JP6124154B2 - 置換ピラゾロ[1,5−a]ピリジン、その製造方法及び薬剤としての使用 - Google Patents
置換ピラゾロ[1,5−a]ピリジン、その製造方法及び薬剤としての使用 Download PDFInfo
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- JP6124154B2 JP6124154B2 JP2014558095A JP2014558095A JP6124154B2 JP 6124154 B2 JP6124154 B2 JP 6124154B2 JP 2014558095 A JP2014558095 A JP 2014558095A JP 2014558095 A JP2014558095 A JP 2014558095A JP 6124154 B2 JP6124154 B2 JP 6124154B2
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- JP
- Japan
- Prior art keywords
- pyridin
- tetrahydropyrazolo
- pyrazolo
- maleate
- yloxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000000034 method Methods 0.000 title claims description 41
- 239000003814 drug Substances 0.000 title claims description 14
- DVUBDHRTVYLIPA-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine Chemical class C1=CC=CN2N=CC=C21 DVUBDHRTVYLIPA-UHFFFAOYSA-N 0.000 title description 9
- 238000002360 preparation method Methods 0.000 title description 7
- 230000008569 process Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 146
- -1 aliphatic radical Chemical class 0.000 claims description 79
- 238000006243 chemical reaction Methods 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 125000004122 cyclic group Chemical group 0.000 claims description 21
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 239000003960 organic solvent Substances 0.000 claims description 19
- 108010085082 sigma receptors Proteins 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 150000007529 inorganic bases Chemical class 0.000 claims description 16
- 208000004454 Hyperalgesia Diseases 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
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- 125000003118 aryl group Chemical group 0.000 claims description 14
- 150000003254 radicals Chemical class 0.000 claims description 13
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- 230000036407 pain Effects 0.000 claims description 9
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
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- BMBFOANWIRSBRT-JQUKZVPISA-N (4ar,8as)-2-(4-pyrazolo[1,5-a]pyridin-2-yloxybutyl)-3,4,4a,5,6,7,8,8a-octahydro-1h-isoquinoline;(z)-but-2-enedioic acid Chemical compound OC(=O)\C=C/C(O)=O.C1=C2C=CC=CN2N=C1OCCCCN1C[C@H]2CCCC[C@@H]2CC1 BMBFOANWIRSBRT-JQUKZVPISA-N 0.000 claims description 2
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- IFMNCHZFPFUABL-KAMYIIQDSA-N (Z)-2-[4-[2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yloxy)ethyl]-1,4-oxazepan-2-yl]but-2-enedioic acid Chemical compound C1CCN2C(=CC(=N2)OCCN3CCCOC(C3)/C(=C/C(=O)O)/C(=O)O)C1 IFMNCHZFPFUABL-KAMYIIQDSA-N 0.000 claims description 2
- RQXPFWLOOUJPLW-SSZFMOIBSA-N (Z)-2-[4-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yloxy)butyl]-1,4-oxazepan-2-yl]but-2-enedioic acid Chemical compound C1CCN2C(=CC(=N2)OCCCCN3CCCOC(C3)/C(=C/C(=O)O)/C(=O)O)C1 RQXPFWLOOUJPLW-SSZFMOIBSA-N 0.000 claims description 2
- LDMNOEUNZHKACQ-SPIKMXEPSA-N (Z)-but-2-enedioic acid 2-[4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.C1CN(C)CCC1N1CCN(CCCCOc2cc3ccccn3n2)CC1 LDMNOEUNZHKACQ-SPIKMXEPSA-N 0.000 claims description 2
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- YLCQWTZJIRKJRL-SPIKMXEPSA-N (z)-but-2-enedioic acid;1'-(2-pyrazolo[1,5-a]pyridin-2-yloxyethyl)spiro[1h-2-benzofuran-3,4'-piperidine] Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.C1=C2C=CC=CN2N=C1OCCN1CCC2(C3=CC=CC=C3CO2)CC1 YLCQWTZJIRKJRL-SPIKMXEPSA-N 0.000 claims description 2
- MFPXSDWQBOFGAY-BTJKTKAUSA-N (z)-but-2-enedioic acid;1'-[2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yloxy)ethyl]spiro[1h-2-benzofuran-3,4'-piperidine] Chemical compound OC(=O)\C=C/C(O)=O.C1=C2CCCCN2N=C1OCCN1CCC2(C3=CC=CC=C3CO2)CC1 MFPXSDWQBOFGAY-BTJKTKAUSA-N 0.000 claims description 2
- SOYUZJUMFMUPLN-BTJKTKAUSA-N (z)-but-2-enedioic acid;1'-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yloxy)butyl]spiro[1h-2-benzofuran-3,4'-piperidine] Chemical compound OC(=O)\C=C/C(O)=O.C1=C2CCCCN2N=C1OCCCCN1CCC2(C3=CC=CC=C3CO2)CC1 SOYUZJUMFMUPLN-BTJKTKAUSA-N 0.000 claims description 2
- BVDCVPPUHHVWQS-BTJKTKAUSA-N (z)-but-2-enedioic acid;1-[4-[3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yloxy)propyl]piperazin-1-yl]ethanone Chemical compound OC(=O)\C=C/C(O)=O.C1CN(C(=O)C)CCN1CCCOC1=NN2CCCCC2=C1 BVDCVPPUHHVWQS-BTJKTKAUSA-N 0.000 claims description 2
- PIMLDMJTMORURW-BTJKTKAUSA-N (z)-but-2-enedioic acid;1-[4-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yloxy)butyl]piperazin-1-yl]ethanone Chemical compound OC(=O)\C=C/C(O)=O.C1CN(C(=O)C)CCN1CCCCOC1=NN2CCCCC2=C1 PIMLDMJTMORURW-BTJKTKAUSA-N 0.000 claims description 2
- SNGUDNYFPMIVMA-BTJKTKAUSA-N (z)-but-2-enedioic acid;2-(2-pyrazolo[1,5-a]pyridin-2-yloxyethyl)-3,4-dihydro-1h-isoquinoline Chemical compound OC(=O)\C=C/C(O)=O.C1=C2C=CC=CN2N=C1OCCN1CC2=CC=CC=C2CC1 SNGUDNYFPMIVMA-BTJKTKAUSA-N 0.000 claims description 2
- ZJHHWWIGNJYUIB-BTJKTKAUSA-N (z)-but-2-enedioic acid;2-(2-pyrrolidin-1-ylethoxymethyl)pyrazolo[1,5-a]pyridine Chemical compound OC(=O)\C=C/C(O)=O.C1=C2C=CC=CN2N=C1COCCN1CCCC1 ZJHHWWIGNJYUIB-BTJKTKAUSA-N 0.000 claims description 2
- HFKIFXISIXWUKC-BTJKTKAUSA-N (z)-but-2-enedioic acid;2-(3-piperidin-1-ylpropoxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine Chemical compound OC(=O)\C=C/C(O)=O.C1=C2CCCCN2N=C1OCCCN1CCCCC1 HFKIFXISIXWUKC-BTJKTKAUSA-N 0.000 claims description 2
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- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
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- PVYVHLQBJZUTTE-UHFFFAOYSA-N n-methyl-4-pyrazolo[1,5-a]pyridin-2-yloxy-n-(pyridin-4-ylmethyl)butan-1-amine;dihydrochloride Chemical compound Cl.Cl.C1=C2C=CC=CN2N=C1OCCCCN(C)CC1=CC=NC=C1 PVYVHLQBJZUTTE-UHFFFAOYSA-N 0.000 claims description 2
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- QVTCTFKPAHYAAN-UHFFFAOYSA-N oxalic acid;2-(4-piperidin-1-ylbutoxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine Chemical compound OC(=O)C(O)=O.C1=C2CCCCN2N=C1OCCCCN1CCCCC1 QVTCTFKPAHYAAN-UHFFFAOYSA-N 0.000 claims description 2
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- 230000006698 induction Effects 0.000 description 1
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- 230000002427 irreversible effect Effects 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
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- 239000001630 malic acid Substances 0.000 description 1
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- 102000006240 membrane receptors Human genes 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 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
- 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 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
- 210000000653 nervous system Anatomy 0.000 description 1
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- 230000000324 neuroprotective effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000000944 neurotransmitter response Effects 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 125000005485 noradamantyl group Chemical group 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- PFPYHYZFFJJQFD-UHFFFAOYSA-N oxalic anhydride Chemical compound O=C1OC1=O PFPYHYZFFJJQFD-UHFFFAOYSA-N 0.000 description 1
- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical compound C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- AYGNAOBAPQNTIL-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine-2-carboxylic acid Chemical compound C1=CC=CN2N=C(C(=O)O)C=C21 AYGNAOBAPQNTIL-UHFFFAOYSA-N 0.000 description 1
- LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical class N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 230000023252 regulation of cell development Effects 0.000 description 1
- 230000025053 regulation of cell proliferation Effects 0.000 description 1
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- LGQCVMYAEFTEFN-VUCTXSBTSA-N skf 10047 Chemical compound C1C2=CC=C(O)C=C2[C@]2(C)[C@@H](C)[C@@H]1N(CC=C)CC2 LGQCVMYAEFTEFN-VUCTXSBTSA-N 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
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- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
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- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
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- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
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- 230000002936 tranquilizing effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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Classifications
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Landscapes
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- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
シグマ受容体に対して薬理活性を有し、効果的かつ選択的であり、優れた「ドラッガビリティ」特性、すなわち、投与、分布、代謝及び排泄に関する優れた薬理学的性質を有する化合物を見出すことが今も要求されている。
又はR1及びR2は、架橋窒素と一緒にN、O若しくはSから選択される環メンバーとしての少なくとも1個の追加のヘテロ原子を含んでいてもよく、置換されていてもよいC3−9シクロアルキルを形成し、
又はR1及びR2は、架橋窒素と一緒にN、O若しくはSから選択される環メンバーとしての少なくとも1個の追加のヘテロ原子を含んでいてもよいC3−9シクロアルキルを形成し、これは、N、O若しくはSから選択される環メンバーとしての少なくとも1個のヘテロ原子を含んでいてもよい他のC3−9シクロアルキルと縮合して環系を形成するか、アリールラジカルと縮合して環系を形成するか、アリール若しくはヘテロアリール基とスピロ融合していてもよく;
R3は、水素又はハロゲンを表し;
nは、0、1又は2であり;
mは、1、2、3又は4であり;
−−−−−は、任意の二重結合を表し;
R1及びR2が架橋窒素と一緒にクロロフェニル、ジクロロフェニル又はメトキシフェニルでN−置換されたピペラジニルラジカルを形成する場合、R3は水素であり、nは0であり、mは4ではなく;
R1及びR2が架橋窒素と一緒にピペリジンを形成する場合、R3は水素であり、nは0であり、mは3ではない)の化合物、又はその薬学的に許容される塩、異性体、プロドラッグ、若しくは溶媒和物に関する。
2−((4−(4−tert−ブチルピペリジン−1−イル)ブトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−((2−(アゼパン−1−イル)エトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
N−(シクロプロピルメチル)−N−プロピル−4−(ピラゾロ[1,5−a]ピリジン−2−イルメチルピラゾロ[1,5−a]ピリジン−2−イルメトキシ)ブタン−1−アミンマレイン酸塩;
2−(4−(ピラゾロ[1,5−a]ピリジン−2−イルメチルピラゾロ[1,5−a]ピリジン−2−イルメトキシ)ブチル)−1,2,3,4−テトラヒドロイソキノリンマレイン酸塩;
N−アダマンチル−4−(ピラゾロ[1,5−a]ピリジン−2−イルメチルピラゾロ[1,5−a]ピリジン−2−イルメトキシ)ブタン−1−アミンマレイン酸塩;
1’−(4−(ピラゾロ[1,5−a]ピリジン−2−イルメチルピラゾロ[1,5−a]ピリジン−2−イルメトキシ)ブチル)−3H−スピロ[イソベンゾフラン−1,4’−ピペリジン]マレイン酸塩;
2−((2−(ピロリジン−1−イル)エトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−((4−(アゼパン−1−イル)ブトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−((4−(4−メチルピペラジン−1−イル)ブトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−((4−(4−シクロヘキシルピペラジン−1−イル)ブトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
1−(4−(4−(ピラゾロ[1,5−a]ピリジン−2−イルメチルピラゾロ[1,5−a]ピリジン−2−イルメトキシ)ブチル)ピペラジン−1−イル)エタノン;
1−ベンジル−N−メチル−N−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)ピペリジン−4−アミン二フマル酸塩;
4−(2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)モルホリン;
2−(2−(ピペリジン−1−イル)エトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
2−(2−(ピロリジン−1−イル)エトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
N,N−ジエチル−2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エタンアミンシュウ酸塩;
4−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)モルホリンシュウ酸塩;
2−(4−(ピペリジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
N,N−ジエチル−4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンシュウ酸塩;
2−(4−(ピロリジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
2−(4−(4−フェニルピペリジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
N−ベンジル−N−メチル−4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンシュウ酸塩;
2−(4−(4−フェノキシピペリジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
N−ベンジル−N−メチル−2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エタンアミンシュウ酸塩;
2−(4−(4−フェニルピペラジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
2−(4−(4−(ナフタレン−2−イル)ピペリジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジン;
1’−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)−3H−スピロ[イソベンゾフラン−1,4’−ピペリジン]シュウ酸塩;
2−(4−(4−シクロヘキシルピペラジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジン2−(4−(4−シクロヘキシルピペラジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジン二マレイン酸塩;
2−(4−(4−tert−ブチルピペリジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジン塩酸塩;
N−メチル−N−フェネチル−4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミン塩酸塩;
N−メチル−4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)−N−(ピリジン−4−イルメチル)ブタン−1−アミン二塩酸塩;
2−(4−(1,4’−ビピペリジン−1’−イル)ブトキシ)ピラゾロ[1,5−a]ピリジン二フマル酸塩;
2−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)デカヒドロイソキノリンフマル酸塩;
N−(シクロプロピルメチル)−N−プロピル−4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンマレイン酸塩;
2−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)−1,2,3,4−テトラヒドロイソキノリンマレイン酸塩;
N−アダマンチル−4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)−ブタン−1−アミンマレイン酸塩;
2−(4−(4−(1−メチルピペリジン−4−イル)ピペラジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジン二マレイン酸塩;
2−(2−(4−tert−ブチルピペリジン−1−イル)エトキシ)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
N−メチル−N−フェネチル−2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エタンアミンマレイン酸塩;
1−ベンジル−N−メチル−N−(2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)ピペリジン−4−アミン二マレイン酸塩;
2−(2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)デヒドロイソキノリンマレイン酸塩;
N−(シクロプロピルメチル)−N−(2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)プロパン−1−アミンマレイン酸塩;
2−(2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)−1,2,3,4−テトラヒドロイソキノリンマレイン酸塩;
2−(2−(1,4’−ビピペリジン−1’−イル)エトキシ)ピラゾロ[1,5−a]ピリジン二マレイン酸塩;
2−(2−(4−(1−メチルピペリジン−4−イル)ピペラジン−1−イル)エトキシ)ピラゾロ[1,5−a]ピリジン二マレイン酸塩;
2−(2−(4−シクロヘキシルピペラジン−1−イル)エトキシ)ピラゾロ[1,5−a]ピリジン二マレイン酸塩;
1’−(2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)−3H−スピロ[イソベンゾフラン−1,4’−ピペリジン]二マレイン酸塩;
2−(4−(アゼパン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
N−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)シクロヘキサンアミンマレイン酸塩;
(4aR,8aS)−2−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)デカヒドロイソキノリンマレイン酸塩;
2−(2−(4−エチルピペラジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(2−(アゼパン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(2−(ピペリジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンシュウ酸塩;
N,N−ジエチル−2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エタンアミンシュウ酸塩;
4−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)モルホリンシュウ酸塩;
4−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)モルホリンシュウ酸塩;
2−(2−(ピロリジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンシュウ酸塩;
2−(4−(ピロリジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンシュウ酸塩;
2−(4−(ピペリジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンシュウ酸塩;
2−(4−(ピペリジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
N,N−ジエチル−4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンシュウ酸塩;
2−(4−(4−フェニルピペリジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンシュウ酸塩;
N−ベンジル−N−メチル−2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エタンアミンシュウ酸塩;
2−(4−(4−tert−ブチルピペリジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(2−(4−tert−ブチルピペリジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
1−ベンジル−N−メチル−N−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)ピペリジン−4−アミン二マレイン酸塩;
2−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)デカヒドロイソキノリンマレイン酸塩;
2−(4−(4−シクロヘキシルピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
1’−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)−3H−スピロ[イソベンゾフラン−1,4’−ピペリジン]マレイン酸塩;
2−(2−(4−シクロヘキシルピペラジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
1−ベンジル−N−メチル−N−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)ピペリジン−4−アミンマレイン酸塩;
2−(2−(4−(1−メチルピペリジン−4−イル)ピペラジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
1’−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)−3H−スピロ[イソベンゾフラン−1,4’−ピペリジン]マレイン酸塩;
N−アダマンチル−2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エタンアミンマレイン酸塩;
2−(2−(1,4’−ビピペリジン−1’−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)−1,2,3,4−テトラヒドロイソキノリンマレイン酸塩;
2−(4−(アゼパン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(4−(1,4’−ビピペリジン−1’−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
N−(シクロプロピルメチル)−N−プロピル−4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンマレイン酸塩;
(4aR,8aS)−2−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)デカヒドロイソキノリンマレイン酸塩;
N−ベンジル−N−メチル−4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンマレイン酸塩;
N−アダマンチル−4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンマレイン酸塩;
2−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)−1,2,3,4−テトラヒドロイソキノリンマレイン酸塩;
N−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)シクロヘキサンアミンマレイン酸塩;
4−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)チオモルホリンマレイン酸塩;
(4aR,8aS)−2−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)デカヒドロイソキノリンマレイン酸塩;
4−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)−1,4−オキサゼパンマレイン酸塩;
4−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)−1,4−オキサゼパンマレイン酸塩;
N−(シクロプロピルメチル)−N−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)プロパン−1−アミンマレイン酸塩;
2−(2−(4−イソプロピルピペラジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(4−(4−イソプロピルピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(4−(4−メチルピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(4−((3S,5R)−3,5−ジメチルピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
1−(4−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)ピペラジン−1−イル)エタノンマレイン酸塩;
2−(4−(4−メチル−1,4−ジアゼパン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(3−(4−メチルピペラジン−1−イル)プロポキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(4−(4−エチルピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(3−(ピペリジン−1−イル)プロポキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(3−(4−シクロヘキシルピペラジン−1−イル)プロポキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
4−(3−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)プロピル)−1,4−オキサゼパン;
2−(4−(4−(テトラヒドロ−2H−ピラン−4−イル)ピペラジン−1−イル)ブチルテトラヒドロ−2H−ピラン−4−イル)ピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ [1,5−a]ピリジンマレイン酸塩;
1−(4−(3−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)プロピル)ピペラジン−1−イル)エタノンマレイン酸塩;
4−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)チオモルホリンマレイン酸塩;
2−(4−(4−tert−ブチルピペリジン−1−イル)ブトキシ)−3−クロロ−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
3−クロロ−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−オールからの3−クロロ−2−(4−クロロブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン;
2−(4−(4−tert−ブチルピペリジン−1−イル)ブトキシ)−3−クロロ−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
N−ベンジル−2−(3−ヨードピラゾロ[1,5−a]ピリジン−2−イルオキシ)−N−メチルエタンアミンシュウ酸塩;
N−ベンジル−2−(3−ヨード−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)−N−メチルエタンアミンシュウ酸塩;
3−クロロ−2−(4−(4−シクロヘキシルピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン、又はそれらの薬学的に許容される塩、立体異性体、溶媒和物、若しくはプロドラッグ。
一般式(I)(nは0とは違い、R3=H、以下のスキームIを参照)の化合物の製造方法について説明する。方法Aは、一般式(Ia)の化合物及び/又は一般式(Ib)の化合物を得るのに適している。
スキームI
方法Bは、nが0であり、R3が水素であり、一般式(Ic)及び(Id)の化合物をもたらす一般式(I)の化合物の調製法を示す(スキームII)。
スキームII
R3がハロゲンである式(I)の化合物は、X2又はハロスクシンイミド(NXS)を用いた直接ハロゲン化により、式(Ia)、(Ib)、(Ic)若しくは(Id)(R3=H)のそれぞれの化合物から、又は例えばスキームIIIに従って調製することができる。
スキームIII
実施例1:2−((4−(4−tert−ブチルピペリジン−1−イル)ブトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩の合成
1a. ピラゾロ[1,5−a]ピリジン−2−イルメタノールの合成
1H NMR(CDCl3)δ ppm:8.40(d,J=7.1Hz,1H),7.51(d,J=8.9Hz,1H),7.18−7.04(m,1H),6.74(td,J=6.9,1.3Hz,1H),6.49(s,1H),6.27(s,2H),4.69(s,2H),3.69−3.50(m,4H),3.05−2.89(m,2H),2.58−2.42(m,2H),1.76(ddd,J=19.7,19.3,10.6Hz,8H),1.33−1.02(m,1H),0.87(s,9H).
2−((2−(アゼパン−1−イル)エトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩の合成
実施例12:1−ベンジル−N−メチル−N−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)ピペリジン−4−アミン二フマル酸塩の合成
12a. 2−(4−クロロブトキシ)ピラゾロ[1,5−a]ピリジンの合成
1H NMR(DMSO)δ ppm:8.43(d,J=6.9Hz,1H),7.43(d,J=8.9Hz,1H),7.37−7.20(m,5H),7.20−7.06(m,1H),6.71(t,J=6.9Hz,1H),6.58(s,4H),5.95(s,1H),4.20(t,J=6.3Hz,2H),3.46(s,2H),2.94−2.79(m,2H),2.75−2.60(m,3H),2.35(s,3H),1.95(t,J=11.2Hz,2H),1.82−1.66(m,4H),1.66−1.39(m,4H).
1H NMR(DMSO)δ ppm:8.46(d,J=6.9Hz,1H),7.46(d,J=8.9Hz,1H),7.26−7.09(m,1H),6.74(td,J=6.9,1.4Hz,1H),6.00(s,1H),4.41(t,J=5.3Hz,2H),3.74−3.60(m,4H),3.07(t,J=5.2Hz,2H),2.92−2.66(m,4H).
実施例52:2−(2−(4−エチルピペラジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩の合成
52a. 4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−オールの合成
1H NMR(CDCl3)δ ppm:5.32(s,1H),3.91(t,J=6.1Hz,2H),2.69(t,J=6.3Hz,2H),2.06−1.91(m,2H),1.86−1.69(m,2H).
1H NMR(CDCl3)δ ppm:6.28(s,2H),5.36(s,1H),4.29−4.21(m,2H),3.93(t,J=6.1Hz,2H),3.58−3.36(m,2H),3.25−3.08(m,2H),3.09−2.97(m,2H),2.97−2.80(m,6H),2.69(t,J=6.4Hz,2H),2.06−1.93(m,2H),1.87−1.73(m,2H),1.37(t,J=7.3Hz,3H).
1H NMR(CDCl3)δ ppm:6.28(s,2H),5.36(s,1H),4.55−4.44(m,2H),3.93 (t,J=6.1Hz,2H),3.77 − 3.53(m,2H),3.55−3.45(m,2H),3.23−3.05(m,2H),2.70(t,J=6.3Hz,2H),2.09−1.87(m,6H),1.87−1.47(m,6H).
実施例105. 2−(4−(4−tert−ブチルピペリジン−1−イル)ブトキシ)−3−クロロ−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩の合成
105a. 3−クロロ−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−オールの合成
1H NMR(CDCl3)δ ppm:3.91(t,J=6.0Hz,2H),2.66(t,J=6.3Hz,2H),2.09−1.92(m,2H),1.90−1.75(m,2H).
1H NMR(CDCl3)δ ppm:6.26(s,2H),4.22(t,J=5.6Hz,2H),3.91(t,J=6.0Hz,2H),3.77−3.59(m,2H),3.20−2.98(m,2H),2.64(t,J=6.4Hz,2H),2.65−2.46(m,2H),2.09−1.64(m,12H),1.31−1.12(m,1H),0.88(s,9H).
脳膜の準備、及びσ1−受容体の結合アッセイは、(DeHaven−Hudkins,D.L,L.C.Fleissner,and F.Y.Ford−Rice,1992,Characterization of the binding of[3H]−(+)−pentazocine to σ recognition sites in guinea pig brain,Eur.J.Pharmacol.227,371−378)の記載を多少修正して実施した。テンジクネズミの脳を、Tris−HCl 50mM/0.32Mスクロースの10vol(w/v)バッファー(pH7.4)中で、Kinematica Polytron PT3000を用いて15000r.p.m.で30秒間均質化した。ホモジネートを4℃で1000g、10分間遠心し、上清を回収し、再度、4℃で48000g、15分間遠心した。沈殿物を10倍量のTris−HClバッファー(50mM,pH7.4)で再懸濁し、37℃で30分間インキュベートし、4℃で48000g、20分間遠心した。次いで、沈殿物を新しいTris−HClバッファー(50mM,pH7.4)で再懸濁し、使用するまで氷上で保存した。
Claims (17)
- 一般式(I)
(式中、R1及びR2は独立して水素;分岐若しくは非分岐の、飽和若しくは不飽和の少なくとも一置換されていてもよい脂肪族ラジカルC1−10;置換若しくは非置換のアリール;置換若しくは非置換のヘテロアリールラジカル;N、O又はSから選択される環メンバーとしての少なくとも1個のヘテロ原子を含んでいてもよい、置換若しくは非置換のC3−9シクロアルキルラジカル;シクロアルキルアルキルラジカルC1−10;アリールアルキルラジカルC1−10:又はヘテロアリールアルキルラジカルC1−10を表わし;
又はR1及びR2は、架橋窒素と一緒にN、O若しくはSから選択される環メンバーとしての少なくとも1個の追加のヘテロ原子を含んでいてもよく、置換されていてもよいC3−9シクロアルキルを形成し、
又はR1及びR2は、架橋窒素と一緒にN、O若しくはSから選択される環メンバーとしての少なくとも1個の追加のヘテロ原子を含んでいてもよく、置換されていてもよいC3−9シクロアルキルを形成し、これは、N、O若しくはSから選択される環メンバーとしての少なくとも1個の追加のヘテロ原子を含んでいてもよい他のC3−9シクロアルキルと縮合して環系を形成するか、アリールラジカルと縮合して環系を形成するか、アリール若しくはヘテロアリール基とスピロ融合していてもよく;
R3は、水素又はハロゲンを表し;
nは、0、1又は2であり;
mは、1、2、3又は4であり;
−−−−−は、任意の結合を表し;
R1及びR2が架橋窒素と一緒にクロロフェニル、ジクロロフェニル又はメトキシフェニルでN−置換されたピペラジニルラジカルを形成する場合、R3は水素であり、nは0であり、mは1、2、又は3であり;
R1及びR2が架橋窒素と一緒にピペリジンを形成する場合、R3は水素であり、nは0であり、mは1、2、又は4である)の化合物、又はその薬学的に許容される塩、若しくは溶媒和物。 - R1及びR2が、独立して水素;分岐若しくは非分岐の、飽和若しくは不飽和の少なくとも一置換されていてもよい脂肪族ラジカルC1−10;N、O又はSから選択される環メンバーとしての少なくとも1個のヘテロ原子を含んでいてもよい、置換若しくは非置換のC3−9シクロアルキルラジカル;シクロアルキルアルキルラジカルC1−10;アリールアルキルラジカルC1−10:又はヘテロアリールアルキルラジカルC1−10を表わす、請求項1記載の化合物。
- R1及びR2が、独立して、水素、メチル、エチル、プロピル、又は
(式中、pは1又は2である)から選択される基を表す、請求項1又は2記載の化合物。 - R1及びR2が、架橋窒素と一緒にN、O又はSから選択される環メンバーとしての少なくとも1個の追加のヘテロ原子を含んでいてもよいC3−9シクロアルキルを形成し、これは、メチル、エチル、イソプロピル、tertブチル、又は
(式中、R’はC 1−6アルキルである)から選択される基で置換されていてもよい、請求項1記載の化合物。 - R1及びR2が、架橋窒素と一緒に以下の構造の一つを表す、請求項1又は4記載の化合物。
- R1及びR2が、架橋窒素と一緒に、C3−9シクロアルキルを形成し、これは他の環又は環系と縮合又はスピロ縮合し、以下の構造の一つを形成する、請求項1記載の化合物。
- 以下から選択される、請求項1〜6のいずれか1項記載の化合物。
2−((4−(4−tert−ブチルピペリジン−1−イル)ブトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−((2−(アゼパン−1−イル)エトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
N−(シクロプロピルメチル)−N−プロピル−4−(ピラゾロ[1,5−a]ピリジン−2−イルメチルピラゾロ[1,5−a]ピリジン−2−イルメトキシ)ブタン−1−アミンマレイン酸塩;
2−(4−(ピラゾロ[1,5−a]ピリジン−2−イルメチルピラゾロ[1,5−a]ピリジン−2−イルメトキシ)ブチル)−1,2,3,4−テトラヒドロイソキノリンマレイン酸塩;
N−アダマンチル−4−(ピラゾロ[1,5−a]ピリジン−2−イルメチルピラゾロ[1,5−a]ピリジン−2−イルメトキシ)ブタン−1−アミンマレイン酸塩;
1’−(4−(ピラゾロ[1,5−a]ピリジン−2−イルメチルピラゾロ[1,5−a]ピリジン−2−イルメトキシ)ブチル)−3H−スピロ[イソベンゾフラン−1,4’−ピペリジン]マレイン酸塩;
2−((2−(ピロリジン−1−イル)エトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−((4−(アゼパン−1−イル)ブトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−((4−(4−メチルピペラジン−1−イル)ブトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−((4−(4−シクロヘキシルピペラジン−1−イル)ブトキシ)メチル)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
1−(4−(4−(ピラゾロ[1,5−a]ピリジン−2−イルメチルピラゾロ[1,5−a]ピリジン−2−イルメトキシ)ブチル)ピペラジン−1−イル)エタノン;
1−ベンジル−N−メチル−N−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)ピペリジン−4−アミン二フマル酸塩;
4−(2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)モルホリン;
2−(2−(ピペリジン−1−イル)エトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
2−(2−(ピロリジン−1−イル)エトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
N,N−ジエチル−2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エタンアミンシュウ酸塩;
4−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)モルホリンシュウ酸塩;
2−(4−(ピペリジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
N,N−ジエチル−4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンシュウ酸塩;
2−(4−(ピロリジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
2−(4−(4−フェニルピペリジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
N−ベンジル−N−メチル−4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンシュウ酸塩;
2−(4−(4−フェノキシピペリジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
N−ベンジル−N−メチル−2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エタンアミンシュウ酸塩;
2−(4−(4−フェニルピペラジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジンシュウ酸塩;
2−(4−(4−(ナフタレン−2−イル)ピペリジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジン;
1’−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)−3H−スピロ[イソベンゾフラン−1,4’−ピペリジン]シュウ酸塩;
2−(4−(4−シクロヘキシルピペラジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジン2−(4−(4−シクロヘキシルピペラジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジン二マレイン酸塩;
2−(4−(4−tert−ブチルピペリジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジン塩酸塩;
N−メチル−N−フェネチル−4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミン塩酸塩;
N−メチル−4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)−N−(ピリジン−4−イルメチル)ブタン−1−アミン二塩酸塩;
2−(4−(1,4’−ビピペリジン−1’−イル)ブトキシ)ピラゾロ[1,5−a]ピリジン二フマル酸塩;
2−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)デカヒドロイソキノリンフマル酸塩;
N−(シクロプロピルメチル)−N−プロピル−4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンマレイン酸塩;
2−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)−1,2,3,4−テトラヒドロイソキノリンマレイン酸塩;
N−アダマンチル−4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)−ブタン−1−アミンマレイン酸塩;
2−(4−(4−(1−メチルピペリジン−4−イル)ピペラジン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジン二マレイン酸塩;
2−(2−(4−tert−ブチルピペリジン−1−イル)エトキシ)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
N−メチル−N−フェネチル−2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エタンアミンマレイン酸塩;
1−ベンジル−N−メチル−N−(2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)ピペリジン−4−アミン二マレイン酸塩;
2−(2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)デヒドロイソキノリンマレイン酸塩;
N−(シクロプロピルメチル)−N−(2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)プロパン−1−アミンマレイン酸塩;
2−(2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)−1,2,3,4−テトラヒドロイソキノリンマレイン酸塩;
2−(2−(1,4’−ビピペリジン−1’−イル)エトキシ)ピラゾロ[1,5−a]ピリジン二マレイン酸塩;
2−(2−(4−(1−メチルピペリジン−4−イル)ピペラジン−1−イル)エトキシ)ピラゾロ[1,5−a]ピリジン二マレイン酸塩;
2−(2−(4−シクロヘキシルピペラジン−1−イル)エトキシ)ピラゾロ[1,5−a]ピリジン二マレイン酸塩;
1’−(2−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)−3H−スピロ[イソベンゾフラン−1,4’−ピペリジン]二マレイン酸塩;
2−(4−(アゼパン−1−イル)ブトキシ)ピラゾロ[1,5−a]ピリジンマレイン酸塩;
N−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)シクロヘキサンアミンマレイン酸塩;
(4aR,8aS)−2−(4−(ピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)デカヒドロイソキノリンマレイン酸塩;
2−(2−(4−エチルピペラジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(2−(アゼパン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(2−(ピペリジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンシュウ酸塩;
N,N−ジエチル−2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エタンアミンシュウ酸塩;
4−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)モルホリンシュウ酸塩;
4−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)モルホリンシュウ酸塩;
2−(2−(ピロリジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンシュウ酸塩;
2−(4−(ピロリジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンシュウ酸塩;
2−(4−(ピペリジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンシュウ酸塩;
2−(4−(ピペリジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
N,N−ジエチル−4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンシュウ酸塩;
2−(4−(4−フェニルピペリジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンシュウ酸塩;
N−ベンジル−N−メチル−2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エタンアミンシュウ酸塩;
2−(4−(4−tert−ブチルピペリジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(2−(4−tert−ブチルピペリジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
1−ベンジル−N−メチル−N−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)ピペリジン−4−アミン二マレイン酸塩;
2−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)デカヒドロイソキノリンマレイン酸塩;
2−(4−(4−シクロヘキシルピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
1’−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)−3H−スピロ[イソベンゾフラン−1,4’−ピペリジン]マレイン酸塩;
2−(2−(4−シクロヘキシルピペラジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
1−ベンジル−N−メチル−N−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)ピペリジン−4−アミンマレイン酸塩;
2−(2−(4−(1−メチルピペリジン−4−イル)ピペラジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
1’−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)−3H−スピロ[イソベンゾフラン−1,4’−ピペリジン]マレイン酸塩;
N−アダマンチル−2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エタンアミンマレイン酸塩;
2−(2−(1,4’−ビピペリジン−1’−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)−1,2,3,4−テトラヒドロイソキノリンマレイン酸塩;
2−(4−(アゼパン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(4−(1,4’−ビピペリジン−1’−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
N−(シクロプロピルメチル)−N−プロピル−4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンマレイン酸塩;
(4aR,8aS)−2−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)デカヒドロイソキノリンマレイン酸塩;
N−ベンジル−N−メチル−4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンマレイン酸塩;
N−アダマンチル−4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブタン−1−アミンマレイン酸塩;
2−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)−1,2,3,4−テトラヒドロイソキノリンマレイン酸塩;
N−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)シクロヘキサンアミンマレイン酸塩;
4−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)チオモルホリンマレイン酸塩;
(4aR,8aS)−2−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)デカヒドロイソキノリンマレイン酸塩;
4−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)−1,4−オキサゼパンマレイン酸塩;
4−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)−1,4−オキサゼパンマレイン酸塩;
N−(シクロプロピルメチル)−N−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)プロパン−1−アミンマレイン酸塩;
2−(2−(4−イソプロピルピペラジン−1−イル)エトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(4−(4−イソプロピルピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(4−(4−メチルピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(4−((3S,5R)−3,5−ジメチルピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
1−(4−(4−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)ブチル)ピペラジン−1−イル)エタノンマレイン酸塩;
2−(4−(4−メチル−1,4−ジアゼパン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(3−(4−メチルピペラジン−1−イル)プロポキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(4−(4−エチルピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(3−(ピペリジン−1−イル)プロポキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
2−(3−(4−シクロヘキシルピペラジン−1−イル)プロポキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
4−(3−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)プロピル)−1,4−オキサゼパン;
2−(4−(4−(テトラヒドロ−2H−ピラン−4−イル)ピペラジン−1−イル)ブチルテトラヒドロ−2H−ピラン−4−イル)ピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ [1,5−a]ピリジンマレイン酸塩;
1−(4−(3−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)プロピル)ピペラジン−1−イル)エタノンマレイン酸塩;
4−(2−(4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)エチル)チオモルホリンマレイン酸塩;
2−(4−(4−tert−ブチルピペリジン−1−イル)ブトキシ)−3−クロロ−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
3−クロロ−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−オールからの3−クロロ−2−(4−クロロブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン;
2−(4−(4−tert−ブチルピペリジン−1−イル)ブトキシ)−3−クロロ−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジンマレイン酸塩;
N−ベンジル−2−(3−ヨードピラゾロ[1,5−a]ピリジン−2−イルオキシ)−N−メチルエタンアミンシュウ酸塩;
N−ベンジル−2−(3−ヨード−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン−2−イルオキシ)−N−メチルエタンアミンシュウ酸塩;
3−クロロ−2−(4−(4−シクロヘキシルピペラジン−1−イル)ブトキシ)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリジン。 - 薬剤として使用するための請求項1〜7のいずれか1項記載の化合物。
- シグマ受容体を介する疾患又は病状の治療又は予防に使用するための請求項1〜7のいずれか1項記載の化合物であって、前記疾患又は病状が、痛み、特に、神経性疼痛、炎症疼痛、又は異痛症及び/若しくは痛覚過敏に関連するその他の疼痛症状、下痢、リポタンパク質異常、脂質異常症、高トリグリセリド血症、高コレステロール血症、肥満、片頭痛、関節炎、高血圧、不整脈、潰瘍、緑内障、学習障害、記憶障害、注意力欠陥、認知障害、神経変性疾患、脱髄疾患、コカイン、アンフェタミン、エタノール及びニコチンを含む薬物及び化学物質中毒;遅発性ジスキネジー、てんかん、脳卒中、ストレス、がん、精神病状態、特にうつ病、不安神経症又は統合失調症;炎症又は自己免疫疾患である、請求項1〜7のいずれか1項記載の化合物。
- 上記異痛症が、機械的アロディニア又は熱的アロディニアである、請求項9記載の化合物。
- 神経性疼痛が痛覚過敏である、請求項9記載の化合物。
- 一般式(Ia)又は(Ib)の化合物を調製する方法であって、
有機又は無機塩基の存在下、活性化剤としてNaIの任意の存在下に、有機溶媒中で、それぞれ一般式(IIa)又は(IIb)の化合物を、一般式(III)の化合物と反応させることを含む方法。
(式中、R1、R2、n及びmは、請求項1と同じ意味を有し、Yは脱離基である) - 一般式(Ia)又は(Ib)の化合物を調製する方法であって、
有機又は無機塩基の存在下、活性化剤としてNaIの任意の存在下に、有機溶媒中で、それぞれ一般式(IVa)及び(IVb)の化合物を、一般式(V)の化合物と反応させることを含む方法。
(式中、R1、R2、n及びmは、請求項1と同じ意味を有し、Xは脱離基である) - 一般式(Ic)又は(Id)の化合物を調製する方法であって、
有機又は無機塩基の存在下、活性化剤としてNaIの任意の存在下に、水又は有機溶媒中で、それぞれ一般式(IIc)及び(IId)の化合物を、一般式(III)の化合物と反応させることを含む方法。
(式中、R1、R2及びmは、請求項1と同じ意味を有し、Yは脱離基である) - 一般式(Ic)又は(Id)の化合物を調製する方法であって、
有機又は無機塩基の存在下、活性化剤としてNaIの任意の存在下に、有機溶媒中で、それぞれ一般式(IVc)及び(IVd)の化合物を、一般式(V)の化合物と反応させることを含む方法。
(式中、R1、R2及びmは、請求項1と同じ意味を有し、Xは脱離基である) - 一般式(Ie)の化合物を調製する方法であって、
式(VII)の化合物を、X2又はハロスクシンイミドにより直接ハロゲン化することを含む方法。
(式中、R1、R2、n及びmは、請求項1と同じ意味を有し、Xはハロゲンである)
- 請求項1〜7のいずれか1項記載の一般式(I)の化合物、又はその薬学的に許容される塩、若しくは溶媒和物と、少なくとも1種の薬学的に許容される担体、添加剤、補助剤又は媒体とを含む医薬組成物。
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