CN1090190C - 杂环稠合的吗啡类衍生物,制备方法和用途 - Google Patents
杂环稠合的吗啡类衍生物,制备方法和用途 Download PDFInfo
- Publication number
- CN1090190C CN1090190C CN97192879A CN97192879A CN1090190C CN 1090190 C CN1090190 C CN 1090190C CN 97192879 A CN97192879 A CN 97192879A CN 97192879 A CN97192879 A CN 97192879A CN 1090190 C CN1090190 C CN 1090190C
- Authority
- CN
- China
- Prior art keywords
- hexahydros
- pyrrolo
- methylenebenzofurans
- dimethyl
- carbonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 claims description 86
- OSCBSTLEJFAUHO-UHFFFAOYSA-N 4h-pyrrolo[2,3-g]isoquinoline;hydrochloride Chemical compound Cl.C1=NC=C2CC3=CC=NC3=CC2=C1 OSCBSTLEJFAUHO-UHFFFAOYSA-N 0.000 claims description 42
- UEGVVERPSDYMKW-UHFFFAOYSA-N 4h-pyrrolo[2,3-g]isoquinoline Chemical compound C1=NC=C2CC3=CC=NC3=CC2=C1 UEGVVERPSDYMKW-UHFFFAOYSA-N 0.000 claims description 37
- -1 methoxyl group Chemical group 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 23
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 18
- 239000012453 solvate Substances 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 150000003233 pyrroles Chemical class 0.000 claims description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 150000002118 epoxides Chemical class 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 230000003444 anaesthetic effect Effects 0.000 claims description 4
- 230000003266 anti-allergic effect Effects 0.000 claims description 4
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
- 239000003018 immunosuppressive agent Substances 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- 208000007848 Alcoholism Diseases 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 206010011224 Cough Diseases 0.000 claims description 3
- 206010012735 Diarrhoea Diseases 0.000 claims description 3
- 206010001584 alcohol abuse Diseases 0.000 claims description 3
- 208000025746 alcohol use disease Diseases 0.000 claims description 3
- 210000004958 brain cell Anatomy 0.000 claims description 3
- 208000030303 breathing problems Diseases 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 210000000056 organ Anatomy 0.000 claims description 3
- 239000003223 protective agent Substances 0.000 claims description 3
- 208000020016 psychiatric disease Diseases 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- HRQRFBJPGPPUIR-UHFFFAOYSA-N Cl.S1C=CC=2C1=CC=1C=CN=CC1C2 Chemical class Cl.S1C=CC=2C1=CC=1C=CN=CC1C2 HRQRFBJPGPPUIR-UHFFFAOYSA-N 0.000 claims description 2
- 208000012902 Nervous system disease Diseases 0.000 claims description 2
- 208000025966 Neurological disease Diseases 0.000 claims description 2
- 206010058141 Skin graft rejection Diseases 0.000 claims description 2
- 206010052779 Transplant rejections Diseases 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000001037 epileptic effect Effects 0.000 claims description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 2
- 230000028327 secretion Effects 0.000 claims description 2
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 13
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 6
- 239000003205 fragrance Substances 0.000 claims 5
- LFDGRWDETVOGDT-UHFFFAOYSA-N 1h-pyrrole;hydrochloride Chemical compound Cl.C=1C=CNC=1 LFDGRWDETVOGDT-UHFFFAOYSA-N 0.000 claims 4
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 claims 3
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 claims 3
- 125000004432 carbon atom Chemical group C* 0.000 claims 3
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- YKYIFUROKBDHCY-ONEGZZNKSA-N (e)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical group CCO\C=C\C(=O)C(F)(F)F YKYIFUROKBDHCY-ONEGZZNKSA-N 0.000 claims 1
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 claims 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical class OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims 1
- 239000000908 ammonium hydroxide Substances 0.000 claims 1
- 150000002168 ethanoic acid esters Chemical class 0.000 claims 1
- 235000019439 ethyl acetate Nutrition 0.000 claims 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical group CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 1
- 239000000556 agonist Substances 0.000 abstract description 8
- 239000005557 antagonist Substances 0.000 abstract description 5
- 230000003389 potentiating effect Effects 0.000 abstract description 3
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 abstract description 2
- 108700023159 delta Opioid Receptors Proteins 0.000 abstract description 2
- 102000048124 delta Opioid Receptors Human genes 0.000 abstract description 2
- 230000001575 pathological effect Effects 0.000 abstract description 2
- 229940127450 Opioid Agonists Drugs 0.000 abstract 1
- 229940035676 analgesics Drugs 0.000 abstract 1
- 239000000730 antalgic agent Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 21
- 239000004593 Epoxy Substances 0.000 description 20
- 150000003254 radicals Chemical class 0.000 description 20
- 239000002904 solvent Substances 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 150000002431 hydrogen Chemical class 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 239000000376 reactant Substances 0.000 description 14
- 150000002576 ketones Chemical class 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 150000001721 carbon Chemical group 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 7
- 229960004126 codeine Drugs 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 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 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 239000011701 zinc Substances 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 108090000137 Opioid Receptors Proteins 0.000 description 4
- 102000003840 Opioid Receptors Human genes 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000005864 Sulphur Substances 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 3
- 108010010803 Gelatin Proteins 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
- 241001465754 Metazoa Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000853 adhesive Substances 0.000 description 3
- 230000001070 adhesive effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical class CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 150000007857 hydrazones Chemical class 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical compound C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000001243 acetic acids Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 125000005024 alkenyl aryl group Chemical group 0.000 description 2
- 125000002877 alkyl aryl group Chemical group 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000011953 bioanalysis Methods 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 2
- 239000000857 delta opiate receptor antagonist Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 235000015177 dried meat Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 230000008570 general process Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960003086 naltrexone Drugs 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000003402 opiate agonist Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229910052725 zinc Inorganic materials 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
- ZHUJMSMQIPIPTF-IBURTVSXSA-N (2r)-2-[[(2s)-2-[[2-[[(2r)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoic acid Chemical compound C([C@@H](C(=O)N[C@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ZHUJMSMQIPIPTF-IBURTVSXSA-N 0.000 description 1
- HPZJMUBDEAMBFI-WTNAPCKOSA-N (D-Ala(2)-mephe(4)-gly-ol(5))enkephalin Chemical compound C([C@H](N)C(=O)N[C@H](C)C(=O)NCC(=O)N(C)[C@@H](CC=1C=CC=CC=1)C(=O)NCCO)C1=CC=C(O)C=C1 HPZJMUBDEAMBFI-WTNAPCKOSA-N 0.000 description 1
- 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 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
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 108700022183 Ala(2)-MePhe(4)-Gly(5)- Enkephalin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 108010087765 Antipain Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108010092674 Enkephalins Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 244000043261 Hevea brasiliensis Species 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 1
- 241000276489 Merlangius merlangus Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- SCIFESDRCALIIM-VIFPVBQESA-N N-methyl-L-phenylalanine Chemical compound C[NH2+][C@H](C([O-])=O)CC1=CC=CC=C1 SCIFESDRCALIIM-VIFPVBQESA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 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
- 241000283984 Rodentia Species 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 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
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004946 alkenylalkyl group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- SDNYTAYICBFYFH-TUFLPTIASA-N antipain Chemical compound NC(N)=NCCC[C@@H](C=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SDNYTAYICBFYFH-TUFLPTIASA-N 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- CLRSZXHOSMKUIB-UHFFFAOYSA-M benzenediazonium chloride Chemical class [Cl-].N#[N+]C1=CC=CC=C1 CLRSZXHOSMKUIB-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000003139 buffering effect Effects 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
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000001944 prunus armeniaca kernel oil Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0834—Compounds having one or more O-Si linkage
- C07F7/0838—Compounds with one or more Si-O-Si sequences
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0896—Compounds with a Si-H linkage
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/48—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule in which at least two but not all the silicon atoms are connected by linkages other than oxygen atoms
- C08G77/50—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule in which at least two but not all the silicon atoms are connected by linkages other than oxygen atoms by carbon linkages
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/54—Silicon-containing compounds
- C08K5/541—Silicon-containing compounds containing oxygen
- C08K5/5415—Silicon-containing compounds containing oxygen containing at least one Si—O bond
- C08K5/5419—Silicon-containing compounds containing oxygen containing at least one Si—O bond containing at least one Si—C bond
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L83/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers
- C08L83/04—Polysiloxanes
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/12—Polysiloxanes containing silicon bound to hydrogen
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/14—Polysiloxanes containing silicon bound to oxygen-containing groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/14—Polysiloxanes containing silicon bound to oxygen-containing groups
- C08G77/16—Polysiloxanes containing silicon bound to oxygen-containing groups to hydroxyl groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/14—Polysiloxanes containing silicon bound to oxygen-containing groups
- C08G77/18—Polysiloxanes containing silicon bound to oxygen-containing groups to alkoxy or aryloxy groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/20—Polysiloxanes containing silicon bound to unsaturated aliphatic groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/22—Polysiloxanes containing silicon bound to organic groups containing atoms other than carbon, hydrogen and oxygen
- C08G77/24—Polysiloxanes containing silicon bound to organic groups containing atoms other than carbon, hydrogen and oxygen halogen-containing groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/22—Polysiloxanes containing silicon bound to organic groups containing atoms other than carbon, hydrogen and oxygen
- C08G77/26—Polysiloxanes containing silicon bound to organic groups containing atoms other than carbon, hydrogen and oxygen nitrogen-containing groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/22—Polysiloxanes containing silicon bound to organic groups containing atoms other than carbon, hydrogen and oxygen
- C08G77/28—Polysiloxanes containing silicon bound to organic groups containing atoms other than carbon, hydrogen and oxygen sulfur-containing groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/70—Siloxanes defined by use of the MDTQ nomenclature
-
- H—ELECTRICITY
- H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
- H05K—PRINTED CIRCUITS; CASINGS OR CONSTRUCTIONAL DETAILS OF ELECTRIC APPARATUS; MANUFACTURE OF ASSEMBLAGES OF ELECTRICAL COMPONENTS
- H05K3/00—Apparatus or processes for manufacturing printed circuits
- H05K3/22—Secondary treatment of printed circuits
- H05K3/28—Applying non-metallic protective coatings
- H05K3/285—Permanent coating compositions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Polymers & Plastics (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Pulmonology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Addiction (AREA)
- Rheumatology (AREA)
- Cardiology (AREA)
- Transplantation (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
取代的式(Ⅰ)单杂环稠合吗啡类衍生物是强效及选择性的δ阿片激动剂及拮抗剂，并具有麻醉剂及用于治疗通常可用δ阿片受体激动剂及拮抗剂治疗的病理病症的作用，其中n=0或1，X、Y、R1－R8如本申请中所定义。
Description
本发明涉及新的吗啡类化合物，其制备方法及其医药方面的用途。
至少三类阿片受体(μ、δ和κ)的存在是公知的并见于文献报道，并且全部三类受体似乎存在于许多动物包括人类的中枢及外周神经系统中(Lord J.A.H.等，Nature 1997，267，495)。
全部三类阿片受体亚型的激活可导致动物模型的无痛觉感。特别是，肽的δ激动剂的研究显示δ受体的激活可导致啮齿类、灵长类动物的无痛觉感，并可诱导人的临床麻醉(D.E.Moulin等，Pain，1985，23，213)。已有证据提示对于δ激动剂的较少嗜好可产生通常伴随μ和κ激活的副作用(Galligan等，J.Pharm.Exp.Ther.，1984，229，641)。
US 5223507及US 5225417(G.D.Searle & Co.)公开了双环稠合的吗啡类化合物，据认为它是具有作为麻醉剂治疗用途的δ阿片激动剂。
WO 94/07896(Toray Ind.Inc.)公开了用作免疫抑制剂，抗过敏及抗炎剂的吲哚稠合的吗啡类化合物。
现在我们已经发现一类新的取代单杂环稠合吗啡类衍生物，由于其为强效的和选择性δ阿片激动剂和拮抗剂，因而具有作为麻醉剂、防止器官移植及皮肤移植时排斥反应的免疫抑制剂、抗过敏及抗炎剂、脑细胞保护剂、治疗药物及酒精滥用、胃炎、腹泄、心血管及呼吸道疾病、咳漱、精神病及癫痫的药物，一句话治疗那些通常可用δ阿片受体激动剂及拮抗剂治疗的病理性病症的药物，因而具有潜在的治疗用途。
根据本发明提供了式(I)化合物，或其溶剂化物或盐，所述式(I)如下：
其中，R1为氢、直链或支链C1-6烷基、C3-7环烷基、C4-6环烷基烷基，后三个基团中的每一个任选由羟基(当C≥2时)、C3-5链烯基、芳基、芳烷基或呋喃-2或3-基烷基或(CH2)mCOR(其中m是0-5及R为直链或支链C1-6烷基、羟基、C1-5烷氧基、OC3-6链烯基或烷基芳基)、NR10R11(其中R10和R11可以相同或不同，并且每一个为氢、直链或支链C1-6烷基、C4-6环烷基烷基、C3-5链烯基、芳基或芳烷基)取代；或者R1为A-B基团，其中A表示C1-10亚烷基及B表示取代的或未取代的芳基或杂芳基；R2为氢、羟基或C1-5烷氧基(优选甲氧基)、卤素、硝基、NR10R11、SR10，其中R10及R11的定义同上述，此外R10是COR1，优选乙酰基；R3为氢、直链或支链C1-6烷基(优选乙基)、羟基、C1-5烷氧基(优选甲氧基)、卤素(优选溴)或(CH2)mCOR(其中m和R的定义同上)、SR10、硝基、NR10R11、NHCOR10、NHSO2R10(其中R10及R11的定义同上述，优选氢或甲基)；R4和R5可以相同或不同，各自独立为氢、羟基、C1-5烷氧基(优选甲氧基、O-苯氧基)或可一起形成氧基团(-O-)；或R4与R3一起形成亚甲基二氧基团(-OCH2O-)；R6为基团：
或含有多至三个杂原子如O、S及N并由具有上述定义的R3取代的五或六元杂芳基团，该环上有多至3个R3基团，或者R6为C(Z)R12基团，其中Z是氧或硫，R12是直链或支链的C1-18烷基、羟基、直链或支链C1-18烷氧基、芳烷氧基或NR13R14，其中R13及R14(可以相同或不同)为氢、直链或支链的C1-6烷基、C3-7环烷基、C4-6环烷基烷基，后三个基团中的每一个任选由多至三个氟原子或羟基团(C≥2)、C3-6链烯基、芳基、芳烷基或任选取代的杂环取代或R13及R14可以一起形成可插入氧或NR1的C3-6烷环，其中R1的定义同上；或R6是CH2WA基团，其中W是氧、硫或NR14，及A是氢、直链或支链的烷基或COR14(其中R14的定义如上且优选为甲基)；或R6为COCOR12基团，其中R12具有与上相同的定义并优选为C1-18烷氧基；或R6为NR13R14基团，其中R13和R14具有与上相同的定义，或R13可以为(CH2)mCOR基团，其中m和R具有与上相同的定义；或R6为P(Z)R12基团，其中Z和R12具有与上相同的定义，以及优选Z＝O和R12＝C1-18烷氧基；或R6为S(O)iR12基团，其中i＝1，2及R12具有与上相同的定义。R7为氢、C1-18烷基、C2-18链烯基、卤素、卤代-C1-6烷基、(CH2)mCOR其中m和R具有与上相同的定义或为基团：
或含有多至三个杂原子如O、S及N并由具有上述定义的R3取代的五或六元杂芳基团；R8为氢、C1-6烷基，优选甲基；n是0或1；当n＝0时，X和Y独立为氧、硫、CH或R6-或R7-取代的碳原子、及NR9(其中所述R9为氢、直链或支链的C1-6烷基、C3-7环烷基、C4-6环烷基烷基，其中后三个基团中的每一个任选由羟基取代(当C≥2时)，或可含有NR10R11基团，其中所述R10及R11具有与上相同的定义)、C3-5链烯基、芳基、芳烷基、或(CH2)mCOR(其中m是0-5及R代表羟基、C1-5烷氧基、OC3-6链烯基或烷基芳基、NR10R11，其中R10和R11(可以相同或不同)为氢、直链或支链的C1-6烷基、C4-6环烷基烷基)；及当n＝1时，则X和Y均为N，或N和CH。当R1是芳基时，优选为苯基，当其为芳烷基时，优选为苯基-C1-6烷基。R1的实施例为氢、甲基、乙基、丙基、异丙基、烯丙基、苄基、苯基-乙基、CH2CH2OH、CH2COOH、CH2COOEt、CH2CONH2及COMe。R2的实施例为氢、羟基及甲氧基。R3的实施例为氢、羟基、乙基、溴、羟基、甲氧基、乙氧基、异丙氧基、COMe及OCH2COOH。R4和R5的实施例为氢、羟基、乙酰氧基、甲氧基、O-苯基、一起作为氧基或R4与R3一起为亚甲基二氧基。R6的实施例为CONH2、CONMe2、CONEt2、CON(i-Pr)2、CON(i-Pr)CH2Ph、CON(i-Pr)(CH2)2OH、CON(CH2CF3)(i-Pr)、COOMe、COOEt、COO-n-Pr、COO-i-Pr、及COO-i-Bu、COOCH(i-Pr)2、CSNEt2、CSN(i-Pr)2、COOH、COMe、CO-i-Pr、CO-i-Bu、CO-t-Bu、CO-3-戊基、COPh、
及PO(OEt)2。R7的实施例为甲基、异丙基、三氟甲基、CH2COOH及CH2COOEt。R8的实施例为氢。R9的实施例为氢、甲基、CH2COOH、CH2COOEt、CH2CONHCH2Ph、CH2CONHMe、CH2CONMe2。X的实施例为NR9，其中R9与上述实施例相同，及S。Y的实施例为CR7，其中R7与上述实施例相同。优选的式(I)化合物的基团是其中n＝0，X是NH及Y是CH或R6-或R7取代的碳原子，其中R6是-C(Z)-R12基团(其中R12是C1-6烷基、C1- 4烷氧基)或NR13R14，其中R13及R14的定义同上及Z是氧；R7是甲基或卤代-C1-2烷基。
特别优选的式(I)化合物为其中R6是CONEt2、CON(i-Pr)2或COO-i-Bu，R7是甲基，及R9是氢、甲基或CH2COOH。
式(I)化合物或其盐或溶剂化物优选为药学可接受的或基本上纯的形式。药学可接受的形式特别是指不包括常规药用添加剂例如稀释剂及载体的药学可接受的浓度或纯度，也不包括在常规剂量下有毒的物质。
基本上纯的形式一般含有至少50％(不包括常规药用添加剂)，优选75％，更优选90％及最优选95％的式(I)化合物或其盐或溶剂化物。
一种优选的药学可接受的形式为结晶形式，包括此种形式的药用组合物。在盐及溶剂化物的情况下加入的离子及溶剂部分也必须是无毒的。
式(I)化合物药学可接受的盐的实施例包括用常规药用酸的酸加成盐，所用常规酸例如，马来酸、盐酸、氢溴酸、磷酸、乙酸、富马酸、水杨酸、柠檬酸、乳酸、扁桃酸、酒石酸、琥珀酸、苯甲酸、抗坏血酸及甲磺酸。
式(I)化合物可以多于一种的立体异构形式存在，本发明扩展至全部此类形式及其混合物，包括外消旋体。
本发明也提供了制备式(I)化合物或其溶剂化物或盐的制备方法，包括式(a)化合物与式(b)化合物缩合，及然后使式(I)化合物任选转变成其盐或溶剂化物。所述式(a)及式(b)化合物如下：
其中，式(a)中，K为H、Br、COR7、＝CHOH或=NOH；式(b)中，Q为COR7、CHClR7、COR7、SH或NH2，及J是＝NNHPh、＝O、＝H2或＝CHR7，其中R7及R6具有与上述相同的定义。当K＝H、Q＝COR7及J＝＝NNHPh时，优选的反应条件是于60-100℃的温度范围内在AcONa存在下的AcOH/Zn。当K＝COR7、Q＝SH及J＝＝H2时，优选的反应条件是i)于RT下在醇介质中的干燥HCl，ii)强碱，例如MeONa在MeOH中。当K＝H、Q＝CHClR7及J＝＝O时，优选的反应条件是NaH在THF中。
式(I)化合物或其盐或溶剂化物可以通过下述一般反应图式介绍的方法或通过其改进的方法，使用容易得到的原料、试剂及常规合成步骤制备。如果期望获得本发明的特定对映体，可从所需对映体原料开始及进行不包括消旋化过程的反应合成，或可由手性合成或由手性辅助剂的衍生化制备，其中所得的非对映体混合物可被分离并可通过裂解其辅助基团以得到纯的所需对映体。此外，当分子中含有碱性官能基例如氨基或酸性官能基例如羧基时，使用合适的旋光酸或旋光碱生成非对映异构体盐，然后经分级结晶拆分非对映异构体盐及随后回收纯的对映体。
式(I)化合物(其中n＝0，X＝NH及Y为R7-取代的碳原子)可如图式1所述由式(II)酮与式(III)腙起始(Organic Reactions，1959，3-142)，在Zn及CH3COONa存在下，以CH3COOH为溶剂(Khimiya Geterot.Soed.，1972，342)而得到：流程1
式(I)化合物(其中n＝0，X＝NH及Y为R6取代的碳原子)可如图式2所述由式(IV)(J.Org.Chem，1964，29，3459)卤代酮与式(V)酮(Can.J.Chem.，1970，48，1689)在NH4OH存在下环化得到：流程2
式(I)化合物(其中n＝0，X＝O及Y为R7取代的碳原子)可如图式3所述由式(II)酮与式(VI)α-卤代酮(优选α-氯代酮)在碱(J.Org.Chem.，1984，49，2317)存在下环化得到：
流程3
式(I)化合物(其中n＝0，X＝O及Y为R6取代的碳原子)可如图式4所述由式(IV)溴代酮与式(V)酮于醇中在碱(优选EtONa)存在下环化(J.Chem.Soc.Perkin I，1972，2372)得到：
流程4
式(I)化合物(其中n＝0，X＝S及Y为R7取代的碳原子)可如图式5所述由通式(VII)β-二酮(由酮(II)和式R7-COOEt的酯起始经Claisen反应合成；J.Am.Chem.Soc.，1945，67，1510；J.Med.Chem.1982，25，983)与式(VIII)巯基衍生物在HCl存在下制备(DE 1，088，507；C.A.，1962，56，456；Synthesis，1992，526)：
流程5
式(I)化合物(其中n＝0，Y＝S及X为R6取代的碳原子)可如图式6所述通过α-巯基酮(IX)(由溴代酮(IV)和H2S/KOH起始制备，J.Am.Chem.Soc.，1985，107，4175)与式(X)炔衍生物，在溶剂如DMSO中，在碱如t-BuOK存在下反应(Chem Ber.，1964，97，2109)得到：
流程6
式(I)化合物(其中n＝0，X及Y均为N)可如图式7所述由肟基衍生物(XV)及式(XVI)R6-R7-取代的亚胺氯(imidoyl chlorides)在碱性介质中，接着用在回流甲苯中的H+处理中间产物(J.Org.Chem.，1993，58，7092)而得到：
流程7式(I)化合物(其中n＝1，X＝N及Y＝CH)可如图式8所述由羟基亚甲基酮(XI)(由酮(II)与HCOOEt在碱存在下缩合制备；Org.Synth.Coll.，1963，4，536)与烯胺(XII)反应(J.Ind.Chem.Soc.，1935，12，289)得到：
流程8
式(I)化合物(其中n＝1，X＝Y＝N)可如图式9所述由羟基亚胺酮(XIII)(由酮(II)与亚硝酸异戊酯/t-BuOK按J.Med.Chem.，1991，34，1715所述的方法制得)与乙二胺(XIV)起始，并接着对在碱性介质中使中间体芳香化(Chem.Ber.，1967，100，555)而得到：
流程9式(I’)化合物(其中n＝0，X＝NH及Y为R6-或R7-取代的碳原子)可如一般图式10所述通过使用烷基化试剂R9Br在DMF中的NaH存在下转化成通式(I)的其它化合物(其中吡咯氮由R9基团取代)：
流程10
通式(I’)化合物(其中R4＝OH及R5＝H)可如图式11所述按照上述图式所述由已知的式(II)酮或(作为另一种选择)由通式(I)化合物(其中R4及R5一起形成氧基团(-O-))经与Zn在沸腾MeOH/HCl或沸腾AcOH中反应制得：
流程11
式(I)化合物(其中n＝0、X＝S及Y＝N，R6为NR13R14，其中R13是(CH2)mCOR基团(m＝0)及R14是氢)可如图式12所述由溴代酮(IV)在碱存在下(优选Na2CO3)与在异丙醇中的硫脲环合(J.Chem.Soc.，1945，455)，接着使所得的胺与合适的酰基氯或与相应的羧酸在偶合剂如DCC存在下酰化得到：
流程12
通式(I)化合物(其中R6为C(Z)R12基团(其中Z是硫))可由化合物(其中Z为氧)经与硫杂化剂例如Lawesson试剂反应制得。
通式(I)化合物(其中R6为CH2WA)可由通式(I)化合物经文献中公知的R6基团如酯酰胺、硫代酰胺(tioamides)的常规化学反应制得。
通式(I)化合物可与合适的有机或无机酸反应而转变成其药学上可接受的盐。
式(I)化合物的溶剂化物可通过在合适的溶剂中结晶或重结晶生成。例如，水合物可通过在水溶液，或含水有机溶剂的溶液的结晶或重结晶生成。
非药学上可接受的式(I)化合物的盐或溶剂化物可用于生产药学上可接受的盐或溶剂化物的中间体。因而这样的盐或溶剂化物也成为本发明的一部分。
一般来说，可作为选择性δ受体配体的式(I)化合物可以用作麻醉剂、预防器官移植及皮肤移植排斥反应的免疫抑制剂、抗过敏及抗炎剂、脑细胞保护剂、治疗药物及酒精滥用、减少胃分泌、用于腹泄、心血管及呼吸道疾病、咳漱和呼吸抑制、精神病及癫痫发作及其它神经紊乱(此后称作‘病症’)的药物。特别是在标准试验中作为δ激动剂的式(I)化合物的活性显示它们具有作为改善或消除疼痛的麻醉剂的潜在的治疗用途。
按照本发明也可提供用作活性治疗物质的式(I)化合物或其药学上可接受的盐或溶剂化物。
按照本发明进一步提供包括式(I)化合物或其药学上可接受的盐或溶剂化物，及药学上可接受的载体的药用组合物。
本发明也提供式(I)化合物或其药学上可接受的盐或溶剂化物在用于治疗所述病症的药品的生产中的用途。
此种药品及本发明的组合物可以通过本发明化合物与适当的载体混合制得。它可以包含常规形式的稀释剂、粘合剂、填充剂、崩解剂、调味剂、着色剂、润滑剂或防腐剂。
这些常规赋形剂可以用于例如在治疗所述病症的已知药物的组合物的制备中。
优选本发明的药用组合物为单位剂量形式及应用于医学或兽医学领域所采用的形式。例如，此种制剂可以是附有用作治疗所述病症药物的文字印刷说明书的包装形式。
本发明化合物的合适剂量范围取决于所用的化合物及患者的病情。特别是也取决于药效与吸收性的关系及给药的次数及途径。
本发明化合物或组合物可配制成任何途径给药的制剂形式，优选单一剂型或者是病人可以单一剂量自己服用的形式。有利的是，所述组合物适于口服、直肠、局部、胃肠外、静脉或肌肉内给药。制剂可设计成缓慢释放有效成分的形式。
组合物可为例如片剂、胶囊、香囊剂(sachets)、小瓶剂(vials)、粉剂、颗粒剂、锭剂、可复制的粉剂，或液体制剂，例如溶液或悬浮液，或栓剂。
所述组合物例如适于口服的组合物可含有常规赋形剂诸如粘合剂例如糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶，或聚乙烯吡咯烷酮；填充剂例如乳糖、糖、玉米淀粉、磷酸钙、山梨醇或甘油；制片润滑剂例如硬脂酸镁；崩解剂例如淀粉、聚乙烯吡咯烷酮、淀粉甘醇酸钠或微晶纤维素；或药学上可接受的凝固剂例如十二烷基硫酸钠。
固体制剂可通过混合、填充、制片等常规方法得到。反复混合操作可使活性试剂分散至应用大量添加剂的组合物中。当所述组合物是片剂、粉剂或锭剂时，可以使用任何适于配制固体药用组合物的载体，实例如硬脂酸镁、淀粉、葡萄糖、乳糖、蔗糖、米粉及白垩粉。片剂可以按照常规药用实践中公知的方法包衣，特别是包肠溶衣。所述组合物可为易吸收的胶囊的形式例如包含所述化合物的明胶的形式，如果需要，还含有载体或其它赋形剂。
用于口服的组合物如液体可为，例如乳剂、糖浆或酏剂的形式，或可作为使用前用水或其它合适的溶媒重新组合的干燥产物存在。此种液体组合物可含有常规添加剂诸如悬浮剂例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶、氢化食用脂肪；乳化剂例如卵磷脂、脱水山梨醇单油酸酯，或阿拉伯胶；水的或非水溶媒包括食用油例如杏仁油、精馏椰子油、油酯例如甘油酯，或丙烯乙二醇、或乙醇、甘油、水或常规盐水；防腐剂例如对羟基苯甲酸甲酯或丙酯或山梨酸；及如果需要还可含有常规的调味剂或着色剂。
本发明化合物也可以通过非口服途径给药。按照常规药用方法，所述组合物可制成例如作为栓剂用于直肠给药。它们也可以配制成在水的或非水溶液中，在药学上可接受的液体如灭菌的无热原水或胃肠道外可接受的油或液体混合物的悬浮液或乳液中的可注射形式。所述液体可含有抑菌剂、抗氧剂或其它防腐剂、提供使所述溶液与血液等渗的缓冲剂或溶质、增稠剂、悬浮剂或其它药学上可接受的添加剂。此种形式将以单位剂量形式如安瓿或一次性的注射装置或以多剂量形式如可以抽出合适剂量的瓶或可以用于制备注射剂型的固体形式或浓缩物形式存在。
本发明化合物也可以通过鼻或口的途径吸入给药。此种给药可通过使用包括优选悬浮于例如烃抛射剂中的本发明化合物及合适的载体的喷雾制剂进行。
优选的喷雾制剂包括微米化的化合物粒子与表面剂、溶剂或防止悬浮粒子沉降的分散剂的结合。优选所述化合物的粒度为2-10微米。
本发明化合物给药的另外的形式包括利用皮肤膏贴制剂的透皮传递。优选的制剂包括使本发明化合物分散于粘附于皮肤的压力敏感的胶粘剂中，进而使所述化合物由所述胶粘剂通过皮肤扩散传递至患者。为了获得经皮吸收的稳定速率，可以使用本领域中已知的压力敏感的胶粘剂如天然橡胶或硅氧烷。
如上所述，所述化合物的有效剂量取决于所用的特定化合物，患者的病情及给药的次数及途径。一般单位剂量为20-1000mg，优选30-50mg，特别优选50、100、150、200、250、300、350、400、450或500mg。所述组合物可以一天给药一次或多次，例如每天2、3或4次，对于70kg的成人，全部的日剂量通常为100-3000mg。此外单位剂量也可含有2-20mg的活性成分并且(如果需要)可多次给药以达到上述日剂量。
当按照本发明给药时，期望本发明的化合物没有毒性作用。
本发明也提供治疗和/或预防脯乳动物，特别是人类的所述病症的方法，其包括给予需要此种治疗和/或预防的脯乳动物以有效量的式(I)化合物或其药学上可接受的盐或溶剂化物。
作为选择性δ配体的本发明化合物的活性由下述放射配体结合分析确定。
小鼠脑膜由Kosterlitz所述的方法制得(Br.J Pharmacol.，1981，73，939.)。优选的δ配体[3H]-[D-Ala2，D-Leu5]-脑腓肽(DADLE)以在40nM未标记的μ配体[D-Ala2，MePhe4，Gly-ol5]脑腓肽(DAMGO)存在下的KD浓度(1.3nM)进行评估。所述μ配体[3H]-DAMGO(Eur.J.Pharmacol.，1989，166，213)的结合及κ配体[3H]-U69593(Excerpta Medica，1990，211)的结合以0.5nM进行。非特异结合是在纳络酮(10μm)存在下对全部氚化的配体测得的。结合常数表示为抑制百分数并符合下述方程：f(x)＝100·X/(IC50+X)，其中X为cold drug浓度值。所得的IC50用于按照Cheng和Prusoff关系(relation)计算抑制常数(Ki)(Biochem.Pharmcol，1973，22，3099)。
本发明化合物δ激动剂/拮抗剂活性以如下述的在NG108-15细胞系中的cAMP生物分析法测定。
使NG108-15细胞于37℃在5％CO2及95％空气的潮湿气氛中在补充有含2mM谷氨酰胺，2％HATx50添加物，50ug链霉素和50I.U.青霉素/ml的胎牛血清的DMEM(使用无丙酮酸钠的4500mg/l葡萄糖)中生长，并用在无Ca/Mg磷酸盐缓冲盐水中的机械搅拌的1MEDTA收获融合的细胞。每两天换一次培养基在实验前一天将所述细胞分散于17mm培养板(约10×106个细胞/板)。1天后，除去生长培养基并用由hepesNaOH200nM，pH7.4，含有(mmol/l)NaCl(125)，KCl(5)，KH2PO4(0.4)，MgSO4及CaCl2(1.2)，NaHCO3(25)，葡萄糖(12)缓冲的改良Krebs-Ringer培养基洗涤细胞两次。培养基也包括1mM 3-异丁基-1-甲基黄质(isobuthyl-1-methylxantine)(IBMX)。实验于室温下进行。培养10分钟后掺入IBMX，NG108-15细胞用1μmforskolin及所述待测化合物处理10分钟。通过加入冷的0.4N HClO4使该反应中止。15分钟后，小心收集冷的上清液并用1M K2CO3中和。于4℃培养过夜后所述实验管以9000rpm离心5分钟并将100ul等分试样通过使用商业购得的125I cAMP RIA标准试剂诊断盒(Amersham Inc.)测定cAMP含量。得自初始培养板的小颗粒溶于NaOH0.5N及其蛋白质含量用Bradfort所述的方法测定(Anal.Biochem.1976，72，248)。所得数据标准化成蛋白质含量。
本发明所述的最强效的化合物显示对δ受体的亲合力的范围为0.5-200nM，对δ的选择性的范围为对其它阿片受体类型的20-1500倍。在cAMP抑制生物分析中这些化合物也显示强的δ激动剂或拮抗剂的性质。选择性δ激动剂(由选择性δ拮抗剂纳曲酮(Nalrindole)拮抗)显示IC50的范围为1-500mnM。例如，实施例10的化合物显示Kiδ＝2.9nM，Kiμ/Kiδ＝840及Kiκ/Kiδ＝600。实施例1的化合物显示对forskolin-刺激的在NG108-15细胞(IC50＝15nM)(完全由选择性δ拮抗剂纳曲酮所拮抗，100nM)中的cAMP抑制的激动剂活性。
小鼠腹部狭窄(abdomianl constriction)(MAC)(Proc.Soc.Exp.Biol.Med，1957，95，729)，大鼠摆尾(tail-flick)(MTF)(J.Pharm.Exp.Ther.，1941，72，74)及大鼠温水摆尾(tail-flick warm water)(MTF-WW)(LifeSci.，1986，39，1795)用来对本发明化合物的抗痛觉能力进行评价。
下述制备1-7介绍得到作为本发明一部分的通式(II)的新酮的合成途径。特别是4，5-环氧基-17-甲基-3-乙烯基吗啡烷-6-酮、4，5-环氧基-3-(1-乙氧基乙烯基)-17-甲基吗啡烷-6-酮、4，5-环氧基-3-乙基-17-甲基吗啡烷-6-酮、3-溴-4，5-环氧基-14-羟基-17-甲基吗啡烷-6-酮及3-溴-4，5-环氧基-17-甲基吗啡烷-6-酮为新化合物并被用作制备实施例28、30、33、35、41、52、61及64化合物的原料。其它用作原料的酮在文献中是公知的。制备8介绍用作制备实施例89化合物原料的通式(III)新的磷酰腙的制备。实施例1介绍由通式(II)的相应酮与相应通式(III)已知腙起始的制备本发明通式(I)化合物的方法。实施例2、49及52介绍由相应式(I)化合物的化学转移依次制备的通式(I)化合物的制备方法。实施例105描述通式(I)化合物(其中n＝0，X＝S及Y为取代的碳原子)的制备。此处介绍的实施例可按照如实施例1、2、49、52及105所述相同的步骤制备。
实施例1-105的化合物归纳在化学表中。制备通式(II)化合物(其中R3＝CH＝CH2及C(OEt)＝CH2)的一般过程。制备14，5-环氧基-1 7-甲基-3-三氟甲基磺酰基氧基吗啡烷-6-酮
在氮气下将5.5g(19.3mmol)4，5-环氧基-3-羟基-17-甲基吗啡烷-6-酮溶于20ml吡啶中。将该溶液冷至0℃并滴加入3.56ml(21.2mmol)三氟甲基磺酸酐。该溶液于0℃搅拌5分钟，然后温热至室温过夜。将该反应混合物倒至水中并用AcOEt萃取该水相。有机相用Na2SO4干燥并真空除去溶剂。所得粗品反应混合物经快速层析，分别用CH2Cl2/MeOH/浓NH4OH90∶7∶0.7的混合物洗脱，得6.26g标题产物。N.M.R.300MHz(CDCl3)：δ7.0(d，1H).6.7(d，1H)，4.7(s，1H)，3.2(m，1H)，3.1(d，1H)，2.7-2.3(m，8H)，2.1(m，2H)，1.9-1.7(m，2H)，1.3-1.1(m，1H).MS(TSP)m/z＝417.2(M+)制备24，5-环氧基-17-甲基-3-乙烯基吗啡烷-6-酮
在氮气下将2g(4.8mmol)4，5-环氧基-17-甲基-3-三氟甲基磺酰氧基吗啡烷-6-酮溶解于25ml二甲基甲酰胺中，然后加入1.46ml(5mmol)乙烯基三丁基锡、1.6g(38.4mmol)LiCl、0.337g(0.48mmol)双(三苯基膦)钯(II)氯化物及0.5g(1.9mmol)三苯基膦。该反应混合物加热至100℃3小时，然后将该反应混合物倒至水中并用AcOEt萃取该水相。有机相用Na2SO4干燥并真空除去溶剂。所得粗品反应混合物经快速层析纯化，分别用CH2Cl2/MeOH/浓NH4OH 90∶7∶0.7的混合物洗脱，得1.1g标题产物。N.M.R.300MHz(CDCl3)：δ7.1(d，1H)，6.8-6.6(m，2H)，6.0(d，1H)，5.4(d，1H)，4.6(s，1H)，3.2-1.7(m，13H)，1.2(m，2H).MS(TSP)m/z＝295.1(M+)制备34，5-环氧基-3-(1-乙氧基乙烯基)-17-甲基吗啡烷-6-酮
2.5g(6.0mmol)4，5-环氧基-17-甲基-3-三氟甲基磺酰基氧基吗啡烷-6-酮、2.1ml(6.2mmol)(1-乙氧基乙烯基)三丁基锡、2g(48mmol)LiCl、0.42g(0.6mmol)双(三苯基膦)钯(II)氯化物及0.63g(2.4mmol)三苯基膦在25ml二甲基甲酰胺中如制备2所述处理。所得粗品反应混合物经快速层析纯化，分别用CH2Cl2/MeOH/浓N-H4OH 90∶7∶0.7的混合物洗脱，得1.95g标题产物。I.R.(KBr)：2932，1728，1674 cm-1.N.M.R.300MHz(CDCl3)：δ7.4(d，1H)，6.6(d，1H)，5.2(s，1H)，4.65(s，1H)，4.45(s，1H)，3.9(q，2H)，3.2-1.4(m，18H).MS(TSP)m/z＝339.1(M+).制备44，5-环氧基-3-乙基-17-甲基吗啡烷-6-酮
将1.2g(4.06mmol)4，5-环氧基-17-甲基-3-乙烯基吗啡烷-6-酮溶于150ml无水乙醇中。加入1g 10％Pd-碳并将该反应混合物于室温在Parr装置中在35psi下氢化8小时。滤除催化剂并真空除去溶剂，得到0.77g标题化合物。N.M.R.300MHz(CDCl3)：δ6.9(d，1H)，6.6(d，1H)，4.6(s，1H)，3.2-1.7(m，18H)，0.9(m，2H).MS(TSP)m/z＝297.1(M+)制备通式(II)化合物(其中R3＝Br)的一般过程。制备53-溴-4，5-环氧基-17-甲基吗啡烷-6-醇
将3.1g(11.4mmol)4，5-环氧基-17-甲基吗啡烷-6-醇溶于150ml冰乙酸中并滴加入11.4rml1M在AcOH中的Br2溶液。1小时后，真空除去AcOH，残留物溶于水中，该水溶液用饱和NaHCO3溶液调至pH7并用AcOEt萃取。有机相用Na2SO4干燥并真空除去溶剂。得3.6g标题产物。I.R.(KBr)：3580，2930，1452 cm-1.N.M.R.300MHz(CDCl3)：δ7.2(d，1H)，6.6(d，1H)，4.6(d，1H)，4.0(m，1H)，3.1(m，1H)，2.9(d，1H)，2.5-1.5(m，12H)，1.1(m，1H).MS(TSP)m/z＝349.0(M-1)制备63-溴-4，5-环氧基-14-羟基-17-甲基吗啡烷-6-酮
如制备5中所述用3.8ml 1M在AcOH中的Br2溶液处理1.1g(3.8mmol)4，5-环氧基-14-羟基-17-甲基吗啡烷-6-酮在50ml冰AcOH中的溶液，得1.1g标题产物。I.R.(KBr)：3348，2910，1738 cm-1.制备73-溴-4，5-环氧基-17-甲基吗啡烷-6-酮
于-55℃在氮气下，将在4.8ml CH2Cl2中的1.6ml DMSO溶液缓慢加至在21mlCH2Cl2中的0.9ml草酰氯溶液中。2分钟后加入在20mlCH2Cl2中的3.6g(10.3mmol)3-溴-4，5-环氧基-17-甲基吗啡烷-6-醇，然后于15分钟后，加入6.6ml Et3N。将该反应混合物于2小时内温热至室温，然后，用50ml H2O使之骤冷。分离各相，有机相用Na2SO4干燥并真空除去溶剂。所得粗品反应混合物经快速层析，分别用CH2Cl2/MeOH/浓NH4OH 90∶7∶0.7的混合物洗脱，得2.87g标题产物。I.R.(KBr)：2940，1716，1446 cm-1.N.M.R.300MHz(CDCl3)：δ7.2(d，1H)，6.6(d，1H)，5.4(s，1H)，3.3(m，1H)，2.95(d，1H)，2.6-1.7(m，12H)，1.2(m，1H).MS(TSP)m/z＝347.0(M-1)制备81-苯基亚肼基-2-氧丙基膦酸二乙酯
于0-10℃将7.1g(0.05 17mol)K2CO3及0.0257mol苯基重氮氯化物加至5.0g(0.0257mol)二乙基(2-氧丙基)膦酸二乙酯在25ml乙醇/水4∶1中的溶液中。搅拌所得悬浮液直至温度达室温。然后加入30ml水和100mlCH2Cl2。有机相用Na2SO4干燥并真空蒸发得7g红色油状标题化合物，其可直接用于下一步骤中。C13H19N2O4PIR(neat)：3498，1716，1666，1268，1026 cm-1N.M.R.300MHz(CDCl3)：12.9(bs，1H)；7.5-7.0(m，5H)，4.2(m，4H)；2.3(s.3H)；1.5(m，6H).实施例1[8R-(4bS*，8α，8aβ，12bβ)]-11(N-苄基-N-异丙基氨基羰基)-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐
将0.65g(2.17mmol)7，8-二氢可待因酮盐酸盐，2.2g(6.51mmol)N-苄基-N-异丙基-2-苯基腙-3-氧代butiramide溶于10ml冰乙酸及0.54g(6.51mmol)CH3COONa的混合物中。所得反应混合物加热至60℃，然后在氮气下分次加入0.57g(8.6mmol)锌粒。使该混合物回流2小时，然后冷至室温。通过倾倒除去所得盐并用乙酸洗涤。收集该酸性溶液然后调至pH8并用AcOEt提取数次。干燥所得有机相并真空蒸发至干。所得残留物经使用硅胶(15-25u)中压层析纯化并用AcOEt/MeOH/浓NH4OH 90∶10∶0.5的混合物作洗脱剂纯化。所得产物溶于丙酮/MeOH1∶1的混合物并将溶液用HCl/Et2O调pH至酸性。过滤所得沉淀，洗涤并干燥得到0.5g标题化合物。M.P.＝304℃分解。实施例2[8R-(4bS*，8α，8aβ，12bβ)]-11(二乙基氨基硫代羰基)-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐
将1g(2.3mmol)[8R-(4bS*，8α，8aβ，12bβ)]-11(二乙基氨基羰基)-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉，0.950g(2.3mmol)Lawesson试剂溶于40ml甲苯中并将混合物回流4小时。真空除去溶剂，然后残留物溶于CH2Cl2中并用s.s.NaHCO3洗涤。有机层用Na2SO4干燥。蒸发除去溶剂后，残留物经硅胶快速层析(CH2Cl2/MeOH/NH4OH(浓)86∶10∶0.6)纯化，然后产物溶于丙酮。所得溶液用HCl/Et2O调至pH酸性。过滤沉淀物，在炭存在下溶于沸腾的MeOH 30分钟。滤除该炭，并将该溶液蒸发至干。残留物用沸腾Et2O研磨得到0.41g标题化合物。M.P.＞250℃。
实施例73化合物按照上述相同方法制备。实施例49[8R-(4bS*，8α，8aβ，12bβ)]-11-异丙基羰基-7，10，12-三甲基-1-甲氧基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐
于氮气下将0.52g(1.2mmol)[8R-(4bS*，8α，8aβ，12bβ)]-11(异丙基羰基)-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉(实施例34)溶于5mlDMF中。在保持0℃温度的同时分次加入0.051g 60％NaH。30分钟后滴加入0.2gMeI溶于1mlDMF的溶液。1小时后用碎冰使该反应骤停。所得溶液用Et2O萃取。有机层用Na2SO4干燥，然后真空除去溶剂。使生成的残留物溶于丙酮中，所得溶液用Et2O/HCl调至pH酸性。依次蒸发该溶剂并将所得残留物用沸腾Et2O研磨。将该固体过滤，洗涤并干燥得到0.25g标题化物。M.P.240-243℃。
实施例62和82的化合物按照上述方法制备。
实施例74，79及80按照相同方法使用溴乙酸乙酯作烷化剂制备。所得乙基酯依次在酸性条件下水解成上述实施例的相应酸的衍生物。实施例52[10R，4bS-(4bb，9ab)]-3-溴-7-二异丙基氨基羰基-8，14-二甲基-4b，5，9，9a，10，11-六氢-4-羟基-(6H)-10，4b-(亚氨基桥亚乙基)菲并[3，2-b]吡咯
于氮气下将0.3g(0.58mmol)[8R-(4bS*，8α，8ab，12bb)]-1-溴-11-异丙基氨基羰基-7，10-二甲基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉(实施例30)溶于10ml冰AcOH中并加入0.15g(1.8mmol)AcONa。反应混合物加热至80℃并分次加入0.23g(3.5mmol)锌粒。该反应混合物加热回流4小时，然后倒至冰中，用浓NH4OH调pH至9并用CH2Cl2萃取。有机相用Na2SO4干燥并真空除去溶剂。所得粗品反应混合物经快速层析纯化，分别用CH2Cl2/MeOH/浓NH4OH 90∶7∶0.7的混合物洗脱，所得固体在Et2O中研磨，得0.15g标题产物。实施例105[8R-(4bS*，8α，8aβ，12bβ)]-11-甲氧基羰基-7，10-二甲基-1-甲氧基-5，6，7，8，9，12b-六氢-4，8-亚甲基苯并呋喃[3，2-e]噻吩并[2，3-g]异喹啉盐酸盐
将7-乙酰基-4，5-环氧基-1-甲氧基-17-甲基吗啡烷-6-酮(1g，2.9mmol)(J.Med.Chem.1982，25，983)在MeOH(40ml)中的溶液冷至-10℃并将干燥HCl鼓泡进入该系统直至饱和(约1h)。然后加入硫代乙醇酸(0.4ml，5.8mmol)，继续于-10℃鼓泡HCl4小时。该反应混合物于RT下放置6天。真空蒸发该溶剂，用浓NH4OH处理残留物并用AcOEt萃取。分离有机层，用水洗涤，干燥(Na2SO4)并真空蒸发。所得粗产物直接用于下一步骤。
将2N MeONa(10ml)加至上述产物于12ml MeOH中的溶液中并于氮气下保持24小时。蒸除溶剂并用冰-冷水处理残留物。用6N HCl酸化该混合物至pH＝1。用AcOEt洗涤后，水层用NaOH处理至pH＝9并用AcOEt萃取。干燥溶剂，蒸发并将粗产物经硅胶层析(CH2Cl2/MeOH/浓NH4OH；95∶5∶0.5)纯化。所得产物用HCl/Et2O处理，得55mg标题产物。化学表
Claims (6)
1.式(I)化合物，或其溶剂化物或其盐：其中，R1为氢、甲基、乙基、丙基、异丙基、烯丙基、苄基、苯基乙基、CH2CH2OH、CH2COOH、CH2COOEt、CH2CONH2或COMe；R2为氢、羟基或甲氧基；R3为氢、羟基、乙基、溴、甲氧基、乙氧基、异丙氧基、COMe或OCH2COOH；R4和R5可以相同或不同，各自独立为氢、羟基、C1-5烷氧基、O-苯基或可一起形成-O-；或R4与R3一起形成-OCH2O-；R6是CONH2、CONMe2、CONEt2、CON(i-Pr)2、CON(i-Pr)CH2Ph、CON(i-Pr)(CH2)2OH、CON(CH2CF3)(i-Pr)、COOMe、COOEt、COO-n-Pr、COO-i-Pr、COO-i-Bu、COOCH(i-Pr)2、CSNEt2、CSN(i-Pr)2、COOH、COMe、CO-i-Pr、CO-i-Bu、CO-t-Bu、CO-3-戊基、COPh、R7为甲基或卤代-C1-2烷基；R8为氢、C1-6烷基；n是0；X是NH并且Y是CH或R6-或R7-取代的碳原子。
2.权利要求1的化合物，其中R4和R5各自为氢、羟基、乙酰氧基、甲氧基、O-苯基、或一起形成氧基、或R4与R3一起为亚甲基二氧基。
3.一种化合物，它选自：[8R-(4bS*，8α，8aβ，12bβ)]-11-(N-苄基N-异丙基氨基羰基)-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-(二乙基氨基硫代羰基)-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[10R，4bS-(4bβ，9aβ)]-7-二乙基氨基羰基-8，14-二甲基-4-羟基-4b，5，9，9a，10，11-六氢-(6H)-[2，3-h]吡咯-[10，4-b]-亚氨基菲；[10R，4bS-(4bβ，9aβ)]-7-二乙基氨基羰基-3，4-二甲氧基-8，14-二甲基-4b，5，9，9a，10，11-六氢-(6H)-[2，3-h]吡咯-[10，4-b]-亚氨基菲盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-二乙基氨基羰基-1，8a-二甲氧基-7，10-二甲基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-11-(乙氧羰基)-5，6，7，8，12，12b-六氢-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-(二乙基氨基羰基)-8a-羟基-1-甲氧基-10-甲基-7-(2-丙烯基)-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[10R，4bS-(4bβ，9aβ)]-7-二乙基氨基羰基-8，14-二甲基-3-甲氧基-4-氧基苯基-4b，5，9，9a，10，11-六氢-(6H)-[2，3-h]吡咯并[10，4-b]-亚氨基菲；[10R，4bS-(4bβ，9aβ)]-7-二乙基氨基羰基-8，14-二甲基-3-甲氧基-4b，5，9，9a，10，11-六氢-(6H)-[2，3-h]吡咯并[10，4b]-亚氨基菲；[8R-(4bS*，8α，8aβ，12bβ)]-11-(乙氧基羰基)-7-甲基-1-甲氧基-10-三氟甲基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-11-(乙氧基羰基)-7-甲基-10-(1-甲基乙基)-1-甲氧基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-(二乙基羰基)-10-甲基-1-甲氧基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-苄氧基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-11-羧酸；[8R-(4bS*，8α，8aβ，12bβ)]-11-二乙基氨基羰基-1-甲氧基-10-甲基-7-(2-苯基乙基)-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-11-二乙基氨基羰基-7-乙基-10-甲基-5，6，7，8，12，12b-六氢-(9H)-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-11-乙酰基-7，10-二甲基-1-甲氧基-11(2-甲基丙基)ossi羰基-5，6，7，8，12，12b-六氢-[9H]4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-11-异丁基羰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7-苄基-11-二乙基氨基羰基-10-甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-11-二乙基氨基羰基-7-异丙基-10-甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-11-二乙氨基羰基-10-甲基-1-甲氧基-7-异丙基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-二异丙基氨基羰基-7，10-二甲基-1-乙氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-二异丙基氨基羰基-7，10-二甲基-1-异丙基氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-二异丙基氨基羰基-7-甲基-1-甲氧基-10-三氟甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-7-烯丙基-11-异丁基羰基-10-甲基-1-甲氧基-5，6，7，8，12，12b-六氢-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-(9H)-8a-醇盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7-烯丙基-11-异丁基羰基-10-甲基-5，6，7，8，12，12b-六氢-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-1，8a-(9H)-二醇盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7烯丙基-11-异丁基羰基-1-乙氧基-10-甲基-5，6，7，8，12，12b-六氢-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-(9H)-8a-醇盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-二异丙氨基羰基-7，10-二甲基-1-乙基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11(3-甲基-1，2，4-噁二唑-5-基)-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-1-溴-11-二异丙氨基羰基-7，10-二甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉8a-(9H)-醇盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-乙氧基羰基-10-乙氧基羰基亚甲基-1-甲氧基-7-甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉8a-(9H)-醇盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-叔丁基羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-1-溴-11-二异丙氨基羰基-7，10-二甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-异丙基羰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-1-溴-7，10-二甲基-11-异丁基羰基-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[10R，4bS-(4bβ，9aα)]-7-二异丙基氨基羰基-8，14-二甲基-4b，5，9，9a，10，11-六氢-[6H]-10，4b-(亚氨基桥亚乙基)菲并[2，3-b]吡咯；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-(2-丙基)氧基羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-11-(1，1-二甲基乙基)氧基羰基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-11-甲氧基羰基-1-甲氧基-11-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-(1-丙基)氧基羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-1-乙酰基-7，10-二甲基-5，6，7，8，12，12b-六氢-[9H]-11-异丁基羰基-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-乙基草酰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[10R，4bS-(4bβ，9aα)]-7-异丁基羰基-8，14-二甲基-4-羟基-3-甲氧基-4b，5，9，9a，10，11-六氢-[6H]-10，4b-(亚氨基桥亚乙基)菲并[3，2-b]吡咯盐酸盐；[10R，4bS-(4bβ，9aα)]-14-烯丙基-7-异丁基羰基-4-羟基-8-甲基-3-甲氧基-4b，5，9，9a，10，11-六氢-[6H]-10，4b-(亚氨基桥亚乙基)菲并[3，2-b]吡咯-9a-醇盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7-烯丙基-11-异丁基羰基-1-甲氧基-10-甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[10R，4bS-(4bβ，9aα)]-4-乙酰氧基-7-异丙氨基羰基-8，14-二甲基-3-甲氧基-4b，5，9，9a，10，11-六氢-[6H]-10，4b-(亚氨基桥亚乙基)菲并[3，2-b]吡咯；[10R，4bS-(4bβ，9aα)]-14-烯丙基-7-异丁基羰基-8-甲基-3-甲氧基-4b，5，9，9a，10，11-六氢-[6H]-10，4b-(亚氨基桥亚乙基)菲并[3，2-b]吡咯-9a-醇盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-(戊基-3-羰基)-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-异丙基羰基-7，10，12-三甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-二异丙基氨基羰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-8a-(9H)-醇盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10，11-三甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-3-溴-7-二异丙氨基羰基-8，14-二甲基-1-甲氧基-4b，5，9，9a，10，11-六氢-4-羟基-[6H]-10，4b-(亚氨基桥亚乙基)菲并[3，2-b]吡咯；[8R-(4bS*，8α，8aβ，12bβ)]-11-异丙基氨基羰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-7-烯丙基-11-二异丙基氨基羰基-10-甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-7-异丁基羰基-3-甲氧基-8，14-二甲基-4b，5，9，9a，10，11-六氢-4-羟基[6H]-10，4b-(亚氨基桥亚乙基)菲并[3，2-b]吡咯；[8R-(4bS*，8α，8aβ，12bβ)]-11-二异丙基氨基羰基-7-羟乙基-1-甲氧基-10-甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-11-羧酰胺-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-11-(N-苄基N-异丙基)氨基羰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-8a-(9H)-醇盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-异丙基氨基羰基-8，14-二甲基-4-羟基-3-甲氧基-4b，5，9，9a，10，11-六氢-[6H]-[2，3-h]吡咯并-[10，4b]-(亚氨基桥亚乙基)菲；[8R-(4bS*，8α，8aβ，12bβ)]-11-苄氧基羰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-1-乙酰基-7，10-二甲基-5，6，7，8，12，12b-六氢-[9H]-11-(2-甲基丙基)氧基羰基-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-二异丙氨基羰基-7，10，12-三甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-(2，4-二甲基-3-戊氧基)羰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-1-溴-7，10-二甲基-5，6，7，8，12，12b-六氢-[9H]-11-(2甲基丙基)氧基羰基-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[10R-4bS-(4bβ，9aβ)]-8，10-二甲基-4b，5，9，9a，10，11-六氢-[9H]-7-(2-甲基丙基)氧基羰基-10，4b-(亚氨基桥亚乙基)菲并[3，2-b]吡咯盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7-乙氧基羰基亚甲基-11-二异丙氨基羰基-1-甲氧基-10-甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7-氧基羰基亚甲基-11-二异丙基氨基羰基-1-甲氧基-10-甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-11-二甲基氨基羰基-1-甲氧基-10-甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[10R，4bS-(4bβ，9aβ)]-8，14-二甲基-7-异丁氧基羰基-3-甲氧基-4b，5，9，9a，10，11-六氢-[6H]-[2，3-h]吡咯-[10，4b]-亚氨基桥亚乙基菲盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-二异丙基氨基羰基-1-甲氧基-10-甲基-5，6，7，8，12，12b-六氢-[9H]-11-(2-甲基丙基)氧基羰基-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-1-甲氧基-7-甲基-10-氧基羰基-11-氧基羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-7-氨基羰基甲基-11-二异丙氨基羰基-1-甲氧基-10-甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12b-11-二异丙基氨基硫代羰基-1-甲氧基-7，10-二甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12b-7，10-二甲基-1-甲氧基-11-(2-甲基丙基)氧基羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-12-基]乙酸盐酸盐；[10R，4bS-(4bβ，9aβ)]-7-二异丙基氨基羰基-8，14-二甲基-4b，5，9，9a，10，11-六氢-9a-羟基-[6H]-10，4b-(亚氨基桥亚乙基)菲并-[3，2-b]吡咯；[10R，4bS-(4bβ，9aβ)]-8，14-二甲基4b，5，9，9a，10，11-六氢-9a-羟基-7-(2-甲基丙基)氧基羰基-10，4b-(亚氨基桥亚乙基)菲并-[3，2-b]吡咯盐酸盐；[10R，4bS-(4bβ，9aβ)]-14-烯丙基-7-二异丙基羰基-4b，5，9，9a，10，11-六氢-9a-羟基-10，4b-(亚氨基)菲-[3，2-b]吡咯盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7-烯丙基-11-二异丙基氨基硫代羰基-1-乙氧基-10-甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-8a-醇盐酸盐；[[8R-(4bS*，8α，8aβ，12bβ)]-11-二异丙基氨基羰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-12-基]乙酸盐酸盐；[[8R-(4bS*，8α，8aβ，12bβ)]-11-(N-苄基N-异丙基)氨基羰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-12-基]乙酸盐酸盐；[(8R-(4bS*，8α，8aβ，12bβ)-7-烯丙基-11-(2-甲基丙基)氧基羰基-1-乙氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-8a-醇盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10，12-三甲基-1-甲氧基-11-甲氧基羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-11-二异丙基氨基羰基-7-乙酰氧基-10-甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[(8R-(4bS*，8α，8aβ，12bβ)]-11-二异丙基氨基羰基-4，8-二乙酰氧基-14-甲基-3-甲氧基-4b，5，9，9a，10，11-六氢-[6H]-[2，3-h]吡咯并-[10，11-b]亚氨基桥亚乙基菲；乙基-[[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-(2-甲基丙基)氧基羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-12-基]乙酸酯盐酸盐；N-苄基-[[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-(2-甲基丙基)氧基羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-12-基]乙酰胺盐酸盐；乙基-[[8R-(4bS*，8α，8aβ，12bβ)]-11-二异丙基氨基羰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-12-基]乙酸酯；乙基-[[8R-(4bS*，8α，8aβ，12bβ)-11-异丁基羰基-7，10，12-三甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；乙基-[[8R-(4bS*，8α，8aβ，12bβ)-11-二乙基膦酰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-11-[(2，2，2-三氟乙基)-异丙基氨基]羰基-7，10-二甲基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-10-甲基-1-甲氧基-11-(2-甲基丙基)氧基羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-羟基-11-(2-甲基丙基)氧基羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[[8R-(4bS*，8α，8aβ，12bβ)]-7-烯丙基-11-(2-甲基丙基)氧基羰基-8a-羟基-10-甲基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g](1-异喹啉基氧基)]乙酸；N-甲基-[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-(甲基丙基)氧基羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-12-基]乙酰胺盐酸盐；N，N-二甲基-[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-(甲基丙基)氧基羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉-12-基]乙酰胺盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-(吡咯烷-1-基)羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-(哌啶-1-基)羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-(吗啉-4-基)羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-(4-甲基-哌嗪-1-基)羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-(4-(2-羟乙基)-哌嗪-1-基)羰基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-11-[N-(4-乙氧基羰基)苯基甲基-N-异丙基]氨基羰基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-[N-(4-羧基)苯基甲基-N-异丙基]氨基羰基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-11-[N-(3-乙氧基羰基)苯基甲基-N-异丙基]氨基羰基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-7，10-二甲基-1-甲氧基-[N-(3-羧基)苯基甲基-N-异丙基]氨基羰基-1-甲氧基-5，6，7，8，12，12b-六氢-[9H]-4，8-亚甲基苯并呋喃[3，2-e]吡咯并[2，3-g]异喹啉盐酸盐；[8R-(4bS*，8α，8aβ，12bβ)]-11-甲氧基羰基-7，10-二甲基-1-甲氧基-5，6，7，8，9，12b-六氢-4，8-亚甲基苯并呋喃[3，2-e]噻吩并[2，3-g]异喹啉盐酸盐。
4.包括按照权利要求1-3中的任一项的化合物及药学上可接受的载体的药用组合物。
5.按照权利要求1-3中的任一项的化合物在生产用作麻醉剂、防止器官移植及皮肤移植排斥反应的免疫抑制剂、抗过敏及抗炎剂、脑细胞保护剂、治疗药物及酒精滥用、减少胃分泌、治疗腹泄、心血管及呼吸道疾病、咳漱和呼吸抑制、精神病及癫痫发作及其它神经紊乱的药物中的用途。
6.制备如权利要求1的式(I)化合物或其溶剂化物或盐的方法，包括：
当n＝0，X＝NH，Y是R7取代的碳原子时，使式(II)化合物与式(III)化合物反应
；或
当n＝0，X＝NH，Y是R6取代的碳原子时，使式(IV)化合物与式(V)化合物在氢氧化铵的存在下反应：
其中R1、R2、R3、R4、R5、R6、R7及R8如权利要求1所定义，其后任选将式(I)化合物转化为其溶剂化物或盐。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI96A000029 | 1996-01-10 | ||
| ITMI960029 IT1282950B1 (it) | 1996-01-10 | 1996-01-10 | Derivati eterociclo-condensati di morfinoidi |
| ITMI96A002291 | 1996-11-05 | ||
| IT96MI002291 IT1287130B1 (it) | 1996-11-05 | 1996-11-05 | Derivati eterociclo-condensati di morfinoidi |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1213372A CN1213372A (zh) | 1999-04-07 |
| CN1090190C true CN1090190C (zh) | 2002-09-04 |
Family
ID=26331345
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97192879A Expired - Fee Related CN1090190C (zh) | 1996-01-10 | 1997-01-08 | 杂环稠合的吗啡类衍生物,制备方法和用途 |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US6365594B1 (zh) |
| EP (1) | EP0880526B1 (zh) |
| JP (1) | JP2000503019A (zh) |
| KR (1) | KR19990077125A (zh) |
| CN (1) | CN1090190C (zh) |
| AR (1) | AR005423A1 (zh) |
| AT (1) | ATE229958T1 (zh) |
| AU (1) | AU706370B2 (zh) |
| BR (1) | BR9707136A (zh) |
| CA (1) | CA2242609A1 (zh) |
| CZ (1) | CZ218298A3 (zh) |
| DE (1) | DE69717967T2 (zh) |
| ES (1) | ES2188888T3 (zh) |
| HU (1) | HUP9900974A3 (zh) |
| IL (1) | IL125226A0 (zh) |
| NO (1) | NO983169L (zh) |
| NZ (1) | NZ326331A (zh) |
| PL (1) | PL327943A1 (zh) |
| TR (1) | TR199801348T2 (zh) |
| TW (1) | TW357148B (zh) |
| WO (1) | WO1997025331A1 (zh) |
Families Citing this family (37)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6103722A (en) * | 1997-07-23 | 2000-08-15 | The Medical College Of Wisconsin Research Foundation Inc. | Ischemic preconditioning |
| IT1312083B1 (it) | 1999-04-20 | 2002-04-04 | Smithkline Beecham Spa | Derivati morfinoidi, procedimento per la loro preparazione e loroimpiego terapeutico. |
| ATE267014T1 (de) * | 1999-08-13 | 2004-06-15 | Southern Res Inst | Pyridomorphinanen und ihre verwendung |
| CA2380814A1 (en) * | 1999-08-13 | 2001-02-22 | Southern Research Institute | Pyridomorphinans, thienomorphinans and use thereof |
| US6284769B1 (en) * | 1999-12-03 | 2001-09-04 | The Board Of Trustees Of The University Of Illinois | Nonpeptide kappa opioid receptor antagonists |
| GB0025056D0 (en) * | 2000-10-12 | 2000-11-29 | Smithkline Beecham Spa | Novel compounds |
| GB0025057D0 (en) * | 2000-10-12 | 2000-11-29 | Smithkline Beecham Spa | Novel compounds |
| WO2002036573A2 (en) * | 2000-10-31 | 2002-05-10 | Rensselaer Polytechnic Institute | 8- substituted-2, 6-methano-3-benzazocines and 3-substituted morphinanes as opioid receptor binding agents |
| EP1660088A4 (en) * | 2003-08-27 | 2009-04-29 | Southern Res Inst | PYRIDOMORPHINANES, PYRIDAZINOMORPHINANES AND USE THEREOF |
| MX2007005389A (es) | 2004-11-05 | 2007-12-07 | Rensselaer Polytech Inst | 4-hidroxibenzomorfanos. |
| CN1298720C (zh) * | 2005-03-18 | 2007-02-07 | 中国科学院上海有机化学研究所 | C环连接有五元杂环的青藤碱衍生物和合成方法 |
| WO2006126529A1 (ja) | 2005-05-25 | 2006-11-30 | Shionogi & Co., Ltd. | ６，７－不飽和－７－カルバモイル置換モルヒナン誘導体 |
| CN101210016B (zh) * | 2006-12-29 | 2011-07-20 | 中国科学院上海药物研究所 | 一类杂环并吗啡喃类化合物、制备方法及用途 |
| MX2009012281A (es) * | 2007-05-16 | 2009-12-01 | Rensselaer Polytech Inst | Opioides heterociclicos de anillo fusionado. |
| AU2008286979B2 (en) * | 2007-08-09 | 2013-03-28 | Rensselaer Polytechnic Institute | Quaternary opioid carboxamides |
| WO2010107457A1 (en) * | 2009-03-19 | 2010-09-23 | Alkermes, Inc. | Morphinan derivatives with high oral bioavailability |
| US8623888B2 (en) * | 2009-07-15 | 2014-01-07 | Mallinckrodt Llc | 3-oxy-hydromorphone derivatives |
| AU2010326676B2 (en) | 2009-12-04 | 2013-03-14 | Alkermes Pharma Ireland Limited | Morphinan derivatives for the treatment of drug overdose |
| JP5964809B2 (ja) | 2010-03-22 | 2016-08-03 | レンセラール ポリテクニック インスティチュート | オピオイド受容体リガンドとしてのカルボキサミド基を含有するモルヒネ誘導体 |
| FI3446565T3 (fi) | 2010-08-23 | 2024-01-30 | Alkermes Pharma Ireland Ltd | Menetelmiä antipsykoottisten lääkkeiden aiheuttaman painonnousun hoitamiseksi |
| US9029543B2 (en) | 2011-04-05 | 2015-05-12 | Alkermes, Inc. | Process for the synthesis of quaternary amine compounds |
| JP5981992B2 (ja) | 2011-06-29 | 2016-08-31 | アルカーメス，インコーポレイテッド | 末梢作用オピオイド化合物 |
| US9211293B2 (en) | 2011-12-15 | 2015-12-15 | Alkermes Pharma Ireland Limited | Opioid agonist antagonist combinations |
| EP2790702B1 (en) | 2011-12-15 | 2020-04-01 | Alkermes Pharma Ireland Limited | Compositions of buprenorphine and mu-opioid receptor antagonists |
| EP2844661B1 (en) * | 2012-05-02 | 2019-01-09 | Southern Research Institute | Heterocycle-fused morphinans, use thereof and preparation thereof |
| ES2621305T3 (es) | 2012-12-14 | 2017-07-03 | Purdue Pharma Lp | Morfinanos espirocíclicos y su uso |
| ES2631197T3 (es) * | 2012-12-14 | 2017-08-29 | Purdue Pharma Lp | Análogos de piridonamorfinano y actividad biológica sobre los receptores opiodes |
| JP6159417B2 (ja) | 2012-12-28 | 2017-07-05 | パーデュー、ファーマ、リミテッド、パートナーシップ | 置換モルフィナンおよびその使用 |
| JP6173431B2 (ja) * | 2013-03-08 | 2017-08-02 | 学校法人北里研究所 | モルヒナン誘導体 |
| US9656961B2 (en) | 2013-05-24 | 2017-05-23 | Alkermes Pharma Ireland Limited | Methods for treating depressive symptoms |
| EP3004114B1 (en) | 2013-05-24 | 2019-12-25 | Alkermes Pharma Ireland Limited | Morphan and morphinan analogues, and methods of use |
| US9340542B2 (en) | 2013-12-26 | 2016-05-17 | Purdue Pharma L.P. | Propellane-based compounds and the use thereof |
| EP3089978B1 (en) * | 2013-12-30 | 2018-08-29 | Purdue Pharma L.P. | Pyridone-sulfone morphinan analogs as opioid receptor ligands |
| WO2015183780A1 (en) * | 2014-05-27 | 2015-12-03 | Purdue Pharma L.P. | Spirocyclic morphinans and use thereof |
| MA40170A (fr) | 2014-06-13 | 2017-04-19 | Purdue Pharma Lp | Dérivés hétérocycliques de morphinan et leur utilisation |
| CN112047951A (zh) * | 2020-10-16 | 2020-12-08 | 吉林大学 | 手性螺[吡咯-2，2’-呋喃]化合物及其制备方法 |
| EP4243768A1 (en) | 2020-11-12 | 2023-09-20 | Alkermes Pharma Ireland Limited | Immediate release multilayer tablet |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225417A (en) * | 1992-01-21 | 1993-07-06 | G. D. Searle & Co. | Opioid agonist compounds |
| EP0614898A1 (en) * | 1992-09-29 | 1994-09-14 | Toray Industries, Inc. | Indole derivative, process for producing the same, and medicinal use thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU196376B (en) * | 1985-05-23 | 1988-11-28 | Sandoz Ag | Process for preparing morphinane derivatives and pharmaceutical compositions containing such compounds |
| US4816586A (en) | 1987-07-29 | 1989-03-28 | Regents Of The University Of Minnesota | Delta opioid receptor antagonists |
| JP2906654B2 (ja) | 1989-11-28 | 1999-06-21 | 東レ株式会社 | 免疫抑制剤及びその製造方法 |
| US5223507A (en) | 1992-01-21 | 1993-06-29 | G. D. Searle & Co. | Method of using opioid compounds as delta opioid selective agonist analgesics |
| IT1270612B (it) * | 1994-07-14 | 1997-05-07 | Smithkline Beecham Farma | Derivati eterociclo-condensatori di morfinoidi |
-
1997
- 1997-01-08 DE DE69717967T patent/DE69717967T2/de not_active Expired - Fee Related
- 1997-01-08 AR ARP970100077A patent/AR005423A1/es unknown
- 1997-01-08 TR TR1998/01348T patent/TR199801348T2/xx unknown
- 1997-01-08 AT AT97901009T patent/ATE229958T1/de not_active IP Right Cessation
- 1997-01-08 KR KR1019980705261A patent/KR19990077125A/ko not_active Application Discontinuation
- 1997-01-08 WO PCT/EP1997/000120 patent/WO1997025331A1/en not_active Application Discontinuation
- 1997-01-08 JP JP9524871A patent/JP2000503019A/ja not_active Withdrawn
- 1997-01-08 EP EP97901009A patent/EP0880526B1/en not_active Expired - Lifetime
- 1997-01-08 BR BR9707136-6A patent/BR9707136A/pt not_active IP Right Cessation
- 1997-01-08 PL PL97327943A patent/PL327943A1/xx unknown
- 1997-01-08 US US09/101,213 patent/US6365594B1/en not_active Expired - Fee Related
- 1997-01-08 ES ES97901009T patent/ES2188888T3/es not_active Expired - Lifetime
- 1997-01-08 CN CN97192879A patent/CN1090190C/zh not_active Expired - Fee Related
- 1997-01-08 CA CA002242609A patent/CA2242609A1/en not_active Abandoned
- 1997-01-08 HU HU9900974A patent/HUP9900974A3/hu unknown
- 1997-01-08 AU AU14410/97A patent/AU706370B2/en not_active Ceased
- 1997-01-08 CZ CZ982182A patent/CZ218298A3/cs unknown
- 1997-01-08 NZ NZ326331A patent/NZ326331A/xx unknown
- 1997-01-08 IL IL12522697A patent/IL125226A0/xx unknown
- 1997-01-10 TW TW086100197A patent/TW357148B/zh active
-
1998
- 1998-07-09 NO NO983169A patent/NO983169L/no not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225417A (en) * | 1992-01-21 | 1993-07-06 | G. D. Searle & Co. | Opioid agonist compounds |
| EP0614898A1 (en) * | 1992-09-29 | 1994-09-14 | Toray Industries, Inc. | Indole derivative, process for producing the same, and medicinal use thereof |
Non-Patent Citations (1)
| Title |
|---|
| HETEROCYCLES工VOL.39,NO.1 1994. 1. 1 PETER SCHWARZ * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR19990077125A (ko) | 1999-10-25 |
| NZ326331A (en) | 2000-01-28 |
| JP2000503019A (ja) | 2000-03-14 |
| HUP9900974A3 (en) | 2000-09-28 |
| CA2242609A1 (en) | 1997-07-17 |
| CZ218298A3 (cs) | 1999-08-11 |
| PL327943A1 (en) | 1999-01-04 |
| AR005423A1 (es) | 1999-06-23 |
| IL125226A0 (en) | 1999-03-12 |
| AU1441097A (en) | 1997-08-01 |
| DE69717967D1 (de) | 2003-01-30 |
| EP0880526A1 (en) | 1998-12-02 |
| DE69717967T2 (de) | 2003-08-28 |
| TW357148B (en) | 1999-05-01 |
| US6365594B1 (en) | 2002-04-02 |
| ATE229958T1 (de) | 2003-01-15 |
| CN1213372A (zh) | 1999-04-07 |
| TR199801348T2 (xx) | 1998-10-21 |
| ES2188888T3 (es) | 2003-07-01 |
| BR9707136A (pt) | 1999-08-31 |
| EP0880526B1 (en) | 2002-12-18 |
| WO1997025331A1 (en) | 1997-07-17 |
| AU706370B2 (en) | 1999-06-17 |
| NO983169L (no) | 1998-09-09 |
| HUP9900974A2 (hu) | 1999-08-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1090190C (zh) | 杂环稠合的吗啡类衍生物,制备方法和用途 | |
| EP0356128B1 (en) | 3-(aminopropyl)methyl phosphinic acid as a therapeutic agent | |
| JPH06500124A (ja) | セロトニン作動性５―ｈｔ３拮抗薬として新規イミダゾピリジン | |
| EP2128154A1 (en) | Benzimidazole compound and pharmaceutical use thereof | |
| JPH03163083A (ja) | 抗咳剤としてのエンドエテノ／エンドエタノ―エポキシモルヒナン誘導体の（＋）―アイソマー | |
| JPH09505052A (ja) | 免疫調節障害の治療 | |
| WO1995001178A1 (fr) | Antitussif | |
| JP2000501080A (ja) | アセチルコリン受容体の修飾因子として役立つ新規置換アリール化合物 | |
| JPH09505030A (ja) | ヒドロイソキノリン誘導体 | |
| CN1051086C (zh) | 杂环稠合的类吗啡衍生物及其应用 | |
| JPS62240665A (ja) | 新規化合物、その製造方法及びそれを含む医薬組成物 | |
| WO1997010216A1 (en) | Substituted hydroisoquinoline derivatives and their use as pharmaceuticals | |
| GB2120662A (en) | New azepinoindoles, their production and pharmaceutical compositions containing them | |
| CN1087339A (zh) | 哌啶衍生物及其制备和在医疗中的应用 | |
| US6054474A (en) | Heterocyclic compounds for the treatment of pain and use thereof | |
| BRPI0608560A2 (pt) | sais da ocaperidona e composições farmacêuticas contendo os mesmos | |
| MXPA98000281A (en) | New heterociclic compounds for the treatment of pains and use of mis | |
| CA2206519A1 (en) | Dibenz¬cd,f|indole derivatives | |
| ITMI962291A1 (it) | Derivati eterociclo-condensati di morfinoidi | |
| HU210353A9 (hu) | Új triciklusos vegyületek és ezeket tartalmazó gyógyszerkészítmények Az átmeneti oltalom a(z) 1-43. és 48. igénypontokra vonatkozik. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |