CN101918409A - 联芳基取代的二氮杂双环烷衍生物 - Google Patents
联芳基取代的二氮杂双环烷衍生物 Download PDFInfo
- Publication number
- CN101918409A CN101918409A CN2008801251989A CN200880125198A CN101918409A CN 101918409 A CN101918409 A CN 101918409A CN 2008801251989 A CN2008801251989 A CN 2008801251989A CN 200880125198 A CN200880125198 A CN 200880125198A CN 101918409 A CN101918409 A CN 101918409A
- Authority
- CN
- China
- Prior art keywords
- diazabicyclo
- pyridin
- methyl
- heptan
- indoles
- 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.)
- Pending
Links
- 125000005841 biaryl group Chemical group 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 259
- 239000000203 mixture Substances 0.000 claims abstract description 62
- 238000011282 treatment Methods 0.000 claims abstract description 41
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 30
- -1 4-thiadiazolyl group Chemical group 0.000 claims description 270
- 125000000217 alkyl group Chemical group 0.000 claims description 81
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 68
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 65
- 238000000034 method Methods 0.000 claims description 56
- 125000003545 alkoxy group Chemical group 0.000 claims description 41
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 125000004076 pyridyl group Chemical group 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 33
- 125000002521 alkyl halide group Chemical group 0.000 claims description 30
- 208000002193 Pain Diseases 0.000 claims description 29
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 28
- 150000002431 hydrogen Chemical class 0.000 claims description 27
- 201000010099 disease Diseases 0.000 claims description 26
- 230000036407 pain Effects 0.000 claims description 19
- 208000024827 Alzheimer disease Diseases 0.000 claims description 18
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims description 15
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims description 15
- 239000000556 agonist Substances 0.000 claims description 15
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 12
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 12
- 206010012289 Dementia Diseases 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 201000000980 schizophrenia Diseases 0.000 claims description 11
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 10
- 210000003169 central nervous system Anatomy 0.000 claims description 10
- 208000010877 cognitive disease Diseases 0.000 claims description 10
- 230000004770 neurodegeneration Effects 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- FOHZPZZBMVVWJG-DOTOQJQBSA-N (1s,5s)-3-[5-(1-benzothiophen-5-yl)pyridin-3-yl]-3,6-diazabicyclo[3.2.0]heptane Chemical compound C1=C2SC=CC2=CC(C=2C=NC=C(C=2)N2C[C@H]3NC[C@H]3C2)=C1 FOHZPZZBMVVWJG-DOTOQJQBSA-N 0.000 claims description 8
- BNBQQYFXBLBYJK-UHFFFAOYSA-N 2-pyridin-2-yl-1,3-oxazole Chemical compound C1=COC(C=2N=CC=CC=2)=N1 BNBQQYFXBLBYJK-UHFFFAOYSA-N 0.000 claims description 8
- 206010040070 Septic Shock Diseases 0.000 claims description 8
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 8
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 8
- 210000000056 organ Anatomy 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 238000002054 transplantation Methods 0.000 claims description 8
- 108700006085 alpha7 Nicotinic Acetylcholine Receptor Proteins 0.000 claims description 7
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 7
- 239000003693 atypical antipsychotic agent Substances 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 230000012010 growth Effects 0.000 claims description 7
- 208000013403 hyperactivity Diseases 0.000 claims description 7
- 108010052671 nicotinic receptor alpha4beta2 Proteins 0.000 claims description 7
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
- 230000001105 regulatory effect Effects 0.000 claims description 7
- NVPFDGXNZDLBDX-UHFFFAOYSA-N 3-pyridin-2-yl-1,2-oxazole Chemical compound O1C=CC(C=2N=CC=CC=2)=N1 NVPFDGXNZDLBDX-UHFFFAOYSA-N 0.000 claims description 6
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 6
- 231100000736 substance abuse Toxicity 0.000 claims description 6
- 208000011117 substance-related disease Diseases 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 208000000094 Chronic Pain Diseases 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 206010065390 Inflammatory pain Diseases 0.000 claims description 5
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 5
- 208000005298 acute pain Diseases 0.000 claims description 5
- 102000047725 alpha7 Nicotinic Acetylcholine Receptor Human genes 0.000 claims description 5
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 5
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 230000036039 immunity Effects 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 230000007823 neuropathy Effects 0.000 claims description 5
- 201000001119 neuropathy Diseases 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 5
- 239000000651 prodrug Substances 0.000 claims description 5
- 229940002612 prodrug Drugs 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 201000009032 substance abuse Diseases 0.000 claims description 5
- 230000009529 traumatic brain injury Effects 0.000 claims description 5
- 230000029663 wound healing Effects 0.000 claims description 5
- KWTSXDURSIMDCE-MRVPVSSYSA-N (R)-amphetamine Chemical compound C[C@@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-MRVPVSSYSA-N 0.000 claims description 4
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 claims description 4
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 4
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- 201000010374 Down Syndrome Diseases 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 206010039966 Senile dementia Diseases 0.000 claims description 4
- 206010053879 Sepsis syndrome Diseases 0.000 claims description 4
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 claims description 4
- 206010044248 Toxic shock syndrome Diseases 0.000 claims description 4
- 231100000650 Toxic shock syndrome Toxicity 0.000 claims description 4
- 206010044688 Trisomy 21 Diseases 0.000 claims description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- 230000001154 acute effect Effects 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 claims description 4
- 208000026278 immune system disease Diseases 0.000 claims description 4
- 230000002757 inflammatory effect Effects 0.000 claims description 4
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 229940099204 ritalin Drugs 0.000 claims description 4
- 230000036303 septic shock Effects 0.000 claims description 4
- ZFRKQXVRDFCRJG-UHFFFAOYSA-N skatole Chemical compound C1=CC=C2C(C)=CNC2=C1 ZFRKQXVRDFCRJG-UHFFFAOYSA-N 0.000 claims description 4
- PRPQOUIYRIWCMI-DOTOQJQBSA-N 5-[5-[(1s,5s)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyridin-3-yl]-1h-pyrrolo[2,3-b]pyridine Chemical compound N1=C2NC=CC2=CC(C=2C=NC=C(C=2)N2C[C@@H]3CN([C@@H]3C2)C)=C1 PRPQOUIYRIWCMI-DOTOQJQBSA-N 0.000 claims description 3
- MUYABXKYYURZSJ-XJKSGUPXSA-N 5-[6-[(1s,5s)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyrazin-2-yl]-2-(trifluoromethyl)-1h-indole Chemical class C1=C2NC(C(F)(F)F)=CC2=CC(C=2C=NC=C(N=2)N2C[C@@H]3CN([C@@H]3C2)C)=C1 MUYABXKYYURZSJ-XJKSGUPXSA-N 0.000 claims description 3
- NPQLIXMTEVLIBP-KBXCAEBGSA-N 6-[5-[(1s,5s)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyridin-3-yl]-1h-benzimidazole Chemical class C1=C2NC=NC2=CC(C=2C=NC=C(C=2)N2C[C@@H]3CN([C@@H]3C2)C)=C1 NPQLIXMTEVLIBP-KBXCAEBGSA-N 0.000 claims description 3
- KDTOIZLLWBQRLV-GOEBONIOSA-N 7-[5-[(1s,5s)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyridin-3-yl]-1h-pyrrolo[2,3-c]pyridine Chemical compound C([C@@H]1CN([C@@H]1C1)C)N1C(C=1)=CN=CC=1C1=NC=CC2=C1NC=C2 KDTOIZLLWBQRLV-GOEBONIOSA-N 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 229960003162 iloperidone Drugs 0.000 claims description 3
- XMXHEBAFVSFQEX-UHFFFAOYSA-N iloperidone Chemical compound COC1=CC(C(C)=O)=CC=C1OCCCN1CCC(C=2C3=CC=C(F)C=C3ON=2)CC1 XMXHEBAFVSFQEX-UHFFFAOYSA-N 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 208000021267 infertility disease Diseases 0.000 claims description 3
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- GJJFMKBJSRMPLA-HIFRSBDPSA-N (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-1-cyclopropanecarboxamide Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1CN GJJFMKBJSRMPLA-HIFRSBDPSA-N 0.000 claims description 2
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims description 2
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 2
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 2
- VACQPNANKMBSNB-UQBPGWFLSA-N 1-(benzenesulfonyl)-3-[5-[(1s,5s)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyridin-3-yl]indole Chemical class C([C@@H]1CN([C@@H]1C1)C)N1C(C=1)=CN=CC=1C(C1=CC=CC=C11)=CN1S(=O)(=O)C1=CC=CC=C1 VACQPNANKMBSNB-UQBPGWFLSA-N 0.000 claims description 2
- YFGHCGITMMYXAQ-UHFFFAOYSA-N 2-[(diphenylmethyl)sulfinyl]acetamide Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 claims description 2
- ISRLFBABYLJOBL-UHFFFAOYSA-N 3-(1H-indazol-3-yl)-1,2-oxazole Chemical compound O1C=CC(C=2C3=CC=CC=C3NN=2)=N1 ISRLFBABYLJOBL-UHFFFAOYSA-N 0.000 claims description 2
- UBOOKRVGOBKDMM-UHFFFAOYSA-N 3h-imidazo[4,5-c]pyridine Chemical compound C1=NC=C2NC=NC2=C1 UBOOKRVGOBKDMM-UHFFFAOYSA-N 0.000 claims description 2
- BIEMHHVPBROVNK-MAUKXSAKSA-N 5-[5-[(1s,5s)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyridin-3-yl]-2-(trifluoromethyl)-1h-indole Chemical class C1=C2NC(C(F)(F)F)=CC2=CC(C=2C=NC=C(C=2)N2C[C@@H]3CN([C@@H]3C2)C)=C1 BIEMHHVPBROVNK-MAUKXSAKSA-N 0.000 claims description 2
- 102000012440 Acetylcholinesterase Human genes 0.000 claims description 2
- 108010022752 Acetylcholinesterase Proteins 0.000 claims description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims description 2
- 229940022698 acetylcholinesterase Drugs 0.000 claims description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 2
- 229960003805 amantadine Drugs 0.000 claims description 2
- 125000005605 benzo group Chemical group 0.000 claims description 2
- 125000005873 benzo[d]thiazolyl group Chemical group 0.000 claims description 2
- YXKTVDFXDRQTKV-HNNXBMFYSA-N benzphetamine Chemical compound C([C@H](C)N(C)CC=1C=CC=CC=1)C1=CC=CC=C1 YXKTVDFXDRQTKV-HNNXBMFYSA-N 0.000 claims description 2
- 229960002837 benzphetamine Drugs 0.000 claims description 2
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 claims description 2
- 229960001058 bupropion Drugs 0.000 claims description 2
- 229960002896 clonidine Drugs 0.000 claims description 2
- 230000000994 depressogenic effect Effects 0.000 claims description 2
- 229960000632 dexamfetamine Drugs 0.000 claims description 2
- 229950005223 levamfetamine Drugs 0.000 claims description 2
- 229960000600 milnacipran Drugs 0.000 claims description 2
- 229960001165 modafinil Drugs 0.000 claims description 2
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 claims description 2
- 229960005017 olanzapine Drugs 0.000 claims description 2
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 claims description 2
- 229960000761 pemoline Drugs 0.000 claims description 2
- NRNCYVBFPDDJNE-UHFFFAOYSA-N pemoline Chemical compound O1C(N)=NC(=O)C1C1=CC=CC=C1 NRNCYVBFPDDJNE-UHFFFAOYSA-N 0.000 claims description 2
- 229960001534 risperidone Drugs 0.000 claims description 2
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 claims description 2
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 claims description 2
- 229960003946 selegiline Drugs 0.000 claims description 2
- 229960000607 ziprasidone Drugs 0.000 claims description 2
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 claims description 2
- 229960004496 zotepine Drugs 0.000 claims description 2
- HDOZVRUNCMBHFH-UHFFFAOYSA-N zotepine Chemical compound CN(C)CCOC1=CC2=CC=CC=C2SC2=CC=C(Cl)C=C12 HDOZVRUNCMBHFH-UHFFFAOYSA-N 0.000 claims description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims 2
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 claims 1
- 229930003427 Vitamin E Natural products 0.000 claims 1
- 229940127236 atypical antipsychotics Drugs 0.000 claims 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims 1
- 235000019154 vitamin C Nutrition 0.000 claims 1
- 239000011718 vitamin C Substances 0.000 claims 1
- 235000019165 vitamin E Nutrition 0.000 claims 1
- 229940046009 vitamin E Drugs 0.000 claims 1
- 239000011709 vitamin E Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 abstract description 5
- 239000002585 base Substances 0.000 description 105
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 95
- 239000000047 product Substances 0.000 description 76
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 75
- 235000019439 ethyl acetate Nutrition 0.000 description 46
- 238000005160 1H NMR spectroscopy Methods 0.000 description 44
- 230000008878 coupling Effects 0.000 description 41
- 238000010168 coupling process Methods 0.000 description 41
- 238000005859 coupling reaction Methods 0.000 description 41
- 229910052760 oxygen Inorganic materials 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- 238000004364 calculation method Methods 0.000 description 36
- 101150003085 Pdcl gene Proteins 0.000 description 35
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 34
- 239000001301 oxygen Substances 0.000 description 33
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- 230000000694 effects Effects 0.000 description 29
- 229940071104 xylenesulfonate Drugs 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 27
- 229910052799 carbon Inorganic materials 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 19
- 239000000370 acceptor Substances 0.000 description 19
- 239000002253 acid Substances 0.000 description 19
- 229910052796 boron Inorganic materials 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 18
- 150000001721 carbon Chemical group 0.000 description 18
- 239000003054 catalyst Substances 0.000 description 18
- 229910052763 palladium Inorganic materials 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 16
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 16
- 238000012545 processing Methods 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 13
- 229910004298 SiO 2 Inorganic materials 0.000 description 13
- 238000011097 chromatography purification Methods 0.000 description 13
- 125000000623 heterocyclic group Chemical group 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 229910052717 sulfur Inorganic materials 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000003513 alkali Substances 0.000 description 12
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 11
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- 238000010790 dilution Methods 0.000 description 11
- 239000012895 dilution Substances 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 229960002715 nicotine Drugs 0.000 description 11
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 10
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 10
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 10
- 125000004414 alkyl thio group Chemical group 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 10
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 9
- 210000004556 brain Anatomy 0.000 description 9
- 238000006555 catalytic reaction Methods 0.000 description 9
- 229940027564 cytisine Drugs 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 102000015296 acetylcholine-gated cation-selective channel activity proteins Human genes 0.000 description 8
- 108040006409 acetylcholine-gated cation-selective channel activity proteins Proteins 0.000 description 8
- 239000004327 boric acid Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 239000002502 liposome Substances 0.000 description 8
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000012266 salt solution Substances 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 235000008504 concentrate Nutrition 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- WGLLSSPDPJPLOR-UHFFFAOYSA-N tetramethylethylene Natural products CC(C)=C(C)C WGLLSSPDPJPLOR-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 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 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 6
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- 210000004204 blood vessel Anatomy 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 6
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 6
- NKBWMBRPILTCRD-UHFFFAOYSA-N 2-Methylheptanoic acid Chemical compound CCCCCC(C)C(O)=O NKBWMBRPILTCRD-UHFFFAOYSA-N 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 5
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 5
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 5
- 125000004181 carboxyalkyl group Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000019771 cognition Effects 0.000 description 5
- 230000001149 cognitive effect Effects 0.000 description 5
- 230000003920 cognitive function Effects 0.000 description 5
- 230000002950 deficient Effects 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- ANJTVLIZGCUXLD-UHFFFAOYSA-N ent-cytisine Natural products C1NCC2CN3C(=O)C=CC=C3C1C2 ANJTVLIZGCUXLD-UHFFFAOYSA-N 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 125000001113 thiadiazolyl group Chemical group 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- 239000000080 wetting agent Substances 0.000 description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- ANJTVLIZGCUXLD-BDAKNGLRSA-N (-)-Cytisine Natural products C1NC[C@@H]2CN3C(=O)C=CC=C3[C@H]1C2 ANJTVLIZGCUXLD-BDAKNGLRSA-N 0.000 description 4
- QFHVHZJGQWMBTE-UHFFFAOYSA-N 2-(trifluoromethyl)-1h-indole Chemical class C1=CC=C2NC(C(F)(F)F)=CC2=C1 QFHVHZJGQWMBTE-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 4
- OKSJGKZXJBALIC-UHFFFAOYSA-N [O]c1cccnc1 Chemical compound [O]c1cccnc1 OKSJGKZXJBALIC-UHFFFAOYSA-N 0.000 description 4
- ILLGYRJAYAAAEW-QMMMGPOBSA-N abt-418 Chemical compound CN1CCC[C@H]1C1=CC(C)=NO1 ILLGYRJAYAAAEW-QMMMGPOBSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000002131 composite material Substances 0.000 description 4
- 229930017327 cytisine Natural products 0.000 description 4
- ANJTVLIZGCUXLD-DTWKUNHWSA-N cytisine Chemical compound C1NC[C@H]2CN3C(=O)C=CC=C3[C@@H]1C2 ANJTVLIZGCUXLD-DTWKUNHWSA-N 0.000 description 4
- 238000013016 damping Methods 0.000 description 4
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 230000008030 elimination Effects 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 4
- 239000001530 fumaric acid Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- WZAKJCZTMYYSMD-UHFFFAOYSA-N heptane;hydroiodide Chemical compound I.CCCCCCC WZAKJCZTMYYSMD-UHFFFAOYSA-N 0.000 description 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 150000002632 lipids Chemical class 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
- 230000015654 memory Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- XLTANAWLDBYGFU-VTLKBQQISA-N methyllycaconitine Chemical compound C([C@]12CN([C@@H]3[C@@]4(O)[C@]5(O)[C@H]6[C@@H](OC)[C@@H]([C@H](C5)OC)C[C@H]6[C@@]3([C@@H]1[C@@H]4OC)[C@@H](OC)CC2)CC)OC(=O)C1=CC=CC=C1N1C(=O)C[C@H](C)C1=O XLTANAWLDBYGFU-VTLKBQQISA-N 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 4
- 239000006072 paste Substances 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 210000000582 semen Anatomy 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- SOSPMXMEOFGPIM-UHFFFAOYSA-N 3,5-dibromopyridine Chemical compound BrC1=CN=CC(Br)=C1 SOSPMXMEOFGPIM-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- 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 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 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 3
- 229930006000 Sucrose Natural products 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 206010053648 Vascular occlusion Diseases 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 235000010419 agar Nutrition 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 125000004171 alkoxy aryl group Chemical group 0.000 description 3
- 125000005081 alkoxyalkoxyalkyl group Chemical group 0.000 description 3
- 125000005133 alkynyloxy group Chemical group 0.000 description 3
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 3
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 125000005110 aryl thio group Chemical group 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 239000000440 bentonite Substances 0.000 description 3
- 235000012216 bentonite Nutrition 0.000 description 3
- 229910000278 bentonite Inorganic materials 0.000 description 3
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 3
- 150000005347 biaryls Chemical group 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000006251 butylcarbonyl group Chemical group 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000004567 concrete Substances 0.000 description 3
- 235000009508 confectionery Nutrition 0.000 description 3
- GCUVBACNBHGZRS-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(diphenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.c1cc[c-](c1)P(c1ccccc1)c1ccccc1 GCUVBACNBHGZRS-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000012417 linear regression Methods 0.000 description 3
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 208000015122 neurodegenerative disease Diseases 0.000 description 3
- 230000009871 nonspecific binding Effects 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 210000000664 rectum Anatomy 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 208000021331 vascular occlusion disease Diseases 0.000 description 3
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 2
- 229940058015 1,3-butylene glycol Drugs 0.000 description 2
- WQADWIOXOXRPLN-UHFFFAOYSA-N 1,3-dithiane Chemical compound C1CSCSC1 WQADWIOXOXRPLN-UHFFFAOYSA-N 0.000 description 2
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 description 2
- RJWUMFHQJJBBOD-UHFFFAOYSA-N 2-methylheptadecane Chemical compound CCCCCCCCCCCCCCCC(C)C RJWUMFHQJJBBOD-UHFFFAOYSA-N 0.000 description 2
- LTBWKAYPXIIVPC-UHFFFAOYSA-N 3-bromo-9h-carbazole Chemical compound C1=CC=C2C3=CC(Br)=CC=C3NC2=C1 LTBWKAYPXIIVPC-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- CIKZMEIJDDBAGA-KPVRICSOSA-N 4-methylbenzenesulfonic acid;5-[5-[(1s,5s)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyridin-3-yl]-1h-pyrrolo[2,3-b]pyridine Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.N1=C2NC=CC2=CC(C=2C=NC=C(C=2)N2C[C@@H]3CN([C@@H]3C2)C)=C1 CIKZMEIJDDBAGA-KPVRICSOSA-N 0.000 description 2
- BQINBAYTRRYGEK-QFBILLFUSA-N 5-[5-[(1s,5s)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyridin-3-yl]-1h-indole Chemical class C1=C2NC=CC2=CC(C=2C=NC=C(C=2)N2C[C@@H]3CN([C@@H]3C2)C)=C1 BQINBAYTRRYGEK-QFBILLFUSA-N 0.000 description 2
- GDQXDVJFMLNXHX-UHFFFAOYSA-N 5-bromo-3-methyl-1h-indole Chemical compound C1=C(Br)C=C2C(C)=CNC2=C1 GDQXDVJFMLNXHX-UHFFFAOYSA-N 0.000 description 2
- RDSVSEFWZUWZHW-UHFFFAOYSA-N 7-bromo-1h-indole Chemical compound BrC1=CC=CC2=C1NC=C2 RDSVSEFWZUWZHW-UHFFFAOYSA-N 0.000 description 2
- 108010013043 Acetylesterase Proteins 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 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 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 125000003302 alkenyloxy group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000001118 alkylidene group Chemical group 0.000 description 2
- 125000004419 alkynylene group Chemical group 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 230000007131 anti Alzheimer effect Effects 0.000 description 2
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 2
- 125000005164 aryl thioalkyl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 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 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical group CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- 235000019437 butane-1,3-diol Nutrition 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 2
- 125000005366 cycloalkylthio group Chemical group 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000000645 desinfectant Substances 0.000 description 2
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 2
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 2
- 229940093471 ethyl oleate Drugs 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 235000011194 food seasoning agent Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000004967 formylalkyl group Chemical group 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000005367 heteroarylalkylthio group Chemical group 0.000 description 2
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 2
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 2
- 125000005945 imidazopyridyl group Chemical group 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 206010027175 memory impairment Diseases 0.000 description 2
- 125000005358 mercaptoalkyl group Chemical group 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 230000036651 mood Effects 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 230000007472 neurodevelopment Effects 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 210000004681 ovum Anatomy 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 238000011020 pilot scale process Methods 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- YRVIKLBSVVNSHF-JTQLQIEISA-N pozanicline Chemical compound CC1=NC=CC=C1OC[C@H]1NCCC1 YRVIKLBSVVNSHF-JTQLQIEISA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005728 strengthening Methods 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- DUVYHIZCDHCKLV-KCJUWKMLSA-N (1r,5r)-3-(5-bromopyridin-3-yl)-6-methyl-3,6-diazabicyclo[3.2.0]heptane Chemical compound C([C@H]1CN([C@H]1C1)C)N1C1=CN=CC(Br)=C1 DUVYHIZCDHCKLV-KCJUWKMLSA-N 0.000 description 1
- OGULMRQWNAMFPB-GMSGAONNSA-N (1r,5s)-6-(5-bromopyridin-3-yl)-3,6-diazabicyclo[3.2.0]heptane Chemical compound BrC1=CN=CC(N2[C@@H]3CNC[C@@H]3C2)=C1 OGULMRQWNAMFPB-GMSGAONNSA-N 0.000 description 1
- GVEXLWBYZVDZNF-LDYMZIIASA-N (1r,5s)-6-(5-bromopyridin-3-yl)-3-methyl-3,6-diazabicyclo[3.2.0]heptane Chemical compound C([C@H]1CN(C[C@H]11)C)N1C1=CN=CC(Br)=C1 GVEXLWBYZVDZNF-LDYMZIIASA-N 0.000 description 1
- DUVYHIZCDHCKLV-GZMMTYOYSA-N (1s,5s)-3-(5-bromopyridin-3-yl)-6-methyl-3,6-diazabicyclo[3.2.0]heptane Chemical compound C([C@@H]1CN([C@@H]1C1)C)N1C1=CN=CC(Br)=C1 DUVYHIZCDHCKLV-GZMMTYOYSA-N 0.000 description 1
- AYYHTQXPQNZSHX-NKWVEPMBSA-N (1s,5s)-3-(6-chloropyrazin-2-yl)-3,6-diazabicyclo[3.2.0]heptane Chemical compound ClC1=CN=CC(N2C[C@H]3NC[C@H]3C2)=N1 AYYHTQXPQNZSHX-NKWVEPMBSA-N 0.000 description 1
- FKJJMKVTVJVZKH-JGVFFNPUSA-N (1s,5s)-3-(6-chloropyrazin-2-yl)-6-methyl-3,6-diazabicyclo[3.2.0]heptane Chemical compound C([C@@H]1CN([C@@H]1C1)C)N1C1=CN=CC(Cl)=N1 FKJJMKVTVJVZKH-JGVFFNPUSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- NXVDLRZYGVQORS-JOYOIKCWSA-N (3as,6as)-1-(5-bromopyridin-3-yl)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole Chemical class C([C@H]1CN(C[C@H]11)C)CN1C1=CN=CC(Br)=C1 NXVDLRZYGVQORS-JOYOIKCWSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 229930182840 (S)-nicotine Natural products 0.000 description 1
- GVRWIAHBVAYKIZ-FNORWQNLSA-N (e)-dec-3-ene Chemical compound CCCCCC\C=C\CC GVRWIAHBVAYKIZ-FNORWQNLSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 1
- HCMLNPZTRYNCMA-UHFFFAOYSA-N 1,3-benzodithiole Chemical compound C1=CC=C2SCSC2=C1 HCMLNPZTRYNCMA-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 1
- VDWLCYCWLIKWBV-UHFFFAOYSA-N 1-(benzenesulfonyl)indole Chemical class C1=CC2=CC=CC=C2N1S(=O)(=O)C1=CC=CC=C1 VDWLCYCWLIKWBV-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 description 1
- WYBQOWXCLDXZNR-UHFFFAOYSA-N 2-(1,3,2-benzodioxaborol-2-yl)-1,3,2-benzodioxaborole Chemical compound O1C2=CC=CC=C2OB1B1OC2=CC=CC=C2O1 WYBQOWXCLDXZNR-UHFFFAOYSA-N 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- GGRLKHMFMUXIOG-UHFFFAOYSA-M 2-acetyloxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC(=O)OCC[N+](C)(C)C GGRLKHMFMUXIOG-UHFFFAOYSA-M 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 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 description 1
- 125000005975 2-phenylethyloxy group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- XKEYAOJRNJYJMM-UHFFFAOYSA-N 3,6-diazabicyclo[3.2.0]heptane Chemical group C1NCC2CNC21 XKEYAOJRNJYJMM-UHFFFAOYSA-N 0.000 description 1
- PFBQQOLEUPSSLB-UHFFFAOYSA-N 3,6-diazabicyclo[3.2.0]heptane-3-carboxylic acid Chemical compound C1N(C(=O)O)CC2CNC21 PFBQQOLEUPSSLB-UHFFFAOYSA-N 0.000 description 1
- XODWLINXEKYQPP-UHFFFAOYSA-N 3,6-diazabicyclo[3.2.0]heptane-6-carboxylic acid Chemical compound C1NCC2N(C(=O)O)CC21 XODWLINXEKYQPP-UHFFFAOYSA-N 0.000 description 1
- MFTVEBMBTBLCEF-KSFYIVLOSA-N 3-[5-[(1s,5s)-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyridin-3-yl]-9h-carbazole Chemical compound C1=CC=C2C3=CC(C=4C=NC=C(C=4)N4C[C@H]5NC[C@H]5C4)=CC=C3NC2=C1 MFTVEBMBTBLCEF-KSFYIVLOSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- BUBRFWDEAVIFMV-UHFFFAOYSA-N 3-chloro-6-phenylpyridazine Chemical compound N1=NC(Cl)=CC=C1C1=CC=CC=C1 BUBRFWDEAVIFMV-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- GUUULVAMQJLDSY-UHFFFAOYSA-N 4,5-dihydro-1,2-thiazole Chemical compound C1CC=NS1 GUUULVAMQJLDSY-UHFFFAOYSA-N 0.000 description 1
- WEDKTMOIKOKBSH-UHFFFAOYSA-N 4,5-dihydrothiadiazole Chemical compound C1CN=NS1 WEDKTMOIKOKBSH-UHFFFAOYSA-N 0.000 description 1
- CPGFQLIXICGYSN-UHFFFAOYSA-N 4,7-diazabicyclo[4.2.0]octane Chemical group C1NCCC2CNC21 CPGFQLIXICGYSN-UHFFFAOYSA-N 0.000 description 1
- CBOQYUWSGVWBCH-UHFFFAOYSA-N 4-$l^{1}-oxidanylpyridine Chemical compound O=C1C=CN=C[CH]1 CBOQYUWSGVWBCH-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- STVHMYNPQCLUNJ-UHFFFAOYSA-N 5-bromo-1h-indazole Chemical compound BrC1=CC=C2NN=CC2=C1 STVHMYNPQCLUNJ-UHFFFAOYSA-N 0.000 description 1
- LPTVWZSQAIDCEB-UHFFFAOYSA-N 5-bromo-1h-pyrrolo[2,3-b]pyridine Chemical compound BrC1=CN=C2NC=CC2=C1 LPTVWZSQAIDCEB-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- HTQAZKOPQOXNHI-UHFFFAOYSA-N 7-bromo-1h-pyrrolo[2,3-c]pyridine Chemical compound BrC1=NC=CC2=C1NC=C2 HTQAZKOPQOXNHI-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 125000006847 BOC protecting group Chemical group 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- FHMAIQCXHWLYKH-UHFFFAOYSA-N C1(=CC=CC=C1)S(=O)(=O)N1C=C(C2=CC=CC=C12)OB(O)O Chemical compound C1(=CC=CC=C1)S(=O)(=O)N1C=C(C2=CC=CC=C12)OB(O)O FHMAIQCXHWLYKH-UHFFFAOYSA-N 0.000 description 1
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000009660 Cholinergic Receptors Human genes 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- ZSLGDWXKCUFAKJ-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C12.N1(CCOCC1)C=1N=NOC1 Chemical compound N1=CC=CC2=CC=CC=C12.N1(CCOCC1)C=1N=NOC1 ZSLGDWXKCUFAKJ-UHFFFAOYSA-N 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- QACUPNAKIPYZAW-RMQWDSPGSA-N O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O 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)OC(O)[C@H](O)[C@H]1O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O QACUPNAKIPYZAW-RMQWDSPGSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 239000005922 Phosphane Substances 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 241000219161 Theobroma Species 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- NTKYMBKHSGRGCB-UHFFFAOYSA-N [O].BrC1=CC=CC=C1 Chemical compound [O].BrC1=CC=CC=C1 NTKYMBKHSGRGCB-UHFFFAOYSA-N 0.000 description 1
- VAKKJWXZRREDEX-UHFFFAOYSA-N [O].CC#CC Chemical compound [O].CC#CC VAKKJWXZRREDEX-UHFFFAOYSA-N 0.000 description 1
- HHNKDEPSLDAJMU-UHFFFAOYSA-N [O]c1ccc(nc1)C(F)(F)F Chemical compound [O]c1ccc(nc1)C(F)(F)F HHNKDEPSLDAJMU-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 1
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000030120 acrosome reaction Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001343 alkyl silanes Chemical group 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 125000005336 allyloxy group Chemical group 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003429 antifungal agent Substances 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
- 238000003556 assay Methods 0.000 description 1
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 239000000064 cholinergic agonist Substances 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000003931 cognitive performance Effects 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000003792 cranial nerve Anatomy 0.000 description 1
- 150000005676 cyclic carbonates Chemical class 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 description 1
- 125000006639 cyclohexyl carbonyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- JLQNHALFVCURHW-UHFFFAOYSA-N cyclooctasulfur Chemical compound S1SSSSSSS1 JLQNHALFVCURHW-UHFFFAOYSA-N 0.000 description 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 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 description 1
- 230000006735 deficit Effects 0.000 description 1
- 229920006237 degradable polymer Polymers 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000004639 dihydroindenyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- MMXKVMNBHPAILY-UHFFFAOYSA-N dodecanoic acid ethyl ester Natural products CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 1
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 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
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000028023 exocytosis Effects 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 description 1
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 230000008571 general function Effects 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- RPCVIAXDAUMJJP-PZBABLGHSA-N ispronicline Chemical compound CN[C@@H](C)C\C=C\C1=CN=CC(OC(C)C)=C1 RPCVIAXDAUMJJP-PZBABLGHSA-N 0.000 description 1
- 229950001646 ispronicline Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical group [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229960000967 memantine hydrochloride Drugs 0.000 description 1
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 1
- 230000006996 mental state Effects 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 125000003136 n-heptyl 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])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 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 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- 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 description 1
- 125000005447 octyloxy 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])O* 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 229910000064 phosphane Inorganic materials 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000002745 poly(ortho ester) Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 238000011809 primate model Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical group CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 230000009151 sensory gating Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- MKTAGSRKQIGEBH-SSDOTTSWSA-N tebanicline Chemical compound C1=NC(Cl)=CC=C1OC[C@@H]1NCC1 MKTAGSRKQIGEBH-SSDOTTSWSA-N 0.000 description 1
- FQJRZOYTUCCBQR-UHFFFAOYSA-N tert-butyl 2-methylheptanoate Chemical compound CCCCCC(C)C(=O)OC(C)(C)C FQJRZOYTUCCBQR-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 239000010496 thistle oil Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Psychiatry (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Psychology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Toxicology (AREA)
- Communicable Diseases (AREA)
- Transplantation (AREA)
- Oncology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及式(I)的联芳基取代的二氮杂双环烷,更具体地是联环杂芳基取代的稠合的二氮杂双环烷衍生物,包含这样的化合物的组合物,以及这样的化合物用于治疗或预防与α7和α4β2nAChR活性相关的状况和病症。
Description
与相关申请的交叉参考
本申请要求2007年11月21日提交的临时申请系列号60/989,607的优先权。
发明领域
本发明涉及联芳基取代的二氮杂双环烷,且更具体地涉及二环杂芳基取代的稠合的二氮杂双环烷衍生物,包含此种化合物的组合物,使用此种化合物及组合物预防或治疗状况和病症的方法,制备此种化合物的方法,以及在制备该化合物的过程中获得的中间体。
相关技术的描述
烟碱性乙酰胆碱受体(nAChRs)广泛分布遍及中枢(CNS)和外周(PNS)神经系统。此种受体在调节CNS功能中起着重要的作用,尤其是通过调制多种神经递质例如乙酰胆碱、去甲肾上腺素、多巴胺、5-羟色胺及GABA的释放。因此,烟碱性受体介导多种生理学作用,并且已经被靶向用于治疗与认知功能、学习及记忆、神经变性、疼痛及炎症、精神病及感觉门控、心境与情绪等有关的病症。
植物生物碱烟碱与nAChRs的所有亚型相互作用。虽然烟碱已被证明具有很多生物学活性,但由烟碱介导的所有作用并非都是合乎需要的。例如,烟碱在治疗剂量发挥胃肠及心血管副作用,并且是上瘾及急性毒性(acutelyoxic)的。对仅与nAChRs的某些亚型相互作用具有选择性的配体提供了达到具有改进的安全余量(margin)的有益治疗作用的潜能。
在CNS及外周中已观察到很多nAChR亚型。每个亚型对调节全部生理学功能具有不同的作用。通常,nAChRs是由五聚体构建的离子通道。在神经元组织中已经鉴定了至少12个亚单位蛋白质,α2-α10及β2-β4。这些亚单位提供导致不同受体亚型的大量同构(homomeric)及异构(heteromeric)组合。例如,在脑组织中负责烟碱的高亲和力结合的主要受体是(α4)2(β2)3(α4β2亚型),而另一种主要受体群体是同五聚 体(homopentamer)(α7)5(α7亚型)。
α7及α4β2nAChRs:起多种作用的受体
α7及α4β2nAChRs在多种过程中起作用,所述过程包括认知功能、保护免于神经元变性、减轻疼痛及精神分裂症;以及似乎与神经元活性不大相关的其它功能,例如血管发生及卵受精过程中的精子顶体反应。
α-7nAChRs和神经发育方面例如脑神经发生牵连。(Falk,L.等人,Developmental Brain Research 142:151-160,2003;Tsuneki,H.,等人,J.Physiol.(London)547:169-179,2003;Adams,C.E.,等人,Developmental Brain Research 139:175-187,2002)。同样,调节α7nAChRs可以用于预防或治疗与神经发育受损有关的状况或病症,例如精神分裂症。(Sawa A.,Mol.Med.9:3-9,2003)。
α7及α4β2nAChRs在提高包括学习、记忆及注意力方面在内的认知功能中起着重要作用(Levin,E.D.,J.Neurobiol.53:633-640,2002)。例如,除了其它全身性活动以外,α7nAChRs还与和注意力缺陷障碍(ADD)、注意力不集中的过度反应症(ADHD)、阿尔茨海默病(AD)、轻度认知缺损、老年性痴呆、与Lewy小体有关的痴呆、与唐氏综合征有关的痴呆、艾滋病痴呆、Pick氏病以及与精神分裂症相关的认知缺陷相关的状况和病症有联系。α4β2受体亚型与注意力、认知、精神分裂症、癫痫及疼痛控制牵连(Paterson和Norberg,Progress in Neurobiology 6175-111,2000)。
除了其在提高认知功能中的作用以外,含α7的nAChRs还与体外(Jonnala,R.B.和Buccafusco,J.J.,J.Neurosci.Res.66:565-572,2001)及体内(Shimohama,S.等人,Brain Res.779:359-363,1998)的烟碱的神经保护作用有关。更具体地,神经变性构成几种进行性CNS病症的基础,所述病症例如阿尔茨海默病、帕金森病、肌萎缩性侧索硬化症、Huntington氏病、具有Lewy小体的痴呆以及由创伤性脑损伤造成的CNS功能减弱。例如,与阿尔茨海默病相联系的由β-淀粉状肽造成的α7nAChRs功能损害被暗示为与该疾病相关的认知缺陷发展中的关键因素(Liu,Q.-S.,Kawai,H.,Berg,D.K.,PNAS 98:4734-4739,2001)。α7nAChRs激活可阻断这种神经毒性(Kihara,T.等人,J.Biol.Chem.276:13541-13546,2001)。同样,提高α7活性的选择性配体可对抗阿尔茨海默病及其它神经变性疾病的缺陷。
精神分裂症是以知觉、认知及情绪中的异常为特点的复杂性疾病。大量证据暗示α7nAChRs牵涉于这种疾病,包括在死后的患者中测量的这些受体的缺陷(Leonard,S.Eur.J.Pharmacol.393:237-242,2000)。感觉处理(门控)中的缺陷是精神分裂症的特征之一。运作在α7nAChR的烟碱性受体可使这些缺陷正常化(Adler L.E.等人,Schizophrenia Bull.24:189-202,1998;Stevens,K.E.等人,Psychopharmacology 136:320-327,1998)。
与精神分裂症相关的认知缺损通常限制患者正常发挥功能的能力,而这是一种用常见治疗(例如用非典型抗精神病药治疗)不能充分治疗的症状。(Rowley,M.等人,J.Med.Chem.44:477-501,2001)。这样的认知缺陷与烟碱性胆碱能系统的功能异常(尤其伴随活性受体减少)有关联。(Friedman,J.I.等人,Biol Psychiatry,51:349-357,2002)。
血管发生,与新血管的生长有关的过程,在有益的全身性功能例如伤口愈合、皮肤移植物的血管形成以及循环的增强(例如在血管闭塞周围的循环增强)中是很重要的。非选择性nAChR激动剂如烟碱可刺激血管发生(Heeschen,C.等人,Nature Medicine 7:833-839,2001)。改善的血管发生涉及α7nAChR激活(Heeschen,C.等人.,J.Clin.Invest.110:527-536,2002)。
脊髓中的α7nAChRs群体调节与烟碱性化合物的疼痛减轻作用相关的5-羟色胺能的传递(Cordero-Erausquin,M.和Changeux,J.-P.PNAS 98:2803-2807,2001)。α7nAChR配体是治疗疼痛状态,包括急性疼痛及外科手术后疼痛;以及慢性疼痛状态,包括炎性疼痛及神经病疼痛的治疗靶。而且,α7nAChRs是在与炎症反应有关的初级巨噬细胞的表面上表达的。α7受体的激活抑制TNF释放以及引发炎症反应的其它细胞因子(Wang,H.等人,Nature 421:384-388,2003)。TNF介导的疾病包括,例如,类风湿性关节炎、Crohn氏病、溃疡性结肠炎、炎性肠病、器官移植排斥、与器官移植有关的急性免疫性疾病、与器官移植有关的慢性免疫性疾病、感染性休克、中毒性休克综合征、脓毒病综合征、抑郁及类风湿性脊椎炎。
哺乳动物精子顶体反应是在卵由精子的受精中重要的胞吐作用过程。精子上的α7nAChR的激活对于顶体反应是至关重要的(Son,J.-H.和Meizel,S.Biol.Reproduct.68:1348-13532003)。
α7及α4β2nAChRs上的活性可以通过施用亚型选择性nAChR配体来予以修饰或调节。该配体可表现出拮抗剂、激动剂或不全激动剂特性。起正变构调节剂作用的化合物也是已知的。
事实上,对α4β2NNRs具有高亲和力的几种化合物已被表明在与注意力不集中的过度反应症(ADHD)有关的临床前模型中改善注意和认知表现,注意力不集中的过度反应症(ADHD)是一种以活动过强、不注意及冲动为核心症状的疾病。例如,ABT-418,一种对α4β2NNRs的完全激动剂,在许多临床前认知模型中是有效的。经皮施用的ABT-418被表明在32个成人的受控临床试验中有效治疗一般的ADHD以及具体的注意/认知缺陷(Wilens TE,Biederman J,Spencer TJ,Bostic J,Prince J,Monuteaux MC,Soriano J,Fine C,Abrams A,Rater M,Polisner D.1999.Apilot controlled clinical trial of ABT-418,a cholinergic agonist,in thetreatment of adults with attention deficit hyperactivity disorder.Am JPsychiatry.1999 Dec;156(12):1931-7)。同样,在中试(pilot)阿尔茨海默病试验中,ABT-418显示出有功效的信号。ABT-089,一种α4β2选择性不全激动剂,已经被被表明在啮齿类动物及灵长类动物模型中改善注意、学习及记忆缺陷。ABT-089及另一α4β2激动剂,伊普尼可林(ispronicline)已经在中试临床试验中表明有效。除了认知以外,与α4β2nAChRs相互作用的化合物例如ABT-594等在疼痛的临床前及临床模型中也是有效的。同样,调节α7及α4β2活性的配体在诸如涉及认知及注意缺陷的那些、疼痛、神经变性疾病等的疾病状态中可具有更大范围的治疗功效。
虽然非选择性调节包括α4β2及α7nAChRs在内的烟碱性受体亚型的化合物例如烟碱是已知的,但是选择性地与包含α7的神经元nAChRs、α4β2nAChRs相互作用或者与α7及α4β2nAChRs两者都相互作用的化合物是合乎需要的,因为这些受体在疼痛、认知、病症和疾病中的起着很多作用。
发明概述
本发明涉及联芳基取代的二氮杂双环烷,包含此种化合物的组合物,制备此种化合物的方法,以及在此种制备过程中获得的中间体。更具体地,本发明尤其涉及二环杂芳基取代的稠合的二氮杂双环烷化合物 及其相关使用方法和过程。
本发明的一个方面涉及式(I)化合物
或其可药用盐或前药,其中
R1选自氢、烷基、环烷基、卤烷基、芳基、杂芳基;
a及c各自独立地选自0、1或2;b及d各自独立地选自1、2或3,条件是当b及d两者都是1时,a及c不能同时是1;
Ar1是下式的5或6元芳基
A1、A2、A3及A4各自独立地是-N-或-CRa;
X1、X3、X4独立地选自-CRa、-NRa、-O-及-S-;
X2是-C-或-N-,条件是当X2是-C-时,X1、X3及X4中的至少一个不是-C-;
Ra选自氢或烷基、环烷基、卤烷基、芳基、杂芳基、卤素、-CO2R1、-COR1、-CONR1、-OR1及-NR1,其中R1选自氢、烷基、环烷基、卤烷基、芳基及杂芳基;
Ar2选自下式的稠合双环芳基
B1、B2、B3、B4、B5、B6各自独立地是-N-或-CRa-;
Y选自-NRd-、-O-及-S-;
Ra选自氢、烷基、环烷基、卤烷基、芳基、杂芳基、卤素、-CO2R1、-COR1、-CONR1、-OR1及-NR1;并且
Rd选自氢、烷基及环烷基。
本发明的另一方面涉及包含本发明化合物的药物组合物。此种组合物可以按照本发明方法施用,所述方法通常作为治疗或预防与nAChR活性相关,且更具体是与α7nAChR活性、α4β2nAChR活性相关,或者与α7nAChR活性及α4β2nAChR活性都相关的状况和病症的治疗方案的部分。
本发明的还另一方面涉及调节α7及α4β2nAChR两者活性的方法。所述方法可用于,尤其是在哺乳动物中,治疗、预防或者既治疗又预防与α7及α4β2nAChR两者活性都相关的状况和病症。
本发明的更进一步的方面涉及选择性调节nAChR活性例如α7nAChR活性的方法。该方法可用于在哺乳动物中治疗、预防或者既治疗又预防与α7nAChR活性相关的状况和病症。更具体地,该方法可用于与下列相关的状况和病症:注意力缺陷障碍,注意力不集中的过度反应症(ADHD),阿尔茨海默病(AD),精神分裂症,轻度认知缺损,年龄相关的记忆缺陷(AAMI),老年性痴呆,艾滋病痴呆,Pick氏病,与Lewy小体有关的痴呆,与唐氏综合征有关的痴呆,精神分裂症,肌萎缩性侧索硬化症,Huntington氏病,与创伤性脑损伤相关的CNS功能减弱,急性疼痛,外科手术后疼痛,慢性疼痛,炎性疼痛,神经病疼痛,不孕,循环不足,与伤口愈合相关的新血管生长的需要,更具体是血管闭塞周围的循环,与皮肤移植物的血管形成相关的新血管生长的需要,缺血,炎症,脓毒症,伤口愈合,和与糖尿病相关的其它并发症,以及全身及神经免疫调谐活性。
选择性调节nAChR活性例如α4β2nAChR活性的方法也是预期的。
本发明化合物、包含本发明化合物的组合物、本发明化合物的使用方法、制备本发明化合物的方法以及在此种方法中获得的中间体,本文予以进一步描述。
详述
术语的定义
如贯穿本说明书及所附权利要求中使用的,下面术语具有以下含义:
术语″链烯基″是指含有2-10个碳原子且含有至少一个通过去掉两个氢形成的碳-碳双键的直链或支链烃。链烯基的代表性实例包括但不限于 乙烯基、2-丙烯基、2-甲基-2-丙烯基、3-丁烯基、4-戊烯基、5-己烯基、2-庚烯基、2-甲基-1-庚烯基及3-癸烯基。
术语″亚链烯基″是指由含有至少一个双键的2-10个碳原子的直链或支链烃衍生的二价基团。亚链烯基的代表性实例包括但不限于-CH=CH-、-CH=CH2CH2-及-CH=C(CH3)CH2-。
术语″链烯氧基″是指通过氧原子与母分子部分连接的本文定义的链烯基。链烯氧基的代表性实例包括但不限于烯丙氧基、2-丁烯氧基及3-丁烯氧基。
术语″烷氧基″是指通过氧原子与母分子部分连接的本文定义的烷基。烷氧基的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基及己氧基。
术语″烷氧基烷氧基″是指通过另一个本文定义的烷氧基与母分子部分连接的本文定义的烷氧基。烷氧基烷氧基的代表性实例包括但不限于叔丁氧基甲氧基、2-乙氧基乙氧基、2-甲氧基乙氧基及甲氧基甲氧基。
术语″烷氧基烷氧基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的烷氧基烷氧基。烷氧基烷氧基烷基的代表性实例包括但不限于叔丁氧基甲氧基甲基、乙氧基甲氧基甲基、(2-甲氧基乙氧基)甲基及2-(2-甲氧基乙氧基)乙基。
术语″烷氧基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的烷氧基。烷氧基烷基的代表性实例包括但不限于叔丁氧基甲基、2-乙氧基乙基,2-甲氧基乙基及甲氧基甲基。
术语″烷氧羰基″是指通过本文定义的羰基与母分子部分连接的本文定义的烷氧基。烷氧羰基的代表性实例包括但不限于甲氧羰基、乙氧羰基及叔丁氧羰基。
术语″烷氧羰基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的烷氧羰基。烷氧羰基烷基的代表性实例包括但不限于3-甲氧羰基丙基、4-乙氧羰基丁基及2-叔丁氧羰基乙基。
术语″烷氧基磺酰基″是指通过本文定义的磺酰基与母分子部分连接的本文定义的烷氧基。烷氧基磺酰基的代表性实例包括但不限于甲氧基磺酰基、乙氧基磺酰基及丙氧基磺酰基。
术语″烷基″是指含有1-10个碳原子的直链或支链烃。烷基的代表性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异 丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基及正癸基。
术语″烷基羰基″是指通过本文定义的羰基与母分子部分连接的本文定义的烷基。烷基羰基的代表性实例包括但不限于乙酰基、1-氧代丙基、2,2-二甲基-1-氧代丙基、1-氧代丁基及1-氧代戊基。
术语″烷基羰基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的烷基羰基。烷基羰基烷基的代表性实例包括但不限于2-氧代丙基、3,3-二甲基-2-氧代丙基、3-氧代丁基及3-氧代戊基。
术语″烷基羰基氧基″是指通过氧原子与母分子部分连接的本文定义的烷基羰基。烷基羰基氧基的代表性实例包括但不限于乙酰氧基、乙基羰基氧基及叔丁基羰基氧基。
术语″亚烷基″是指由1-10个碳原子的直链或支链烃衍生的二价基团。亚烷基的代表性实例包括但不限于-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-及-CH2CH(CH3)CH2-。
术语″烷基亚磺酰基″是指通过本文定义的亚磺酰基与母分子部分连接的本文定义的烷基。烷基亚磺酰基的代表性实例包括但不限于甲基亚磺酰基及乙基亚磺酰基。
术语″烷基亚磺酰基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的烷基亚磺酰基。烷基亚磺酰基烷基的代表性实例包括但不限于甲基亚磺酰基甲基及乙基亚磺酰基甲基。
术语″烷基磺酰基″是指通过本文定义的磺酰基与母分子部分连接的本文定义的烷基。烷基磺酰基的代表性实例包括但不限于甲基磺酰基及乙基磺酰基。
术语″烷基磺酰基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的烷基磺酰基。烷基磺酰基烷基的代表性实例包括但不限于甲基磺酰基甲基及乙基磺酰基甲基。
术语″烷硫基″是指通过硫原子与母分子部分连接的本文定义的烷基。烷硫基的代表性实例包括但不限于甲硫基、乙硫基、叔丁硫基及己硫基。
术语″烷硫基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的烷硫基。烷硫基烷基的代表性实例包括但不限于甲硫基甲基及2-(乙硫基)乙基。
术语″炔基″是指含有2-10个碳原子且含有至少一个碳-碳三键的直链或支链烃基。炔基的代表性实例包括但不限于乙炔基、1-丙炔基、2-丙炔基、3-丁炔基、2-戊炔基及1-丁炔基。
术语″亚炔基″是指由含有至少一个三键的2-10个碳原子的直链或支链烃衍生的二价基团。亚炔基的代表性实例包括但不限于-C≡C-、-CH2C≡C-、-CH(CH3)CH2C≡C-、-C≡CCH2-及-C≡CCH(CH3)CH2-。
术语″炔氧基″是指通过氧原子与母分子部分连接的本文定义的炔基。炔氧基的代表性实例包括但不限于2-丙炔氧基及2-丁炔氧基。
术语″芳基″是指苯基、双环芳基或三环芳基。双环芳基是萘基、与环烷基稠合的苯基或与环烯基稠合的苯基。双环芳基的代表性实例包括但不限于二氢茚基、茚基、萘基、二氢萘基及四氢萘基。三环芳基是蒽或菲,或者与环烷基稠合的双环芳基,或者与环烯基稠合的双环芳基,或者与苯基稠合的双环芳基。三环芳基环的代表性实例包括但不限甘菊环基、二氢蒽基、芴基及四氢菲基。
本发明芳基可以被1、2、3、4或5个独立地选自下列的取代基取代:链烯基、烷氧基、烷氧基烷氧基、烷氧基烷氧基烷基、烷氧基烷基、烷氧羰基、烷氧羰基烷基、烷基、烷基羰基、烷基羰基烷基、烷基羰基氧基、烷基亚磺酰基、烷基亚磺酰基烷基、烷基磺酰基、烷基磺酰基烷基、烷硫基、烷硫基烷基、炔基、羧基、羧基烷基、氰基、氰基烷基、甲酰基、甲酰烷基、卤素、卤烷基、羟基、羟烷基、巯基、硝基、-NZ1Z2及(NZ3Z4)羰基。
术语″芳基烷氧基″是指通过本文定义的烷氧基与母分子部分连接的本文定义的芳基。芳基烷氧基的代表性实例包括但不限于2-苯基乙氧基、3-萘-2-基丙氧基及5-苯基戊氧基。
术语″芳基烷氧羰基″是指通过本文定义的羰基与母分子部分连接的本文定义的芳基烷氧基。芳基烷氧羰基的代表性实例包括但不限于苄氧羰基及萘-2-基甲氧羰基。
术语″芳基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的芳基。芳基烷基的代表性实例但不限于苄基、2-苯基乙基、3-苯基丙基及2-萘-2基乙基。
术语″芳基烷硫基″是指通过硫原子与母分子部分连接的本文定义的芳基烷基。芳基烷硫基的代表性实例包括但不限于2-苯基乙硫基、3-萘 -2-基丙硫基及5-苯基戊硫基。
术语″芳基羰基″是指通过本文定义的羰基与母分子部分连接的本文定义的芳基。芳基羰基的代表性实例包括但不限于苯甲酰基及萘甲酰基。
术语″芳氧基″是指通过氧原子与母分子部分连接的本文定义的芳基。芳氧基的代表性实例包括但不限于苯氧基、萘氧基、3-溴苯氧基、4-氯苯氧基、4-甲基苯氧基及3,5-二甲氧基苯氧基。
术语″芳氧基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的芳氧基。芳氧基烷基的代表性实例包括但不限于2-苯氧基乙基、3-萘-2-基氧基丙基及3-溴苯氧基甲基。
术语″芳硫基″是指通过硫原子与母分子部分连接的本文定义的芳基。芳硫基的代表性实例包括但不限于苯硫基及2-萘硫基。
术语″芳硫基烷基″是指通过本文定义的烷基与母分子部分连接的本身定义的芳硫基。芳硫基烷基的代表性实例包括但不限于苯硫基甲基、2-萘-2-基硫基乙基及5-苯硫基甲基。
术语″叠氮基″是指-N3基团。
术语″羰基″是指-C(O)-基团。
术语″羧基″是指-CO2H基团。
术语″羧基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的羧基。羧基烷基的代表性实例包括但不限于羧甲基、2-羧乙基及3-羧丙基。
术语″氰基″是指-CN基团。
术语″氰基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的氰基。氰基烷基的代表性实例包括但不限于氰基甲基、2-氰基乙基及3-氰基丙基。
术语″环烯基″是指含有3-8个碳且含有至少一个通过去掉两个氢形成的碳-碳双键的环烃。环烯基的代表性实例包括但不限于2-环己烯-1-基、3-环己烯-1-基、2,4-环己二烯-1-基及3-环戊烯-1-基。
本文所用术语″环烷基″是指单环、双环或三环环系统。单环环系统以含有3-8个碳原子的饱和环烃基为例示。单环环系统的实例包括环丙基、环丁基、环戊基、环己基、环庚基及环辛基。双环环系统以桥连的单环环系统为例示,其中单环的两个相邻或不相邻碳原子是通过1-3个 另外的碳原子之间的亚烷基桥连接的。双环环系统的代表性实例包括但不限于双环[3.2.0]庚烷、双环[3.3.0]辛烷、双环[4.3.0]壬烷、双环[4.2.0]辛烷、双环[5.2.0]壬烷、双环[5.3.0]癸烷及双环[4.4.0]癸烷。
本发明环烷基任选被1、2、3、4或5个选自下列的取代基取代:链烯基、烷氧基、烷氧基烷氧基、烷氧基烷基、烷氧羰基、烷氧基磺酰基、烷基、烷基羰基、烷基羰基氧基、烷基磺酰基、烷硫基、烷硫基烷基、炔基、羧基、氰基、甲酰基、卤烷氧基、卤烷基、卤素、羟基、羟烷基、巯基、氧代、-NZ1Z2及(NZ3Z4)羰基。
术语″环烷基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的环烷基。环烷基烷基的代表性实例包括但不限于环丙基甲基、2-环丁基乙基、环戊基甲基、环己基甲基及4-环庚基丁基。
术语″环烷基羰基″是指通过本文定义的羰基与母分子部分连接的本文定义的环烷基。环烷基羰基的代表性实例包括但不限于环丙基羰基、2-环丁基羰基及环己基羰基。
术语″环烷氧基″是指通过本文定义的氧原子与母分子部分连接的本文定义的环烷基。环烷氧基的代表性实例包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基、环庚氧基及环辛氧基。
术语″环烷硫基″是指通过本文定义的硫原子与母分子部分连接的本文定义的环烷基。环烷硫基的代表性实例包括但不限于环丙硫基、环丁硫基、环戊硫基、环己硫基、环庚硫基及环辛硫基。
术语“亚乙二氧基”是指-O(CH2)2O-基团,其中亚乙二氧基的氧原子经由一个碳原子与母分子部分连接,形成5-元环,或者亚乙二氧基的氧原子经由两个相邻碳原子与母分子部分连接,形成6-元环。
术语″甲酰基″是指-C(O)H基团。
术语″甲酰烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的甲酰基。甲酰基烷基的代表性实例包括但不限于甲酰甲基及2-甲酰乙基。
术语″卤″或″卤素″是指-Cl、-Br、-I或-F。
术语″卤烷氧基″是指通过本文定义的烷氧基与母分子部分连接的至少一个本文定义的卤素。卤烷氧基的代表性实例包括但不限于氯甲氧基、2-氟乙氧基、三氟甲氧基及五氟乙氧基。
术语″卤烷基″是指通过本文定义的烷基与母分子部分连接的至少一 个本文定义的卤素。卤烷基的代表性实例包括但不限于氯甲基、2-氟乙基、三氟甲基、五氟乙基及2-氯-3-氟戊基。
术语″杂芳基″是指单环杂芳基或双环杂芳基。单环杂芳基是含有至少一个选自氮、氧及硫的杂原子的5或6元环。5元环含有两个双键,而6元环含有三个双键。5元或6元杂芳基通过杂芳基内所含的任何碳原子或任何可取代的氮原子与母分子部分连接,条件是保持正确的价。单环杂芳基的代表性实例包括但不限于呋喃基、咪唑基、异噁唑基、异噻唑基、噁二唑基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基及三嗪基。双环杂芳基由与苯基稠合的单环杂芳基,或者与环烷基稠合的单环杂芳基,或者与环烯基稠合的单环杂芳基,或者与单环杂芳基稠合的单环杂芳基组成。双环杂芳基通过双环杂芳基内所含的任何碳原子或任何可取代的氮原子与母分子部分连接,条件是保持正确的价。双环杂芳基的代表性实例包括但不限于氮杂吲哚基、苯并咪唑基、苯并呋喃基、苯并噁二唑基、苯并异噁唑、苯并异噻唑、苯并噁唑、1,3-苯并噻唑基、苯并噻吩基、噌啉基、呋喃并吡啶、吲哚基、吲唑基、异苯并呋喃、异氮茚基、异喹啉基、萘啶基、噁唑并吡啶、喹啉基、喹喔啉基及噻吩并吡啶基。
本发明杂芳基任选被1、2、3或4个独立地选自以下的取代基取代:链烯基、烷氧基、烷氧基烷氧基、烷氧基烷基、烷氧羰基、烷氧羰基烷基、烷氧基磺酰基、烷基、烷基羰基、烷基羰基烷基、烷基羰基氧基、烷硫基、烷硫基烷基、炔基、羧基、羧基烷基、氰基、氰基烷基、甲酰基、卤烷氧基、卤烷基、卤素、羟基、羟烷基、巯基、硝基、-NZ1Z2及(NZ3Z4)羰基。被羟基取代的本发明杂芳基可以作为互变异构体存在。本发明杂芳基包含包括非芳族互变异构体在内的所有互变异构体。
术语″杂芳基烷氧基″是指通过本文定义的烷氧基与母分子部分连接的本文定义的杂芳基。杂芳基烷氧基的代表性实例包括但不限于呋喃-3-基甲氧基、1H-咪唑-2-基甲氧基、1H-咪唑-4-基甲氧基、1-(吡啶-4-基)乙氧基、吡啶-3-基甲氧基、6-氯吡啶-3-基甲氧基、吡啶-4-基甲氧基、(6-(三氟甲基)吡啶-3-基)甲氧基、(6-(氰基)吡啶-3-基)甲氧基、(2-(氰基)吡啶-4-基)甲氧基、(5-(氰基)吡啶-2-基)甲氧基、(2-(氯)吡啶-4-基)甲氧基、嘧啶-5-基甲氧基、2-(嘧啶-2-基)丙氧基、噻吩-2-基甲氧基及噻吩-3-基甲氧基。
术语″杂芳基烷基″是指通过本文定义的烷基与母分子部分连接的本 文定义的杂芳基。杂芳基烷基的代表性实例包括但不限于呋喃-3-基甲基、1H-咪唑-2-基甲基、1H-咪唑-4-基甲基、1-(吡啶-4-基)乙基、吡啶-3-基甲基、6-氯吡啶-3-基甲基、吡啶-4-基甲基、(6-(三氟甲基)吡啶-3-基)甲基、(6-(氰基)吡啶-3-基)甲基、(2-(氰基)吡啶-4-基)甲基、(5-(氰基)吡啶-2-基)甲基、(2-(氯)吡啶-4-基)甲基、嘧啶-5-基甲基、2-(嘧啶-2-基)丙基、噻吩-2-基甲基及噻吩-3-基甲基。
术语″杂芳基烷基羰基″是指通过本文定义的羰基与母分子部分连接的本文定义的杂芳基烷基。
术语″杂芳基烷硫基″是指通过硫原子与母分子部分连接的本文定义的杂芳基烷基。杂芳基烷硫基的代表性实例包括但不限于呋喃-3-基甲硫基、1H-咪唑-2-基甲硫基、1H-咪唑-4-基甲硫基、吡啶-3-基甲硫基、6-氯吡啶-3-基甲硫基、吡啶-4-基甲硫基、(6-(三氟甲基)吡啶-3-基)甲硫基、(6-(氰基)吡啶-3-基)甲硫基、(2-(氰基)吡啶-4-基)甲硫基、(5-(氰基)吡啶-2-基)甲硫基、(2-(氯)吡啶-4-基)甲硫基、嘧啶-5-基甲硫基、2-(嘧啶-2-基)丙硫基、噻吩-2-基甲硫基及噻吩-3-基甲硫基。
术语″杂芳基羰基″是指通过本文定义的羰基与母分子部分连接的本文定义的杂芳基。杂芳基羰基的代表性实例包括但不限于呋喃-3-基羰基、1H-咪唑-2-基羰基、1H-咪唑-4-基羰基、吡啶-3-基羰基、6-氯吡啶-3-基羰基、吡啶-4-基羰基、(6-(三氟甲基)吡啶-3-基)羰基、(6-(氰基)吡啶-3-基)羰基、(2-(氰基)吡啶-4-基)羰基、(5-(氰基)吡啶-2-基)羰基、(2-(氯)吡啶-4-基)羰基、嘧啶-5-基羰基、嘧啶-2-基羰基、噻吩-2-基羰基及噻吩-3-基羰基。
术语″杂芳基氧基″是指通过氧原子与母分子部分连接的本文定义的杂芳基。杂芳基氧基的代表性实例包括但不限于呋喃-3-基氧基、1H-咪唑-2-基氧基、1H-咪唑-4-基氧基、吡啶-3-基氧基、6-氯吡啶-3-基氧基、吡啶-4-基氧基、(6-(三氟甲基)吡啶-3-基)氧基、(6-(氰基)吡啶-3-基)氧基、(2-(氰基)吡啶-4-基)氧基、(5-(氰基)吡啶-2-基)氧基、(2-(氯)吡啶-4-基)氧基、嘧啶-5-基氧基、嘧啶-2-基氧基、噻吩-2-基氧基及噻吩-3-基氧基。
术语″杂芳基氧基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的杂芳基氧基。杂芳基氧基烷基的代表性实例包括但不限于吡啶-3-基氧基甲基及2-喹啉-3-基氧基乙基。
术语″杂芳基硫基″是指通过硫原子与母分子部分连接的本文定义的杂芳基。杂芳基硫基的代表性实例包括但不限于吡啶-3-基硫基及喹啉-3-基硫基。
术语″杂芳基硫基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的杂芳基硫基。杂芳基硫基烷基的代表性实例包括但不限于吡啶-3-基硫基甲基及2-喹啉-3-基硫基乙基。
术语″杂环″或″杂环的″是指单环杂环、双环杂环或三环杂环。单环杂环是含有至少一个独立地选自O、N及S的杂原子的3、4、5、6或7元环。3或4-元环含有一个选自O、N及S的杂原子。5元环含有0或1个双键以及1、2或3个选自O、N及S的杂原子。6或7元环含有0、1或2个双键以及1、2或3个选自O、N及S的杂原子。单环杂环通过单环杂环内所含的任何碳原子或任何氮原子与母分子部分连接。单环杂环的代表性实例包括但不限于氮杂环丁烷基、氮杂环庚烷基(azepanyl)、吖丙啶基、二氮杂环庚烷基、1,3-二噁烷基、1,3-二氧戊环基、1,3-二硫戊环基、1,3-二噻烷基、咪唑啉基、咪唑烷基、异噻唑啉基、异噻唑烷基、异噁唑啉基、异噁唑烷基、吗啉基、噁二唑啉基、噁二唑烷基、噁唑啉基、噁唑烷基、哌嗪基、哌啶基、吡喃基、吡唑啉基、吡唑烷基、吡咯啉基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻二唑啉基、噻二唑烷基、噻唑啉基、噻唑烷基、硫代吗啉基、1,1-二氧硫代吗啉基(硫代吗啉砜)、噻喃基及三噻烷基。双环杂环是与与苯基稠合的5或6元单环杂环,或者与环烷基稠合的5或6元单环杂环,或者与环烯基稠合的5或6元单环杂环,或者与单环杂环稠合的5或6元单环杂环。双环杂环通过双环杂环内所含的任何碳原子或任何氮原子与母分子部分连接。双环杂环的代表性实例包括但不限于1,3-苯并间二氧杂环戊烯基、1,3-苯并二硫杂环戊二烯基、2,3-二氢-1,4-苯并二噁烯基、苯并间二氧杂环戊烯基、2,3-二氢-1-苯并呋喃基、2,3-二氢-1-苯并噻吩基、色烯基及1,2,3,4-四氢喹啉基。
本发明杂环任选被1、2、3或4个独立地选自下列的取代基取代:链烯基、烷氧基、烷氧基烷氧基、烷氧基烷基、烷氧羰基、烷氧羰基烷基、烷氧基磺酰基、烷基、烷基羰基、烷基羰基烷基、烷基羰基氧基、烷硫基、烷硫基烷基、炔基、羧基、羧基烷基、氰基、氰基烷基、甲酰基、卤烷氧基、卤烷基、卤素、羟基、羟烷基、巯基及氧代。
术语″杂环烷氧基″是指通过本文定义的烷氧基与母分子部分连接的本文定义的杂环基。杂环烷氧基的代表性实例包括但不限于2-吡啶-3-基乙氧基、3-喹啉-3-基丙氧基及5-吡啶-4-基戊氧基。
术语″杂环烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的杂环。
术语″杂环烷基羰基″是指通过本文定义的羰基与母分子部分连接的本文定义的杂环烷基。杂环烷基羰基的代表性实例包括但不限于哌啶-4-基甲基羰基、哌嗪-1-基甲基羰基、3-甲基-1-吡咯烷-1-基丁基羰基、(1R)-3-甲基-1-吡咯烷-1-基丁基羰基、(1S)-3-甲基-1-吡咯烷-1-基丁基羰基。
术语″杂环烷硫基″是指通过硫原子与母分子部分连接的本文定义的杂环烷基。杂环烷硫基的代表性实例包括但不限于2-吡啶-3-基乙硫基、3-喹啉-3-基丙硫基及5-吡啶-4-基戊硫基。
术语″杂环羰基″是指通过本文定义的羰基与母分子部分连接的本文定义的杂环。
术语″杂环羰基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的杂环羰基。
术语″杂环氧基″是指通过氧原子与母分子部分连接的本文定义的杂环基。杂环氧基的代表性实例包括但不限于吡啶-3-基氧基及喹啉-3-基氧基。
术语″杂环氧基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的杂环氧基。杂环氧基烷基的代表性实例包括但不限于吡啶-3-基氧基甲基及2-喹啉-3-基氧基乙基。
术语″杂环硫基″是指通过硫原子与母分子部分连接的本文定义的杂环基。杂环硫基的代表性实例包括但不限于吡啶-3-基硫基及喹啉-3-基硫基。
术语″杂环硫基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的杂环硫基。杂环硫基烷基的代表性实例包括但不限于吡啶-3-基硫基甲基及2-喹啉-3-基硫基乙基.
术语″羟基″是指-OH烷基。
术语″羟烷基″是指通过本文定义的烷基与母分子部分连接的至少一个本文定义的羟基。羟烷基的代表性实例包括但不限于羟甲基、2-羟乙基、3-羟丙基、2,3-二羟戊基及2-乙基-4-羟庚基。
术语″羟基-保护基″或″O-保护基″是指在合成程序过程中保护羟基免于进行不合乎需要的反应的取代基。羟基-保护基的实例包括但不限于取代的甲基醚,例如,甲氧基甲基、苄氧基甲基、2-甲氧基乙氧基甲基、2-(三甲基甲硅烷基)-乙氧基甲基、苄基及三苯基甲基;四氢吡喃基醚;取代的乙基醚,例如2,2,2-三氯乙基及叔丁基;甲硅烷基醚,例如,三甲基甲硅烷基、叔丁基二甲基甲硅烷基及叔丁基二苯基甲硅烷基;环状缩醛及缩酮,例如亚甲基缩醛(methylene acetal),丙酮化合物及亚苄基缩醛(benzylidene acetal);环状原酸酯,例如甲氧基亚甲基;环状碳酸酯;以及环状硼酸酯(boronate)。通常使用的羟基-保护基公开于T.W.Greene和P.G.M.Wuts,Protective Groups in Organic Synthesis,3rd edition,John Wiley & Sons,New York(1999)。
术语″低级链烯基″是本文定义的链烯基的子集,并且是指含有2-4个碳原子的链烯基。低级链烯基的实例是乙烯基、丙烯基及丁烯基。
术语″低级烷氧基″是本文定义的烷氧基的子集,并且是指通过本文定义的氧原子与母分子部分连接的本文定义的低级烷基。低级烷氧基的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基及叔丁氧基。
术语″低级烷基″是本文定义的烷基的子集,并且是指含有1-4个碳原子的直链或支链烃基。低级烷基的实例是甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基及叔丁基。
术语″低级烷硫基″是烷硫基的子集,是指通过硫原子与母分子部分连接的本文定义的低级烷基。低级烷硫基的代表性实例包括但不限于甲硫基、乙硫基及叔丁硫基。
术语″低级炔基″是本文定义的炔基的子集,并且是指含有2-4个碳原子的炔基。低级炔基的实例是乙炔基、丙炔基及丁炔基。
术语″低级卤烷氧基″是本文定义的卤烷氧基的子集,并且是指含有1-4个碳原子的直链或支链卤烷氧基。低级卤烷氧基的代表性实例包括但不限于三氟甲氧基、三氯甲氧基、二氯甲氧基、氟甲氧基及五氟乙氧基。
术语″低级卤烷基″是本文定义的卤烷基的子集,并且是指含有1-4个碳原子的直链或支链卤烷基。低级卤烷基的代表性实例包括但不限于三氟甲基、三氯甲基、二氯甲基、氟甲基及五氟乙基。
术语″巯基″是指-SH基。
术语″巯基烷基″是指通过本文定义的烷基与母分子部分连接的本文定义的巯基。巯基烷基的代表性实例包括但不限于2-巯基乙基及3-巯基丙基。
术语″亚甲二氧基″是指-OCH2O-基团,其中亚甲二氧基的氧原子通过两个相邻碳原子与母分子部分连接。
术语″氮保护基″是指在合成程序过程中意图保护氨基免于进行不合乎需要的反应的那些基团。优选的氮保护基是乙酰基、苯甲酰基、苄基、苄氧羰基(Cbz)、甲酰基、苯基磺酰基、叔丁氧羰基(Boc)、叔丁基乙酰基、三氟乙酰基及三苯基甲基(三苯甲基)。
术语″硝基″是指-NO2基团。
术语″NZ1Z2″是指通过氮原子与母分子部分连接的两个基团Z1及Z2。Z1及Z2各自独立地选自氢、烷基、烷基羰基、烷氧羰基、芳基、芳基烷基、甲酰基及(NZ5Z6)羰基。在本发明的某些情况下,Z1及Z2与其连接的氮原子一起形成杂环。NZ1Z2的代表性实例包括但不限于氨基、甲氨基、乙酰氨基、乙酰基甲氨基、苯基氨基、苄氨基、氮杂环丁烷基、吡咯烷基及哌啶基。
术语″NZ3Z4″是指通过氮原子与母分子部分连接的两个基团Z3及Z4。Z3及Z4各自独立地选自氢、烷基、芳基及芳基烷基。NZ3Z4的代表性实例包括但不限于氨基、甲氨基、苯基氨基及苄氨基。
术语″NZ5Z6″是指通过氮原子与母分子部分连接的两个基团Z5及Z6。Z5及Z6各自独立地选自氢、烷基、芳基及芳基烷基。NZ5Z6的代表性实例包括但不限于氨基、甲氨基、苯基氨基及苄氨基。
术语″(NZ3Z4)羰基″是指通过本文定义的羰基与母分子部分连接的本文定义的NZ3Z4基团。(NZ3Z4)羰基的代表性实例包括但不限于氨基羰基、(甲氨基)羰基、(二甲氨基)羰基及(乙基甲氨基)羰基。
术语″氧代″是指=O部分。
术语″亚磺酰基″是指-S(O)-基团。
术语″磺酰基″是指-SO2-基团。
术语″互变异构体″是指从化合物一个原子到该相同化合物的另一个原子的质子移动,其中两个或多个结构不同的化合物互相平衡。
虽然通常可能公认的是使用星号来表示受体的精确亚单位组成是 不确定的,例如αb4*表示含有α和β4蛋白与其它亚单位的受体,但本文所用术语α7意图包括其中精确的亚单位组成是确定的及不确定的受体。例如,本文所用的α7包括同构(α7)5受体和α7*受体,其表示含有至少一个α7亚单位的nAChR。
本发明化合物
本发明化合物具有式(I)
或其可药用盐或前药,其中
R1选自氢、烷基、环烷基、卤烷基、芳基及杂芳基;
a及c各自独立地选自0、1或2;b及d各自独立地选自1、2或3,条件是当b及d都是1时,a及c不能同时是1,
Ar1选自下式的5-或6-元芳基
A1、A2、A3及A4各自独立地选自-N-及-CRa;
X1、X3、X4独立地选自-CRa、-NRa、-O-及-S-;
X2是-C-或-N-,条件是当X2是-C-时,X1、X3、X4中的至少一个不是-C-;
Ra选自氢或烷基、环烷基、卤烷基、芳基、杂芳基、卤素、-CO2R1、-COR1、-CONR1、-OR1及-NR1,其中R1选自氢、烷基、环烷基、卤烷基、芳基及杂芳基;
Ar2选自下式的稠合双环芳基
B1、B2、B3、B4、B5、B6各自独立地是-N-或-CRa-;
Y选自-NRd-、-O-及-S-;
Ra选自氢、烷基、环烷基、卤烷基、芳基、杂芳基、卤素、-CO2R1、-COR1、-CONR1、-OR1及-NR1;并且
Rd选自氢、烷基及环烷基。
更具体地,式(I)化合物是式(II)的具有稠合二氮杂双环烷的化合物
变量a及c各自独立地选自0、1、2;b及d各自独立地选自1、2、
3。稠合二氮杂双环烷的实例至少包括:
Ar1部分独立地选自式(III)及(IV)的5或6元芳基
在式(III)中,A1、A2、A3、A4各自独立地选自N或CRa,其中Ra独立地选自氢、烷基、环烷基、卤烷基、芳基、杂芳基、卤素、-CO2R1、-COR1、-CONR1、-OR1及-NR1。该部分通过1,3-取代或间位附着与稠合的二氮杂双环烷及Ar2基团附着。优选地,由式(III)代表的部分含有至少一个氮原子。
式(IV)代表5元杂芳基,其中X1、X3、X4独立地选自-CRa、-NRa、-O-及-S-;X2是-C-及-N-,条件是当X2是-C-时,X1、X3、X4中的至少一个不是-CRa。Ra独立地选自氢、烷基、环烷基、卤烷基、芳基、杂芳基、卤素、-CO2R1、-COR1、-CONR1、-OR1及-NR1。该部分一般通过1,3-取代与稠合的二氮杂双环烷及Ar2基团附着。
适合于Ar1的具体6或5元芳环的实例包括咪唑基、异噁唑基、异噻唑基、呋喃基、噁唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、苯基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻吩基、噻唑基、1,2,4-噻二唑基及1,3,4-噻二唑基。优选的Ar1基团是哒嗪基、吡啶基、噻唑基、1,3,4-噻二唑基及1,3,4-噁二唑基。适用于式(III)或(IV)的芳环的实例至少包括:
R2、R3、R4及R5各自独立地选自氢、烷基、烷氧基、烷氧羰基、氰基、卤、硝基及-NRbRc;Rb及Rc各自独立地是氢、烷基、烷氧羰基或烷基羰基。
Ar2部分独立地选自式(V)的稠合的二环杂芳基
B1、B2、B3、B4、B5、B6各自独立地是-N-或-CRa。
Y选自-NRd-、-O-及-S-。
Ra选自氢或烷基、环烷基、卤烷基、芳基、杂芳基、卤素、-CO2R1、-COR1、-CONR1、-OR及-NR1。
Rd独立地选自氢、烷基及环烷基。
部分Ar2通过B1、B2、B3、B4、B5及B6的C与Ar1基团附着。优 选地,式(V)代表的部分含有至少一个选自N、O及S的杂原子。适合于Ar2的具体稠合的双环杂芳环的实例包括苯并呋喃基、苯并[d]咪唑基、苯并[d]异噁唑基、苯并[d]异噻唑基、苯并[d]噁唑基、苯并[d]噻唑基、苯并[b]噻吩基、呋喃并[3,2-b]吡啶基、呋喃并[3,2-c]吡啶基、咪唑并[4,5-b]吡啶基、咪唑并[4,5-c]吡啶、吲哚基、吲唑基、异噁唑并[4,5-b]吡啶基、异噁唑并[4,5-c]吡啶基、异噁唑并[5,4-b]吡啶基、异噁唑并[5,4-c]吡啶基、异噻唑并[4,5-c]吡啶基、异噻唑并[4,5-c]吡啶基、异噻唑并[5,4-b]吡啶基、异噻唑并[5,4-c]吡啶基、噁唑并[4,5-b]吡啶基、噁唑并[4,5-c]吡啶基、噁唑并[5,4-b]吡啶基、噁唑并[5,4-c]吡啶基、吡唑并[3,4-b]吡啶基、吡唑并[3,4-c]吡啶基、吡唑并[4,3-b]吡啶基、吡唑并[4,3-c]吡啶基、吡咯并[2,3-b]吡啶基、吡咯并[2,3-c]吡啶基、吡咯并[3,2-b]吡啶基、吡咯并[3,2-c]吡啶基、噻唑并[4,5-b]吡啶基、噻唑并[4,5-c]吡啶基、噻唑并[5,4-b]吡啶基、噻唑并[5,4-c]吡啶基、噻吩并[2,3-b]吡啶基、噻吩并[2,3-c]吡啶基、噻吩并[3,2-b]吡啶基及噻吩并[3,2-c]吡啶基。适宜的Ar2部分的实例至少包括:
Ru及Rv各自独立地选自烷氧基、烷基、氰基、卤烷基、羟基、卤素及NR1。
变量m及n各自独立地选自0、1及2。
本发明式(I)化合物的具体实施方案的具体实例是其中二氮杂双环烷是3,6-二氮杂双环[3.2.0]庚烷,例如:
及
R1是氢、烷基、环烷基或卤烷基;更优选氢、烷基或环烷基。Ar1是噁唑基、噁二唑基、哒嗪基、吡嗪基、吡啶基、噻二唑基或噻唑基;更优选吡啶基、噻二唑基或噻唑基。Ar2是苯并呋喃基、苯并[d]咪唑基、吲哚基、吲唑基或吡咯并吡啶基、吡唑并吡啶基、咪唑并吡啶基,更优选吲哚基或吡咯并吡啶基。
本发明式(I)化合物的具体实施方案的另一实例是其中二氮杂双环 烷是3,8-二氮杂双环[4.2.0]辛烷,例如:
R1是氢、烷基、环烷基、卤烷基;更优选氢、烷基或环烷基。Ar1是噁唑基、噁二唑基、哒嗪基、吡嗪基、吡啶基、噻二唑基或噻唑基;更优选吡啶基、噻二唑基或噻唑基。Ar2是苯并呋喃基、苯并[d]咪唑基、吲哚基、吲唑基吡咯并吡啶基、吡唑并吡啶基或咪唑并吡啶基,更优选吲哚基或吡咯并吡啶基。
作为本发明部分预期的具体实施方案包括式(I)化合物或者其盐或前药,例如:
5-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
4-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
4-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
6-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
6-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-2-(三氟甲基)-1H-吲哚;
(1S,5S)-3-(5-(苯并呋喃-5-基)吡啶-3-基)-6-甲基-3,6-二氮杂双环[3.2.0]庚烷;
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲唑;
(1S,5S)-3-[5-(苯并[b]噻吩-5-基)吡啶-3-基]-3,6-二氮杂双环[3.2.0]庚烷;
(1S,5S)-3-[5-(苯并[b]噻吩-5-基)吡啶-3-基]-3,6-二氮杂双环[3.2.0]庚烷;
7-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H- 吲哚;
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-苯并[d]咪唑;
3-甲基-5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
3-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-9H-咔唑;
5-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-3-甲基-1H-吲哚;
3-(5-((1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基)吡啶-3-基)-9H-咔唑;
7-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吡咯并[2,3-c]吡啶;
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吡咯并[2,3-b]吡啶;
3-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1-(苯基磺酰基)-1H-吲哚;
3-(5-((1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基)吡啶-3-基)-1H-吲哚;
4-{6-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚;
4-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚;
5-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚;
6-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚;
5-(6-((1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基)吡嗪-2-基)-2-(三氟甲基)-1H-吲哚
5-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
4-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
6-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H- 吲哚;
5-{5-[(1R,5S)-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚;
5-{5-[(1R,5S)-3-甲基-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚;
6-{5-[(1R,5S)-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚;
6-{5-[(1R,5S)-3-甲基-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚;
4-(5-((1R,5S)-3-甲基-3,6-二氮杂双环[3.2.0]庚-6-基)吡啶-3-基)-1H-吲哚;
6-{5-[(3aS,6aS)-5-甲基六氢吡咯并[3,4-b]吡咯-1(2H)-基]吡啶-3-基}-1H-吲哚;及
5-{5-[(3aS,6aS)-5-甲基六氢吡咯并[3,4-b]吡咯-1(2H)-基]吡啶-3-基}-1H-吲哚。
本发明化合物可以以其中存在不对称或手性中心的立体异构体形式存在。这些立体异构体是“R”或“S ”,这取决于手性元素周围取代基的构型。本文所用术语“R”及“S”是如IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry,Pure Appl.Chem.,1976,45:13-30中定义的构型。本发明预期各种立体异构体及其混合物并特别包括在本发明范围之内。立体异构体包括对映体、非对映体以及对映体或非对映体的混合物。本发明的个别立体异构体可以由含有不对称或手性中心的商购可得的原材料来合成制备,或者通过制备外消旋混合物然后拆分来制备。这些拆分方法的实例有:(1)将对映体混合物与手性助剂连接,通过再结晶或色谱法来分离所得非对映体混合物,并且将旋光纯的产物从助剂进行任选释放,如Furniss,Hannaford,Smith,和Tatchell,″Vogel′s Textbook of Practical Organic Chemistry″,第5版(1989),Longman Scientific & Technical,Essex CM202JE,England中所描述,或者(2)在手性色谱柱上直接分离旋光性对映体的混合物,或(3)分级再结晶方法。
本发明化合物的制备方法
如方案及实施例的描述所用,某些缩写意欲具有以下含义:Bu代 表丁基;DMAP代表4-二甲氨基吡啶;DMF代表二甲基甲酰胺;DME代表1,2-二甲氧基乙烷;Et代表乙基;EtOAc代表乙酸乙酯;HPLC代表高压液相色谱法;Me代表甲基;MeOH代表甲醇;OAc代表乙酰氧基;Pd/C代表披钯碳;Ph代表苯基;以及THF代表四氢呋喃。
在方案中例示的反应是在适合使用的试剂及材料并适合实施转化的溶剂中进行的。根据分子上存在的官能度,所述转化可以要求更改合成步骤的次序,或选择一种比另一种特别的过程方案,以获得所需的本发明化合物。
氮保护基可以用来保护所述化合物中的氨基。这样的方法及一些适宜的氮保护基描述于Greene和Wuts(Protective Groups In Organic Synthesis,Wiley and Sons,1999)。例如,适宜的氮保护基包括叔丁氧羰基(Boc)、苄氧羰基(Cbz)、苄基(Bn)、乙酰基及三氟乙酰基。更具体地,BOC保护基可以通过用酸例如三氟乙酸或盐酸处理来除去。Cbz及Bn保护基可以通过催化氢化来除去。乙酰基及三氟乙酰基保护基可以用氢氧离子来除去。
方案1
式(8)化合物,其中R1、a、b、c、d、A1、A2、A3、A4及Ar2如式(I)中所定义,可以按照方案1中的描述制备。式(1)化合物(可以从市场上 买到,或者通过众所周知的方法制备),当在以下条件下用式(2)化合物(其中Z1是溴化物、氯化物或碘化物,并且Z2是溴化物、氯化物、碘化物或Ar2)处理时,提供式(3)化合物:在配体及钯催化剂存在下,所述配体例如BINAP、Xantphos、二环己基(2′,4′,6′-三异丙基联苯-2-基)膦、二环己基(2′,6′-二异丙氧基联苯-2-基)膦及2′-(二环己基膦基)-N,N-二甲基联苯基-2-胺,所述钯催化剂例如Pd(OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd2(dba)3,(具有碱,例如tBuONa及Cs2CO3),在溶剂例如甲苯中,在110℃,如Org.Lett.,2005,7,3965中所述。当Z2是Ar2时,式(3)化合物代表本发明。当Z2是卤素时,式(3)化合物,当在钯催化剂例如PdCl2(PPh3)2、PdCl2(dppf)存在下,用六甲基二锡或式(4)的有机硼烷化合物(例如双(频哪醇合)二硼(bis(pinacolato)diboron)或双(儿茶酚合)二硼(bis(catecholato)diboron),其中Rm是氢、烷基或芳基)处理时,提供式(5)的相应的锡或硼酸/酯,其中M是-SnMe3或-B(ORm)2。式(5)化合物,当在钯催化剂例如Pd(OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd2(dba)3)存在下用式(6)化合物(其中Ar2如式(I)中所定义,并且卤是溴化物、氯化物或碘化物)处理时,将提供式(8)化合物。或者,式(6)化合物,当在钯催化剂例如PdCl2(PPh3)2、PdCl2(dppf)存在下用六甲基二锡或式(4)的含二硼烷的化合物例如双(频哪醇合)二硼及双(儿茶酚合)二硼处理时,提供式(7)的含有机锡或有机硼酸/酯的化合物,其中Ar2如式(I)中所定义,并且M是-SnMe3或-B(ORm)2。式(7)化合物,当在钯催化剂例如Pd(OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd2(dba)3存在下用(3)化合物处理时,提供式(8)化合物。
方案2
或者,式(8)化合物(其中A1及A4中的至少一个是N,R1、a、b、c、d、A2、A3及Ar2如式(I)中所定义),可以按照方案2中的描述制备。式(1)化合物,当在以下条件下用式(2)化合物(其中Z1是溴化物、氯化物或碘化物,并且Z2是溴化物、氯化物、碘化物或Ar2)处理时,提供式(3)化合物:在碱(例如但不限于Na2CO3、K2CO3、Cs2CO3及N,N-二异丙基乙胺)存在下,在溶剂例如DMSO或NMP中,在110℃下。可以如方案1中所述将式(3)化合物转化为式(8)化合物。
方案3
生成式(8)化合物(其中A1及A4中的至少一个是N,R1、a、b、c、d、A2、A3及Ar2如式(I)中所定义)的另一种方法,描述于方案3。式(2)化合物(其中Z1及Z2各自独立地是溴化物、氯化物或碘化物),当在钯催化剂(例如PdCl2(PPh3)2、PdCl2(dppf))存在下用六甲基二锡或式(4)的有机硼烷化合物(例如双(频哪醇合)二硼或双(儿茶酚合)二硼,其中Rm是氢、烷基或芳基)处理时,提供式(9)的相应的锡或硼酸/酯,其中M是-SnMe3或-B(ORm)2。式(9)化合物,当在钯催化剂(例如Pd(OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd2(dba)3)存在下用式(6)化合物(其中Ar2如所定义,并且卤是溴化物、氯化物或碘化物)处理时,提供式(10)化合物。或者,式(2)化合物,当在钯催化剂(例如Pd(OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd2(dba)3)存在下用式(7)化合物处理时,提供式(10)化合物。可以按照方案1及2中的描述将式(10)化合物转化为式(8)化合物。
方案4
式(14)化合物(其中R1、a、b、c、d、X1、X2、X3、X4及Ar2如式(I)中所定义)可以按照方案4中的描述来制备。式(1)化合物,当在以下条件下用式(11)化合物(其中Z1是溴化物、氯化物或碘化物,并且Z2是溴化物、氯化物、碘化物或Ar2,条件是当Z2是溴化物、氯化物或碘化物时,X2是C)处理时,提供式(12)化合物:在配体、钯催化剂以及碱存在下,所述配体例如BINAP、Xantphos、二环己基(2′,4′,6′-三异丙基联苯-2- 基)膦、二环己基(2′,6′-二异丙氧基联苯-2-基)膦及2′-(二环己基膦基)-N,N-二甲基联苯-2-胺,所述钯催化剂例如Pd(OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd2(dba)3,所述碱例如BuONa及Cs2CO3,在溶剂例如甲苯中,在110℃下,如Org.Lett.,2005,7,3965中所述。当Z2是Ar2时,式(12)化合物代表本发明。当Z2是卤素时,式(12)化合物,当在钯催化剂(例如PdCl2(PPh3)2、PdCl2(dppf))存在下用六甲基二锡或式(4)的有机硼烷化合物(例如双(频哪醇合)二硼或双(儿茶酚合)二硼,其中Rm是氢、烷基或芳基)处理时,提供式(13)的相应的锡或硼酸/酯,其中M是-SnMe3或-B(ORm)2。式(13)化合物,当在钯催化剂(例如Pd(OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd2(dba)3)存在下,用式(6)化合物(其中Ar2如所定义,并且卤是溴化物、氯化物或碘化物)处理时,提供式(14)化合物。或者,式(6)化合物,当在钯催化剂(例如PdCl2(PPh3)2、PdCl2(dppf))存在下,用六甲基二锡或式(4)的包含二硼烷的化合物(例如双(频哪醇合)二硼及双(儿茶酚合)二硼)处理时,将提供式(7)的包含有机锡或有机硼酸/酯的化合物,其中Ar2如所定义,并且M是-SnMe3或-B(ORm)2。式(7)化合物,当在钯催化剂例如Pd(OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd2(dba)3存在下,用式(13)化合物处理时,可以提供式(14)化合物。
方案5
或者,式(14)化合物(其中X1及X4中的至少一个是N,并且R1、a、b、c、d、X2、X3及Ar2如先前式(I)中所定义)可以按照方案5中的描述来制备。式(1)化合物,当在下述条件下用式(11)化合物(其中Z1是溴化物、氯化物或碘化物,并且Z2是溴化物、氯化物、碘化物或Ar2,条件 是当Z2是溴化物、氯化物或碘化物时X2是C)处理时,提供式(12)化合物:在碱例如Na2CO3、K2CO3、Cs2CO3及N,N-二异丙基乙胺存在下,在溶剂例如DMSO或NMP中,在110℃。可以按照方案4中的描述将式(12)化合物转化为式(14)化合物。
方案6
方案6中描述了生成式(14)化合物(其中X1及X4中的至少一个是N,并且R1、a、b、c、d、X2、X3及Ar2如先前式(I)中所定义)的另一种方法。式(11)化合物(其中Z1及Z2各自是溴化物、氯化物或碘化物,并且X1、X3及X4如先前所定义),当在钯催化剂例如PdCl2(PPh3)2、PdCl2(dppf)存在下用六甲基二锡或式(4)的有机硼烷化合物(例如双(频哪醇合)二硼或双(儿茶酚合)二硼,其中Rm是氢、烷基或芳基)处理时,提供式(15)的相应的锡或硼酸/酯,其中M是-SnMe3或-B(ORm)2。式(15)化合物,当在钯催化剂例如Pd(OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd2(dba)3存在下,用式(6)化合物(其中Ar2如式(I)中所定义,并且卤是溴化物、氯化物或碘化物)处理时,提供式(16)化合物。或者,式(11)化合物,当在钯催化剂例如Pd(OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd2(dba)3存在下用式(7)化合物处理时,提供式(16)化合物。可以按照方 案4及5中的描述将式(16)化合物转化为式(14)化合物。
可以用有机合成领域技术人员众所周知的方法对本发明化合物及中间体进行分离及纯化。分离和纯化化合物的常规方法的实例包括,固体支持体如硅胶、氧化铝或用烷基硅烷基团衍生的二氧化硅上的色谱法;通过在高温或低温下在用活性炭任选预处理下进行再结晶,薄层色谱法,在各种压力下蒸馏;在真空下升华;以及研制,如例如″Vogel′s Textbook of Practical Organic Chemistry″,第5版(1989),Furniss,Hannaford,Smith,和Tatchell,pub.Longman Scientific & Technical,Essex CM202JE,England中所描述。
本发明化合物含有至少一个碱性氮,因此可以将化合物用酸处理以形成所需的盐。例如,可以使化合物在室温或室温以上与酸反应以提供所需的盐,其在冷却后沉积并通过过滤收集。适合于该反应的酸的实例包括甲苯磺酸、延胡索酸、三氟乙酸等。
通过参考以下实施例可以更好地理解本发明化合物及制备这些化合物的方法。以下实施例意图例证说明本发明的范围而不是限制本发明的范围。
实施例1
5-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
实施例1A
3-(5-溴吡啶-3-基)-3,6-二氮杂双环[3.2.0]庚烷-6-羧酸(1R,5S)-叔丁酯
在Pd2(dba)3(Aldrich,183.6mg,0.2mmo1)及2,2′-二(二苯基膦基)-1,1′-联萘(Aldrich,373mg,0.6mmol)催化下,在Cs2CO3(Aldrich,6.50g,20.0mmol)存在下,在甲苯(无水,Aldrich,50mL)中,于110℃,将3,5-二溴吡啶(Aldrich,2.60g,15mmol)与3,6-二氮杂双环[3.2.0]庚烷-6-羧酸(1R,5S)-叔-丁酯(US 2006035936,1.98g,10mmol)偶联48小时。反应完成后,将反应混合物冷却至环境温度,并用EtOAc(100mL)稀释。过滤去无机固体。有机溶液用盐水(2x20mL)洗涤并减压浓缩。残余物用色谱法纯化(SiO2,EtOAc/己烷,v.50/50,Rf=0.40),以给出本标题化合物(3.05g,得率,86%)。1H NMR(300MHz,CD3OD)δppm 1.45(s,9H), 2.95(dd,J=11.02,4.24Hz,1H),3.05(dd,J=10.51,6.44Hz,1H),3.16-3.28(m,1H),3.51-3.67(m,1H),3.79(d,J=10.51Hz,1H),3.87-3.98(m,1H),4.03-4.19(m,1H),4.83-4.91(m,Hz,1H),7.40(t,J=2.20Hz,1H),7.97(d,J=1.70Hz,1H)8.05(d,J=2.37Hz,1H);MS(DCI/NH3)m/z 354(M+1)+,356(M+1)+.
实施例1B
3-[5-(1H-吲哚-5-基)吡啶-3-基]-3,6-二氮杂双环[3.2.0]庚烷-6-羧酸(1R,5S)-叔丁酯
在Pd2(dba)3(Aldrich,18.4mg,0.02mmol)和Pd(tBu3P)2(Strem Chemicals,20.5mg,0.04mmol)及CsF(Aldrich,2.55g,17mmol)催化下,在二噁烷(50mL)中,于80℃,将实施例1A的产物(1.0g,2.82mmol)与1H-吲哚-5-基硼酸(Frontier,677mg,4.23mmol)偶联15小时。反应完成后,将其冷却至环境温度,并用EtOAc(100mL)稀释。然后将混合物用盐水(2x20mL)洗涤并浓缩。残余物用色谱法纯化(SiO2,EtOAc/己烷,v.50/50,Rf=0.40),以给出本标题化合物(1.05g,得率,95%)。1H NMR(300MHz,CD3OD)δppm 1.45[s(br.),9H],2.87-2.99(m,1H),3.05(dd,J=10.22,6.56Hz,1H),3.15-3.30(m,2H),3.55-3.75(m,1H),3.82-3.93(m,1H),3.96-4.26(m,3H),6.53(d,J=2.75Hz,1H),7.28(d,J=3.05Hz,1H)7.39(dd,1H)7.43(s,1H)7.49(d,J=8.54Hz,1H)7.83(s,1H)8.01(d,J=2.44Hz,1H)8.21(s,1H);MS(DCI/NH3)m/z 391(M+1)+.
实施例1C
5-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚
在二氯甲烷(5.0mL)中,于环境温度,将实施例1B的产物(500mg,1.28mmol)用2,2,2-三氟乙酸(Aldrich,2mL)处理10小时。然后将溶液减压浓缩。残余物用CHCl3(50mL)稀释并用饱和Na2CO3(2x5mL)洗涤。将有机溶液浓缩,并且残余物用色谱法纯化(SiO2,EtOAc/MeOH(含2v.%NH3·H2O),50/50,Rf=0.20),以给出本标题化合物(360mg,得率,97.0%)。1H NMR(300MHz,CD3OD)δppm 2.91-3.09(m,2H),3.36-3.51(m,2H),3.69-3.83(m,2H),3.85-3.97(m,1H),4.49-4.69(m,1H),6.55(t,J=7.36Hz,1H),6.77-6.93(m,2H),7.00(t,J=7.21Hz,1H), 7.15(s,1H),7.25-7.40(m,2H),8.00(s,1H),MS(DCI/NH3)m/z291(M+1)+.
实施例1D
5-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
于80℃将实施例1C的产物(360mg,1.24mmol)用在EtOAc(20mL)中的p-TsOH·H2O(570mg,3.0mmol)处理1小时,然后于环境温度过夜,以给出本标题化合物(400mg,得率,69.8%)。1H NMR(300MHz,CD3OD)δppm 3.33(dd,J=12.88,6.40Hz,1H),3.44(dd,J=12.88,5.09Hz,1H),3.57-3.64(m,1H),3.82(dd,J=11.30,5.40Hz,,1H),4.12(d,J=10.85Hz,1H),4.28-4.38(m,2H),5.15(dd,J=6.78,5.42Hz,1H),6.60(d,J=3.05Hz,1H),7.19(d,J=8.14Hz,4H),7.37(d,J=3.05Hz,1H),7.48-7.61(m,2H),7.67(d,J=8.14Hz,4H),8.02(s,1H),8.11-8.17(m,1H),8.22(d,J=2.71Hz,1H),8.48(s,1H);MS(DCI/NH3)m/z 291(M+1)+.C18H18N4·2.00TsOH·0.90H2O的分析计算值:C,59.60;H,5.73;N,8.42.实测值:C,59.26;H,5.34;N,8.50.
实施例2
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二延胡索酸盐
实施例2A
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚
在NaBH(OAc)3(Aldrich,212mg,1.0mmol)存在下,在MeCN(3.0mL)及水(1.0mL)中,于环境温度,将实施例1D的产物(200mg,0.32mmol)用甲醛(Aldrich,37%,33L,0.40mmol)处理10小时。过滤去固体,并将滤液直接用色谱法纯化(SiO2,EtOAc/MeOH(含2v.%NH3·H2O),50/50,Rf=0.20),以给出本标题化合物(80mg,得率,82.0%)。1H NMR(300MHz,CD3OD)δppm 2.62(s,3H),3.08(dd,J=11.66,4.60Hz,1H),3.19(dd,J=10.13,7.06Hz,1H),3.32-3.41(m,1H),3.59(dd,J=9.36,4.14Hz,1H),3.71(t,J=8.75Hz,1H),3.89(d,J=10.13Hz,1H),4.01(d, J=11.66Hz,1H),4.40(dd,J=6.75,4.60Hz,1H),6.52(d,J=3.07Hz,1H),7.29(d,J=3.07Hz,1H),7.39(dd,J=8.29,1.53Hz,1H),7.43-7.54(m,2H),7.83(s,1H),8.03(d,J=2.45Hz,1H),8.23(s,1H);MS(DCI/NH3)m/z305(M+1)+.
实施例2B
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二延胡索酸盐
于环境温度,将实施例2A的产物(80mg,0.26mmol)用在EtOAc/EtOH(v.10/1,5mL)中的延胡索酸(Aldrich,58mg,0.5mmol)处理过夜,以给出本标题化合物(110mg,得率,78.9%).1H NMR(300MHz,CD3OD)δppm 2.97(s,3H)3.11(dd,J=8.50,6.20Hz1H),3.19(dd,J=12.90,4.70Hz,1H)3.46-3.64(m,1H),3.97-4.09(m,2H),4.19-4.37(m,2H),4.93-5.02(m,1H),6.53(d,J=3.05Hz,1H),6.76(s,5H),7.30(d,J=3.05Hz,1H),7.41(dd,J=8.40,1.70Hz1 H)7.51(d,J=8.20Hz,1H)7.62(t,J=2.03Hz,1H),7.86(d,J=1.70Hz,1H)8.15(d,J=2.37Hz,1H)8.34(d,J=1.70Hz,1H);MS(DCI/NH3)m/z 305(M+1)+.C19H20N4·2.41C4H4O4·2.40H2O的分析计算值:C,54.83;H,5.53;N,8.93.实测值:C,54.41;H,5.13;N,9.33.
实施例3
4-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
实施例3A
3-[5-(1H-吲哚-4-基)吡啶-3-基]-3,6-二氮杂双环[3.2.0]庚烷-6-羧酸(1R,5S)-叔-丁酯
在Pd(PPh3)4(Aldrich,7.8mg,0.007mmol)催化下,在二噁烷(4.0mL)及K2CO3水溶液(2M,1.0mL)中,于80℃,将实施例1A的产物(240mg,0.68mmol)与1H-吲哚-4-基硼酸(Frontier,164mg,1.02mmol)偶联12小时。反应完成后,将其冷却至环境温度并用EtOAc(40mL)稀释。然后将混合物用盐水(2x10mL)洗涤并浓缩。将残余物用色谱法纯化(SiO2, EtOAc/己烷,v.75/25,Rf=0.30),以给出本标题化合物(220mg,得率,83%)。1H NMR(300MHz,CD3OD)δppm 1.45[s(br.),9H],2.98(dd,J=10.85,4.41Hz,1H),3.08(dd,J=10.51,6.44Hz,1H),3.21-3.28(m,1H),3.59-3.72(m,1H),3.87(d,J=10.17Hz,1H),3.98-4.19(m,2H),4.78-4.93(m,1H),6.59(d,J=2.71Hz,1H),7.13(dd,J=7.40,2.00Hz,1H),7.22(t,J=7.63Hz,1H),7.32(d,J=3.39Hz,1H),7.44(d,J=8.14Hz,1H),7.47-7.50(m,1H),8.09(d,J=2.71Hz,1H),8.23(d,J=1.70Hz,1H);MS(DCI/NH3)m/z 391(M+1)+.
实施例3B
4-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
于80℃,将实施例3A的产物(220mg,0.56mmol)用在EtOAc(20mL)中的p-TsOH·H2O(235mg,1.24mmol)处理4小时,然后于环境温度处理过夜,以给出本标题化合物(210mg,得率,59.1%)。1H NMR(300MHz,CD3OD)δppm 3.33(dd,J=12.88,6.40Hz,1H),3.44(dd,J=12.88,5.09Hz,1H),3.57-3.64(m,1H),3.82(dd,J=11.30,5.40Hz,,1H),4.12(d,J=10.85Hz,1H),4.28-4.38(m,2H),5.15(dd,J=6.78,5.42Hz,1H),6.60(d,J=3.05Hz,1H),7.19(d,J=8.14Hz,4H),7.37(d,J=3.05Hz,1H),7.48-7.61(m,2H),7.67(d,J=8.14Hz,4H),8.02(s,1H),8.11-8.17(m,1H),8.22(d,J=2.71Hz,1H),8.48(s,1H);MS(DCI/NH3)m/z 291(M+1)+.C18H18N4·2.40TsOH·0.80H2O的分析计算值:C,58.21;H,5.45;N,7.80.实测值:C,58.06;H,5.44;N,7.67.
实施例4
4-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
实施例4A
4-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚
将实施例3B的产物(200mg,0.32mmol)按照实施例2A的程序用甲醛(Aldrich,37%,33μL,0.40mmol)处理。本标题化合物通过制备型 HPLC纯化(Gilson, 柱,7μm,40x100mm,洗脱溶剂,MeCN/H2O(含0.1M NH4HCO3/NH4OH,PH=10)(v.90/10至10/90经由25分钟),流速,40mL/min.,uv,254nm)(60mg,得率,62.0%)。1H NMR(300MHz,CD3OD)δppm 2.78(s,3H),3.10-3.22(m,2H),3.38-3.51(m,1H),3.79(dd,J=10.17,4.41Hz,1H),3.90-4.01(m,2H),4.12(dd,J=12.50,7.80Hz,1H),4.66(dd,J=7.12,4.75Hz,1H),6.59(d,J=3.05Hz,1H),7.14(d,J=7.12Hz,1H),7.22(t,J=7.50Hz,1H),7.33(d,J=3.05Hz,1H),7.46(d,J=8.14Hz,1H),7.54-7.61(m,1H),8.16(d,J=2.71Hz,1H),8.30(d,J=1.70Hz,1H);MS(DCI/NH3)m/z 305(M+1)+.
实施例4B
4-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
于环境温度,将实施例4A的产物(50mg,0.16mmol)用在EtOAc/EtOH(v.10/1,5mL)中的TsOH·H2O(Aldrich,62mg,0.33mmol)处理过夜,以给出本标题化合物(45mg,得率,43.4%)。1H NMR(300MHz,吡啶-D5)δppm 2.16(s,6H),3.04(s,3H),3.08(dd,J=12.73,5.06Hz,1H),3.09(dd,J=12.50,4.90Hz,1H),3.43-3.56(m,1H),3.80(d,J=10.13Hz,1H),3.97(dd,J=10.59,5.37Hz,1H),4.45(t,J=9.67Hz,1H),4.53(d,J=12.89Hz,1H),5.23(t,J=5.40Hz,1H),6.98(s,1H),7.15(d,J=7.80Hz,4H),7.34-7.44(m,2H),7.63(dt,J=8.90,2.30Hz,1H),7.72(dd,J=6.40,2.8Hz,1H),8.34(d,J=8.0Hz,4H),8.52(d,J=2.50Hz,1H),8.91(d,J=1.50Hz,1H),12.38(s,1H);MS(DCI/NH3)m/z 305(M+1)+.C19H20N4·2.25TsOH·1.20H2O的分析计算值:C,57.96;H,5.53;N,8.01.实测值:C,58.14;H,5.20;N,7.63.
实施例5
6-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
实施例5A
3-[5-(1H-吲哚-6-基)吡啶-3-基]-3,6-二氮杂双环[3.2.0]庚烷-6-羧酸
(1R,5S)-叔-丁酯
按照实施例3A的程序,将实施例1A的产物(240mg,0.68mmol)与1H-吲哚-4-基硼酸(Frontier,164mg,1.02mmol)偶联。将本标题化合物用色谱法纯化(SiO2,EtOAc/己烷,v.50/50,Rf=0.40)(240mg,得率,91%)。 1H NMR(300MHz,CD3OD)δppm 1.46[s(br.),9H],2.96(dd,J=10.85,4.07Hz,1H),3.06(dd,J=10.17,6.44Hz,1H),3.21-3.30(m,1H),3.54-3.75(m,1H),3.88(d,J=10.17Hz,1H),3.96-4.20(m,2H),4.85-4.90(m,1H),6.48(d,J=3.05Hz,1H),7.26-7.36(m,2H),7.39-7.47(m,1H),7.61-7.69(m,2H),8.03(d,J=2.37Hz,1H),8.22(d,J=1.70Hz,1H);MS(DCI/NH3)m/z 391(M+1)+.
实施例5B
6-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
将实施例5A的产物(240mg,0.61mmol)用在EtOAc(20mL)中的p-TsOH·H2O(257mg,1.35mmol)于80℃处理4小时,然后于环境温度处理过夜,以给出本标题化合物(230mg,得率,59.4%)。1H NMR(400MHz,吡啶-D5)δppm 2.17(s,6H),2.91(dd,J=10.40,6.20Hz,1H),2.98(dd,J=12.20,4.90Hz,1H),3.35-3.51(m,1H),3.82-3.92(m,2H),4.40(d,J=12.27Hz,1H),4.58(dd,J=10.74,8.59Hz,1H),5.47(dd,J=7.06,4.91Hz,1H),6.75-6.83(m,1H),7.17(d,J=7.67Hz,4H),7.46-7.51(m,1H),7.56(dd,J=8.13,1.69Hz,1H),7.60-7.62(m,1H),7.92(d,J=8.29Hz,1H),8.03(s,1H),8.36(d,J=7.98Hz,4H),8.41(d,J=2.76Hz,1H),8.79(d,J=1.84Hz,1H),12.26(s,1H);MS(DCI/NH3)m/z 291(M+1)+.C18H18N4·2.25TsOH·1.20H2O的分析计算值:C,57.96;H,5.53;N,8.01.实测值:C,58.14;H,5.20;N,7.63.
实施例6
6-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚甲苯磺酸盐
实施例6A
6-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚
按照实施例2A的程序,将实施例5B的产物(200mg,0.32mmol)用甲醛(Aldrich,37%,33μL,0.40mmol)处理。将本标题化合物通过制备型HPLC纯化(Gilson, 柱,7μm,40x100mm,洗脱溶剂,MeCN/H2O(含0.1M NH4HCO3/NH4OH,PH=10)(v.90/10至10/90经由25分钟),流速,40mL/min.,uv,254nm)(50mg,得率,51.8%).1H NMR(300MHz,CD3OD)δppm 2.39(s,3H)3.01(dd,J=11.02,4.58Hz,1H),3.17-3.29(m,3H),3.30-3.37(m,1H),3.73-3.87(m,2H),4.01(dd,J=6.10,4.41Hz,1H),4.26(s,1H),7.08(s,1H),7.22-7.29(m,1H),7.34-7.39(m,1H),7.57-7.67(m,2H),7.96(d,J=2.37Hz,1H),8.16(s,1H);MS(DCI/NH3)m/z 305(M+1)+.
实施例6B
6-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚甲苯磺酸盐
于环境温度,将实施例6A的产物(50mg,0.16mmol)用在EtOAc/EtOH(v.10/1,5mL)的p-TsOH·H2O(Aldrich,62mg,0.33mmol)处理过夜,以给出本标题化合物(55mg,得率,74.4%)。1H NMR(300MHz,CD3OD)δppm 1H NMR(400MHz,吡啶-D5)δppm 2.14(s,4.2H)2.87(s,3H),2.91(dd,J=10.28,6.60Hz,1H),2.98(dd,J=12.43,4.76Hz,1H),3.26-3.39(m,1H),3.73(d,J=10.13Hz,1H),3.78(dd,J=10.13,4.60Hz,1H),4.11-4.21(m,1H),4.36(d,J=12.27Hz,1H),4.61(s,1H),4.84-4.97(m,J=6.14Hz,1H),7.13(d,J=7.90Hz,2.8H),7.50(t,J=2.30Hz,1H),7.54-7.58(m,2H),8.03-8.09(m,3H),8.34(d,J=7.98Hz,2.8H),8.83(d,J=1.90Hz,1H),12.05(s,1H);MS(DCI/NH3)m/z 305(M+1)+.C19H20N4·1.42TsOH·1.00H2O的分析计算值:C,61.31;H,5.93;N,9.88.实测值:C,61.29;H,6.11;N,9.53.
实施例7
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-2-(三氟甲基)-1H-吲哚双三氟乙酸盐
实施例7A
(1S,5S)-3-(5-溴吡啶-3-基)-6-甲基-3,6-二氮杂双环[3.2.0]庚烷
于90℃,将实施例1A的产物(4.50g,12.7mmol)用在HCO2H(Aldrich,88%,30mL)中的HCHO(Aldrich,37%,5mL)处理1小时。然后将溶液减压浓缩。将残余物小心地用饱和Na2CO3碱化至pH9。将混合物用CHCl3(3x100mL)萃取。合并的萃取液用盐水(2x20mL)洗涤并浓缩。残余物用色谱法纯化(SiO2,CH2Cl2/MeOH(含2v.%NH3·H2O),90/10,Rf=0.10),以给出本标题化合物(3.36g,得率,99%)。1H NMR(300MHz,CD3OD)δppm 2.89(s,3H),3.09(dd,J=10.51,6.44Hz,1H),3.15(dd,J=12.89,4.75Hz,1H),3.41-3.60(m,1H),3.85-3.98(m,2H),4.09-4.25(m,2H),4.87-4.97(m,1H),7.55(t,J=2.20Hz,1H),8.09(d,J=1.70Hz,1H),8.17(d,J=2.37Hz,1H);MS(DCI/NH3)m/z 268(M+1)+,270(M+1)+.
实施例7B
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-2-(三氟甲基)-1H-吲哚双三氟乙酸盐
在以下条件下将实施例7A的产物(100mg,0.37mmol)与5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-2-(三氟甲基)-1H-吲哚(US2005043347,300mg,0.965mmol)偶联15分钟:在二(三苯膦)氯化钯(II)(Aldrich,7.0mg,0.01mmol,)及联苯-2-基-二环己基-膦(phosphane)(Strem Chemicals,10.5mg,0.03mmol)催化下,在二噁烷/EtOH/Na2CO3(aq.,1M)(v.1/1/13ml)中,于130℃(150瓦特max.),在EmryTM Creator微波炉中。将无机固体通过注射器式过滤器过滤去,并且液体混合物通过制备型HPLC纯化(Gilson,柱, 5μm,40x100mm;洗脱溶剂,MeCN/H2O(含0.1%v.TFA)(v.90/10至10/90经由25min.),流速,40mL/min.,uv,254nm)。收集所需产物级分并浓缩,并将残余物在醚/乙醇(v.10/1,5mL)中于室温搅拌16小时,以给出本标题化合物(56.1mg,得率,22.8%)。1H NMR(300MHz,CD3OD)δppm 2.74-3.14(m,4H),3.41(dd,J=13.2,4.7Hz,1H),3.56-3.68(m,1H),4.02-4.27(m,3H),4.39(d,J=12.9Hz,1H),5.92-5.05(m,1H),7.03(s,1H),7.60-7.73(m,2H),8.05(s,1H),8.11(s,1H),8.26(s,1H),8.51(s,1H);MS(DCI/NH3)m/z 373(M+1)+;C20H19F3N4·2.5C2F3O2H的分析计算值:C,45.67;H,3.30;N,8.52.实测值:C,45.62;H,3.31;N,8.47.
实施例8
(1S,5S)-3-(5-(苯并呋喃-5-基)吡啶-3-基)-6-甲基-3,6-二氮杂双环[3.2.0]庚烷双三氟乙酸盐
按照实施例7B的程序,将实施例7A的产物(100mg,0.37mmol)与苯并呋喃-5-基硼酸(Maybridge,150mg,0.93mmol)偶联,以给出本标题化合物(156.7mg,得率,76.7%)。1H NMR(300MHz,CD3OD)δppm2.74-3.13(m,4H),3.39(dd,J=13.1,4.9Hz,1H),3.55-3.66(m,1H),4.03-4.24(m,3H),4.40(d,J=12.9Hz,1H),4.96-5.04(m,1H),6.97(d,J=2.0Hz,1H),7.70(s,2H),7.88(d,J=2.0Hz,1H),7.99-8.08(m,2H),8.29(s,1H),8.50(s,1H);MS(DCI/NH3)m/z 306(M+1)+.C19H19N3O·2.1CF3CO2H的分析计算值:C,51.15;H,3.90;N,7.71.实测值:C,51.14;H,3.47;N,7.70.
实施例9
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲唑双三氟乙酸盐
实施例9A
5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吲唑
在Pd(dppf)2Cl2·CH2Cl2(Aldrich,985mg,1.2mmol)催化下,在KOAc(Aldrich,16.7g,170mmol)存在下,在无水DMF(160ml)中,于90℃,将5-溴-1H-吲唑(US2003199511,9.45g,48mmol,)与双(频哪醇合)二硼(Combi-Blocks,15.5g,61mmol)偶联24小时。反应完成后,将其冷却至环境温度,用EtOAc(250mL)稀释并用水(2x 50mL)洗涤。将有机相减压浓缩,并且残余物用色谱法纯化(SiO2,己烷∶EtOAc(v.10∶1),Rf=0.6),以给出本标题化合物(9.8g,得率,84%)。1H NMR(300MHz,CD3OD)δppm 1.36(s,12H)7.51(dt,J=8.5,1.0Hz,1H)7.73(dd,J=8.5,1.0Hz,1H)8.08(d,J=1.0Hz,1H)8.23(t,J=1.0Hz,1H);MS(DCI/NH3)m/z 245(M+1)+.
实施例9B
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲唑双三氟乙酸盐
按照实施例7B的程序,将实施例7A的产物(100mg,0.37mmol)与实施例9A产物(200mg,0.82mmol)偶联,以给出本标题化合物(128.2mg,0.235mmol,得率,62.7%)。1H NMR(300MHz,CD3OD)δppm 2.75-3.12(m,4H),3.38(dd,J=13.1,4.9Hz,1H),3.55-3.66(m,1H),4.05-4.23(m,3H),4.38(d,J=12.2Hz,1H),4.96-5.06(m,1H),7.69-7.83(m,2H),8.00(s,1H),8.18(d,J=1.0Hz,1H),8.21(s,1H),8.29(m,1H),8.51(s,1H);MS(DCI/NH3)m/z 306(M+1)+.C18H19N52.10CF3CO2H的分析计算值:C,48.94;H,3.90;N,12.85.实测值:C,48.90;H,3.73;N,12.82.
实施例10
(1S,5S)-3-[5-(苯并[b]噻吩-5-基)吡啶-3-基]-3,6-二氮杂双环[3.2.0]庚烷二甲苯磺酸盐
实施例10A
5-[(1R,5S)-6-(叔丁氧羰基)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基硼酸
将实施例1A的产物(0.71g,2mmol)在以下条件下与4,4,4′,4′,5,5,5′,5′-八甲基-2,2′-二(1,3,2-二氧硼杂环戊烷)(Aldrich,0.76g,3.0mmol)偶联15小时:在{1,1’-双(二苯基膦基)-二茂铁]二氯钯(II)二氯甲烷络合物PdCl2(dppf)·CH2Cl2(Aldrich,33mg,0.04mmol)与KOAc(Aldrich,392mg,4.0mmol)催化下,在二噁烷(无水,20mL)中,于80℃。然后将溶液冷却至环境温度,并用EtOAc(100mL)稀释。然后将混合物用盐水(2x10mL)洗涤。将有机溶液浓缩,以给出本标题化合物(0.62g,得率,96.9%)。1H NMR(300MHz,CD3OD)δppm 1.41-1.49(m,9H),2.98(dd,J=10.85,4.07Hz,1H),3.07(dd,J=10.25,6.40Hz,,1H),3.20-3.32(m,3H),3.52-3.67(m,1H),3.83(d,J=10.51Hz,1H),3.99(d,J=10.85Hz,1H),4.10(t,J=7.80Hz,1H),7.77(d,J=2.03Hz,1H),7.90(d,J=2.37Hz,1H),7.98(s,1H);MS(DCI/NH3)m/z 320(M+1)+.
实施例10B
5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基硼酸二甲苯磺酸盐
将实施例10A的产物(0.62g,1.94mmol)于80℃用在EtOH(20mL)中的p-TsOH·H2O(0.95g,5.0mmol)处理4小时,并冷却至环境温度。加入EtOAc(20mL)。将混合物于室温搅拌过夜,以给出本标题化合物(1.10g,得率,97.5%).1H NMR(300MHz,CD3OD)δppm 2.36(s,6H),3.26(dd,J=10.50,6.10Hz,1H),3.37(dd,J=12.72,5.26Hz,1H),3.52-3.66(m,1H),3.78(dd,J=11.19,5.09Hz,1H),4.03(d,J=10.85Hz,1H),4.24-4.37(m,2H),5.13(dd,J=6.95,5.26Hz,1H),7.21(d,J=7.80Hz,4H),7.68(d,J=8.48Hz,4H),8.13(d,J=2.37Hz,1H),8.26(s,1H),8.30(d,J=3.05Hz,1H);MS(DCI/NH3)m/z 220(M+1)+.
实施例10C
(1S,5S)-3-[5-(苯并[b]噻吩-5-基)吡啶-3-基]-3,6-二氮杂双环[3.2.0]庚烷二甲苯磺酸盐
按照实施例3A的程序,将实施例10B的产物(280mg,0.50mmol)与5-溴苯并[b]噻吩偶联(Alfa Aesar,160mg,1.5mmol)。将本标题化合物的游离碱用制备型HPLC纯化(Gilson, 柱,7μm,40x100mm,洗脱溶剂,MeCN/H2O(含0.1M NH4HCO3/NH4OH,PH=10)(v.90/10至10/90经由25分钟),流速,40mL/min.,uv,254nm)(40mg,得率,26%)。然后将该游离碱(40mg,0.13mmol)于环境温度用在EtOAc(5.0mL)中的TsOH·H2O(57mg,0.3mmol)处理,以给出本标题化合物(50mg,得率,59.4%)。1H NMR(400MHz,CD3OD)δppm 2.35(s,6H),3.31-3.36(m,1H),3.42(dd,J=12.72,5.26Hz,1H),3.54-3.69(m,1H),3.82(dd,J=11.02,5.26Hz,1H),4.12(d,J=10.85Hz,1H),4.27-4.33(m,1H),4.37(d,J=12.55Hz,1H),5.15(dd,J=6.78,5.43Hz,1H),7.19(d,J=7.80Hz,4H),7.51(d,J=5.43Hz,1H),7.68(d,J=8.14Hz,4H),7.71-7.77(m,2H),8.07-8.15(m,2H),8.28(d,J=1.70Hz,1H),8.30(d,J=2.71Hz,1H),8.52(d,J=1.36Hz,1H);MS(DCI/NH3)m/z 308(M+1)+.C18H17N3S2.05TsOH·1.60H2O的分析计算值:C,56.37;H,5.35;N,6.10.实测值:C,56.03;H,5.63;N,6.10.
实施例11
(1S,5S)-3-[5-(苯并[b]噻吩-5-基)吡啶-3-基]-3,6-二氮杂双环[3.2.0]庚烷二甲苯磺酸盐
实施例11A
5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基硼酸基硼酸
将实施例7A的产物(2.50g,9.3mmol)与4,4,4′,4′,5,5,5′,5′-八甲基-2,2′-二(1,3,2-二氧硼杂环戊烷)(Aldrich,2.53g,10.0mmol)在以下条件下偶联15小时:在{1,1’-双(二苯基膦基)-二茂铁]二氯钯(II)二氯甲烷络合物PdCl2(dppf)·CH2Cl2(Aldrich,163mg,0.2mmol)与KOAc(Aldrich,1.96g,20.0mmol)催化下,在二噁烷(无水,50mL),于80℃。然后将溶液冷却至环境温度,浓缩并用水(20mL)稀释。然后将混合物用乙醚(2x10mL)萃取。将水溶液浓缩,以给出本标题化合物。1H NMR(300MHz,CD3OD)δppm 2.95(dd,J=10.85,4.41Hz,1H),3.12-3.27(m,3H),3.31-3.39(m,1H),3.68-3.79(m,2H),4.00(dd,J=6.44,4.41Hz,1H),7.24(d,J=4.75Hz,1H),7.87(dd,J=4.41,1.36Hz,1H),8.03(d,J=2.71Hz,1H);MS(DCI/NH3)m/z 234(M+1)+.
实施例11B
(1S,5S)-3-[5-(苯并[b]噻吩-5-基)吡啶-3-基]-3,6-二氮杂双环[3.2.0]庚烷二甲苯磺酸盐
按照实施例10C的程序,将实施例11A的产物(117mg,0.50mmol)与5-溴苯并[b]噻吩(Alfa Aesar,160mg,0.75mmol)偶联,以给出本标题化合物(60mg,得率,18%)。1H NMR(400MHz,吡啶-D5)δppm 2.14(s,6H),2.95(dd,J=10.13,6.14Hz,1H),3.09(s,3H),3.13(dd,J=12.89,4.91Hz,1H),3.48-3.62(m,1H),3.86(d,J=10.13Hz,1H),3.99-4.13(m,1H),4.41-4.38(m,1H),4.68(d,J=12.89Hz,1H),5.32-5.49(m,1H),7.13(d,J=7.98Hz,4H),7.50(d,J=5.22Hz,1H),7.61(t,J=2.15Hz,1H),7.69(d,J=5.22Hz,1H),7.73(dd,J=8.29,1.53Hz,1H),8.05(d,J=8.59Hz,1H),8.27(d,J=1.53Hz,1H),8.33(d,J=7.98Hz,4H),8.49(d,J=2.45Hz,1H),8.74(d,J=1.53Hz,1H);
MS(DCI/NH3)m/z 322(M+1)+.C19H19N3S·2.00TsOH·1.20H2O的分析计算值:C,57.65;H,5.48;N,6.11.实测值:C,57.51;H,5.24;N,5.83.
实施例12
7-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚三甲苯磺酸盐
实施例12A
7-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚
按照实施例3A的程序,将实施例11A的产物(117mg,0.50mmol)与7-溴吲哚(Aldrich,147mg,0.75mmol)偶联。将本标题化物通过制备型HPLC纯化(Gilson, 柱,7μm,40x100mm,洗脱溶剂,MeCN/H2O(含0.1M NH4HCO3/NH4OH,PH=10)(v.90/10至10/90经由25分钟),流速,40mL/min.,uv,254nm)(40mg,得率,26%)。1H NMR(300MHz,CD3OD)δppm 2.42(s,3H),3.06(dd,J=11.02,4.24Hz,1H),3.20-3.28(m,2H),3.33-3.41(m,2H),3.80(t,J=10.51Hz,2H),4.03(dd,J=6.27,4.24Hz,1H),6.53(d,J=3.05Hz,1H),7.06-7.18(m,2H),7.26(d,J=3.39Hz,1H),7.34-7.42(m,1H),7.59(dd,J=6.61,2.20Hz,1H),8.07(d,J=2.37Hz,1H),8.13(d,J=1.36Hz,1H);MS(DCI/NH3)m/z 305(M+1)+.
实施例12B
7-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚三甲苯磺酸盐
将实施例12A的产物(40mg,0.13mmol)于环境温度用在EtOAc(5mL)中的p-TsOH·H2O(74mg,0.39mmol)处理过夜,以给出本标题化合物(35mg,得率,32.8%).1H NMR(400MHz,吡啶-D5)δppm 2.16(s,9H),2.85(dd,J=10.13,6.14Hz,1H),2.92-3.06(m,4H),3.37-3.51(m,1H),3.81(d,J=10.13Hz,1H),3.97-4.05(m,1H),4.28(t,J=9.36Hz,1H),4.67(d,J=12.89Hz,1H),5.05-5.19(m,1H),6.61-6.87(m,2H),7.15(d,J=7.67Hz,6H),7.32(t,J=7.52Hz,1H),7.36-7.42(m,1H),7.64-7.77(m,2H),7.87(d,J=7.98Hz,1H),8.30(d,J=7.98Hz,6H),8.42(d,J=2.46 Hz,1H),12.00(s,1H);MS(DCI/NH3)m/z305(M+1)+.C19H20N4·3.00TsOH·1.00H2O的分析计算值:C,56.64;H,5.61;N,6.77.实测值:C,56.70;H,5.34;N,6.97.
实施例13
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-苯并[d]咪唑二甲苯磺酸盐
实施例13A
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-苯并[d]咪唑
按照的实施例12A程序,将实施例11A产物(117mg,0.50mmol)与7-溴吲哚(Aldrich,147mg,0.75mmol)偶联,以给出本标题化合物(80mg,得率,52%).1H NMR(300MHz,CD3OD)δppm 2.41(s,3H),3.06(dd,J=11.19,4.41Hz,1H),3.22-3.28(m,2H),3.33-3.39(m,2H),4.03-4.06(m,1H),7.37-7.42(m,1H),7.58(dd,J=8.48,1.70Hz,1H),7.72(d,J=8.48Hz,1H),7.87(s,1H),8.03(d,J=2.71Hz,1H),8.18(d,J=1.70Hz,1H),8.23(s,1H);MS(DCI/NH3)m/z 306(M+1)+.
实施例13B
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-苯并[d]咪唑二甲苯磺酸盐
将实施例13A的产物(80mg,0.26mmol)于环境温度用在EtOAc(5mL)中的p-TsOH·H2O(114mg,0.60mmol)处理过夜,以给出本标题化合物(100mg,得率,47.5%)。1H NMR(400MHz,吡啶-D5)δppm 2.16(s,6H),2.91(dd,J=10.43,6.14Hz,1H),3.03-3.12(m,4H),3.42-3.57(m,1H),3.82(d,J=10.13Hz,1H),4.01(dd,J=10.43,4.91Hz,1H),4.33-4.51(m,J=9.21Hz,1H),4.62(d,J=12.89Hz,1H),5.15-5.30(m,1H),7.15(d,J=7.67Hz,4H),7.71(dd,J=8.29,1.53Hz,1H),7.84-7.95(m,1H),8.01(d,J=8.29Hz,1H),8.29-8.37(m,J=7.98Hz,5H),8.47(d,J=2.45Hz,1H),8.67(s,1H),8.78(d,J=1.53Hz,1H);MS(DCI/NH3)m/z 306(M+1)+.C18H19N5·2.00TsOH·1.50H2O的分析计算值:C,56.79;H,5.66;N,10.35. 实测值:C,56.58;H,5.26;N,10.63.
实施例14
3-甲基-5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡
啶-3-基}-1H-吲哚二甲苯磺酸盐
实施例14A
3-甲基-5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚
按照实施例7B的程序,将实施例11A的产物(117mg,0.5mmol)与5-溴-3-甲基-1H-吲哚(Aldrich,210mg,1.0mmol)偶联。反应完成后,将无机固体经由注射器式过滤器过滤去,并将滤液通过制备型HPLC纯化(Gilson,柱, 7μm,40x100mm.洗脱溶剂,MeCN/H2O(含0.1MNH4HCO3/NH4OH,pH=10)(v.90/10至10/90经由25min.);流速,40mL/min.,uv,254nm),以给出本标题化物的游离碱(15mg,得率,9.4%)。 1H NMR(300MHz,CD3OD)δppm 2.35(s,3H),2.39(s,3H),3.03(dd,J=11.19,4.41Hz,1H),3.20-3.29(m,2H),3.31-3.39(m,2H),3.77-3.90(m,2H),4.03(dd,J=6.27,4.24Hz,2H),7.04(s,1H),7.34-7.46(m,3H),7.74(s,1H),7.97(d,J=2.71Hz,2H),8.17(d,J=1.70Hz,1H);MS(DCI/NH3)m/z 319(M+1)+.
实施例14B
3-甲基-5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
将实施例14A的产物(15mg,0.047mmol)于室温用在EtOAc/EtOH(v.5/1,5mL)中的p-TsOH(Aldrich,19mg,0.1mmol)处理16小时,以给出本标题化合物(20mg,得率,64.3%)。1H NMR(300MHz,CD3OD)δppm2.33(s,6H),2.38(s,3H),3.04(s,3H),3.35-3.49(m,2H),3.57-3.71(m,1H),4.05-4.24(m,3H),4.45(d,J=12.9Hz,1H),5.02(dd,J=7.1,4.7Hz,1H),7.13(d,J=1.02Hz,1H),7.18(d,J=7.8Hz,4H),7.49-7.55(m,2H),7.67(d,J=8.1Hz,4H),7.94(t,J=1.36Hz,1H),8.12-8.33(m,2H),8.51(d,J=1.02Hz,1H);MS(DCI/NH3)m/z319(M+1)+. C20H22N4·2.30C7H8O3S·1.30H2O的分析计算值:C,58.76;H,5.87;N,7.59.实测值:C,58.97;H,5.52;N,7.71.
实施例15
3-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-9H-咔唑半延胡索酸盐
按照实施例14A的程序,将实施例10B的产物(109mg,0.5mmol)与3-溴-9H-咔唑(Aldrich,245mg,1.0mmol)偶联,以给出本标题化合物的游离碱(68mg,得率,40%)。将该游离碱于室温用在EtOAc/EtOH(v.5/1,5mL)中的延胡索酸(Aldrich,23mg,0.2mmol)处理16小时,以给出本标题化合物(64mg,得率,72%)。1H NMR(300MHz,CD3OD)δppm 3.12(dd,J=10.3,6.3Hz,1H),3.21(dd,J=12.2,5.1Hz,1H),3.48-3.60(m,1H),3.78(dd,J=11.2,5.1Hz,1H),4.05(d,J=10.5Hz,1H),4.22-4.33(m,2H),5.06(dd,J=7.1,4.7Hz,1H),6.68(s,1.8H),7.19(ddd,J=7.9,6.9,1.2Hz,1H),7.40(td,J=7.5,1.2Hz,1H),7.45-7.51(m,1H),7.54-7.60(m,1H),7.64-7.67(m,1H),7.67-7.72(m,1H),8.12-8.19(m,2H),8.38(dd,J=9.7,1.5Hz,2H);MS(DCI/NH3)m/z 341(M+1)+.C22H20N40.90C4H4O4的分析计算值:C,69.11;H,5.35;N,12.59.实测值:C,68.93;H,5.40;N,12.74.
实施例16
5-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-3-甲基-1H-吲
哚双三氟乙酸盐
按照实施例7B的程序,将实施例10B的产物(109mg,0.5mmol)与5-溴-3-甲基-1H-吲哚(Aldrich,210mg,1.0mmol)偶联,以给出本标题化合物(90mg,得率,30.6%)。1H NMR(300MHz,CD3OD)δppm 2.38(d,J=1.4Hz,3H),3.28-3.36(m,1H),3.42(dd,J=12.7,5.3Hz,1H),3.57-3.66(m,1H),3.81(dd,J=11.4,5.3Hz,1H),4.13(d,J=10.8Hz,1H),4.28-4.39(m,2H),5.15(dd,J=7.1,5.1Hz,1H),7.12(q,J=1.0Hz,1H),7.50(d,J=1.4Hz,2H),7.93(t,J=1.4Hz,1H),8.11(dd,J=2.4,1.7Hz,1H),8.23(d,J=2.7Hz,1H),8.52(d,J=1.4Hz,1H),;MS(DCI/NH3)m/z 305(M+1)+.C19H20N42.50CF3CO2H的分析计算值:C,48.90;H,3.85;N,9.50. 实测值:C,49.13;H,4.00;N,9.50.
实施例17
3-(5-((1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基)吡啶-3-基)-9H-咔唑双三氟乙酸盐
按照实施例7B的程序,将实施例11A的产物(117mg,0.5mmol)与3-溴-9H-咔唑(Aldrich,245mg,1.0mmol)偶联,以给出本标题化合物(24.8mg,得率,7.3%)。1H NMR(300MHz,CD3OD)δppm 2.77-3.12(m,4H),3.43(dd,J=13.4,4.9Hz,1H),3.56-3.66(m,1H),4.07-4.26(m,3H)4.43(d,J=12.5Hz,1H),4.96-5.05(m,1H),7.23(ddd,J=8.0,7.0,1.4Hz,1H),7.44(ddd,J=8.1,7.0,1.2Hz,1H),7.51(dt,J=8.1,1.0Hz,1H),7.63(d,J=8.5Hz,1H),7.80(dd,J=8.5,1.7Hz,1H),8.12-8.21(m,2H),8.25(s(br),1H),8.53(s,1H),8.60(s,1H);MS(DCI/NH3)m/z 355(M+1)+.C23H22N42.70CF3CO2H·1.2H2O的分析计算值:C,49.87;H,3.99;N,8.19.实测值:C,49.67;H,3.86;N,8.43.
实施例18
7-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吡咯并[2,3-c]吡啶三甲苯磺酸盐
实施例18A
7-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吡咯并[2,3-c]吡啶
按照实施例12A的程序,将实施例11A的产物(117mg,0.50mmol)与7-溴-1H-吡咯并[2,3-c]吡啶(AstaTech,197mg,1.0mmol)偶联,以给出本标题化合物(40mg,得率,26.1%)。1H NMR(300MHz,CD3OD)δppm2.41(s,3H),3.10(dd,J=11.19,4.41Hz,1H),3.20-3.28(m,1H),3.33-3.42(m,3H),3.77-3.89(m,2H),4.04(dd,J=6.78,4.41Hz,1H),6.66(d,J=3.05Hz,1H),7.52-7.55(m,1H),7.57(d,J=3.05Hz,1H),7.63(d,J=5.76Hz,1H),8.13-8.23(m,2H),8.33(d,J=1.70Hz,1H);MS(DCI/NH3)m/z 306(M+1)+.
实施例18B
7-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吡咯并[2,3-c]吡啶三甲苯磺酸盐
将实施例18A的产物(80mg,0.13mmol)于环境温度用在EtOAc(5mL)中的p-TsOH·H2O(76mg,0.40mmol)处理过夜,以给出本标题化合物(50mg,得率,46.8%)。1H NMR(400MHz,吡啶-D5)δppm 2.17(s,9H),2.94(dd,J=10.43,6.14Hz,1H),3.03-3.14(m,4H),3.40-3.57(m,1H),3.94(d,J=10.13Hz,1H),4.10-4.14(m,1H),4.28-4.38(m,1H),4.78(d,J=12.89Hz,1H),5.18(dd,J=7.06,4.91Hz,1H),6.79(d,J=2.76Hz,1H),7.16(d,J=7.98Hz,6H),7.77(d,J=5.52Hz,1H),8.01(d,J=3.07Hz,1H),8.06-8.11(m,1H),8.31(d,J=7.98Hz,6H),8.47(d,J=2.46Hz,1H),8.60(d,J=5.52Hz,1H),9.14(d,J=1.53Hz,1H);MS(DCI/NH3)m/z306(M+1)+.C18H19N5·3.05TsOH·2.90H2O的分析计算值:C,53.53;H,5.62;N,7.93.实测值:C,53.17;H,5.22;N,7.87.
实施例19
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吡咯并[2,3-b]吡啶甲苯磺酸盐
实施例19A
5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡咯并[2,3-b]吡啶
将5-溴-1H-吡咯并[2,3-b]吡啶(Alfa Aesar,1.00g,5.0mmol)在以下条件下与4,4,4′,4′,5,5,5′,5′-八甲基-2,2′-二(1,3,2-二氧硼杂环戊烷)(Aldrich,1.52g,6.0mmol)偶联10小时:在{1,1’-双(二苯基膦基)-二茂铁]二氯-钯(II)二氯甲烷络合物PdCl2.(dppf)·CH2Cl2(Aldrich,82mg,0.1mmol)与KOAc(Aldrich,0.98g,10.0mmol)催化下,在二噁烷(无水,20mL)中,于80℃。然后将其冷却至环境温度,浓缩并用EtOAc(100mL)稀释。然后将混合物用盐水(2x10mL)洗涤。将有机溶液浓缩,并且残余物用色谱法纯化(SiO2,EtOAc/己烷,v.50/50,Rf=0.40),以给出本标题化合物(1.15g,得率,94.2%)。1H NMR(300MHz,CD3OD)δppm 1.38(s,12H)6.52(d,J=3.39Hz,1H)7.38(d,J=3.39Hz,1H)8.34(d,J=1.70Hz,1H)8.49(d,J=1.36Hz,1H);MS(DCI/NH3)m/z 245(M+1)+.
实施例19B
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吡咯并[2,3-b]吡啶
按照实施例12A的程序,将实施例19A的产物(244mg,1.0mmol)与实施例7A的产物(216mg,0.8mmol)偶联,以给出本标题化合物(110mg,得率,45.1%)。1H NMR(300MHz,CD3OD)δppm 2.40(s,3H),3.06(dd,J=11.19,4.41Hz,1H),3.20-3.29(m,2H),3.33-3.38(m,2H),3.78-3.88(m,2H),4.03(dd,J=6.44,4.07Hz,1H),6.58(d,J=3.39Hz,1H),7.39(dd,J=2.71,2.03Hz,1H),7.45(d,J=3.39Hz,1H),8.04(d,J=2.71Hz,1H),8.17(d,J=1.70Hz,1H),8.27(d,J=2.03Hz,1H),8.46(d,J=2.03Hz,1H);MS(DCI/NH3)m/z 306(M+1)+.
实施例19C
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吡咯并[2,3-b]吡啶甲苯磺酸盐
将实施例19B的产物(110mg,0.36mmol)于环境温度用在EtOAc(5mL)中的p-TsOH·H2O(76mg,0.40mmol)处理过夜,以给出本标题化合物(170mg,得率,99.0%)。1H NMR(300MHz,CD3OD)δppm 2.34(s,4.5H),3.02(s,3H),3.10-3.26(m,2H),3.48-3.69(m,2H),4.00-4.21(m,2H),4.33(d,J=13.90Hz,1H),4.89-5.07(m,1H),6.60(d,J=3.73Hz,1H),7.20(d,J=8.14Hz,3H),7.48(d,J=3.73Hz,1H),7.65-7.76(m,4H),8.19-8.27(m,1H),8.32(d,J=2.03Hz,1H),8.39(d,J=1.70Hz,1H),8.50(d,J=2.03Hz,1H);MS(DCI/NH3)m/z306(M+1)+.C18H19N5·1.45TsOH 0.75H2O的分析计算值:C,59.53;H,5.70;N,12.39.实测值:C,59.93;H,5.81;N,12.00.
实施例20
3-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1-(苯基磺酰基)-1H-吲哚双三氟乙酸盐
按照实施例7B的程序,将实施例7A的产物(120mg,0.45mmol)与1-(苯基磺酰基)-1H-吲哚-3-基硼酸(Aldrich,350mg,1.16mmol)偶联,以 给出本标题化合物(300mg,得率,92.8%)。1H NMR(300MHz,CD3OD)δppm 2.74-2.88(m,1H),3.03(s,3H),3.33-3.40(m,1H),3.54-3.66(m,1H),4.02-4.24(m,3H),4.35(d,J=12.5Hz,1H),4.95-5.04(m,1H),7.34-7.41(m,1H),7.46(td,J=7.8,1.4Hz,1H),7.51-7.59(m,2H),7.62-7.69(m,1H),7.82(d,J=7.5Hz,1H),7.92(s,1H),8.01-8.07(m,2H),8.11(d,J=8.1Hz,1H),8.20(s,1H),8.29(s,1H),8.47(s,1H);MS(DCI/NH3)m/z 445(M+1)+.C25H24N4O2S 2.40CF3CO2H的分析计算值:C,49.84;H,3.70;N,7.80.实测值:C,49.85;H,3.76;N,7.71.
实施例21
3-(5-((1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基)吡啶-3-基)-1H-吲哚双三氟乙酸盐
将实施例20的产物(250mg,0.35mmol)于50℃用在甲醇(8mL)中的KOH(0.15g,2.68mmol)处理2小时。浓缩后,将混合物通过制备型HPLC纯化(Gilson,柱, 5μm,40x100mm.洗脱溶剂,MeCN/H2O(含0.1%v.TFA)(v.90/10至10/90经由25分钟),流速,40mL/min.,uv,254nm)。收集所需产物级分并浓缩。将残余物在醚/乙醇(v.10/1,5mL)中于室温搅拌16小时,以给出本标题化合物(128.4mg,得率,62.5%)。 1H NMR(300MHz,CD3OD)δppm 2.76-2.86(m,1H),3.04(s,3H),3.42(dd,J=13.1,4.9Hz,1H),3.56-3.65(m,1H),4.03-4.25(m,3H),4.39(d,J=11.9Hz,1H),4.95-5.03(m,1H),7.18-7.30(m,2H),7.52(dd,J=7.0,1.5Hz,1H),7.88(s,1H),7.90-7.96(m,1H),8.10[s(br),1H],8.15[s(br),1H],8.53(s,1H);MS(DCI/NH3)m/z 305(M+1)+.C19H20N4·2.50CF3CO2H的分析计算值:C,48.90;H,3.85;N,9.50.实测值:C,48.98;H,3.62;N,9.67.
实施例22
4-{6-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚二甲苯磺酸盐
实施例22A
3-(6-氯吡嗪-2-基)-3,6-二氮杂双环[3.2.0]庚烷-6-羧酸(1R,5S)-叔-丁酯
将3,6-二氮杂双环[3.2.0]庚烷-6-羧酸(1R,5S)-叔丁酯(US2006035936,0.99g,5.0mmol)在DMSO(5.0mL)中于110℃与含Na2CO3(Aldrich,1.06g,10mmol)的2,6-二氯吡嗪(Aldrich,1.12g,7.5mmol)偶联10小时。反应完成后,将其用EtOAc(50mL)稀释并用盐水(2x10mL)洗涤。将有机溶液浓缩,并且残余物用色谱法纯化(SiO2,EtOAc/己烷,v.50/50,Rf=0.10),以给出本标题化合物(1.32g,得率,84.9%)。1H NMR(300MHz,CD3OD)δppm 1.44(s,9H),3.13-3.29(m,2H),3.31-3.35(m,1H),3.46-3.63(m,1H),4.02(d,J=10.85Hz,1H),4.06-4.15(m,2H),4.19(d,J=12.55Hz,1H),4.83-4.86(m,1H),7.80(s,1H),7.97(s,1H);MS(DCI/NH3)m/z 311(M+1)+,313(M+1)+.
实施例22B
4-{6-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚
按照实施例12A的程序,将实施例22A的产物(103mg,0.3mmol)与1H-吲哚-4-基硼酸(Frontier,80mg,0.5mmol)偶联。反应完成后,将其浓缩,并将残余物用三氟乙酸(2mL)于环境温度处理1.0小时。浓缩之后,将粗混合物用制备型HPLC纯化(Gilson, 柱,7μm,40x100mm,洗脱溶剂,MeCN/H2O(含0.1M NH4HCO3/NH4OH,PH=10)(v.90/10至10/90经由25分钟),流速,40mL/min.,uv,254nm),以给出本标题化合物(30mg,得率,32.8%).1H NMR(300MHz,CD3OD)δppm3.32-3.50(m,4H),3.96(t,J=8.31Hz,1H),4.08-4.26(m,2H),4.64-4.75(m,1H),7.07(dd,J=3.22,0.85Hz,1H),7.19-7.26(m,1H),7.35(d,J=3.39Hz,1H),7.50(dt,J=8.14,0.85Hz,1H),7.56(dd,J=7.46,1.02Hz,1H),7.99(s,1H),8.38(s,1H);MS(DCI/NH3)m/z 292(M+1)+.
实施例22C
4-{6-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚二甲苯磺酸盐
将实施例22B的产物(30mg,0.10mmol)于环境温度用在EtOAc(5mL)中的p-TsOH·H2O(38mg,0.20mmol)处理过夜,以给出本标题化合物(65mg,得率,99.0%)。1H NMR(500MHz,吡啶-D5)δppm 2.17(s,6H),3.27(dd,J=10.98,6.41Hz,1H),3.39(dd,J=13.12,5.19Hz,1H),3.47 -3.59(m,1H),3.96(dd,J=10.98,5.19Hz,1H),4.23(d,J=11.29Hz,1H),4.67(dd,J=10.83,8.70Hz,1H),4.79(d,J=13.43Hz,1H),5.53(dd,J=6.71,5.19Hz,1H),7.18(d,J=7.93Hz,4H),7.40-7.49(m,2H),7.71(t,J=2.75Hz,1H),7.79(d,J=7.93Hz,1H),7.89(d,J=7.02Hz,1H),8.22(s,1H),8.39(d,J=8.24Hz,4H),8.94(s,1H),12.46(s,1H);MS(DCI/NH3)m/z 292(M+1)+.C17H17N5·2.00TsOH 0.85H2O的分析计算值:C,57.19;H,5.37;N,10.76.实测值:C,57.38;H,5.29;N,11.04.
实施例23
4-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚二甲苯磺酸盐
实施例23A
(1S,5S)-3-(6-氯吡嗪-2-基)-3,6-二氮杂双环[3.2.0]庚烷
将实施例22A的产物(1.30g,4.18mmol)于80℃用在EtOAc(30mL)中的p-TsOH·H2O(1.78g,9.36mmol)处理2小时,以给出本标题化合物(1.50g,得率,93.4%)。1H NMR(300MHz,CD3OD)δppm 2.38(s,3H),3.33(dd,J=11.60,6.50Hz,1H),3.44(dd,J=13.73,5.26Hz,1H),3.50-3.63(m,1H),3.72(dd,J=11.02,5.26Hz,1H),4.12(d,J=11.87Hz,1H),4.26(dd,J=11.02,8.65Hz,1H),4.39(d,J=13.56Hz,1H),5.03-5.15(m,1H),7.23(d,J=7.80Hz,2H),7.69(d,J=8.48Hz,2H),7.95(s,1H),8.11(s,1H);MS(DCI/NH3)m/z 211(M+1)+,213(M+1)+.
实施例23B
(1S,5S)-3-(6-氯吡嗪-2-基)-6-甲基-3,6-二氮杂双环[3.2.0]庚烷
按照实施例2A的程序,将实施例23A的产物(1.30g,4.18mmol)在NaBH(OAc)3存在下用甲醛处理,以给出本标题化合物(1.50g,得率,93.4%)。1H NMR(300MHz,CD3OD)δppm 2.66(s,3H),3.32-3.52(m,3H),3.53-3.64(dd,J=9.50,3.80Hz,1H),3.61-3.76(m,1H),3.99(d,J=11.19Hz,1H),4.15(d,J=13.22Hz,1H),4.44(dd,J=6.78,4.75Hz,1H),7.84(s,1H),7.99(s,1H);MS(DCI/NH3)m/z 225(M+1)+,227(M+1)+.
实施例23C
4-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚
按照实施例12A的程序,将实施例23B的产物(112mg,0.5mmol)与1H-吲哚-4-基硼酸(Frontier,160mg,1.0mmol)偶联,以给出本标题化合物(140mg,得率,92.0%)。1H NMR(300MHz,CD3OD)δppm 2.40(s,3H),3.18-3.38(m,4H),3.61(dd,J=11.19,8.14Hz,1H),4.00-4.08(m,3H),7.06(dd,J=3.22,0.85Hz,1H),7.18-7.26(m,1H),7.34(d,J=3.39Hz,1H),7.47-7.52(m,1H),7.49(d,J=8.14Hz,1H),7.91(s,1H),8.32(s,1H);MS(DCI/NH3)m/z 306(M+1)+.
实施例23D
4-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚二甲苯磺酸盐
将实施例23C的产物(140mg,0.46mmol)于环境温度用在EtOAc(10mL)中的p-TsOH·H2O(190mg,1.0mmol)处理过夜,以给出本标题化合物(170mg,得率,56.9%)。1H NMR(300MHz,CD3OD)δppm 2.31(s,6H),3.04(s,3H),3.55-3.77(m,3H),4.15-4.22(m,2H),4.32(d,J=11.19Hz,1H),4.72(d,J=14.24Hz,1H),5.03(dd,J=6.95,4.92Hz,1H),6.57(d,J=3.05Hz,1H),7.17(d,J=7.80Hz,4H),7.24-7.33(m,1H),7.44-7.48(m,1H),7.61-7.68(m,5H),7.72(d,J=7.46Hz,1H),8.12(s,1H),8.53(s,1H);MS(DCI/NH3)m/z 306(M+1)+.C18H19N5·2.08TsOH 1.70H2O的分析计算值:C,56.34;H,5.67;N,10.09.实测值:C,56.66;H,5.39;N,9.70.
实施例24
5-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚甲苯磺酸盐
实施例24A
5-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚
按照实施例12A的程序,将实施例23B的产物(112mg,0.5mmol)与1H-吲哚-5-基硼酸(Frontier,160mg,1.0mmol)偶联,以给出本标题化 合物(120mg,得率,78.7%)。1H NMR(300MHz,CD3OD)δppm 3.20-3.39(m,4H),3.58(dd,J=11.53,8.14Hz,1H),4.00-4.08(m,3H),6.54(d,J=2.37Hz,1H),7.28(d,J=3.05Hz,1H),7.46(d,J=8.82Hz,1H),7.81-7.88(m,2H),8.29-8.30(m,1H),8.31(s,1H);MS(DCI/NH3)m/z306(M+1)+.
实施例24B
4-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚甲苯磺酸盐
将实施例24A的产物(120mg,0.39mmol)于环境温度用在EtOAc(10mL)中的p-TsOH·H2O(950mg,0.5mmol)处理过夜,以给出本标题化合物(170mg,得率,91.4%)。1H NMR(300MHz,CD3OD)δppm 2.34(s,4.5H),3.05(s,3H),3.41-3.72(m,3H),4.09-4.19(m,2H),4.27(d,J=11.53Hz,1H),4.67(d,J=13.90Hz,1H),4.99(dd,J=7.29,4.92Hz,1H),6.57(d,J=3.05Hz,1H),7.19(d,J=8.14Hz,3H)7.32(d,J=3.05Hz,1H),7.50(d,J=8.82Hz,1H),7.68(d,J=8.14Hz,3H),7.91(dd,J=8.48,1.70Hz,1H),8.04(s,1H),8.39(s,1H),8.53(s,1H);MS(DCI/NH3)m/z 306(M+1)+.C18H19N5·1.49TsOH 1.00H2O的分析计算值:C,58.88;H,5.72;N,12.08.实测值:C,58.85;H,5.23;N,11.68.
实施例25
6-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚二甲苯磺酸盐
实施例25A
6-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚
按照实施例12A的程序,将实施例23B的产物(112mg,0.5mmol)与1H-吲哚-6-基硼酸(Frontier,160mg,1.0mmol)偶联,以给出本标题化合物(80mg,得率,52.4%)。1H NMR(300MHz,CD3OD)δppm 2.40(s,3H),3.20-3.28(m,2H),3.32-3.41(m,2H),3.59(dd,J=11.53,8.14Hz,1H),3.97-4.13(m,3H),6.48(dd,J=3.22,0.85Hz,1H),7.32(d,J=3.05Hz,1H),7.62(d,J=7.80Hz,1H)7.74(dd,J=8.50,1.70Hz,1H),7.85(s,1H), 8.15(s,1H,)8.32(s,1H);MS(DCI/NH3)m/z 306(M+1)+.
实施例25B
4-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚二甲苯磺酸盐
将实施例25A的产物(80mg,0.26mmol)于环境温度用在EtOAc(10mL)中的p-TsOH·H2O(114mg,0.6mmol)处理过夜,以给出本标题化合物(120mg,得率,70.6%)。1H NMR(300MHz,CD3OD)δppm 2.30s,6H),3.04(s,3H),3.55-3.67(m,3H),4.14-4.21(m,2H),4.31(d,J=11.53Hz,1H),4.72(d,J=14.24Hz,1H),5.03(dd,J=7.12,5.09Hz,1H),6.55(d,J=3.05Hz,1H)7.17(d,J=8.48Hz,4H),7.41-7.47(m,1H),7.66(d,J=8.14Hz,4H),7.70(d,J=8.48Hz,1H),7.82(dd,J=8.40,1.40Hz,1H),8.06(s,1H),8.24(s,1H),8.51(s,1H);MS(DCI/NH3)m/z 306(M+1)+.C18H19N5·2.00TsOH·0.70H2O的分析计算值:C,58.02;H,5.54;N,10.57.实测值:C,57.71;H,5.24;N,10.35.
实施例26
5-(6-((1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基)吡嗪-2-基)-2-(三氟甲基)-1H-吲哚二延胡索酸盐
按照实施例14A的程序,将实施例23B的产物(105mg,0.469mmol)与5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-2-(三氟甲基)-1H-吲哚(US 2005043347,225mg,0.723mmol)偶联,以给出本标题化合物的游离碱(15mg,得率,10%)。将该游离碱(15mg,0.04mmol)于室温用在醚/乙醇(v.10/1,5mL)中的延胡索酸(12mg,0.1mmol)处理16小时,以给出本标题化合物(17.8mg,得率,53.3%).1H NMR(300MHz,CD3OD)δppm2.96(s,3H),3.37(dd,J=11.2,6.4Hz,1H),3.46(dd,J=13.9,4.7Hz,1H),3.59(dt,J=13.6,6.9Hz,1H),3.99(dd,J=11.2,5.1Hz,1H),4.19-4.28(m,2H),4.64(d,J=13.9Hz,1H),4.97(dd,J=7.0,4.9Hz,1H),6.98-7.01(m,1H),7.56(d,J=8.8Hz,1H),8.03-8.10(m,2H),8.45(d,J=1.0Hz,1H),8.54(s,1H),;MS(DCI/NH3)m/z 374(M+1)+;C19H18F3N5·2.33C4O4H41.20H2O·的分析计算值:C,51.12;H,4.50;N,10.52.实测值:C,51.51;H,4.13;N,10.14.
实施例27
5-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
实施例27A
3-(5-溴吡啶-3-基)-3,6-二氮杂双环[3.2.0]庚烷-6-羧酸(1S,5R)-叔-丁酯
按照实施例1A的程序,将3,5-二溴吡啶(Aldrich,1.00g,4.5mmol)与3,6-二氮杂双环[3.2.0]庚烷-6-羧酸(1S,5R)-叔-丁酯(WO 2001081347,0.60g,3mmol)偶联,以给出本标题化合物(0.55g,得率,50%)。1H NMR(300MHz,CD3OD)δppm 1.45(s,9H),2.95(dd,J=11.19,4.41Hz,1H),3.05(dd,J=10.51,6.78Hz,1H),3.18-3.29(m,1H),3.51-3.67(m,1H),3.79(d,J=10.51Hz,1H),3.93(d,J=11.53Hz,1H),4.02-4.19(m,1H),4.83-4.91(m,Hz,1H),7.39(t,J=2.20Hz,1H),7.97(d,J=1.70Hz,1H),8.05(d,J=2.37Hz,1H);MS(DCI/NH3)m/z 354(M+1)+,356(M+1)+.
实施例27B
(1R,5R)-3-(5-溴吡啶-3-基)-6-甲基-3,6-二氮杂双环[3.2.0]庚烷
按照实施例7A的程序,将实施例27A的产物(0.55g,12.7mmol)用在HCO2H(Aldrich,88%,10mL)中的HCHO(Aldrich,37%,5mL)处理,以给出本标题化合物(0.33g,得率,79%)。1H NMR(300MHz,CD3OD)δppm 2.37(s,3H),3.02(dd,J=11.19,4.41Hz,1H),3.15-3.38(m,4H),3.60-3.79(m,2H),3.99(dd,J=6.44,4.41Hz,1H),7.27-7.35(t,J=2.00Hz,1H),7.92(d,J=2.03Hz,1H),7.99(d,J=2.37Hz,1H);MS(DCI/NH3)m/z 268(M+1)+,270(M+1)+.
实施例27C
5-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚
按照实施例12A的程序,将实施例27B的产物(100mg,0.37mmol)与吲哚-5-基-硼酸(Frontier,81.6mg,0.51mmol)偶联,以给出本标题化合物(40mg,得率,41.0%)。1H NMR(300MHz,CD3OD)δppm 2.44(s,3H),3.04(dd,J=11.02,4.24Hz,1H),3.18-3.28(m,2H),3.34-3.47(m,2H), 3.78-3.91(m,2H),4.09(dd,J=6.10,4.75Hz,1H),6.52(d,J=3.05Hz,1H),7.28(d,J=3.05Hz,1H),7.36-7.43(m,2H),7.45-7.52(m,1H),7.83(s,1H),7.98(d,J=2.71Hz,1H),8.18(s,1H);MS(DCI/NH3)m/z 305(M+1)+.
实施例27D
5-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
将实施例27C的产物(40mg,0.13mmol)于环境温度用在EtOAc(5mL)中的p-TsOH·H2O(49mg,0.26mmol)处理过夜,以给出本标题化合物(50mg,得率,59.4%)。1H NMR(500MHz,吡啶-D5)δppm 2.16(s,6H),2.90(dd,J=10.07,6.10Hz,1H),2.98-3.12(m,4H),3.41-3.57(m,1H),3.82(d,J=10.07Hz,1H),3.92-4.02(m,1H),4.44(t,J=9.46Hz,1H),4.59(d,J=12.82Hz,1H),5.16-5.29(m,1H),6.82(s,1H),7.15(d,J=7.93Hz,4H),7.59-7.61(m,1H),7.62-7.69(m,2H),7.77(d,J=8.54Hz,1H),8.18(s,1H),8.35(d,J=7.93Hz,4H),8.47(d,J=2.44Hz,1H),8.84(d,J=1.53Hz,1H),12.34(s,1H),MS(DCI/NH3)m/z 305(M+1)+.C19H20N4·2.25TsOH 0.40H2O的分析计算值:C,59.71;H,5.59;N,8.01.实测值:C,59.77;H,5.19;N,8.12.
实施例28
4-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚三甲苯磺酸盐
实施例28A
4-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚
按照实施例12A的程序,将实施例27B的产物(100mg,0.37mmol)与吲哚-4-基-硼酸(Frontier,81.6mg,0.51mmol)偶联,以给出本标题化合物(15mg,得率,13%).1H NMR(300MHz,CD3OD)δppm 3.02(s,3H),3.17-3.27(m,2H),3.46-3.67(m,1H),3.98-4.22(m,3H),4.30(dd,dd,J=11.87,2.37Hz,1H),4.93-5.04(m,1H),6.62(d,J=2.37Hz,1H),7.15-7.30(m,2H),7.35-7.40(m,1H),7.51(d,J=8.14Hz,1H),7.85(s,1H), 8.25(d,J=3.05Hz,1H),8.42(s,1H);MS(DCI/NH3)m/z 305(M+1)+.
实施例28B
5-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚三甲苯磺酸盐
将实施例28A的产物(15mg,0.05mmol)于环境温度用在EtOAc(5mL)中的p-TsOH·H2O(27mg,0.15mmol)处理过夜,以给出本标题化合物(15mg,得率,36.5%)。1H NMR(500MHz,吡啶-D5)δppm 2.16(s,9H),2.93(dd,J=10.07,6.10Hz,1H),3.01(s,3H),3.07(dd,J=12.51,4.88Hz,1H),3.41-3.54(m,1H),3.79(d,J=10.07Hz,1H),3.87-3.98(m,1H),4.40(t,J=9.92Hz,1H),4.49(d,J=12.82Hz,1H),5.14-5.20(m,1H),6.99(s,1H),7.14(d,J=7.93Hz,6H),7.36-7.45(m,2H),7.60-7.62(m,1H),7.63-7.67(m,1H),7.71(dd,J=6.10,2.75Hz,1H),8.37(d,J=7.93Hz,6H),8.53(d,J=2.75Hz,1H),8.91(d,J=1.83Hz,1H),12.44(s,1H);MS(DCI/NH3)m/z 305(M+1)+.C19H20N43.00TsOH·1.20H2O的分析计算值:C,57.02;H,5.55;N,6.65.实测值:C,57.06;H,5.23;N,6.26.
实施例29
6-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
实施例29A
6-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚
按照实施例12A的程序,将实施例27B的产物(100mg,0.37mmol)与吲哚-6-基-硼酸(Frontier,81.6mg,0.51mmol)偶联,以给出本标题化合物(50mg,得率,44%)。1H NMR(300MHz,CD3OD)δppm 2.40(s,3H),3.04(dd,J=11.19,4.41Hz,1H),3.20-3.28(m,2H),3.32-3.44(m,2H),3.74-3.90(m,2H),4.04(dd,J=6.10,4.41Hz,1H),6.48(d,J=3.05Hz,1H),7.28-7.33(m,2H),7.38(t,J=2.40Hz,1H),7.59-7.70(m,2H),7.98(d,J=2.71Hz,1H),8.17(d,J=1.70Hz,1H);MS(DCI/NH3)m/z 305(M+1)+.
实施例29B
6-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚三甲苯磺酸盐
将实施例29A的产物(50mg,0.16mmol)于环境温度用在EtOAc(5mL)中的p-TsOH·H2O(38mg,0.20mmol)处理过夜,以给出本标题化合物(55mg,得率,53.0%).1H NMR(500MHz,吡啶-D5)δppm 2.15(s,6H),2.87(dd,J=10.07,6.10Hz,1H),2.98-3.12(m,4H),3.40-3.53(m,1H),3.78(d,J=10.37Hz,1H),3.89-4.00(m,1H),4.41(t,J=9.76Hz,1H),4.57(d,J=12.82Hz,1H)5.09-5.36(m,1H),6.79(s,1H),7.14(d,J=7.93Hz,4H),7.58-7.65(m,2H),7.93(d,J=8.24Hz,1H),8.12(s,1H),8.34(d,J=8.24Hz,4H),8.44(d,J=2.44Hz,1H),8.81(d,J=1.83Hz,1H),12.30(s,1H);MS(DCI/NH3)m/z305(M+1)+.C19H20N42.00TsOH·0.80H2O的分析计算值:C,59.76;H,5.71;N,8.45.实测值:C,59.37;H,5.64;N,8.19.
实施例30
5-{5-[(1R,5S)-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚双三氟乙酸盐
实施例30A
6-(5-溴吡啶-3-基)-3,6-二氮杂双环[3.2.0]庚烷-3-羧酸(1S,5S)-苄酯
将3,5-二溴吡啶(Aldrich,2.60g,11mmol)在以下条件下与3,6-二氮杂双环[3.2.0]庚烷-3-羧酸(1S,5S)-苄酯甲苯磺酸盐(US 2006035936,4.05g,10mmol)偶联16小时:在Pd2(dba)3(Aldrich,45mg,0.05mmol)及4,5-双(二苯基膦基)-9,9-二甲基呫吨(Aldrich,80mg,0.138mmol)催化下,在叔丁醇钠(Aldrich,2.88g,30.0mmol)存在下,在甲苯(无水,Aldrich,40mL)中,于100℃。反应完成后,将其冷却至环境温度,并用EtOAc(100mL)稀释,用盐水(2x20mL)洗涤,并减压浓缩。将残余物用色谱法纯化(SiO2,EtOAc/己烷,v.50/50,Rf=0.40),以给出本标题化合物(2.57g,得率,66%)。1H NMR(300MHz,CD3OD)δppm 3.21(dd,J=12.9,4.1Hz,1H),3.62(dd,J=7.8,3.4Hz,1H),3.93-4.12(m,4H),4.73(dd,J=6.1,4.1Hz,1H),5.12(s,2H),7.01-7.07(m,1H),7.18-7.41(m,5H),7.69(d, J=2.4Hz,1H),7.90(d,J=1.7Hz,1H);MS(DCI/NH3)m/z 388(M+1)+,390(M+1)+.
实施例30B
(1R,5S)-6-(5-溴吡啶-3-基)-3,6-二氮杂双环[3.2.0]庚烷
将实施例30A的产物(2.57g,6.6mmol)于75℃用三氟乙酸(Aldrich,15mL)处理1.5小时。然后将混合物冷却至环境温度并浓缩。将残余物用CHCl3(100mL)稀释,用饱和Na2CO3(2x10mL)洗涤,然后减压浓缩。将残余物用色谱法纯化(SiO2,EtOAc/MeOH-NH4OH,v.70/30),以给出本标题化合物(1.6g,得率,95%)。1H NMR(300MHz,CD3OD)δppm3.03(dd,J=12.7,3.6Hz,1H),3.19(dd,J=12.4,7.3Hz,1H),3.36-3.43(m,1H),3.60(t,J=13.1Hz,2H),3.74(dd,J=8.1,3.4Hz,1H),4.02(t,J=8.0Hz,1H),4.89(dd,J=6.3,3.6Hz,1H),7.16-7.20(m,1H)7.80(d,J=2.7Hz,1H)7.98(d,J=2.0Hz,1H);MS(DCI/NH3)m/z 254(M+1)+,256(M+1)+.
实施例30C
5-{5-[(1R,5S)-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚双三氟乙酸盐
按照实施例7B中描述的程序,将实施例30B的产物(120mg,0.47mmol)与1H-吲哚-5-基硼酸(Frontier,160mg,1.0mmol)偶联,以给出本标题化合物(135.5mg,得率,52%)。1H NMR(300MHz,CD3OD)δppm3.22-3.29(m,1H),3.39(dd,J=12.9,7.8Hz,1H),3.52-3.63(m,1H),3.78(d,J=12.5Hz,1H),3.85-3.96(m,2H),4.24(t,J=8.3Hz,1H),5.16(dd,J=6.4,3.7Hz,1H),6.56-6.59(m,1H),7.33-7.36(m,1H),7.45-7.51(m,1H),7.53-7.57(m,1H),7.72-7.77(m,1H),7.96(d,J=2.4Hz,1H),7.98(d,J=1.7Hz,1H),8.42(d,J=1.7Hz,1H);MS(DCI/NH3)m/z291(M+1)+.C18H18N4·2.20CF3CO2H·0.70H2O的分析计算值:C,48.58;H,3.93;N,10.12.实测值:C,48.61;H,3.99;N,9.75.
实施例31
5-{5-[(1R,5S)-3-甲基-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚甲苯磺酸盐
实施例31A
(1R,5S)-6-(5-溴吡啶-3-基)-3-甲基-3,6-二氮杂双环[3.2.0]庚烷
将实施例30B的产物(1.2g,4.7mmol)于室温用在MeCN(20mL)中的甲醛(Aldrich,aq.,wt.37%,5mL,62mmol)及NaBH(OAc)3(Aldrich,600mg,2.83mmol)处理16小时。然后将混合物用CHCl3(3x20mL)萃取。将合并的萃取液浓缩,并且残余物用色谱法纯化(SiO2,EtOAc/MeOH-NH4OH,v.70/30,Rf=0.20),以给出本标题化合物(1.1g,得率,87.7%).1H NMR(300MHz,CD3OD)δppm 2.33(dd,J=11.5,3.7Hz,1H),2.43(dd,J=10.9,6.4Hz,1H),2.57(s,3H),3.30-3.38(m,2H),3.44(d,J=11.5Hz,1H),3.75(dd,J=8.0,3.9Hz,1H),3.98(t,J=8.0Hz,1H),4.73-4.78(m,1H),7.05(t,J=2.2Hz,1H)7.70(d,J=2.4Hz,1H)7.88(d,J=1.7Hz,1H);MS(DCI/NH3)m/z 268(M+1)+,270(M+1)+.
实施例31B
5-(5-((1R,5S)-3-甲基-3,6-二氮杂双环[3.2.0]庚-6-基)吡啶-3-基)-1H-吲哚二甲苯磺酸盐
按照实施例14的程序,将实施例31A产物(120mg,0.47mmol)与1H-吲哚-5-基硼酸(Frontier,160mg,1.0mmol)偶联,以给出本标题化合物(204.4mg,0.291mmol,得率,62%)。1H NMR(300MHz,CD3OD)δppm 2.31(s,6H),3.10(s,3H),3.25(dd,J=12.7,3.6Hz,1H),3.30-3.38(m,1H),3.56-3.65(m,1H),3.98-4.06(m,2H),4.12-4.19(m,1H),4.24(t,J=8.5Hz,1H),5.20(dd,J=6.8,3.4Hz,1H),6.58(dd,J=3.2,0.8Hz,1H),7.17(d,J=8.1Hz,4H),7.36(d,J=3.1Hz,1H),7.45-7.52(m,1H),7.53-7.59(m,1H),7.66(d,J=8.5Hz,4H),7.80(dd,J=2.4,1.7Hz,1H),7.94-7.98(m,1H),7.99(dd,J=2.0,0.7Hz,1H),8.41(d,J=0.7Hz,1H);MS(DCI/NH3)m/z 305(M+1)+.C19H20N4·2.10C7H8O3S 1.30H2O的分析计算值:C,57.66;H,5.86;N,7.98.实测值:C,57.81;H,5.72;N,7.76.
实施例32
6-{5-[(1R,5S)-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚双三氟乙酸盐
按照实施例7B中描述的程序,将实施例30B的产物(130mg,0.514mmol)与1H-吲哚-6-基硼酸(Frontier,158mg,1.0mmol)偶联,以给出本标题化合物(139.2mg,得率,50.6%)。1H NMR(300MHz,CD3OD)δppm3.22-3.30(m,1H),3.39(dd,J=12.4,7.6Hz,1H),3.53-3.62(m,1H),3.78(d,J=12.2Hz,1H),3.86-3.97(m,2H),4.24(t,J=8.3Hz,1H),5.16(dd,J=6.4,3.4Hz,1H),6.53(dd,J=3.2,0.8Hz,1H),7.35-7.41(m,2H),7.69-7.74(m,2H),7.75-7.78(m,1H),7.98(d,J=2.4Hz,1H),8.42(d,J=1.4Hz,1H);MS(DCI/NH3)m/z 291(M+1)+.C18H18N42.15CF3CO2H的分析计算值:C,50.02;H,3.79;N,10.46.实测值:C,50.02;H,3.75;N,10.50.
实施例33
6-{5-[(1R,5S)-3-甲基-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚二甲苯磺酸盐
按照实施例14的程序,将实施例31A的产物(130mg,0.487mmol)与1H-吲哚-6-基硼酸(Frontier,160mg,1.0mmol)偶联,以给出本标题化合物(189.8mg,0.296mmol,得率,60.9%)。1H NMR(300MHz,CD3OD)δppm 2.30(s,6H),3.10(s,3H),3.24(dd,J=12.5,3.4Hz,1H),3.30-3.37(m,1H),3.55-3.65(m,1H),3.97-4.04(m,2H),4.13(d,J=12.5Hz,1H),4.21(t,J=8.3Hz,1H),5.16(dd,J=6.8,3.4Hz,1H),6.51-6.54(m,1H),7.16(d,J=7.8Hz,4H),7.35-7.40(m,2H),7.65(d,J=8.1Hz,4H),7.69-7.74(m,2H),7.76-7.79(m,1H),7.95(d,J=2.4Hz,1H),8.39(d,J=1.7Hz,1H);MS(DCI/NH3)m/z 305(M+1)+.C19H20N4·1.70C7H8SO32.40H2O的分析计算值:C,57.96;H,6.04;N,8.75.实测值:C,57.82;H,5.74;N,8.71.
实施例34
4-(5-((1R,5S)-3-甲基-3,6-二氮杂双环[3.2.0]庚-6-基)吡啶-3-基)-1H-吲哚甲苯磺酸盐
按照实施例14的程序,将实施例31A的产物(140mg,0.52mmol)与1H-吲哚-4-基硼酸(Frontier,160mg,1.0mmol)偶联,以给出本标题化合物(132.3mg,得率,42.1%)。1H NMR(300MHz,CD3OD)δppm 2.32(s,4.2H),3.10(s,3H),3.23(dd,J=12.4,3.6Hz,1H),3.31-3.37(m,1H),3.54-3.65(m,1H),3.94-4.04(m,2H),4.05-4.12(m,1H),4.21(t,J=8.1Hz,1H),5.13(dd,J=6.8,3.4Hz,1H),6.60(d,J=1.7Hz,1H),7.18(d,J=7.8Hz,2.8H),7.20-7.29(m,2H),7.37-7.41(m,1H),7.53(d,J=8.1Hz,1H),7.61-7.64(m,1H),7.67(d,J=8.1Hz,2.8H)8.01(d,J=2.7Hz,1H),8.37(d,J=1.4Hz,1H);MS(DCI/NH3)m/z 305(M+1)+.C19H20N41.39C7H8O3S·2.62H2O的分析计算值:C,58.39;H,6.20;N,9.48.实测值:C,58.71;H,5.98;N,9.08.
实施例35
6-{5-[(3aS,6aS)-5-甲基六氢吡咯并[3,4-b]吡咯-1(2H)-基]吡啶-3-基}-1H-吲哚双三氟乙酸盐
实施例35A
1-(5-溴吡啶-3-基)六氢吡咯并[3,4-b]吡咯-5(1H)-羧酸(3aS,6aS)-叔丁酯
按照实施例30A的程序,将3,5-二溴吡啶(Aldrich,2.82g,12mmol)与六氢吡咯并[3,4-b]吡咯-5(1H)-羧酸(3aS,6aS)-叔丁酯(WO 2001081347,2.12g,10mmol)偶联,以给出本标题化合物(2.75g,得率,74.5%)。1HNMR(300MHz,CD3OD)δppm 1.42(s,9H),1.93(td,J=12.7,6.1Hz,1H),2.21(td,J=13.2,7.5Hz,1H),3.02-3.16(m,1H),3.33-3.42(m,3H),3.50-3.63(m,2H),3.67(dd,J=11.9,6.1Hz,1H),4.27(td,J=6.7,2.9Hz,1H),7.14-7.19(m,1H),7.84(d,J=2.7Hz,1H),7.89(d,J=2.0Hz,1H);MS(DCI/NH3)m/z 368(M+1)+,370(M+1)+.
实施例35B
(3aS,6aS)-1-(5-溴吡啶-3-基)-5-甲基八氢吡咯并[3,4-b]吡咯
按照实施例7A的程序,将实施例35A的产物(2.1g,5.7mmol)于100℃用在甲酸(Aldrich,10mL)中的甲醛(Aldrich,aq.37%,4mL)处理2小时,以给出本标题化合物(1.4g,得率,87%)。1H NMR(300MHz, CD3OD)δppm 1.92-2.05(m,1H),2.18-2.35(m,1H),2.57(s,3H),2.94-3.00(m,2H),3.00-3.10(m,2H),3.13-3.26(m,1H),3.35(dd,J=7.8,6.1Hz,1H),3.60(ddd,J=9.3,7.1,7.0Hz,1H),4.32(ddd,J=8.2,5.3,3.1Hz,1H),7.18-7.24(m,1H),7.88(d,J=2.7Hz,1H),7.93(d,J=1.7Hz,1H);MS(DCI/NH3)m/z 282(M+1)+,284(M+1)+.
实施例35C
6-{5-[(3aS,6aS)-5-甲基六氢吡咯并[3,4-b]吡咯-1(2H)-基]吡啶-3-基}-1H-吲哚双三氟乙酸盐
按照实施例7B中描述的程序,将实施例35B的产物(140mg,0.50mmol)与1H-吲哚-6-基硼酸(Frontier,165mg,1.04mmol)偶联,以给出本标题化合物(173.7mg,得率,61.1%)。1H NMR(300MHz,CD3OD)δppm2.06-2.19(m,1H),2.31-2.49(m,1H),2.97(s,3H),3.37-3.97(m,7H),4.67-4.76(m,1H),6.54(d,J=3.1Hz,1H),7.36-7.43(m,2H),7.73(d,J=8.1Hz,1H),7.78(s,1H),7.81(s,1H),8.05(d,J=2.7Hz,1H),8.41(s,1H);MS(DCI/NH3)m/z 319(M+1)+.C20H22N4·2.20CF3CO2H的分析计算值:C,51.48;H,4.28;N,9.84.实测值:C,51.30;H,4.35;N,9.93.
实施例36
5-{5-[(3aS,6aS)-5-甲基六氢吡咯并[3,4-b]吡咯-1(2H)-基]吡啶-3-基}-1H-吲哚二延胡索酸盐
按照实施例26的程序,将实施例35B的产物(140mg,0.50mmol)与1H-吲哚-5-基硼酸(Frontier,158mg,1.0mmol)偶联,以给出本标题化合物(124.2mg,0.214mmol,得率,42.8%)。1H NMR(300MHz,CD3OD)δppm 1.98-2.14(m,1H),2.32-2.38(m,1H),2.91(s,3H),3.35-3.66(m,6H),3.75-3.86(m,1H),4.50-4.58(m,1H),6.53(dd,J=3.2,0.8Hz,1H),6.71(s,4H),7.27-7.32(m,2H),7.36-7.43(m,1H),7.46-7.53(m,1H),7.83(d,J=1.0Hz,1H),7.89(d,J=2.7Hz,1H),8.23(d,J=1.7Hz,1H);MS(DCI/NH3)m/z 319(M+1)+.C20H22N4·2.10C4O4H4·H2O的分析计算值:C,58.79;H,5.63;N,9.66.实测值:C,58.87;H,5.76;N,9.30.
组合物及本发明组合物的用途
本发明还提供包含与可药用载体结合的治疗有效量的式(I)化合物的药物组合物。该组合物包含与一种或多种可药用载体配制的本发明化合物。所述组合物可以被配制用于以固体或液体形式经口施用,用于肠胃外注射或用于直肠施用。
可药用载体是指无毒的惰性固体、半固体或液体填料、稀释剂、胶囊化材料或任何类型的制剂助剂。可作为可药用载体的材料的一些实例是:糖类,例如乳糖、葡萄糖及蔗糖;淀粉,例如玉米淀粉及土豆淀粉;纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素;粉状西黄蓍胶;麦芽;明胶;滑石;可可油及栓剂蜡;油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及豆油;二醇类,例如丙二醇;酯,例如油酸乙酯及月桂酸乙酯;琼脂;缓冲剂例如氢氧化镁及氢氧化铝;藻酸;无致热原水;等渗盐水;林格液;乙醇及磷酸盐缓冲溶液。其它组分,例如无毒、相容的润滑剂,例如十二烷基硫酸钠及硬脂酸镁;着色剂,释放剂,包被剂,甜味、调味及芳香剂,防腐剂及抗氧化剂也可以存在于组合物中。
本发明药物组合物可以经口、直肠、肠胃外、脑池内、阴道内、腹膜内、局部(如通过粉末、软膏或滴剂)、口腔含化或者口或鼻喷雾施用于人及其它哺乳动物。本文所用术语“肠胃外”是指施用途径,包括静脉内、肌内、腹膜内、胸骨内、皮下、关节内注射及输注。
用于肠胃外注射的药物组合物包括可药用无菌水或非水溶液、分散体、悬浮液或乳剂以及用于重构成无菌注射溶液或分散体的无菌粉末。适宜的水及非水载体、稀释剂、溶剂或媒介物的实例包括水,乙醇,多元醇(丙二醇、聚乙二醇、丙三醇等及其适宜的混合物),植物油(例如橄榄油),以及可注射有机酯,例如油酸乙酯,或者其适宜的混合物。例如,通过使用包衣例如卵磷脂,在分散体的情况下通过保持所需颗粒大小,以及通过使用表面活性剂,可以保持组合物的适当流动性。
这些组合物也可以含有佐剂,例如防腐剂、湿润剂、乳化剂及分散剂。使用各种抗细菌及抗真菌剂可以确保预防微生物的作用,例如对羟基苯甲酸酯类、氯代丁醇、酚、山梨酸等。也可以合乎需要的包含等渗剂,例如糖、氯化钠等。通过使用延迟吸收剂例如单硬脂酸铝及明胶,可以导致可注射药物形式的延长的吸收。
在一些情况下,为了延长药物的作用,可以将吸收放慢。这可以通 过使用水溶性差的晶态或非晶态材料的液体悬浮液来实现。药物的吸收速度可取决于其溶解速度,溶解速度反过来又取决于晶体尺寸及结晶形式。或者,将药物溶解或悬浮在油媒介物中可以施用肠胃外施用的药物形式。
悬浮液可以含有活性化合物及悬浮剂,例如乙氧基化异十八烷醇、聚氧乙烯山梨糖醇及脱水山梨醇酯、微晶纤维素、偏氢氧化铝、皂土、琼脂、西黄蓍胶及其混合物。
如果需要且为了更有效的分配,可以将本发明化合物掺入缓释或靶向递送系统例如聚合物基质、脂质体及小球体中。可以通过以下方式将本发明化合物灭菌,例如通过细菌滤器(bacteria-retaining filter)过滤,或者通过将灭菌剂以无菌固体组合物形式掺入,紧在使用前可将所述无菌固体组合物形式溶解在无菌水或一些其他无菌注射介质中。
可注射的贮存(depot)形式是通过在生物可降解聚合物例如聚交酯-聚乙醇酸交酯(polylactide-polyglycolide)中形成药物的微囊化基质来制备的。依赖于药物与聚合物的比率以及所使用的特定聚合物的性质,可以控制药物的释放速度。其他生物可降解聚合物的实例包括聚(原酸酯)及聚(酐)。贮存可注射制剂也可以通过将药物包封在与身体组织相容的脂质体或微乳剂中来制备。
注射制剂可以例如通过细菌滤器过滤或者通过将灭菌剂以无菌固体组合物形式掺入来灭菌,紧在使用前可将所述无菌固体组合物形式溶解或分散在无菌水或其他无菌注射介质中。
注射制剂,例如,无菌注射水或油质悬浮液,可以使用适宜的分散或湿润剂及悬浮剂来配制。无菌注射制剂可以是在无毒、肠胃外可接受的稀释剂或溶剂中的无菌注射溶液、悬浮液或乳剂,例如在1,3-丁二醇中的溶液。可以使用的可接受的媒介物及溶剂是水、林格液、U.S.P.及等渗氯化钠溶液。另外,无菌、固定油常规用作溶剂或悬浮介质。为了这个目的,包括合成的单酸甘油酯或甘油二酯在内的任何温和的固定油都是可以使用的。此外,可以使用脂肪酸,例如油酸。
经口施用的固体剂型包括胶囊、片剂、丸剂、粉末及颗粒。在这样的固体剂型中,一种或多种本发明化合物与以下物质混合:至少一种惰性可药用载体,例如柠檬酸钠或磷酸二钙及/或填料或膨胀剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇及水杨酸;粘合剂,例如羧甲基纤维素、 藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖及阿拉伯胶;湿润剂,例如甘油;崩解剂,例如琼脂、碳酸钙、土豆或木薯淀粉、藻酸、某些硅酸盐以及碳酸钠;溶液阻滞剂,例如石蜡;吸收促进剂,例如季铵化合物;湿润剂,例如十六醇及甘油单硬脂酸酯;吸收剂,例如高岭土及皂土;以及润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,以及它们的混合物。在胶囊、片剂及丸剂的情况下,剂型也可以包含缓冲剂。
也可以将相似类型的固体组合物在使用乳糖(lactose)或乳糖(milk sugar)以及高分子量聚乙二醇的软及硬填充的明胶胶囊中用作填料。
可以用包衣及壳例如肠溶衣来制备片剂、锭剂、胶囊、丸剂及颗粒的固体剂型。它们可以任选含有不透明剂,并且还可以是只释放活性成分的组合物,或者优选以延迟的方式在肠道的某个部分释放活性成分。用于延迟释放活性剂的材料的实例包括聚合物质及蜡。
用于直肠或阴道施用的组合物优选是能够通过将本发明化合物与适宜的非刺激性载体例如可可油、聚乙二醇或栓剂蜡混合来制备的栓剂,所述载体在环境温度下是固体但在体温下是液体,且因此在直肠或阴道腔内熔化以释放活性化合物。
用于经口施用的液体剂型包括可药用乳剂、微乳剂、溶液、悬浮液、糖浆及酏剂。除了活性化合物外,液体剂型可以含有惰性稀释剂例如水或其它溶剂,加溶剂及乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺;油类,例如棉籽油、花生油、玉米油、胚芽(germ)油、橄榄油、蓖麻油及芝麻油;甘油,四氢糠醇、聚乙二醇及脱水山梨糖醇的脂肪酸酯,以及它们的混合物。
除了惰性稀释剂以外,经口组合物也可以包括佐剂,例如湿润剂、乳化剂及悬浮剂、甜味剂、调味剂及芳香剂。
用于局部或经皮施用本发明化合物的剂型包括软膏、糊剂、乳膏、洗剂、凝胶、粉末、溶液、喷雾剂、吸入剂或贴片。眼科制剂、滴耳剂、眼软膏、粉末及溶液也是预期的。
软膏、糊剂、乳膏及凝胶除了本发明化合物以外还可以含有动物及植物脂肪、油类、蜡类、石蜡、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇、硅氧烷、皂土、硅酸、滑石及氧化锌,或者它们的混合物。
粉末及喷雾剂除了本发明化合物以外还可以含有乳糖、滑石、硅酸、氢氧化铝、硅酸钙及聚酰胺粉末,或者这些物质的混合物。喷雾剂还可以另外含有通常的推进剂例如含氯氟烃。
可以将本发明化合物以脂质体的形式施用。脂质体通常衍生自磷脂或其它脂质物质。脂质体是通过分散在含水介质中的单层或多层水合液态晶体形成的。能够形成脂质体的任何无毒、生理学可接受以及可代谢的脂质都是可以使用的。脂质体形式的本发明组合物除了本发明化合物外还可以含有稳定剂、防腐剂等。优选的脂质是分别或共同使用的天然及合成的磷脂及磷脂酰胆碱(卵磷脂)。形成脂质体的方法是本领域已知的。参见例如Prescott,Ed.,Methods in Cell Biology,Volume XIV,Academic Press,New York,N.Y.,(1976),p 33et seq。
生物活性测定
为了测定本发明代表性化合物作为α7nAChR调节剂的有效性,将所述化合物按照[3H]-甲基牛扁亭(MLA)结合测定、[3H]-DPPB结合测定及/或[3H]-野靛碱结合测定进行评估,所述测定的进行描述如下。
[3H]-野靛碱结合
通过将测试化合物与已知的α4β2nAChR配体野靛碱共同温育,来分析本发明化合物的竞争α4β2nAChR的能力。结合条件改良自Pabreza LA,Dhawan,S,Kellar KJ,[3H]-Cytisine Binding to Nicotinic Cholinergic Receptors in Brain,Mol.Pharm.39:9-12,1991中描述的程序。将富含膜的去小脑的大鼠脑的级分(ABS Inc.,Wilmington,DE)在4℃缓慢解冻,洗涤,并重悬浮于30体积的BSS-Tris缓冲液(120mM NaCl/5mM KCl/2mM CaCl2/2mM MgCl2/50mM Tris-Cl,pH 7.4,4℃)中。将包含100-200μg蛋白和0.75nM[3H]-野靛碱(30Ci/mmol;Perkin Elmer/NEN Life Science Products,Boston,MA)的样品以终体积500μL在4℃温育75分钟。对每种化合物的七种对数稀释(log-dilution)浓度进行一式两份的测试。在10μM(-)-烟碱存在下测定非特异性结合。通过用96-孔过滤装置(Packard Instruments,Meriden,CT)真空过滤在预湿的玻璃纤维滤板(Millipore,Bedford,MA)上,然后迅速用2mL冰冷的BSS缓冲液(120mM NaCl/5mM KCl/2mM CaCl2/2mM MgCl2)漂洗,来分离结合的放射性。将PACKARD MICROSCINT- 闪烁液(40μL)加入各个孔内,且用 PACKARD 仪器测定放射性。通过MICROSOFT 软件的非线性回归确定IC50值。使用Cheng-Prusoff方程式由IC50计算Ki值,其中Ki=IC50/(1+[配体]/KD)。
[3H]-甲基牛扁亭(MLA)结合
通过将测试化合物与已知的α7nAChR配体MLA共同温育,来分析本发明化合物的竞争α7nAChR的能力。结合条件类似于[3H]-野靛碱结合的那些。将富含膜的去小脑的大鼠脑的级分(ABS Inc.,Wilmington,DE)在4℃缓慢解冻,洗涤,并重悬浮于30体积的BSS-Tris缓冲液(120mM NaCl,5mM KCl,2mM CaCl2,2mM MgCl2,和50mM Tris-Cl,pH7.4,22℃)中。将包含100-200μg蛋白,5nM[3H]-MLA(25Ci/mmol;Perkin Elmer/NEN Life Science Products,Boston,MA)和0.1%牛血清清蛋白(BSA,Millipore,Bedfbrd,MA)的样品以终体积500μL在22℃温育60分钟。对每种化合物的七种对数稀释浓度进行一式两份的测试。在10μMMLA存在下测定非特异性结合。通过用96孔过滤装置(Packard Instruments,Meriden,CT)真空过滤在用2%BSA预湿的玻璃纤维滤板上,然后迅速用2mL冰冷的BSS漂洗,来分离结合的放射性。将Packard MICROSCINT- 闪烁液(40μL)加入各个孔内,且用Packard 仪器测定放射性。通过Microsoft 软件的非线性回归确定IC50值。使用Cheng-Prusoff方程式由IC50计算Ki值,其中Ki=IC50/(1+[配体]/KD)。
[3H]-DPPB结合
通过将测试化合物与已知的α7nAChR配体DPPB共同温育,来分析本发明化合物的竞争α7nAChR的能力,DPPB是(S,S)-2,2-二甲基-5-(6-苯基-哒嗪-3-基)-5-氮杂-2-氮鎓-双环[2.2.1]庚烷碘化物。下文中描述了制备放射性标记的DPPB,[3H]-DPPB的程序。用富含膜的去小脑的大鼠脑或人皮质级分(ABS Inc.,Wilmington,DE)测定与α7nAChR亚型的结合。将沉淀在4℃解冻,洗涤,用设置为7的Polytron重悬浮于30体积BSS-Tris缓冲液(120mM NaCl,5mM KCl,2mM CaCl2,2mM MgCl2,和50mM Tris-Cl,pH 7.4,4℃)中。一式两份地将七种对数稀释浓度的包含100-200μg蛋白的测试化合物和0.5nM[3H]-DPPB(62.8Ci/mmol;R46V,Abbott Labs)以500μl终体积在4℃温育75分钟。在10μM甲基牛扁亭的存在下确定非特异性结合。用Packard细胞收获器将结合的放 射性收集在用0.3%PEI预浸渍的Millipore 收获板FB上,用2.5m1冰冷缓冲液洗涤,且用Packard 微量培养板β计数器测定放射性。用 Excel或Assay Explorer的非线性回归确定IC50值。使用Cheng-Prusoff方程式由IC50计算Ki值,其中Ki=IC50/(1+[配体]/KD)。根据下文描述的制备程序获得[3H]-DPPB。
制备[甲基-3H]2,2-二甲基-5-(6-苯基-哒嗪-3-基)-5-氮杂-2-氮鎓-双环[2.2.1]庚烷碘化物
按照以下程序制备用于上述[3H]-DPPB结合测定的[甲基-3H]2,2-二甲基-5-(6-苯基-哒嗪-3-基)-5-氮杂-2-氮鎓-双环[2.2.1]庚烷碘化物。
步骤1:制备(S,S)-5-(6-苯基-哒嗪-3-基)-2,5-二氮杂-双环[2-2.1]庚烷-2-羧酸叔丁酯
把三乙胺(20mL)加到(S,S)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(3.43g,17.3mmol,Aldrich Chemical Company)及3-氯-6-苯基哒嗪(3.30g,17.3mmol,Aldrich Chemical Company)在甲苯(50mL)中的悬浮液内,并将混合物于100℃在氮下加热7天。将该暗混合物冷却至室温,并过滤分离所得沉淀,用甲苯(15mL)洗涤并在真空下干燥,以提供本标题化合物,为灰白色固体(3.00g)。将滤液浓缩,并且残余物通过硅胶柱色谱法纯化,用乙酸乙酯洗脱,以提供另外的产物(0.41g,总得率3.41g,56%):MS(DCI/NH3)m/z 353(M+H)+.
步骤2:制备(S,S)-2-甲基5-(6-苯基-哒嗪-3-基)-2,5-二氮杂-双环[2.2.1]庚烷
将得自步骤1的产物(3.41g,9.7mmol)溶解在甲酸(20mL)中,并用福尔马林(37重量%,1.0g,12.3mmol)处理。该混合物于100℃加热1小时,且将褐色溶液冷却至室温并在真空下浓缩。所得残余物通过硅胶柱色谱法纯化,用CH2Cl2-CH3OH-NH4OH(95∶5∶1)洗脱,以提供本标题化合物,为灰白色固体(2.50g,96%):MS(DCI/NH3)m/z 267(M+H)+.
步骤3:制备[
3
H]-(S,S)-2,2-二甲基-5-(6-苯基-哒嗪-3-基)-5-氮杂-2-氮鎓-双环[2.2.1]庚烷碘化物([
3
H]-DPPB)
将在甲苯中的[3H]甲基碘(250mCi在0.1mL中,85Ci/mmol,American Radiolabeled Chemicals,Inc.)与得自步骤2的产物在二氯甲烷中的溶液(0.788mg,2.96μmole在0.45mL中)混合。将小瓶封盖并使混合物于室温反应过夜。加入甲醇,并将溶剂蒸发以给出42mCi。把产 物溶解在甲醇中用于HPLC纯化。
步骤4:用高效液相色谱法(HPLC)进行纯化
将约7mCi[3H]-DPPB蒸发至干燥,且将残余物溶于总共约4.5ml的乙腈∶水∶TFA(15∶85∶0.1)中。应用Agilent HPLC系统,每次注射约0.9mL至PhenomenexLuna C18(2)柱(5μm,250mm×4.6mm ID)上。通过在20分钟内从10%B至20%B梯度的流动相洗脱[3H]-DPPB,其中流动相A=0.1%三氟乙酸的水溶液,且流动相B=0.1%三氟乙酸的乙腈溶液,流速约1mL/min。用设定在275nm的Agilent可调波长UV检测器获得峰值检测和色谱图。用Agilent级分收集器在约14分钟收集包含[3H]-DPPB的级分。合并级分,且真空蒸发溶剂。将残余物溶于200proof乙醇(2mL)中,以给出0.7mCi。
步骤5:纯度和比活度的测定
用Agilent 1100系列HPLC系统测定[3H]-DPPB,该系统由四元泵、自动进样器和光敏二极管阵列UV检测器组成。将Packard Radiomatic A500放射性检测器连接到HPLC系统上。对于放射性检测(radiodetection),使用500μL流动池和3∶1比率的Ultima-Flo M闪烁液∶HPLC流动相。使用Phenomenex Luna C18(2)柱(5μm,250mm×4.6mm ID)进行分析。流动相由以下梯度组成:以10%B开始,20分钟内斜升到20%B,接着1分钟内斜升到90%B,并在90%B保持9分钟,其中流动相A=0.1%三氟乙酸的水溶液,且流动相B=0.1%三氟乙酸的乙腈溶液。流速设定为约1mL/min,且UV检测设定在275nm。
当通过[3H]-MLA测定进行测试时,本发明化合物具有约1纳摩尔至约10微摩尔的Ki值,许多本发明化合物具有小于1微摩尔的Ki。本发明化合物的[3H]-野靛碱结合值为约50纳摩尔到至少100微摩尔。优选的化合物对α7受体比对α4β2受体一般表现出更大的效力。优选化合物的确定一般考虑:考虑到通过[3H]-野靛碱结合测量的Ki值的通过MLA测定测量的Ki值,这样在式D=Ki 3 H-野靛碱/Ki MLA中,D大于约50。或者,可使用通过[3H]-DPPB测定测量的Ki值来代替Ki MLA,这样在式D′=Ki 3 H-野靛碱/Ki[3H]-DPPB中,D′大于约50。
本发明化合物是通过改变受体的活性或发信号来调节α7nAChRs功能的α7nAChRs配体。该化合物可以是抑制受体的基础活性的逆激动剂,或者是完全阻断激活受体的激动剂作用的拮抗剂。该化合物也可以 是部分阻断或部分激活α7nAChR受体的不全激动剂,或者是激活该受体的激动剂。与α7受体结合还触发涉及对影响记忆、细胞保护作用、基因转录及疾病修饰来说重要的各种激酶及磷酸酶及蛋白质间的相互作用的关键发信号过程。
本发明方法
本发明化合物和组合物用于调节nAChRs且更具体是α7nAChRs及α4β2nAChRs的作用。具体地,本发明化合物及组合物可以用于治疗及预防由α7nAChRs介导的病症。通常,通过在动物例如人中选择性调节α7nAChRs,优选通过单独或与另一种活性剂联合施用本发明化合物或组合物,例如,作为治疗方案的部分,此种病症可以得到改善。同样,本发明的一些化合物除了对α7nAChRs具有亲和力外,还对α4β2nAChRs具有亲和力,而对两种受体亚型具有双重亲和力的选择性化合物具有有益作用。
状况、疾病和病症
由于含α7的nAChRs已被体外及体内表明与烟碱的神经保护作用有关,因此本发明化合物可以用来治疗构成几种进行性CNS病症(例如阿尔茨海默病、帕金森病、肌萎缩性侧索硬化症、Hungtington氏病、具有Lewy小体的痴呆以及由创伤性脑损伤引起的CNS功能减弱)基础的神经变性。激活α7nAChRs的化合物可用来对抗阿尔茨海默病及其它神经变性疾病的缺陷。
因此,可以将α7配体用于治疗精神分裂症。α7受体的活化剂用以提高用非典型抗精神病药治疗的精神分裂症患者中的认知功能。因此,α7nAChR配体与非典型抗精神病药的联合可以提供改善的治疗效用。适宜的非典型抗精神病药的具体实例包括但不限于氯氮平、利哌利酮、奥氮平、quietapine、齐拉西酮、佐替平、伊潘立酮(iloperidone)等。
由于改善的血管发生已被表明涉及α7nAChR的激活,因此对α7亚型有选择性的nAChR配体可以用来刺激具有改善的副作用概况的血管发生。
α7nAChR配体可以用来治疗疼痛,包括急性疼痛,外科手术后疼痛以及慢性疼痛,包括炎性疼痛及神经病疼痛。其也可以用于治疗涉及TNF介导的疾病的状况,例如类风湿性关节炎、Crohn氏病、溃疡性结 肠炎、炎性肠病、器官移植排斥、与器官移植有关的急性免疫性疾病、与器官移植有关的慢性免疫性疾病、感染性休克、中毒性休克综合征、脓毒病综合征、抑郁及类风湿性脊椎炎。
由于α7nAChR对精细胞的激活已被表明对于顶体反应是至关重要的,所以本发明的选择性α7试剂可以用来治疗生育力病症。
本发明化合物是α7nAChRs配体,其通过改变受体的活性或发信号来调节α7nAChRs的功能。该化合物可以是抑制受体的基础活性的逆激动剂,或者是完全阻断激活受体的激动剂的作用的拮抗剂。该化合物也可以是部分阻断或部分激活α7nAChR受体的不全激动剂,或者是激活该受体的激动剂。与α7受体结合还触发涉及对影响记忆、细胞保护作用、基因转录及疾病修饰来说是重要的各种激酶及磷酸酶以及蛋白质间的相互作用的关键的发信号过程。因此,向哺乳动物施用治疗有效量的式(I)化合物提供了选择性调节α4β2、α7或者α4β2及α7烟碱性乙酰胆碱受体的方法。
dopine传递的烟碱性受体调节已被鉴定为构成各种形式的物质滥用基础的重要机制,所述物质滥用包括例如戒烟、酒精瘾、大麻瘾以及其它形式的物质滥用。(Rose,J.E.,Biochem Pharmacol.,74(8):1263-1270,2007;Rollema H.,Coe J.W.,Chambers L.K.,Hurst R.S.,Stahl S.M.,Williams K.E.,Trends Pharmacol Sci.,28(7):316-25,2007;Steensland P.,Simms J.A.,Holgate J.,Richards J.K.,Bartlett S.E.,Proc Nat′l Acad Sci U.S.A.,104(30):12518-23,2007;和Scherma M.,Fattor Le.,Stoik J.,Wertheim C.,Tanda G.,Fratta W.,Goldberg S.R.,27(21):5615-20,2007)。例如,包括α4β2及α7nAChRs在内的烟碱性受体存在于与瘾牵连的脑通路中。因此,选择性调节α4β2、α7或者α4β2及α7烟碱性乙酰胆碱受体作用的方法可以用于治疗或预防物质滥用。
因此,向哺乳动物施用治疗有效量的式(I)化合物提供了治疗或预防选自以下的状况或病症的方法:注意力缺陷障碍,注意力不集中的过度反应症(ADHD),阿尔茨海默病(AD),轻度认知缺损,老年性痴呆,艾滋病痴呆,Pick氏病,与Lewy小体有关的痴呆,与唐氏综合征有关的痴呆,肌萎缩性侧索硬化症,Huntington氏病,与创伤性脑损伤相关的CNS功能减弱,急性疼痛,外科手术后疼痛,慢性疼痛,炎性疼痛,神经病疼痛,不孕,对与伤口愈合相关的新血管生长的需要,对与皮肤移 植物的血管形成相关的新血管生长的需要,以及循环不足,更具体是血管闭塞周围的循环,类风湿性关节炎,Crohn氏病,溃疡性结肠炎,炎性肠病,器官移植排斥,与器官移植有关的急性免疫性疾病,与器官移植有关的慢性免疫性疾病,感染性休克,中毒性休克综合征,脓毒病综合征,抑郁,类风湿性脊椎炎以及物质滥用。更优选地,向哺乳动物施用治疗有效量的式(I)化合物提供了治疗认知障碍、神经变性及精神分裂症的方法。
可以将本发明化合物与其它药物同时,以组合制剂的形式,或者采用将化合物单独施用的方案施用。除了先前所列的非典型抗精神病药以外,本发明化合物还可以与治疗注意力不集中的过度反应症的其它化合物例如右旋苯丙胺、左旋苯丙胺、右旋苏哌醋甲酯(dextrothreomethylphenidate)、左旋苏哌醋甲酯(levothreomethylphenidate)、金刚烷胺、安扑定、苄非他明、安非布他酮、可乐定、莫达非尼、匹莫林、司来吉兰及米那普仑;与治疗阿尔茨海默病的化合物例如乙酰胆碱酯酶抑制剂(例如他克林、多奈哌齐、加兰他敏及雷司替明)及美金刚胺以及其它NMDA拮抗剂联合施用。
施用-剂量
可以改变在本发明的药物组合物中的活性成分的实际剂量水平,以便获得对特定患者、组合物和施用方式有效达到所需治疗响应的活性化合物的量。所选的剂量水平取决于具体化合物的活性、施用途径、所治疗状况的严重程度以及所治疗患者的状况和之前病史。然而,本领域技术人员知道,在低于为达到所需的治疗效果所需之量的水平起始化合物剂量,并逐渐增大剂量直至达到所需的效果。
当在上述或其它治疗中使用时,本发明化合物之一的治疗有效量可以纯的形式使用,或者当存在这样的形式时,可以以药学上可接受的盐或前药的形式使用。或者,所述化合物可以药物组合物的形式施用,所述药物组合物含有与一种或多种可药用载体结合的目的化合物。本发明化合物的″治疗有效量″是指该化合物以适用于任何医学治疗的合理的利/害比治疗病症的足够量。然而,将理解,本发明的化合物和组合物的总日剂量由主治医师在合理的医学判断范围内决定。
施用于人或低等动物的本发明化合物的总日剂量在约0.010mg/kg体重至约1g/kg体重的范围内。更优选的剂量可以在约0.010mg/kg体 重至约100mg/kg体重范围之内。如果需要,为了施用目的,所述有效日剂量可以被分成多剂。单剂组合物可以含有这样的量或其亚倍量,以达到所述日剂量。
可以理解,本详细描述及伴随的实施例仅仅是例证性的,而不限制本发明的范围,其仅仅由所附的权利要求以及它们的同等方案进行限定。在此公开的实施方案的各种改变和修饰对本领域技术人员来说是显而易见的。这样的改变和修饰,包括但不限于涉及化学结构、取代基、衍生物、中间体、合成、制剂和/或本发明的使用方法的那些改变和修饰,可以在不背离本发明精神和范围的基础上进行。
Claims (20)
1.式(I)化合物
或者其可药用盐或前药,其中
R1选自氢、烷基、环烷基、卤烷基、芳基及杂芳基;
a及c各自独立地选自0、1、2;b及d各自独立地选自1、2或3;条件是当b及d两者都是1时,a及c不能同时是1;
Ar1选自下式的5或6元芳基:
其中
A1、A2、A3及A4各自是-N-或-CRa;
X1、X3、X4独立地选自-CRa、-NRa、-O-及-S-;
X2是-C-或-N-,条件是当X2是-C-的,X1、X3、X4中的至少一个不是-C-;
Ra选自氢、烷基、环烷基、卤烷基、芳基、杂芳基、卤素、-CO2R1、-COR1、-CONR1、-OR1及-NR1;
Ar2是下式的稠合双环芳基
其中
B1、B2、B3、B4、B5、B6各自独立地是-N-或-CRa-;
Y选自-NRd-、-O-及-S-;
Ra选自氢、烷基、环烷基、卤烷基、芳基、杂芳基、卤素、-CO2R1、-COR1、-CONR1、-OR1及-NR1;并且
Rd选自氢、烷基及环烷基。
2.权利要求1的化合物,其中所述稠合的二氮杂双环烷部分选自
3.权利要求1的化合物,其中Ar1选自咪唑基(midazolyl)、异噁唑基、异噻唑基、呋喃基、噁唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、苯基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻吩基、噻唑基、1,2,4-噻二唑基及1,3,4-噻二唑基。
4.权利要求3的化合物,其中Ar1选自哒嗪基、吡啶基、噻唑基、1,3,4-噻二唑基及1,3,4-噁二唑基,其中Ar1被0、1或2个选自烷氧基、烷基、氰基、卤烷基、羟基、卤素及NR1的取代基取代。
5.权利要求1的化合物,其中Ar2选自苯并呋喃基、苯并[d]咪唑基、苯并[d]异噁唑基、苯并[d]异噻唑基、苯并[d]噁唑基、苯并[d]噻唑基、苯并[b]噻吩基、呋喃并[3,2-b]吡啶基、呋喃并[3,2-c]吡啶基、咪唑并[4,5-b]吡啶基、咪唑并[4,5-c]吡啶、吲哚基、吲唑基、异噁唑并[4,5-b]吡啶基、异噁唑并[4,5-c]吡啶基、异噁唑并[5,4-b]吡啶基、异噁唑并[5,4-c]吡啶基、异噻唑并[4,5-c]吡啶基、异噻唑并[4,5-c]吡啶基、异噻唑并[5,4-b]吡啶基、异噻唑并[5,4-c]吡啶基、噁唑并[4,5-b]吡啶基、噁唑并[4,5-c]吡啶基、噁唑并[5,4-b]吡啶基、噁唑并[5,4-c]吡啶基、吡唑并[3,4-b]吡啶基、吡唑并[3,4-c]吡啶基、吡唑并[4,3-b]吡啶基、吡唑并[4,3-c]吡啶基、吡咯并[2,3-b]吡啶基、吡咯并[2,3-c]吡啶基、吡咯并[3,2-b]吡啶基、吡咯并[3,2-c]吡啶基、噻唑并[4,5-b]吡啶基、噻唑并[4,5-c]吡啶基、噻唑并[5,4-b]吡啶基、噻唑并[5,4-c]吡啶基、噻吩并[2,3-b]吡啶基、噻吩并[2,3-c]吡啶基、噻吩并[3,2-b]吡啶基及噻吩并[3,2-c]吡啶基。
6.权利要求2的化合物,其中所述稠合的二氮杂双环烷部分是
9.权利要求1的化合物,其中所述化合物是选自下列的之一
5-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
4-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
4-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
6-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
6-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-2-(三氟甲基)-1H-吲哚;
(1S,5S)-3-(5-(苯并呋喃-5-基)吡啶-3-基)-6-甲基-3,6-二氮杂双环[3.2.0]庚烷;
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲唑;
(1S,5S)-3-[5-(苯并[b]噻吩-5-基)吡啶-3-基]-3,6-二氮杂双环[3.2.0]庚烷;
(1S,5S)-3-[5-(苯并[b]噻吩-5-基)吡啶-3-基]-3,6-二氮杂双环[3.2.0]庚烷;
7-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-苯并[d]咪唑;
3-甲基-5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
3-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-9H-咔唑;
5-{5-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-3-甲基-1H-吲哚;
3-(5-((1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基)吡啶-3-基)-9H-咔唑;
7-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吡咯并[2,3-c]吡啶;
5-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吡咯并[2,3-b]吡啶;
3-{5-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1-(苯基磺酰基)-1H-吲哚;
3-(5-((1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基)吡啶-3-基)-1H-吲哚;
4-{6-[(1S,5S)-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚;
4-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚;
5-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚;
6-{6-[(1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡嗪-2-基}-1H-吲哚;
5-(6-((1S,5S)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基)吡嗪-2-基)-2-(三氟甲基)-1H-吲哚
5-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
4-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
6-{5-[(1R,5R)-6-甲基-3,6-二氮杂双环[3.2.0]庚-3-基]吡啶-3-基}-1H-吲哚;
5-{5-[(1R,5S)-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚;
5-{5-[(1R,5S)-3-甲基-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚;
6-{5-[(1R,5S)-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚;
6-{5-[(1R,5S)-3-甲基-3,6-二氮杂双环[3.2.0]庚-6-基]吡啶-3-基}-1H-吲哚;
4-(5-((1R,5S)-3-甲基-3,6-二氮杂双环[3.2.0]庚-6-基)吡啶-3-基)-1H-吲哚;
6-{5-[(3aS,6aS)-5-甲基六氢吡咯并[3,4-b]吡咯-1(2H)-基]吡啶-3-基}-1H-吲哚;及
5-{5-[(3aS,6aS)-5-甲基六氢吡咯并[3,4-b]吡咯-1(2H)-基]吡啶-3-基}-1H-吲哚。
10.包含治疗有效量的权利要求1的化合物及可药用载体的药物组合物。
11.在哺乳动物中选择性调节α7烟碱性乙酰胆碱受体、α4β2烟碱性乙酰胆碱受体、或者α7及α4β2烟碱性乙酰胆碱受体的方法,所述方法包括施用有效量的权利要求1的化合物。
12.权利要求11的方法,其中所述化合物是至少一种α7或α4β2烟碱性乙酰胆碱受体的激动剂。
13.治疗α7及α4β2烟碱性乙酰胆碱受体介导的受试者的状况或病症的方法,所述方法包括向所述受试者施用权利要求1的化合物。
14.权利要求13的方法,其中所述α7及α4β2烟碱性乙酰胆碱受体介导的状况或病症选自注意力缺陷障碍,注意力不集中的过度反应症,阿尔茨海默病(AD),轻度认知缺损,老年性痴呆,艾滋病痴呆,Pick氏病,与Lewy小体有关的痴呆,与唐氏综合征有关的痴呆,肌萎缩性侧索硬化症,Huntington氏病,与创伤性脑损伤相关的CNS功能减弱,急性疼痛,外科手术后疼痛,慢性疼痛,炎症,炎性疼痛,神经病疼痛,不孕,对与伤口愈合相关的新血管生长的需要,对与皮肤移植物的血管形成相关的新血管生长的需要,以及循环不足,类风湿性关节炎,Crohn氏病,溃疡性结肠炎,炎性肠病,器官移植排斥,与器官移植有关的急性免疫性疾病,与器官移植有关的慢性免疫性疾病,感染性休克,中毒性休克综合征,脓毒病综合征,抑郁,类风湿性脊椎炎以及物质滥用。
15.权利要求14的方法,其中所述α7及α4β2烟碱性乙酰胆碱受体介导的状况或病症是α7烟碱性乙酰胆碱受体介导的状况或病症,并且选自认知障碍、神经变性及精神分裂症。
16.权利要求15的方法,其中所述化合物是至少一种α7烟碱性乙酰胆碱受体的激动剂,并且其中所述方法还包括施用非典型抗精神病药。
17.权利要求16的方法,其中所述非典型抗精神病药物是选自以下的至少一种:氯氮平、利哌利酮、奥氮平、quietapine、齐拉西酮、佐替平及伊潘立酮。
18.权利要求11的方法,所述方法还包括施用权利要求1的化合物与治疗认知障碍的第二种组合物。
19.权利要求18的方法,其中所述认知障碍是注意力缺陷障碍,并且所述第二种组合物包含至少一种选自以下的化合物:右旋苯丙胺、左旋苯丙胺、右旋苏哌醋甲酯、左旋苏哌醋甲酯、金刚烷胺、安扑定、苄非他明、安非布他酮、可乐定、莫达非尼、匹莫林、司来吉兰及米那普仑。
20.权利要求18的方法,其中所述认知障碍是阿尔茨海默病,并且所述第二种组合物包括选自下列的至少一种:乙酰胆碱酯酶抑制剂、NMDA拮抗剂、维生素C及维生素E。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US98960707P | 2007-11-21 | 2007-11-21 | |
US60/989607 | 2007-11-21 | ||
PCT/US2008/084165 WO2009067586A1 (en) | 2007-11-21 | 2008-11-20 | Biaryl substituted diazabicycloalkane derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101918409A true CN101918409A (zh) | 2010-12-15 |
Family
ID=40316922
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2008801251989A Pending CN101918409A (zh) | 2007-11-21 | 2008-11-20 | 联芳基取代的二氮杂双环烷衍生物 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20090197860A1 (zh) |
EP (2) | EP2231672B1 (zh) |
JP (2) | JP5628043B2 (zh) |
CN (1) | CN101918409A (zh) |
CA (1) | CA2705011A1 (zh) |
MX (1) | MX2010005650A (zh) |
WO (1) | WO2009067586A1 (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX2010005650A (es) * | 2007-11-21 | 2010-06-02 | Abbott Lab | Derivados de diazabicicloalcano substituidos con biarilo. |
US8148408B2 (en) * | 2008-05-09 | 2012-04-03 | Abbott Laboratories | Selective substituted pyridine ligands for neuronal nicotinic receptors |
US8697708B2 (en) | 2010-09-15 | 2014-04-15 | F. Hoffmann-La Roche Ag | Azabenzothiazole compounds, compositions and methods of use |
EP3623371A1 (en) | 2014-12-16 | 2020-03-18 | Axovant Sciences GmbH | Geminal substituted quinuclidine amide compounds as agonists of alpha-7 nicotinic acetylcholine receptors |
WO2016201096A1 (en) | 2015-06-10 | 2016-12-15 | Forum Pharmaceuticals, Inc. | Aminobenzisoxazole compounds as agonists of a7-nicotinic acetylcholine receptors |
US10428062B2 (en) | 2015-08-12 | 2019-10-01 | Axovant Sciences Gmbh | Geminal substituted aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors |
US11225484B2 (en) | 2017-08-08 | 2022-01-18 | Vanderbilt University | Substituted octahydropyrrolo[3,4-b]pyrroles as antagonists of the muscarinic acetylcholine receptor M4 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU1996301A (en) | 1999-12-14 | 2001-06-25 | Neurosearch A/S | Novel heteroaryl-diazabicycloalkanes |
MY145722A (en) * | 2000-04-27 | 2012-03-30 | Abbott Lab | Diazabicyclic central nervous system active agents |
US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
US7354937B2 (en) * | 2004-05-21 | 2008-04-08 | Abbott Laboratories | (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane |
US7202363B2 (en) | 2003-07-24 | 2007-04-10 | Abbott Laboratories | Thienopyridine and furopyridine kinase inhibitors |
US20050065178A1 (en) * | 2003-09-19 | 2005-03-24 | Anwer Basha | Substituted diazabicycloakane derivatives |
US7399765B2 (en) * | 2003-09-19 | 2008-07-15 | Abbott Laboratories | Substituted diazabicycloalkane derivatives |
US7728031B2 (en) * | 2006-02-24 | 2010-06-01 | Abbott Laboratories | Octahydro-pyrrolo[3,4-b]pyrrole derivatives |
EP2018380B1 (en) * | 2006-05-19 | 2011-10-19 | Abbott Laboratories | Cns active fused bicycloheterocycle substituted azabicyclic alkane derivatives |
MX2010005650A (es) * | 2007-11-21 | 2010-06-02 | Abbott Lab | Derivados de diazabicicloalcano substituidos con biarilo. |
-
2008
- 2008-11-20 MX MX2010005650A patent/MX2010005650A/es active IP Right Grant
- 2008-11-20 CA CA2705011A patent/CA2705011A1/en not_active Abandoned
- 2008-11-20 WO PCT/US2008/084165 patent/WO2009067586A1/en active Application Filing
- 2008-11-20 US US12/274,532 patent/US20090197860A1/en not_active Abandoned
- 2008-11-20 JP JP2010535056A patent/JP5628043B2/ja not_active Expired - Fee Related
- 2008-11-20 CN CN2008801251989A patent/CN101918409A/zh active Pending
- 2008-11-20 EP EP08853111.6A patent/EP2231672B1/en active Active
- 2008-11-20 EP EP20120194563 patent/EP2604611A1/en not_active Withdrawn
-
2014
- 2014-09-30 JP JP2014199884A patent/JP2015028063A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
EP2604611A1 (en) | 2013-06-19 |
CA2705011A1 (en) | 2009-05-28 |
WO2009067586A1 (en) | 2009-05-28 |
US20090197860A1 (en) | 2009-08-06 |
JP2011504182A (ja) | 2011-02-03 |
EP2231672B1 (en) | 2014-12-17 |
MX2010005650A (es) | 2010-06-02 |
JP5628043B2 (ja) | 2014-11-19 |
EP2231672A1 (en) | 2010-09-29 |
JP2015028063A (ja) | 2015-02-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101939324B (zh) | 吡咯并吡嗪激酶抑制剂 | |
CN101868464B (zh) | 作为pi3抑制剂的噻吩并嘧啶衍生物 | |
KR101654073B1 (ko) | 아자아다만탄 유도체 및 니코틴성 아세틸콜린 수용체 리간드로서의 이의 용도 | |
CN101925599A (zh) | 作为烟碱性乙酰胆碱受体活性调节剂的联芳基取代的氮杂双环烷衍生物 | |
CN101918409A (zh) | 联芳基取代的二氮杂双环烷衍生物 | |
TW200526667A (en) | Substituted diazabicycloalkane derivatives | |
CN107406462B (zh) | 三环dlk抑制剂及其用途 | |
AU2006276890A1 (en) | Fused bicycloheterocycle substituted quinuclidine derivatives | |
EP3921319B1 (en) | Imidazo [2, 1-f] [1, 2, 4] triazin-4-amine derivatives as tlr7 agonist | |
CN111511744A (zh) | 二氮杂吲哚化合物 | |
CN101437519A (zh) | 吲唑化合物 | |
CN101448825A (zh) | Cns活性的稠合的双环杂环取代的氮杂双环烷烃衍生物 | |
AU2004325725A1 (en) | Fused bicycloheterocycle substituted quinuclidine derivatives | |
CN102459268A (zh) | 二氮杂高金刚烷衍生物和其使用方法 | |
CN101641355A (zh) | 氮杂金刚烷酯和氨基甲酸酯衍生物及其使用方法 | |
WO2021121294A1 (zh) | 三唑并哒嗪类衍生物、其制备方法、药物组合物和用途 | |
CN114907338B (zh) | 含氮多环稠环类化合物,其药物组合物、制备方法和用途 | |
CN101675049A (zh) | 作为α7-神经元烟碱样乙酰胆碱受体(NNRS)的选择性调节剂的氨基甲基氮杂金刚烷衍生物及其用途 | |
CN101641356A (zh) | 氮杂金刚烷的乙酰胺和甲酰胺衍生物及其使用方法 | |
TWI841679B (zh) | -4-胺衍生物 | |
CN101541792A (zh) | 氮杂金刚烷衍生物和应用方法 | |
CN101568541A (zh) | 螺环氮杂金刚烷衍生物和使用方法 | |
KR20070085053A (ko) | 융합된 바이사이클로헤테로사이클 치환된 퀴누클리딘유도체 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
ASS | Succession or assignment of patent right |
Owner name: ABBVIE COMPANY Free format text: FORMER OWNER: ABBOTT GMBH. + CO. KG Effective date: 20130621 |
|
C41 | Transfer of patent application or patent right or utility model | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20130621 Address after: Illinois State Applicant after: ABBVIE company Address before: Illinois State Applicant before: Abbott GmbH. & Co. Kg |
|
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20101215 |