CN1568188A - 伤害感受肽类似物 - Google Patents
伤害感受肽类似物 Download PDFInfo
- Publication number
- CN1568188A CN1568188A CNA028121686A CN02812168A CN1568188A CN 1568188 A CN1568188 A CN 1568188A CN A028121686 A CNA028121686 A CN A028121686A CN 02812168 A CN02812168 A CN 02812168A CN 1568188 A CN1568188 A CN 1568188A
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- Prior art keywords
- alkyl
- group
- piperidyl
- cycloalkyl
- chemical compound
- 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.)
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- PULGYDLMFSFVBL-SMFNREODSA-N nociceptin Chemical class C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 PULGYDLMFSFVBL-SMFNREODSA-N 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 146
- 229910052721 tungsten Inorganic materials 0.000 claims abstract description 4
- -1 amino- Chemical class 0.000 claims description 187
- 229910052736 halogen Inorganic materials 0.000 claims description 83
- 150000002367 halogens Chemical class 0.000 claims description 83
- 239000000203 mixture Substances 0.000 claims description 65
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 56
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 48
- 125000001424 substituent group Chemical group 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 38
- 150000002431 hydrogen Chemical class 0.000 claims description 37
- 229910052799 carbon Inorganic materials 0.000 claims description 34
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- 125000004043 oxo group Chemical group O=* 0.000 claims description 18
- 208000002193 Pain Diseases 0.000 claims description 17
- 125000002950 monocyclic group Chemical group 0.000 claims description 17
- 125000002619 bicyclic group Chemical group 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
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- 150000001721 carbon Chemical group 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 239000004305 biphenyl Substances 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
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- 241000790917 Dioxys <bee> Species 0.000 claims description 6
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 6
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 5
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 5
- NHNUFAASKXPOQA-UHFFFAOYSA-N (3-acetamido-2-hydroxyphenyl)arsonic acid Chemical compound C(C)(=O)NC=1C(=C(C=CC1)[As](O)(=O)O)O NHNUFAASKXPOQA-UHFFFAOYSA-N 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 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 description 4
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 3
- XYVMOLOUBJBNBF-UHFFFAOYSA-N 3h-1,3-oxazol-2-one Chemical compound OC1=NC=CO1 XYVMOLOUBJBNBF-UHFFFAOYSA-N 0.000 claims description 3
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 3
- 150000003233 pyrroles Chemical class 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
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- 150000003457 sulfones Chemical group 0.000 claims 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 57
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 54
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- 239000003112 inhibitor Substances 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
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- SPDZFJLQFWSJGA-UHFFFAOYSA-N uredepa Chemical compound C1CN1P(=O)(NC(=O)OCC)N1CC1 SPDZFJLQFWSJGA-UHFFFAOYSA-N 0.000 description 1
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- 229940005605 valeric acid Drugs 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- OMOMUFTZPTXCHP-UHFFFAOYSA-N valpromide Chemical compound CCCC(C(N)=O)CCC OMOMUFTZPTXCHP-UHFFFAOYSA-N 0.000 description 1
- 229960001930 valpromide Drugs 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- XLQGICHHYYWYIU-UHFFFAOYSA-N veramine Natural products O1C2CC3C4CC=C5CC(O)CCC5(C)C4CC=C3C2(C)C(C)C21CCC(C)CN2 XLQGICHHYYWYIU-UHFFFAOYSA-N 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 description 1
- 229960005318 vigabatrin Drugs 0.000 description 1
- 229960001255 viloxazine Drugs 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
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- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- KLFUUCHXSFIPMH-YBFGSCICSA-N vinepidine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@H](C2)CC)N2CCC2=C1NC1=CC=CC=C21 KLFUUCHXSFIPMH-YBFGSCICSA-N 0.000 description 1
- 229950001270 vinepidine Drugs 0.000 description 1
- YNSIUGHLISOIRQ-SWSODSCOSA-N vinglycinate Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 YNSIUGHLISOIRQ-SWSODSCOSA-N 0.000 description 1
- 229950008883 vinglycinate Drugs 0.000 description 1
- 229950009832 vinleurosine Drugs 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
- 229950003670 vinrosidine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229950005839 vinzolidine Drugs 0.000 description 1
- 229950001124 xibenolol Drugs 0.000 description 1
- RKUQLAPSGZJLGP-UHFFFAOYSA-N xibenolol Chemical compound CC1=CC=CC(OCC(O)CNC(C)(C)C)=C1C RKUQLAPSGZJLGP-UHFFFAOYSA-N 0.000 description 1
- 229950005561 zanoterone Drugs 0.000 description 1
- 229950007802 zidometacin Drugs 0.000 description 1
- 229960002791 zimeldine Drugs 0.000 description 1
- OYPPVKRFBIWMSX-SXGWCWSVSA-N zimeldine Chemical compound C=1C=CN=CC=1C(=C/CN(C)C)\C1=CC=C(Br)C=C1 OYPPVKRFBIWMSX-SXGWCWSVSA-N 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- FYQZGCBXYVWXSP-STTFAQHVSA-N zinostatin stimalamer Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1OC1C/2=C/C#C[C@H]3O[C@@]3([C@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(C)C=CC2=C(C)C=C(OC)C=C12 FYQZGCBXYVWXSP-STTFAQHVSA-N 0.000 description 1
- 229950009233 zinostatin stimalamer Drugs 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
通式(I)或(II)的化合物,其中,Z,A,B,C,R1,R2,Q,W和n如这里所描述。
Description
本申请要求提交于2001年4月18日的美国临时申请第60/284,666;60/284,667;60/284,668;60/284,669号的优先权,在此将这些公开并入以供参考。
发明背景
慢性疼痛是造成残疾的主要原因并会造成无法言语的痛苦。成功治疗急性和慢性疼痛是医生的主要目的,阿片样物质镇痛药是优选的药物。
直到最近,才证明在中枢神经系统(CNS)中有三大类阿片样物质受体,且每类都有亚型受体。这些受体类型被称为μ,δ和κ。尽管在体内不是内源的,但鸦片剂对这些受体有非常高的亲和力,随后的研究是为了鉴定并分离这些受体的内源配体。这些配体被称为脑啡肽,内啡肽和强啡肽。
最近的实验已经鉴定了编码与已知受体类型具有高度同源性的阿片样物质受体样(ORL1)受体的cDNA。仅仅根据结构将这种新发现的受体归为阿片样物质受体,但这种受体没有显示药理学同源性。最初证明,对μ,δ和κ受体有高亲和性的非同源性受体对ORL1有低亲和性。由这一特征,以及事实表明还未发现内源配体,导致提出了“孤独受体”这一术语。
随后的研究得以分离ORL1受体的内源配体并确定其结构。这种配体是一种与阿片样物质肽家族成员类结构似的有17个氨基酸的肽。
ORL1受体的发现为新型化合物的发现提供了机会,这种化合物可用于控制疼痛或受这种受体调节的综合病症。
这里提到的所有文件,包括国外的,都全文并入以供参考。
本发明的目的和概述
根据本发明的某些实施方案,其一个目的是提供对ORL1受体具有亲和力的新型化合物。
本发明某些实施方案的目的是提供对ORL1受体和μ,δ或κ受体中的一种或多种具有亲和力的新型化合物。
本发明某些实施方案的目的是提供通过施用对ORL1受体具有亲和力的化合物来治疗慢性或急性疼痛的化合物。
本发明某些实施方案的目的是提供新型化合物,它对μ,δ和κ受体的激动活性远大于现有的化合物,如吗啡。
本发明某些实施方案的目的是提供通过施用对μ,δ和κ受体的激动活性大于现有的化合物的化合物来治疗慢性和急性疼痛的方法。
本发明某些实施方案的目的是提供通过施用非-阿片样物质化合物来治疗慢性和急性疼痛的方法,这种化合物对μ,δ和κ受体具有激动活性且产生的副作用小于现有现有化合物。
本发明某些实施方案的目的是提供化合物,所述化合物可有效用作镇痛药、消炎药、利尿药、麻醉药和神经保护剂、抗高血压药、抗焦虑药;食欲控制剂;听力调节剂;止咳药、抗哮喘药、运动活力调节剂、学习和记忆力调节剂、神经递质和激素释放控制剂、肾功能调节剂、抗抑郁药、治疗由于阿尔茨海默病或其它痴呆病症造成的记忆力损失的药剂、抗癫痫药、抗惊厥药、治疗乙醇或成瘾药物断瘾的药剂、控制水平衡(water balance)的药剂、控制钠排泄的药剂和控制动脉血压力紊乱的药剂,以及施用所述化合物的方法。
本发明的化合物可在中枢和/或外周有效调节一种或多种阿片样物质受体(ORL-1,μ,δ和κ)的药效学响应。这种响应是化合物刺激(激动药)或抑制(拮抗剂)一种或多种受体的结果。某些化合物可刺激一种受体(如,μ激动药)并抑制不同的受体(如,ORL-1拮抗药)。
通过以下详细描述可显见本发明的其它目的和优点。本发明在某些实施方案中包括具有通式(I)的化合物:
其中,W是氢,C1-10烷基,C3-12环烷基,C3-12环烷基C1-4烷基-,C1-10烷氧基,C3-12环烷氧基-,被1-3个卤素取代的C1-10烷基,被1-3个卤素取代的C3-12环烷基,被1-3个卤素取代的C3-12环烷基C1-4烷基-,被1-3个卤素取代的C1-10烷氧基,被1-3个卤素取代的C3-12环烷氧基-,-COOV1,-C1-4COOV1,-CH2OH,-SO2N(V1)2,羟基C1-10烷基-,羟基C3-10环烷基-,氰基C1-10烷基-,氰基C3-10环烷基-,-CON(V1)2,NH2SO2C1-4烷基-,NH2SOC1-4烷基-,磺酰氨基C1-10烷基-,二氨基烷基-,-磺酰基G1-4烷基,六元杂环,六元杂芳环,六元杂环C1-4烷基-,六元杂芳C1-4烷基-,六元芳环,六元芳香C1-4烷基-,任选被氧代或硫代取代的五元杂环,五元杂芳环,任选被氧代或硫代取代的五元杂环C1-4烷基-,五元杂芳C1-4烷基-,-C1-5(=O)W1,-C1- 5(=NH)W1,-C1-5NHC(=O)W1,-C1-5NHS(=O)2W1,-C1-5NHS(=O)W1,其中,W1是氢,C1-10烷基,C3-12环烷基,C1-10烷氧基,C3-12环烷氧基,-CH2OH,氨基,C1-4烷基氨基-,二C1-4烷基氨基-任选被1-3个低级烷基取代的五元杂芳环;
其中,每个V1独立选自H,C1-6烷基,C3-6环烷基,苄基和苯基;
Q是5-8元环烷基,5-8元杂环或6元芳基或杂芳基;
各个n分别是0-3的整数;
A,B和C分别是氢,C1-10烷基,C3-12环烷基,C1-10烷氧基,C3-12环烷氧基,-CH2OH,-NHSO2,羟基C1-10烷基-,氨基羰基-,C1-4烷基氨基羰基-,二C1-4烷基氨基羰基-,酰氨基-,酰氨基烷基-,酰胺,磺酰氨基C1-10烷基-或A-B可以一起形成C2-6桥或B-C可以一起形成C3-7桥或A-C可以一起形成C1-5桥;
Z选自键、直链或支链C1-6烯烃基,-NH-,-CH2O-,-CH2NH-,-CH2N(CH3)-,-NHCH2-,-CH2CONH-,-NHCH2CO-,-CH2CO-,-COCH2-,-CH2COCH2-,-CH(CH3)-,-CH=,-O-和-HC=CH-,其中碳和/或氮原子未被取代或被一个或多个低级烷基,羟基,卤素或烷氧基取代;
R1选自氢,C1-10烷基,C3-12环烷基,C2-10链烯基,氨基,C1-10烷基氨基-,C3-12环烷基氨基-,-COOV1,-C1-4COOV1,氰基,氰基C1-10烷基-,氰基C3-10环烷基-,NH2SO2-,NH2SO2C1-4烷基-,NH2SOC1-4烷基-,氨基羰基-,C1-4烷基氨基羰基-,二C1-4烷基氨基羰基-,苄基,C3-12环烯基-,单环、二环或三环芳基或杂芳环,杂-单环,杂-二环系统和式(III)的螺环系:
其中,X1和X2分别选自NH,O,S和CH2;且其中所述R1的烷基,环烷基,链烯基,C1-10烷基氨基-,C3-12环烷基氨基-或苄基任选地被1-3个选自卤素,羟基,G1-10烷基,C1-10烷氧基,硝基,三氟甲基-,氰基,-COOV1,-C1-4COOV1,氰基C1-10烷基-,-C1-5(=O)W1,-C1-5NHS(=O)2W1,-C1-5NHS(=O)W1,五元杂芳C0-4烷基-,苯基,苄基,苄氧基的取代基取代,所述苯基,苄基和苄氧基任选被1-3个选自卤素,C1-10烷基-,C1-10烷氧基-和氰基的取代基取代;且其中所述C3-12环烷基,C3-12环烯基,单环、二环或三环芳基,杂芳环,杂-单环,杂-二环系统或式(III)的螺环系任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基,硝基,三氟甲基-,苯基,苄基,苯氧基和苄氧基的取代基取代,其中所述苯基,苄基,苯氧基或苄氧基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基和氰基的取代基取代;
R2选自氢,C1-10烷基,C3-12环烷基-和卤素,所述烷基或环烷基任选被氧代,氨基,烷基氨基或二烷基氨基取代;
以及其药学上可接受的盐或其溶剂合物。
本发明在一些实施方案中包含具有通式(IA)的化合物:
其中,
各个n分别是0-3的整数;
Z选自键,-CH2-,-NH-,-CH2O-,-CH2CH2-,-CH2NH-,-CH2N(CH3)-,-NHCH2-,-CH2CONH-,-NHCH2CO-,-CH2CO-,-COCH2-,-CH2COCH2-,-CH(CH3)-,-CH=和-HC=CH-,其中碳和/或氮原子未被取代或被低级烷基,卤素,羟基或烷氧基取代;
R1选自氢,C1-10烷基,C3-12环烷基,C2-10链烯基,氨基,C1-10烷基氨基-,C3-12环烷基氨基-,苄基,C3-12环烯基-,单环、二环或三环芳基或杂芳环,杂-单环,杂-二环系统和式(III)的螺环系:
其中,X1和X2分别选自NH,O,S和CH2;
其中所述单环芳基优选为苯基;
其中所述双环芳基优选为萘基;
其中所述烷基,环烷基,链烯基,C1-10烷基氨基,C3-12环烷基氨基或苄基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基,硝基,三氟甲基,氰基,苯基,苄基,苄氧基的取代基取代,所述苯基,苄基和苄氧基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基和氰基的取代基取代;
其中所述C3-12环烷基,C3-12环烯基,单环、二环或三环芳基,杂芳环,杂-单环,杂-二环系统和式(II)的螺环系任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基,硝基,三氟甲基,苯基,苄基,苯氧基和苄氧基的基团取代,其中所述苯基,苄基,苯氧基和苄氧基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基和氰基的基团取代;
R2选自氢,C1-10烷基,C3-12环烷基和卤素,所述烷基任选被氧代基团取代;
以及其药学上可接受的盐和其溶剂合物。
本发明在一些实施方案中包含具有通式(II)的化合物:
其中,W是氢,C1-10烷基,C3-12环烷基,C3-12环烷基C1-4烷基-,C1-10烷氧基,C3-12环烷氧基-,被1-3个卤素取代的C1-10烷基,被1-3个卤素取代的C3-12环烷基,被1-3个卤素取代的C3-12环烷基C1-4烷基-,被1-3个卤素取代的C1-10烷氧基,被1-3个卤素取代的C3-12环烷氧基-,-COOV1,-C1-4COOV1,-CH2OH,-SO2N(V1)2,羟基C1-10烷基-,羟基C3-10环烷基-,氰基C1-10烷基-,氰基C3-10环烷基-,-CON(V1)2,NH2SO2C1-4烷基-,NH2SOC1-4烷基-,磺酰氨基C1-10烷基-,二氨基烷基-,-磺酰基C1-4烷基,六元杂环,六元杂芳环,六元杂环C1-4烷基-,六元杂芳C1-4烷基-,六元芳环,六元芳香C1-4烷基-,任选被氧代或硫代取代的五元杂环,五元杂芳环,任选被氧代或硫代取代的五元杂环C1-4烷基-,五元杂芳C1-4烷基-,-C1-5(=O)W1,-C1- 5(=NH)W1,-C1-5NHC(=O)W1,-C1-5NHS(=O)2W1,-C1-5NHS(=O)W1,其中,W1是氢,C1-10烷基,C3-12环烷基,C1-10烷氧基,C3-12环烷氧基,-CH2OH,氨基,C1-4烷基氨基-,二C1-4烷基氨基-任选被1-3个低级烷基取代的五元杂芳环;
其中,每个V1独立选自H,C1-6烷基,C3-6环烷基,苄基和苯基;
Q是5-8元环烷基,5-8元杂环或6元芳基或杂芳基;
各个n分别是0-3的整数;
A,B和C分别是氢,C1-10烷基,C3-12环烷基,C1-10烷氧基,C3-12环烷氧基,-CH2OH,-NHSO2,羟基C1-10烷基-,氨基羰基-,C1-4烷基氨基羰基-,二C1-4烷基氨基羰基-,酰氨基-,酰氨基烷基-,酰胺,磺酰氨基C1-10烷基-或A-B可以一起形成C2-6桥或B-C可以一起形成C3-7桥或A-C可以一起形成C1-5桥;
Z选自键、直链或支链C1-6烯烃基,-NH-,-CH2O-,-CH2NH-,-CH2N(CH3)-,-NHCH2-,-CH2CONH-,-NHCH2CO-,-CH2CO-,-COCH2-,-CH2COCH2-,-CH(CH3)-,-CH=,-O-和-HC=CH-,其中碳和/或氮原子未被取代或被一个或多个低级烷基,羟基,卤素或烷氧基取代;
R1选自氢,C1-10烷基,C3-12环烷基,C2-10链烯基,氨基,C1-10烷基氨基-,C3-12环烷基氨基-,-COOV1,-C1-4COOV1,氰基,氰基C1-10烷基-,氰基C3-10环烷基-,,NH2SO2-,NH2SO2C1-4烷基-,NH2SOC1-4烷基-,氨基羰基-,C1-4烷基氨基羰基-,二C1-4烷基氨基羰基-,苄基,C3-12环烯基-,单环、二环或三环芳基或杂芳环,杂-单环,杂-二环系统和式(III)的螺环系:
其中,X1和X2分别选自NH,O,S和CH2;且其中所述R1的烷基,环烷基,链烯基,C1-10烷基氨基-,C3-12环烷基氨基-或苄基任选地被1-3个选自卤素,羟基,C1-10烷基,C1-10烷氧基,硝基,三氟甲基-,氰基,-COOV1,-C1-4COOV1,氰基C1-10烷基-,-C1-5(=O)W1,-C1-5NHS(=O)2W1,-C1-5NHS(=O)W1,五元杂芳C0-4烷基-,苯基,苄基,苄氧基的取代基取代,所述苯基,苄基和苄氧基任选被1-3个选自卤素,C1-10烷基-,C1-10烷氧基-和氰基的取代基取代;且其中所述C3-12环烷基,C3-12环烯基,单环、二环或三环芳基,杂芳环,杂-单环,杂-二环系统或式(III)的螺环系任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基,硝基,三氟甲基-,苯基,苄基,苯氧基和苄氧基的取代基取代,其中所述苯基,苄基,苯氧基或苄氧基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基和氰基的取代基取代;
R2选自氢,C1-10烷基,C3-12环烷基-和卤素,所述烷基或环烷基任选被氧代,氨基,烷基氨基或二烷基氨基取代;
以及其药学上可接受的盐或其溶剂合物。
本发明在一些实施方案中包含具有通式(IIA)的化合物:
其中,
n是0-3的整数;
Z选自键,-CH2-,-NH-,-CH2O-,-CH2CH2-,-CH2NH-,-CH2N(CH3)-,-NHCH2-,-CH2CONH-,-NHCH2CO-,-CH2CO-,-COCH2-,-CH2COCH2-,-CH(CH3)-,-CH=和-HC=CH-,其中碳和/或氮原子未被取代或被低级烷基,卤素,羟基或烷氧基取代;
R1选自氢,C1-10烷基,C3-12环烷基,C2-10链烯基,氨基,C1-10烷基氨基-,C3-12环烷基氨基-,苄基,C3-12环烯基-,单环、二环或三环芳基或杂芳环,杂-单环,杂-二环系统和式(III)的螺环系:
其中,X1和X2分别选自NH,O,S和CH2;
其中所述单环芳基优选为苯基;
其中所述双环芳基优选为萘基;
其中所述烷基,环烷基,链烯基,C1-10烷基氨基,C3-12环烷基氨基或苄基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基,硝基,三氟甲基,氰基,苯基,苄基,苄氧基的取代基取代,所述苯基,苄基和苄氧基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基和氰基的取代基取代;
其中所述C3-12环烷基,C3-12环烯基,单环、二环或三环芳基,杂芳环,杂-单环,杂-二环系统和式(II)的螺环系任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基,硝基,三氟甲基,苯基,苄基,苯氧基和苄氧基的基团取代,其中所述苯基,苄基,苯氧基和苄氧基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基和氰基的基团取代;
R2选自氢,C1-10烷基,C3-12环烷基和卤素,所述烷基任选被氧代基团取代;
以及其药学上可接受的盐和其溶剂合物。
在某些优选的式(I)或式(II)的实施方案中,Q是苯基或含有1-3个氮原子的六元杂芳基。
在某些优选的式(I)、(II)、(IA)或(IIA)的实施方案中,R1烷基是甲基,乙基,丙基,丁基,戊基或己基。
在某些优选的式(I)、(II)、(IA)或(IIA)的实施方案中,R1环烷基是环己基,环庚基,环辛基,环壬基,环癸基或降冰片基。
在其它优选的式(I)、(II)、(IA)或(IIA)的实施方案中,R1二环系统是萘基。在其它优选的式(I)或式(IA)的实施方案中,R1二环系统是四氢萘基或十氢萘基,且R1三环系统是二苯并环庚基。在其它优选的实施方案中,R1是苯基或苄基。
在其它优选的式(I)、(II)、(IA)或(IIA)的实施方案中,R1二环芳环是10元环,优选喹啉或萘基。
在其它优选的式(I)、(II)、(IA)或(IIA)的实施方案中,R1二环芳环是9元环,优选茚基。
在某些式(I)、(II)、(IA)或(IIA)的实施方案中,Z是键,甲基或乙基。
在某些式(I)、(II)、(IA)或(IIA)的实施方案中,Z基团被最大限度地取代,即在Z基团上没有任何氢取代基。例如,如果Z基团是-CH2-,用两个甲基进行取代便可从Z基团上除去氢。
在其它优选的式(I)、(II)、(IA)或(IIA)的实施方案中,n是0。
在某些式(I)、(II)、(IA)或(IIA)的实施方案中,X1和X2都是氧。
在某些式(I)或(II)的实施方案中,W是-CH2C=ONH2,-C(NH)NH2,吡啶基甲基,环戊基,环己基,呋喃甲基,-C=OCH3,-CH2CH2NHC=OCH3,-SO2CH3,CH2CH2NHSO2CH3,呋喃羰基-,甲基吡咯羰基-,二唑羰基-,吡咯甲基-,三氟乙基-,羟基乙基-,氰基甲基-,氧代-噁唑甲基-或二唑甲基-。
在某些式(I)或(II)的实施方案中,ZR1是环己基乙基-,环己基甲基-,环戊基甲基-,二甲基环己基甲基-,苯乙基-,吡咯基三氟乙基-,噻吩基三氟乙基-,吡啶基乙基-,环戊基-,环己基-,甲氧基环己基-,四氢吡喃基-,丙基哌啶基-,吲哚基甲基-,吡唑基戊基-,噻唑基乙基-,苯基三氟乙基-,羟基己基-,甲氧基己基-,异丙氧基丁基-,己基-或氧杂环辛基丙基-。
在某些式(I)或(II)的实施方案中,至少ZR1或W其中之一是-CH2COOV1,四唑基甲基-,氰基甲基-,NH2SO2甲基-,NH2SO甲基-,氨基羰基甲基-,C1-4烷基氨基羰基甲基-或二C1-4烷基氨基羰基甲基-。
在某些式(I)或(II)的实施方案中,ZR1是3,3二苯基丙基,它任选在丙基的第3个碳上被-COOV1,四唑基C0-4烷基-,氰基-,氨基羰基-,C1-4烷基氨基羰基-或二C1-4烷基氨基羰基-取代。
在式(I),(II),(IA)或(IIA)的其它实施方案中,ZR1是
其中,
Y1是R3-(C1-C12)烷基,R4-芳基,R5-杂芳基,R6-(C3-C12)环-烷基,R7-(C3-C7)杂环烷基,-CO2(C1-C6)烷基,CN或-C(O)NR8R9;Y2是氢或Y1;Y3是氢或(C1-C6)烷基;或Y1,Y2和Y3,和它们所连接的碳原子一起形成以下结构:
其中,r是0-3;w和u分别为0-3,条件是w和u的和是1-3;c和d分别是1或2;s是1-5;和环E是稠合的R4-苯基或R5-杂芳环;
R10是独立选自H,(C1-C6)烷基,-OR8,-(C1-C6)烷基-OR8,-NR8R9和-(C1-C6)烷基-NR8R9的1-3个取代基;
R11是独立选自R10,-CF3,-OCF3,NO2和卤素的1-3个取代基,或者相邻环碳原子上的R11取代基可以一起形成亚甲基二氧基或次乙基二氧基环;
R8和R9分别选自氢,(C1-C6)烷基,(C3-C12)环烷基,芳基和芳基(C1-C6)烷基;
R3是独立选自H,R4-芳基,R6-(C3-C12)环烷基,R5-杂芳基,R7-(C3-C7)杂环烷基,-NR8R9,-OR12和-S(O)0-2R12的1-3个取代基;
R6是独立选自H,(C1-C6)烷基,R4-芳基,-NR8R9,-OR12和-SR12的1-3个取代基;
R4是1-3个取代基,所述取代基独立选自氢,卤素,(C1-C6)烷基,R13-芳基,(C3-C12)环烷基,-CN,-CF3,-OR8,-(C1-C6)烷基-OR8,-OCF3,-NR8R9,-(C1-C6)烷基-NR8R9,-NHSO2R8,-SO2N(R14)2,-SO2R8,-SOR8,-SR8,-NO2,-CONR8R9,-NR9COR8,-COR8,-COCF3,-OCOR8,-OCO2R8,-COOR8,-(C1-C6)烷基-NHCOOC(CH3)3,-(C1-C6)烷基-NHCOCF3,-(C1-C6)烷基-NHSO2-(C1-C6)烷基,-(C1-C6)烷基-NHCONH-(C1-C6)-烷基和
其中,f是0-6;或者相邻环碳原子上的R4取代基可以一起形成亚甲基二氧基或次乙基二氧基环;
R5是独立选自氢,卤素,(C1-C6)烷基,R13-芳基,(C3-C12)环烷基,-CN,-CF3,-OR8,-(C1-C6)烷基-OR8,-OCF3,-NR8R9,-(C1-C6)烷基-NR8R9,-NHSO2R8,-SO2N(R14)2,-NO2,-CONR8R9,-NR9COR8,-COR8,-OCOR8,-OCO2R8和-COOR8的1-3个取代基;
R7是H,(C1-C6)烷基,-OR8,-(C1-C6)烷基-OR8,-NR8R9或-(C1-C6)烷基-NR8R9;
R12是H,(C1-C6)烷基,R4-芳基,-(C1-C6)烷基-OR8,-(C1-C6)烷基-NR8R9,-(C1-C6)烷基-SR8,或芳基(C1-C6)烷基;
R13是独立选自H,(C1-C6)烷基,(C1-C6)烷氧基和卤素的1-3个取代基;
R14独立选自H,(C1-C6)烷基和R13-C6H4-CH2-。
当用在这里时,术语“烷基”表示具有单价根和1-10个碳原子的直链或支链的饱和脂肪族烃基。烷基的例子包括甲基,丙基,异丙基,丁基,正-丁基,异丁基,仲-丁基,叔-丁基和戊基。支链烷基是指一个或多个烷基,如甲基,乙基或丙基,取代线性烷基链中-CH2-基团上的一个或两个氢的烷基。术语“低级烷基”是指具有1-3个碳原子的烷基。
术语“烷氧基”是指与氧基团结合的如上定义的“烷基”。
术语“环烷基”表示具有单价根和3-12个碳原子的非芳香性单环或多环烃环系统。单环环烷基环的例子包括环丙基,环戊基和环己基。多环环烷基环的例子包括金刚烷基和降冰片基。
术语“链烯基”表示具有单价根和2-10个碳原子的含有碳碳双键的直链或支链脂肪族烃基。“支链”链烯基是指一个或多个烷基,如甲基,乙基或丙基,取代线性链烯基链中-CH2-或-CH=上的一个或两个氢的链烯基。链烯基包括乙烯基,1-和2-丙烯基,1-,2-和3-丁烯基,3-甲基丁-2-烯基,2-丙烯基,庚烯基,辛烯基和癸烯基。
术语“环烯基”表示非芳香性具有单价根和3-12个碳原子的含有碳碳双键的单环或多环烃环系统。单环环烯基环的例子包括环丙烯基,环戊烯基,环己烯基或环庚烯基。多环环烯基环的例子有降冰片烯基。
术语“芳基”表示含有1、2或3个环并含有单价根的碳环芳环系统,这些可以侧接或稠合的方式连接在一起。芳基的例子包括苯基,萘基和苊基。
术语“杂环”在环中有一个或多个杂原子(碳以外的原子)并含有单价根的环状化合物。环可以是饱和、部分饱和或不饱和的,且所述杂原子可选自氮,硫和氧。饱和的杂环基的例子包括饱和的含有1-4个氮原子的3-6元杂-单环基团,如吡咯烷基,咪唑烷基,哌啶子基,哌嗪基;饱和的含有1-2个氧原子和1-3个氮原子的3-6元杂-单环基团,如吗啉基;饱和的含有1-2个硫原子和1-3个氮原子的3-6元杂-单环基团,如噻唑烷基。部分饱和的杂环基的例子包括二氢噻吩,二氢吡喃和二氢呋喃。其它杂环基团可以是被杂原子取代的7-10元碳环,如氧杂环辛基和硫杂环辛基(thiocanyl)。当杂原子是硫是,硫可以是二氧化硫,如二氧化硫杂环辛基(thiocanyldioxide)。
术语“杂芳基”是指不饱和的杂环基,其中“杂环”如上所述。杂芳基的例子包括不饱和的含有1-4个氮原子的3-6元杂-单环基团,如吡咯基,吡啶基,嘧啶基和吡嗪基;不饱和的含有1-5个氮原子的稠合杂环基团,如吲哚基,喹啉基和异喹啉基;不饱和的含有一个氧原子的3-6元杂-单环基团,如呋喃基;不饱和的含有一个硫原子的3-6元杂-单环基团,如噻吩基;不饱和的含有1-2个氧原子和1-3个氮原子的3-6元杂-单环基团,如噁唑基;不饱和的含有1-2个氧原子和1-3的氮原子的稠合的杂环基团,如苯并噁唑基;不饱和的含有1-2个硫原子和1-3个氮原子的3-6元杂-单环基团,如噻唑基;以及不饱和的含有1-2个硫原子和1-3个氮原子的稠合的杂环基团,如苯并噻唑基。术语“杂芳基”还包括不饱和的杂环基,其中,“杂环”如上所述,其中,所述杂环基团与芳基稠合,其中的芳基如上所述。稠合的基的例子包括苯并呋喃,苯并间二氧杂环戊烯(benzdioxole)和苯并噻吩。
当用在这里时,术语“杂环C1-4烷基”,“杂芳C1-4烷基”等是指与C1-4烷基键合的环状结构。
这里所述的所有环状结构都可连接在任何可能的结合点,这些结合点是精通此领域的技术人员已知的。
当用在这里时,术语“患者”包括人或动物,如宠物或家畜。
当用在这里时,术语“卤素”包括氟、溴、氯、碘或砹(alabamide)。
这里揭示的本发明包括所述化合物所有的药学上可接受的盐。药学上可接受的盐包括但不限于金属盐如钠盐,钾盐,铯盐等;碱土金属盐如钙盐,镁盐等;有机胺盐如三乙胺盐,吡啶盐,甲基吡啶盐,乙醇胺盐,三乙醇胺盐,二环己胺盐,N,N’-二苄基二乙胺盐等;无机酸盐如氯化物,溴化物,硫酸盐,硫酸盐等;有机酸盐如甲酸盐,乙酸盐,三氟乙酸盐,马来酸盐,延胡索酸盐,酒石酸盐等;磺酸盐如甲烷磺酸盐,苯磺酸盐,对-甲苯磺酸盐等;氨基酸盐如精氨酸盐,天冬氨酸盐,甘氨酸盐等。
这里揭示的本发明还包括所述化合物的所有前药。前药是指可在体内释放活性亲本的任何共价结合的载体。
这里揭示的本发明还包括所述化合物的体内代谢产物。例如,这种产物可由所施用的化合物经过氧化、还原、水解、酰胺化、酯化等作用而来,主要是经过酶过程。因此,本发明包括通过使本发明的化合物与哺乳动物接触一段足以产生其代谢产物的时间而制得的化合物。这种产物通常通过以下方法加以鉴定:制备经放射性标记的本发明的化合物,在肠胃外将可测剂量的这种化合物施用于动物,如大鼠,小鼠,豚鼠,猴或人,经过充足的代谢时间后从尿液、血液或其它生物样品中分离其转化产物。
这里揭示的本发明还包括被同位素标记的所示化合物,标记是用有不同原子量或原子质量数的原子替代一个或多个原子。可掺入所示化合物的同位素的例子包括氢、碳、氮、氧、磷、氟和氯的同位素,例如分别是2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F和36Cl。这里所示的一些化合物可含有一个或多个不对称中心,因此有对映异构体、非对映异构体和其它立体异构体形式。本发明还包括其所有可能的形式以及它们的外消旋和拆分形式以及它们的混合物。当这里所述的化合物含有烯族双键或其它几何不对称中心时,除非另有说明,是指E和Z几何异构体。所有的互变异构体都包括在本发明内。
当用在这里时,术语″立体异构″通常是指各种分子所有的异构体,它们仅在原子的空间取向上不同。它包括对映异构体和有一个以上手性中心的化合物的异构体,它们相互不成镜像(非对映异构体)。
术语″手性中心″是指连有四个不同基团的碳原子。
术语″对映异构体″或″对映异构体的″是指与其镜像不重叠因而具有光学活性的分子,其中,所述对映异构体在一个方向上旋转偏振光平面,其镜像在相反方向上旋转偏振光平面。
术语″外消旋的″是指等量的对映异构体的混合物,它没有光学活性。
术语″拆分″是指将一个分子的两种对映异构形式之一分离或集中或除去。
术语“调节”在这里用于ORL-1受体是指在受试者中通过(1)抑制或活化该受体,或(2)直接或间接影响受体活性的正常调节来调节药效学响应(如镇痛)。可调节受体活性的化合物包括激动药,拮抗药,激动药/拮抗药的混合物以及直接或间接影响受体活性调节的化合物。
某些优选的式(I)和(IA)的化合物包括:
1-[1-(萘-2-基-甲基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(p-苯基苄基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(3,3-二(苯基)丙基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(p-苄氧基苄基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(4-丙基环己基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(5-甲基己-2-基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(4-(2-丙基)-环己基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(环辛基甲基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(1,2,3,4-四氢-2-萘基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(十氢-2-萘基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(1,3-二氢茚-2-基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(环辛基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(萘-2-基-甲基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(p-苄氧基苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(p-苯基苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(十氢-2-萘基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(4-(2-丙基)-环己基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(4-丙基环己基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(10,11-二氢-5H-二苯并[a,d]-环庚烯-5-基)-4-哌啶基]-2H-苯并噻二嗪-2,2-二酮;
1-[1-(1,2,3,4-四氢-2-萘基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(5-甲基己-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(降冰片-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(环辛基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(1,3-二氢茚-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(3,3-二(苯基)丙基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;和
其药学上可接受的盐及其溶剂合物。
其它优选的式(I)的化合物包括:
3-丁基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
3-乙酰氨基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
3-(2-甲烷磺酰氨基)-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
3-甲氧羰基甲基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
3-氰甲基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
3-(2-羟乙基)-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
3-丁氧羰基甲基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;和
其药学上可接受的盐以及其溶剂合物。
一些优选的本发明式(II)和(IIA)的化合物包括:
1,2,3,4-四氢-1-[1-(萘-2-基-甲基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(p-苯基苄基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-[4,4-二(4-氟苯基)丁基]-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(p-苄氧基苄基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(1,2,3,4-四氢-2-萘基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(4-丙基-环己基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(5-甲基己-2-基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(降冰片-2-基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(十氢-2-萘基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(10,11-二氢-5H-二苯并[a,d]-环庚烯-5-基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(3,3-二苯基丙基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(环辛基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-[4-(1-甲基乙基)-环己基]-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(1,3-二氢茚-2-基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(环辛基甲基)-4-哌啶基]-喹啉-2-酮;和
其药学上可接受的盐及其溶剂合物。
发明详述
本发明的化合物可以给需要调节阿片样物质和OPL1受体的任何人服用。服用方式可以口服或局部用药,通过栓剂、吸入或者肠道外用药。
本发明还包括上述化合物的所有药学上可接受的盐。本领域的技术人员认识,本发明所述化合物的酸加合盐可以通过各种已知的方法使所述化合物和合适的酸反应来制备。
可以使用各种口服剂型,包括固体形式如药片、软胶囊、胶囊、囊片、颗粒剂锭剂和散粉,以及液体形式如乳液、溶液和悬浮液。本发明的化合物可以单独服用或者和本领域的那些技术人员已知的各种药学上可接受的载体和赋形剂一起使用,包括但不限于稀释剂、悬浮剂、增溶剂、粘合剂、崩解剂、防腐剂、着色剂和润滑剂等。
当本发明的化合物掺入口服药片中时,这种药片可以被压缩、药片研磨、上肠溶衣、包糖衣、包薄膜、多次压缩或多次分层。液体口服剂型包括水性和非水性溶液、乳液、悬浮液和溶液和/或由非泡腾颗粒重新形成的含有合适溶剂、防腐剂、乳化剂、悬浮剂、稀释剂、甜味剂、着色剂和增香剂的悬浮液。当本发明的化合物通过肠道外注射时,它们可以呈例如等渗压的无菌溶液形式。或者,当本发明的化合物被吸入时,它们可以配制成干燥的气溶胶,或者配制成水溶液或部分为水溶液。
此外,当本发明的化合物掺入口服剂型中时,这种剂型可以立即将所述化合物释放到胃肠道中,或者通过胃肠道进行控释和/或缓释。本领域的那些技术人员熟知各种控释制剂和/或缓释制剂,并可以和本发明所述的制剂一起使用。所述控释和/或缓释可以通过例如口服剂型上的涂层或通过将本发明的化合物掺入控释基质和/或缓释基质中。
在《药物赋形剂手册》(Handbook of Pharmaceutical Excipients),美国药学学会(1986)中描述了可以用于配制口服剂型的药学上可接受的载体和赋形剂的具体例子。在《药物剂型:片剂》(Pharmaceutical Dosage Forms:Tablets)(Lieberman,Lachman and Schwartz编著)第2版Marcel Dekker,Inc.出版中描述了制备固体口服剂型的技术和组合物。在《Remington药物科学》(Remington’sPharmaceutical Sciences)(Arthur Osol编,),1553B1593(1980)中也描述了用于制备药片(压制和模制)、胶囊(硬和软凝胶)和药丸的技术和组合物。在《药物剂型:分散系统》(Pharmaceutical Dosage Forms:Disperse Systems),(Lieberman,Rieger and Banker,编著)Marcel Dekker,Inc.出版中描述了制备液体口服剂型的技术和组合物。
当本发明的化合物通过注射(例如,连续输注或推注)进行肠胃外给药时,用于肠胃外给药的制剂可是呈油状或水性载体中的悬浮液、溶液、乳液形式,这种制剂还可以包含药学上必需的添加剂,如稳定剂、悬浮剂、分散剂等。本发明的化合物可以成粉末状,用于重新形成可注射制剂。
在某些实施方式中,本发明的化合物可以和至少一种其它的治疗剂联合使用。治疗剂包括但不限于μ-阿片样物质激动剂;非-阿片样物质镇痛药;非类固醇消炎药;Cox-II抑制剂;止吐剂;β-肾上腺素能阻滞剂;抗惊厥药;抗抑郁药;Ca2+-通道阻断剂;抗癌剂以及它们的混合物。
在某些实施方式中,本发明的化合物可以和μ-阿片样物质激动剂混合配制成药物剂型。在本发明制剂中包含的μ-阿片样物质激动剂包括但不限于阿芬太尼,烯丙罗定,阿法罗定,阿尼利定,苄基吗啡,贝齐米特,丁丙诺啡,布托啡诺,氯尼他秦,可待因,地素吗啡,右吗拉胺,地佐辛,地恩丙胺,二乙酰吗啡,双氢可待因,双氢吗啡,地美沙朵,地美庚醇,二甲噻丁,吗苯丁酯,地匹哌酮,依地佐辛,依索庚嗪,乙甲噻丁,乙基吗啡,依托尼秦芬太奴,海洛因,氢可酮,氢吗啡酮,羟哌替啶,异美沙酮,凯托米酮,左啡诺,左芬啡烷,洛芬太尼,哌替啶,美普他酚,美他佐辛,美沙酮,麦托朋,吗啡,麦罗啡,纳布啡,那碎因,尼可吗啡,去甲左啡诺,去甲美沙酮,纳洛芬,去甲吗啡,诺匹哌酮,鸦片,羟考酮,羟吗啡酮,阿片全碱,戊唑辛,苯吗庚酮,非诺啡烷,苯唑星,苯哌利定,匹米诺定,哌腈米特,普罗庚嗪,普鲁米多,丙哌利定,丙吡兰,丙氧芬,舒芬太尼,替利定,曲马多,其药学上可接受的盐以及它们的混合物。
在某些优选的实施方式中,所述μ-阿片样物质激动剂选自可待因,氢吗啡酮,氢可酮,羟考酮,双氢可待因,双氢吗啡,吗啡,曲马多,羟吗啡酮,其药学上可接受的盐以及它们的混合物。
在本发明另一实施方式中,所述药剂包含用于治疗疼痛和/或炎症的Cox-II抑制剂和5-脂氧化酶抑制剂的混合物。在美国专利No.6,136,839中描述了合适的Cox-II抑制剂和5-脂氧化酶抑制剂以及它们的混合物,这里全部引入作为参考。抑制剂包括但不限于罗非昔布(Vioxx),塞来昔布(Celebrex),DUP-697,氟舒胺,美洛昔康,6-MNA,L-745337,萘丁美酮,尼美舒利,NS-398,SC-5766,T-614,L-768277,GR-253035,JTE-522,RS-57067-000,SC-58125,SC-078,PD-138387,NS-398,氟舒胺,D-1367,SC-5766,PD-164387,依托里昔布,伐地昔布和帕瑞昔布或其药学上可接受的盐,其对映异构体或互变异构体。
本发明的化合物也可以和非-阿片样物质镇痛药例如非类固醇消炎药一起混合成剂型,它包括阿斯匹林,布洛芬,双氯芬酸,萘普生,苯恶洛芬,氟比洛芬,非诺洛芬,氟布芬,酮洛芬,吲哚洛芬,吡罗洛芬,卡洛芬,奥沙普秦,普拉昔洛芬,莫罗洛芬,三噁洛芬,舒洛芬,氨基洛芬,噻洛芬酸,氟洛芬,布氯酸,茚甲新,舒林酸,托美丁,氯苯酰二甲基吡咯乙酸,二氢氧二苯并硫杂,齐多美辛,阿西美辛,芬替酸,环氯茚酸,oxpinac,甲灭酸,甲氯芬那酸,氟芬那酸,尼氟酸托芬那酸,二氟尼柳,氟苯柳,吡罗昔康,舒多昔康或伊索昔康,其药学上可接受的盐及其混合物。本发明剂型中包括的其它合适的非-阿片样物质镇痛药包括但不限于以下镇痛药、解热药和非类固醇消炎药类的化学物质:水杨酸衍生物,包括阿斯匹林,水杨酸钠,胆碱镁三水杨酸盐,双水杨酸,二氟尼柳,水杨基水杨酸,柳氮胺吡啶和奥沙拉嗪;对-氨基苯酚衍生物包括醋氨酚;吲哚和茚乙酸,包括茚甲新,舒林酸和依托度酸;杂芳基乙酸,包括托美丁,双氯芬酸和酮咯酸;邻-胺基苯甲酸(芬那酸),包括甲灭酸和甲氯芬那酸;烯醇酸,包括oxicams(吡罗昔康,替诺昔康)和吡唑烷二酮(二苯丁唑酮,oxyphenthartazone);和alkanones,包括萘丁美酮。本发明所用药物内包括的NSAID的详细描述可见Paul A.Insel“用于治疗痛风的镇痛药和消炎剂及药物”刊于Goodman & Gilman的《治疗学的药理基础》(The Pharmacological Basis of Therapeutics),617-57(Perry B.Molinhoffand Raymond W.Ruddon编,第9版,1996),和Glen R.Hanson“镇痛药、解热药和消炎药”刊于Remington:《药学的科学和实践》(The Science and Practiceof Pharmacy)第II卷,1196-1221(A.R.Gennaro编,第19版1995),这里全部引入作为参考。
在某些实施方式中,本发明的化合物可以和抗偏头痛药一起混合,配制成药物剂型。抗偏头痛药包括但不限于阿吡必利,双氢麦角胺,多拉司琼,麦角可宁碱,麦角异可宁碱,麦角隐亭,麦角,麦角胺,醋酸氟美烯酮,二甲替嗪,利舒脲,洛美利嗪,美西麦角奥昔托隆,苯噻啶以及它们的混合物。
也可以使用其它治疗剂如止吐药作为助剂来降低任何潜在的副作用。合适的止吐药包括但不限于用氧氯普胺,多潘立酮,普鲁氯嗪,异丙嗪,氯丙嗪,曲美苄胺,昂丹司琼,格拉司琼,羟嗪,乙酰亮氨酸单乙醇胺(acethylleucinemonoethanolamine),阿立必利,阿扎司琼,苯喹胺,氨醇醋茶碱,溴必利,布克力嗪,氯波必利,赛克利嗪,乘晕宁,地芬尼多,多拉司琼,美其敏,每沙拉妥,美托哌丙嗪,大麻隆,奥昔喷地,匹哌马嗪,东莨菪碱,舒必利,四氢大麻醇,硫乙拉嗪,硫丙拉嗪,托烷司琼以及它们的混合物。
在某些实施方式中,本发明的化合物可以和β-肾上腺素能阻滞剂混合,配制成药物剂型。合适的β-肾上腺素能阻滞剂包括但不限于醋丁洛尔,阿普洛尔,amosulabol,阿罗洛尔,阿替洛尔,苯呋洛尔,倍他洛尔,倍凡洛尔,比索洛尔,波吲洛尔,布库洛尔,布非洛尔,丁呋洛尔,布尼洛尔,布拉洛尔,盐酸布替君,丁非洛尔,卡拉洛尔,卡替洛尔,卡维地洛,赛利洛尔,塞他洛尔,氯拉洛尔,地来洛尔,依泮洛尔,艾司洛尔,茚诺洛尔,拉贝洛尔,左布诺洛尔,甲吲洛尔,美替洛尔,美托洛尔,莫普洛尔,纳多洛尔,萘肟洛尔,奈必洛尔,硝苯洛尔,尼普地洛,氧烯洛尔,喷布洛尔,心得乐,醋氨心安,普罗纳赛洛,心得安,心得怡,硫氧洛尔,他林洛尔,特他洛尔,替利洛尔,噻吗洛尔,托利洛尔和希苯洛尔。
在某些实施方式中,本发明的化合物可以和抗惊厥药混合,配制成药物剂型。合适的抗惊厥药包括但不限于乙酰苯丁酰脲,阿布妥因,阿洛双酮,氨鲁米特,4-氨基3-羟丁酸,苯乳胺,苄氯丙酰胺,布拉氨酯,溴化钙,氨甲酰氮草,桂溴胺,氯美噻唑,氯硝西泮,癸氧酰胺,地沙双酮,二甲双酮,去氧苯妥英,依特比妥,依沙双酮,乙琥胺,乙苯妥英,非尔氨酯,氟苯乙砜,加巴喷丁,5-羟基色氨酸,拉莫三嗪,溴化镁,硫酸镁,美芬妥英,甲苯比妥,美沙比妥,美替妥英,甲琥胺,5-甲基-5-(3-菲基)-乙内醯,3-甲基-5-苯基乙内酰脲,那可比妥,尼美西泮,硝基安定,奥卡西平,甲乙双酮,苯乙酰脲,苯二乙巴比妥,苯丁酰脲,苯巴比妥,苯琥胺,苯基甲基巴比妥酸,苯妥英,苯噻妥英钠,溴化钾,普瑞巴林,普里米酮,普鲁加比,溴化钠,茄属(solanum),溴化锶,琥氯非尼,硫噻嗪,替群妥英,噻加宾,托吡酯,三甲双酮,丙戊酸,丙戊酰胺,氨己烯酸和唑尼沙胺。
在某些实施方式中,本发明的化合物可以和抗抑郁药混合,配制成药物剂型。合适的抗抑郁药包括但不限于苯奈达林,卡罗沙酮,西酞普兰,二甲沙生,芬咖明,吲达品,盐酸茚洛嗪,奈福泮,诺米芬辛,羟色氨酸,奥昔哌汀,帕罗西汀,舍曲林,硫西新,曲唑酮,苯莫辛,异丙氯肼,异烟酰异丙肼,异恶唑肼,烟肼酰胺,奥她莫辛,苯乙肼,可替宁,罗利普令,咯利普兰,马普替林,美曲吲哚,米安色林,米氮平,阿地唑仑,阿密曲替林,氧阿米替林,阿莫沙平,布替林,氯米帕明,地美替林,地昔帕明,二苯西平,二甲他林,度硫平,多虑平,氟西嗪,丙咪嗪,丙咪嗪正-氧化物,伊普吲哚,洛菲帕明,美利曲辛,美他帕明,去甲替林,诺昔替林,奥匹哌醇,苯噻啶,丙吡西平,普罗替林,奎纽帕明,噻奈普汀,曲米帕明,阿屈非尼,苯乃静,安非他酮,布他西丁,地奥沙屈,度洛西汀,依托哌酮,非巴氨酯,非莫西汀,氯苯己基戊二醇,氟西汀,氟伏沙明,血卟啉,金丝桃素,苯基六氢吡啶甲醇乙酸酯,美地沙明,米那普仑,米那普令,吗氯贝胺,奈法唑酮,奥沙氟生,吡贝拉林,普罗林坦,吡啶琥醇,利坦色林,罗克吲哚,氯化铷,舒必利,坦度螺酮,托扎啉酮,托芬那辛,托洛沙酮,强内心百乐明,左旋色氨酸,文拉法辛,维洛沙秦和齐美定。
在某些实施方式中,本发明的化合物可以和Ca2+通道阻断剂混合,配制成药物剂型。合适的Ca2+通道阻断剂包括但不限于苄普地尔,clentiazem,地尔硫,芬地林,戈洛帕米,米贝拉地尔,甲基乙烯胺,司莫地尔,特罗地林,戊脉安,氨氯地平,阿雷地平,巴尼地平,贝尼地平,西尼地平,依福地平,依高地平,非洛地平,伊拉地平,拉西地平,乐卡地平,马尼地平,尼卡地平,硝苯地平,尼伐地平,尼莫地平,尼索地平,尼群地平,桂利嗪,氟桂利嗪,利多氟嗪,洛美利嗪,苄环烷,依他苯酮,泛托法隆和哌克昔林。
在某些实施方式中,本发明的化合物可以和抗癌药混合,配制成药物剂型。合适的抗癌药包括,但不限于阿西维辛;阿柔比星;盐酸阿考达唑;阿克罗宁;阿多来新;阿地白介素;六甲蜜胺;安波霉素;醋酸阿美蒽醌;氨鲁米特;安吖啶;阿那曲唑;安曲霉素;天冬酰胺酶;曲林霉素;阿扎胞苷;阿扎替派;含氮霉素;巴马司他;苯佐替派;比卡鲁胺;盐酸必桑郡(bisantrene hydrochloride);双奈法德二甲磺酸盐甲磺酸盐;比折来新;硫酸博来霉素;布喹那钠;溴匹立明;白消安;放线菌素C;卡普睾酮;卡醋胺;卡贝替姆;卡铂;亚硝脲氮芥;盐酸卡柔比星;卡折来新;西地芬戈;苯丁酸氮芥;西罗霉素;顺铂;克拉曲滨;克立那托甲磺酸盐(crisnatol mesylate);环磷酰胺;阿糖胞苷;达卡巴嗪;放线菌素D;盐酸柔红霉素;地西他滨;右奥马铂;地扎胍宁;地扎胍宁甲磺酸盐;地吖醌;多西他赛;阿霉素;盐酸阿霉素;屈洛昔芬;屈洛昔芬柠檬酸盐;屈他雄酮丙酸盐;偶氮霉素;依达曲沙;盐酸依氟鸟氨酸;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;盐酸表柔比星;厄布洛唑;盐酸依索比星;雌莫司汀;雌莫司汀磷酸盐钠;依他硝唑;依托泊甙;依托泊甙磷酸盐;艾托卜宁;盐酸法倔唑;法扎拉滨;芬维A胺;氮尿苷;氟达拉滨磷酸盐;氟尿嘧啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;盐酸吉西他滨;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福新;白介素2(包括重组白介素2或rIL2),干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-Ia;干扰素γ-Ib;异丙铂;盐酸伊立替康;醋酸兰瑞肽;来曲唑;醋酸亮丙瑞林;盐酸利阿唑;洛美曲索钠;洛莫司汀;盐酸洛索蒽醌;马索罗酚;美登素I;盐酸氮芥;醋酸甲地孕酮;醋酸美仑孕酮;美法仑;美诺立尔;巯基嘌呤;氨甲喋呤;氨甲喋呤钠;氯苯氨啶;美妥替哌;米丁度胺;米特卡辛;丝裂红素;米托洁林;丝裂马菌素;丝裂霉素;米托司培;米托坦;盐酸米托蒽醌;霉酚酸;诺考达唑;诺加霉素;奥马铂;奥昔舒仑;紫衫醇;培门冬酶;培利霉素;奈莫司汀;硫酸培洛霉素;培磷酰胺;哌泊溴烷;哌泊舒凡;盐酸吡罗蒽醌;普卡霉素;普洛美坦;卟吩姆钠;泊非霉素;波尼莫司汀;盐酸丙卡巴肼;嘌呤霉素;盐酸嘌呤霉素;吡唑呋喃菌素;利波腺苷;罗谷亚胺;沙芬戈;盐酸沙芬戈;司莫司汀;辛曲秦;斯帕磷酸钠;稀疏霉素;盐酸锗螺胺;螺莫司汀;螺铂;链黑菌素;链佐星;磺氯苯脲;他利霉素;替可加兰钠;替加氟;盐酸替洛蒽醌;替莫泊芬;替尼泊甙;替罗昔隆;睾内酪;硫唑鸟嘌呤;巯鸟嘌呤;噻替派;磺唑呋啉;替拉扎明;托瑞米芬柠檬酸盐;醋酸曲托龙;曲西立滨磷酸盐;三甲曲沙;三甲曲沙葡糖醛酸;曲普瑞林;盐酸妥布氯唑;乌拉莫司汀;乌瑞替派;伐普肽;维替泊芬;硫酸长春碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春匹定;硫酸长春甘酯;硫酸长春罗新;长春瑞宾酒石酸盐;硫酸长春罗定;硫酸长春利定;伏氯唑;折尼铂;净司他丁;盐酸佐柔比星。其他的抗癌药包括,但不限于20-表-1,25二羟维生素D3(20-epi-1,25 dihydroxyvitamin D3);5-乙炔尿嘧啶;阿比特龙;阿柔比星;acylfulvene;adecypenol;阿多来新;阿地白介素;ALL-TK拮抗剂;六甲蜜胺;氨莫司汀;amidox;氨磷汀;基酮戊酸;氨柔比星;安吖啶;阿那格雷;阿那曲唑;雄茸交酯;血管发生抑制剂;拮抗剂D;拮抗剂G;安雷利克斯;抗-背根化形态发生蛋白-1(anti-dorsalizing morphogenetic protein-1);抗雄激素,前列腺癌;抗雌激素;抗瘤酮(antineoplaston);反义寡核苷酸;蚜肠菌素甘氨酸盐;细胞凋亡基因调剂;细胞凋亡调节剂;外尿酸;ara-CDP-DL-PTBA;精氨酸脱氨酸;asulacrine;阿他美坦;阿莫司汀;axinastatin 1;axinastatin 2;axinastatin3;阿扎司琼;重氮毒素;重氮酪氨酸;浆果赤霉素III衍生物;balanol;巴马司他;BCR/ABL拮抗剂;苯并二氢卟酚;苯甲酰星形孢菌素;β-内酰胺衍生物;β-alethine;betaclamycin B;桦木酸;bFGF抑制剂;比卡鲁胺;必桑郡;bisaziridinylspermine;双奈法德;bistratene A;比折来新;breflate;溴匹立明;布度钛;buthionine sulfoximine;卡泊三醇;抑激酶素C;喜树碱衍生物;canarypox IL-2;卡培他滨;羧酰胺-氨基三唑;羧酰氨基三唑CaRest M3;CARN 700;软骨衍生的抑制剂;卡折来新;酪蛋白激酶抑制剂(ICOS);粟精胺;杀菌肽B;西曲瑞克;chlorlns;氯喹噁啉磺胺;西卡前列素;顺式-卟啉;克拉曲滨;氯米芬类似物;克霉唑;collismycin A;collismycin B;combretastatin A4;combretastatin类似物;conagenin;crambescidin 816;克立那托;cryptophycin8;cryptophycin A衍生物;curacin A;环戊蒽醌(cyclopentanthraquinones);cycloplatam;cypemycin;阿糖胞苷酯(ocfosfate);细胞溶解因子;细胞抑制素达昔单抗;地西他滨;脱氢海鞘环肽B;地洛瑞林;地塞美松;dexifosfamide;右雷佐生;右维拉帕米;地吖醌;海鞘环肽B;didox;二乙基去甲精胺;二氢-5-氮胺苷;二氢紫杉醇,9-;二噁霉素;苯基苯螺莫司汀;多西他赛;docosanol;多拉司琼;去氧氟尿苷;屈洛昔芬;屈大麻酚;duocarmycin SA;依布硒;依考莫司汀;依地福新;依决洛单抗;依氟鸟氨酸;榄烯;乙嘧替氟;表柔比星;依立雄胺;雌莫司汀类似物;雌激素激动剂;雌激素拮抗剂;依他硝唑;依托泊甙磷酸盐;依西美坦;法倔唑;法扎拉滨;芬维A胺;非格司亭;非那雄胺;黄酮吡醇;氟噻司汀;氟甾酮;氟达拉滨;盐酸氟桑红霉素(fluorodaunorubicin hydrochloride);福酚美克;氟美坦;福司曲星;福莫司汀;钆替沙林(gadolinium texaphyrin);硝酸镓;加洛他滨;加尼瑞克;白明胶酶抑制剂;吉西他滨;谷胱甘抑制剂;hepsulfam;调蛋白(heregulin);六亚甲基二乙酰胺;金丝桃素;伊班膦酸;伊达比星;艾多昔芬;伊决孟酮;伊莫福新;伊洛马司他;咪唑吖啶酮;咪喹莫特;免疫增强药肽;胰岛素样生长因子-1受体抑制剂;干扰素激动剂;干扰素类;白介素类;碘苄胍;磺阿霉素;呋喃戊酮醇,4-;伊罗普拉;伊索拉定;isobengazole;isohomohalicondrin B;伊他司琼;jasplakinolide;kahalalide F;lamellarin-N三乙酸盐;兰瑞肽;leinamycin;来格司亭;硫酸香菇多糖(lentinan sulfate);leptolstatin;来曲唑;白血病抑制因子;白血球a干扰素;亮丙瑞林+雌激素+孕酮;亮丙瑞林;左旋咪唑;利阿唑;线性的聚胺类似物;亲脂的二糖肽;亲脂的铂化合物;lissoclinamide 7;洛铂;蚯蚓磷脂;洛美曲索;氯尼达明;洛索蒽醌;洛伐他汀;洛索立宾;勒托替康;texaphyrin镥(lutetium texaphyrin);lysofylline;裂解肽;美坦新;甘露糖抑制素A;马力马司他;马索罗酚;脉丝平;竹桃溶素抑制剂;基质金属蛋白酶抑制剂;美诺立尔;merbarone;美替瑞林;甲硫氨酸酶;甲氧氯普胺;MIF抑制剂;mifepristone;米替福新;米立司亭,错配的双链RNA;米托胍腙;二溴卫矛醇;丝裂霉素类似物;米托萘胺;丝裂毒素成纤维细胞生长因子-皂草素;米托蒽醌;莫法罗汀;莫拉司亭;单克隆抗体,人绒促性素;单磷酰基脂A+分枝杆菌细胞壁骨骼;莫哌达醇;多抗药性基因抑制剂;基于多肿瘤抑制基因-1的治疗;芥末抗癌剂;mycaperoxide B;分枝杆菌细胞壁提取物;myriaporone;N-乙酰地那林;N-取代的苯甲酰胺;那法瑞林;nagrestip;纳洛酮+戊唑辛;napavin;naphterpin;那托司亭;奈达铂;奈莫柔比星;奈立膦酸;中性内肽酶;尼鲁米特;尼沙霉素;一氧化氮调节子;硝基氧抗氧剂;nitrullyn;O6-苄基鸟嘌呤;奥曲肽;okicenone;寡核苷酸;奥那司酮;昂丹司琼;昂丹司琼;oracin;口服细胞因子诱导物;奥马铂;奥沙特隆;奥沙利铂;oxaunomycin;紫衫醇;紫衫醇类似物;紫衫醇衍生物;派劳胺;棕榈酰根霉素;帕米磷酸;人参三醇;帕诺米芬;parabactin;帕折普汀;培门冬酶;培得星;戊聚糖聚硫酸钠;喷司他丁;pentrozole;全氟溴烷;培磷酰胺;紫苏子醇;吩嗪霉素;乙酸苯酯;磷酸抑制剂;picibanil;盐酸毛果芸香碱;吡柔比星;吡曲克辛;placetin A;placetinB;纤溶酶原激活药抑制剂;铂复合物;铂混合;铂-三胺复合物;卟吩姆钠;泊非霉素;强体松;丙基-二-吖啶酮;前列腺素J2;蛋白酶体抑制剂;基于A蛋白的免疫调节物;蛋白激酶C抑制剂;蛋白激酶C抑制剂,微藻;蛋白质的酪胺酸磷酸抑制剂;嘌呤核苷磷酸化抑制剂;红紫素;吡唑啉吖啶;吡哆基化的血红素聚氧乙烯结合物;raf拮抗剂;雷替曲塞;雷莫司琼;ras法尼基蛋白质转移酶抑制剂;ras抑制剂;ras-GAP抑制剂;去甲基化瑞替普汀;铼关于186依替膦酸钠;根霉素;核酶;RII视黄酰胺;罗谷亚胺;rohitukine;罗莫肽;罗喹美克;rubiginoneB1;ruboxyl;沙芬戈;saintopin;SarCNU;sarcophytol A;沙格司亭;Sdi 1个拟态的;司莫司汀老年化得自抑制剂1;感觉寡核苷酸;信号转导抑制剂;信号转导调节子;单一链抗原结合蛋白质;西佐喃;索布佐生;硼卡钠;苯基乙酸钠;solverol;生长调节素结合蛋白质;索钠明;斯帕磷酸;spicamycin D;螺莫司汀;斯耐潘定;海绵抑制素1;鲨胺;干细胞抑制剂;干细胞分裂抑制剂;stipiamide;溶基质素;抑制剂;sulfinosine;超活性血管活性肠肽拮抗剂;suradista;苏拉明;豌豆素;合成物质糖胺聚糖;他莫司汀;他莫昔芬甲碘化物;牛磺莫司汀;他扎罗汀;替可加兰钠;替加氟;tellurapyrylium;端粒酶抑制剂;替莫泊芬;替莫唑胺;替尼泊甙;四氯癸氧化物;tetrazomine;thaliblastine;硫代珊瑚精;凝血细胞生成素;凝血细胞生成素模拟物;胸腺法新;促胸腺生成素受体激动剂;胸腺曲南;甲状腺刺激激素;锡乙基初红紫素;替拉扎明;环戊二烯钛二氯化物;topsentin;托瑞米芬;多能干细胞因子;翻译抑制剂;维A酸;三乙酰尿苷;曲西立滨;三甲曲沙;曲普瑞林;托烷司琼;妥罗雄脲;酪氨酸激酶抑制剂;tyrphostins;UBC抑制剂;乌苯美司;窦衍生的生长因子;尿激酶受体拮抗剂;伐普肽;variolin B;载体系统,红血球基因疗法;维拉雷锁;veramine;verdins;维替泊芬;长春瑞宾;vinxaltine;vitaxin;伏氯唑;扎诺特隆;折尼铂;亚苄维C;和净司他丁stimalamer。
本发明的化合物和其它治疗剂可以起叠加作用,或者更优选是起协同作用。在优选的实施方式中,服用包含本发明化合物的组合物的同时可以服用另一种治疗剂,它可以是和所述包含本发明化合物的组合物相同的组合物部分或者不同的组合物。在另一实施方式中,包含本发明化合物的组合物在服用另一种治疗剂之前或之后服用。
当通过口腔、胃肠外或者局部途径给哺乳动物给药时,患者每天单独服用本发明化合物的剂量或者作为分剂量约为0.01-3000mg/kg/体重,优选约为0.01-1000mg/kg体重。但是,根据治疗对象的体重和身体条件(例如,肝脏和肾脏功能)、治疗的疼痛程度、症状的严重程度、给药的途径、剂量间隔的频率、存在的任何有害副作用和使用的具体化合物等必定然出现变化。
本发明的化合物对人类ORL-1受体的结合亲和性Ki优选约为500nM或以下、100nM或以下、50nM或以下、20nM或以下,或者5nM或以下。如下所述,本领域的技术人员可以通过使用来自表达人类阿片样物质受体样受体(ORL-1)的重组HEK-293细胞的膜进行试验来测量结合亲和性Ki。
以下实施例说明本发明的各种情况,并不是以任何方式限制所述权利要求书。
实施例1
“5-元SO2”首基的合成
步骤:
在搅拌条件下,将1,2-苯二胺1(160g,1.50mol)和4-氧代-哌啶-叔-丁酯2(100g,0.50mol)溶解在1,2-二氯乙烷(2.0L)中。加入(31.6mL)乙酸,之后加入三乙酸基硼氢化钠(148g,0.70mol),并在室温下搅拌所得混合物18小时蒸发所述溶剂,并且所述残留物在乙醚和1M乙酸之间分配。将所述有机层分离,并用1M乙酸(3x)洗涤,之后再用碳酸氢钠洗涤(1X)。用乙醚(1x)反萃取所述水相,并使用MgSO4干燥所述混合的有机萃取物,过滤并蒸发溶剂制得有机凝胶。加入600mL乙醚/己烷(1∶1)之后进行晶种诱导结晶。15分钟之后,过滤所述混合物,并用300ML乙醚/己烷(1∶1)洗涤,制得呈白色固体的纯产物3(79.2g,53%)。
熔点=107.1-107.6℃。
1H-NMR(CDCl):d 1.30(bd,2H),1.40(s,9H),1.95(bd,2H),3.90(bt,2H),3.25(b,2H),3.30(m,1H),3.95(b,2H),6.60-6.80(m,4H)。
将二胺3(5.4g,18.6mmol)溶解在无水吡啶(30mL)中。加入硫酰胺(3.58g,37.2mmol),并加热回流所述混合物2小时。将所述混合物冷却至室温,并蒸干溶剂。所述残留物在二氯甲烷∶甲醇(10∶1,500mL)和0.1M盐酸(500mL)之间分配,分离所述有机相,并用盐水(500mL)洗涤,经过MgSO4干燥,过滤并蒸发所述溶剂。将所述残留物用乙酸乙酯研磨,制得呈粉红色固体的纯产物4(5.15g,79%)。
熔点=204.7°-205.4℃。
1H-NMR(DMSO):d 1.30(s,9H),1.80-1.95(m,4H),2.80(b,2H),3.95(m,2H),4.10(m,1H),6.70-7.00(m,4H),11.25(bs,1H)。
将化合物4(5.15g,14.57mmol)悬浮在100ML乙酸乙酯中,并加入20mL浓盐酸/乙酸乙酯的1∶1混合物中,并在室温下搅拌所述悬浮液2小时。过滤所述混合物,并用乙酸乙酯洗涤所述过滤物,制得呈粉红色固体的纯产物5(盐酸盐)(3.82g,91%)。
1H-NMR(DMSO)(盐酸盐):[D 2.10(m,2H),2.50(m,2H),3.12(m,2H),3.52(m,2H),4.40(m,1H),5.80(b,1H),6.90-7.20(NEZ]3H),7.35(m,1H),9.20(b,1H),9.40(b,1H),11.70(b,1H)。
元素分析:
C11H15N302S.HCI.0.75H2O需要值:C,43.56;H,5.81;N,13.85。
实测值:C,43.90;H,5.78;N,13.51。
实施例2
“6-元SO2”首基的合成
步骤:
在氮气气氛下,在15分钟内将氨茴酸6(15.0g,110.1mmol)和N-苄基-4-哌啶酮(20.96g,110.1mmol)在搅拌过程中溶解在冰醋酸(150mL)中。一次性加入三乙酸基硼氢化钠(35.14g,165.8mmol),并在室温下搅拌所得的混合物60小时。将所述混合物倒入水中,并用乙酸乙酯(1x)萃取。用水(3x)反萃取所述乙酸乙酯萃取物。使用氢氧化纳小粒将所述混合的水性萃取物小心碱化至pH12,并过滤所述混合物,制得白色固体,使用丙酮将其研磨,制得白色结晶固体7(19.8g,58%)。
熔点=249.8-250.7℃(dec.)。
将7(10.0g,32.3mmol)在100mL无水二噁烷中的悬浮液滴加到氢化铝锂(3.58g,96.7mmol)在50mL无水二噁烷中的悬浮液中。在室温下搅拌所得混合物1小时,然后加热回流过夜。将所述混合物冷却至室温,并在1小时内用水终止反应。加入硫酸镁(约20g),通过硅藻土过滤所述混合物,并使用二氯甲烷洗涤所述滤饼。经过MgSO4干燥所述过滤液,并进行过滤和蒸发.使用乙醚将所述残留物研磨,制得呈白色固体的纯产物8(6.70g,71%)。
熔点=116-118℃。
1H-NMR(CDCl3):d 1.60(m,2H),2.10(m,2H),2.25(bt,2H),2.85(b,2H),3.40(m,1H),3.60(s,2H),3.91(s,2H),6.63(m,2H),7.05(d,1H),7.20(m,1H),7.25-7.4(m,5H)。
往8(7.00g,23.7mmol)在50mL吡啶中的溶液中加入硫酰胺(4.55g,47.4mmol),并加热回流所得溶液18小时。冷却至室温之后,蒸发所述混合物,制得褐色胶状物。它在氯仿和1M碳酸钾溶液之间分配,并分离所述有机相。使用氯仿(2x)萃取所述水相,并经过MgSO4干燥所述混合有机萃取物,进行过滤和蒸发。进行色谱层析所述残留物,制得淡黄色泡沫体(6.00g)。将它溶解在60mL乙酸乙酯中,并加入4mL浓盐酸∶乙酸乙酯的1∶1混合物中。静置所述混合物30分钟,直到完成结晶。过滤所述混合物,并用乙酸乙酯洗涤所述固体,制得呈白色结晶固体的纯产物9(6.28g,67%)。
mp=248-249.9℃。
1H-NMR(DMSO)(盐酸盐):d 2.05(m,2H),2.32(m,2H),3.12(m,2H),3.40(b,2H),4.30(b,3H),4.45(b,2H),7.10-7.30(m,4H),7.40-7.60(m,5H),7.85(m,1H)。
在100mL甲醇/水(3∶1)中用Pd/C氢化所述化合物9(4.0g,11mmol)24小时。进行过滤和蒸发形成残留物,使用乙酸乙酯/甲醇(1∶1)将所述残留物研磨,制得呈白色结晶固体的纯产物10(2.72g,89%)。
MS:M/Z 268.1(M+1)
1H-NMR(CDCl)(HCl]salt):d 2.00(m,4H),2.70(m,2H),3.2(m,2H),4.15(m,1H),4.52(s,2H),7.15-7.35(m,5H)。
元素分析:C12H17N302S.HCl.0.4H2O需要值:C,46.34;H,6.09;N,13.51。
实测值:C,46.36;H,5.88;N,13.37。
实施例3
将尾基连接到5-元SO2和6-元SO2首基上
按以下步骤将尾基连接到所述首基上:
烷化的一般步骤:
往胺(1当量)和三乙胺(1当量)的二甲基甲酰胺溶液中一次加入1当量溴代烷或氯代烷。搅拌所述混合物并在80℃下加热过夜。TLC指示所述反应已完全。通过加入水并且之后使用1N的NaOH将pH调至10来终止所述反应。使用Et2O提取所述混合物2次。使用碳酸钾干燥所述混合的有机提取物,并蒸发溶剂,之后使用色谱法制得纯产物。
还原性胺化的一般步骤:
往甲醇中的酮或醛(1当量)、胺(1当量)和乙酸(1当量)混合物中一次加入氰基氢硼化钠(1.4当量)。在室温下将所述混合物搅拌过夜。TLC指示所述反应已完全。通过加入水并且之后使用1N的NaOH将pH调至10来终止所述反应。使用Et2O提取所述混合物2次。使用碳酸钾干燥所述混合的有机提取物,并蒸发溶剂,之后使用色谱法制得纯产物。
使用所述一般步骤通过连接所述尾基来制备以下化合物::
[1-[1-(萘-2-基-甲基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮
LC:93.2%
MS:m/z 394.2(M+1)
1H-NMR(DMSO):d 1.95(b,2H),2.22(m,2H),2.40(b,2H),3.10(m,2H),3.80-4.00(b,3H),6.60-6.80(m,4H),7.50(m,3H),7.90(m,4H),10.8(b,1H)。
[1-[1-(对-苯基苄基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮
LC:96.4%
MS:m/z 420.6(M+1)
1H-NMR(CDCl3):d 2.07(m,2H),2.30(m,2H),2.48(m,2H),3.15(m,2H),3.65(s,2H),3.90(m,1H),6.78-6.95(m,4H),7.30-7.60(m,9H)。
[1-[1-(3,3-二(苯基)丙基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮
LC:100%
MS:m/z 448.2(M+1)
1H-NMR(DMSO):d 2.00(b,2H),2.20-2.40(m,4H),2.60-2.85(m,4H),3.20-3.50(m,2H),3.90(bt,1H),4.00(t,1H),6.40-6.60(m,4H),7.18(m,2H),7.25-7.40(m,8H)。
[1-[1-(对-苄氧基苄基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮
LC:98%
MS:m/z 450.7(M+1)
1H-NMR(CDCl):d 2.23(m,2H),2.75(m,2H),2.90(m,2H),3.62(s,2H),3.85(m,2H),4.12(m,1H),5.10(s,2H),6.90-7.48(m,13H)。
[1-[1-(1,2,3,4-四氢-2-萘基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮
LC:100%
MS:m/z 384.6(M+1)
1H-NMR(DMSO-d6):d 1.20-2.60(m,10H),2.75-3.10(m,5H),3.90(m,1H),6.40(b,2H),[6.55(b,2H),7.10(b,4H)。
[1-[1-(4-丙基环己基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮
LC:92.7%
MS:m/z 378.3(M+1)
1H-NMR(DMSO-d6):d 0.85(t,3H),1.15(m,1H),1.30(m,4H),1.35-1.55(m,2H),1.55-1.65(m,4H),1.70(b,1H),1.85(b,1H),1.90-2.10(m,2H),2.35-2.50(b,2H),3.00(b,3H),3.55(b,2H),3.92(m,1H),6.30(m,2H),6.50(m,2H),10.1(b,1H)。
1-[1-(5-甲基己-2-基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮
LC:100%
MS:m/z 352.3(M+1)
1H-NMR(DMSO):d 0.85(m,6H),1.10-1.30(m,6H),1.40(m,1H),1.50(m,1H),1.70(b,1H),2.05(bd,2H),2.45(m,2H),2.90-3.20(m,3H),3.90-4.10(m,2H),6.30(m,2H),6.50(m,2H)。
1-[1-(十氢-2-萘基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮
LC:95%
MS:m/z 390.7(M+1)
1H-NMR(DMSO-d6):d 0.8-2.10(m,20H),2.90-3.60(m,5H),3.95(m,1H),6.30(b,2H),6.50(b,2H)。
[1-[1-(环辛基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮
LC:100%
MS:m/z 364.3(M+1)
1H-NMR(DMSO-d6):d 1.30-2.10(m,18H),2.35-2.55(m,2H),2.90-3.40(m,3H),4.00(m,1H),6.30(m,2H),6.50(m,2H)。
[1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-噻二唑-2,2-二酮
LC:95.1%
MS:m/z 378.3(M+1)
1H-NMR(DMSO-d6):d 0.80-0.95(m,6H),1.03(b,1H),1.15(m,1H),1.30-1.50(m,2H),1.55-1.90(m,6H),2.05(b,2H),2.30-2.50(m,2H),2.80-3.20(b,3H),3.40-3.60(b,2H),3.95(m,1H),6.38(m,2H),6.45(m,2H),7.00(b,1H)。
1-[[1-(1,3,-二氢茚-2-基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮
LC:96.5%
MS:m/z 370.6(M+1)
1H-NMR(DMSO-d6):d 2.00(b,2H),2.30(m,2H),2.70(m,2H),3.10(m,2H),3.20-3.60(m,5H),3.90(m,1H),6.40-6.65(m,4H),7.10-7.30(m,4H)。
1-[[1-(环辛基甲基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮
LC:100%
MS:m/z 392.7(M+15)
1H-NMR(MeOH):d 1.30-1.80(m,14H),2.05(m,1H),2.22(m,2H),2.50(m,2H),2.85(m,2H),3.00(m,2H),3.60(m,2H),4.30(m,1H),4.50(s,2H),7.10-7.40(m,4H)。
1-[1-(苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
1H-NMR(DMSO-D6)]OF HCl Salt form:d 2.05(m,2H),2.32(m,2H),3.12(m,2H),3.40(b,2H),4.30(b,3H),4.45(b,2H),7.10-7.30(m,4H),7.40-7.60(m,5H),7.85(m,1H)。
[1-[1-(萘-2-基-甲基)-4-哌啶基]-2,I,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:m/z 408.3(M+1)
1H-NMR(CDCl3):d 1.95(b,2H),2.20(m,4H),3.05(m,2H),3.70(s,2H),4.10(m,1H),4.50(s,2H),7.10(m,2H),7.20(m,1H),7.30(m,1H),7.45(m,3H),7.75(s,1H),7.85(m,3H)。
1-[1-(对-苯基苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:92.3%
MS:m/z 434.1(M+1)
1H-NMR(CDCl):d 1.95-2.30(m,6H),3.10(b,2H),3.65(s,2H),4.10(m,1H),4.50(s,2H),7.10-7.70(m,13H)。
[1-[1-(10,11-二氢-5H-二苯并[a,d]-环庚烯-5-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:m/z 482.2
1H-NMR(DMSO):d 1.75(b,4H),1.92(m,2H),2.60-2.80(m,4H),3.82(m,3H),4.00(s,1H),4.30(s,2H),7.00-7.40(m,12H)。
[1-[1-(2,2-二(苯基)丙基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:[M/Z 461.7
1H-NMR(DMSO):d 1.75-2.00(m,6H),2.17(b,4H),2.82(m,2H),3.85(m,1H),3.95(m,1H),4.35(s,2H),7.05-7.20(m,5H),7.22-7.35(m,9H)。
[1-[1-(对-苄氧基苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:[M/Z 464(M+1)
1H-NMR(CDCl3):d 1.90(m,2H),2.10(m,4H),2.98(m,2H),3.45(s,2H),4.10(m,1H),4.45(s,2H),5.10(s,2H),6.90(d,2H),7.10-7.50(m,11H)。
[1-[1-(1,2,3,4-四氢萘基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:m/z 398.5(M+1)
1H-NMR(MeOH-d4):d 1.75-3.45(m,14H),3.60(m,LH),4.30(m,1H),4.50(s,2H),7.10-7.40(m,8H)。
[1-[1-(4-丙基环己基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:95.1%
MS:m/z 391.9
1H-NMR(CDCl):d 0.90(m,4H),1.20(m,1H),1.30(m,5H),1.60-1.95(m,6H),2.00(m,2H),2.17(m,2H),2.30-2.50(m,3H),3.20(m,2H),4.10(m,1H),4.50(s,2H),7.15(m,2H),7.23(d,1H),7.35(t,1H)。
1-[1-(5-甲基己-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:77.0%
MS:m/z 366.2(M+1)
1H-NMR(CDCl3):d 0.85(d,6H),0.95(d,3H),1.15-2.15(m,9H),2.22-2.60(m,3H),2.90(m,2H),4.01(m,1H),4.50(s,2H),7.08-7.40(m,4H)。
[1-[1-[降冰片-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:m/z 362.6(M+1)
1H-NMR(CDCl3):d 1.10(m,1H),1.40-1.75(m,6H),2.05(m,1H),2.15(m,2H),2.30-2.55(m,3H),2.60(b,1H),2.80(m,2H),3.10(m,1H),3.51(m,2H),4.25(m,1H),4.50(s,2H),7.20-7.40(m,4H)。
[1-[1-(十氢-2-萘基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:m/z 404.2(M+1)
1H-NMR(DMSO):d 1.15-1.78(m,16H),1.85(m,1H),1.90-2.10(m,3H),2.32(m,2H),2.51(m,1H),2.98(m,2H),4.05(m,1H),4.50(s,2H),7.10-7.35(m,4H)。
1-[1-(环辛基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:96.0%
MS:m/z 378.5(M+1)
1H-NMR(MeOH):d 1.5-2.05(m,14H),2.30(m,2H),2.50(m,2H),3.30(m,2H),3.52(m,3H),4.35(m,1H),4.50(s,2H),7.10-7.40(m,4H)。
1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:m/z 392.2(M+1)
1H-NMR(CDCl3):d 0.90(m,5H),1.12(m,1H),1.25(m,2H),1.47(b,2H),1.65(m,2H),1.80-2.00(m,3H),2.18(m,3H),2.54(m,2H),3.08(m,3H),3.50(m,2H),4.29(m,1H),4.53(s,2H),7.10-7.30(m,3H),7.40(t,1H)。
[1-[[1-(1,3-二氢茚-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:m/z 384.3(M+1)
1H-NMR(DMSO):d 1.78-2.10(m,6H),2.70(m,2H),2.90-3.10(m,5H),3.89(m,1H),4.35(s,2H),7.00-7.25(m,8H)。
3-丁基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:448.4
H-NMR(DMSO):7.35t(1H);7.11-7.23m(3H);6.60s(2H);4.48s(2H);3.88-3.97m(1H);][3.25d(2H);2.95t(2H);2.41bs(1H);2.25bs(2H);1.87m(4H);1.65m(7H);1.51m(2H);1.33m(4H);0.88t(3H);0.81d(6H)
3-乙酰氨基-1-[[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:449.2
H-NMR(CDCl3):7.48s(1H);7.35t(1H);7.25-7.33m(3H);6.55s(2H);4.51s(2H);3.90m(1H);3.56s(2H);3.18d(2H);2.45bs(1H);2.33bs(2H);1.75-1.95m(4H);1.50-1.68m(6H);1.44m(1H);1.33m(1H);1.12m(1H);0.78d(6H)
3-(2-甲烷亚磺酰氨基)-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:513.2
H-NMR(DMSO):7.09-7.30m(4H);6.58s(2H);]4.54s(2H);4.46d(2H);3.99m(4H);3.12m(5H);2.88s(3H);2.33bs(3H);1.98s(3H);1.89m(5H);1.34m(6H);1.18m(4H);1.16t(2H);0.82d(6H)
3-甲氧羰基甲基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:464.2
H-NMR(DMSO):7.41m(1H);7.33m(3H);6.67s(4H);4.65s(2H);3.95s(3H);3.65s(3H);2.49m(1H);2.38m(2H);2.05m(2H);1.77m(2H);1.56m(6H);1.35m(2H);1.25m(1H);0.80d(6H)
3-氰基甲基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;。
LC:100%
MS:431.3
H-NMR(DMSO):7.10-7.48m(4H);4.60s(2H);4.45s(2H);3.77m(1H);2.91d(2H);2.25m(1H);1.90t(2H);1.85d(2H);1.50-1.66m(7H);1.21-1.44m(5H);1.07m(1H);0.82d(6H)
3-(2-羟乙基)-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2二酮
LC:100%
MS:436.2
H-NMR(CDCl3):7.38t(1H);7.22m(3H);6.67s(2H);4.55s(2H);3.95m(1H);3.62m(2H);3.11m(4H);2.44bs(1H);2.35bs(2H);1.85bs(4H);1.55-1.65m(5H);1.48m(2H);1.33m(2H);1.12m(1H);0.82d(6H)
3-丁氧羰基甲基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮
LC:100%
MS:506.2
H-NMR(DMSO):7.31m(1H);7.22m(3H);4.50s(2H);3.71s(3H);2.90d(2H);2.22m(1H);1.98t(2H);1.80d(2H);1.50-1.70m(4H);1.44-1.58m(12H);1.28m(5H);1.01m(1H)0.81d(6H)
通过类似技术可以合成本发明通式(I)或(IA)范围内的其它化合物。
实施例4
使用以下检测方法获得在优选化合物ORL1受体处的伤害感受肽(Nociceptin)亲合力:
通过将细胞溶解在冰水冷却的低渗透性缓冲液(2.5mM MgCl2,50mM HEPES,pH7.4)(10ml/10cm皿),之后用组织磨碎器/聚四氟乙烯研棒进行均化,来制备来自表达人类阿片样物质受体样受体(ORL-1)的重组细胞HEK-293的薄膜(受体生物学)。通过在4℃下以30,000x速度进行离心分离15分钟来收集薄膜,并将小丸再次悬浮在低渗缓冲液中,最终浓度为1-3mg/ml。使用BioRad蛋白质检测试剂,并以牛血清蛋白作为标准对照样来确定蛋白质浓度。将所述ORL-1受体薄膜的等分量存储在-80℃下。
如下所述进行功能SGTPgS粘合检测。通过继续往冰上的粘合缓冲液(100mMNaCl、10mM MgCl2、20mM HEPES,pH7.4)中加入最终浓度为0.066mg/ml的ORL-1薄膜蛋白质、10mg/ml皂角苷、3mM GDP和0.20nM[35S]GTPgS来制备ORL-1薄膜溶液。将所得薄膜溶液(190ml/井孔)转移到96浅井聚丙烯皿中,其中包含在DMSO中制得的10ml浓缩20x的促效药原液。在室温下振动孵化所述皿30分钟。通过使用96-井组织采集器(Brandel)在96井Unifilter GF/B过滤皿(Packard)进行快速过滤来终止所述反应,并且之后用200ml冰水冷却粘合缓冲液(10mMNa2H2PO4、10mM Na2HPO4,pH7.4)过滤洗涤三次。之后在50℃下干燥所述过滤皿2-3小时。加入50ml/井闪烁混合试剂(scintillation cocktail)(BetaScinit,Wallac),并在Packard Top-Count中以每井1分钟来计算皿的数量。
在GraphPad PRISMO,v3.0中使用曲线拟合函数来分析数据,并将结果列于下表1中::
表1
伤害感受肽亲合性
化合物 | 计算的Ki(nM) |
1-1-[1-(萘-2-基-甲基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | >10,000 |
1-1-[1-(对-苯基苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | >10,000 |
1-1-[1-(2,2-二(苯基)丙基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 4461 |
1-1-[1-(对-苄氧基苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 7114 |
1-1-[1-(环辛基甲基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 49 |
1-[1-(4-丙基环己基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮 | 5102 |
1-[1-(5-甲基己-2-基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮 | 3592 |
1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-噻二唑-2,2-二酮 | 357 |
1-[1-(1,2,3,4-四氢-2-萘基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮 | 3454 |
1-[1-(十氢-2-萘基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮 | 225 |
1-[1-(1,3,-二氢茚-2-基)-4-哌啶基]-2,1,3-噻二唑-2,2-二酮 | 5670 |
1-[1-(环辛基)-4-哌啶基]-2,1,3-噻二唑-2,2二酮 | 2297 |
1-[1-(萘-2-基-甲基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 609 |
1-[1-(对-苄氧基苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 1878 |
1-[1-(对-苯基苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2二酮 | 9535 |
1-[1-(十氢-2-萘基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 28.7 |
1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 35.3 |
1-1-[1-(4-丙基环己基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 231 |
1-1-[1-(苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 3900 |
1-1-[I-(10,11-二氢-5H-苯并[a,d]-环庚烯-5-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 505 |
1-1-[1-(1,2,3,4-四氢萘基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 2614 |
1-1-[1-(5-甲基己-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 40 |
1-1-[1-(降冰片-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 6329 |
1-1-[1-(环辛基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2二酮 | 187 |
1-1-[1-(1,3-二氢茚-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 46 |
1-[1-(2,2-二(苯基)丙基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 83 |
3-丁基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 18 |
3-乙酰氨基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 3.9 |
3-(2-甲烷亚磺酰氨基)-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 5 |
3-甲氧羰基甲基-1-[1-[4-(2-丙基)-环己基]-4-iperidinyl]-2,1,3-苯并噻二嗪-2,2-二酮 | 41 |
3-氰基甲基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 33 |
3-(2-羟乙基)-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 7.4 |
3-丁氧羰基甲基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并 | 63 |
噻二嗪-2,2-二酮 |
实施例5
合成喹啉首基
步骤:
在室温下将NaBH4(1.9g,50.2mmol)分批加入1(5g,25.1mmol)在125 mLMeOH的溶液中,并搅拌所述反应混合物2小时。将所述混合物蒸干,并加入饱和NH4Cl溶液。使用EtOAc(5x)萃取所述混合物。经过K2CO3干燥所述混合有机萃取物,在减压条件下进行过滤和蒸发,制得白色固体粗产物2。这种原料可以直接用于下一步,而无需进一步纯化。
1H-NMR(CDCl3):d 1.40-1.55(m,11H),1.85(m,2H),3.00(m,2H),3.85(m,3H)。
将Et3N(5.25mL,37.6mmol)和CH3SO2Cl(2.14mL,27.6mmol)加入2(5.05g,25.1mmol)在50mL 0℃的THF中的溶液中。在室温下搅拌所述反应物2小时。使用乙醚稀释所得混合物,用饱和NH4Cl溶液(3x)洗涤,并经过MgSO4干燥,并进行蒸发,制得固体粗产物。用己烷进行研磨,制得乳白色固体3(6.30g,两步产率90%)。
1H-NMR(CDCl):d 1.45(s,9H),1.80(m,2H),1.95(m,2H),3.02(s,3H),3.30(m,2H),3.72(m,2H),4.90(m,1H)。
在室温下将NaH(1.63g,40.8mmol)加入化合物4(5.00g,34.0mmol)在500mL二甲苯中的溶液中。之后,将所述混合物加热回流2小时。冷却至室温之后,一次性加入3(11.39g,40.8mmol)。加热所述反应混合物,缓和回流并保持20小时。所述冷却的溶液在溴和EtOAc之间分配。分离各层,并用EtOAc(1x)萃取所述水层。经过MgSO4干燥所述混合的有机萃取剂,制得呈油状的粗产物5,它可以直接用于下一步,而无需干燥。
在室温下,将浓盐酸和EtOAc的混合物(150ml,1∶10)加入化合物5(11.2g,34.0mmol)中。通过TLC监控所述反应。当反应完成时,加入水和EtOAc,分离各层并使用EtOAc(1x)。排干所述有机洗涤物,用K2CO3碱化所述水层,并用EtOAc(3x)萃取。经过MgSO4干燥所述有机萃取物,进行干燥和蒸发,制得粗产物,所述粗产物使用色谱柱进行纯化,制得透明玻璃状产物6(4.30g,两步产率为55%)。
1H-NMR(CDCl3):d 1.75(m,2H),2.47-2.88(m,8H),3.20(m,2H),4.35(m,1H),7.02(m,1H),7.12-7.25(m,3H)。
实施例6
连接尾基
按以下步骤将尾基连接到喹啉首基上:
烷化的一般步骤:
往胺(1当量)和三乙胺(1当量)的二甲基甲酰胺溶液中一次加入1当量溴代烷或者氯代烷。搅拌所述混合物并在80℃下加热过夜。TLC指示所述反应已完全。通过加入水并且之后使用1N的NaOH将pH调至10来终止所述反应。使用Et2O提取所述混合物2次。使用碳酸钾干燥所述混合的有机提取物,并蒸发溶剂,之后使用色谱法制得纯产物。
还原性胺化的一般步骤:
往甲醇中的酮或醛(1当量)、胺(1当量)和乙酸(1当量)混合物中加入部分氰基氢硼化钠(1.4当量)。在室温下将所述混合物搅拌过夜。TLC指示所述反应已完全。通过加入水并且之后使用1N的NaOH将pH调至10来终止所述反应。使用Et2O提取所述混合物2次。使用碳酸钾干燥所述混合的有机提取物,并蒸发溶剂,之后使用色谱法制得纯产物。
使用所述一般步骤通过连接所述尾基来制备以下化合物:
1,2,3,4-四氢-1-[[1-(萘-2-基-甲基)-4-哌啶基]-喹啉-2-酮
LC:97.4%
MS:m/z 371.2(M+1)
1H-NMR(CDCl3):d 1.70(m,2H),2.20(m,2H),2.55(m,2H),2.68(m,2H),2.82(m,2H),3.05(b,2H),3.70(s,2H),4.32(m,1H),7.02(m,1H),7.15(d,1H),7.20-7.30(m,2H),7.42(m,2H),7.51(d,1H),7.75(s,1H),7.85(m,3H)。
1,2,3,4-四氢-1-[[1-(对-苯基苄基)-4-哌啶基]-喹啉-2-酮
LC:100%
MS:m/z 397.2(M+1)
1H-NMR(CDCl3):d 1.75(b,2H),2.20(m,2H),2.60(m,2H),2.72(m,2H),2.85(m,2H),3.08(b,2H),3.62(s,2H),4.35(m,1H),7.00-7.70(m,13H)。
1,2,3,4-四氢-1-[1-[4,4-二(4-氟苯基)丁基]-4-哌啶基]-喹啉-2-酮
LC:93.6%
MS:m/z 475.3(M+1)
1H-NMR(CDCl3):d 1.50(m,2H),1.75(m,2H),2.05(m,4H),2.4(m,2H),2.65(m,4H),2.80(m,2H),3.01(m,2H),3.90(t,1H),4.35(m,1H),6.90-7.35(m,12H)。
1,2,3,4-四氢-1-[1-(对-苄氧基苄基)-4-哌啶基]-喹啉-2-酮
LC:100%
MS:m/z 427.2(M+1)
1H-NMR(CDCl3):d 1.75(m,2H),2.10(m,2H),2.78-2.90(m,4H),2.85(m,2H),3.05(m,2H),3.50(s,2H),4.40(m,1H),5.05(s,2H),7.00-7.60(m,13H)。
1,2,3,4-四氢-1-[1-(1,2,3,4-四氢-2-萘基)-4-哌啶基]-喹啉-2-酮
LC:98.8%
MS:m/z 361.2(M+1)
1H-NMR(CDCl3):d 1.88-2.12(m,3H),2.45(m,1H),2.65(m,2H),2.80-2.35(m,8H),3.50-3.75(m,3H),3.90(m,2H),4.80(m,1H),7.05-7.55(m,8H)。
[1,2,3,4-四氢-1-[1-(4-丙基-环己基)-4-哌啶基]-喹啉-2-酮
LC:100%
MS:m/z 355.2(M+1)
1H-NMR(CDCl3):d 0.80-2.25(m,18H),3.55-3.70(m,2H),2.85-3.30(m,6H),3.45-3.80(m,4H),7.00-7.50(m,4H)。
[1,2,3,4-四氢-1-[1-(5-甲基己-2-基)-4-哌啶基]-喹啉-2-酮
LC:100%
MS:m/z 329.6(M+1)
1H-NMR(CDCl3):d 0.95(m,6H),1.25-1.35(m,3H),1.42(d,3H),1.53-1.70(m,2H),2.10(m,2H),3.60(m,2H),2.85-3.55(m,12H),7.05-7.40(m,4H)。
[1,2,3,4-四氢-1-[1-(降冰片-2-基)-4-哌啶基]-喹啉-2-酮
LC:100%
MS:m/z 325.2(M+1)
1H-NMR(CDCl3):d 1.22(m,1H),1.40-1.65(m,5H),1.80-2.10(m,5H),2.30(b,1H),2.50(m,2H),2.61(b,1H),2.85(m,2H),2.90-3.20(m,4H),3.50(m,2H),4.45(m,1H),7.02(t,1H),7.22(d,1H),7.28-7.40(m,2H)。
1,2,3,4-四氢-1-[[1-(十氢-2-萘基)-4-哌啶基]-喹啉-2-酮
LC:100%
MS:m/z 367.2(M+1)
1H-NMR(CDCl3):d 1.20-2.15(m,12H),3.63(m,2H),2.85-3.75(m,14H),4.25-4.45(m,2H),7.05-7.45(m,4H)。
1,2,3,4-四氢-1-[1-(10,11-二氢-5H-苯并[a,d]-环庚烯-5-基)-4-哌啶基]-喹啉-2-酮
LC:100%
1H-NMR(CDCl3):d 1.62(b,2H),2.00(m,2H),2.51-2.70(m,4H),3.85(m,6H),4.00(s,1H),4.05-4.25(m,3H),7.00-7.30(m,12H)。
1,2,3,4-四氢-1-[1-(2,2-二苯基丙基)-4-哌啶基]-喹啉-2-酮
LC:99.3%
MS:m/z 425.3(M+1)
1H-NMR(CDCl3):d 1.70(b,2H),2.05(m,2H),2.30(m,4H),2.55-2.70(m,4H),2.80(m,2H),3.02(b,2H),4.02(m,1H),4.30(m,1H),7.00(m,1H),7.12-7.35(m,13H)。
1,2,3,4-四氢-1-[1-(环辛基)-4-哌啶基]-喹啉-2-酮
LC:100%
MS:m/z 341.2(M+1)
1H-NMR(CDCl3):d 1.36-1.76(m,11H),1.78-1.89(m,2H),1.92-1.95(m,2H),1.98-2.09(m,2H),2.58-2.62(m,2H),2.79-2.82(m,2H),3.00-3.08(m,3H),3.28-3.42(m,3H),4.90-4.98(m,1H),7.05(t,1H),7.14(d,1H),7.40(d,1H),7.51(t,1H)。
1,2,3,4-四氢-1-[[1-[4-(1-甲基乙基)-环己基]-4-哌啶基]-喹啉-2-酮
LC:100%
MS:m/z 355.2(M+1)
1H-NMR(CDCl3):d 0.90-1.05(m,6H),1.05-2.30(m,13H),2.60(m,2H),2.80-3.80(m,6H),4.35(m,2H),4.55(m,1H),7.05-7.45(m,4H)。
[1,2,3,4-四氢-1-[1-(1,3-二氢茚-2-基)-4-哌啶基]-喹啉-2-酮
LC:90.4%
MS:m/z 347.2(M+1)
1H-NMR(CDCl3):d 1.90(b,2H),2.60(m,2H),2.70-3.00(m,6H),3.25(m,4H),3.40(b,2H),3.80(m,1H),4.70(m,1H),7.00-7.40(m,8H)。
[1,2,3,4-四氢-1-[1-(环辛基甲基)-4-哌啶基]-喹啉-2-酮
LC:100%
MS:m/z 355.3(M+1)
1H-NMR(CDCl3):d 1.15-1.28(m,2H),1.39-1.78(m,15H),1.98-2.10(m,4H),2.51-2.68(m,4H),2.79(t,2H),2.98(d,2H),4.21-4.31(m,1H),6.95-7.01(m,1H),7.11-7.14(m,1H),7.20-7.24(m,2H)。
通过类似技术可以合成本发明通式(II)或(IIA)范围内的其它化合物。
实施例7
使用以下检测方法获得在优选化合物ORL1受体处的伤害感受肽亲合力:
通过将细胞溶解在冰水冷却的低渗透性缓冲液(2.5mM MgCl2,50mM HEPES,pH7.4)(10ml/10cm皿),之后用组织磨碎器/聚四氟乙烯研棒进行均化,来制备来自表达人类阿片样物质受体样的受体(ORL-1)的重组细胞HEK-293的薄膜(受体生物学)。通过在4℃下以30,000x速度进行离心分离15分钟来收集薄膜,并将小丸再次悬浮在低渗缓冲液中,最终浓度为1-3mg/ml。使用BioRad蛋白质检测试剂,并以牛血清蛋白作为标准对照样来确定蛋白质浓度。将所述0RL-1受体薄膜的等分量存储在-80℃下。
如下所述进行功能SGTPgS粘合检测。通过继续往冰上的粘合缓冲液(100mMNaCl、10mM MgCl2、20mM HEPES,pH7.4)中加入最终浓度为0.066mg/ml的ORL-1薄膜蛋白质、10mg/ml皂角苷、3mM GDP和0.20nM[35S]GTPgS来制备ORL-1薄膜溶液。将所得薄膜溶液(190ml/井孔)转移到96浅井聚丙烯皿中,其中包含在DMSO中制得的10ml浓缩20x的促效药原液。在室温下振动孵化所述皿30分钟。通过使用96-井组织采集器(Brandel)在96井Unifilter GF/B过滤皿(Packard)进行快速过滤来终止所述反应,并且之后用200ml冰水冷却粘合缓冲液(10mM Na2H2PO4、10mMNa2HPO4,pH7.4)过滤洗涤三次。之后在50℃下干燥所述过滤皿2-3小时。加入50ml/井闪烁混合试剂(scintillation cocktail)(BetaScinit,Wallac),并在PackardTop-Count中以每井1分钟来计算皿的数量。
在GraphPad PRISMO,v3.0中使用曲线拟合函数来分析数据,并将结果列于下表2中:
表2
伤害感受肽亲和力
化合物 | 计算Ki(nM) |
1,2,3,4-四氢-1-[1-(萘-2-基-甲基)-4-哌啶基]-喹啉-2-酮 | 3389 |
1,2,3,4-四氢-1-1-(对-苯基苄基)-4-哌啶基]-喹啉-2-酮 | >10,000 |
1,2,3,4-四氢-1-[1-[4,4-二(4-氟苯基)丁基]-4-哌啶基]-喹啉-2-酮 | 2898 |
1,2,3,4-四氢-1-[1-(对-苄氧基苄基)-4-哌啶基]-喹啉-2-酮 | 3502 |
1,2,3,4-四氢-1-[1-(1,2,3,4-四氢-2-萘基)-4-哌啶基]-喹啉-2-酮- | 176 |
1,2,3,4-四氢-1-[1-(4-丙基-环己基)-4-哌啶基]-喹啉-2-酮 | 1257 |
1,2,3,4-四氢-1-[1-(5-甲基己-2-基)-4-哌啶基]-喹啉-2-酮 | 505 |
1,2,3,4-四氢-1-[1-(降冰片-2-基)-4-哌啶基]-喹啉-2-酮 | 781 |
1,2,3,4-四氢-1-[I-(十氢-2-萘基)-4-哌啶基]-喹啉-2-酮 | 105 |
1,2,3,4-四氢-1-[1-(10,11-二氢-5H-苯并[a,d]-环庚烯-5-基)-4-哌啶基]-喹啉-2-酮 | 95 |
1,2,3,4-四氢-1-[1-(2,2-二苯基丙基)-4-哌啶基]-喹啉-2-酮 | 71 |
1,2,3,4-四氢-1-[1-[4-(1-甲基乙基)-环己基]-4-哌啶基]-喹啉-2-酮 | 80 |
1,2,3,4-四氢-1-[1-(1,3-二氢茚-2-基)-4-哌啶基]-喹啉-2-酮 | 71 |
1,2,3,4-四氢-1-[1-(环辛基)-4-哌啶基]-喹啉-2-酮 | 14 |
实施例8
按以下检测方法获得化合物在μ受体处的亲合力:
通过继续往冰上的粘合缓冲液(100mM NaCl、10mM MgCl2、20mM HEPES,pH7.4)中加入最终浓度为0.075μg/μl所需薄膜蛋白质、10μg/ml皂角苷、3μM GDP和0.20nM[35S]GTPγS来制备Mu阿片样物质受体。将所得薄膜溶液(190ml/井孔)转移到96浅井聚丙烯皿中,其中包含在DMSO中制得的10μl浓缩20x的促效药原液。在室温下振动孵化所述皿30分钟。通过使用96-井组织采集器(Brandel)在96井Unifilter GF/B过滤皿(Packard)进行快速过滤来终止所述反应,并且之后用200ml冰水冷却粘合缓冲液(10mM Na2H2PO4、10mM Na2HPO4,pH7.4)过滤洗涤三次。之后在50℃下干燥所述过滤皿2-3小时。加入50μl/井闪烁混合试剂(scintillationcocktail)(BetaScinit,Wallac),并在Packard Top-Count中以每井1分钟来计算皿的数量。
在GraphPad PRISMTM,v3.0中使用曲线拟合函数来分析数据,并将结果列于下表3中:
表3
Mu受体亲合力
化合物 | 计算Ki(nM) |
1-[1-(十氢-2-萘基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 91.7 |
1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 207 |
1-1-[1-(环辛基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 1376 |
1-1-[1-(1,3-二氢茚-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮 | 660 |
1,2,3,4-四氢-1-[1-(环辛基)-4-哌啶基]-喹啉-2-酮 | 86 |
1,2,3,4-四氢-1-[1-(5-甲基己-2-基)-4-哌啶基]-喹啉-2-酮 | 156 |
1,2,3,4-四氢-1-[1-(降冰片-2-基)-4-哌啶基]-喹啉-2-酮 | 957 |
1,2,3,4-四氢-1-[1-(十氢-2-萘基)-4-哌啶基]-喹啉-2-酮 | 341 |
Claims (62)
1.式(I)的化合物:
其中,W是氢,C1-10烷基,C3-12环烷基,C3-12环烷基C1-4烷基-,C1-10烷氧基,C3-12环烷氧基-,被1-3个卤素取代的C1-10烷基,被1-3个卤素取代的C3-12环烷基,被1-3个卤素取代的C3-12环烷基C1-4烷基-,被1-3个卤素取代的C1-10烷氧基,被1-3个卤素取代的C3-12环烷氧基-,-COOV1,-C1-4COOV1,-CH2OH,-SO2N(V1)2,羟基C1-10烷基-,羟基C3-10环烷基-,氰基C1-10烷基-,氰基C3-10环烷基-,-CON(V1)2,NH2SO2C1-4烷基-,NH2SOC1-4烷基-,磺酰氨基C1-10烷基-,二氨基烷基-,-磺酰基C1-4烷基,六元杂环,六元杂芳环,六元杂环C1-4烷基-,六元杂芳C1-4烷基-,六元芳环,六元芳香C1-4烷基-,任选被氧代或硫代取代的五元杂环,五元杂芳环,任选被氧代或硫代取代的五元杂环C1-4烷基-,五元杂芳C1-4烷基-,-C1-5(=O)W1,-C1-5(=NH)W1,-C1-5NHC(=O)W1,-C1-5NHS(=O)2W1,-C1-5NHS(=O)W1,其中,W1是氢,C1-10烷基,C3-12环烷基,C1-10烷氧基,C3-12环烷氧基,-CH2OH,氨基,C1-4烷基氨基-,二C1-4烷基氨基-或任选被1-3个低级烷基取代的五元杂芳环;
其中,每个V1独立选自H,C1-6烷基,C3-6环烷基,苄基和苯基;
Q是5-8元环烷基,5-8元杂环或6元芳基或杂芳基;
各个n分别是0-3的整数;
A,B和C分别是氢,C1-10烷基,C3-12环烷基,C1-10烷氧基,C3-12环烷氧基,-CH2OH,-NHSO2,羟基C1-10烷基-,氨基羰基-,C1-4烷基氨基羰基-,二C1-4烷基氨基羰基-,酰氨基-,酰氨基烷基-,酰胺,磺酰氨基C1-10烷基-或A-B可以一起形成C2-6桥或B-C可以一起形成C3-7桥或A-C可以一起形成C1-5桥;
Z选自键、直链或支链C1-6烯烃基,-NH-,-CH2O-,-CH2NH-,-CH2N(CH3)-,-NHCH2-,-CH2CONH-,-NHCH2CO-,-CH2CO-,-COCH2-,-CH2COCH2-,-CH(CH3)-,-CH=,-O-和-HC=CH-,其中碳和/或氮原子未被取代或被一个或多个低级烷基,羟基,卤素或烷氧基取代;
R1选自氢,C1-10烷基,C3-12环烷基,C2-10链烯基,氨基,C1-10烷基氨基-,C3-12环烷基氨基-,-COOV1,-C1-4COOV1,氰基,氰基C1-10烷基-,氰基C3-10环烷基-,NH2SO2-,NH2SO2C1-4烷基-,NH2SOC1-4烷基-,氨基羰基-,C1-4烷基氨基羰基-,二C1-4烷基氨基羰基-,苄基,C3-12环烯基-,单环、二环或三环芳基或杂芳环,杂-单环,杂-二环系统和式(III)的螺环系:
其中,X1和X2分别选自NH,O,S和CH2;且其中所述R1的烷基,环烷基,链烯基,C1-10烷基氨基-,C3-12环烷基氨基-或苄基任选地被1-3个选自卤素,羟基,C1-10烷基,C1-10烷氧基,硝基,三氟甲基-,氰基,-COOV1,-C1-4COOV1,氰基C1-10烷基-,-C1-5(=O)W1,-C1-5NHS(=O)2W1,-C1-5NHS(=O)W1,五元杂芳C0-4烷基-,苯基,苄基,苄氧基的取代基取代,所述苯基,苄基和苄氧基任选被1-3个选自卤素,C1-10烷基-,C1-10烷氧基-和氰基的取代基取代;且其中所述C3-12环烷基,C3-12环烯基,单环、二环或三环芳基,杂芳环,杂-单环,杂-二环系统或式(III)的螺环系任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基,硝基,三氟甲基-,苯基,苄基,苯氧基和苄氧基的取代基取代,其中所述苯基,苄基,苯氧基或苄氧基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基和氰基的取代基取代;
R2选自氢,C1-10烷基,C3-12环烷基-和卤素,所述烷基或环烷基任选被氧代,氨基,烷基氨基或二烷基氨基取代;
或其药学上可接受的盐或其溶剂合物。
2.如权利要求1所述的化合物,其中,Q是苯基或含有1-3个氮原子的六元杂芳基。
3.如权利要求1所述的化合物,其中,W是-CH2C=ONH2,-C(NH)NH2,吡啶基甲基,环戊基,环己基,呋喃甲基,-C=OCH3,-CH2CH2NHC=OCH3,-SO2CH3,CH2CH2NHSO2CH3,呋喃羰基-,甲基吡咯羰基-,二唑羰基-,吡咯甲基-,三氟乙基-,羟基乙基-,氰基甲基-,氧代-噁唑甲基-或二唑甲基-。
4.如权利要求1所述的化合物,其中,ZR1是环己基乙基-,环己基甲基-,环戊基甲基-,二甲基环己基甲基-,苯乙基-,吡咯基三氟乙基-,噻吩基三氟乙基-,吡啶基乙基-,环戊基-,环己基-,甲氧基环己基-,四氢吡喃基-,丙基哌啶基-,吲哚基甲基-,吡唑基戊基-,噻唑基乙基-,苯基三氟乙基-,羟基己基-,甲氧基己基-,异丙氧基丁基-,己基-或氧杂环辛基丙基-。
5.如权利要求1所述的化合物,其中,至少ZR1或W其中之一是-CH2COOV1,四唑基甲基-,氰基甲基-,NH2SO2甲基-,NH2SO甲基-,氨基羰基甲基-,C1-4烷基氨基羰基甲基-或二C1-4烷基氨基羰基甲基-。
6.如权利要求1所述的化合物,其中,ZR1是3,3二苯基丙基,它任选在丙基的第3个碳上被-COOV1,四唑基C0-4烷基-,氰基-,氨基羰基-,C1-4烷基氨基羰基-或二C1-4烷基氨基羰基-取代。
7.式(IA)的化合物:
其中,
各个n分别是0-3的整数;
Z选自键,-CH2-,-NH-,-CH2O-,-CH2CH2-,-CH2NH-,-CH2N(CH3)-,-NHCH2-,-CH2CONH-,-NHCH2CO-,-CH2CO-,-COCH2-,-CH2COCH2-,-CH(CH3)-,-CH=和-HC=CH-,其中碳和/或氮原子未被取代或被低级烷基,卤素,羟基或烷氧基取代;
R1选自氢,C1-10烷基,C3-12环烷基,C2-10链烯基,氨基,C1-10烷基氨基-,C3-12环烷基氨基-,苄基,C3-12环烯基-,单环、二环或三环芳基或杂芳环,杂-单环,杂-二环系统和式(III)的螺环系:
其中,X1和X2分别选自NH,O,S和CH2;
其中所述烷基,环烷基,链烯基,C1-10烷基氨基,C3-12环烷基氨基或苄基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基,硝基,三氟甲基,氰基,苯基,苄基,苄氧基的取代基取代,所述苯基,苄基和苄氧基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基和氰基的取代基取代;
其中所述C3-12环烷基,C3-12环烯基,单环、二环或三环芳基,杂芳环,杂-单环,杂-二环系统和式(III)的螺环系任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基,硝基,三氟甲基,苯基,苄基,苯氧基和苄氧基的基团取代,其中所述苯基,苄基,苯氧基和苄氧基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基和氰基的基团取代;
R2选自氢,C1-10烷基,C3-12环烷基和卤素,所述烷基任选被氧代基团取代;
或其药学上可接受的盐。
8.如权利要求7所述的化合物,其中,R1是选自甲基,乙基,丙基,丁基,戊基和己基的烷基。
9.如权利要求7所述的化合物,其中,R1是选自环己基,环庚基,环辛基,环壬基,环癸基和降冰片基的环烷基。
10.如权利要求7所述的化合物,其中,R1是四氢萘基,十氢萘基或二苯并环庚基。
11.如权利要求7所述的化合物,其中,R1是苯基或苄基。
12.如权利要求7所述的化合物,其中,R1是二环芳环。
13.如权利要求12所述的化合物,其中所述二环芳环是茚基,喹啉或萘基。
14.如权利要求7所述的化合物,其中,Z是键,甲基或乙基。
15.如权利要求7所述的化合物,其中,各个n是0。
16.如权利要求7所述的化合物,其中,砜环中的“n”是0或1。
17.如权利要求7所述的化合物,其中,X1和X2都是氧。
18.选自以下物质的化合物:
1-[1-(萘-2-基-甲基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(p-苯基苄基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(3,3-二(苯基)丙基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(p-苄氧基苄基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(4-丙基环己基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(5-甲基己-2-基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(4-(2-丙基)-环己基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(环辛基甲基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(1,2,3,4-四氢-2-萘基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(十氢-2-萘基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(1,3-二氢茚-2-基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(环辛基)-4-哌啶基]-2,1,3-苯并噻二唑-2,2-二酮;
1-[1-(萘-2-基-甲基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(p-苄氧基苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(p-苯基苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(十氢-2-萘基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(4-(2-丙基)-环己基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(4-丙基环己基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(苄基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(10,11-二氢-5H-二苯并[a,d]-环庚烯-5-基)-4-哌啶基]-2H-苯并噻二嗪-2,2-二酮;
1-[1-(1,2,3,4-四氢-2-萘基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(5-甲基己-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(降冰片-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(环辛基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(1,3-二氢茚-2-基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
1-[1-(3,3-二(苯基)丙基)-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;和
其药学上可接受的盐。
19.选自以下物质的化合物:
3-丁基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
3-乙酰氨基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
3-(2-甲烷磺酰氨基)-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
3-甲氧羰基甲基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
3-氰甲基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
3-(2-羟乙基)-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
3-丁氧羰基甲基-1-[1-[4-(2-丙基)-环己基]-4-哌啶基]-2,1,3-苯并噻二嗪-2,2-二酮;
及其药学上可接受的盐以及其溶剂合物。
20.一种药物组合物,其特征在于,所述组合物含有权利要求1所述的化合物和至少一种药学上可接受的赋形剂。
21.一种治疗疼痛的方法,其特征在于,所述方法包括对此需要的患者施用有效量的权利要求1所述的镇痛化合物。
22.一种调节ORL1受体药理学响应的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求1所述的化合物。
23.一种药物组合物,其特征在于,所述组合物含有权利要求7所述的化合物和至少一种药学上可接受的赋形剂。
24.一种治疗疼痛的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求7所述的镇痛化合物。
25.一种调节ORL1受体药理学响应的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求7所述的化合物。
26.式(IA)的化合物:
其中,
R2选自氢,C1-10烷基,C3-12环烷基和卤素,所述烷基任选被氧代基团取代;
各个n分别是0-3的整数;
且ZR1是
其中,
Y1是R3-(C1-C12)烷基,R4-芳基,R5-杂芳基,R6-(C3-C12)环-烷基,R7-(C3-C7)杂环烷基,-CO2(C1-C6)烷基,CN或-C(O)NR8R9;Y2是氢或Y1;Y3是氢或(C1-C6)烷基;或Y1,Y2和Y3,和它们所连接的碳原子一起形成以下结构:
或
其中,r是0-3;w和u分别为0-3,条件是w和u的和是1-3;c和d分别是1或2;s是1-5;和环E是稠合的R4-苯基或R5-杂芳环;
R10是独立选自H,(C1-C6)烷基,-OR8,-(C1-C6)烷基-OR8,-NR8R9和-(C1-C6)烷基-NR8R9的1-3个取代基;
R11是独立选自R10,-CF3,-OCF3,NO2和卤素的1-3个取代基,或者相邻环碳原子上的R11取代基可以一起形成亚甲基二氧基或次乙基二氧基环;
R8和R9分别选自氢,(C1-C6)烷基,(C3-C12)环烷基,芳基和芳基(C1-C6)烷基;
R3是独立选自H,R4-芳基,R6-(C3-C12)环烷基,R5-杂芳基,R7-(C3-C7)杂环烷基,-NR8R9,-OR12和-S(O)0-2R12的1-3个取代基;
R6是独立选自H,(C1-C6)烷基,R4-芳基,-NR8R9,-OR12和-SR12的1-3个取代基;
R4是1-3个取代基,所述取代基独立选自氢,卤素,(C1-C6)烷基,R13-芳基,(C3-C12)环烷基,-CN,-CF3,-OR8,-(C1-C6)烷基-OR8,-OCF3,-NR8R9,-(C1-C6)烷基-NR8R9,-NHSO2R8,-SO2N(R14)2,-SO2R8,-SOR8,-SR8,-NO2,-CONR8R9,-NR9COR8,-COR8,-COCF3,-OCOR8,-OCO2R8,-COOR8,-(C1-C6)烷基-NHCOOC(CH3)3,-(C1-C6)烷基-NHCOCF3,-(C1-C6)烷基-NHSO2-(C1-C6)烷基,-(C1-C6)烷基-NHCONH-(C1-C6)-烷基和
其中,f是0-6;或者相邻环碳原子上的R4取代基可以一起形成亚甲基二氧基或次乙基二氧基环;
R5是独立选自氢,卤素,(C1-C6)烷基,R13-芳基,(C3-C12)环烷基,-CN,-CF3,-OR8,-(C1-C6)烷基-OR8,-OCF3,-NR8R9,-(C1-C6)烷基-NR8R9,-NHSO2R8,-SO2N(R14)2,-NO2,-CONR8R9,-NR9COR8,-COR8,-OCOR8,-OCO2R8和-COOR8的1-3个取代基;
R7是H,(C1-C6)烷基,-OR8,-(C1-C6)烷基-OR8,-NR8R9或-(C1-C6)烷基-NR8R9;
R12是H,(C1-C6)烷基,R4-芳基,-(C1-C6)烷基-OR8,-(C1-C6)烷基-NR8R9,-(C1-C6)烷基-SR8,或芳基(C1-C6)烷基;
R13是独立选自H,(C1-C6)烷基,(C1-C6)烷氧基和卤素的1-3个取代基;
R14独立选自H,(C1-C6)烷基和R13-C6H4-CH2-;
或其药学上可接受的盐。
27.一种药物组合物,其特征在于,所述组合物含有权利要求26所述的化合物和至少一种药学上可接受的赋形剂。
28.一种治疗疼痛的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求26所述的镇痛化合物。
29.一种调节ORL1受体药理学响应的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求26所述的化合物。
30.一种调节阿片样物质受体药理学响应的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求1所述的化合物。
31.一种调节阿片样物质受体药理学响应的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求7所述的化合物。
32.一种调节阿片样物质受体药理学响应的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求26所述的化合物。
33.式(II)的化合物:
其中,W是氢,C1-10烷基,C3-12环烷基,C3-12环烷基C1-4烷基-,C1-10烷氧基,C3-12环烷氧基-,被1-3个卤素取代的C1-10烷基,被1-3个卤素取代的C3-12环烷基,被1-3个卤素取代的C3-12环烷基C1-4烷基-,被1-3个卤素取代的C1-10烷氧基,被1-3个卤素取代的C3-12环烷氧基-,-COOV1,-C1-4COOV1,-CH2OH,-SO2N(V1)2,羟基C1-10烷基-,羟基C3-10环烷基-,氰基C1-10烷基-,氰基C3-10环烷基-,-CON(V1)2,NH2SO2C1-4烷基-,NH2SOC1-4烷基-,磺酰氨基C1-10烷基-,二氨基烷基-,-磺酰基C1-4烷基,六元杂环,六元杂芳环,六元杂环C1-4烷基-,六元杂芳C1-4烷基-,六元芳环,六元芳香C1-4烷基-,任选被氧代或硫代取代的五元杂环,五元杂芳环,任选被氧代或硫代取代的五元杂环C1-4烷基-,五元杂芳C1-4烷基-,-C1-5(=O)W1,-C1-5(=NH)W1,-C1-5NHC(=O)W1,-C1-5NHS(=O)2W1,-C1-5NHS(=O)W1,其中,W1是氢,C1-10烷基,C3-12环烷基,C1-10烷氧基,C3-12环烷氧基,-CH2OH,氨基,C1-4烷基氨基-,二C1-4烷基氨基-任选被1-3个低级烷基取代的五元杂芳环;
其中,每个V1独立选自H,C1-6烷基,C3-6环烷基,苄基和苯基;
Q是5-8元环烷基,5-8元杂环或6元芳基或杂芳基;
各个n分别是0-3的整数;
A,B和C分别是氢,C1-10烷基,C3-12环烷基,C1-10烷氧基,C3-12环烷氧基,-CH2OH,-NHSO2,羟基C1-10烷基-,氨基羰基-,C1-4烷基氨基羰基-,二C1-4烷基氨基羰基-,酰氨基-,酰氨基烷基-,酰胺,磺酰氨基C1-10烷基-或A-B可以一起形成C2-6桥或B-C可以一起形成C3-7桥或A-C可以一起形成C1-5桥;
Z选自键、直链或支链C1-6烯烃基,-NH-,-CH2O-,-CH2NH-,-CH2N(CH3)-,-NHCH2-,-CH2CONH-,-NHCH2CO-,-CH2CO-,-COCH2-,-CH2COCH2-,-CH(CH3)-,-CH=,-O-和-HC=CH-,其中碳和/或氮原子未被取代或被一个或多个低级烷基,羟基,卤素或烷氧基取代;
R1选自氢,C1-10烷基,C3-12环烷基,C2-10链烯基,氨基,C1-10烷基氨基-,C3-12环烷基氨基-,-COOV1,-C1-4COOV1,氰基,氰基C1-10烷基-,氰基C3-10环烷基-,NH2SO2-,NH2SO2C1-4烷基-,NH2SOC1-4烷基-,氨基羰基-,C1-4烷基氨基羰基-,二C1-4烷基氨基羰基-,苄基,C3-12环烯基-,单环、二环或三环芳基或杂芳环,杂-单环,杂-二环系统和式(III)的螺环系:
其中,X1和X2分别选自NH,O,S和CH2;且其中所述R1的烷基,环烷基,链烯基,C1-10烷基氨基-,C3-12环烷基氨基-或苄基任选地被1-3个选自卤素,羟基,C1-10烷基,C1-10烷氧基,硝基,三氟甲基-,氰基,-COOV1,-C1-4COOV1,氰基C1-10烷基-,-C1-5(=O)W1,-C1-5NHS(=O)2W1,-C1-5NHS(=O)W1,五元杂芳C0-4烷基-,苯基,苄基,苄氧基的取代基取代,所述苯基,苄基和苄氧基任选被1-3个选自卤素,C1-10烷基-,C1-10烷氧基-和氰基的取代基取代;且其中所述C3-12环烷基,C3-12环烯基,单环、二环或三环芳基,杂芳环,杂-单环,杂-二环系统或式(III)的螺环系任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基,硝基,三氟甲基-,苯基,苄基,苯氧基和苄氧基的取代基取代,其中所述苯基,苄基,苯氧基或苄氧基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基和氰基的取代基取代;
R2选自氢,C1-10烷基,C3-12环烷基-和卤素,所述烷基或环烷基任选被氧代,氨基,烷基氨基或二烷基氨基取代;
或其药学上可接受的盐及其溶剂合物。
34.如权利要求33所述的化合物,其中,Q是苯基或含有1-3个氮原子的六元杂芳基。
35.如权利要求33所述的化合物,其中,W选自-CH2C=ONH2,-C(NH)NH2,吡啶基甲基,环戊基,环己基,呋喃甲基,-C=OCH3,-CH2CH2NHC=OCH3,-SO2CH3,CH2CH2NHSO2CH3,呋喃羰基-,甲基吡咯羰基-,二唑羰基-,吡咯甲基-,三氟乙基-,羟基乙基-,氰基甲基-,氧代-噁唑甲基-和二唑甲基-。
36.如权利要求33所述的化合物,其中,ZR1选自环己基乙基-,环己基甲基-,环戊基甲基-,二甲基环己基甲基-,苯乙基-,吡咯基三氟乙基-,噻吩基三氟乙基-,吡啶基乙基-,环戊基-,环己基-,甲氧基环己基-,四氢吡喃基-,丙基哌啶基-,吲哚基甲基-,吡唑基戊基-,噻唑基乙基-,苯基三氟乙基-,羟基己基-,甲氧基己基-,异丙氧基丁基-,己基-或氧杂环辛基丙基-。
37.如权利要求33所述的化合物,其中,至少ZR1或W之-选自-CH2COOV1,四唑基甲基-,氰基甲基-,NH2SO2甲基-,NH2SO甲基-,氨基羰基甲基-,C1-4烷基氨基羰基甲基-或二C1-4烷基氨基羰基甲基-。
38.如权利要求33所述的化合物,其中,ZR1是3,3二苯基丙基,它任选在丙基的第3个碳上被-COOH,-COOV1,四唑基C0-4烷基-,氰基-,氨基羰基-,C1-4烷基氨基羰基-或二C1-4烷基氨基羰基-取代。
39.式(IIA)的化合物:
其中,
n是0-3的整数;
Z选自键,-CH2-,-NH-,-CH2O-,-CH2CH2-,-CH2NH-,-CH2N(CH3)-,-NHCH2-,-CH2CONH-,-NHCH2CO-,-CH2CO-,-COCH2-,-CH2COCH2-,-CH(CH3)-,-CH=和-HC=CH-,其中碳和/或氮原子未被取代或被低级烷基,卤素,羟基或烷氧基取代;
R1选自氢,C1-10烷基,C3-12环烷基,C2-10链烯基,氨基,C1-10烷基氨基-,C3-12环烷基氨基-,苄基,C3-12环烯基-,单环、二环或三环芳基或杂芳环,杂-单环,杂-二环系统和式(III)的螺环系:
其中,X1和X2分别选自NH,O,S和CH2;
其中所述烷基,环烷基,链烯基,C1-10烷基氨基,C3-12环烷基氨基或苄基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基,硝基,三氟甲基,氰基,苯基,苄基,苄氧基的取代基取代,所述苯基,苄基和苄氧基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基和氰基的取代基取代;
其中所述C3-12环烷基,C3-12环烯基,单环、二环或三环芳基,杂芳环,杂-单环,杂-二环系统和式(II)的螺环系任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基,硝基,三氟甲基,苯基,苄基,苯氧基和苄氧基的基团取代,其中所述苯基,苄基,苯氧基和苄氧基任选被1-3个选自卤素,C1-10烷基,C1-10烷氧基和氰基的基团取代;
R2选自氢,C1-10烷基,C3-12环烷基和卤素,所述烷基任选被氧代基团取代;
或其药学上可接受的盐。
40.如权利要求39所述的化合物,其中,R1是选自甲基,乙基,丙基,丁基,戊基和己基的烷基。
41.如权利要求39所述的化合物,其中,R1是选自环己基,环庚基,环辛基,环壬基,环癸基和降冰片基的环烷基。
42.如权利要求39所述的化合物,其中,R1是四氢萘基,十氢萘基或二苯并环庚基。
43.如权利要求39所述的化合物,其中,R1是苯基或苄基。
44.如权利要求39所述的化合物,其中,R1是二环芳环。
45.如权利要求44所述的化合物,其中所述二环芳环是茚基,喹啉或萘基。
46.如权利要求39所述的化合物,其中,Z是键,甲基或乙基。
47.如权利要求39所述的化合物,其中,n是0。
48.如权利要求39所述的化合物,其中,X1和X2都是氧。
49.选自以下物质的化合物:
1,2,3,4-四氢-1-[1-(萘-2-基-甲基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(p-苯基苄基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-[4,4-二(4-氟苯基)丁基]-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(p-苄氧基苄基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(1,2,3,4-四氢-2-萘基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(4-丙基-环己基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(5-甲基己-2-基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(降冰片-2-基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(十氢-2-萘基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(10,11-二氢-5H-二苯并[a,d]-环庚烯-5-基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(3,3-二苯基丙基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(环辛基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-[4-(1-甲基乙基)-环己基]-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(1,3-二氢茚-2-基)-4-哌啶基]-喹啉-2-酮;
1,2,3,4-四氢-1-[1-(环辛基甲基)-4-哌啶基]-喹啉-2-酮;和
其药学上可接受的盐。
50.一种药物组合物,其特征在于,所述组合物含有权利要求33所述的化合物和至少一种药学上可接受的赋形剂。
51.一种治疗疼痛的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求33所述的镇痛化合物。
52.一种调节ORL1受体药理学响应的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求33所述的化合物。
53.一种药物组合物,其特征在于,所述组合物含有权利要求39所述的化合物和至少一种药学上可接受的赋形剂。
54.一种治疗疼痛的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求39所述的镇痛化合物。
55.一种调节ORL1受体药理学响应的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求39所述的化合物。
56.式(IIA)的化合物:
其中
R2选自氢,C1-10烷基,C3-12环烷基和卤素,所述烷基任选被氧代基团取代;
n是0-3的整数;
且ZR1是
其中,
Y1是R3-(C1-C12)烷基,R4-芳基,R5-杂芳基,R6-(C3-C12)环-烷基,R7-(C3-C7)杂环烷基,-CO2(C1-C6)烷基,CN或-C(O)NR8R9;Y2是氢或Y1;Y3是氢或(C1-C6)烷基;或Y1,Y2和Y3,和它们所连接的碳原子一起形成以下结构:
或
其中,r是0-3;w和u分别为0-3,条件是w和u的和是1-3;c和d分别是1或2;s是1-5;和环E是稠合的R4-苯基或R5-杂芳环;
R10是独立选自H,(C1-C6)烷基,-OR8,-(C1-C6)烷基-OR8,-NR8R9和-(C1-C6)烷基-NR8R9的1-3个取代基;
R11是独立选自R10,-CF3,-OCF3,NO2和卤素的1-3个取代基,或者相邻环碳原子上的R11取代基可以一起形成亚甲基二氧基或次乙基二氧基环;
R8和R9分别选自氢,(C1-C6)烷基,(C3-C12)环烷基,芳基和芳基(C1-C6)烷基;
R3是独立选自H,R4-芳基,R6-(C3-C12)环烷基,R5-杂芳基,R7-(C3-C7)杂环烷基,-NR8R9,-OR12和-S(O)0-2R12的1-3个取代基;
R6是独立选自H,(C1-C6)烷基,R4-芳基,-NR8R9,-OR12和-SR12的1-3个取代基;
R4是1-3个取代基,所述取代基独立选自氢,卤素,(C1-C6)烷基,R13-芳基,(C3-C12)环烷基,-CN,-CF3,-OR8,-(C1-C6)烷基-OR8,-OCF3,-NR8R9,-(C1-C6)烷基-NR8R9,-NHSO2R8,-SO2N(R14)2,-SO2R8,-SOR8,-SR8,-NO2,-CONR8R9,-NR9COR8,-COR8,-COCF3,-OCOR8,-OCO2R8,-COOR8,-(C1-C6)烷基-NHCOOC(CH3)3,-(C1-C6)烷基-NHCOCF3,-(C1-C6)烷基-NHSO2-(C1-C6)烷基,-(C1-C6)烷基-NHCONH-(C1-C6)-烷基和
其中,f是0-6;或者相邻环碳原子上的R4取代基可以一起形成亚甲基二氧基或次乙基二氧基环;
R5是独立选自氢,卤素,(C1-C6)烷基,R13-芳基,(C3-C12)环烷基,-CN,-CF3,-OR8,-(C1-C6)烷基-OR8,-OCF3,-NR8R9,-(C1-C6)烷基-NR8R9,-NHSO2R8,-SO2N(R14)2,-NO2,-CONR8R9,-NR9COR8,-COR8,-OCOR8,-OCO2R8和-COOR8的1-3个取代基;
R7是H,(C1-C6)烷基,-OR8,-(C1-C6)烷基-OR8,-NR8R9或-(C1-C6)烷基-NR8R9;
R12是H,(C1-C6)烷基,R4-芳基,-(C1-C6)烷基-OR8,-(C1-C6)烷基-NR8R9,-(C1-C6)烷基-SR8,或芳基(C1-C6)烷基;
R13是独立选自H,(C1-C6)烷基,(C1-C6)烷氧基和卤素的1-3个取代基;
R14独立选自H,(C1-C6)烷基和R13-C6H4-CH2-;
或其药学上可接受的盐。
57.一种药物组合物,其特征在于,所述组合物含有权利要求56所述的化合物和至少一种药学上可接受的赋形剂。
58.一种治疗疼痛的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求56所述的镇痛化合物。
59.一种调节ORL1受体药理学响应的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求56所述的化合物。
60.一种调节阿片样物质受体药理学响应的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求33所述的化合物。
61.一种调节阿片样物质受体药理学响应的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求39所述的化合物。
62.一种调节阿片样物质受体药理学响应的方法,其特征在于,所述方法包括对有此需要的患者施用有效量的权利要求56所述的化合物。
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