JP2017503765A - ガバペンチノイドおよびシグマ受容体の組み合わせ - Google Patents
ガバペンチノイドおよびシグマ受容体の組み合わせ Download PDFInfo
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- JP2017503765A JP2017503765A JP2016536584A JP2016536584A JP2017503765A JP 2017503765 A JP2017503765 A JP 2017503765A JP 2016536584 A JP2016536584 A JP 2016536584A JP 2016536584 A JP2016536584 A JP 2016536584A JP 2017503765 A JP2017503765 A JP 2017503765A
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- JP
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- Prior art keywords
- dichlorophenyl
- pyrazol
- yloxy
- substituted
- methyl
- 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.)
- Ceased
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- 108010085082 sigma receptors Proteins 0.000 title description 2
- 208000002193 Pain Diseases 0.000 claims abstract description 64
- 230000036407 pain Effects 0.000 claims abstract description 49
- 239000003446 ligand Substances 0.000 claims abstract description 40
- 239000011885 synergistic combination Substances 0.000 claims abstract description 31
- 238000011282 treatment Methods 0.000 claims abstract description 22
- 230000002265 prevention Effects 0.000 claims abstract description 14
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 41
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 229940002612 prodrug Drugs 0.000 claims description 28
- 239000000651 prodrug Substances 0.000 claims description 28
- 239000012453 solvate Substances 0.000 claims description 27
- 230000000202 analgesic effect Effects 0.000 claims description 25
- 229960002870 gabapentin Drugs 0.000 claims description 24
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- -1 morpholine-4-yl group Chemical group 0.000 claims description 22
- 229960001233 pregabalin Drugs 0.000 claims description 22
- 208000004296 neuralgia Diseases 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 208000021722 neuropathic pain Diseases 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 8
- DGPGXHRHNRYVDH-UHFFFAOYSA-N 4-[2-(5-methyl-1-naphthalen-2-ylpyrazol-3-yl)oxyethyl]morpholine Chemical compound N=1N(C=2C=C3C=CC=CC3=CC=2)C(C)=CC=1OCCN1CCOCC1 DGPGXHRHNRYVDH-UHFFFAOYSA-N 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- SHRYQZBTQDMGLZ-UHFFFAOYSA-N 4-[2-(5-methyl-1-naphthalen-2-ylpyrazol-3-yl)oxyethyl]morpholine;hydrochloride Chemical compound Cl.N=1N(C=2C=C3C=CC=CC3=CC=2)C(C)=CC=1OCCN1CCOCC1 SHRYQZBTQDMGLZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000002708 enhancing effect Effects 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- SVRATFOTJLMBDJ-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-5-methyl-3-(2-pyrrolidin-1-ylethoxy)pyrazole Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C)=CC=1OCCN1CCCC1 SVRATFOTJLMBDJ-UHFFFAOYSA-N 0.000 claims description 4
- XKGSRQAKFXSURB-UHFFFAOYSA-N 1-[2-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxyethyl]piperidine Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C)=CC=1OCCN1CCCCC1 XKGSRQAKFXSURB-UHFFFAOYSA-N 0.000 claims description 3
- HLAPBHGJHLAYSD-UHFFFAOYSA-N 4-[2-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxyethyl]morpholine Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C)=CC=1OCCN1CCOCC1 HLAPBHGJHLAYSD-UHFFFAOYSA-N 0.000 claims description 3
- 108090000312 Calcium Channels Proteins 0.000 claims description 3
- 102000003922 Calcium Channels Human genes 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 3
- NWFCYGKUUJSQBC-GASCZTMLSA-N (2r,6s)-4-[4-[1-(3,4-dichlorophenyl)pyrazol-3-yl]oxybutyl]-2,6-dimethylmorpholine Chemical compound C1[C@@H](C)O[C@@H](C)CN1CCCCOC1=NN(C=2C=C(Cl)C(Cl)=CC=2)C=C1 NWFCYGKUUJSQBC-GASCZTMLSA-N 0.000 claims description 2
- ABXFIBVLIGBXTL-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-3-(2-imidazol-1-ylethoxy)-5-methylpyrazole Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C)=CC=1OCCN1C=CN=C1 ABXFIBVLIGBXTL-UHFFFAOYSA-N 0.000 claims description 2
- QRWJBFSZVYNGBO-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-3-(2-imidazol-1-ylethoxy)-5-phenylpyrazole Chemical compound C1=C(Cl)C(Cl)=CC=C1N1C(C=2C=CC=CC=2)=CC(OCCN2C=NC=C2)=N1 QRWJBFSZVYNGBO-UHFFFAOYSA-N 0.000 claims description 2
- WZWRZEMDVNTYDE-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-3-(2-pyrrolidin-1-ylethoxy)pyrazole Chemical compound C1=C(Cl)C(Cl)=CC=C1N1N=C(OCCN2CCCC2)C=C1 WZWRZEMDVNTYDE-UHFFFAOYSA-N 0.000 claims description 2
- WBERJAVNUCODIT-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-3-(3-pyrrolidin-1-ylpropoxy)pyrazole Chemical compound C1=C(Cl)C(Cl)=CC=C1N1N=C(OCCCN2CCCC2)C=C1 WBERJAVNUCODIT-UHFFFAOYSA-N 0.000 claims description 2
- ORJIYYSDOLEENL-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-3-(4-imidazol-1-ylbutoxy)-5-methylpyrazole Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C)=CC=1OCCCCN1C=CN=C1 ORJIYYSDOLEENL-UHFFFAOYSA-N 0.000 claims description 2
- SMFVSSIDEBMGKS-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-3-(4-pyrrolidin-1-ylbutoxy)pyrazole Chemical compound C1=C(Cl)C(Cl)=CC=C1N1N=C(OCCCCN2CCCC2)C=C1 SMFVSSIDEBMGKS-UHFFFAOYSA-N 0.000 claims description 2
- HDGCQFMGTWJBQY-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-4,5-dimethyl-3-(2-pyrrolidin-1-ylethoxy)pyrazole Chemical compound CC1=C(C)N(C=2C=C(Cl)C(Cl)=CC=2)N=C1OCCN1CCCC1 HDGCQFMGTWJBQY-UHFFFAOYSA-N 0.000 claims description 2
- JPEOXNKQTJGJEA-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-4,5-dimethyl-3-(3-pyrrolidin-1-ylpropoxy)pyrazole Chemical compound CC1=C(C)N(C=2C=C(Cl)C(Cl)=CC=2)N=C1OCCCN1CCCC1 JPEOXNKQTJGJEA-UHFFFAOYSA-N 0.000 claims description 2
- CKFICICIBJLUOG-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-5-methyl-3-(3-pyrrolidin-1-ylpropoxy)pyrazole Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C)=CC=1OCCCN1CCCC1 CKFICICIBJLUOG-UHFFFAOYSA-N 0.000 claims description 2
- LUAPJOUYJPEKMR-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-5-methyl-3-(4-pyrrolidin-1-ylbutoxy)pyrazole Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C)=CC=1OCCCCN1CCCC1 LUAPJOUYJPEKMR-UHFFFAOYSA-N 0.000 claims description 2
- YIHOEUXXNWSJFU-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-5-phenyl-3-(2-pyrrolidin-1-ylethoxy)pyrazole Chemical compound C1=C(Cl)C(Cl)=CC=C1N1C(C=2C=CC=CC=2)=CC(OCCN2CCCC2)=N1 YIHOEUXXNWSJFU-UHFFFAOYSA-N 0.000 claims description 2
- CORXGPVXXVKBKZ-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-5-phenyl-3-(3-pyrrolidin-1-ylpropoxy)pyrazole Chemical compound C1=C(Cl)C(Cl)=CC=C1N1C(C=2C=CC=CC=2)=CC(OCCCN2CCCC2)=N1 CORXGPVXXVKBKZ-UHFFFAOYSA-N 0.000 claims description 2
- ZHVGGHRGDGANTC-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-5-propan-2-yl-3-(2-pyrrolidin-1-ylethoxy)pyrazole Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C(C)C)=CC=1OCCN1CCCC1 ZHVGGHRGDGANTC-UHFFFAOYSA-N 0.000 claims description 2
- UMYVOONRBLZJEF-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-5-propan-2-yl-3-(3-pyrrolidin-1-ylpropoxy)pyrazole Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C(C)C)=CC=1OCCCN1CCCC1 UMYVOONRBLZJEF-UHFFFAOYSA-N 0.000 claims description 2
- UOTUAMQAHGZANC-UHFFFAOYSA-N 1-(4-methoxyphenyl)-5-methyl-3-(2-pyrrolidin-1-ylethoxy)pyrazole Chemical compound C1=CC(OC)=CC=C1N1C(C)=CC(OCCN2CCCC2)=N1 UOTUAMQAHGZANC-UHFFFAOYSA-N 0.000 claims description 2
- ZKKRRGSMXFZHHN-UHFFFAOYSA-N 1-(4-methoxyphenyl)-5-methyl-3-(3-pyrrolidin-1-ylpropoxy)pyrazole Chemical compound C1=CC(OC)=CC=C1N1C(C)=CC(OCCCN2CCCC2)=N1 ZKKRRGSMXFZHHN-UHFFFAOYSA-N 0.000 claims description 2
- LBOYKWCERHEJQD-UHFFFAOYSA-N 1-[1-(3,4-dichlorophenyl)-3-[2-(diethylamino)ethoxy]-5-methylpyrazol-4-yl]ethanone Chemical compound CC1=C(C(C)=O)C(OCCN(CC)CC)=NN1C1=CC=C(Cl)C(Cl)=C1 LBOYKWCERHEJQD-UHFFFAOYSA-N 0.000 claims description 2
- FFDSTJZVYSACEY-UHFFFAOYSA-N 1-[1-(3,4-dichlorophenyl)-5-methyl-3-(2-morpholin-4-ylethoxy)pyrazol-4-yl]ethanone Chemical compound CC(=O)C1=C(C)N(C=2C=C(Cl)C(Cl)=CC=2)N=C1OCCN1CCOCC1 FFDSTJZVYSACEY-UHFFFAOYSA-N 0.000 claims description 2
- OVOUCHJXFOYDKF-UHFFFAOYSA-N 1-[1-(3,4-dichlorophenyl)-5-methyl-3-(2-piperidin-1-ylethoxy)pyrazol-4-yl]ethanone Chemical compound CC(=O)C1=C(C)N(C=2C=C(Cl)C(Cl)=CC=2)N=C1OCCN1CCCCC1 OVOUCHJXFOYDKF-UHFFFAOYSA-N 0.000 claims description 2
- DVDXCZSOOXRPTE-UHFFFAOYSA-N 1-[1-(3,4-dichlorophenyl)-5-methyl-3-(2-pyrrolidin-1-ylethoxy)pyrazol-4-yl]ethanone Chemical compound CC(=O)C1=C(C)N(C=2C=C(Cl)C(Cl)=CC=2)N=C1OCCN1CCCC1 DVDXCZSOOXRPTE-UHFFFAOYSA-N 0.000 claims description 2
- TYQPLZVNSCAIFI-UHFFFAOYSA-N 1-[2-(5-methyl-1-naphthalen-2-ylpyrazol-3-yl)oxyethyl]piperidine Chemical compound N=1N(C=2C=C3C=CC=CC3=CC=2)C(C)=CC=1OCCN1CCCCC1 TYQPLZVNSCAIFI-UHFFFAOYSA-N 0.000 claims description 2
- BDZJQOPZDLUPID-UHFFFAOYSA-N 1-[2-[1-(3,4-dichlorophenyl)-4,5-dimethylpyrazol-3-yl]oxyethyl]piperidine Chemical compound CC1=C(C)N(C=2C=C(Cl)C(Cl)=CC=2)N=C1OCCN1CCCCC1 BDZJQOPZDLUPID-UHFFFAOYSA-N 0.000 claims description 2
- HZJLMGJUIYTSMU-UHFFFAOYSA-N 1-[2-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxyethyl]-4-methylpiperazine Chemical compound C1CN(C)CCN1CCOC1=NN(C=2C=C(Cl)C(Cl)=CC=2)C(C)=C1 HZJLMGJUIYTSMU-UHFFFAOYSA-N 0.000 claims description 2
- JLIOGNLMAGIFJN-UHFFFAOYSA-N 1-[2-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxyethyl]piperazine Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C)=CC=1OCCN1CCNCC1 JLIOGNLMAGIFJN-UHFFFAOYSA-N 0.000 claims description 2
- NZHDCIRJGVMNRD-UHFFFAOYSA-N 1-[2-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxyethyl]pyrrolidin-3-amine Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C)=CC=1OCCN1CCC(N)C1 NZHDCIRJGVMNRD-UHFFFAOYSA-N 0.000 claims description 2
- NHRAAWXMMGSTHI-UHFFFAOYSA-N 1-[2-[1-(3,4-dichlorophenyl)-5-phenylpyrazol-3-yl]oxyethyl]piperidine Chemical compound C1=C(Cl)C(Cl)=CC=C1N1C(C=2C=CC=CC=2)=CC(OCCN2CCCCC2)=N1 NHRAAWXMMGSTHI-UHFFFAOYSA-N 0.000 claims description 2
- ZRKJSQZRBMJLSH-UHFFFAOYSA-N 1-[2-[1-(3,4-dichlorophenyl)-5-propan-2-ylpyrazol-3-yl]oxyethyl]piperidine Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C(C)C)=CC=1OCCN1CCCCC1 ZRKJSQZRBMJLSH-UHFFFAOYSA-N 0.000 claims description 2
- PUZILSCHNRFUBL-UHFFFAOYSA-N 1-[2-[1-(3,4-dichlorophenyl)pyrazol-3-yl]oxyethyl]piperidine Chemical compound C1=C(Cl)C(Cl)=CC=C1N1N=C(OCCN2CCCCC2)C=C1 PUZILSCHNRFUBL-UHFFFAOYSA-N 0.000 claims description 2
- UJVRCYKFYBUMPY-UHFFFAOYSA-N 1-[2-[1-(4-methoxyphenyl)-5-methylpyrazol-3-yl]oxyethyl]piperidine Chemical compound C1=CC(OC)=CC=C1N1C(C)=CC(OCCN2CCCCC2)=N1 UJVRCYKFYBUMPY-UHFFFAOYSA-N 0.000 claims description 2
- RGFIAPCESXOYMJ-UHFFFAOYSA-N 1-[4-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxybutyl]-4-methylpiperazine Chemical compound C1CN(C)CCN1CCCCOC1=NN(C=2C=C(Cl)C(Cl)=CC=2)C(C)=C1 RGFIAPCESXOYMJ-UHFFFAOYSA-N 0.000 claims description 2
- PKBREWIOYKTNBB-UHFFFAOYSA-N 1-[4-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxybutyl]-4-phenylpiperidine Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C)=CC=1OCCCCN(CC1)CCC1C1=CC=CC=C1 PKBREWIOYKTNBB-UHFFFAOYSA-N 0.000 claims description 2
- JCOUIYIXJGWNGZ-UHFFFAOYSA-N 1-[4-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxybutyl]-6,7-dihydro-5h-indol-4-one Chemical compound CC1=CC(OCCCCN2C3=C(C(CCC3)=O)C=C2)=NN1C1=CC=C(Cl)C(Cl)=C1 JCOUIYIXJGWNGZ-UHFFFAOYSA-N 0.000 claims description 2
- XKEZHFHUXSUJGC-UHFFFAOYSA-N 1-[4-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxybutyl]piperidine Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C)=CC=1OCCCCN1CCCCC1 XKEZHFHUXSUJGC-UHFFFAOYSA-N 0.000 claims description 2
- GPJDXYIXLDTRMO-UHFFFAOYSA-N 1-[4-[1-(3,4-dichlorophenyl)pyrazol-3-yl]oxybutyl]piperidine Chemical compound C1=C(Cl)C(Cl)=CC=C1N1N=C(OCCCCN2CCCCC2)C=C1 GPJDXYIXLDTRMO-UHFFFAOYSA-N 0.000 claims description 2
- AGNVOWYHQMEDGN-UHFFFAOYSA-N 1-[4-[2-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxyethyl]piperazin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCN1CCOC1=NN(C=2C=C(Cl)C(Cl)=CC=2)C(C)=C1 AGNVOWYHQMEDGN-UHFFFAOYSA-N 0.000 claims description 2
- OKJXJRVWXYRSAN-TXULWXBWSA-N 2-[(1r,5s,6s)-6-(aminomethyl)-3-ethyl-6-bicyclo[3.2.0]hept-3-enyl]acetic acid;benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1.C1C(CC)=C[C@H]2[C@](CC(O)=O)(CN)C[C@H]21 OKJXJRVWXYRSAN-TXULWXBWSA-N 0.000 claims description 2
- CESIREDMWGMYGW-UHFFFAOYSA-N 2-[1-(3,4-dichlorophenyl)-4,5-dimethylpyrazol-3-yl]oxy-n,n-diethylethanamine Chemical compound CC1=C(C)C(OCCN(CC)CC)=NN1C1=CC=C(Cl)C(Cl)=C1 CESIREDMWGMYGW-UHFFFAOYSA-N 0.000 claims description 2
- IZCFYFTZCBGMLV-UHFFFAOYSA-N 2-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxy-n,n-diethylethanamine Chemical compound N1=C(OCCN(CC)CC)C=C(C)N1C1=CC=C(Cl)C(Cl)=C1 IZCFYFTZCBGMLV-UHFFFAOYSA-N 0.000 claims description 2
- OAOLNHZAEJOOKR-UHFFFAOYSA-N 2-[1-(3,4-dichlorophenyl)-5-propan-2-ylpyrazol-3-yl]oxy-n,n-diethylethanamine Chemical compound N1=C(OCCN(CC)CC)C=C(C(C)C)N1C1=CC=C(Cl)C(Cl)=C1 OAOLNHZAEJOOKR-UHFFFAOYSA-N 0.000 claims description 2
- IFFHSCILSPCXEC-UHFFFAOYSA-N 2-[1-(3,4-dichlorophenyl)pyrazol-3-yl]oxy-n,n-diethylethanamine Chemical compound N1=C(OCCN(CC)CC)C=CN1C1=CC=C(Cl)C(Cl)=C1 IFFHSCILSPCXEC-UHFFFAOYSA-N 0.000 claims description 2
- OUSQOQYBXVCFBD-UHFFFAOYSA-N 2-[2-[1-(3,4-dichlorophenyl)-5-phenylpyrazol-3-yl]oxyethyl]-3,4-dihydro-1h-isoquinoline Chemical compound C1=C(Cl)C(Cl)=CC=C1N1C(C=2C=CC=CC=2)=CC(OCCN2CC3=CC=CC=C3CC2)=N1 OUSQOQYBXVCFBD-UHFFFAOYSA-N 0.000 claims description 2
- PPRYPHBDCCNNFF-UHFFFAOYSA-N 2-[2-[1-(3,4-dichlorophenyl)-5-propan-2-ylpyrazol-3-yl]oxyethyl]-3,4-dihydro-1h-isoquinoline Chemical compound CC(C)C1=CC(OCCN2CC3=CC=CC=C3CC2)=NN1C1=CC=C(Cl)C(Cl)=C1 PPRYPHBDCCNNFF-UHFFFAOYSA-N 0.000 claims description 2
- BXKUTCWIZMNQHG-UHFFFAOYSA-N 2-[4-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxybutyl]-3,4-dihydro-1h-isoquinoline Chemical compound CC1=CC(OCCCCN2CC3=CC=CC=C3CC2)=NN1C1=CC=C(Cl)C(Cl)=C1 BXKUTCWIZMNQHG-UHFFFAOYSA-N 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- QDAIRBQSHDSRDX-UHFFFAOYSA-N 3-(2-imidazol-1-ylethoxy)-1-(4-methoxyphenyl)-5-methylpyrazole Chemical compound C1=CC(OC)=CC=C1N1C(C)=CC(OCCN2C=NC=C2)=N1 QDAIRBQSHDSRDX-UHFFFAOYSA-N 0.000 claims description 2
- JUIHLROADBKASM-UHFFFAOYSA-N 3-[1-[2-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxyethyl]piperidin-4-yl]imidazo[4,5-b]pyridine Chemical compound CC1=CC(OCCN2CCC(CC2)N2C3=NC=CC=C3N=C2)=NN1C1=CC=C(Cl)C(Cl)=C1 JUIHLROADBKASM-UHFFFAOYSA-N 0.000 claims description 2
- NPRFZTVJNINRBD-UHFFFAOYSA-N 4-[1-(3,4-dichlorophenyl)-5-methylpyrazol-3-yl]oxy-n,n-diethylbutan-1-amine Chemical compound N1=C(OCCCCN(CC)CC)C=C(C)N1C1=CC=C(Cl)C(Cl)=C1 NPRFZTVJNINRBD-UHFFFAOYSA-N 0.000 claims description 2
- NWRIDVFHFNJXNR-UHFFFAOYSA-N 4-[1-(3,4-dichlorophenyl)pyrazol-3-yl]oxy-n,n-diethylbutan-1-amine Chemical compound N1=C(OCCCCN(CC)CC)C=CN1C1=CC=C(Cl)C(Cl)=C1 NWRIDVFHFNJXNR-UHFFFAOYSA-N 0.000 claims description 2
- WXPMREWEDTUEDC-UHFFFAOYSA-N 4-[1-(3,4-dichlorophenyl)pyrazol-3-yl]oxy-n-(2-methoxyethyl)-n-methylbutan-1-amine Chemical compound N1=C(OCCCCN(C)CCOC)C=CN1C1=CC=C(Cl)C(Cl)=C1 WXPMREWEDTUEDC-UHFFFAOYSA-N 0.000 claims description 2
- DDCOJLWCGGUJJE-UHFFFAOYSA-N 4-[2-[1-(3,4-dichlorophenyl)-4,5-dimethylpyrazol-3-yl]oxyethyl]morpholine Chemical compound CC1=C(C)N(C=2C=C(Cl)C(Cl)=CC=2)N=C1OCCN1CCOCC1 DDCOJLWCGGUJJE-UHFFFAOYSA-N 0.000 claims description 2
- UFMLSFNIQLSGBU-UHFFFAOYSA-N 4-[2-[1-(3,4-dichlorophenyl)-5-phenylpyrazol-3-yl]oxyethyl]morpholine Chemical compound C1=C(Cl)C(Cl)=CC=C1N1C(C=2C=CC=CC=2)=CC(OCCN2CCOCC2)=N1 UFMLSFNIQLSGBU-UHFFFAOYSA-N 0.000 claims description 2
- FDCUMMFFJKZKJA-UHFFFAOYSA-N 4-[2-[1-(3,4-dichlorophenyl)-5-propan-2-ylpyrazol-3-yl]oxyethyl]morpholine Chemical compound N=1N(C=2C=C(Cl)C(Cl)=CC=2)C(C(C)C)=CC=1OCCN1CCOCC1 FDCUMMFFJKZKJA-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
Description
R1は、水素、置換または非置換のアルキル、置換または非置換のシクロアルキル、置換または非置換のアルケニル、置換または非置換のアリール、置換または非置換のアリールアルキル、置換または非置換の芳香族または非芳香族のヘテロシクリル、置換または非置換のヘテロシクリルアルキル、−COR8、−C(O)OR8、−C(O)NR8R9、−CH=NR8、−CN、−OR8、−OC(O)R8、−S(O)t−R8、−NR8R9、−NR8C(O)R9、−NO2、−N=CR8R9およびハロゲンからなる群から選択され、
R2は、水素、置換または非置換のアルキル、置換または非置換のシクロアルキル、置換または非置換のアルケニル、置換または非置換のアリール、置換または非置換のアリールアルキル、置換または非置換の芳香族または非芳香族のヘテロシクリル、置換または非置換のヘテロシクリルアルキル、−COR8、−C(O)OR8、−C(O)NR8R9、−CH=NR8、−CN、−OR8、−OC(O)R8、−S(O)t−R8、−NR8R9、−NR8C(O)R9、−NO2、−N=CR8R9およびハロゲンからなる群から選択され、
R3およびR4は、各々独立して、水素、置換または非置換のアルキル、置換または非置換のシクロアルキル、置換または非置換のアルケニル、置換または非置換のアリール、置換または非置換のアリールアルキル、置換または非置換の芳香族または非芳香族のヘテロシクリル、置換または非置換のヘテロシクリルアルキル、−COR8、−C(O)OR8、−C(O)NR8R9、−CH=NR8、−CN、−OR8、−OC(O)R8、−S(O)t−R8、−NR8R9、−NR8C(O)R9、−NO2、−N=CR8R9およびハロゲンからなる群から選択されるか、またはフェニルと一緒になって、場合により置換されていてもよい縮合環系を形成し、
R5およびR6は、各々独立して、水素、置換または非置換のアルキル、置換または非置換のシクロアルキル、置換または非置換のアルケニル、置換または非置換のアリール、置換または非置換のアリールアルキル、置換または非置換の芳香族または非芳香族のヘテロシクリル、置換または非置換のヘテロシクリルアルキル、−COR8、−C(O)OR8、−C(O)NR8R9、−CH=NR8、−CN、−OR8、−OC(O)R8、−S(O)t−R8、−NR8R9、−NR8C(O)R9、−NO2、−N=CR8R9およびハロゲンからなる群から選択されるか、
または、R5およびR6が結合している窒素原子と一緒になって、置換または非置換の芳香族または非芳香族のヘテロシクリル基を形成し、
nは、1、2、3、4、5、6、7および8から選択され、
tは、0、1または2であり、
R8およびR9は、各々独立して、水素、置換または非置換のアルキル、置換または非置換のシクロアルキル、置換または非置換のアルケニル、置換または非置換のアリール、置換または非置換の芳香族または非芳香族のヘテロシクリル、置換または非置換のアルコキシ、置換または非置換のアリールオキシおよびハロゲンから選択される)
またはその医薬的に許容可能な塩、異性体、プロドラッグ、もしくは溶媒和物とを含んでなる、相乗的組み合わせ物に関する。
[1]4−{2−(1−(3,4−ジクロロフェニル)−5−メチル−1Hピラゾール−3−イルオキシ)エチル}モルホリン、
[2]2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]−N,N−ジエチルエタンアミン、
[3]1−(3,4−ジクロロフェニル)−5−メチル−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール
[4]1−(3,4−ジクロロフェニル)−5−メチル−3−[3−(ピロリジン−1−イル)プロポキシ]−1H−ピラゾール、
[5]1−{2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}ピペリジン、
[6]1−{2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}−1H−イミダゾール、
[7]3−{1−[2−(1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ)エチル]ピペリジン−4−イル}−3H−イミダゾ[4,5−b]ピリジン、
[8]1−{2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}−4−メチルピペラジン、
[9]エチル 4−{2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}ピペラジンカルボキシレート、
[10]1−(4−(2−(1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ)エチル)ピペラジン−1−イル)エタノン、
[11]4−{2−[1−(4−メトキシフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}モルホリン、
[12]1−(4−メトキシフェニル)−5−メチル−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール、
[13]1−(4−メトキシフェニル)−5−メチル−3−[3−(ピロリジン−1−イル)プロポキシ]−1H−ピラゾール、
[14]1−[2−(1−(4−メトキシフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ)エチル]ピペリジン、
[15]1−{2−[1−(4−メトキシフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}−1H−イミダゾール、
[16]4−{2−[1−(3,4−ジクロロフェニル)−5−フェニル−1H−ピラゾール−3−イルオキシ]エチル}モルホリン、
[17]1−(3,4−ジクロロフェニル)−5−フェニル−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール、
[18]1−(3,4−ジクロロフェニル)−5−フェニル−3−[3−(ピロリジン−1−イル)プロポキシ]−1H−ピラゾール、
[19]1−{2−[1−(3,4−ジクロロフェニル)−5−フェニル−1H−ピラゾール−3−イルオキシ]エチル}ピペリジン、
[20]1−{2−[1−(3,4−ジクロロフェニル)−5−フェニル−1H−ピラゾール−3−イルオキシ]エチル}−1H−イミダゾール、
[21]2−{2−[1−(3,4−ジクロロフェニル)−5−フェニル−1H−ピラゾール−3−イルオキシ]エチル}−1,2,3,4−テトラヒドロイソキノリン、
[22]4−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}モルホリン、
[23]1−(3,4−ジクロロフェニル)−5−メチル−3−[4−(ピロリジン−1−イル)ブトキシ]−1H−ピラゾール、
[24]1−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}ピペリジン、
[25]1−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}−4−メチルピペラジン、
[26]1−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}−1H−イミダゾール、
[27]4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]−N,N−ジエチルブタン−1−アミン、
[28]1−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}−4−フェニルピペリジン、
[29]1−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}−6,7−ジヒドロ−1H−インドール−4(5H)−オン、
[30]2−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}−1,2,3,4−テトラヒドロイソキノリン、
[31]4−{2−[1−(3,4−ジクロロフェニル)−5−イソプロピル−1H−ピラゾール−3−イルオキシ]エチル}モルホリン、
[32]2−[1−(3,4−ジクロロフェニル)−5−イソプロピル−1H−ピラゾール−3−イルオキシ]−N,N−ジエチルエタンアミン、
[33]1−(3,4−ジクロロフェニル)−5−イソプロピル−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール、
[34]1−(3,4−ジクロロフェニル)−5−イソプロピル−3−[3−(ピロリジン−1−イル)プロポキシ]−1H−ピラゾール、
[35]1−{2−[1−(3,4−ジクロロフェニル)−5−イソプロピル−1H−ピラゾール−3−イルオキシ]エチル}ピペリジン、
[36]2−{2−[1−(3,4−ジクロロフェニル)−5−イソプロピル−1H−ピラゾール−3−イルオキシ]エチル}−1,2,3,4−テトラヒドロイソキノリン、
[37]4−{2−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]エチル}モルホリン、
[38]2−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]N,N−ジエチルエタンアミン、
[39]1−(3,4−ジクロロフェニル)−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール、
[40]1−{2−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]エチル}ピペリジン、
[41]1−(3,4−ジクロロフェニル)−3−[3−(ピロリジン−1−イル)プロポキシ]−1H−ピラゾール、
[42]1−{2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}ピペラジン、
[43]1−{2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}ピロリジン−3−アミン、
[44]4−{2−[1−(3,4−ジクロロフェニル)−4,5−ジメチル−1H−ピラゾール−3−イルオキシ]エチル}モルホリン、
[46]2−[1−(3,4−ジクロロフェニル)−4,5−ジメチル−1H−ピラゾール−3−イルオキシ]−N,N−ジエチルエタンアミン、
[47]1−(3,4−ジクロロフェニル)−4,5−ジメチル−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール、
[48]1−(3,4−ジクロロフェニル)−4,5−ジメチル−3−[3−(ピロリジン−1−イル)プロポキシ]−1H−ピラゾール、
[49]1−{2−[1−(3,4−ジクロロフェニル)−4,5−ジメチル−1H−ピラゾール−3−イルオキシ]エチル}ピペリジン、
[50]4−{4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]ブチル}モルホリン、
[51](2S,6R)−4−{4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]ブチル}−2,6−ジメチルモルホリン、
[52]1−{4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]ブチル}ピペリジン、
[53]1−(3,4−ジクロロフェニル)−3−[4−(ピロリジン−1−イル)ブトキシ]−1H−ピラゾール、
[55]4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]−N,N−ジエチルブタン−1−アミン、
[56]N−ベンジル−4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]−N−メチルブタン−1−アミン、
[57]4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]−N−(2−メトキシエチル)−N−メチルブタン−1−アミン、
[58]4−{4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]ブチル}チオモルホリン、
[59]1−[1−(3,4−ジクロロフェニル)−5−メチル−3−(2−モルホリノエトキシ)−1H−ピラゾール−4−イル]エタノン、
[60]1−{1−(3,4−ジクロロフェニル)−5−メチル−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール−4−イル}エタノン、
[61]1−{1−(3,4−ジクロロフェニル)−5−メチル−3−[2−(ピペリジン−1−イル)エトキシ]−1H−ピラゾール−4−イル}エタノン、
[62]1−{1−(3,4−ジクロロフェニル)−3−[2−(ジエチルアミノ)エトキシ]−5−メチル−1H−ピラゾール−4−イル}エタノン、
[63]4−{2−[5−メチル−1−(ナフタレン−2−イル)−1H−ピラゾール−3−イルオキシ]エチル}モルホリン、
[64]N,N−ジエチル−2−[5−メチル−1−(ナフタレン−2−イル)−1H−ピラゾール−3−イルオキシ]エタンアミン、
[65]1−{2−[5−メチル−1−(ナフタレン−2−イル)−1H−ピラゾール−3−イルオキシ]エチル}ピペリジン、および
[66]5−メチル−1−(ナフタレン−2−イル)−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール、
または薬学的に許容されるその塩、異性体、溶媒和物もしくはプロドラッグから選択される。
a)両者が常に同時に投与される、同一医薬製剤の一部である組み合わせ物として、
b)各々が、同時、逐次または個別投与の可能性を生じさせる2単位の組み合わせ物として、投与してよいということを含意する。特定の実施形態では、一般式(I)のシグマリガンドは、ガバペンチノイドから独立して(すなわち、2つの単位で)、しかし同時に投与される。別の特定の実施形態では、式(I)のシグマリガンドは最初に投与され、次いでガバペンチノイドが個別にまたは逐次投与される。さらに別の特定の実施形態では、ガバペンチノイドが最初に投与され、次いで一般式(I)のシグマリガンドが、定義される通り個別にまたは逐次投与される。
化合物63(6.39g)を、HClを飽和させたエタノールに溶解し、次いでこの混合物を何分間か撹拌し、蒸発乾固した。残留物を、イソプロパノールから結晶化させた。最初の結晶化から得た母液は、濃縮することによって第2の結晶化をもたらした。両方の結晶化によって、対応する塩酸塩が、まとめて5.24g(63%)得られた(融点=197〜199℃)。
1H−NMR (DMSO−d6) δ ppm: 10,85 (bs, 1H)、 7,95 (m,4H)、 7,7 (dd、 J=2,2、 8,8 Hz、 1H)、 7,55 (m、 2H)、 5、9 (s、 1H)、 4,55 (m、 2H)、 3,95 (m、 2H)、 3,75 (m、 2H)、 3,55−3、4 (m、 4H)、 3,2 (m、 2H)、 2,35 (s、 3H).
HPLC純度: 99.8%
2.1 一般的手順
ラットにおける麻酔の導入は、家畜用の3%イソフルランを使って行い、OHmeda気化器と麻酔チャンバを使用した。麻酔は、イソフルランガスを被験動物の鼻に向ける管によって外科手術中も維持された。ラットに麻酔がかかると、腹臥位の状態で寝かし、その右後ろ足をアルコールで洗浄した。
プレガバリンの投与量を一定(0.04mg/kg)に保ちながら、化合物63・HClを様々な量(5mg/kg、 10mg/kg、 20mg/kg、 40mg/kgおよび80mg/kg)投与することで、プレガバリンおよび化合物63・HClを組み合わせて使用することの有効性が試験された。投与は術後3.5時間後に実施された。投与された被験動物は、上記の機械的異痛症の手順に従って試験された(図1)。
ガバペンチンの投与量を一定(10mg/kg)に保ちながら、化合物63・HClを様々な量(10mg/kg、 20mg/kg、 40mg/kgおよび80mg/kg)投与することで、ガバペンチンおよび化合物6・HClを組み合わせて使用することの有効性が試験された。投与は術後3.5時間後に実施された。投与された被験動物は、上記の機械的異痛症の手順に従って試験された(図2)。
図1に示される通り、化合物63・HClは、最大43%の効果を伴う投与依存性効果を生じた。本図ではまた、有意でない結果を生じた準活性投与(0.04 mg/kg)でのプレガバリンも示されている。最終的に、(準活性投与での)プレガバリンと化合物63・HClの組み合わせにより、ED50=7.3 mg/kgの投与依存性効果が得られた。それゆえ、術後疼痛の治療において、化合物63・HClおよびプレガバリンは、相乗的に作用して鎮痛効果を生じる。
Claims (16)
- 1000nM以下の阻害定数(Ki)を有する、α2δサブユニットカルシウムチャネルのリガンドから選択される少なくとも1種のガバペンチノイドと、一般式(I)の少なくとも1種のシグマリガンド:
R1は、水素、置換または非置換のアルキル、置換または非置換のシクロアルキル、置換または非置換のアルケニル、置換または非置換のアリール、置換または非置換のアリールアルキル、置換または非置換の芳香族または非芳香族のヘテロシクリル、置換または非置換のヘテロシクリルアルキル、−COR8、−C(O)OR8、−C(O)NR8R9、−CH=NR8、−CN、−OR8、−OC(O)R8、−S(O)t−R8、−NR8R9、−NR8C(O)R9、−NO2、−N=CR8R9およびハロゲンからなる群から選択され、
R2は、水素、置換または非置換のアルキル、置換または非置換のシクロアルキル、置換または非置換のアルケニル、置換または非置換のアリール、置換または非置換のアリールアルキル、置換または非置換の芳香族または非芳香族のヘテロシクリル、置換または非置換のヘテロシクリルアルキル、−COR8、−C(O)OR8、−C(O)NR8R9、−CH=NR8、−CN、−OR8、−OC(O)R8、−S(O)t−R8、−NR8R9、−NR8C(O)R9、−NO2、−N=CR8R9およびハロゲンからなる群から選択され、
R3およびR4は、各々独立して、水素、置換または非置換のアルキル、置換または非置換のシクロアルキル、置換または非置換のアルケニル、置換または非置換のアリール、置換または非置換のアリールアルキル、置換または非置換の芳香族または非芳香族のヘテロシクリル、置換または非置換のヘテロシクリルアルキル、−COR8、−C(O)OR8、−C(O)NR8R9、−CH=NR8、−CN、−OR8、−OC(O)R8、−S(O)t−R8、−NR8R9、−NR8C(O)R9、−NO2、−N=CR8R9およびハロゲンからなる群から選択されるか、またはフェニルと一緒になって、場合により置換されていてもよい縮合環系を形成し、
R5およびR6は、各々独立して、水素、置換または非置換のアルキル、置換または非置換のシクロアルキル、置換または非置換のアルケニル、置換または非置換のアリール、置換または非置換のアリールアルキル、置換または非置換の芳香族または非芳香族のヘテロシクリル、置換または非置換のヘテロシクリルアルキル、−COR8、−C(O)OR8、−C(O)NR8R9、−CH=NR8、−CN、−OR8、−OC(O)R8、−S(O)t−R8、−NR8R9、−NR8C(O)R9、−NO2、−N=CR8R9およびハロゲンからなる群から選択されるか、
または、R5およびR6が結合している窒素原子と一緒になって、置換または非置換の芳香族または非芳香族のヘテロシクリル基を形成し、
nは、1、2、3、4、5、6、7および8から選択され、
tは、0、1または2であり、
R8およびR9は、各々独立して、水素、置換または非置換のアルキル、置換または非置換のシクロアルキル、置換または非置換のアルケニル、置換または非置換のアリール、置換または非置換の芳香族または非芳香族のヘテロシクリル、置換または非置換のアルコキシ、置換または非置換のアリールオキシおよびハロゲンから選択される)
またはその医薬的に許容可能な塩、異性体、プロドラッグ、もしくは溶媒和物とを含んでなる、相乗的組み合わせ。 - R1が、H、−COR8および置換または非置換のアルキルから選択される、請求項1に記載の相乗的組み合わせ。
- R2が、Hまたは置換または非置換のアルキルである、請求項1または2のいずれか一項に記載の相乗的組み合わせ。
- R3およびR4が、フェニル基と一緒になってナフチル環系を形成する、請求項1〜3のいずれか一項に記載の相乗的組み合わせ。
- nが、2、3および4から選択される、請求項1〜4のいずれか一項に記載の相乗的組み合わせ。
- R5およびR6が、一緒になってモルホリン−4−イル基を形成する、請求項1〜5のいずれか一項に記載の相乗的組み合わせ。
- 前記一般式(I)のシグマリガンドが、
[1]4−{2−(1−(3,4−ジクロロフェニル)−5−メチル−1Hピラゾール−3−イルオキシ)エチル}モルホリン、
[2]2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]−N,N−ジエチルエタンアミン、
[3]1−(3,4−ジクロロフェニル)−5−メチル−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール
[4]1−(3,4−ジクロロフェニル)−5−メチル−3−[3−(ピロリジン−1−イル)プロポキシ]−1H−ピラゾール、
[5]1−{2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}ピペリジン、
[6]1−{2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}−1H−イミダゾール、
[7]3−{1−[2−(1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ)エチル]ピペリジン−4−イル}−3H−イミダゾ[4,5−b]ピリジン、
[8]1−{2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}−4−メチルピペラジン、
[9]エチル 4−{2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}ピペラジンカルボキシレート、
[10]1−(4−(2−(1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ)エチル)ピペラジン−1−イル)エタノン、
[11]4−{2−[1−(4−メトキシフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}モルホリン、
[12]1−(4−メトキシフェニル)−5−メチル−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール、
[13]1−(4−メトキシフェニル)−5−メチル−3−[3−(ピロリジン−1−イル)プロポキシ]−1H−ピラゾール、
[14]1−[2−(1−(4−メトキシフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ)エチル]ピペリジン、
[15]1−{2−[1−(4−メトキシフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}−1H−イミダゾール、
[16]4−{2−[1−(3,4−ジクロロフェニル)−5−フェニル−1H−ピラゾール−3−イルオキシ]エチル}モルホリン、
[17]1−(3,4−ジクロロフェニル)−5−フェニル−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール、
[18]1−(3,4−ジクロロフェニル)−5−フェニル−3−[3−(ピロリジン−1−イル)プロポキシ]−1H−ピラゾール、
[19]1−{2−[1−(3,4−ジクロロフェニル)−5−フェニル−1H−ピラゾール−3−イルオキシ]エチル}ピペリジン、
[20]1−{2−[1−(3,4−ジクロロフェニル)−5−フェニル−1H−ピラゾール−3−イルオキシ]エチル}−1H−イミダゾール、
[21]2−{2−[1−(3,4−ジクロロフェニル)−5−フェニル−1H−ピラゾール−3−イルオキシ]エチル}−1,2,3,4−テトラヒドロイソキノリン、
[22]4−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}モルホリン、
[23]1−(3,4−ジクロロフェニル)−5−メチル−3−[4−(ピロリジン−1−イル)ブトキシ]−1H−ピラゾール、
[24]1−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}ピペリジン、
[25]1−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}−4−メチルピペラジン、
[26]1−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}−1H−イミダゾール、
[27]4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]−N,N−ジエチルブタン−1−アミン、
[28]1−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}−4−フェニルピペリジン、
[29]1−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}−6,7−ジヒドロ−1H−インドール−4(5H)−オン、
[30]2−{4−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]ブチル}−1,2,3,4−テトラヒドロイソキノリン、
[31]4−{2−[1−(3,4−ジクロロフェニル)−5−イソプロピル−1H−ピラゾール−3−イルオキシ]エチル}モルホリン、
[32]2−[1−(3,4−ジクロロフェニル)−5−イソプロピル−1H−ピラゾール−3−イルオキシ]−N,N−ジエチルエタンアミン、
[33]1−(3,4−ジクロロフェニル)−5−イソプロピル−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール、
[34]1−(3,4−ジクロロフェニル)−5−イソプロピル−3−[3−(ピロリジン−1−イル)プロポキシ]−1H−ピラゾール、
[35]1−{2−[1−(3,4−ジクロロフェニル)−5−イソプロピル−1H−ピラゾール−3−イルオキシ]エチル}ピペリジン、
[36]2−{2−[1−(3,4−ジクロロフェニル)−5−イソプロピル−1H−ピラゾール−3−イルオキシ]エチル}−1,2,3,4−テトラヒドロイソキノリン、
[37]4−{2−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]エチル}モルホリン、
[38]2−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]N,N−ジエチルエタンアミン、
[39]1−(3,4−ジクロロフェニル)−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール、
[40]1−{2−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]エチル}ピペリジン、
[41]1−(3,4−ジクロロフェニル)−3−[3−(ピロリジン−1−イル)プロポキシ]−1H−ピラゾール、
[42]1−{2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}ピペラジン、
[43]1−{2−[1−(3,4−ジクロロフェニル)−5−メチル−1H−ピラゾール−3−イルオキシ]エチル}ピロリジン−3−アミン、
[44]4−{2−[1−(3,4−ジクロロフェニル)−4,5−ジメチル−1H−ピラゾール−3−イルオキシ]エチル}モルホリン、
[46]2−[1−(3,4−ジクロロフェニル)−4,5−ジメチル−1H−ピラゾール−3−イルオキシ]−N,N−ジエチルエタンアミン、
[47]1−(3,4−ジクロロフェニル)−4,5−ジメチル−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール、
[48]1−(3,4−ジクロロフェニル)−4,5−ジメチル−3−[3−(ピロリジン−1−イル)プロポキシ]−1H−ピラゾール、
[49]1−{2−[1−(3,4−ジクロロフェニル)−4,5−ジメチル−1H−ピラゾール−3−イルオキシ]エチル}ピペリジン、
[50]4−{4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]ブチル}モルホリン、
[51](2S,6R)−4−{4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]ブチル}−2,6−ジメチルモルホリン、
[52]1−{4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]ブチル}ピペリジン、
[53]1−(3,4−ジクロロフェニル)−3−[4−(ピロリジン−1−イル)ブトキシ]−1H−ピラゾール、
[55]4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]−N,N−ジエチルブタン−1−アミン、
[56]N−ベンジル−4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]−N−メチルブタン−1−アミン、
[57]4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]−N−(2−メトキシエチル)−N−メチルブタン−1−アミン、
[58]4−{4−[1−(3,4−ジクロロフェニル)−1H−ピラゾール−3−イルオキシ]ブチル}チオモルホリン、
[59]1−[1−(3,4−ジクロロフェニル)−5−メチル−3−(2−モルホリノエトキシ)−1H−ピラゾール−4−イル]エタノン、
[60]1−{1−(3,4−ジクロロフェニル)−5−メチル−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール−4−イル}エタノン、
[61]1−{1−(3,4−ジクロロフェニル)−5−メチル−3−[2−(ピペリジン−1−イル)エトキシ]−1H−ピラゾール−4−イル}エタノン、
[62]1−{1−(3,4−ジクロロフェニル)−3−[2−(ジエチルアミノ)エトキシ]−5−メチル−1H−ピラゾール−4−イル}エタノン、
[63]4−{2−[5−メチル−1−(ナフタレン−2−イル)−1H−ピラゾール−3−イルオキシ]エチル}モルホリン、
[64]N,N−ジエチル−2−[5−メチル−1−(ナフタレン−2−イル)−1H−ピラゾール−3−イルオキシ]エタンアミン、
[65]1−{2−[5−メチル−1−(ナフタレン−2−イル)−1H−ピラゾール−3−イルオキシ]エチル}ピペリジン、および
[66]5−メチル−1−(ナフタレン−2−イル)−3−[2−(ピロリジン−1−イル)エトキシ]−1H−ピラゾール、
またはこれらの医薬的に許容可能な塩、異性体、プロドラッグ、もしくは溶媒和物
から選択される、請求項1に記載の相乗的組み合わせ。 - 前記組み合わせ物、4−{2−[5−メチル−1−(ナフタレン−2−イル)−1H−ピラゾール−3−イルオキシ]エチル}モルホリンまたは薬学的に許容されるその塩、異性体、プロドラッグもしくは溶媒和物を含んでなる、請求項7に記載の相乗的組み合わせ。
- 前記組み合わせ物が、4−{2−[5−メチル−1−(ナフタレン−2−イル)−1H−ピラゾール−3−イルオキシ]エチル}モルホリン塩酸塩を含んでなる、請求項請求項1〜8のいずれか一項に記載の相乗的組み合わせ。
- 前記ガバペンチノイドが、ガバペンチン、プレガバリン、アタガバリン、イマガバリン、DS−5565およびガバペンチンエナカルビルまたは薬学的に許容されるその塩、異性体、プロドラッグまたは溶媒和物からなる群から選択される、請求項1〜9のいずれか一項に記載の相乗的組み合わせ。
- 前記組み合わせが、4−{2−[5−メチル−1−(ナフタレン−2−イル)−1H−ピラゾール−3−イルオキシ]エチル}モルホリン塩酸塩およびプレガバリンを含んでなる、請求項1〜10のいずれか一項に記載の相乗的組み合わせ。
- 前記組み合わせが、4−{2−[5−メチル−1−(ナフタレン−2−イル)−1H−ピラゾール−3−イルオキシ]エチル}モルホリン塩酸塩およびガバペンチンを含んでなる、請求項1〜11のいずれか一項に記載の相乗的組み合わせ。
- 医療用途に用いられる、請求項1〜12のいずれか一項に記載の相乗的組み合わせ。
- 疼痛の予防および/または治療に用いられる、請求項請求項1〜13のいずれか一項に記載の相乗的組み合わせ。
- 前記ガバペンチノイドの鎮痛効果を強化することによって疼痛の予防および/または治療する用途に用いられる、請求項請求項1〜14のいずれか一項に記載の相乗的組み合わせ。
- 前記疼痛が神経障害性疼痛である、疼痛の予防および/または治療に用いられる、請求項請求項1〜15のいずれか一項に記載の相乗的組み合わせ。
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- 2014-12-16 WO PCT/EP2014/077992 patent/WO2015091505A1/en active Application Filing
- 2014-12-16 KR KR1020167018971A patent/KR20160098426A/ko not_active Application Discontinuation
- 2014-12-16 AU AU2014364644A patent/AU2014364644A1/en not_active Abandoned
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- 2014-12-16 EP EP14823952.8A patent/EP3082790A1/en not_active Withdrawn
- 2014-12-16 US US15/104,752 patent/US20160310501A1/en not_active Abandoned
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- 2014-12-16 MX MX2016007286A patent/MX2016007286A/es unknown
- 2014-12-16 MA MA39146A patent/MA39146A1/fr unknown
- 2014-12-16 CA CA2933057A patent/CA2933057A1/en not_active Abandoned
- 2014-12-16 JP JP2016536584A patent/JP2017503765A/ja not_active Ceased
- 2014-12-16 TW TW103143904A patent/TW201607539A/zh unknown
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WO2007090661A2 (en) * | 2006-02-10 | 2007-08-16 | Laboratorios Del Dr. Esteve, S.A. | Active substance combination comprising azolylcarbinol compounds |
WO2012156497A1 (en) * | 2011-05-19 | 2012-11-22 | Laboratorios Del Dr. Esteve, S.A. | Use of sigma ligands in diabetes type-2 associated pain |
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US20160310501A1 (en) | 2016-10-27 |
CA2933057A1 (en) | 2015-06-25 |
AU2014364644A1 (en) | 2016-06-23 |
IL245977A0 (en) | 2016-07-31 |
MA39146A1 (fr) | 2017-11-30 |
TW201607539A (zh) | 2016-03-01 |
KR20160098426A (ko) | 2016-08-18 |
EP3082790A1 (en) | 2016-10-26 |
CN105873580B (zh) | 2020-08-25 |
MX2016007286A (es) | 2016-08-04 |
TN2016000229A1 (en) | 2017-10-06 |
AR101637A1 (es) | 2017-01-04 |
WO2015091505A1 (en) | 2015-06-25 |
SG11201604478UA (en) | 2016-07-28 |
PH12016501095A1 (en) | 2016-07-11 |
CN105873580A (zh) | 2016-08-17 |
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