JP5184354B2 - 新規1−アリール−3−アザビシクロ[3.1.0]ヘキサン:調製および神経精神障害の処理への使用 - Google Patents
新規1−アリール−3−アザビシクロ[3.1.0]ヘキサン:調製および神経精神障害の処理への使用 Download PDFInfo
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- JP5184354B2 JP5184354B2 JP2008524100A JP2008524100A JP5184354B2 JP 5184354 B2 JP5184354 B2 JP 5184354B2 JP 2008524100 A JP2008524100 A JP 2008524100A JP 2008524100 A JP2008524100 A JP 2008524100A JP 5184354 B2 JP5184354 B2 JP 5184354B2
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- Prior art keywords
- hexane
- aza
- bicyclo
- naphthalen
- methyl
- Prior art date
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- 238000011282 treatment Methods 0.000 title abstract description 32
- 238000002360 preparation method Methods 0.000 title description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 153
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 56
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 19
- -1 C 1 -C 6 alkoxy Chemical group 0.000 claims description 172
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 129
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 97
- 125000000217 alkyl group Chemical group 0.000 claims description 75
- 150000003839 salts Chemical class 0.000 claims description 59
- 229910052736 halogen Inorganic materials 0.000 claims description 55
- 208000015114 central nervous system disease Diseases 0.000 claims description 54
- 229910052739 hydrogen Inorganic materials 0.000 claims description 50
- 239000001257 hydrogen Substances 0.000 claims description 50
- 125000003118 aryl group Chemical group 0.000 claims description 49
- 125000005843 halogen group Chemical group 0.000 claims description 39
- 150000002367 halogens Chemical group 0.000 claims description 36
- 150000002431 hydrogen Chemical class 0.000 claims description 35
- 208000024891 symptom Diseases 0.000 claims description 35
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 32
- 125000001424 substituent group Chemical group 0.000 claims description 32
- 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 claims description 31
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 125000000304 alkynyl group Chemical group 0.000 claims description 26
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 21
- 125000004104 aryloxy group Chemical group 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 20
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 19
- 229960002748 norepinephrine Drugs 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 16
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 16
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 16
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 229960003638 dopamine Drugs 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 12
- 230000000035 biogenic effect Effects 0.000 claims description 12
- 229940076279 serotonin Drugs 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 7
- 150000004677 hydrates Chemical class 0.000 claims description 7
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 6
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- LXRGASPBMFUCBR-UHFFFAOYSA-N 1-(4-fluoronaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=C2C(F)=CC=C(C34C(C3)CNC4)C2=C1 LXRGASPBMFUCBR-UHFFFAOYSA-N 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 239000003981 vehicle Substances 0.000 claims description 5
- ZQDUBTPWXSFQGA-UHFFFAOYSA-N 1-(6-methoxynaphthalen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC2=CC(OC)=CC=C2C=C1C1(CN(C)C2)C2C1 ZQDUBTPWXSFQGA-UHFFFAOYSA-N 0.000 claims description 4
- CIRWXGMYHWXKHE-UHFFFAOYSA-N 3-ethyl-1-naphthalen-2-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=CC2=CC(C34CC3CN(C4)CC)=CC=C21 CIRWXGMYHWXKHE-UHFFFAOYSA-N 0.000 claims description 4
- NOINBIBBSXQXQL-UHFFFAOYSA-N 3-methyl-1-naphthalen-1-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=C2C(C34CC3CN(C4)C)=CC=CC2=C1 NOINBIBBSXQXQL-UHFFFAOYSA-N 0.000 claims description 4
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- CCWSHTWDGSAUAU-UHFFFAOYSA-N 1-(4-fluoronaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=C2C(C34CC3CN(C4)C)=CC=C(F)C2=C1 CCWSHTWDGSAUAU-UHFFFAOYSA-N 0.000 claims description 3
- JXCCCXJMHZUFOM-UHFFFAOYSA-N 1-naphthalen-1-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=C2C(C34CNCC4C3)=CC=CC2=C1 JXCCCXJMHZUFOM-UHFFFAOYSA-N 0.000 claims description 3
- RBSUWUVPTHHLHV-UHFFFAOYSA-N 1-naphthalen-2-yl-3-propan-2-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=CC2=CC(C34CC3CN(C4)C(C)C)=CC=C21 RBSUWUVPTHHLHV-UHFFFAOYSA-N 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- PZSAUCRKLIVWSM-UHFFFAOYSA-N 1-(6-ethoxynaphthalen-2-yl)-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC2=CC(OCC)=CC=C2C=C1C1(CNC2)C2C1 PZSAUCRKLIVWSM-UHFFFAOYSA-N 0.000 claims description 2
- XEECWPXYCFHQRV-UHFFFAOYSA-N 1-(6-ethoxynaphthalen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC2=CC(OCC)=CC=C2C=C1C1(CN(C)C2)C2C1 XEECWPXYCFHQRV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- PWPCFNCTRMMLFC-UHFFFAOYSA-N 3-methyl-1-(4-methylnaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=C2C(C34CC3CN(C4)C)=CC=C(C)C2=C1 PWPCFNCTRMMLFC-UHFFFAOYSA-N 0.000 claims description 2
- QRDSDKAGXMWBID-UHFFFAOYSA-N 5-azabicyclo[3.1.0]hexane Chemical compound C1CCN2CC21 QRDSDKAGXMWBID-UHFFFAOYSA-N 0.000 claims description 2
- COLJOGVSPPXZNW-CVEARBPZSA-N (1r,5s)-3-methyl-1-naphthalen-2-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=CC2=CC([C@@]34C[C@@H]3CN(C4)C)=CC=C21 COLJOGVSPPXZNW-CVEARBPZSA-N 0.000 claims 3
- HKHCSWPSUSWGLI-LSDHHAIUSA-N (1s,5r)-1-naphthalen-2-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=CC2=CC([C@]34CNC[C@@H]4C3)=CC=C21 HKHCSWPSUSWGLI-LSDHHAIUSA-N 0.000 claims 3
- COLJOGVSPPXZNW-JKSUJKDBSA-N (1s,5r)-3-methyl-1-naphthalen-2-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=CC2=CC([C@]34C[C@H]3CN(C4)C)=CC=C21 COLJOGVSPPXZNW-JKSUJKDBSA-N 0.000 claims 3
- 230000004700 cellular uptake Effects 0.000 claims 3
- HKHCSWPSUSWGLI-CABCVRRESA-N (1r,5s)-1-naphthalen-2-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=CC2=CC([C@@]34CNC[C@H]4C3)=CC=C21 HKHCSWPSUSWGLI-CABCVRRESA-N 0.000 claims 2
- RBSUWUVPTHHLHV-MSOLQXFVSA-N (1r,5s)-1-naphthalen-2-yl-3-propan-2-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=CC2=CC([C@@]34C[C@@H]3CN(C4)C(C)C)=CC=C21 RBSUWUVPTHHLHV-MSOLQXFVSA-N 0.000 claims 2
- NOINBIBBSXQXQL-CZUORRHYSA-N (1r,5s)-3-methyl-1-naphthalen-1-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=C2C([C@@]34C[C@@H]3CN(C4)C)=CC=CC2=C1 NOINBIBBSXQXQL-CZUORRHYSA-N 0.000 claims 2
- JXCCCXJMHZUFOM-WFASDCNBSA-N (1s,5r)-1-naphthalen-1-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=C2C([C@]34CNC[C@@H]4C3)=CC=CC2=C1 JXCCCXJMHZUFOM-WFASDCNBSA-N 0.000 claims 2
- RBSUWUVPTHHLHV-ZWKOTPCHSA-N (1s,5r)-1-naphthalen-2-yl-3-propan-2-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=CC2=CC([C@]34C[C@H]3CN(C4)C(C)C)=CC=C21 RBSUWUVPTHHLHV-ZWKOTPCHSA-N 0.000 claims 2
- NOINBIBBSXQXQL-BBRMVZONSA-N (1s,5r)-3-methyl-1-naphthalen-1-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=C2C([C@]34C[C@H]3CN(C4)C)=CC=CC2=C1 NOINBIBBSXQXQL-BBRMVZONSA-N 0.000 claims 2
- JBEISIMRAMNVTP-UHFFFAOYSA-N 1-(4-methylnaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=C2C(C)=CC=C(C34C(C3)CNC4)C2=C1 JBEISIMRAMNVTP-UHFFFAOYSA-N 0.000 claims 2
- HKHCSWPSUSWGLI-UHFFFAOYSA-N 1-naphthalen-2-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=CC2=CC(C34CNCC4C3)=CC=C21 HKHCSWPSUSWGLI-UHFFFAOYSA-N 0.000 claims 2
- COLJOGVSPPXZNW-UHFFFAOYSA-N 3-methyl-1-naphthalen-2-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=CC2=CC(C34CC3CN(C4)C)=CC=C21 COLJOGVSPPXZNW-UHFFFAOYSA-N 0.000 claims 2
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- JXCCCXJMHZUFOM-IUODEOHRSA-N (1r,5s)-1-naphthalen-1-yl-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC=C2C([C@@]34CNC[C@H]4C3)=CC=CC2=C1 JXCCCXJMHZUFOM-IUODEOHRSA-N 0.000 claims 1
- QGLYIJQWOLIXCL-UHFFFAOYSA-N 1-(6-methoxynaphthalen-2-yl)-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC2=CC(OC)=CC=C2C=C1C1(CNC2)C2C1 QGLYIJQWOLIXCL-UHFFFAOYSA-N 0.000 claims 1
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Description
本出願は、2005年7月25日出願の米国仮出願第60/703,364号の優先権を主張し、その開示は、参照により全てが本明細書に組み入れられる。
式I
Arは、ハロゲン、C1〜C3アルキル、C2〜C4アルケニル、C2〜C4アルキニル、ハロ(C1〜C3)アルキル、シアノ、ヒドロキシ、C3〜C5シクロアルキル、C1〜C3アルコキシ、C1〜C3アルコキシ(C1〜C3)アルキル、カルボキシ(C1〜C3)アルキル、C1〜C3アルカノイル、ハロ(C1〜C3)アルコキシ、ニトロ、アミノ、C1〜C3アルキルアミノ、およびジ(C1〜C3)アルキルアミノから独立して選択される二つの置換基で置換されたフェニル基であり;
R1およびR2は、水素、非置換のC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニル、ならびに置換基が一つまたは複数のヒドロキシ、シアノ、ハロゲン、C1〜C6アルコキシ、アリール置換C1〜C6アルコキシ、アリールオキシ、一つまたは複数のハロゲンで置換されたアリールオキシ、C1〜C6アルキル、一つまたは複数のシアノおよびハロゲンで独立して置換されたC1〜C6アルキル、C1〜C4アルコキシ、ならびにC1〜C4ハロアルコキシである、置換したC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニルから独立して選択され;かつ
R3は、水素、C1〜C6アルキル、C1〜C6アルコキシカルボニル、C2〜C6アルカノイル、C3〜C8シクロアルキル、C4〜C9シクロアルカノイル、アリール、ヘテロアリール、飽和複素環、C2〜C10アルケニル、C2〜C10アルキニル、ならびに置換基が一つまたは複数のシアノ、ハロゲン、ヒドロキシ、C1〜C6アルコキシ、C1〜C6アルコキシカルボニル、C2〜C6アルキルオキシカルボニルオキシ、C1〜C6アルカノイル、C1〜C6アルカノイルオキシ、C3〜C8シクロアルキル、C3〜C8シクロアルキルオキシ、C4〜C9シクロアルカノイル、アリール、アリールオキシ、ヘテロアリール、および飽和複素環である置換したC1〜C6アルキル、C2〜C10アルケニル、およびC2〜C10アルキニルから選択され;ただしArが3,4-ジクロロフェニルの時は、R3は水素であってはならない。
式II
R1およびR2は、水素、非置換のC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニル、ならびに置換基が一つまたは複数のヒドロキシ、シアノ、ハロゲン、C1〜C6アルコキシ、アリール置換C1〜C6アルコキシ、アリールオキシ、一つまたは複数のハロゲンで置換されたアリールオキシ、C1〜C6アルキル、一つまたは複数のシアノおよびハロゲンで独立して置換されたC1〜C6アルキル、C1〜C4アルコキシ、ならびにC1〜C4ハロアルコキシである、置換したC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニルから独立して選択され;
R3は、水素、C1〜C6アルキル、C1〜C6アルコキシカルボニル、C2〜C6アルカノイル、C3〜C8シクロアルキル、C4〜C9シクロアルカノイル、アリール、ヘテロアリール、飽和複素環、C2〜C10アルケニル、C2〜C10アルキニル、ならびに置換基が一つまたは複数のシアノ、ハロゲン、ヒドロキシ、C1〜C6アルコキシ、C1〜C6アルコキシカルボニル、C2〜C6アルキルオキシカルボニルオキシ、C1〜C6アルカノイル、C1〜C6アルカノイルオキシ、C3〜C8シクロアルキル、C3〜C8シクロアルキルオキシ、C4〜C9シクロアルカノイル、アリール、アリールオキシ、ヘテロアリール、および飽和複素環である、置換したC1〜C6アルキル、C2〜C10アルケニル、およびC2〜C10アルキニルから選択され;かつ
R4およびR5は、独立して水素またはハロゲン、C1〜C3アルキル、C2〜C4アルケニル、C2〜C4アルキニル、ハロ(C1〜C3)アルキル、シアノ、ヒドロキシ、C3〜C5シクロアルキル、C1〜C3アルコキシ、C1〜C3アルコキシ(C1〜C3)アルキル、カルボキシ(C1〜C3)アルキル、C1〜C3アルカノイル、ハロ(C1〜C3)アルコキシ、ニトロ、アミノ、C1〜C3アルキルアミノ、およびジ(C1〜C3)アルキルアミノから独立して選択される1〜4個の置換基である。
式III
R1およびR2は、水素、非置換のC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニル、ならびに置換基が一つまたは複数のヒドロキシ、シアノ、ハロゲン、C1〜C6アルコキシ、アリール置換C1〜C6アルコキシ、アリールオキシ、一つまたは複数のハロゲンで置換されたアリールオキシ、C1〜C6アルキル、一つまたは複数のシアノおよびハロゲンで独立して置換されたC1〜C6アルキル、C1〜C4アルコキシ、ならびにC1〜C4ハロアルコキシである、置換したC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニルから独立して選択され;
R3は、水素、C1〜C6アルキル、C1〜C6アルコキシカルボニル、C2〜C6アルカノイル、C3〜C8シクロアルキル、C4〜C9シクロアルカノイル、アリール、ヘテロアリール、飽和複素環、C2〜C10アルケニル、C2〜C10アルキニル、ならびに置換基が一つまたは複数のシアノ、ハロゲン、ヒドロキシ、C1〜C6アルコキシ、C1〜C6アルコキシカルボニル、C2〜C6アルキルオキシカルボニルオキシ、C1〜C6アルカノイル、C1〜C6アルカノイルオキシ、C3〜C8シクロアルキル、C3〜C8シクロアルキルオキシ、C4〜C9シクロアルカノイル、アリール、アリールオキシ、ヘテロアリール、および飽和複素環である、置換したC1〜C6アルキル、C2〜C10アルケニル、およびC2〜C10アルキニルから選択され;かつ
R4およびR5は、独立して水素、またはハロゲン、C1〜C3アルキル、C2〜C4アルケニル、C2〜C4アルキニル、ハロ(C1〜C3)アルキル、シアノ、ヒドロキシ、C3〜C5シクロアルキル、C1〜C3アルコキシ、C1〜C3アルコキシ(C1〜C3)アルキル、カルボキシ(C1〜C3)アルキル、C1〜C3アルカノイル、ハロ(C1〜C3)アルコキシ、ニトロ、アミノ、C1〜C3アルキルアミノ、およびジ(C1〜C3)アルキルアミノから独立して選択される1〜4個の置換基である。
式I
Arは、ハロゲン、C1〜C3アルキル、C2〜C4アルケニル、C2〜C4アルキニル、ハロ(C1〜C3)アルキル、シアノ、ヒドロキシ、C3〜C5シクロアルキル、C1〜C3アルコキシ、C1〜C3アルコキシ(C1〜C3)アルキル、カルボキシ(C1〜C3)アルキル、C1〜C3アルカノイル、ハロ(C1〜C3)アルコキシ、ニトロ、アミノ、C1〜C3アルキルアミノ、およびジ(C1〜C3)アルキルアミノから独立して選択される二つの置換基で置換されたフェニル基であり;
R1およびR2は、水素、非置換のC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニル、ならびに置換基は一つまたは複数のヒドロキシ、シアノ、ハロゲン、C1〜C6アルコキシ、アリール置換C1〜C6アルコキシ、アリールオキシ、一つまたは複数のハロゲンで置換されたアリールオキシ、C1〜C6アルキル、一つまたは複数のシアノおよびハロゲンで独立して置換されたC1〜C6アルキル、C1〜C4アルコキシ、ならびにC1〜C4ハロアルコキシである、置換したC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニルから独立して選択され;かつ
R3は、水素、C1〜C6アルキル、C1〜C6アルコキシカルボニル、C2〜C6アルカノイル、C3〜C8シクロアルキル、C4〜C9シクロアルカノイル、アリール、ヘテロアリール、飽和複素環、C2〜C10アルケニル、C2〜C10アルキニル、ならびに置換基が一つまたは複数のシアノ、ハロゲン、ヒドロキシ、C1〜C6アルコキシ、C1〜C6アルコキシカルボニル、C2〜C6アルキルオキシカルボニルオキシ、C1〜C6アルカノイル、C1〜C6アルカノイルオキシ、C3〜C8シクロアルキル、C3〜C8シクロアルキルオキシ、C4〜C9シクロアルカノイル、アリール、アリールオキシ、ヘテロアリール、および飽和複素環である置換したC1〜C6アルキル、C2〜C10アルケニル、およびC2〜C10アルキニルから選択され;ただしArが3,4-ジクロロフェニルの時は、R3は水素であってはならない。
式II
R1およびR2は、水素、非置換のC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニル、ならびに置換基が一つまたは複数のヒドロキシ、シアノ、ハロゲン、C1〜C6アルコキシ、アリール置換C1〜C6アルコキシ、アリールオキシ、一つまたは複数のハロゲンで置換されたアリールオキシ、C1〜C6アルキル、一つまたは複数のシアノおよびハロゲンで独立して置換されたC1〜C6アルキル、C1〜C4アルコキシ、ならびにC1〜C4ハロアルコキシである、置換したC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニルから独立して選択され;
R3は、水素、C1〜C6アルキル、C1〜C6アルコキシカルボニル、C2〜C6アルカノイル、C3〜C8シクロアルキル、C4〜C9シクロアルカノイル、アリール、ヘテロアリール、飽和複素環、C2〜C10アルケニル、C2〜C10アルキニル、ならびに置換基が一つまたは複数のシアノ、ハロゲン、ヒドロキシ、C1〜C6アルコキシ、C1〜C6アルコキシカルボニル、C2〜C6アルキルオキシカルボニルオキシ、C1〜C6アルカノイル、C1〜C6アルカノイルオキシ、C3〜C8シクロアルキル、C3〜C8シクロアルキルオキシ、C4〜C9シクロアルカノイル、アリール、アリールオキシ、ヘテロアリール、および飽和複素環である、置換したC1〜C6アルキル、C2〜C10アルケニル、およびC2〜C10アルキニルから選択され;かつ
R4およびR5は、独立して水素またはハロゲン、C1〜C3アルキル、C2〜C4アルケニル、C2〜C4アルキニル、ハロ(C1〜C3)アルキル、シアノ、ヒドロキシ、C3〜C5シクロアルキル、C1〜C3アルコキシ、C1〜C3アルコキシ(C1〜C3)アルキル、カルボキシ(C1〜C3)アルキル、C1〜C3アルカノイル、ハロ(C1〜C3)アルコキシ、ニトロ、アミノ、C1〜C3アルキルアミノ、およびジ(C1〜C3)アルキルアミノから独立して選択される1〜4個の置換基である。
式III
R1およびR2は、水素、非置換のC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニル、ならびに置換基が一つまたは複数のヒドロキシ、シアノ、ハロゲン、C1〜C6アルコキシ、アリール置換C1〜C6アルコキシ、アリールオキシ、一つまたは複数のハロゲンで置換されたアリールオキシ、C1〜C6アルキル、一つまたは複数のシアノおよびハロゲンで独立して置換されたC1〜C6アルキル、C1〜C4アルコキシ、ならびにC1〜C4ハロアルコキシである、置換したC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニルから独立して選択され;
R3は、水素、C1〜C6アルキル、C1〜C6アルコキシカルボニル、C2〜C6アルカノイル、C3〜C8シクロアルキル、C4〜C9シクロアルカノイル、アリール、ヘテロアリール、飽和複素環、C2〜C10アルケニル、C2〜C10アルキニル、ならびに置換基が一つまたは複数のシアノ、ハロゲン、ヒドロキシ、C1〜C6アルコキシ、C1〜C6アルコキシカルボニル、C2〜C6アルキルオキシカルボニルオキシ、C1〜C6アルカノイル、C1〜C6アルカノイルオキシ、C3〜C8シクロアルキル、C3〜C8シクロアルキルオキシ、C4〜C9シクロアルカノイル、アリール、アリールオキシ、ヘテロアリール、および飽和複素環である、置換したC1〜C6アルキル、C2〜C10アルケニル、およびC2〜C10アルキニルから選択され;かつ
R4およびR5は、独立して水素、またはハロゲン、C1〜C3アルキル、C2〜C4アルケニル、C2〜C4アルキニル、ハロ(C1〜C3)アルキル、シアノ、ヒドロキシ、C3〜C5シクロアルキル、C1〜C3アルコキシ、C1〜C3アルコキシ(C1〜C3)アルキル、カルボキシ(C1〜C3)アルキル、C1〜C3アルカノイル、ハロ(C1〜C3)アルコキシ、ニトロ、アミノ、C1〜C3アルキルアミノ、およびジ(C1〜C3)アルキルアミノから独立して選択される1〜4個の置換基である。
式IV
(a)式中のArが上記に定義された通りである次式(i)
(b)式(ii)の化合物を還元して、次式(iii)
(c)式(iii)の化合物を結晶化して1-アリール-3-アザビシクロ[3.1.0]ヘキサン、またはそのエナンチオマーもしくはジアステレオマーを生成する段階を含む方法を提供する。
式IV
(a)式中のArが上記に定義された通りである次式(i)
(b)化合物(ii)を還元して、次式(iii)
(c)式(iii)の化合物を(Boc)2Oと反応させて、次式(iv)
(d)式(iv)の化合物を結晶化させて、次式(v)
(e)式(v)の化合物を脱保護化して次式(vi)
(f)式(vi)の化合物を還元して1-アリール-3-アザビシクロ[3.1.0]ヘキサンを生成する段階を含む方法を提供する。
式V
(a)式中のRが上記の定義通りである次式(vii)の化合物、
(b)式(viii)の化合物をシクロプロパン化して次式(ix)の化合物
(c)式(ix)の化合物を還元して1-アリール-3-アザビシクロ[3.1.0]ヘキサンを生成する段階を含む方法を提供する。
置換1-アリール-3-アザビシクロ[3.1.0]ヘキサンを調製するための合成法
発明の多くの新規1-アリール-3-アザビシクロ[3.1.0]ヘキサンは、当業者に公知である方法によって調製できるが、それらはまた、例えば以下記載の例示的反応スキームによっても生成できる。これら新規スキームは、様々な中間物質および出発原料を用いるが、例示の工程はまた、スキームの中で描かれたものとは異なる構造、置換基のパターン、またはこれら立体化学を有する化合物にも応用できることを理解しなければならない。
アザ-置換-1-(3,4-ジクロロフェニル)-3-アザ-ビシクロ[3,1,0]ヘキサンヒドロクロリド化合物およびそのエナンチオマーの調製
A. 1-(3,4-ジクロロフェニル)-3-メチル-3-アザ-ビシクロ[3.1.0]ヘキサンの合成
本実施例IIのセクションA、B、およびCで合成した上記三種類のラセミ混合物は、次の条件を用いたキラルクロマトグラフィーにかけた:
反応スキーム19を用いた1-(3,4-ジクロロフェニル)-3-プロピル-3-アザビシクロ[3.1.0]ヘキサンヒドロクロリドの調製
反応スキーム13を用いた(1R,5S)-1-(3,4-ジクロロフェニル)-3-プロピル-3-アザビシクロ[3,1,0]ヘキサンヒドロクロリドの調製
反応スキーム13を用いた(1S,5R)-1-(3,4-ジクロロフェニル)-3-プロピル-3-アザビシクロ[3,1,0]ヘキサンヒドロクロリドの調製
反応スキーム19を用いた3-ブチル-1-(3,4-ジクロロフェニル)-3-アザ-ビシクロ[3,1,0]ヘキサンヒドロクロリドの調製
反応スキーム20を用いた3-tert-ブチル-1-(3,4-ジクロロフェニル)-3-アザ-ビシクロ[3,1,0]ヘキサンヒドロクロリドの調製
A. 1-(3,4-ジクロロフェニル)-3-オキソ-ビシクロ[3.1.0]ヘキサン-2,4-ジオンの合成
反応スキーム14を用いた1-アリール-3-メチル-3-アザ-ビシクロ[3.1.0]ヘキサンヒドロクロリドの調製
A. 3-ブロモ-1-メチル-1H-ピロール-2,5-ジオンの合成
反応スキーム14の段階cに従って、以下に3-アリール-1-メチル-ピロール-2,5-ジオンを合成するための一般的手順を示す。N-メチル臭化マレイミド(1,4-ジオキサンの0.5M溶液20mL、正味量1.96g、10mmol)、アリールボロン酸(11mmol、1.1当量)、フッ化セシウム(3.4g、22mmol、2.2当量)、および[1,1’-ビス-(ジフェニルホスフィノ)フェロセン]パラジウム(II)クロリド(0.4g、0.5mmol、5モル%)を40℃で1〜6時間攪拌した。反応液を濾過し、固体を1,4-ジオキサン(5mL)で洗浄し、溶媒を真空で除いた(この段階で、二種類の固体がジクロロメタンによる追加洗浄を必要とした)。残留物をDCM(5mL)内に取り、次にフラッシュシリカクロマトグラフィーカートリッジ(20gシリカ)を通すか、またはカラムクロマトグラフィー(30gシリカ、4:1ヘキサン:酢酸エチル、次に2:1ヘキサン:酢酸エチルで溶出)のいずれかによって精製した。溶媒を真空で取り除き、必要とする組成生物を固体の形で得た。以下に示す化合物(NMRデータも以下に記載する)は、上記一般手順を用いて調製された:
反応スキーム14の段階dに従って、トリメチルスルホキソニウムクロリド(1.2当量)および水素化ナトリウム(鉱油の60%分散液、1.2当量)をTHF(50倍容積)に懸濁し、還流しながら2時間加熱(66℃)した。反応液を50℃まで冷まし、1-メチル-3-(アリール)ピロール-2,5-ジオン(1当量)のTHF(10mL)溶液を一回で加えた。反応液を50℃で2〜4時間加熱し、次に必要に応じて(TLCによる出発材料の消失から判断して)65℃で更に2時間加熱してから室温まで冷却した。IMS(5mL)を加えて反応液を冷却し、真空で溶媒を取り除いた。残留物をDCM(35mL)に取り、水(3x35mL)で洗浄した。一つにまとめた水性洗浄物をDCM(15mL)で逆抽出し、有機部分を一つにまとめ、溶媒を真空で除去した。反応物をカラムクロマトグラフィー(30gシリカ、酢酸エチルのヘキサン溶液の極性分画を増やしながら溶出する)で精製し、溶媒を真空で取り除いて粗固形物として3-メチル-1-(アリール)-3-アザ-ビシクロ[3.1.0]ヘキサン-2,4-ジオンを得た。以下に示す化合物(NMRデータも以下に記載する)は、上記一般手順を用いて調製された:
反応スキーム14の段階eに従って、ボラン(1M錯体のTHF溶液、5当量)を<0℃まで冷却し、3-メチル-1-(アリール)-3-アザ-ビシクロ[3.1.0]ヘキサン-2,4-ジオン(1当量)のTHF溶液(10倍容積)を、温度を<0℃に保ちながら滴下して加えた。反応液を室温で15分間温めてから、加熱(67℃)して2時間還流した。反応液を<0℃まで冷却し、6MのHCl(5倍体積、温度を<0℃に維持)を滴下して加えて急冷した。溶媒を真空で除去し、生じた白色の残留物を、5MのNaOH(25mL)を加えて塩基性にし、DCM(2x20mL)で抽出した。有機物を水(3x30mL)で洗浄し、次に真空で〜1mL体積まで濃縮した。生じた油をカラムクロマトグラフィー(15gシリカ、DCM、次に5%MeOHのDCM溶液で溶出)で精製し、粗遊離塩基を得た。サンプルはジエチルエーテル(1mL)に溶解し、1MのHClのエーテル(10mL)溶液を加えた。生じた白色の沈殿物は、-20℃で16時間保存してから遠心分離にかけた。エーテルをデカンテーションして、固体は更に三回に分けたエーテルで洗浄した(洗浄する度に遠心分離で物質を単離し、エーテルをデカンテーションした)。物質を真空、30℃で乾燥させて、必要生成物を白色の固体として得た。以下に示す化合物(NMRデータも以下に記載する)は、上記一般手順を用いて調製された:
反応スキーム15を用いた1-アリール-3-エチル-3-アザ-ビシクロ[3.1.0]ヘキサンヒドロクロリドの調製
A. 3-ブロモ-1-エチルマレイミドの合成
反応スキーム16を用いた1-アリール-3-イソプロピル-3-アザ-ビシクロ[3.1.0]ヘキサンヒドロクロリドの調製
A. 3-ブロモ-1-(1-メチルエチル)マレイミドの合成
反応スキーム17を用いた1-アリール-3-アザビシクロ[3.1.0]ヘキサンヒドロクロリドの調製
A. 3-ブロモ-1(3,4-ジメトキシベンジル)マレイミドの合成
。
反応スキーム4を用いた1-アリール-3-アザ-ビシクロ[3.1.0]ヘキサンヒドロクロリドの調製
A. 1-(3-フルオロ-4-トリフルオロメトキシフェニル)-3-アザビシクロ[3.1.0]ヘキサンヒドロクロリドの合成
反応スキーム11を用いた1-アリール-3-メチル-3-アザ-ビシクロ[3.1.0]ヘキサンの調製
A. 3-メチル-1-(ナフタレン-1-イル)-3-アザビシクロ[3.1.0]ヘキサンヒドロクロリドの合成
反応スキーム5、6、および13を用いた1-アリール-3-アザ-ビシクロ[3.1.0]ヘキサンおよび1-アリール-3-メチル-3-アザ-ビシクロ[3.1.0]ヘキサンの調製
A. シクロプロパンカルボニトリルの合成
(1) (1)〜(6)の代表的手順としての(1S,2R)-2-ヒドロキシメチル-1-ナフチル-シクロプロパンカルボニトリルの合成
(1) (1)〜(6)の代表的手順としての(1R,2S)-(2-アミノメチル-2-(1-ナフチル)シクロプロピル)-メタノールの合成
(1) (1)〜(6)の代表的手順としての1S,5R-(-)-(1-ナフチル)-3-アザビシクロ[3.1.0]ヘキサンヒドロクロリドの合成
-クロロ-3-トリフルオロメチルフェニル)シクロプロピル)-メタノール(2.35g、8.4mmol)のジクロロメタン(DCE)50mLの溶液に、室温、窒素下で、注射器を用いて温度を40℃以下に保ちながら、SOCl2を0.8mL(10.1mmoles、1.3当量)ゆっくり加えた。生じた反応液を室温で2時間攪拌し、その後のTLC分析(SiO2プレート、CH2Cl2/MeOH/NH4OH(20:1:0.1〜10:1:0.1))は出発材料を示さなかった。混合液は水125mLを用いて急冷し、CH2Cl2(75mL)で希釈して2〜3分間攪拌し、静置して層を分離した。有機層はH2O(75mL)で洗浄した。水層を一つにまとめ、10NのNaOHを用いてpH=10(pH試験紙)に塩基性化し、2x100mLのCH2Cl2で抽出した。一つにまとめた有機物をNa2SO4で乾燥し、濾過、濃縮して油を得た。油をMeOH(40mL)に溶解し、20mlの 2M HCl/Et2Oで処理し、真空で総体積〜5〜10mLに濃縮して、30mLのEt2Oおよび5mLのヘプタンで希釈した。生じたスラリーを濾過し、35mLの冷Et2Oで洗浄した。固体生成物を一晩乾燥させ(〜29mmHg、50℃)、白色の固体として純粋生成物を1.8g(72%)得た。1H NMR(400MHz、CDCl3)δ1.01-1.07(m、1H)、1.13-1.18(m、1H)、1.77-1.85(m、1H)、3.19-3.33(m、3H)、3.42(d、J=11.13Hz、1H)、5.10(br.s、2H)、7.29(dd、J~8.20、2.15Hz、1H)、7.42(d、J=8.40Hz、1H)、7.47(d、J=2.34Hz、1H);13C NMR(101MHz、CDCl3)δ15.81、23.59、31.02、47.75、50.68、121.35、124.07、126.38、129.14(d、J=31.45Hz)、131.63(d、J=1.72Hz)、131.94(d、J=0.96Hz)、132.21、137.50、LC/MS(m/z M+1 262.0)、[α]D(c=1、MeOH)、=-54.2。
(1) 1S,5R-(-)-1-(1-ナフチル)-3-メチル-3-アザビシクロ[3.1.0]ヘキサンヒドロクロリド
反応スキーム21を用いた1-アリール-4-メチル-3-アザ-ビシクロ[3.1.0]ヘキサンの調製
A. (±)-1-(3,4-ジクロロ-フェニル)-(r/s)-2-ヒドロキシメチル-シクロプロパンカルボニトリルの調製
バイアルに上記実施例XV F由来の化合物130mg、ジエチルエーテル1mL、および2NのHClのジエチルエーテル溶液0.2mLを加えた。白色の沈殿が直ぐに出現し、懸濁液を室温で1時間攪拌した。懸濁液を濾過し、集め、乾燥して白色の固体18mgを得た。LCMS(+)ESI:m/z=242[MH]+(100);244[MH+2]+(65);UV(λmax=218)=95%;1H NMR(300MHz、MeOH-d4)δ7.48-52(m、2H、ArH)、7.23-26(m、1H、ArH)、4.63(s(br)、2H、NH2)、3.93(q、1H、J=7Hz、CHCH3)、3.68(m、2H、CH2N)、2.08(dd、1H、J=8Hz、5Hz、CHCH2)、1.45(m、3H、CHCH3)、1.29(m、1H、CH)、1.16(m、2H、ArCCH2)。
反応スキーム22を用いた1-アリール-4-メチル-3-アザ-ビシクロ[3.1.0]ヘキサンおよび1-アリール-3,4-ジメチル-3-アザ-ビシクロ[3.1.0]ヘキサンの調製
A. (±)-5-(3’,4’-ジクロロフェニル)-3-アザ-ビシクロ[3.1.0]ヘキサン-2-オンの調製
反応スキーム23を用いた1-アリール-2-メチル-3-アザ-ビシクロ[3.1.0]ヘキサンおよび1-アリール-2,3-ジメチル-3-アザ-ビシクロ[3.1.0]ヘキサンの調製
A. (±)-1-(3,4-ジクロロ-フェニル)-3-アザ-ビシクロ[3.1.0]ヘキサン-2-オンの調製
1.21(m、1H、ArCCH2)、1.14(d、3H、J=7Hz、CH3)、1.01(m、1H、ArCCH2)。
反応スキーム24を用いた1-アリール-2-メチル-3-アザ-ビシクロ[3.1.0]ヘキサンおよび1-アリール2,3-ジメチル-3-アザ-ビシクロ[3.1.0]ヘキサンの調製
A. (±)-1-(3,4-ジクロロ-フェニル)-2-メチル-3-アザ-ビシクロ[3.1.0]ヘキサン-2-エンの調製
95%;1HNMR(300MHz、CDCl3)δ:7.40(d、1H、J=8Hz、ArH)、7.35(d、1H、J=2Hz、ArH)、7.10(dd、1H、J=8Hz、J=2Hz、ArH)、4.09(m、1H、CH2N)、3.80(d、1H、CH2N)、2.09(m、1H、CH2CH)、1.92(m、3H、CH3)、1.44(dd、1H、J=12Hz、4Hz、ArCCH2)、0.60(t、1H、J=4Hz、ArCCH2)。
頂部セット:バイアルに、上記の頂部セット分画から得た黄色の油50mg、ジエチルエーテル0.5mL、および2NのHClのジエチルエーテル0.12mLを加えた。直ちに白色の沈殿が現れ、懸濁液を周囲温度で1時間半攪拌した。懸濁液を濾過し、集め、乾燥させて白色の固体を55mg得た。
頂部セット:(+)ESI:m/z=256[MH]+(100)、258[MH+2]+(65);UV(λmax=218)=99%;底部:(+)ESI:m/z=256〔MH〕+(100)、258〔MH+2〕+(65);UV(λmax=218)=99%
頂部セット:(300MHz、CDCl3)δ:7.45(d、1H、J=9Hz、ArH)、7.40(m、1H、ArH)、7.14(dd、1H、J=9Hz、J=1Hz、ArH)、4.07(dd、1H、J=25Hz、J=6Hz、CH2N)、3.77(q、2H、CH2N、CHCH3)、2.88(d、3H、J=5Hz、NCH3)、2.29(m、1H、CHCH2)、1.89(q、1H、J=5Hz、ArCCH2)、1.56-65(m、3H、CHCH3)、1.24(t、1H、J=8Hz、ArCCH2);底部セット:(300MHz、CDCl3)δ:7.43(d、1H、J=9Hz、ArH)、7.4(d、1H、J=2Hz、ArH)、7.14(dd、1H、J=9Hz、J=2Hz、ArH)、4.06(d、1H、J=11Hz、CH2N)、3.77(m、1H、CHCH3)、3.30(m、1H、CHCH3)、2.88(s、3H、NCH3)、2.30(m、1H、CHCH2)、1.88(q、1H、J=4Hz、ArCCH2)、1.63(d、3H、J=7Hz、CHCH3)、1.23(t、1H、J=8、ArCCH2).
頂部セット:(75MHz、MeOH-d4)δ:139.6、132.4、132.1、130.3、70.2、58.8、39.6、37.1、23.4、12.3、11.3
底部セット:バイアルに、上記実施例XVII Bに記載した底部セット分画から得た白色の固体47mg、ジエチルエーテル1.0mL、および2NのHClのジエチルエーテル溶液0.12mLを加えた。EtOH(0.5mL)を加えて均一な溶液を得た。直ぐに黄色の沈殿が現れ、懸濁液を周囲温度で1時間半攪拌した。懸濁液を濾過し、集め、乾燥させて黄色の固体を40mg得た。LCMS底部セット:(+)ESI:m/z=256[MH]+(100)、258[MH+2]+(65);UV(λmax=218)=99%;1HNMR 底部セット:(300MHz、MeOH-d4)δ:7.68(m、1H、ArH)、7.54(d、1H、J=8Hz、ArH)、7.40(m、1H、ArH)、3.97(q、1H、J=6Hz、CH2N)、3.76(m、1H、CH2N)、2.99(m、3H、NCH3)、2.0(m、1H、CHCH3)、1.37(d、3H、J=9Hz、CHCH3 )、1.30(t、1H、J=5Hz、ArCCH2)、1.21(m、1H、ArCCH2)
モノアミン神経伝達物質取込に関する本発明の例示的化合物の効果
本発明の例示的化合物の、ノルエピネフィリン(NE)、ドーパミン(DA)、およびセロトニン(5-HT)の細胞取込への作用を、以下に参照する、既に報告されている技術を用いて、各種ラット脳領域からのシナプトソーム標本について試験した。
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Claims (33)
- 次式IIの化合物、ならびにそのエナンチオマーおよび薬学的に許容しうる塩であって、
式II
R1およびR2は、水素、非置換のC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニル、ならびに置換基が一つまたは複数のヒドロキシ、シアノ、ハロゲン、C1〜C6アルコキシ、アリール置換C1〜C6アルコキシ、アリールオキシ、一つまたは複数のハロゲンで置換されたアリールオキシ、C1〜C6アルキル、一つまたは複数のシアノおよびハロゲンで独立して置換されたC1〜C6アルキル、C1〜C4アルコキシ、ならびにC1〜C4ハロアルコキシである、置換したC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニルから独立して選択され;
R3は、水素、C1〜C6アルキル、C1〜C6アルコキシカルボニル、C2〜C6アルカノイル、C3〜C8シクロアルキル、C4〜C9シクロアルカノイル、アリール、ヘテロアリール、飽和複素環、C2〜C10アルケニル、C2〜C10アルキニル、ならびに置換基が一つまたは複数のシアノ、ハロゲン、ヒドロキシ、C1〜C6アルコキシ、C1〜C6アルコキシカルボニル、C2〜C6アルキルオキシカルボニルオキシ、C1〜C6アルカノイル、C1〜C6アルカノイルオキシ、C3〜C8シクロアルキル、C3〜C8シクロアルキルオキシ、C4〜C9シクロアルカノイル、アリール、アリールオキシ、ヘテロアリール、および飽和複素環である、置換したC1〜C6アルキル、C2〜C10アルケニル、およびC2〜C10アルキニルから選択され;かつ
R4およびR5は、独立して水素またはハロゲン、C1〜C3アルキル、C2〜C4アルケニル、C2〜C4アルキニル、ハロ(C1〜C3)アルキル、シアノ、ヒドロキシ、C3〜C5シクロアルキル、C1〜C3アルコキシ、C1〜C3アルコキシ(C1〜C3)アルキル、カルボキシ(C1〜C3)アルキル、C1〜C3アルカノイル、ハロ(C1〜C3)アルコキシ、ニトロ、アミノ、C1〜C3アルキルアミノ、およびジ(C1〜C3)アルキルアミノから独立して選択される1〜4個の置換基である化合物、ならびにそのエナンチオマーおよび薬学的に許容しうる塩。 - R4およびR5、水素、またはメチル、エチル、フルオロ、クロロ、トリフルオロメチル、シアノ、ニトロ、メトキシ、エトキシ、およびトリフルオロメトキシから独立して選択される1〜4置換基である、請求項1記載の化合物。
- R1およびR2は水素であり、R3は水素、メチル、エチル、またはイソプロピルであり、R4およびR5は水素、メチル、クロロ、フルオロ、プロピル、メトキシ、およびエトキシから独立して選択される、請求項1記載の化合物。
- 1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
(1R,5S)−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
(1S,5R)−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
3−メチル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
(1R,5S)−3−メチル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−メチル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
3−エチル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
3−イソプロピル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
(1R,5S)−3−イソプロピル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−イソプロピル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
1−(2−メトキシナフタレン−6−イル)−3−アザビシクロ[3.1.0]ヘキサン;
1−(2−メトキシナフタレン−6−イル)−3−メチル−3−アザ−ビシクロ[3.1.0]ヘキサン;
1−(2−エトキシナフタレン−6−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;および
1−(2−エトキシナフタレン−6−イル)−3−メチル−3−アザ−ビシクロ[3.1.0]ヘキサン、ならびに薬学的に許容しうるその塩、エナンチオマー、多形体、溶媒和物、および水和物から成る群より選択される、請求項3記載の化合物。 - 1−(2−メトキシナフタレン−6−イル)−3−メチル−3−アザ−ビシクロ[3.1.0]ヘキサン、ならびに薬学的に許容しうるその塩およびエナンチオマーである、請求項4記載の化合物。
- (1R,5S)−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサンおよび薬学的に許容しうるその塩である、請求項4記載の化合物。
- (1S,5R)−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサンおよび薬学的に許容しうるその塩である、請求項4記載の化合物。
- (1R,5S)−3−メチル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサンおよびその薬学的に許容しうるその塩である、請求項4記載の化合物。
- (1S,5R)−3−メチル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサンおよびその薬学的に許容しうるその塩である、請求項4記載の化合物。
- 3−イソプロピル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン、ならびに薬学的に許容しうるその塩およびエナンチオマーである、請求項4記載の化合物。
- 3−エチル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン、ならび薬学的に許容しうるその塩およびエナンチオマーである、請求項4記載の化合物。
- 実質的にその対応する(−)エナンチオマーを含まない、請求項1〜11のいずれか1項に記載の単離された(+)エナンチオマー。
- 実質的にその対応する(+)エナンチオマーを含まない、請求項1〜11のいずれか1項に記載の単離された(−)エナンチオマー。
- 有効量の請求項1〜13のいずれか1項に記載の化合物、および薬学的に許容しうるその担体またはビークルを含む薬学的組成物。
- 有効量の請求項1〜13のいずれか1項に記載の化合物、および薬学的に許容しうるその担体またはビークルを含む、CNS障害を処理または防止する、あるいはCNS障害に関連する一つまたは複数の症状を緩和するための薬学的組成物。
- CNS障害は抑鬱である、請求項15記載の薬学的組成物。
- CNS障害は不安障害である、請求項15記載の薬学的組成物。
- CNS障害は注意欠損障害である、請求項15記載の薬学的組成物。
- 次式IIIの化合物、ならびにそのエナンチオマーおよび薬学的に許容しうる塩であって、
式III
R1およびR2は、水素、非置換のC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニル、ならびに置換基が一つまたは複数のヒドロキシ、シアノ、ハロゲン、C1〜C6アルコキシ、アリール置換C1〜C6アルコキシ、アリールオキシ、一つまたは複数のハロゲンで置換されたアリールオキシ、C1〜C6アルキル、一つまたは複数のシアノおよびハロゲンで独立して置換されたC1〜C6アルキル、C1〜C4アルコキシ、ならびにC1〜Cハロアルコキシである、置換したC1〜C10アルキル、C3〜C10アルケニル、およびC3〜C10アルキニルから独立して選択され;
R3は、水素、C1〜C6アルキル、C1〜C6アルコキシカルボニル、C2〜C6アルカノイル、C3〜C8シクロアルキル、C4〜C9シクロアルカノイル、アリール、ヘテロアリール、飽和複素環、C2〜C10アルケニル、C2〜C10アルキニル、ならびに置換基が一つまたは複数のシアノ、ハロゲン、ヒドロキシ、C1〜C6アルコキシ、C1〜C6アルコキシカルボニル、C2〜C6アルキルオキシカルボニルオキシ、C1〜C6アルカノイル、C1〜C6アルカノイルオキシ、C3〜C8シクロアルキル、C3〜C8シクロアルキルオキシ、C4〜C9シクロアルカノイル、アリール、アリールオキシ、ヘテロアリール、および飽和複素環である、置換したC1〜C6アルキル、C2〜C10アルケニル、およびC2〜C10アルキニルから選択され;かつ
R4およびR5は、独立して水素、またはハロゲン、C1〜C3アルキル、C2〜C4アルケニル、C2〜C4アルキニル、ハロ(C1〜C3)アルキル、シアノ、ヒドロキシ、C3〜C5シクロアルキル、C1〜C3アルコキシ、C1〜C3アルコキシ(C1〜C3)アルキル、カルボキシ(C1〜C3)アルキル、C1〜C3アルカノイル、ハロ(C1〜C3)アルコキシ、ニトロ、アミノ、C1〜C3アルキルアミノ、およびジ(C1〜C3)アルキルアミノから独立して選択される1〜4個の置換基である化合物、ならびにエナンチオマーおよび薬学的に許容しうる塩。 - R4およびR5は、メチル、エチル、フルオロ、クロロ、トリフルオロメチル、シアノ、ニトロ、メトキシ、エトキシ、およびトリフルオロメトキシから独立して選択される、請求項19記載の化合物。
- R1およびR2は水素であり、R3は水素、メチル、エチル、またはイソプロピルであり、R4およびR5は水素、メチル、クロロ、フルオロ、プロピル、メトキシ、およびエトキシから独立して選択される、請求項20記載の化合物。
- 1−(ナフタレン−1−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
(1R,5S)−1−(ナフタレン−1−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
(1S,5R)−1−(ナフタレン−1−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
3−メチル−1−(ナフタレン−1−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
(1R,5S)−3−メチル−1−(ナフタレン−1−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−メチル−1−(ナフタレン−1−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
1−(1−フルオロナフタレン−4−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;
1−(1−フルオロナフタレン−4−イル)−3−メチル−3−アザ−ビシクロ[3.1.0]ヘキサン;
1−(1−メチルナフタレン−4−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;および
3−メチル−1−(1−メチルナフタレン−4−イル)−3−アザ−ビシクロ[3.1.0]ヘキサンから成る群から選択される請求項14記載の化合物、ならびに薬学的に許容しうるその塩、エナンチオマー、多形体、溶媒和物、および水和物。 - 実質的にその対応する(−)エナンチオマーを含まない、請求項19〜22のいずれか1項に記載の単離された(+)エナンチオマー。
- 実質的にその対応する(+)エナンチオマーを含まない、請求項19〜22のいずれか1項に記載の単離された(−)エナンチオマー。
- 有効量の請求項19〜24のいずれか1項に記載の化合物、および薬学的に許容しうるその担体またはビークルを含む薬学的組成物。
- 有効量の請求項19〜24のいずれか1項に記載の化合物、および薬学的に許容しうるその担体またはビークルを含む、CNS障害を処理または防止する、あるいはCNS障害に関連する一つまたは複数の症状を緩和するための薬学的組成物。
- CNS障害は抑鬱である、請求項26記載の薬学的組成物。
- CNS障害は不安障害である、請求項26記載の薬学的組成物。
- CNS障害は注意欠損障害である、請求項26記載の薬学的組成物。
- 1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;(1R,5S)−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;(1S,5R)−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;3−メチル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;(1R,5S)−3−メチル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;(1S,5R)−3−メチル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;3−エチル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;3−イソプロピル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;(1R,5S)−3−イソプロピル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;(1S,5R)−3−イソプロピル−1−(ナフタレン−2−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;1−(2−メトキシナフタレン−6−イル)−3−アザビシクロ[3.1.0]ヘキサン;1−(2−メトキシナフタレン−6−イル)−3−メチル−3−アザ−ビシクロ[3.1.0]ヘキサン;1−(2−エトキシナフタレン−6−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;および1−(2−エトキシナフタレン−6−イル)−3−メチル−3−アザ−ビシクロ[3.1.0]ヘキサンから成る群より選択される化合物、または薬学的に許容しうるその塩、エナンチオマー、多形体、溶媒和物、および水和物を有効量、ならびに薬学的に許容しうる担体または賦形剤を含む、ノルエピネフィリン、セロトニン、おおびドーパミンから選択される一種類または複数の生体アミン神経伝達物質の哺乳動物被験体における細胞取込みを阻害するのに有効である神経生物学的に活性な化合物。
- 細胞取込は、哺乳動物細胞または組織内で阻害される、請求項30記載の神経生物学的に活性な化合物。
- 1−(ナフタレン−1−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;(1R,5S)−1−(ナフタレン−1−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;(1S,5R)−1−(ナフタレン−1−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;3−メチル−1−(ナフタレン−1−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;(1R,5S)−3−メチル−1−(ナフタレン−1−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;(1S,5R)−3−メチル−1−(ナフタレン−1−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;1−(1−フルオロナフタレン−4−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;1−(1−フルオロナフタレン−4−イル)−3−メチル−3−アザ−ビシクロ[3.1.0]ヘキサン;1−(1−メチルナフタレン−4−イル)−3−アザ−ビシクロ[3.1.0]ヘキサン;および3−メチル−1−(1−メチルナフタレン−4−イル)−3−アザ−ビシクロ[3.1.0]ヘキサンから成る群から選択される化合物、または薬学的に許容しうるその塩、エナンチオマー、多形体、溶媒和物、および水和物を有効量、ならびに薬学的に許容しうる担体または賦形剤を含む、ノルエピネフィリン、セロトニン、およびドーパミンから選択される一種類または複数の生体アミン神経伝達物質の哺乳動物被験体における細胞取込みを阻害するのに有効である神経生物学的に活性な化合物。
- 細胞取込は、哺乳動物細胞または組織内で阻害される、請求項32記載の神経生物学的に活性な化合物。
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