CZ292065B6 - Použití derivátů aryl (nebo heteroaryl)azolylkarbinolů pro přípravu léčiv k léčení chorob zprostředkovaných přebytkem substance P - Google Patents
Použití derivátů aryl (nebo heteroaryl)azolylkarbinolů pro přípravu léčiv k léčení chorob zprostředkovaných přebytkem substance P Download PDFInfo
- Publication number
- CZ292065B6 CZ292065B6 CZ2001412A CZ2001412A CZ292065B6 CZ 292065 B6 CZ292065 B6 CZ 292065B6 CZ 2001412 A CZ2001412 A CZ 2001412A CZ 2001412 A CZ2001412 A CZ 2001412A CZ 292065 B6 CZ292065 B6 CZ 292065B6
- Authority
- CZ
- Czechia
- Prior art keywords
- methyl
- imidazole
- dimethylamino
- pyrazole
- benzyl
- Prior art date
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 17
- 201000010099 disease Diseases 0.000 title claims abstract description 13
- 230000001404 mediated effect Effects 0.000 title claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 title claims abstract description 5
- 125000001072 heteroaryl group Chemical group 0.000 title claims abstract description 5
- 239000003814 drug Substances 0.000 title claims description 5
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 title abstract 2
- -1 N-methylpiperidyl group Chemical group 0.000 claims abstract description 49
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 7
- 230000036506 anxiety Effects 0.000 claims abstract description 7
- 210000003169 central nervous system Anatomy 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 201000001880 Sexual dysfunction Diseases 0.000 claims abstract description 6
- 208000010877 cognitive disease Diseases 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 6
- 231100000872 sexual dysfunction Toxicity 0.000 claims abstract description 6
- 241000124008 Mammalia Species 0.000 claims abstract description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 58
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 53
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 43
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 43
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 24
- JLKUMSHHQYQLSG-UHFFFAOYSA-N 3-carboxy-3,5-dihydroxy-5-oxopentanoate;dimethyl-[2-[(2-methylpyrazol-3-yl)-phenylmethoxy]ethyl]azanium Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=NN1C JLKUMSHHQYQLSG-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 208000020925 Bipolar disease Diseases 0.000 claims description 5
- 208000028683 bipolar I disease Diseases 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 claims description 4
- 208000011117 substance-related disease Diseases 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- KORIJXKQGMTQTO-UHFFFAOYSA-N 1h-pyrrol-2-ylmethanol Chemical class OCC1=CC=CN1 KORIJXKQGMTQTO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- DCMJBKFKXGPPMT-UHFFFAOYSA-N n,n-dimethyl-2-[(2-methylpyrazol-3-yl)-phenylmethoxy]ethanamine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=NN1C DCMJBKFKXGPPMT-UHFFFAOYSA-N 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 20
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 14
- YJQRNWFHOPZNKJ-UHFFFAOYSA-N (1-methylimidazol-2-yl)-(3,4,5-trimethoxyphenyl)methanol Chemical compound COC1=C(OC)C(OC)=CC(C(O)C=2N(C=CN=2)C)=C1 YJQRNWFHOPZNKJ-UHFFFAOYSA-N 0.000 claims 2
- CWJSTOWNJMEMTI-UHFFFAOYSA-N (4-chlorophenyl)-(1h-imidazol-2-yl)methanol Chemical compound C=1C=C(Cl)C=CC=1C(O)C1=NC=CN1 CWJSTOWNJMEMTI-UHFFFAOYSA-N 0.000 claims 2
- POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 claims 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 2
- PLTSXNZBXQRFSL-UHFFFAOYSA-N (1-butylimidazol-2-yl)-(4-chlorophenyl)-(1-methylpiperidin-4-yl)methanol Chemical compound CCCCN1C=CN=C1C(O)(C=1C=CC(Cl)=CC=1)C1CCN(C)CC1 PLTSXNZBXQRFSL-UHFFFAOYSA-N 0.000 claims 1
- IMFOYQOQIODGQW-UHFFFAOYSA-N (1-butylimidazol-2-yl)-[4-(trifluoromethyl)phenyl]methanol Chemical compound CCCCN1C=CN=C1C(O)C1=CC=C(C(F)(F)F)C=C1 IMFOYQOQIODGQW-UHFFFAOYSA-N 0.000 claims 1
- DVHHTIGJNVCFDE-UHFFFAOYSA-N (1-dodecylimidazol-2-yl)-(3,4,5-trimethoxyphenyl)methanol Chemical compound CCCCCCCCCCCCN1C=CN=C1C(O)C1=CC(OC)=C(OC)C(OC)=C1 DVHHTIGJNVCFDE-UHFFFAOYSA-N 0.000 claims 1
- IVWSNLPIJWOKEL-UHFFFAOYSA-N (1-methylimidazol-2-yl)-[3-(trifluoromethyl)phenyl]methanol Chemical compound CN1C=CN=C1C(O)C1=CC=CC(C(F)(F)F)=C1 IVWSNLPIJWOKEL-UHFFFAOYSA-N 0.000 claims 1
- DGBUCHZPKPTBTF-UHFFFAOYSA-N (1-methylimidazol-2-yl)-[4-(trifluoromethyl)phenyl]methanol Chemical compound CN1C=CN=C1C(O)C1=CC=C(C(F)(F)F)C=C1 DGBUCHZPKPTBTF-UHFFFAOYSA-N 0.000 claims 1
- GOVKUSQTCDGAMA-UHFFFAOYSA-N (2-butylpyrazol-3-yl)-(3,4,5-trimethoxyphenyl)methanol Chemical compound CCCCN1N=CC=C1C(O)C1=CC(OC)=C(OC)C(OC)=C1 GOVKUSQTCDGAMA-UHFFFAOYSA-N 0.000 claims 1
- VRNGWCCYQAXTAY-UHFFFAOYSA-N (2-butylpyrazol-3-yl)-phenylmethanol Chemical compound CCCCN1N=CC=C1C(O)C1=CC=CC=C1 VRNGWCCYQAXTAY-UHFFFAOYSA-N 0.000 claims 1
- DTFRMDPZSMEBEB-UHFFFAOYSA-N (2-chlorophenyl)-(2-methylpyrazol-3-yl)methanol Chemical compound CN1N=CC=C1C(O)C1=CC=CC=C1Cl DTFRMDPZSMEBEB-UHFFFAOYSA-N 0.000 claims 1
- ASSGWIAWMIEYER-UHFFFAOYSA-N (2-methylphenyl)-(2-methylpyrazol-3-yl)methanol Chemical compound CC1=CC=CC=C1C(O)C1=CC=NN1C ASSGWIAWMIEYER-UHFFFAOYSA-N 0.000 claims 1
- ZNJRRTXKOHJOOJ-UHFFFAOYSA-N (2-methylpyrazol-3-yl)-(3,4,5-trimethoxyphenyl)methanol Chemical compound COC1=C(OC)C(OC)=CC(C(O)C=2N(N=CC=2)C)=C1 ZNJRRTXKOHJOOJ-UHFFFAOYSA-N 0.000 claims 1
- BMASPICGFTWBED-UHFFFAOYSA-N (3,4-dichlorophenyl)-(1-methylimidazol-2-yl)methanol Chemical compound CN1C=CN=C1C(O)C1=CC=C(Cl)C(Cl)=C1 BMASPICGFTWBED-UHFFFAOYSA-N 0.000 claims 1
- FIOLCQAELMTXNL-UHFFFAOYSA-N (3-chlorophenyl)-(1-methylimidazol-2-yl)methanol Chemical compound CN1C=CN=C1C(O)C1=CC=CC(Cl)=C1 FIOLCQAELMTXNL-UHFFFAOYSA-N 0.000 claims 1
- QIWSOABYAGHUCV-UHFFFAOYSA-N (3-chlorophenyl)-(2-methylpyrazol-3-yl)methanol Chemical compound CN1N=CC=C1C(O)C1=CC=CC(Cl)=C1 QIWSOABYAGHUCV-UHFFFAOYSA-N 0.000 claims 1
- ISOFRRQGTLHGQB-UHFFFAOYSA-N (4-bromo-2-methylpyrazol-3-yl)-phenylmethanol Chemical compound CN1N=CC(Br)=C1C(O)C1=CC=CC=C1 ISOFRRQGTLHGQB-UHFFFAOYSA-N 0.000 claims 1
- CEJLGKWTVRUHIP-UHFFFAOYSA-N (4-chloro-2-methylpyrazol-3-yl)-phenylmethanol Chemical compound CN1N=CC(Cl)=C1C(O)C1=CC=CC=C1 CEJLGKWTVRUHIP-UHFFFAOYSA-N 0.000 claims 1
- PHHMEHHGCXZGHE-UHFFFAOYSA-N (4-chlorophenyl)-(1-methylimidazol-2-yl)-(1-methylpiperidin-4-yl)methanol Chemical compound C1CN(C)CCC1C(O)(C=1C=CC(Cl)=CC=1)C1=NC=CN1C PHHMEHHGCXZGHE-UHFFFAOYSA-N 0.000 claims 1
- RTEQGPTVSNWJNT-UHFFFAOYSA-N (4-chlorophenyl)-(1-methylimidazol-2-yl)methanol Chemical compound CN1C=CN=C1C(O)C1=CC=C(Cl)C=C1 RTEQGPTVSNWJNT-UHFFFAOYSA-N 0.000 claims 1
- PNIZZSHYLPCPHI-UHFFFAOYSA-N (4-chlorophenyl)-cyclohexyl-(1-methylimidazol-2-yl)methanol Chemical compound CN1C=CN=C1C(O)(C=1C=CC(Cl)=CC=1)C1CCCCC1 PNIZZSHYLPCPHI-UHFFFAOYSA-N 0.000 claims 1
- KJCSIXINJKNLAE-UHFFFAOYSA-N (4-fluorophenyl)-(1-methylimidazol-2-yl)methanol Chemical compound CN1C=CN=C1C(O)C1=CC=C(F)C=C1 KJCSIXINJKNLAE-UHFFFAOYSA-N 0.000 claims 1
- JUCIFKDNNZUYCN-UHFFFAOYSA-N (4-methoxyphenyl)-(2-methylpyrazol-3-yl)methanol Chemical compound C1=CC(OC)=CC=C1C(O)C1=CC=NN1C JUCIFKDNNZUYCN-UHFFFAOYSA-N 0.000 claims 1
- VBOGEAZGCIWJME-UHFFFAOYSA-N (4-methylphenyl)-(2-methylpyrazol-3-yl)methanol Chemical compound C1=CC(C)=CC=C1C(O)C1=CC=NN1C VBOGEAZGCIWJME-UHFFFAOYSA-N 0.000 claims 1
- RZEZKKLIJRPJST-UHFFFAOYSA-N 1-(1-benzylimidazol-2-yl)-1-[3-(trifluoromethyl)phenyl]pentan-1-ol Chemical compound C=1C=CC(C(F)(F)F)=CC=1C(O)(CCCC)C1=NC=CN1CC1=CC=CC=C1 RZEZKKLIJRPJST-UHFFFAOYSA-N 0.000 claims 1
- GQCLQIPBAOEHDS-UHFFFAOYSA-N 1-(1-butylimidazol-2-yl)-1-(2,4-dichlorophenyl)pentan-1-ol Chemical compound CCCCN1C=CN=C1C(O)(CCCC)C1=CC=C(Cl)C=C1Cl GQCLQIPBAOEHDS-UHFFFAOYSA-N 0.000 claims 1
- KETRWBCPIUBRDE-UHFFFAOYSA-N 1-(1-butylimidazol-2-yl)-1-(2-chlorophenyl)pentan-1-ol Chemical compound CCCCN1C=CN=C1C(O)(CCCC)C1=CC=CC=C1Cl KETRWBCPIUBRDE-UHFFFAOYSA-N 0.000 claims 1
- QFLHAYYEBGPZRS-UHFFFAOYSA-N 1-(1-butylimidazol-2-yl)-1-(4-chlorophenyl)ethanol Chemical compound CCCCN1C=CN=C1C(C)(O)C1=CC=C(Cl)C=C1 QFLHAYYEBGPZRS-UHFFFAOYSA-N 0.000 claims 1
- QOELUNSKQVIOIZ-UHFFFAOYSA-N 1-(1-butylimidazol-2-yl)-1-(4-chlorophenyl)pentan-1-ol Chemical compound CCCCN1C=CN=C1C(O)(CCCC)C1=CC=C(Cl)C=C1 QOELUNSKQVIOIZ-UHFFFAOYSA-N 0.000 claims 1
- NYQSCMIJHPKRSK-UHFFFAOYSA-N 1-(1-dodecylimidazol-2-yl)-1-(3,4,5-trimethoxyphenyl)pentan-1-ol Chemical compound CCCCCCCCCCCCN1C=CN=C1C(O)(CCCC)C1=CC(OC)=C(OC)C(OC)=C1 NYQSCMIJHPKRSK-UHFFFAOYSA-N 0.000 claims 1
- HJWSQRCHXSOMQM-UHFFFAOYSA-N 1-(1-methylimidazol-2-yl)-1-(3,4,5-trimethoxyphenyl)ethanol Chemical compound COC1=C(OC)C(OC)=CC(C(C)(O)C=2N(C=CN=2)C)=C1 HJWSQRCHXSOMQM-UHFFFAOYSA-N 0.000 claims 1
- DOEYYTQISIVAMY-UHFFFAOYSA-N 1-(1-methylimidazol-2-yl)-1-[3-(trifluoromethyl)phenyl]pentan-1-ol Chemical compound C=1C=CC(C(F)(F)F)=CC=1C(O)(CCCC)C1=NC=CN1C DOEYYTQISIVAMY-UHFFFAOYSA-N 0.000 claims 1
- XHAZUBPMLWQYNT-UHFFFAOYSA-N 1-(1-methylimidazol-2-yl)-1-[4-(trifluoromethyl)phenyl]ethanol Chemical compound CN1C=CN=C1C(C)(O)C1=CC=C(C(F)(F)F)C=C1 XHAZUBPMLWQYNT-UHFFFAOYSA-N 0.000 claims 1
- MLLHMGAXTPMXJX-UHFFFAOYSA-N 1-(2-butylpyrazol-3-yl)-1-(4-chlorophenyl)ethanol Chemical compound CCCCN1N=CC=C1C(C)(O)C1=CC=C(Cl)C=C1 MLLHMGAXTPMXJX-UHFFFAOYSA-N 0.000 claims 1
- BCGAWUVOMNNRPE-UHFFFAOYSA-N 1-(2-butylpyrazol-3-yl)-1-phenylprop-2-en-1-ol Chemical compound CCCCN1N=CC=C1C(O)(C=C)C1=CC=CC=C1 BCGAWUVOMNNRPE-UHFFFAOYSA-N 0.000 claims 1
- WVRVNOMMWKEQED-UHFFFAOYSA-N 1-(2-chlorophenyl)-1-(1-methylimidazol-2-yl)ethanol Chemical compound CN1C=CN=C1C(C)(O)C1=CC=CC=C1Cl WVRVNOMMWKEQED-UHFFFAOYSA-N 0.000 claims 1
- XPXNVYSLUHGWHD-UHFFFAOYSA-N 1-(2-chlorophenyl)-1-(1-methylimidazol-2-yl)pentan-1-ol Chemical compound C=1C=CC=C(Cl)C=1C(O)(CCCC)C1=NC=CN1C XPXNVYSLUHGWHD-UHFFFAOYSA-N 0.000 claims 1
- PJVPJYXENRKSMH-UHFFFAOYSA-N 1-(2-methylpyrazol-3-yl)-1-(3,4,5-trimethoxyphenyl)ethanol Chemical compound COC1=C(OC)C(OC)=CC(C(C)(O)C=2N(N=CC=2)C)=C1 PJVPJYXENRKSMH-UHFFFAOYSA-N 0.000 claims 1
- MFPQHUMVIGZVPG-UHFFFAOYSA-N 1-(2-methylpyrazol-3-yl)-1-phenylethanol Chemical compound CN1N=CC=C1C(C)(O)C1=CC=CC=C1 MFPQHUMVIGZVPG-UHFFFAOYSA-N 0.000 claims 1
- XEBCHPNMVGYZCJ-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-1-(1-methylimidazol-2-yl)ethanol Chemical compound CN1C=CN=C1C(C)(O)C1=CC=C(Cl)C(Cl)=C1 XEBCHPNMVGYZCJ-UHFFFAOYSA-N 0.000 claims 1
- XMPXFKVLHVGEFZ-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-1-(1-methylimidazol-2-yl)pentan-1-ol Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(O)(CCCC)C1=NC=CN1C XMPXFKVLHVGEFZ-UHFFFAOYSA-N 0.000 claims 1
- DWDVLGPIYRLKRH-UHFFFAOYSA-N 1-(3-chlorophenyl)-1-(1-methylimidazol-2-yl)ethanol Chemical compound CN1C=CN=C1C(C)(O)C1=CC=CC(Cl)=C1 DWDVLGPIYRLKRH-UHFFFAOYSA-N 0.000 claims 1
- SFHYMEZVPKTHKV-UHFFFAOYSA-N 1-(3-chlorophenyl)-1-(1-methylimidazol-2-yl)pentan-1-ol Chemical compound C=1C=CC(Cl)=CC=1C(O)(CCCC)C1=NC=CN1C SFHYMEZVPKTHKV-UHFFFAOYSA-N 0.000 claims 1
- KTHPEZGAKABABA-UHFFFAOYSA-N 1-(4-chlorophenyl)-1-(1-methylimidazol-2-yl)ethanol Chemical compound CN1C=CN=C1C(C)(O)C1=CC=C(Cl)C=C1 KTHPEZGAKABABA-UHFFFAOYSA-N 0.000 claims 1
- BDHNPQBABBNTNE-UHFFFAOYSA-N 1-(4-chlorophenyl)-1-(1-methylimidazol-2-yl)pentan-1-ol Chemical compound C=1C=C(Cl)C=CC=1C(O)(CCCC)C1=NC=CN1C BDHNPQBABBNTNE-UHFFFAOYSA-N 0.000 claims 1
- ZQQAEIBJOGBKHF-UHFFFAOYSA-N 1-(4-chlorophenyl)-1-(1-methylimidazol-2-yl)propan-1-ol Chemical compound C=1C=C(Cl)C=CC=1C(O)(CC)C1=NC=CN1C ZQQAEIBJOGBKHF-UHFFFAOYSA-N 0.000 claims 1
- XSWMNDDYGZVTNX-UHFFFAOYSA-N 1-(4-chlorophenyl)-1-[1-(2-piperidin-1-ylethyl)imidazol-2-yl]ethanol Chemical compound C=1C=C(Cl)C=CC=1C(O)(C)C1=NC=CN1CCN1CCCCC1 XSWMNDDYGZVTNX-UHFFFAOYSA-N 0.000 claims 1
- BLIIGCBWMDJXSY-UHFFFAOYSA-N 1-(4-chlorophenyl)-1-[1-[3-(dimethylamino)propyl]imidazol-2-yl]ethanol Chemical compound CN(C)CCCN1C=CN=C1C(C)(O)C1=CC=C(Cl)C=C1 BLIIGCBWMDJXSY-UHFFFAOYSA-N 0.000 claims 1
- BQWWWOBZYLAWTJ-UHFFFAOYSA-N 1-(4-fluorophenyl)-1-(1-methylimidazol-2-yl)ethanol Chemical compound CN1C=CN=C1C(C)(O)C1=CC=C(F)C=C1 BQWWWOBZYLAWTJ-UHFFFAOYSA-N 0.000 claims 1
- PGZIXIJCMBPHCS-UHFFFAOYSA-N 1-[2-[1-(1-methylimidazol-2-yl)-1-[3-(trifluoromethyl)phenyl]ethoxy]ethyl]piperidine Chemical compound CN1C=CN=C1C(C)(C=1C=C(C=CC=1)C(F)(F)F)OCCN1CCCCC1 PGZIXIJCMBPHCS-UHFFFAOYSA-N 0.000 claims 1
- XLJKDXRRCUIRAX-UHFFFAOYSA-N 1-methyl-5-[2-(1-methylpyrrolidin-2-yl)ethoxy-phenylmethyl]pyrazole Chemical compound CN1CCCC1CCOC(C=1C=CC=CC=1)C1=CC=NN1C XLJKDXRRCUIRAX-UHFFFAOYSA-N 0.000 claims 1
- APKDHLMIBHYURQ-UHFFFAOYSA-N 1h-imidazol-2-yl(phenyl)methanol Chemical compound C=1C=CC=CC=1C(O)C1=NC=CN1 APKDHLMIBHYURQ-UHFFFAOYSA-N 0.000 claims 1
- UHWMCCCMUUTOFT-UHFFFAOYSA-N 2-[(1-butylimidazol-2-yl)-[4-(trifluoromethyl)phenyl]methoxy]-n,n-dimethylethanamine Chemical compound CCCCN1C=CN=C1C(OCCN(C)C)C1=CC=C(C(F)(F)F)C=C1 UHWMCCCMUUTOFT-UHFFFAOYSA-N 0.000 claims 1
- IUHGHUIFWRTGTR-UHFFFAOYSA-N 2-[(2,5-dimethylpyrazol-3-yl)-phenylmethoxy]-n,n-dimethylethanamine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC(C)=NN1C IUHGHUIFWRTGTR-UHFFFAOYSA-N 0.000 claims 1
- BVXGNJYVUAMMCA-UHFFFAOYSA-N 2-[(3,4-dichlorophenyl)-(1-methylimidazol-2-yl)methoxy]-n,n-dimethylethanamine Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(OCCN(C)C)C1=NC=CN1C BVXGNJYVUAMMCA-UHFFFAOYSA-N 0.000 claims 1
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- 230000002411 adverse Effects 0.000 description 3
- 230000001713 cholinergic effect Effects 0.000 description 3
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 3
- 206010013663 drug dependence Diseases 0.000 description 3
- 230000003137 locomotive effect Effects 0.000 description 3
- IUQJDHJVPLLKFL-UHFFFAOYSA-N 2-(2,4-dichlorophenoxy)acetate;dimethylazanium Chemical compound CNC.OC(=O)COC1=CC=C(Cl)C=C1Cl IUQJDHJVPLLKFL-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 229960004373 acetylcholine Drugs 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 210000003050 axon Anatomy 0.000 description 2
- 210000004227 basal ganglia Anatomy 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 210000001153 interneuron Anatomy 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical group NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 102000003141 Tachykinin Human genes 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000338 anxiogenic effect Effects 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000002536 noncholinergic effect Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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Abstract
Deriv ty aryl (nebo heteroaryl)azolylkarbinol obecn ho vzorce I, kde Ar je p° padn substituovan² nebo nesubstituovan² fenylov² nebo thienylov² zbytek, R1 je atom vod ku, cyklohexylov skupina, N-methylpiperidylov skupina, fenylov skupina, vinylov skupina nebo alkylov skupina s 1 a 4 atomy uhl ku; R2 je atom vod ku, dialkylaminoalkyl, alkylazaheterocyklylalkyl nebo azaheterocyklylalkyl; a Het je heterocyklick² dus kat² aromatick² 5- lenn² kruh, kter² obsahuje jeden a t°i atomy dus ku, nesubstituovan² nebo substituovan², jsou u ite n pro l bu chorob, kter jsou zprost°edkov ny p°ebytkem substance P, zejm na chorob centr ln ho nervov ho syst mu, jako je ·zkost, deprese, schizofrenie, maniak ln depresivn psych zy, sexu ln dysfunkce, narkomanie, kognitivn choroby, pohybov choroby, atd. u savc , v etn lid .\
Description
Předkládaný vynález se týká použití derivátů aryl (nebo heteroaryl)azolylkarbinolů obecného vzorce I a jejich fyziologicky přijatelných soli pro přípravu léčiv používaných v humánní a/nebo veterinární terapii pro léčbu chorob zprostředkovaných přebytkem substance P, zejména chorob centrálního nervového systému, jako je úzkost, deprese, schizofrenie, maniakální depresivní psychózy, sexuální dysfunkce, narkomanie, kognitivní choroby, pohybové choroby, atd.
Dosavadní stav techniky
Substance P je peptid, tachykinin, který může být izolován z mozkových tkání a z gastrointestinálního traktu. V mozku, substantia nigra a bazální gangliony obsahují relativně vysoké koncentrace substance P.
Existuje evidentní názor, že substance P působí jako neurotransmiter. V bazálních ganglionech se substance P syntetizuje v páteřních striatálních neuronech střední velikosti, které vyčnívají z substantia nigra pars reticulata. Studie o distribuci receptorů indikují, že receptory NK] se nacházejí v striatu v relativně vysoké hustotě, ale pro jakýkoliv účel a rozsah chybějí v substantia nigra. Nicméně substantia nigra obsahuje jednu znejvyšších úrovní tkáňové substance P v centrálním nervovém systému. Ačkoliv se zdá, že receptor a ligand jsou nepárové, substance P může vzájemně reagovat s receptory ve striatu uvolněním se z kolaterálních lokálních axonů striatonigrálních neuronů. Bylo zjištěno, že konce obsahující substanci P zabezpečují synaptický kontakt s cholinergními buněčnými tělísky v striatu. Zdá se, že ve striatu jsou receptory NK] exprimovány zejména cholinergními inter-neurony, ačkoliv malé množství necholinergních striatálních neuronů může exprimovat tyto receptory.
Dále bylo prokázáno, že stimulace receptorů NK] substancí P zvyšuje uvolnění acetylcholinu (Ach) jak in vitro, tak in vivo. Jako důsledek, byl popsán anatomický okruh, ve kterém substance P uvolněná lokálně ve striatu z kolaterálních axonů striatonigrálních neuronů se může vázat k receptorům NK! striatálních cholinergních inter-neuronů a stimuluje uvolnění acetylcholinu (J. J. Anderson, J. Pharmacol. Exp. Ther., 1995, 274, 928-936).
Substance P je také zahrnuta v patofyziologii několika neuropsychiatrických chorob, jako jsou schizofrenie, maniakální depresivní psychózy, sexuální dysfunkce, narkomanie, kognitivní choroby, pohybové choroby nebo deprese (M. Bianchi, Inflamm. Res., 1995., 44 (11), 466-469). Podobně může být předpokládána relace mezi depresivními stavy a úrovněmi substance P, jelikož produkty, které působí jako inhibitory substance P, mají zřetelně antidepresivní složku, což bylo prokázáno ve studiích na různých zvířecích modelech.
Na druhé straně existuje také vztah mezi procesy úzkosti (ůzkost/anxiogeneze) a úrovněmi substance P. Bylo prokázáno, že produkty, které působí jako antagonisty receptorů NKj vykazují anxiolytickou účinnost ve zkoušce vzájemného působení (S. Filé, Pharmacol. Biochem. Behav., 1997, 58 (3), 747-752) s malou tendencí vůči vývoji tolerance. Podobně podání substance P je anxiogenní činidlo, při zkoušce v bludišti (R. M. Teixeira, Eur. J. Pharmacol., 1996,31 (1), 7-14) a blokátory receptorů substance P mají opačný účinek. Bylo proto odvozeno, že úrovně substance P hrají důležitou úlohu v expresi úzkosti.
(I),
V patentech EP 289 380 a ES 9800793 jsou popsány karbinolové deriváty obecného vzorce I
R1
Ar--Het
O \
R2 kde Ar znamená benzenový kruh nebo substituovaný nebo nesubstituovaný thiofenový kruh, Rl znamená atom vodíku nebo nižší alkylovou skupinu s 1 až 4 atomy uhlíku; R2 znamená dialkylaminoalkylový nebo heterocyklylalkylový zbytek a Het znamená azol, rovněž jejich fyziologicky přijatelné soli, které jsou nárokovány pro léčbu bolesti.
V patentech EP 808 308, ES 9701538, ES 9701728 a ES 9800793 jsou také popsány některé postupy pro přípravu enantiomemě čistých sloučenin obecného vzorce I.
Nyní bylo nalezeno, že sloučeniny obecného vzorce I, jejich fyziologicky přijatelné soli, jsou zejména užitečné při přípravě léčiv užitečných ve veterinární a humánní terapii, pro léčení chorob které jsou zprostředkovány přebytkem substance P, zejména chorob centrálního nervového systému, jako je úzkost, deprese, schizofrenie, maniakální depresivní psychózy, sexuální dysfunkce, narkomanie, kognitivní choroby, pohybové choroby, atd.
Podstata vynálezu
Předkládaný vynález se týká použití derivátů aryl (nebo heteroaryl)azolylkarbinolů obecného vzorce I
R1
Ar--Het o ®’ XR2 kde
Ar je fenylový nebo thienylový zbytek, nesubstituovaný nebo případně substituovaný 1, 2 nebo 3 stejnými nebo různými substituenty vybranými ze souboru, který zahrnuje fluor, chlor, brom, methyl, trifluormethyl a methoxyskupinu;
Rl je atom vodíku, cyklohexylová skupina, N-methylpiperidylová skupina, fenylová skupina, vinylová skupina nebo alkylová skupina s 1 až 4 atomy uhlíku;
R2 je atom vodíku nebo di(Ci-C4 alkyl)amino(C2-C3 alkyl), (Ci-C2 alkyl)azaheterocyklyl(C2-C3 alkyl) nebo azaheterocyklyl(Cr-C3 alkyl); a
Het je heterocyklický dusíkatý aromatický 5-členný kruh, který obsahuje jeden až tři atomy dusíku, nesubstituovaný nebo substituovaný 1 nebo 2 stejnými nebo různými substituenty vybranými ze souboru, který zahrnuje fluor, chlor, brom, alkylovou skupinu s 1 až 12 atomy uhlíku, benzylovou skupinu, kyano(C2-C3alkyl)skupinu, karboxyíCr-Qalkyl) skupinu, methoxykarbo
-2CZ 292065 B6 nyl(C2-C3alkyl) skupinu, hydroxy(C2-C3alkyl) skupinu, amino(C2-C3alkyl) skupinu, di(CiC4alkyl)amino(C2-C3alkyl) skupinu a azaheterocyklyl(C2-C3alkyl) skupinu;
nebo jejich fyziologicky přijatelných solí, pro přípravu léčiva pro léčení chorob, které jsou zprostředkovány přebytkem substance P, zejména chorob centrálního nervového systému, jako je úzkost, deprese, schizofrenie, maniakální depresivní psychózy, sexuální dysfunkce, narkomanie, kognitivní choroby, pohybové choroby, atd. u savců, včetně lidí.
Výraz „alkylová skupina s 1 až 4 atomy uhlíku“ znamená nasycený uhlovodíkový zbytek s 1 až 4 atomy uhlíku s přímým nebo rozvětveným řetězcem, jako je například methyl, ethyl, propyl, izopropyl, butyl, izobutyl, sek.butyl a terc.butyl.
Výraz ,,di(Ci-C4alkyl)aminoalkyl(C2-C3) a (Ci-C2alkyl)azaheterocyklyl(C2-C3alkyl) nebo azaheterocyklyl(C2-C3alkyl)“ znamená alkylovou skupinu se dvěma nebo třemi atomy uhlíku vázanými k di(Ci-C4alkyl)aminu nebo k cyklickému aminu, jako je dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidylethyl, N-ethylpiperidylethyl, N-methylpyrrolidinylethyl, morfolinylpropyl, pyrrolidinylalkyl, atd.
Výraz ,,kyano(C2-C3alkyl)“ znamená alkylovou skupinu se dvěma nebo třemi atomy uhlíku vázanou ke kyanové funkční skupině.
Výraz ,,karboxy(C2-C3alkyl)“ znamená alkylovou skupinu se dvěma nebo třemi atomy uhlíku vázanou ke karboxylové funkční skupině.
Výraz „methoxykarbonyl(C2-C3alkyl)‘‘ znamená alkylovou skupinu se dvěma až třemi atomy uhlíku vázanou k methoxykarbonylové funkční skupině.
Výraz ,,hydroxy(C2-C3alkyl)“ znamená alkylovou skupinu se dvěma až třemi atomy uhlíku vázanou k hydroxylové funkční skupině.
Výraz ,,amino(C2-C3alkyl)“ znamená alkylovou skupinu se dvěma až třemi atomy uhlíku vázanou k aminové funkční skupině.
Sloučeniny obecného vzorce I se mohou připravit podle postupů popsaných v patentech EP 289 380 nebo ES 9800793. Sloučeniny obecného vzorce I mají stereogenní centrum a vynález se týká jak použití čistého enantiomeru, tak směsi enantiomerů. Enantiomery se mohou připravit podle některého z postupů popsaných v patentech EP 808 308, ES 9701538, ES 9701728 nebo ES 9800793.
Příklady farmaceutických prostředků, které obsahují sloučeniny obecného vzorce I, jsou popsány v patentech EP 289 380 nebo ES 900793.
Ilustrativní příklady sloučenin poskytovaných předkládaným vynálezem zahrnují sloučeniny, které jsou charakterizovány daty uvedenými v tabulkách 1 až 7.
-3CZ 292065 B6
| Přiklad čislo | Ra | Rt | Ra | z, | Za | R< | Ra |
| 1 | H | H | Me | CH | N | H | DMA |
| 2 | 4-CI | Me | Me | CH | N | H | DMA |
| 3 | 4-CI | H | Me | CH | N | H | DMA |
| 4 | 3-CI | H | Me | CH | N | H | DMA |
| 5 | 2-CI | Me | Me | CH | N | H | DMA |
| 6 | 4-F | Me | Me | CH | N | H | DMA |
| 7 | 3-CFj | Me | Me | CH | N | H | DMA |
| 8 | 3-CI | Me | Me | CH | N | H | DMA |
| 9 | 3-CI | n-But | Me | CH | N | H | DMA |
| 10 | 4-CI | Me | n-But | CH | N | H | DMA |
| 11 | 4-OMe | Me | Me | CH | N | H | DMA |
| 12 | 3-CI | Me | Me | CH | N | H | Pyr |
| 13 | 3,4,5-tri-OMe | n-But | Cl2Hjs- | CH | N | H | DMA |
| 14 | 4-CFj | H | n-But | CH | N | H | DMA |
| 15 | 3-CFa | Me | Me | CH | N | H | Píp |
| 16 | 3,4-di-Cl | Θ | Me | CH | N | H | DMA |
| 17 | 3,4-di-Cl | n-But | Me | CH | N | H | DMA |
| 18 | 3,4-di-Cl | Me | Me | CH | N | H | DMA |
| 19 | 3,4-di-Cl | H | Me | CH | N | H | DMA |
| 20 | 4-CI | Me | CH | N | H | DMA | |
| 21 | 4-CI | Me | Ohcha- | CH | N | H | DMA |
| 22 | 4-CI | H | NeC-(CH2)3- | CH | N | H | DMA |
| 23 | 4-CI | -O- | Me | CH | N | H | DMA |
| 24 | 4-CI | H | -ch3-^Q> | CH | N | H | MBA |
-4CZ 292065 B6
| Přiklad číslo | Rs | R, | Ra | z, | zs | R. | Rs |
| 25 | 4-Cl | Me | -(CH2)3-N(CH3)-CH2- | N | H | DMA | |
| 26 | 4-Cl | H | -(CH2)3-N(CH3)-CH2- | N | H | DMA | |
| 27 | H | H | n-But | N | CH | H | DMA |
| 28 | 4-Cl | o- | Me | N | CH | H | DMA |
| 29 | 3.4,5-tri-OMe | H | n-But | N | CH | H | DMA |
| 30 | 4-Cl | Me | n-But | N | CH | H | DMA |
| 31 | H | H | Me | N | CH | H | DMA |
| 32 | H | Me | Me | N | CH | H | DMA |
| 33 | 3,4,5-tri-OMe | H | Me | N | CH | H | DMA |
| 34 | H | H | Me | N | CH | H | Pyr |
| 35 | H | H | Me | N | CH | H | Mor |
| 36 | 3,4,5-tri-OMe | Me | Me | N | CH | H | DMA |
| 37 | H | H | Me | N | CBr | H | DMA |
| 38 | H | Me | Me | N | CH | CH3 | DMA |
| 39 | H | H | Me | N | CH | ch3 | DMA |
| 40 | 2-Me | H | Me | N | CH | Η | DMA |
| 41 | 4-Cl | H | Me | N | CCI | H | DMA |
| 42 | 4-Cl | H | Me | N | CH | Η | DMA |
| 43 | 3-CI | H | Me | N | CH | H | DMA |
| 44 | 4-Me | H | Me | N | CH | Η | DMA |
| 45 | 2-CI | H | Me | N | CH | H | DMA |
| 46 | H | H | Me | N | CH | H | Píp |
| 47 | H | H | Me | N | CH | H | Pr ó- |
| 48 | H | H | Me | N | CH | H | ,Et O |
| 49 | H | H | Me | N | CH | H | Me 0- |
| 50 | H | H | Me | N | CH | H | DIPA |
| 51 | H | H | Me | N | CH | H | Me <5- |
| 52 | 4-Cl | Me | Me | CH | N | H | DMAP |
| 53 | 3-CI | H | Me | CH | N | H | DMAP |
| 54 | 4-Cl | Et | Me | CH | N | H | DMAP |
| 55 | 3-CI | n-But | Me | CH | N | H | DMAP |
-5CZ 292065 B6
| Přiklad číslo | Rs | Ri | Rj | Zi | R< | r2 | |
| 56 | 4-Cl | Θ | Me | CH | N | H | DMAP |
| 57 | 4-F | Me | Me | CH | N | H | DMAP |
| 58 | 3-CFa | Me | Me | CH | N | H | DMAP |
| 59 | 2-CI | Me | Me | CH | N | H | DMAP |
| 60 | 3-CI | Me | Me | CH | N | H | DMAP |
| 61 | 3,4,5-tri-OMe | Me | Me | CH | N | H | DMAP |
| 62 | 4-OMe | Me | Me | CH | N | H | DMAP |
| 63 | 4-Cl | H | Me | CH | N | H i | DMAP |
| 64 | 3,4,5-tri-OMe | H | Me | CH | N | H ! | DMAP |
| 65 | 4-CFj | Me | Me | CH | N | H í | DMAP |
| 66 | 3-CFj | H | Me | CH | N | H í | DMAP |
| 67 | 4-CFa | H | Me | CH | N | H i | DMAP |
| 68 | 4-OMe | H | Me | CH | N | H | DMAP |
| 69 | 3-CFa | n-Bul | Me | CH | N | H | DMAP |
| 70 | 4-Cl | Me | n-But | CH | N | H | DMAP |
| 71 | 3,4,5-tri-OMe | n-But | n-But | CH | N | H | DMAP |
| 72 | 2-CI | n-But | n-But | CH | N | H | DMAP |
| 73 | 2,4-ďi-CI | n-But | n-But | CH | N | H | DMAP |
| 74 | 4-CF, | H | n-But | CH | N | H | DMAP |
| 75 | 4-Cl | H | Mé | CH | N | H | PipP |
| 76 | 4-CF3 | Me | Me | CH | N | H | PipP |
| 77 | 2-CI | n-But | Me | CH | N | H | DMAP |
| 78 | 3,4-di-CI | n-But | Me | CH | N | H | DMAP |
| 79 | 3,4-di-CI | Me | Me | CH | N | H | DMAP |
| 80 | 3,4-di-CI | H | Me | CH | N | H | DMAP |
| 81 | 3,4-di-CI | Θ | Me | CH | N | H | DMAP |
| 82 | 4-Cl | Me | O<cha- | CH | N | H | DMAP |
| 83 | 4-Cl | Me | CH | N | H | DMAP | |
| 84 | 4-Cl | CHj-θ- | Me | CH | N | H | DMAP |
| 85 | H | H | n-But | N | CH | H | DMAP |
| 86 | 4-Cl | Me | n-But | N | CH | H | DMAP |
| 87 | H | H | Me | N | CH | H | DMAP |
| 88 | H | Me | Me | N | CH | H | DMAP |
| 89 | H | Me | Me | N | CH | Me | DMAP |
-6CZ 292065 B6
| Příklad číslo | Rs | Rt | Ra | Z, | z2 | Rx | Rí |
| 90 | H | H | Me | N | CH | Me | DMAP |
| 91 | 2-Me | H | Me | N | CH | H | DMAP |
| 92 | 4 Cl | H | Me | N | CH | H | DMAP |
| 93 | H | H | Me | N | CH | H | PipP |
| 94 | H | H | Me | N | CH | H | PirP |
DMA = dimethylaminoethyl
Pyr = pyrrolidinylethyl
Pip = piperidylelhyl
MBA - (methyt-benzylamino)ethyl Mor = morfolinylethyl
DIPA = diizopropylaminoethyl DMAP = dimethylaminopropyl PipP = piperidylpropyl
PirP = pyrrolidinylpropyl
Tabulka 2
| Pfiklad čisto | Rs | Rt | r3 | r2 |
| 95 | 4-CI | H | Me | DMA |
| 96 | 4-CI | Me | Me | DMA |
| 97 | 4-CI | H | Me | Λ O |
| 98 | 4-CI | H | Me | jvle Cr- |
| 99 | 4-CI | H | Me | Et z /-N O- |
| 100 | 4-CI | H | Me | DIPA |
| 101 | 4-CI | H | Me | }Ae cy |
| 102 | H | H | Me | DMAP |
| 103 | 4-CI | H | Me | MorP |
| 104 | 4-CI | H | Me | PirP |
DMA = dimethylaminoethyf DIPA = diisopropylaminoethyl DMAP = dimethylaminopropyl MorP = morfolinylpropyl PirP = pyrrolidinylpropyl
-8CZ 292065 B6
Tabulka 3
| Příklad číslo | Rs | Ri | Rj | Zi | Z2 | Rj | T.t. |
| 105 | H | H | H | CH | N | H | 202-3°C |
| 106 | 4-CI | H | H | CH | N | H | 196-7°C |
| 107 | 4-CI | H | Me | CH | N | H | 137-9°C |
| 108 | 3-CI | H | Me | CH | N | H | 126-8°C |
| 109 | 4-F | H | Me | CH | N | H | 112-5°C |
| 110 | 3-CF3 | H | Me | CH | N | H | 125-6°C |
| 111 | 4-CF3 | H | Me | CH | N | H | 124-5’C |
| 112 | 3,4,5-tri-OMe | H | Me | CH | N | H | 160-1’C |
| 113 | 3.4-di-CI | H | Me | CH | N | H | 157-9°C |
| 114 | 4-CF3 | H | n-But | CH | N | H | 111-2°C |
| 115 | 2,4-di-CI | H | n-But | CH | N | H | 94-7°C |
| 116 | 4-CI | H | n-But | CH | N | H | 108-110°C |
| 117 | 3,4,5-tri-OMe | H | n-But | CH | N | H | 122-5°C |
| 118 | 3,4,5-tri-OMe | H | n-dodecyl | CH | N | H | Olej |
| 119 | 3-C) | n-But | Me | CH | N | H | 125-6°C |
| 120 | 3-CI | Me | Me | CH | N | H | 180-1°C |
| 121 | 4-CI | Me | Me | CH | N | H | 191-2°C |
| 122 | 4-CI | Me— | Me | CH | N | H | 183-4°C |
| 123 | 4-CI | Et | Me | CH | N | H | 166-8°C |
| 124 | 4-CI | n-But | Me | CH | N | H | 120-2’C |
| 125 | 4-CI | Me | CH | N | H | 161-2°C | |
| 126 | 2-CI | Me | Me | CH | N | H | 181-2’C |
| 127 | 2-ČI | n-But | Me | CH | N | H | 138-41°C |
| 128 | 3-CF3 | Me | Me | CH | N | H | 193-4°C |
| 129 | 3-CFa | n-But | Me | CH | N | H | 140-1°C |
-9CZ 292065 B6
| Příklad číslo | Rs | Ri | r3 | Zi | Zi | Rs | T.t. |
| 130 | 3-CF3 | 0 | Me | CH | N | H | 156-7°C |
| 131 | 4-CF3 | Me | Me | CH | N | H | 167-8°C |
| 132 | 4-F | Me | Me | CH | N | H | 176-7°C |
| 133 | 4-OMe | Me | Me | CH | N | H | 181-2°C |
| 134 | 3,4-di-CI | Me | Me | CH | N | H | 207-8’C |
| 135 | 3,4-di-CI | n-But | Me | CH | N | 142-4’C | |
| 136 | 3,4-di-CI | 0 | Me | CH | N | H | 158-60°C |
| 137 | 3,4,5-tri-OMe | ch3 | Me | CH | N | H | 181-2°C |
| 138 | 4-Cl | Me | n-But | CH | N | H | 174-5°C |
| 139 | 4-Cl | n-But | n-But | CH | N | H | 134-5°C |
| 140 | 4-Cl | n-But | CH | N | H | 184-5°C | |
| 141 | 3,4,5-tri-OMe | n-But | n-But | CH | N | H | 125-6°C |
| 142 | 2-CI | n-But | n-But | CH | N | H | 132-3’C |
| 143 | 3-CF3 | Et | n-But | CH | N | H | 164-5’C |
| 144 | 2,4-di-CI | n-But | n-But | CH | N | H | 142-3°C |
| 145 | 4-Cl | Me | CH | N | H | 136-7°C | |
| 146 | 4-Cl | Me | Me2N-(CH2)- 3 | CH | N | H | 147-8°C |
| 147 | 3,4,5-tri-OMe | n-But | n-Dodecyl | CH | N | H | 75-7°C |
| 148 | 3-CF3 | n-But | Ph-CH2— | CH | N | H | Olej |
| 149 | 4-Cl | Me | Ph-CH2— | CH | N | H | 154-5°C |
| 150 | 4-Cl | H | -(CH2)-CN | CH | N | H | 134-50C |
| 151 | 4-Cl | H | -(ch2)2-nh2 | CH | N | H | 187-8°C |
| 152 | 3-CI | H | -(CH2)-CO2H | CH | N | H | 212-3°C |
| 153 | 4-Cl | H | -(CH2)2-CH2OH | CH | N | H | 121-2’C |
| 154 | 4-Cl | H | -(CH2)2-CO2Me | CH | N | H | 96-7°C |
| 155 | H | H | -(ch2)2-ch2oh | CH | N | H | 110-1’C |
| 156 | 4-Me | H | -(ch2)2-ch2oh | CH | N | H | 104-5’C |
| 157 | 4-OMe | H | “(CH2)2-CH2OH | CH | N | H | Olej |
- 10CZ 292065 B6
| Přiklad číslo | Rs | Ri | Ra | z, | z. | R< | T.t. |
| 158 | 3,4-di-CI | H | -(ch2)2-ch2oh | CH | N | H | 138-9’C |
| 159 | H | H | -(CH2)2-CO2Me | CH | N | H | 93-6°C |
| 160 | 4-CI | H | -(ch2)4-oh | CH | N | H | 131-2°C |
| 161 | 4-CI | H | -(ch2)3-cn | CH | N | H | Olej |
| 162 | 4-CI | H | ~(ch2)-co2h | CH | N | H | >300°C |
| 163 | 4-CI | H | -(CH2)3-CO2Me | CH | N | H | 85-7°C |
| 164 | H | H | n-But | N | CH | H | 47-8°C |
| 165 | 4-CI | H | Me | N | CH | H | 94-7’C |
| 166 | 3,4,5-tri-OMe | H | Me | N | CH | H | Olej ΐ |
| 167 | 3,4,5-tri-OMe | H | n-But | N | CH | H | Olej |
| 168 | H | H | Me | N | CBr | H | 110-11°C |
| 169 | 4-CI | Ph | Me | N | CH | H | 167-8°C |
| 170 | 4-CI | Me | n-But | N | CH | H | Olej |
| 171 | H | Me | Me | N | CH | H | 99-100°C |
| 172 | 3,4,5-tri-OMe | Me | Me | N | CH | H | 144-5°C |
| 173 | H | Me | Me | N | CH | Me | 137-8°C |
| 174 | H | ch2=ch- | Me | N | CH | H | 95-6°C |
| 175 | 4-CI | ch2=ch- | n-But | N | CH | H | 84-5qC |
| 176 | H | H | Me | N | CCl | H | Olej |
| 177 | 2-Me | H | Me | N | CH | H | 113-4°C |
| 178 | 3-CI | H | Me | N | CH | H | 128-9°C |
| 179 | 4-Me | H | Me | N | CH | H | 123-6°C |
| 180 | 2-CI | H | Me | N | CH | H | 96-8°C |
| 181 | 4-OMe | H | Me | N | CH | H | 129-30°C |
-11 CZ 292065 B6
Tabulka 4
| Přiklad číslo | ’H RMN, δ (CDCIj) |
| 1 | 7,2 (s, 5H); 6.8 (d, 2H); 5,7 (S.1 H); 3,5 (m,2H); 3,35 (s. 3H); 2.6 (l, 2H); 2,3 (s. 6H) |
| 2 | 7,2 (s. 4H); 6,85 (d, 2H); 3,7 (m, 1H); 3,2 (s, 3H); 3,1 (m, 1H); 2,5 (t, 2H); 2,2 (s. 6H); 1,85 (s. 3H) |
| 3 | 7,25 (s, 4H); 6,85 (d, 2H); 6,65 (s, 1H); 3,6 (m. 2H); 3,45 (s. 3H): 2,6 (t, 2H); 2,25 (s. 6H) |
| 4 | 7,3 (m, 4H); 6,9 (d. 2H); 5,7 (s. 1H); 3,6 (m, 2H); 3,5 (s. 3H); 2,65 (t, 2H); 2,35 (s. 6H) |
| 5 | 7,9 (m. 1H); 7,1 (m, 3H); 6,8 (d. 2H); 3,55 (m, 1H); 3,05 (s, 3H); 2,8(m, 1H); 2,4 (t, 2H). 2,15 (s, 6H); 2,0 (s. 3H) |
| 6 | 7,0 (m. 6H); 3,5 (m, 2H); 3,3 (s. 3H); 2,5 (t, 2H); 2,3 (s. 6H); 1,8 (s. 3H) |
| 7 | 7,3 (m. 3H); 6,8 (d. 2H); 3,6 (m. 2H); 3,2 (s, 3H); 2,5 (m, 2H); 2,2 (s, 6H); 1,8 (s, 3H) |
| 8 | 7,0 (m. 3H); 6,8 (d. 2H); 3,55 (m. 2H); 3,2 (s, 3H); 2,5 (m, 2H); 2,2 (s. 6H); 1,8 (s, 3H) |
| 9 | 7,5-6,6 (m. 6H): 3.55 (m, 1H); 3,2 (s, 3H); 3,0 (m, 1H); 2,6 (m. 2H); 2,2 (s. 6H); 1,5-0,5 (m. 7H) |
| 10 | 7,2 (s, 4H); 6,9 (d, 2H); 3,7 (m, 3H); 3,0 (m, 1H); 2,5 (t. 2H); 2,25 (s. 6H); 1.9 (s, 3H); 1,4-0.6 (m. 7H) |
| 11 | 7,0 (q, 4H); 6,75 (d. 2H); 3,7 (s. 3H). 3,6 (m, 1H); 3,25 (s. 3H); 3,0 (m. 1H); 2,55 (t, 2H); 2,2 (s. 6H); 1,9 (s, 3H) |
| 12 | 7,1 (m. 6H); 3,7 (m. 1H); 3,2 (s, 3H); 3,05 (m. 1H); 2,7 (m. 2H); 2,4 (m, 4H): 1,9 (s. 3H); 2,75 (m. 4H) |
| 13 | 6,9 (d, 2H); 6,5 (s, 2H); 3,8 (s. 3H); 3,7 (s, 6H); 3,55 (m, 1H); 3,0 (m. 1H): 2,55 (t. 2H); 2,2 (s. 6H); 1,3-0,7 (m, 34H) |
| 14 | 7,4 (s. 4H); 6,8 (d, 2H); 5,8 (s, 1H); 3,6 (m, 4H); 2,45 (t, 2H); 2,1 (s. 6H); 1,6-0,5 (m. 7H) |
| 15 | 7,7 (s, 1H); 7,35 (m, 3H); 6,9 (d, 2H); 3,7 (m. 3H); 3,2 (s, 3H); 3,1 (m. 1H); 2.6 (m, 2H); 2,4 (m. 4H); 1,9 (s. 3H); 1,45 (4H) |
| 16 | 7,5-6,7 (m, 5H); 3,5 (m. 1H); 3,1 (s. 3H): 2,8 (m, 2H); 2,4 (m, 3H); 2,15 (s. 6H); 2,0-0,3 (m, 9H) |
| 17 | 7,5-6,7 (m, 5H); 3,55 (m. 2H); 3,20 (s, 3H); 1,0 (m. 1H); 3,5 (m, 3H); 2,2 (s, 6H); 1,4-0,6 (m, 7H) |
| 18 | 7,4-6,7 (m, 5H); 3,6 (m, 2H); 3,20 (s, 3H); 3,05 (m, 2H); 2,5 (m, 2H); 2,2 (s. 6H); 1,8 (s, 3H) |
| 19 | 7,6-6,7 (m, 5H); 5,6 (s, 1H); 3,6 (m. 2H); 3,45 (s, 3H); 2,6 (t, 2H); 2,2 (s, 6H) |
| 20 | 7,2 (s. 4H); 6,95 (d. 2H); 3,7 (m, 3H); 3,0 (m. 1H); 2,5 (t, 2H); 2,2 (s. 6H); 2,1 (m, 6H); 1,8 (s. 3H); 1,4 (m. 6H) |
| 21 | 7,25 (s, 4H); 6,9 (d, 2H); 3,7 (m, 3H); 3,1 (m. 1H); 2,6 (t, 2H); 2,20 (s, 6H); 2,15 (m, 6H); 1,9 (m, 5H) |
| 22 | 7,3 (s, 4H); 6.95 (d, 2H); 5,7 (s, 1H); 3,95 (m, 4H); 3.6 (m. 2H): 2,6(t, 2H); 2,2 (m, 8H); 1,9 (m. 2H); 1,45 (m, 6H) |
-12CZ 292065 B6
| Přiklad číslo | . i ’H RMN, δ (CDCIj) 1 |
| 23 | 7,3-6,7 (m, 6H); 3,5 (m, 1H); 3,1 (s. 3H); 2,8 (m, 4H); 2,4 (t. 2H); 2,15-1,0 (m. 15H) |
| 24 | 7.2 (s, 12H); 7,0-6,8 (m, 3H); 5,7 (s, 1H); 5,0 (s, 2H); 3,6 (m, 2H); 3,5 (s, 2H); 2.6 (t, 2H); 2.2 (s. 3H) |
| 25 | 7,25 (m, 4H); 6,9 (s. 1H); 4,0-3,0 (m, 9H); 2,75 (m, 2H); 2,55 (t, 2H); 2,3 (s. 6H); 1,9 (s. 3H); 1,6-1,1 (m, 3H) |
| 26 | 7,3 (s, 4H); 6,8 (s, 1H); 5,6 (s. 1H); 4,5 (m, 2H); 4,1-3,5 (m, 8H); 2.8 (m. 4H); 2,6 (t. 2H); 2,2 (d. 9H); 1,5 (m, 3H) |
| 27 | 7,35 (m, 6H); 5,95 (m, 1H); 5,50 (s. 1H); 4,05 (t, 2H); 3,56 (t, 2H); 2,52 (t, 2H); 2,20 (s. 6H); 1,75-0,7 (m, 7H) |
| 28 | 7,5-7,1 (m, 9H); 6,3 (d, 1H); 3,45 (s, 2H); 3,2 (t, 2H); 2,55 (t, 2H); 2,20 (s, 6H) |
| 29 | 7,35 (m. 1H); 6.6 (m, 2H); 5,9 (t. 1H): 5,45 (s, 1H); 4,05 (t. 2H); 3,8 (m. 9H); 3,55 (l, 2H); 2.6 (t. 2H); 2,25 {d, 6H); 1,9-07 (m, 7H) |
| 30 | 7,45 (m, 1H); 7,2 (s. 4H). 6,3 (m. 1H); 3,7 (t. 2H); 3,15 (t, 2H): 2,5 (t. 2H); 2,25 (s, 6H); 1,75 (s, 3H): 1,65-0,6 (m. 7H) |
| 31 | 7,2 (m, 6H); 5,85 (d, 1H); 5,35 (s, 1H); 3,65 (s. 3H); 3,4 (t, 2H); 2,4 (t, 2H); 2.1 (s, 6H) |
| 32 | 7,45 (d, 1H); 7,2 (s. 5H); 6,4 (d. 1H); 3,6 (m, 1H); 3,4 (s, 3H); 3,15 (m, 1H); 2,55 (t, 2H); 2,25 (s, 6H); 1,8 (s, 3H) |
| 33 | 7,35 (d, 1H); 6,6 (s. 2H); 6.0 (d. 1H); 5.45 (s, 1H); 3.85 (m. 12H); 3.6 (t. 2H); 2.6 (t. 2H); 2.25 (s.6H) |
| 34 | 7,15-7,4 (m, 6H); 5,9 (s. 1H); 5,4 (s, 1H); 3,65 (s. 3H); 3,5 (t. 2H); 2,65 (t, 2H); 2,40 (m. 4H); 1,65 (m. 4H) ; |
| 35 | 7,3 (m, 6H); 5,85 (d, 1H); 5,4 (s. 1H); 3,75 (s, 3H); 3,55 (m. 6H); 2,5 (t, 2H); 2,35 (m. 4H) |
| 36 | 7,45 (d, 1H); 6,5 (s, 2H); 6,35 (d, 1H): 3,8 (s. 3H); 3,75 (s, 6H); 3,5 (s, 3H); 2,5 (t. 2H); 2.3 (s, 6H); 1,8 (s, 2H) |
| 37 | 7,45 (S. 1 h); 7,25 (s. 5H); 5,85 (s, 1H); 3,6 (m, 5H); 2,6 (t, 2H); 2,25 (s, 6H) |
| 38 | 7,2 (s, 5H); 6,15 (s, 1H); 3,65 (m, 1H); 3,35 (s, 3H); 3,2 (m. 1H); 2,5 (1, 2H); 2,2 (s, 9H); 1,75 (s. 3H) |
| 39 | 7,25 (s. 5H); 5,7 (s, 1H); 5,45 (s. 1H); 3.7 (s, 3H); 3,5 (t, 2H); 2,6 (b, 2H); 2,25 (s, 6H); 2,1 (s. 3H) |
| 40 | 7.4-7,0 (m, 5H); 5.7 (s. 1H); 5,6 (s, 1H); 3,85 (s, 3H); 3,5 (t, 2H); 2,55 (i. 2H); £15 (s, 9H) |
| 41 | 7,5-7,0 (m, 6H); 6,1 (s. 1H); 3,6 (m. 5H): £7 (t, 2H); £2 (s, 6H) |
| 42 | 7,3 (m, 5H); 5,9 (s, 1H); 5,5 (s. 1H); 3,8 (s, 3H); 3,5 (t. 2H): £5 (1,2H); 2,2 (s, 6H) |
| 43 | 7,4-7,1 (m, 5H); 6,0 (s. 1H); 5,5 (s, 1H); 3,8 (s, 3H); 3,6 (t. 2H); £6 (t, 2H); 2.2 (s. 6H) |
| 44 | 7,3 (s. 1H); 7,2 <d, 4H): 5,9 (s, 1H); 5,4 (s, 1H); 3,8 (s. 3H); 3,5 (t. 2H). 2,5 (t, 2H); 2,3 (s. 3H); 2,2 (s. 6H) |
- 13 CZ 292065 B6
| Přiklad Číslo | 1H RMN, δ (CDCIj) |
| 45 | 7,7-7,1 (m. 5H); 5,9 (s, 1H): 5,8 (s, 1H); 3,9 (s, 3H); 3,6 (t. 2H); 2.5 (t, 2H); 2,2 (s, 6H) |
| 46 | 7,2 (s. 6H); 5,8 (s, 1H); 5,4 (s, 1H); 3,7 (s, 3H); 3,5 (t, 2H); 2,5 (t. 2H); 2,3 (m, 6H); 1,4 (m, 6H) |
| 47 | 7,4 (s. 6H); 6,0 (s, 1H); 5,4 (s, 1H); 3,7 (s, 3H); 3,6 (t. 2H); 3,0-1 (m. 5H); 0,9 (t. 3H) |
| 48 | 7,3(s, 6H); 6,0 (s. 1H); 5,4 (s. 1H); 3,7 (s. 3H); 3,5 (t. 2H); 2,8-1,1 (m. 13H); 1,0 (t. 3H) |
| 49 | 7,3 (s. 6H); 6,0 (s, 1H); 5,4 (s, 1H); 3,7 (s, 3H); 3,5 (i, 2H); 3,0 (m, 1H); 2,2-1,0 (m. 11H) |
| 50 | 7,3 (s, 6H); 6,0 (s, 1H); 5,5 (s, 1H); 3,7 (s, 3H); 3,4 (t, 2H); 2,9 (m, 2H); 2,6 (I, 2H); 0,95 (d, 12H) |
| 51 | 7,3 (s, 6H); 6,0 (s. 1H); 5,5 (s. 1H); 3,8 (s, 3H); 3,6 (t, 2H); 2,8 (m, 1H); 2,3 (s, 3H); 2,2-1,1 (m. 12H) |
| 52 | 7,2 (m, 4H); 6,85 (d, 2H); 3,6 (m, 1H); 3,2 (s, 3H); 3,0 (m. 1H); 2,4 (m, 2H); 2,15 (s, 6H); 1,8 (s, 3H) |
| 53 | 7,2 (s, 1H); 7,15 (s. 3H); 6,8 (d, 2H); 5,6 (s. 1H); 3,55 (m, 2H); 3,45 (s. 3H); 2,4 (m. 2H); 2,25 (s. 6H); 1,8 (m, 2H) |
| 54 | 7,2 <s. 4H); 6,8 (d, 2H); 3,4 (m, 3H): 3,1 (s, 3H); 2,9 (m, 1H); 2,3 (m. 2H); 2,2 (s. 6H); 1,8 (m. 2H); 0,5 (t. 3H) |
| 55 | 7,2 (s, 1H); 7,0 (s, 3H); 3,4 (m, 3H); 3,1 (s, 3H); 2,9 (m, 1H); 2,3 (m, 2H); 2,25 (s, 6H); 1,8 (m. 2H); 0,5 (t, 3H) |
| 56 | 7,15 (s. 4H); 6,8 (d, 2H); 3,5 (m. 1H); 2,7 (m, 1H); 2,4 (m, 4H); 2,5 (s, 6H); 1,9-0,5 (m. 14H) |
| 57 | 7,3-6,7 (m, 6H): 3,6 (m, 1H); 3,3 (s. 3H); 3,1 (m, 1H); 2,4 (m, 2H); 2,25 (s. 6H); 1J9 (s. 3H); 1,85 (m,2H) |
| 58 | 7,5 (m, 4H); 6,9 (d, 2H); 3,5 (m, 1H); 3,4 (s, 3H); 3,2 (m, 1H); 2,4 (m, 2H); 2,2 (s, 6H): 1,9 (s. 3H); 1,8 (m. 2H) |
| 59 | 8,0 (m. 1H); 7,2 (m, 3H); 6,8 (d, 2H); 3,6 (m, 1H); 3,1 (, 3H); 2# (m, 1H); 2,3 (m, 2H); 2,2 (s, 6H); 2,0 (s, 3H); 1.7 (m, 2H) |
| 60 | 7,3-6,6 (m, 6H); 3,5 (m, 1H); 3,3 (s, 3H); 3,05 (m, 1H); 2,3 (m, 2H); 2,15 (s. 6H); 1,9 (s. 3H); 1,8 (m, 2H) |
| 61 | 6,85 (d, 2H); 6,45 (s, 2H); 3,8 (s, 3H); 3,75 (s, 6H); 3,7 (m, 1H); 3,3 (s, 3H); 3,0 (m. 1H); 2,4 (m, 2H); 2,25 (s, 6H); 1,9 (s, 3H); 1,8 (m, 2H) |
| 62 | 7,2-6,5 (m, 6H); 3,65 (s, 3H); 3,5 (m, 1H); 3,15 (s. 3H); 2,9 (m. 1H); 2,3 (m, 2H); 2,15 (s, 6H); 1,85 (s, 3H); 1,8 (m. 2H) |
| 63 | 7,25 (s, 4H); 6,85 (d. 2H); 5,65 (s, 1H); 3,5 (m. 2H); 3,40 (s, 3H); 2,35 (m, 2H); 2,2 (s. 6H); 1,8 (m, 2H) |
| 64 | 6,8 (d, 2H); 6,55 (s, 2H); 6,6 (s, 1H); 3,75 (s. 9H); 3,55 (m. 2H); 3,45 (s, 3H); 2,3 (m, 2H); 2,2 (s, 6H); 1,8 (m, 2H) |
| 65 | 7,4 (q, 4H): 6,85 (d, 2H); 3.6 (m, 1H); 3,25 (s, 3H); 3,0 (m, 1H); 2,4 (m, 2H); 2,25 (s. 6H): 1,9 (s, 3H); 1,8 (m, 2H) |
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| Přiklad číslo | 1H RMN, δ (CDCIj) |
| 66 | 7,6 (s, 1H); 7,4 (s. 2H); 6,8 (d. 2H); 6,7 (s, 1H); 3,6 (m, 2H); 3,4 (s, 3H); 2,4 (m. 2H), 2,15 (s, 6H); 1,9 (m,2H) |
| 67 | 7,5 (q, 4H); 6,85 (d. 2H); 5,65 (s, 1H); 3,55 (m, 2H); 3/5 (s, 3H); 2,4 (m, 2H); 2,25 (s, 6H); 1,8 i (m. 2H) |
| 68 | 7,3-6,7 (m, 6H); 5,7 (s, 1H); 3,8 (s, 3H); 3,65 (m, 2H); 3,55 (s. 3H); 2/ (m, 2H); 2,25 (s. 6H); 1,9 (m, 2H) |
| 69 | 7,6 (s, 1H); 7,4 (m, 3H); 6,8 (d, 2H); 3,5 (m, 1H); 3,2 (s. 3H); 2.9 (m, 1H); 2,4 (m, 2H); 2,25 (s. 6H); 1,9 (m, 2H); 1,5-0,5 (m, 7H) |
| 70 | 7,2 (s, 4H); 6,9 (d. 2H); 3,6 (m, 3H); 3,0 (m1H); 2,3 (m. 2H); 2,2 (s, 6H); 1,9 (s. 3H); 1,7 (m, 2H); 1,5-0,5 (m, 7H) |
| 71 | 6,8 (d. 2H); 6,4 (s, 2H); 3,75 (s. 3H); 3,65 (s, 6H); 3,6 (m, 9H); 3,6-2,5 (m, 6H); 2,2 (s. 6H); 1,6- 0,4 (m, 16H) |
| 72 | 7,9 (m, 1H); 7,15 (m, 3H); 6,8 (d, 2H); 3,45 (m. 2H); 3,0-2,2 (m. 4H); 2,2 (s. 6H); 2-0,5 (m, 18H) |
| 73 | 7,9 (m. 1H); 7,4 (m. 2H); 6,8 (dd, 2H); 3,4 (m. 3H); 2,7 (m. 2H); 2,3 (m, 3H); 2,1 (d, 6H); 1,9- 0,5 (m, 16H) |
| 74 | 7,4 (q, 4H); 6,8 (d, 2H); 5,6 (s, 1H); 3,5 (m, 4H); 2,2 (m, 2H); 2,05 (s, 6H); 1,8-0,5 (m, 9H) |
| | 75 i | 7,3 (s, 4H); 6,9 (d. 2H); 5,6 (s. 1H); 3,4 (m. 5H); 2,45 (m. 6H): 2-1,2 (m. 8H) |
| 76 | 7,4 (q. 4H); 7,85 (d, 2H); 3,6 (m. 1H); 3,2 (s. 3H); 3,0 (m, 1H); 2,3 (m, 6H); 1,9 (s, 3H); 1,4 (m. 8H) |
| 77 | 8,0 (d, 1H); 7,2 (m, 3H); 6,8 (d. 2H); 3,4 (m. 1H); 3,0 (s, 3H); 2,8 (m, 1H); 2,3 (m, 4H); 2,15 (s. 6H); 1,8-0,5 (m, 9H) j |
| 78 | 7,4-6,6 (m, 5H); 3,4 (m, 1H); 3/ (s. 3H); 2,9 (1H); 2,3 (m. 4H); 2,15 (s, 6H); 1,9-0,5 (m. 2H) |
| 79 | 7,3 (m, 2H); 6.JB (m3H); 3,6 (m, 1H); 3,2 (s, 3H); 2,9 (m, 1H); 2,3 (m, 4H); 2,2 (s, 3H); 1,8 (s, 3H) |
| 80 | 7,5-6,9 (m, 3H); 6,8 (d, 2H); 5,6 (s, 1H); 3,5 (m, 2H); 3,4 (s, 3H); 2,3 (m. 2H); 2,1 (s. 6H); 1,8 (m, 2H) |
| 81 | 7,6-6,7 (m, 5H); 3,4 (m, 1H); 2,7 (m. 1H); 2,4 (m. 4H); 2,15 (s, 6H); 1,9-0,3 (m, 14H) |
| 82 | 7,1 (s, 4H); 6,95 (s, 1H); 6,85 (s, 1H); 3,6 (m, 4H); 2,3 (m, 4H); 2,1 (s, 6H); 2,05 (m, 4H); 1,8 (m, 6H); 1,3 (m, 8H) |
| 83 | 7,2 (s, 4H); 6,9 (s, 1H); 6,85 (s, 1H); 3,6 (m, 4H); 2,3 (m, 4H); 2,1 (s, 6H); 2,05 (m, 4H); 1,0 (m. 6H); 1/ (m. 10H) |
| 84 | 7,2-6,6 (m, 6H); 3/ (m, 1H); 3,1-2,5 (m, 8H); 2,15-1 (m, 14H); 1,0 (m, 4H) |
| 85 | 7,25 (m, 6H); 5,9 (m, 1H); 5,4 (s, 1H); 3,95 (t. 2H); 3/0 (t. 2H); 2,25 (t, 2H); 2,1 (s, 6H); 1,850,5 (m, 9H) |
| 86 | 7/5 (d. 1H); 1,2 (s, 4H); 6,3 (d. 1H); 3,8 (m. 3H); 3,1 (m. 1H); 2,35 (t. 2H); 2,15 (s, 6H); 1,8 (s. |
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| Přiklad číslo | 1H RMN, δ (CDCIj) |
| 3H); 1,9-0,6 (m, 9H) | |
| 87 | 7,3 (s, 6H); 5,95 (d, 1H); 5,45 (s, 1H); 3,75 (s. 3H); 3,5 (t. 2H); 2,35 (t, 2H); 2,15 (s, 6H); 1,8 (m. 2H) I i |
| 88 | 7,4 (d. 1H); 7,2 (s, 5H); 6,35 (d, 1H); 3,55 (m. 2H); 3/4 (s, 3H); 2,35 (l. 2H); 2,2 (s, 6H); 1,95- ! 1,6 (m, 5H) 'i |
| 89 | 7,15 (s. 5H); 6,0 (s, 1H); 3,4 (m, 1H); 3,25 (s, 3H); 3,0 (m. 1H); 2,2 (m, 11H); 1,6 (m. 5H) I |
| 90 | 7,3 (s, 5H); 5,75 (s, 1H); 5,35 (s, 1H); 3,7 (s, 3H); 3,45 (t, 2H); 2,35 (t, 2H); 2,15 (s, 9H): 1,75 ; (m. 2H) i |
| 91 | 7,4-7,1 (m. 5H); 5.7 (s. 1H); 5,5 (s, 1H); 3/8 (s. 3H); 3,5 (t. 2H); 2,3 (m, 2H); 2,2 (s. 9H); 1,8 (m.1 2H) |
| 92 | 7,4-7,2 (m, 5H); 5,9 (š, 1H); 5,4 (s, 1H); 3,7 (s. 3H): 3,5 (t, 2H); 2,3 (m, 2H); 2,15 (s, 6H); 1,8 (m. 2H) |
| 93 | 7,3 (s. 6H); 6,0 (s. 1H); 5,4 (s. 1H); 3,7 (s, 3H); 3,5 (t. 2H); 2,3 (m. 6H); 1,9 (m, 2H), 1,5 (m 6H) |
| 94 | 7,3 (b. 6H); 6,0 (b. 1H): 5,4 (s. 1H); 3,7 (s. 3H); 3,6 (m, 2H); 2,5 (m. 6H); 1,8 (m, 6H) |
| 95 | 7,2 (s, 5H); 7,0 (s, 1H); 3,75 (s, 3H); 3,35 (t. 2H); 2,4 (t. 2H); 2,1 (s. 6H) |
| 96 | 7,2 (m. 6H); 3,7 (s, 3H); 3,25 (t. 2H); 2,4 (t, 2H); 2,15 (s. 6H); 1,7 (s, 3H) |
| 97 | 7,3 (s. 5H); 7,1 (s, 1H); 5,2 (s, 1H): 3,7 (s, 3H); 3,45 (m, 2H); 2,9-1,0 (m, 17H): 0,8 (t, 3H) | |
| 98 | 7,3 (s, 5H); 7,1 (s. 1H); 5,2 (s, 1H); 3,8 (s, 3H); 3,5 (t, 2H); 2,7 (m, 1H); 2,2 (m. 3H); 2,1-1/) (m, í 9H) | |
| 99 | 7,3 (s. 5H); 7,1 (s, 1H); 5,3 (s, 3H); 3,5 (t. 2H); 2,8-1,1 (m, 13H); 1,0 (t, 3H) ί |
| 100 | 7,3 (s, 5H); 7,1 (s, 1H); 5,3 (s, 1H); 3,8 (s. 3H): 3,4 (t. 2H); 3,0 (m, 2H); 2,7 (t, 2H); 1,0 (d. 12H) ; |
| 101 | 7,3 (s. 5H); 7,1 (s, 1H); 5,3 (s, 1H); 3,8 (s, 3H); 3,5 (m, 2H); 3,0 (m. 1H); 2,3 (s, 3H); 2,2-1,2 (m, 8H) |
| 102 | 7,3 (b, 6H); 7,1 (s. 1H): 5,3 (s, 1H); 3,7 (b, 3H); 3,7-3,3 (m, 2H); 2,3 (m, 2H); 2,2 (b, 6H); 1,8 (m. 2H) |
| 103 | 7,3 (b. 5H); 7,1 (s. 1H); 5,2 (s. 1H); 3,8 (s. 3H); 3,6 (m, 6H); 2,4 (m. 6H): 1,9 (m. 2H) |
| 104 | 7,3 (b, 5H); 7,1 (s. 1H): 5,3 (s, 1H); 3,8 (s, 3H); 3,5 (m, 2H); 2,5 (m, 6H); 1,8 (m. 6H) |
| 118 | 6,8 (d, 2H); 6,5 (s. 2H): 4,6 (b, 1H); 3,7 (m, 11H); 2,4 (m, 2H); 1,5-0,6 (m, 22H) |
| 148 | 7,9-6,1 (m, 10H); 4,9 (m, 1H); 2,5 (t, 2H); 1,5-0,5 (m. 9H) |
| 161 | 8,0 (b, 1H); 7,2 (s, 4H); 6,8 (s, 1H); 5,9 (s, 1H): 5,2 (s. 1H); 4,8 (t, 2H): 2^-1,6 (m, 4H) |
| 166 | 7,3 (d, 1H); 6,5 (s. 2H). 5,9 (s, 1H); 5,7 (s-1 H), 3,6 (m, 12H) |
| 167 | 7,2 (d, 1H); (s, 2H); 5,9 (s, 1H), 5,7 (s, 1H). 3,7 (m. 11H), 1,7-0/4 (m, 7H) |
| 176 | 7,3 (s, 6H): 5,8 (s, 1H); 3,6 (m. 5H); 2,6 (t. 2H); 2,3 (s, 6H) |
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Tabulka 5
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Tabulka 6
| Γ- o o | olej | olej |
| Specifická rotace Mo | C4 O k>t t~'O Cl tl o. | o Csl co X v-* O oř II o. |
| Enantiomerní čistota % | | cn σ> | 00 Cn |
| Optic isomer. | T; | 1 |
| Báze nebo sůl | báze | Γ báze 1 |
| £ | X | X |
| d | ó | |
| 3 | f^X x z—o | μ. ,· w |
| Příklad | 1 | 'φ o | 195 |
-21 CZ 292065 B6
| 121-122 | 121-122 | 130-131 i | x— CO 5?“ 1 O CO | 130-131 | 129-131 |
| X o « 4; + O oT II υ | X O Φ M-S 9*0 ojII JO | X o m φ «Ο + of β | X o χ- Φ ep o oj II jj | X O cn φ OÍS 7° v— II o. | X o OJ ® oj-S Τθ X“ II u. |
| 66 | m có~ o | cn cn | in co cn | Ύ“ cn cn | o cn cn |
| + v-* | V | 3 | T | *v* | |
| citrát | Ό | (D)-ditoluoyl- tartarát | >* o o .§ 'S xí TO i s | *TO *5 | ·*-» K0 o |
| X | X | X | X | X | X |
| 6 | d | d | d | ||
| x” z—o w | z—-o | [X x” z—o w | dj | A z—O w | μ |
| 196 | l~ O) x— | co O) T“ | o> 0) | o o OJ | T“ O CN |
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Tabulka 7
CL 292065 B6
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Aktivita sloučenin obecného vzorce I podle předkládaného vynálezu byla prokázána experimentálně pomocí studie in vivo účinku na uvolnění substance P a také dvěma in vivo zkouškami antidepresivní účinností.
V následujících příkladech jsou indikovány některé vlastnosti předmětu vynálezu pro (±)-5-{a[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazolcitrát (příklad 191).
Následující příklady jsou uvedeny pouze pro ilustraci, popisují některé biologické zkoušky 10 a v žádném případě neomezují rozsah vynálezu.
Příklady provedení vynálezu
Příklad 1
Účinek na spinální uvolnění substance P u krys:
Studie se provede in vivo u krys anestetizovaných halothanem. Zkouška se skládá z intratekální perfúze s umělou cerebrospinální kapalinou za účelem sebrání peptidů uvolněných z povrchových vrstev páteře, zatímco produkt, který se zkoumá, se podá lokálně nebo systematicky. Použitou metodu popsal Colin, E. a kol. (Naunyn-Schmiedeberg's Arch. Pharmacol., 1994, 349, 387393).
Aktivita (±)-5-{a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-l H-pyrazolcitrátu (příklad 191) se zkoumá intratekálním podáním vperfúzní kapalině, při koncentraci 1 μΜ. Jak vyplývá ze souhrnu v tabulce 8, produkt inhibuje uvolnění substance P. Systematické podávání 46 mg/kg produktu také redukuje uvolnění substance P.
Je třeba uvést, že účinek systematického podávání produktu na intratekální uvolnění substance P trvá 2 hodiny, přičemž průměrná inhibice během této periody je 50%.
Příklad 2
Studie antidepresivní účinnosti:
Antidepresivní účinnost (±)-5-{a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazol40 citrátu (příklad 191) se zkoumá a demonstruje ve dvou různých zkouškách u myši. V první se zkoumá inhibice ptózy indukovaná reserpinem, a v druhé se zkoumá účinek na mobilitu v nepříznivé situaci
2.1 Inhibice ptózy indukovaná reserpinem u myši
Používá se metoda, kterou popsal S. Garanttini a kol. (Med. Exp., 1960, 3, 315-320). Zkouška se skládá z pozorování možné inhibice ptózy indukované reserpinem (25 mg/kg, ip: intraperitoneálně) u myší, poté co byly produkty, které se zkoumají, podány orálně.
Stanovuje se aktivita (±}-5-{a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazolcitrátu (příklad 191) podaného orálně v různých dávkách. Jak vyplývá z tabulky 9, (±)-5-{a-[2(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazolcitrát (příklad 191) vykazuje zřetelnou antidepresivní aktivitu inhibující účinky reserpinu s dobrou odezvou v závislosti na dávce.
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2.2. Účinek na mobilitu v nepříznivé situaci
Používá se metoda, kterou popsal R. D. Porsolt a kol. (Arch. Int. Pharmacodyn., 1987, 288, 11-30). Zkouška se skládá ze zavěšení myší za jejich ocasy na 6 minut v aparatuře ITEMATICTST, která měří mobilitu a sílu pohybů živočichů. Zvířata vystavené této nepříznivé situaci se po počáteční intenzivní aktivitě stávají zoufalá a ke konci jsou již v klidu. Produkty s antidepresivními účinky podstatně snižují dobu nehybnosti.
Jak vyplývá z tabulky 10, (±)-5-{a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazolcitrát (příklad 191) je zřetelně aktivní v této zkoušce a snižuje periodu nehybnosti podstatě a způsobem, který je závislý na dávce.
Provedené farmakologické zkoušky prokazují, že (±)-5-{a-[2-(dimethylamino)ethoxy]benzyl}1-methyl-lH-pyrazolcitrát (příklad 191), jako příklad vlastností předmětu vynálezu, vykazuje zřetelnou aktivitu jako inhibitor uvolnění substance P, což jej předurčuje k aplikaci v léčbě chorob centrálního nervového systému, kde je uvolnění substance P obsaženo. Dále, a jako příklad, antidepresivní aktivita je prokázána ve dvou různých zkouškách provedených na experimentálních zvířatech.
Tabulka 8: Účinek (±)-5-{a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazolcitrátu (příklad 191) na intratekální uvolnění substance P
| Léčba sloučeninou | % inhibice, vzhledem ke kontrole, intratekálního uvolnění |
| příkladu 191 | substance P |
| 1 μΜ, intratekálně | -58 % |
| 46 mg/kg ip | -50 % |
Tabulka 9: Inhibice ptózy indukované reserpinem u myši
| Produkt | Dávka* (mg/kg, orálně) | % aktivita | SD-50 |
| Příklad 191 | 92 | 84 | |
| 80 | 75 | 38,5 | |
| 23 | 30 | mg/kg, orálně | |
| 12 | 8 |
*Dávka vyjádřená v mg/kg báze sloučeniny příkladu 191
Tabulka 10: Inhibice doby nepohyblivosti v nepříznivé situaci u myši
| Produkt | Dávka’ (mg/kg, orálně) | % inhibice | DE-50 |
| Příklad 191 | 92 | 69 | |
| 46 | 41 | ||
| 23 | 30 | 50,5 | |
| 12 | 20 | mg/kg, orálně |
Claims (5)
1. Použití derivátu aryl (nebo heteroaryl)azolylkarbinolů obecného vzorce I (I), kde
R1
Ar--Het
O \ R2
Ar je fenylový nebo thienylový zbytek, nesubstituovaný nebo případně substituovaný 1, 2 nebo
3 stejnými nebo různými substituenty vybranými ze souboru, který zahrnuje fluor, chlor, brom, io methyl, trifluormethyl a methoxyskupinu;
R1 je atom vodíku, cyklohexylová skupina, N-methylpiperidylová skupina, fenylová skupina, vinylová skupina nebo alkylová skupina s 1 až 4 atomy uhlíku;
15 R2 je atom vodíku nebo di(Ci-C4alkyl)amino(C2-C3alkyl), (C]-C2alkyl)azaheterocyklyl(C2-C3alkyl) nebo azaheterocyklyl(C2-C3alkyl); a
Het je heterocyklický dusíkatý aromatický 5-členný kruh, který obsahuje jeden až tři atomy dusíku, nesubstituovaný nebo substituovaný 1 nebo 2 stejnými nebo různými substituenty 20 vybranými ze souboru, který zahrnuje fluor, chlor, brom, alkylovou skupinu s 1 až 12 atomy uhlíku, benzylovou skupinu, kyano(C2-C3alkyl)skupinu, karboxy(C2-C3alkyl) skupinu, methoxykarbonyl(C2-C3alkyl) skupinu, hydroxy(C2-C3alkyl) skupinu, amino(C2-C3alkyl) skupinu, di(Ci— C4alkyl)amino(C2-C3alkyl) skupinu a azaheterocyklyl(C2-C3alkyl) skupinu;
25 nebo jejich fyziologicky přijatelných solí, pro přípravu léčiva pro léčení chorob, které jsou zprostředkovány přebytkem substance P, zejména chorob centrálního nen ového systému, jako je úzkost, deprese, schizofrenie, maniakální depresivní psychózy, sexuální dysfunkce, narkomanie, kognitivní choroby, pohybové choroby, 30 atd. u savců, včetně lidí.
2. Použití podle nároku 1, kde sloučenina obecného vzorce I se zvolí ze souboru, který zahrnuje:
35 [1] 2-{a-(2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-imidazol, [2] 2-{4-chlor-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-l-methyl-lH-imidazol, [
3] 2-{
4-chlor-a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-imidazol, [4] 2-{3-chlor-a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-imidazol, [5] 2-{4-chlor-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-l-methyl-lH-imidazol,
40 [6] 2-{4-fluor-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-l-methyl-l H-imidazol, [7] 2-{a-[2-(dimethylamino)ethoxy]-a-methyl-3-(trifluormethyl)benzyl}-lH-methyl-lHimidazol, [8] 2-{3-chlor-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-l-methyl-lH-imidazol, [9] 2-{3-chlor-a-[2-(dimethylamino)ethoxy]-a-propylbenzyl}-l-methyl-lH-imidazol,
45 [10] l-butyl-2-{4-chlor-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-l H-imidazol,
-27CZ 292065 B6 [11] 2-{a-[2-(dimethylamino)ethoxy]-a-rnethyl-4-methoxybenzyl}-l-methyl-lH-imidazol, [12] 2-{3-chlor-a-methyl-a-[2-(N-pyrrolidyl)ethoxy]benzyl}-l-methyl-lH-imidazolJ [ 13 ] 2- {a-[2-(dimethylamino)ethoxy]-a-propy 1-3,4,5-trimethoxybenzy 1} -1 -dodecy 1-1Himidazol,
5 [14] l-butyl-2-{a-[2-(dimethylamino)ethoxy]-4-(trifluormethyl)benzyl}-lH-imidazol, [15] l-methyl-2-(a-methyl-a-[2-(N-piperidyl)ethoxy]-3-(trifluormethyl)benzyl}-lHimidazol, [16] 2-{a-cyklohexyl-3,4-dichlor-a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lHimidazol, ío [17] 2-{3,4-dichlor-a-[2-(dimethylamino)ethoxy]-a-propylbenzyl}-l-methyl-lH-imidazol, [ 18] 2-{3,4-dichlor-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-l-methyl-lH-imidazol, [19] 2-{3,4-dichlor-a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-imidazol, [20] 2-{4-chlor-a-(2-(2-dimethylamino)ethoxy]-a-methylbenzyl}-l-[2-(N-piperidyl)ethyl]1 H-imidazol,
15 [21] 2-{4-chlor-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-l-[2-(N-piperidyl)propyl1 H-imidazol, [22] l-(3-kyanopropyl)-2-{4-chlor-a-[2-(dimethylamino)ethoxy]benzyl}-lH-imidazol, [23] 2-{4-chlor-a-[2-(dimethylamino)ethoxy]-a-(N-methyl—4-piperidyl)benzyl}-l-methyl1 H-imidazol,
20 [24] l-benzyl-2-{a-[2-(N-benzyl-N-methylamino)ethoxy]—4-chlorbenzyl}-lH-imidazol, [25] 2-{4-chlor-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-7-methyl-6,7,8,9-tetrahydro-1 H-imidazo[ 1,5-a] [ 1,4]diazepin, [26] 2-{4-chlor-a-[2-(dimethylamino)ethoxy]benzyl}-7-methyl-6,7,8,9-tetrahydro-lHimidazolf 1,5-a][ 1,4]diazepin,
25 [27] l-butyl-5-{a-[2-(dimethylamino)ethoxy]benzyl}-lH-pyrazol, [28] 5-{a-(4-chlorfenyl)-a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazol, [29] l-butyl-5-{a-[2-(dimethylamino)ethoxy]-3,4,5-trimethoxybenzyl}-lH-pyrazol, [30] l-butyl-5-{4-chlor-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-lH-pyrazol, [31] 5-{a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazol,
30 [32] 5-{a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-l-methyl-lH-pyrazol, [33] 5-{a-[2-(dimethylamino)ethoxy]-3,4,5-trimethoxybenzyl}-l-methyl-lH-pyrazol, [34] 1 -methyl-5- {a-[2-(N-pyrrol idyl)ethoxy] benzyl} -1 H-pyrazol, [35] l-methyl-5-{a-[2-(N-morfolinyl)ethoxy]benzyl}-lH-pyrazol, [36] 5-{a-[2-(dimethylamino)ethoxy]-a-methyl-3,4,5-trimethoxybenzyl}-l-methyl-lH-
35 pyrazol, [37] 4-brom-5- {a-[2-(dimethylamino)ethoxy]benzy 1} -1 -methyl-1 H-pyrazol, [3 8] 1,3-dimethyl-5- {a-[2-(dimethylamino)ethoxy]-a-methy lbenzyl }-l H-pyrazol, [3 9] 1,3-dimethyl-5- {a-[2-(dimethylamino)ethoxy] benzyl}-1 H-pyrazol, [40] 5-{a-[2-(dimethylamino)ethoxy]-2-methylbenzyl}-1 -methyl-1 H-pyrazol,
40 [41] 4-chlor-5-{4-chlor-a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazol, [42] 5-{4-chlor-a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazol, [43 ] 5- {3-chlor-a-[2-(dimethylamino)ethoxy]benzy 1} -1 -methyl-1 H-pyrazol, [44] 5-{a-[2-(dimethylamino)ethoxy]-4-methylbenzyl}-l-methyl-lH-pyrazol, [45] 5-{2-chlor-a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazol,
45 [46] l-methyl-5-{a-[2-(N-piperidyl)ethoxy]benzyl}-lH-pyrazol, [47] l-methyl-5-{a-[2-(N-propyl-2-piperidyl)ethoxy]benzyl}-lH-pyrazol, [48] 5-{a-[2-(N-ethyl-2-piperidyl)ethoxy]benzyl}-l-methyl-lH-pyrazol,
-28CZ 292065 B6 [49] l-methyl-5-{a-[2-(N-methyl-2-pyrrolidyl)ethoxy]benzyl}-lH-pyrazol, [5 0] 5- {a-(2-(di izopropylam ino)ethoxy] benzy 1} -1 -methyl-1 H-pyrazo 1, [51 ] l-methyl-5-{a-[2-(N-methyl-2-piperidyl)ethoxy]benzyl}-lH-pyrazol, [52] 2-{4-chlor-a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-l-methyl-lH-imidazol, [53] 2-{3-chlor-a-[3-(dimethylamino)propoxy]benzyl}-l-methyl-lH-imidazol, [54] 2-{4-chlor-a-[3-(dimethylamino)propoxy]-a-ethylbenzyl}-l-methyl-lH-imidazol, [55] 2-{a-butyl-3-chlor-a-[3-(dimethylamino)propoxy]benzyl}-l-methyl-lH-imidazol, [56] 2-{a-cyklohexyl-4-chlor-a-(3-(dimethylammo)propoxy]benzyl}-l-methyl-lHimidazol, [57] 2-{a-[3-(dimethylamino)propoxy]-4-fluor-a-methylbenzyl}-l-methyl-1 H-imidazol, [58] 2-{a-[3-(dimethylamino)propoxy]-a-methyl-3-(trifluormethyl)benzyl}-l-methyl-lHimidazol, [59] 2-{2-chlor-a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-l-methyl-lH-imidazol, [60] 2-{3-chlor-a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-l-methyl-lH-imidazol, [61 ] 2- {a-[3-(dimethylamino)propoxy]-a-methy 1-3,4,5 —trimethoxybenzyl} -1 -methyl-1Himidazol, [62] 2-{a-[3-(dimethylamino)propoxy]-a-methyl-4-methoxybenzyl}-l-methyl-lH-imidazol, [63] 2-{4-chlor-a-[3-(dimethylamino)propoxy]benzyl}-l-methyl-lH-imidazol, [64] 2-{a-[3-(dimethylamino)propoxy]-3,4,5-trimethoxybenzy 1}-1 -methyl-1 H-imidazol, [65] 2-{a-[3-(dimethylamino)propoxy]-a-methyl-4-(trifluormethyl)benzyl}-l-methyl-lHimidazol, [66] 2-{a-[3-(dimethylamino)propoxy]-3-(trifluormethyl)benzyl}-l-methyl-lH-imidazol, [67] 2-{a-[3-(dimethylamino)propoxy]-4-(trifluormethyl)benzyl}-l-methyl-lH-imidazol, [68] 2-{a-[3-(dimethylamino)propoxy]-4-methoxybenzyl}-l-methyl-l H-imidazol, [69] 2-{a-butyl-a-[3-(dimethylamino)propoxy]-3-(trifluormethyl)benzyl}-l-methyl-lHimidazol, [70] l-butyl-2-{4-chlor-a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-l-H-imidazol, [71] l-butyl-2-{a-butyl-a-[3-(dimethylamino)propoxy]-3,4,5-trimethoxybenzyl}-lHimidazol, [72] l-butyl-2-{a-butyl-2-chlor-a-[3-(dimethylamino)propoxy]benzyl}-lH-imidazol, [73] l-butyl-2-{a-butyl-2,4-dichlor-a-[3-(dimethylamino)propoxy]benzyl}-lH-imidazol, [74] l-butyl-2-{a-[3-(dimethylamino)propoxy]-4-(trifluormethyl)benzyl}-l H-imidazol, [75] 2-{4-chlor-a-[3-(N-piperidyl)propoxy]benzyl}-l-methyl-lH-imidazol, [76] 1 -methyl-2- {a-methyl-a-[3-(N-piperidyl)propoxy]-4-(trifluormethyl)benzyl }-l Himidazol, [77] 2-{α-butyl-2-chlor-a-[3-(dimethylamino)propoxy]benzy 1}-1 -methyl-1 H-imidazol, [78] 2-{a-butyl-3,4-dichlor-a-[3-(dimethylamino)propoxy]benzyl}-l-methyl-lH-imidazol, [79] 2-{3,4-dichlor-a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-l-methyl-lH-imidazol, [80] 2-{3,4-dichlor-a-[3-(dimethylamino)propoxy]benzyl}-l-methyl-lH-imidazol, [81 ] 2-{a-cyklohexyl-3,4-dichlor-a-[3-(dimethylamino)propoxy]benzyl}-l-methyl-l Himidazol, [82] 2-{4-chlor-a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-<i-[2-(N-piperidyl)ethyl]-
1 H-imidazol, [83] 2-{4-chlor-a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-l-[2-(N-piperidyl)propyl]-
1 H-imidazol, [84] 2-{4-chlor-<x-[3-(dimethylamino)propoxy]-a-(N-methyl-4-piperidyl)benzyl}-l-methyl-
1 H-imidazol,
-29CZ 292065 B6 [85] l-butyl-5-{a-[3-(dimethylamino)propoxy]benzyl}-lH-pyrazol, [86] l-butyl-5-{4-chlor-a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-l H-pyrazol, [87] 5-{a-[3-(dimethylamino)propoxy]benzyl}-1 -methyl-1 H-pyrazol, [88] 5-{a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-l-methyl-lH-pyrazol, [89] 1,3-dimethyl-5-{a-[3-(dimethylamino)propoxy]-a-methylbenzyl}-l H-pyrazol, [90] l,3-dimethyl-5-[a-[3-(dimethylamino)propoxy]benzyl}-lH-pyrazol, [91 ] 5-{a-[3-(dimethylamino)propoxy]-2-methylbenzyl}-l-methyl-lH-pyrazol, [92] 5-chlor-5-{4-chlor-a-[3-(dimethylamino)propoxy]benzyl}-l-methyl-lH-pyrazol, [93] l-methyl-5-{a-[3-(N-piperidyl)propoxy]benzyl}-lH-pyrazol, [94] l-methyl-5-{a-[3-(N-pyrrolidyl)propoxy]benzyl}-lH-pyrazol, [95] 4-{4-chlor-a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazol, [96] 4-{4-chlor-a-[2-(dimethylamino)ethoxy]-a-methylbenzyl}-l-methyl-lH-pyrazol, [97] 4-{4-chlor-a-[2-(N-propyl-2-piperidyl)ethoxy]benzyl}-l-methyl-lH-pyrazol, [98] 4- {4-chlor-a-[2-(N-methyl-2-piperidyl)ethoxy]benzyl} -1 -methyl-1 H-pyrazol, [99] 4-{4-chlor-a-[2-(N-ethyl-2-piperidyl)ethoxy]benzyl}-l-methyl-lH-pyrazol, [100] 4-{4-ehlor-a-[2-(N-diizopropylamino)ethoxy]benzyl}-l-methyl-lH-pyrazol, [101] 4-{4-chlor-a-[2-(N-methyl-2-pynOlidyl)ethoxy]benzyl}-l-methyl-lH-pyrazol, [ 102] 4-{a-[3-(dimethylamino)propoxy]benzyl}-l-methyl-lH-pyrazol, [103] 4-{4-chlor-a-[3-(N-morfolinyl)propoxy]benzyl}-l-methyl-lH-pyrazol, [104] 4-{4-chIor-a-[3-(N-pyrrolidyl)propoxy]benzyl}-l-methyl-lH-pyrazol, [105] 2-(a-hydroxybenzyl)-l H-imidazol, [ 106] 2-(4-chlor-a-hydroxybenzyl)-lH-imidazol, [ 107] 2-(4-chlor-a-hydroxybenzyl)-l-methyl-l H-imidazol, [108] 2-(3-chlor-a-hydroxybenzyl)-l -methyl-1 H-imidazol, [109] 2-(4-fluor-a-hydroxybenzyl)-l-methyl-lH-imidazol, [110] 2-[a-hydroxy-3-(trifluormethyl)benzyl]-l-methyl-lH-imidazol, [111] 2-[a-hydroxy—4-(trifluormethyl)benzyl]-l-methyl-lH-imidazol, [112] 2-(a-hydroxy-3,4,5-trimethoxybenzyl)-l-methyl-lH-imidazol, [113] 2-(3,4-dichlor-a-hydroxybenzyl)-l-methyl-lH-imidazol, [114] l-butyl-2-[a-hydroxy-4-(trifluormethyl)benzyl]-l H-imidazol, [115] l-butyl-2-(3,4-dichlor-a-hydroxybenzyl)-lH-imidazol, [116] l-butyl-2-(4-chlor-a-hydroxybenzyl)-lH-imidazol, [117] l-butyl-2-(a-hydroxy-3,4,5-trimethoxybenzyl)-lH-imidazol, [118] l-dodecyl-2-(a-hydroxy-3,4,5-trimethoxybenzyl)-l H-imidazol, [119] 2-(a-butyl-3-chlor-a-hydroxybenzyl)-l-methyl-lH-imidazol, [120] 2-(3-chlor-a-hydroxy-a-methylbenzyl)-l-methyl-lH-imidazol, [121] 2-(4-chlor-a-hydroxy-a-methylbenzyl)-l-methyl-lH-imidazol, [122] 2-[4-chlor-a-hydroxy-a-(N-methyl-4-pÍperidyl)benzyl]-l-methyl-lH-imidazol, [123] 2-(4-chlor-a-ethyl-a-hydroxybenzyl)-1 -methyl-1 H-imidazol, [124] 2-(a-butyl-4-chlor-a-hydroxybenzyl)-l -methyl-1 H-imidazol, [125] 2-(a-cyklohexyl-4-chlor-a-hydroxybenzyl)-l-methyl-l H-imidazol, [ 126] 2-(2-chlor-a-hydroxy-a-methylbenzyl)-l-methyl-lH-imidazol, [127] 2-(a-butyl-2-chlor-a-hydroxybenzyl)-l-methyl-l H-imidazol, [ 128] 2-[a-hydroxy-a-methyl-3-(trifluormethyl)benzyl]-l-methyl-lH-imidazol, [ 129] 2-[a-butyl-a-hydroxy-3-(trifluormethyl)benzyl]-l-methyl-l H-imidazol,
-30CZ 292065 B6 [130] 2-[a-cyklohexyl-a-hydroxy-3-(trifluonnethyl)benzyl]-l-methyl-lH-imidazol, [131] 2-[a-hydroxy-a-methyl-4-(trifluormethyl)benzyl]-l-methyl-1 H-imidazol, [ 132] 2-(4-fluoro-a-hydroxy-a-rnethylbenzyl)-l-methyl-1 H-imidazol, [133] 2-(a-hydroxy-a-methyl-4-methoxybenzy 1)-1 -methyl-1 H-imidazol, [134] 2-(3,4-dichlor-a-hydroxy-a-methylbenzyl)-l-methyl-lH-imidazol, [135] 2-(a-butyl-3,4-dichlor-a-hydroxybenzyl)-l -methyl-1 H-imidazol, [136] 2-(a-cyklohexyl-3,4-dichlor-a-hydroxybenzyl)-l-methyl-lH-imidazol, [137] 2-(a-hydroxy-a-methyl-3,4,5-trimethoxybenzyl)-l-methyl-lH-imidazol, [138] l-butyl-2-(4-chlor-a-hydroxy-a-methylbenzyl)-lH-imidazol, [139] 1 -buty l-2-(a-buty 1-4-chlor-a-hydroxybenzyl]-1 H-imidazol, [ 140] l-butyl-2-[4-chlor-a-hydroxy-a-(N-methyI-4-piperidyl)benzyl]-l H-imidazol, [141] l-butyl-2-(a-butyl-a-hydroxy-3,4,5-trimethoxybenzyl)-l H-imidazol, [ 142] l-butyl-2-(a-butyl-2-chlor-a-hydroxybenzyl)-lH-imidazol, [ 143] l-butyl-2-(a-ethyl-a-hydroxy-3-(trifluormethyl)benzyl]-l H-imidazol, [144] 1 -butyl-2-(a-butyl-2,4-dichlor-a-hydroxybenzyl)-l H-imidazol, [145] 2-(4-chlor-a-hydroxy-a-methylbenzyl)-l-[2-(N-piperidyl)ethyl]-lH-imidazol, [146] 2-(4-chlor-a-hydroxy-a-methylbenzyl)-l-(3-dimethylaminopropyl}-lH-imidazol, [147] 2-(a-butyl-a-hydroxy-3,4,5-trimethoxybenzyl)-l-dodecyl-lH-imidazol, [148] l-benzyl-2-[a-butyl-a-hydroxy-3-(trifluormethyl)benzyl]-l H-imidazol, [ 149] l-benzyl-2-(4-chlor-a-hydroxy-3-(trifluormethyl)benzyl]-l H-imidazol, [ 150] l-(2-kyanoethyl)-2-(4-chlor-a-hydroxybenzyl)-lH-imidazol, [151] 1 -(3-aminopropyl)-2-(4-chlor-a-hydroxybenzyl)-l H-imidazol, [ 152] 3-[2-(3-chlor-a-hydroxybenzyl)-lH-imidazol-l-yl]propanová kyselina, [153] 2-(4-chlor-a-hydroxybenzyl)-l-(3-hydroxypropyl)-l H-imidazol, [154] 3-[2-(3-chlor-a-hydroxybenzyl)-lH-imidazol-l-yl]methylpropanoát, [155] 2-(a-hydroxybenzyl)-l-(3-hydroxypropyl)-l H-imidazol, [156] 2-(a-hydroxy-4-methylbenzyl)-l-(3-hydroxypropyl)-lH-imidazol, [157] 2-(a-hydroxy-4-methoxybenzyl)-l-(3-hydroxypropyl)-l H-imidazol, [158] 2-(3,4-dichlor-a-hydroxybenzyl)-l-(3-hydroxypropyl)-l H-imidazol, [159] 3-{2-(a-hydroxybenzyl)-lH-imidazol-l-yl}methylpropanoát, [ 160] 2-(4-chlor-a-hydroxybenzyl)-l -(4-hydroxybutyl)-l H-imidazol, [161] l-(3-kyanopropyl)-2-(4-chlor-a-hydroxybenzyl)-lH-imidazol, [162] 4-[2-(4-chlor-a-hydroxybenzyl)-lH-imidazol-l-yl]butanová kyselina, [163] 4-[2-(4-chlor-a-hydroxybenzyl)-lH-imidazol-l-yl]methylbutanoát, [164] l-butyl-5-(a-hydroxybenzyl)-lH-pyrazol, [165] 5-(4-chlor-a-hydroxybenzyl)-l -methyl-1 H-pyrazol, [ 166] 5-(a-hydroxy-3,4,5-trimethoxybenzyl)-l-methyl-lH-pyrazol, [167] l-butyl-5-(a-hydroxy-3,4,5-trimethoxybenzyl)-lH-pyrazol, [168] 4-brom-5-(a-hydroxybenzyl}-l-methyl-lH-pyrazol, [ 169] 5-[a-(4-chlorfenyl)-a-hydroxybenzyl]-l-methyl-lH-pyrazol, [170] 1 -butyl-5-(4-chlor-a-hydroxy-a-methylbenzyl)-l H-pyrazol, [171] 5-(a-hydroxy-a-methylbenzyl)-l-methyl-l H-pyrazol, [172] 5-(a-hydroxy-a-methyl-3,4,5-trimethoxybenzyl)-l-methyl-lH-pyrazol, [173] 1,3-dimethyl-5-(a-hydroxy-a-methylbenzyl)-l H-pyrazol, [ 174] l-butyl-5-(a-hydroxy-a-vinylbenzyl)-lH-pyrazol,
-31 CZ 292065 B6 [175] 1 -buty 1-5-( 4-chlor-a-hydroxy-a-vinylbenzyl)-l H-pyrazol, [ 176] 4-chlor-5-(a-hydroxybenzyl)-l-methyl-l H-pyrazol, [ 177] 5-(a-hydroxy-2-methylbenzyl)-l-methyl-1 H-pyrazol.
[178] 5-(3-chlor-a-hydroxybenzyl)-l-methyl-lH-pyrazoI, [179] 5-(a-hydroxy-4-methylbenzyl)-l-methyl-lH-pyrazol.
[180] 5-(2-chlor-a-hydroxybenzyl)-1 -methyl-1 H-pyrazol, [181] 5-(a-hydroxy-4-methoxybenzyl)-l-methyl-lH-pyrazol, [ 182] 5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-l-methyl-lH-pyrazol, [183] 5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-l-methyl-lH-pyrazolcitrát, [184] 5-{a-[2-(dimethylamino)ethoxy]-3-thienylmethyl}-l-methyl-lH-pyrazol, [ 185] 2-{a-[2-(dimethylamino)ethoxy]-2-thieny lmethy 1}-1 -methyl-1 H-imidazol, [186] 5-{a-[2-(dimethylamino)ethoxy]-3-methyl-2-thienylmethyl}-l-methyl-lH-pyrazol, [187] 5-{a-[2-(dimethylamino)ethoxy]-5-methyl-2-thienylmethyl}-l-methyl-lH-pyrazol, [188] 5-{ 5-brom-a-[2-(dimethylamino)ethoxy]-2-thienylmethyl }-l -methyl-1 H-pyrazol, [189] 5-{4-brom-a-[2-(dimethylammo)ethoxy]-2-thienylmethyl}-l-methyl-lH-pyrazol, [190] 5-{a-[2-(dimethylamino)ethoxy]-a-methyl-2-thienylmethyl}-l-methyl-lH-pyrazol, [191] 5-{a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazolcitrát, [ 192] (±)-5-{a-[2-(dimethylamino)-l-(methyl)ethoxy] benzyl }-l-methyl-l H-pyrazol, [193] (±)-5-{a-[2-(dimethylamino)-l-(methyl)ethoxy]benzyl}-l-methyl-lH-pyrazol, [194] (+)-5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-l-methyl-lH-pyrazol, [195] (-)-5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-l-methyl-lH-pyrazol, [ 196] (+)-5-{a-(2-(dimethylamino)ethoxy]-2-thienylmethyl}-l-methyl-l H-pyrazolcitrát, [197] (-)-5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-l-methyl-lH-pyrazolcitrát, [198] (+)-5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-l-methyl-lH-pyrazol-D-ditoluoyltartarát, [199] (-)-5-{a-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-l-methyl-lH-pyrazol-L-ditoluoyltartarát, [200] (+)-5-{a-[2-(dimethylamino)ethoxy]benzyl}-l-methyl-lH-pyrazolcitrát, [201] (-)-5-{a-[2-(dimethylamino)ethoxy]benzyl}-1 -methyl-1 H-pyrazolcitrát, [202] 5-(a-hydroxy-2-thienylmethyl)-l-methyl-l H-pyrazol, [203] 5-(a-hydroxy-3-methyl-2-thienylmethyl)-l-methyl-lH-pyrazol, [204] 5-(a-hydroxy-5-methyl-2-thienylmethyl)-l-methyl-l H-pyrazol, [205] 5-(5-brom-a-hydroxy-2-thienylmethyl)-l“methyl-lH-pyrazol, [206] 5-(4-brom-a-hydroxy-2-thienylmethyl)-l -methyl-1 H-pyrazol, [207] 5-(a-hydroxy-a-methyl-2-thienylmethyl)-l-methyl-lH-pyrazol.
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| ES009801708A ES2150378B1 (es) | 1998-08-07 | 1998-08-07 | Empleo de derivados de aril(o heteroaril)azolilcarbinoles en la elaboracion de un medicamento para el tratamiento de los trastornos mediados por un exceso de substancia p. |
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| US (1) | US6518295B1 (cs) |
| EP (1) | EP1103243B1 (cs) |
| JP (1) | JP2002522359A (cs) |
| KR (1) | KR100558506B1 (cs) |
| CN (1) | CN1151789C (cs) |
| AR (1) | AR019999A1 (cs) |
| AT (1) | ATE257379T1 (cs) |
| AU (1) | AU754124B2 (cs) |
| BR (1) | BR9912807A (cs) |
| CA (1) | CA2339661C (cs) |
| CO (1) | CO5080747A1 (cs) |
| CZ (1) | CZ292065B6 (cs) |
| DE (1) | DE69914085T8 (cs) |
| DK (1) | DK1103243T3 (cs) |
| ES (2) | ES2150378B1 (cs) |
| HU (1) | HUP0105428A3 (cs) |
| IL (1) | IL141295A0 (cs) |
| NO (1) | NO20010634L (cs) |
| NZ (1) | NZ509645A (cs) |
| PL (1) | PL193802B1 (cs) |
| PT (1) | PT1103243E (cs) |
| RU (1) | RU2223116C2 (cs) |
| TR (1) | TR200100378T2 (cs) |
| TW (1) | TW445259B (cs) |
| WO (1) | WO2000007542A2 (cs) |
| ZA (1) | ZA200100867B (cs) |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2174756B2 (es) * | 2001-04-06 | 2003-11-16 | Esteve Labor Dr | Derivados de aril (o heteroaril) azolilcarbinoles para el tratamiento de enfermedades respiratorias. |
| US20040142929A1 (en) * | 2001-07-06 | 2004-07-22 | Ramon Merce-Vidal | Derivatives of aryl (or heteroaryl) azolylcarbinoles for the treatment of urinary incontinence |
| ES2180449B1 (es) * | 2001-07-06 | 2004-01-16 | Esteve Labor Dr | Derivados de aril (o heteroaril) azolilcarbinoles para el tratamiento de la incontinencia urinaria. |
| DE10335566A1 (de) * | 2003-07-31 | 2005-02-24 | Grünenthal GmbH | Arzneimittel enthaltend Derivate von Aryl( oder Heteroaryl)azolylcarbinolen |
| ES2244326B1 (es) * | 2004-04-05 | 2007-02-16 | Laboratorios Del Dr. Esteve, S.A. | Combinacion de substancias activas. |
| EP1584335A3 (en) * | 2004-04-05 | 2006-02-22 | Laboratorios Del Dr. Esteve, S.A. | Active substance combination comprising a carbinol composition and an opioid |
| WO2006010627A1 (en) * | 2004-07-30 | 2006-02-02 | Laboratorios Del Dr. Esteve, S.A. | Aryl (or heteroaryl) azolylcarbinols |
| US20080045610A1 (en) * | 2004-09-23 | 2008-02-21 | Alexander Michalow | Methods for regulating neurotransmitter systems by inducing counteradaptations |
| JP2008514612A (ja) * | 2004-09-23 | 2008-05-08 | ミシャロウ、アレクサンダー | 対抗適応を誘発することにより神経伝達物質系を調節する方法 |
| WO2006087147A2 (en) * | 2005-02-15 | 2006-08-24 | Laboratorios Del Dr. Esteve, S.A. | Derivatives of aryl (or heteroaryl) azolylcarbinols for the treatment of fibromyalgia |
| EP1695704A1 (en) * | 2005-02-28 | 2006-08-30 | Laboratorios Del Dr. Esteve, S.A. | Derivatives of aryl (or heteroaryl) azolylcarbinols for the treatment of fibromyalgia |
| EP1690537A1 (en) * | 2005-02-15 | 2006-08-16 | Laboratorios Del Dr. Esteve, S.A. | Derivatives of aryl(or heteroaryl) azolycarbinols for the treatment of fibromyalgia |
| ES2286920B1 (es) * | 2005-02-15 | 2008-08-16 | Laboratorios Del Dr. Esteve, S.A. | Derivados de aril (o heteroaril)azolilcarbinoles para el tratamiento de la fibromialgia. |
| CN101374516A (zh) * | 2006-01-27 | 2009-02-25 | 弗·哈夫曼-拉罗切有限公司 | 取代的咪唑啉的2-咪唑衍生物的用途 |
| EP1820502A1 (en) * | 2006-02-10 | 2007-08-22 | Laboratorios Del Dr. Esteve, S.A. | Active substance combination comprising azolylcarbinol compounds |
| EP2076497B1 (en) | 2006-10-19 | 2012-02-22 | F. Hoffmann-La Roche AG | Aminomethyl-4-imidazoles |
| ES2375578T3 (es) | 2006-11-02 | 2012-03-02 | F. Hoffmann-La Roche Ag | 2-imidazoles sustituidos como moduladores de receptores asociados a aminas trazas. |
| WO2008058867A2 (en) | 2006-11-16 | 2008-05-22 | F. Hoffmann-La Roche Ag | Substituted 4-imidazoles |
| CN101190330A (zh) | 2006-11-30 | 2008-06-04 | 深圳市鼎兴生物医药技术开发有限公司 | 胆碱酯酶在拮抗速激肽药物中的应用 |
| CA2672617A1 (en) | 2006-12-13 | 2008-06-19 | F. Hoffmann-La Roche Ag | Novel 2-imidazoles as ligands for trace amine associated receptors (taar) |
| WO2008092785A1 (en) | 2007-02-02 | 2008-08-07 | F. Hoffmann-La Roche Ag | Novel 2-aminooxazolines as taar1 ligands for cns disorders |
| RU2460725C2 (ru) | 2007-02-15 | 2012-09-10 | Ф. Хоффманн-Ля Рош Аг | Новые 2-аминооксазолины в качестве лигандов taar1 |
| EP2173720A2 (en) | 2007-07-02 | 2010-04-14 | F. Hoffmann-Roche AG | 2-imidazolines having a good affinity to the trace amine associated receptors (taars) |
| EP2173719A1 (en) | 2007-07-03 | 2010-04-14 | F. Hoffmann-Roche AG | 4-imidazolines and their use as antidepressants |
| KR101133862B1 (ko) | 2007-07-27 | 2012-04-06 | 에프. 호프만-라 로슈 아게 | Ｔａａｒ 리간드로서의 2-아제티딘메테인아민 및 2-피롤리딘메테인아민 |
| EP2185502A1 (en) | 2007-08-03 | 2010-05-19 | F. Hoffmann-Roche AG | Pyridinecarboxamide and benzamide derivatives as taar1 ligands |
| US8242153B2 (en) | 2008-07-24 | 2012-08-14 | Hoffmann-La Roche Inc. | 4,5-dihydro-oxazol-2YL derivatives |
| US20100291151A1 (en) * | 2009-04-21 | 2010-11-18 | Auspex Pharmaceuticals, Inc. | 1-methylpyrazole modulators of substance p, calcitonin gene-related peptide, adrenergic receptor, and/or 5-ht receptor |
| US8354441B2 (en) | 2009-11-11 | 2013-01-15 | Hoffmann-La Roche Inc. | Oxazoline derivatives |
| US9452980B2 (en) | 2009-12-22 | 2016-09-27 | Hoffmann-La Roche Inc. | Substituted benzamides |
| MX377836B (es) | 2016-03-17 | 2025-03-11 | F Hoffmann La Roche Ag | Derivado de 5-etil-4-metil-pirazol-3-carboxamida teniendo actividad como agonista de receptor asociado con aminas trazas (taar). |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2613720B1 (fr) * | 1987-04-10 | 1990-01-19 | Esteve Labor Dr | Derives d'aryl-heteroaryl carbinols avec activite analgesique |
| FR2681322B1 (fr) * | 1991-09-12 | 1993-12-17 | Laboratorios Dr Esteve Sa | Derives d'aryl-heteroaryl-{n-[2-(3,4-dimethoxyphenyl)-ethyl]-n-methyl-3-aminopropoxy}-methane leur preparation et leur application en tant que medicaments . |
| CA2154116A1 (en) * | 1994-07-22 | 1996-01-23 | Philip Arthur Hipskind | 1-aryl-2-acetamidopentanone derivatives for use as tachykinin receptor antagonists |
| AU732633B2 (en) * | 1996-12-02 | 2001-04-26 | Merck Sharp & Dohme Limited | Use of NK-1 receptor antagonists for treating schizophrenic disorders |
| JP2001504848A (ja) * | 1996-12-02 | 2001-04-10 | メルク シヤープ エンド ドーム リミテツド | 重症不安障害の治療のためのｎｋ−１受容体拮抗薬の使用 |
| JP2001504847A (ja) * | 1996-12-02 | 2001-04-10 | メルク シヤープ エンド ドーム リミテツド | 重抑鬱障害の治療のためのｎｋ−１受容体拮抗薬の使用 |
| ATE293975T1 (de) * | 1996-12-02 | 2005-05-15 | Merck Sharp & Dohme | Die verwendung von nk-1 rezeptor antagonisten für die behandlung von kognitiven störungen |
| ES2150353B1 (es) * | 1998-04-15 | 2001-07-01 | Esteve Labor Dr | Tienilazolilalcoxietanaminas, su preparacion y su aplicacion como medicamentos. |
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1998
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1999
- 1999-08-04 CO CO99049291A patent/CO5080747A1/es unknown
- 1999-08-04 AR ARP990103870A patent/AR019999A1/es unknown
- 1999-08-05 EP EP99940199A patent/EP1103243B1/en not_active Expired - Lifetime
- 1999-08-05 DE DE69914085T patent/DE69914085T8/de not_active Expired - Fee Related
- 1999-08-05 PT PT99940199T patent/PT1103243E/pt unknown
- 1999-08-05 KR KR1020017001560A patent/KR100558506B1/ko not_active IP Right Cessation
- 1999-08-05 JP JP2000563228A patent/JP2002522359A/ja active Pending
- 1999-08-05 NZ NZ509645A patent/NZ509645A/xx unknown
- 1999-08-05 DK DK99940199T patent/DK1103243T3/da active
- 1999-08-05 CZ CZ2001412A patent/CZ292065B6/cs not_active IP Right Cessation
- 1999-08-05 TW TW088113353A patent/TW445259B/zh not_active IP Right Cessation
- 1999-08-05 RU RU2001106644/15A patent/RU2223116C2/ru not_active IP Right Cessation
- 1999-08-05 TR TR2001/00378T patent/TR200100378T2/xx unknown
- 1999-08-05 CA CA002339661A patent/CA2339661C/en not_active Expired - Fee Related
- 1999-08-05 HU HU0105428A patent/HUP0105428A3/hu unknown
- 1999-08-05 AU AU54229/99A patent/AU754124B2/en not_active Ceased
- 1999-08-05 BR BR9912807-1A patent/BR9912807A/pt not_active Application Discontinuation
- 1999-08-05 CN CNB998109150A patent/CN1151789C/zh not_active Expired - Fee Related
- 1999-08-05 US US09/762,079 patent/US6518295B1/en not_active Expired - Fee Related
- 1999-08-05 WO PCT/ES1999/000255 patent/WO2000007542A2/es active IP Right Grant
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| MM4A | Patent lapsed due to non-payment of fee |
Effective date: 20070805 |