=C(C(N)=S)C=C2N(C(C)CN(C)CCC)C3=CC=CC=C3SC2=C1 FXGFBSKVVNGWKL-UHFFFAOYSA-N 0.000 description 2
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 2
- VJROPLWGFCORRM-UHFFFAOYSA-N 2-methylbutan-1-amine Chemical compound CCC(C)CN VJROPLWGFCORRM-UHFFFAOYSA-N 0.000 description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 description 2
- YFORPUHMUUCQHD-UHFFFAOYSA-N 7-chloro-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbonitrile Chemical compound C12=CC=C(Cl)C=C2SC2=CC=C(C#N)C=C2N1C(C)CN1CCCC1 YFORPUHMUUCQHD-UHFFFAOYSA-N 0.000 description 2
- CTCYEIDVCBNCCZ-UHFFFAOYSA-N 7-chloro-10-[1-(ethylamino)propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(C)CNCC)C3=CC=C(Cl)C=C3SC2=C1 CTCYEIDVCBNCCZ-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HVYAHOQWKVULJE-UHFFFAOYSA-N Cl.C(#N)N=C(N)C1=CC=2N(C3=CC=CC=C3SC=2C=C1)C(CN1CCCC1)C Chemical compound Cl.C(#N)N=C(N)C1=CC=2N(C3=CC=CC=C3SC=2C=C1)C(CN1CCCC1)C HVYAHOQWKVULJE-UHFFFAOYSA-N 0.000 description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
- 208000004880 Polyuria Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 229960004365 benzoic acid Drugs 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 2
- 210000001638 cerebellum Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- LQNHRNOPWKZUSN-UHFFFAOYSA-N cyclobutylmethanamine Chemical compound NCC1CCC1 LQNHRNOPWKZUSN-UHFFFAOYSA-N 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- BLNWTAHYTCHDJH-UHFFFAOYSA-O hydroxy(oxo)azanium Chemical compound O[NH+]=O BLNWTAHYTCHDJH-UHFFFAOYSA-O 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- MBEMGGAYTJFKDO-UHFFFAOYSA-N n'-cyano-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboximidamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(N)=NC#N)C=C2N1C(C)CN1CCCC1 MBEMGGAYTJFKDO-UHFFFAOYSA-N 0.000 description 2
- UONXNBHBZBVSON-UHFFFAOYSA-N n-(2-methylbutyl)-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbothioamide;hydrochloride Chemical compound Cl.C12=CC(C(=S)NCC(C)CC)=CC=C2SC2=CC=CC=C2N1C(C)CN1CCCC1 UONXNBHBZBVSON-UHFFFAOYSA-N 0.000 description 2
- JIXSDKRSAYRSDB-UHFFFAOYSA-N n-(cyclobutylmethyl)-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbothioamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(=S)NCC3CCC3)C=C2N1C(C)CN1CCCC1 JIXSDKRSAYRSDB-UHFFFAOYSA-N 0.000 description 2
- RLEKNTQGTDYJDY-UHFFFAOYSA-N n-(cyclobutylmethyl)-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboxamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(=O)NCC3CCC3)C=C2N1C(C)CN1CCCC1 RLEKNTQGTDYJDY-UHFFFAOYSA-N 0.000 description 2
- JNAYMPDJOHIZFX-UHFFFAOYSA-N n-[(2-methylphenyl)methyl]-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbothioamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(=S)NCC=3C(=CC=CC=3)C)C=C2N1C(C)CN1CCCC1 JNAYMPDJOHIZFX-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- IASVCSHUOARLNA-UHFFFAOYSA-N n-propyl-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbothioamide Chemical compound C12=CC(C(=S)NCCC)=CC=C2SC2=CC=CC=C2N1C(C)CN1CCCC1 IASVCSHUOARLNA-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 2
- 235000011837 pasties Nutrition 0.000 description 2
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000037452 priming Effects 0.000 description 2
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001391 thioamide group Chemical group 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 229940099259 vaseline Drugs 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- CJAAPVQEZPAQNI-UHFFFAOYSA-N (2-methylphenyl)methanamine Chemical compound CC1=CC=CC=C1CN CJAAPVQEZPAQNI-UHFFFAOYSA-N 0.000 description 1
- SEJUQQOPVAUETF-QHLBDZCJSA-N (2r,6r,11s)-3-(cyclopropylmethyl)-6-ethyl-8-hydroxy-11-methyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2h)-one Chemical compound C([C@@]1([C@@H]([C@@H]2C(=O)C=3C1=CC(O)=CC=3)C)CC)CN2CC1CC1 SEJUQQOPVAUETF-QHLBDZCJSA-N 0.000 description 1
- VJROPLWGFCORRM-YFKPBYRVSA-N (2s)-2-methylbutan-1-amine Chemical compound CC[C@H](C)CN VJROPLWGFCORRM-YFKPBYRVSA-N 0.000 description 1
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 description 1
- AZVGMUNWTMZPSA-WLHGVMLRSA-N (e)-but-2-enedioic acid;10-[1-(2,5-dihydropyrrol-1-yl)propan-2-yl]-n-propylphenothiazine-2-carboxamide Chemical compound OC(=O)\C=C\C(O)=O.C12=CC(C(=O)NCCC)=CC=C2SC2=CC=CC=C2N1C(C)CN1CC=CC1 AZVGMUNWTMZPSA-WLHGVMLRSA-N 0.000 description 1
- XKSSANRBGMDJJR-WLHGVMLRSA-N (e)-but-2-enedioic acid;10-[1-(diethylamino)propan-2-yl]-n-(2-methylbutyl)phenothiazine-2-carbothioamide Chemical compound OC(=O)\C=C\C(O)=O.C1=CC=C2N(C(C)CN(CC)CC)C3=CC(C(=S)NCC(C)CC)=CC=C3SC2=C1 XKSSANRBGMDJJR-WLHGVMLRSA-N 0.000 description 1
- BCXOUWIDQQFRBT-WLHGVMLRSA-N (e)-but-2-enedioic acid;n-(cyclobutylmethyl)-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbothioamide Chemical compound OC(=O)\C=C\C(O)=O.C12=CC=CC=C2SC2=CC=C(C(=S)NCC3CCC3)C=C2N1C(C)CN1CCCC1 BCXOUWIDQQFRBT-WLHGVMLRSA-N 0.000 description 1
- RLXRDZGYIJFYCG-WLHGVMLRSA-N (e)-but-2-enedioic acid;n-(cyclobutylmethyl)-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboxamide Chemical compound OC(=O)\C=C\C(O)=O.C12=CC=CC=C2SC2=CC=C(C(=O)NCC3CCC3)C=C2N1C(C)CN1CCCC1 RLXRDZGYIJFYCG-WLHGVMLRSA-N 0.000 description 1
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- AYIKHSYPMAWCJK-UHFFFAOYSA-N 10-[1-(2,5-dihydropyrrol-1-yl)propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C12=CC=CC=C2SC2=CC=C(C#N)C=C2N1C(C)CN1CC=CC1 AYIKHSYPMAWCJK-UHFFFAOYSA-N 0.000 description 1
- LSNANTDBGWGJQN-UHFFFAOYSA-N 10-[1-(2,5-dihydropyrrol-1-yl)propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(N)=S)C=C2N1C(C)CN1CC=CC1 LSNANTDBGWGJQN-UHFFFAOYSA-N 0.000 description 1
- LHVZOWRFZUBCAD-UHFFFAOYSA-N 10-[1-(2,5-dimethylpyrrolidin-1-yl)propan-2-yl]phenothiazine-2-carbothioamide hydrochloride Chemical compound Cl.C12=CC=CC=C2SC2=CC=C(C(N)=S)C=C2N1C(C)CN1C(C)CCC1C LHVZOWRFZUBCAD-UHFFFAOYSA-N 0.000 description 1
- WOVAICAQJLJHDM-UHFFFAOYSA-N 10-[1-(3-methylpiperidin-1-yl)propan-2-yl]-N-propylphenothiazine-2-carbothioamide Chemical compound C12=CC(C(=S)NCCC)=CC=C2SC2=CC=CC=C2N1C(C)CN1CCCC(C)C1 WOVAICAQJLJHDM-UHFFFAOYSA-N 0.000 description 1
- UAAAIKJCOSSPCV-UHFFFAOYSA-N 10-[1-(3-methylpiperidin-1-yl)propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C12=CC=CC=C2SC2=CC=C(C#N)C=C2N1C(C)CN1CCCC(C)C1 UAAAIKJCOSSPCV-UHFFFAOYSA-N 0.000 description 1
- GJXMPGNWWAJOCD-UHFFFAOYSA-N 10-[1-(azepan-1-yl)propan-2-yl]-N-propylphenothiazine-2-carbothioamide hydrochloride Chemical compound Cl.C12=CC(C(=S)NCCC)=CC=C2SC2=CC=CC=C2N1C(C)CN1CCCCCC1 GJXMPGNWWAJOCD-UHFFFAOYSA-N 0.000 description 1
- DEDGFUPCXWARSF-UHFFFAOYSA-N 10-[1-(diethylamino)propan-2-yl]-N-(2-methylpropyl)phenothiazine-2-carbothioamide hydrochloride Chemical compound Cl.C1=C(C(=S)NCC(C)C)C=C2N(C(C)CN(CC)CC)C3=CC=CC=C3SC2=C1 DEDGFUPCXWARSF-UHFFFAOYSA-N 0.000 description 1
- YOZIDRAMEGCQPN-UHFFFAOYSA-N 10-[1-(diethylamino)propan-2-yl]-n-(2-methylpropyl)phenothiazine-2-carbothioamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1=C(C(=S)NCC(C)C)C=C2N(C(C)CN(CC)CC)C3=CC=CC=C3SC2=C1 YOZIDRAMEGCQPN-UHFFFAOYSA-N 0.000 description 1
- YOILWFBIRLKLNV-UHFFFAOYSA-N 10-[1-(diethylamino)propan-2-yl]-n-ethylphenothiazine-2-carbothioamide Chemical compound C1=CC=C2N(C(C)CN(CC)CC)C3=CC(C(=S)NCC)=CC=C3SC2=C1 YOILWFBIRLKLNV-UHFFFAOYSA-N 0.000 description 1
- AFFPCXZZXYYXSI-UHFFFAOYSA-N 10-[1-(diethylamino)propan-2-yl]-n-methylphenothiazine-2-carbothioamide Chemical compound C1=C(C(=S)NC)C=C2N(C(C)CN(CC)CC)C3=CC=CC=C3SC2=C1 AFFPCXZZXYYXSI-UHFFFAOYSA-N 0.000 description 1
- UFDKGQSFUUMBJO-UHFFFAOYSA-N 10-[1-(diethylamino)propan-2-yl]-n-propylphenothiazine-2-carbothioamide;hydrochloride Chemical compound Cl.C1=CC=C2N(C(C)CN(CC)CC)C3=CC(C(=S)NCCC)=CC=C3SC2=C1 UFDKGQSFUUMBJO-UHFFFAOYSA-N 0.000 description 1
- ZGWAPDHLEXRRHP-UHFFFAOYSA-N 10-[1-(dimethylamino)propan-2-yl]-N-[(2-fluorophenyl)methyl]phenothiazine-2-carboxamide Chemical compound C1=C2N(C(CN(C)C)C)C3=CC=CC=C3SC2=CC=C1C(=O)NCC1=CC=CC=C1F ZGWAPDHLEXRRHP-UHFFFAOYSA-N 0.000 description 1
- UJSHIGNULKNOHY-UHFFFAOYSA-N 10-[1-(dimethylamino)propan-2-yl]-n-[(4-fluorophenyl)methyl]phenothiazine-2-carboxamide;hydrochloride Chemical compound Cl.C1=C2N(C(CN(C)C)C)C3=CC=CC=C3SC2=CC=C1C(=O)NCC1=CC=C(F)C=C1 UJSHIGNULKNOHY-UHFFFAOYSA-N 0.000 description 1
- OFJIDWVWPVTPKM-UHFFFAOYSA-N 10-[1-(methylamino)propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C1=C(C(N)=S)C=C2N(C(C)CNC)C3=CC=CC=C3SC2=C1 OFJIDWVWPVTPKM-UHFFFAOYSA-N 0.000 description 1
- MJRGNIMPYOIWRZ-WMCAAGNKSA-N 10-[1-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(N)=S)C=C2N1C(C)CN1CCC[C@H]1CO MJRGNIMPYOIWRZ-WMCAAGNKSA-N 0.000 description 1
- UWISTQHHQGDUAA-UHFFFAOYSA-N 10-[1-[2-hydroxyethyl(methyl)amino]propan-2-yl]-N-propylphenothiazine-2-carbothioamide hydrochloride Chemical compound Cl.C1=CC=C2N(C(C)CN(C)CCO)C3=CC(C(=S)NCCC)=CC=C3SC2=C1 UWISTQHHQGDUAA-UHFFFAOYSA-N 0.000 description 1
- CMKSVEWGJKLEDO-UHFFFAOYSA-N 10-[1-[ethyl(2-hydroxyethyl)amino]propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C1=C(C(N)=S)C=C2N(C(C)CN(CCO)CC)C3=CC=CC=C3SC2=C1 CMKSVEWGJKLEDO-UHFFFAOYSA-N 0.000 description 1
- DSSGZCBNOKXYRV-UHFFFAOYSA-N 10-[1-[ethyl(methyl)amino]propan-2-yl]-N-(2-methylbutyl)phenothiazine-2-carbothioamide hydrochloride Chemical compound Cl.C1=CC=C2N(C(C)CN(C)CC)C3=CC(C(=S)NCC(C)CC)=CC=C3SC2=C1 DSSGZCBNOKXYRV-UHFFFAOYSA-N 0.000 description 1
- PZMRZCBFUOXNEO-UHFFFAOYSA-N 10-[1-[ethyl(methyl)amino]propan-2-yl]-N-methylphenothiazine-2-carbothioamide hydrochloride Chemical compound Cl.C1=C(C(=S)NC)C=C2N(C(C)CN(C)CC)C3=CC=CC=C3SC2=C1 PZMRZCBFUOXNEO-UHFFFAOYSA-N 0.000 description 1
- COFIODGZFIQNNK-UHFFFAOYSA-N 10-[1-[ethyl(methyl)amino]propan-2-yl]-n-(3-methylbutyl)phenothiazine-2-carbothioamide Chemical compound C1=C(C(=S)NCCC(C)C)C=C2N(C(C)CN(C)CC)C3=CC=CC=C3SC2=C1 COFIODGZFIQNNK-UHFFFAOYSA-N 0.000 description 1
- ZGISPSWBLAEAQW-UHFFFAOYSA-N 10-[1-[ethyl(methyl)amino]propan-2-yl]-n-propylphenothiazine-2-carbothioamide Chemical compound C1=CC=C2N(C(C)CN(C)CC)C3=CC(C(=S)NCCC)=CC=C3SC2=C1 ZGISPSWBLAEAQW-UHFFFAOYSA-N 0.000 description 1
- YJZPKWAFELDRNC-UHFFFAOYSA-N 2-(3a,4,5,6,7,7a-hexahydro-1h-benzimidazol-2-yl)-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine;dihydrochloride Chemical compound Cl.Cl.C12=CC=CC=C2SC2=CC=C(C=3NC4CCCCC4N=3)C=C2N1C(C)CN1CCCC1 YJZPKWAFELDRNC-UHFFFAOYSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- GYXWNSDLDXGMGU-UHFFFAOYSA-N 2-chloro-n,n-dimethylpropan-1-amine Chemical compound CC(Cl)CN(C)C GYXWNSDLDXGMGU-UHFFFAOYSA-N 0.000 description 1
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- GPWHFPWZAPOYNO-UHFFFAOYSA-N 3,3-dimethylbutan-1-amine Chemical compound CC(C)(C)CCN GPWHFPWZAPOYNO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- PFCBHFDNVFQUJI-UHFFFAOYSA-N 3-methylbut-2-en-1-amine Chemical compound CC(C)=CCN PFCBHFDNVFQUJI-UHFFFAOYSA-N 0.000 description 1
- ARVPZWJBVAYSNS-UHFFFAOYSA-N 3-methylpentan-1-amine;hydrochloride Chemical compound Cl.CCC(C)CCN ARVPZWJBVAYSNS-UHFFFAOYSA-N 0.000 description 1
- JEGMWWXJUXDNJN-UHFFFAOYSA-N 3-methylpiperidine Chemical compound CC1CCCNC1 JEGMWWXJUXDNJN-UHFFFAOYSA-N 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- YQZPRXHVRLGGFH-UHFFFAOYSA-N 4-methylpentan-1-amine;hydrochloride Chemical compound Cl.CC(C)CCCN YQZPRXHVRLGGFH-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- OAAGDVLVOKMRCQ-UHFFFAOYSA-N 5-piperidin-4-yl-3-pyridin-4-yl-1,2,4-oxadiazole Chemical compound C1CNCCC1C1=NC(C=2C=CN=CC=2)=NO1 OAAGDVLVOKMRCQ-UHFFFAOYSA-N 0.000 description 1
- GQOXGLLYLQFROX-UHFFFAOYSA-N 7-chloro-10-(1-hydroxypropan-2-yl)phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(CO)C)C3=CC=C(Cl)C=C3SC2=C1 GQOXGLLYLQFROX-UHFFFAOYSA-N 0.000 description 1
- YXVIPSONMMEVNO-UHFFFAOYSA-N 7-chloro-10-[1-(diethylamino)propan-2-yl]phenothiazine-2-carbonitrile Chemical compound C1=C(C#N)C=C2N(C(C)CN(CC)CC)C3=CC=C(Cl)C=C3SC2=C1 YXVIPSONMMEVNO-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- HVVNJUAVDAZWCB-RXMQYKEDSA-N D-prolinol Chemical compound OC[C@H]1CCCN1 HVVNJUAVDAZWCB-RXMQYKEDSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000400611 Eucalyptus deanei Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 241001254607 Leander Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- RNFLYFWZVNFRBD-UHFFFAOYSA-N N-(cyclopropylmethyl)-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboxamide hydrochloride Chemical compound Cl.C12=CC=CC=C2SC2=CC=C(C(=O)NCC3CC3)C=C2N1C(C)CN1CCCC1 RNFLYFWZVNFRBD-UHFFFAOYSA-N 0.000 description 1
- TXSDTVNRBCALTP-UHFFFAOYSA-N N-[(3-fluorophenyl)methyl]-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboxamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(=O)NCC=3C=C(F)C=CC=3)C=C2N1C(C)CN1CCCC1 TXSDTVNRBCALTP-UHFFFAOYSA-N 0.000 description 1
- IGLDCBGIELYNAP-UHFFFAOYSA-N N-benzyl-10-[1-[ethyl(2-hydroxyethyl)amino]propan-2-yl]phenothiazine-2-carbothioamide Chemical compound C1=C2N(C(C)CN(CCO)CC)C3=CC=CC=C3SC2=CC=C1C(=S)NCC1=CC=CC=C1 IGLDCBGIELYNAP-UHFFFAOYSA-N 0.000 description 1
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 1
- XWEFQHMXMVSUQM-UHFFFAOYSA-N N-prop-2-ynyl-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboxamide hydrochloride Chemical compound Cl.C12=CC=CC=C2SC2=CC=C(C(=O)NCC#C)C=C2N1C(C)CN1CCCC1 XWEFQHMXMVSUQM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- 208000036366 Sensation of pressure Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- YARBIIVHOCKKRI-UBKPKTQASA-N [(1s)-1-phenylethyl]azanium;phthalate Chemical compound C[C@H]([NH3+])C1=CC=CC=C1.C[C@H]([NH3+])C1=CC=CC=C1.[O-]C(=O)C1=CC=CC=C1C([O-])=O YARBIIVHOCKKRI-UBKPKTQASA-N 0.000 description 1
- ZAMMQGQAIBDMLB-GWQXNCQPSA-N [(2r)-1-[2-[2-(3-methylbutylcarbamoyl)phenothiazin-10-yl]propyl]pyrrolidin-2-yl]methyl acetate Chemical compound C12=CC(C(=O)NCCC(C)C)=CC=C2SC2=CC=CC=C2N1C(C)CN1CCC[C@@H]1COC(C)=O ZAMMQGQAIBDMLB-GWQXNCQPSA-N 0.000 description 1
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 230000002908 adrenolytic effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940121383 antituberculosis agent Drugs 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- UBLYEVLMRSPMOG-UHFFFAOYSA-N cyclopentylmethanamine Chemical compound NCC1CCCC1 UBLYEVLMRSPMOG-UHFFFAOYSA-N 0.000 description 1
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 1
- HXSNGAHNYZBZTH-UHFFFAOYSA-N cyclopropylmethanamine;hydrochloride Chemical compound Cl.NCC1CC1 HXSNGAHNYZBZTH-UHFFFAOYSA-N 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- QGKAMCVLNGGRHE-UHFFFAOYSA-N ethyl 10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboximidate;dihydrochloride Chemical compound Cl.Cl.C12=CC(C(=N)OCC)=CC=C2SC2=CC=CC=C2N1C(C)CN1CCCC1 QGKAMCVLNGGRHE-UHFFFAOYSA-N 0.000 description 1
- ALOLSEWGCHUZIC-UHFFFAOYSA-N ethyl 2-(2-cyanophenothiazin-10-yl)propanoate Chemical compound C1=C(C#N)C=C2N(C(C)C(=O)OCC)C3=CC=CC=C3SC2=C1 ALOLSEWGCHUZIC-UHFFFAOYSA-N 0.000 description 1
- JEAVBVKAYUCPAQ-UHFFFAOYSA-N ethyl 2-chloropropanoate Chemical compound CCOC(=O)C(C)Cl JEAVBVKAYUCPAQ-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- DDRPCXLAQZKBJP-UHFFFAOYSA-N furfurylamine Chemical compound NCC1=CC=CO1 DDRPCXLAQZKBJP-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- RCKJMKAZIJTUMR-UHFFFAOYSA-N n-(3-methylbut-2-enyl)-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboxamide;hydrochloride Chemical compound Cl.C12=CC=CC=C2SC2=CC=C(C(=O)NCC=C(C)C)C=C2N1C(C)CN1CCCC1 RCKJMKAZIJTUMR-UHFFFAOYSA-N 0.000 description 1
- YNXSYUGTVQPEJY-UHFFFAOYSA-N n-(3-methylbutyl)-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbothioamide Chemical compound C12=CC(C(=S)NCCC(C)C)=CC=C2SC2=CC=CC=C2N1C(C)CN1CCCC1 YNXSYUGTVQPEJY-UHFFFAOYSA-N 0.000 description 1
- AXHQXZZYNGVSFM-UHFFFAOYSA-N n-(3-methylbutyl)-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbothioamide;hydrochloride Chemical compound Cl.C12=CC(C(=S)NCCC(C)C)=CC=C2SC2=CC=CC=C2N1C(C)CN1CCCC1 AXHQXZZYNGVSFM-UHFFFAOYSA-N 0.000 description 1
- WADFRUXRLYENMW-UHFFFAOYSA-N n-(3-methylpentyl)-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbothioamide;hydrochloride Chemical compound Cl.C12=CC(C(=S)NCCC(C)CC)=CC=C2SC2=CC=CC=C2N1C(C)CN1CCCC1 WADFRUXRLYENMW-UHFFFAOYSA-N 0.000 description 1
- JJYOZYREDIHARE-UHFFFAOYSA-N n-(cyclopentylmethyl)-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboxamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(=O)NCC3CCCC3)C=C2N1C(C)CN1CCCC1 JJYOZYREDIHARE-UHFFFAOYSA-N 0.000 description 1
- IYNIANOXKQQQJD-UHFFFAOYSA-N n-(cyclopropylmethyl)-10-[1-(dimethylamino)propan-2-yl]phenothiazine-2-carboxamide Chemical compound C1=C2N(C(CN(C)C)C)C3=CC=CC=C3SC2=CC=C1C(=O)NCC1CC1 IYNIANOXKQQQJD-UHFFFAOYSA-N 0.000 description 1
- LNJWLAWMQOBYGD-UHFFFAOYSA-N n-[(2-methylphenyl)methyl]-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboxamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(=O)NCC=3C(=CC=CC=3)C)C=C2N1C(C)CN1CCCC1 LNJWLAWMQOBYGD-UHFFFAOYSA-N 0.000 description 1
- YBIVRXHMDMEHHJ-YDALLXLXSA-N n-[(2s)-2-methylbutyl]-10h-phenothiazine-2-carbothioamide;hydrochloride Chemical compound Cl.C1=CC=C2NC3=CC(C(=S)NC[C@@H](C)CC)=CC=C3SC2=C1 YBIVRXHMDMEHHJ-YDALLXLXSA-N 0.000 description 1
- IMBWBFHCERIEHZ-UHFFFAOYSA-N n-[(3-chlorophenyl)methyl]-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboxamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(=O)NCC=3C=C(Cl)C=CC=3)C=C2N1C(C)CN1CCCC1 IMBWBFHCERIEHZ-UHFFFAOYSA-N 0.000 description 1
- LTQOKEKAXKTMDD-UHFFFAOYSA-N n-[(3-chlorophenyl)methyl]-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboxamide;hydrochloride Chemical compound Cl.C12=CC=CC=C2SC2=CC=C(C(=O)NCC=3C=C(Cl)C=CC=3)C=C2N1C(C)CN1CCCC1 LTQOKEKAXKTMDD-UHFFFAOYSA-N 0.000 description 1
- REZWLSPAOHCTJV-UHFFFAOYSA-N n-[(3-fluorophenyl)methyl]-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbothioamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(=S)NCC=3C=C(F)C=CC=3)C=C2N1C(C)CN1CCCC1 REZWLSPAOHCTJV-UHFFFAOYSA-N 0.000 description 1
- BXWYUXWPTNVMMS-UHFFFAOYSA-N n-benzyl-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carboxamide Chemical compound C12=CC=CC=C2SC2=CC=C(C(=O)NCC=3C=CC=CC=3)C=C2N1C(C)CN1CCCC1 BXWYUXWPTNVMMS-UHFFFAOYSA-N 0.000 description 1
- CLKOMOGXQQLCHI-UHFFFAOYSA-N n-benzyl-10-[1-(dimethylamino)propan-2-yl]phenothiazine-2-carboxamide;oxalic acid Chemical compound OC(=O)C(O)=O.C1=C2N(C(CN(C)C)C)C3=CC=CC=C3SC2=CC=C1C(=O)NCC1=CC=CC=C1 CLKOMOGXQQLCHI-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
- KAMFCPZBEBQXDX-UHFFFAOYSA-N n-butyl-10-(1-pyrrolidin-1-ylpropan-2-yl)phenothiazine-2-carbothioamide;hydrochloride Chemical compound Cl.C12=CC(C(=S)NCCCC)=CC=C2SC2=CC=CC=C2N1C(C)CN1CCCC1 KAMFCPZBEBQXDX-UHFFFAOYSA-N 0.000 description 1
- KYWOXLYIIBDHMQ-UHFFFAOYSA-N n-butyl-10-[1-(diethylamino)propan-2-yl]phenothiazine-2-carbothioamide;hydrochloride Chemical compound Cl.C1=CC=C2N(C(C)CN(CC)CC)C3=CC(C(=S)NCCCC)=CC=C3SC2=C1 KYWOXLYIIBDHMQ-UHFFFAOYSA-N 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229940100684 pentylamine Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- CBMSDILKECEMOT-UHFFFAOYSA-N potassium;2-methylpropan-1-olate Chemical compound [K+].CC(C)C[O-] CBMSDILKECEMOT-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- DKORSYDQYFVQNS-UHFFFAOYSA-N propyl methanesulfonate Chemical compound CCCOS(C)(=O)=O DKORSYDQYFVQNS-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- FKKJJPMGAWGYPN-UHFFFAOYSA-N thiophen-2-ylmethanamine Chemical compound NCC1=CC=CS1 FKKJJPMGAWGYPN-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
- C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Anesthesiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8807771A FR2632521B1 (fr) | 1988-06-10 | 1988-06-10 | Nouveaux derives de la phenothiazine, leur preparation et les compositions pharmaceutiques qui les contiennent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL90560A0 IL90560A0 (en) | 1990-01-18 |
| IL90560A true IL90560A (en) | 1995-08-31 |
Family
ID=9367167
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL9056089A IL90560A (en) | 1988-06-10 | 1989-06-07 | History of phenothiazine, method of preparation and pharmaceutical preparations containing them |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4985419A (de) |
| EP (1) | EP0346239B1 (de) |
| JP (1) | JPH0232070A (de) |
| KR (1) | KR900000349A (de) |
| AT (1) | ATE90085T1 (de) |
| AU (1) | AU621121B2 (de) |
| CA (1) | CA1323027C (de) |
| DE (1) | DE68906826T2 (de) |
| DK (1) | DK283289A (de) |
| ES (1) | ES2057160T3 (de) |
| FR (1) | FR2632521B1 (de) |
| HU (1) | HU212425B (de) |
| IE (1) | IE61601B1 (de) |
| IL (1) | IL90560A (de) |
| PT (1) | PT90814B (de) |
| ZA (1) | ZA894401B (de) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2632522B1 (fr) * | 1988-06-10 | 1990-09-14 | Rhone Poulenc Sante | Nouveaux derives de la phenothiazine, leur preparation et les compositions qui les contiennent |
| FR2632520B1 (fr) * | 1988-06-10 | 1990-09-14 | Rhone Poulenc Sante | Derives de la phenothiazine analgesiques |
| FR2652084B1 (fr) * | 1989-09-21 | 1991-10-31 | Rhone Poulenc Sante | Nouveaux derives de la phenothiazine, leur preparation et les compositions pharmaceutiques qui les contiennent. |
| FR2720940A1 (fr) * | 1994-06-13 | 1995-12-15 | Rhone Poulenc Rorer Sa | Application du (+)-N-propyl [(pyrrolidinyl-1)-1 propyl-2]-10 phénothiazinecarboxamide comme antidépresseur. |
| EP1360180A1 (de) | 2001-01-19 | 2003-11-12 | Cytokinetics, Inc. | Phenothiazinkinesininhibitoren |
| CN1545421A (zh) * | 2001-06-22 | 2004-11-10 | �Ʒ� | 包含低溶解度和/或酸敏感的药物以及中和的酸性聚合物的药物组合物 |
| US20050176650A1 (en) * | 2004-02-09 | 2005-08-11 | Xanodyne Pharmacal, Inc. | Stable parenteral formulation of levomepromazine and a method for stabilizing said formulation |
| JP5828587B2 (ja) | 2009-01-28 | 2015-12-09 | ウェルズ ファーゴ バンク ナショナル アソシエイション | オリゴマー−フェノチアジン結合体 |
| CN113502062A (zh) * | 2021-07-19 | 2021-10-15 | 安徽省奥佳建材有限公司 | 一种抗氧化复合防水卷材材料 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL222355A (de) * | 1957-11-05 | |||
| US2997468A (en) * | 1958-11-06 | 1961-08-22 | Olin Mathieson | Preparation of phenothiazines |
| NL273878A (de) * | 1961-01-24 | |||
| US3112310A (en) * | 1962-01-15 | 1963-11-26 | Searle & Co | 10-alkylaminoalkylphenothiazine-2-carboxamides |
| EP0233461B2 (de) * | 1986-01-13 | 2002-05-29 | American Cyanamid Company | 4,5,6-Substituierte 2-Pyrimidinamine |
| FR2632522B1 (fr) * | 1988-06-10 | 1990-09-14 | Rhone Poulenc Sante | Nouveaux derives de la phenothiazine, leur preparation et les compositions qui les contiennent |
| FR2632520B1 (fr) * | 1988-06-10 | 1990-09-14 | Rhone Poulenc Sante | Derives de la phenothiazine analgesiques |
-
1988
- 1988-06-10 FR FR8807771A patent/FR2632521B1/fr not_active Expired - Lifetime
-
1989
- 1989-06-07 IL IL9056089A patent/IL90560A/en not_active IP Right Cessation
- 1989-06-09 ES ES89401602T patent/ES2057160T3/es not_active Expired - Lifetime
- 1989-06-09 PT PT90814A patent/PT90814B/pt not_active IP Right Cessation
- 1989-06-09 DK DK283289A patent/DK283289A/da not_active Application Discontinuation
- 1989-06-09 ZA ZA894401A patent/ZA894401B/xx unknown
- 1989-06-09 EP EP89401602A patent/EP0346239B1/de not_active Expired - Lifetime
- 1989-06-09 AT AT89401602T patent/ATE90085T1/de active
- 1989-06-09 DE DE89401602T patent/DE68906826T2/de not_active Expired - Fee Related
- 1989-06-09 HU HU893032A patent/HU212425B/hu not_active IP Right Cessation
- 1989-06-09 AU AU36241/89A patent/AU621121B2/en not_active Ceased
- 1989-06-09 CA CA000602378A patent/CA1323027C/fr not_active Expired - Fee Related
- 1989-06-10 KR KR1019890008063A patent/KR900000349A/ko not_active Ceased
- 1989-06-12 US US07/364,465 patent/US4985419A/en not_active Expired - Fee Related
- 1989-06-12 IE IE186689A patent/IE61601B1/en not_active IP Right Cessation
- 1989-06-12 JP JP1149262A patent/JPH0232070A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0232070A (ja) | 1990-02-01 |
| HU212425B (en) | 1996-06-28 |
| EP0346239A1 (de) | 1989-12-13 |
| IL90560A0 (en) | 1990-01-18 |
| DK283289D0 (da) | 1989-06-09 |
| US4985419A (en) | 1991-01-15 |
| PT90814A (pt) | 1989-12-29 |
| AU3624189A (en) | 1989-12-21 |
| DE68906826T2 (de) | 1993-09-30 |
| PT90814B (pt) | 1994-11-30 |
| EP0346239B1 (de) | 1993-06-02 |
| AU621121B2 (en) | 1992-03-05 |
| DK283289A (da) | 1989-12-11 |
| KR900000349A (ko) | 1990-01-30 |
| FR2632521A1 (fr) | 1989-12-15 |
| FR2632521B1 (fr) | 1990-09-14 |
| HUT51607A (en) | 1990-05-28 |
| ES2057160T3 (es) | 1994-10-16 |
| ZA894401B (en) | 1990-02-28 |
| IE61601B1 (en) | 1994-11-16 |
| IE891866L (en) | 1989-12-10 |
| ATE90085T1 (de) | 1993-06-15 |
| CA1323027C (fr) | 1993-10-12 |
| DE68906826D1 (de) | 1993-07-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5451601A (en) | Perhydroisoindole derivatives and pharmaceutical compositions containing them | |
| RU2012559C1 (ru) | Производные изоиндолона в виде (3 аr, 7 аr)- или (3 аrs, 7 аrs)-форм или их смесей или их гидрохлориды, являющиеся антагонистами вещества р | |
| NZ242737A (en) | 6-acyl-4,4-diphenylperhydrothiopyrano(2,3-c)pyrrole derivatives, medicaments | |
| DE69417235T2 (de) | IMIDAZO[1,2-a]PYRAZIN-4-ON-DERIVATE ANTAGONISTEN DER AMPA UND NMDA REZEPTOREN | |
| IL90560A (en) | History of phenothiazine, method of preparation and pharmaceutical preparations containing them | |
| NL8102361A (nl) | 1-(4-chloorbenzhydryl)-4-(2,3-bis-hydroxypropyl)-piperazine, zijn gebruik als anti-hoestmiddel, antihistaminicum, sedativum, analgeticum en ontstekingsremmend middel, alsmede farmaceutische preparaten met deze stof. | |
| IL90559A (en) | History of active anti-pain phenothiazines | |
| FI93108B (fi) | Menetelmä lääkeaineina käyttökelpoisten 2-bentsotiatsoliinijohdannaisten valmistamiseksi | |
| AU671973B2 (en) | Alkyl derivatives of trazodone with CNS activity | |
| US5321026A (en) | Phenothiazine derivatives, their preparation and pharmaceutical compositions containing them | |
| AU621122B2 (en) | New derivatives of phenothiazine, their preparation and the compositions which contain them | |
| NZ206458A (en) | Phenothiazine derivatives and pharmaceutical compositions | |
| US5739334A (en) | Alkyl derivatives of trazodone with CNS activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| RH | Patent void |