PL193802B1 - Zastosowanie pochodnych arylo (lub heteroarylo) azolilokarbinoli do wytwarzania leku do leczenia zaburzeń wywoływanych nadmiarem substancji P - Google Patents
Zastosowanie pochodnych arylo (lub heteroarylo) azolilokarbinoli do wytwarzania leku do leczenia zaburzeń wywoływanych nadmiarem substancji PInfo
- Publication number
- PL193802B1 PL193802B1 PL99346221A PL34622199A PL193802B1 PL 193802 B1 PL193802 B1 PL 193802B1 PL 99346221 A PL99346221 A PL 99346221A PL 34622199 A PL34622199 A PL 34622199A PL 193802 B1 PL193802 B1 PL 193802B1
- Authority
- PL
- Poland
- Prior art keywords
- methyl
- imidazole
- dimethylamino
- pyrazole
- chloro
- Prior art date
Links
- 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 7
- 230000001404 mediated effect Effects 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 title description 4
- 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 1
- -1 N-methylpiperidyl group Chemical group 0.000 claims abstract description 65
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 7
- 230000036506 anxiety Effects 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
- 206010013663 drug dependence 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
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 4
- 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
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 99
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 27
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 24
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 claims description 21
- 102100024304 Protachykinin-1 Human genes 0.000 claims description 21
- 101800003906 Substance P Proteins 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 12
- 150000003254 radicals Chemical class 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 208000020925 Bipolar disease Diseases 0.000 claims description 5
- 208000028683 bipolar I disease Diseases 0.000 claims description 5
- 208000010877 cognitive disease Diseases 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 208000028698 Cognitive impairment Diseases 0.000 claims description 4
- 201000003152 motion sickness 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
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 82
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 72
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 55
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 32
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 8
- DZDYNIMYBBETIC-UHFFFAOYSA-N (1-butylimidazol-2-yl)-(4-chlorophenyl)methanol Chemical compound CCCCN1C=CN=C1C(O)C1=CC=C(Cl)C=C1 DZDYNIMYBBETIC-UHFFFAOYSA-N 0.000 claims 2
- 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 2
- POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 claims 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 2
- 125000006178 methyl benzyl group Chemical group 0.000 claims 2
- 229940095064 tartrate Drugs 0.000 claims 2
- GKFJUJCWQUQWCK-UHFFFAOYSA-N (1-butylimidazol-2-yl)-(3,4,5-trimethoxyphenyl)methanol Chemical compound CCCCN1C=CN=C1C(O)C1=CC(OC)=C(OC)C(OC)=C1 GKFJUJCWQUQWCK-UHFFFAOYSA-N 0.000 claims 1
- ADWWKGSHHTZDGW-UHFFFAOYSA-N (1-butylimidazol-2-yl)-(3,4-dichlorophenyl)methanol Chemical compound CCCCN1C=CN=C1C(O)C1=CC=C(Cl)C(Cl)=C1 ADWWKGSHHTZDGW-UHFFFAOYSA-N 0.000 claims 1
- 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
- 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 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
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- 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
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- CGBHLJFEXGOGFF-UHFFFAOYSA-N 1-(1-butylimidazol-2-yl)-1-(3,4,5-trimethoxyphenyl)pentan-1-ol Chemical compound CCCCN1C=CN=C1C(O)(CCCC)C1=CC(OC)=C(OC)C(OC)=C1 CGBHLJFEXGOGFF-UHFFFAOYSA-N 0.000 claims 1
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- 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
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- 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
- 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
- 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
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- A61K31/33—Heterocyclic compounds
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Abstract
1. Zastosowanie pochodnej arylo (lub heteroarylo) azolilokarbinolu o wzorze ogólnym (l) w którym: Ar oznacza rodnik fenylowy lub tienylowy, niepodstawiony albo ewentualnie podstawiony przez 1, 2 lub 3 takie same lub rózne podstawniki, wybrane z grupy utworzonej przez fluor, chlor, brom, metyl, trifluorometyl i metoksyl; R 1 oznacza atom wodoru, grupe cykloheksylowa, grupe N-metylopiperydylowa, grupe fenylowa, grupe winylowa lub grupe alkilowa C 1-C 4; R 2 oznacza atom wodoru, dialkilo(C 1-C 4)aminoalkil(C 2-C 3), alkilo(C 1-C 2)azaheterocykloalkil(C 2-C 3) lub azahete- rocykloalkil(C 2-C 3); a Het oznacza piecioczlonowy azotowy heterocykliczny pierscien aromatyczny, zawierajacy od jednego do trzech atomów azotu, niepodstawiony lub ewentualnie podstawiony przez 1 lub 2 podstawniki, takie same lub rózne, wybrane z grupy utworzonej z fluoru, chloru, bromu, grupy alkilowej C 1-C 12, rodnika benzylowego, rodnika cyjanoalkilowego (C 2-C 3), rodnika karboksyalkilowego (C 2-C 3), rodnika metoksykarbonyloalkilowego (C 2-C 3), rodnika hydroksyalkilowego (C 2-C 3), rodnika aminoalkilowego (C 2-C 3), rodnika dialkilo(C 1-C 4)aminoalkilowego (C 2-C 3) i rodnika azaheterocykloalkilowego (C 2-C 3); lub jednej z jej fizjologicznie dopuszczalnych soli, do wytwarzania leku do leczenia zaburzen wywolywanych nadmiarem substancji P, w tym leku, depresji, schizofrenii, psychozy maniakalno-depresyjnej, dysfunkcji seksualnych, uzaleznienia od leków, zaburzenia pojmowania, choroby lokomocyjnej, itp., u ssaków, w tym czlowieka. PL PL PL
Description
Opis wynalazku
Dziedzina wynalazku
Wynalazek dotyczy zastosowania pochodnych arylo (lub heteroarylo) azolilokarbinoli o wzorze ogólnym (I), jak również ich fizjologicznie dopuszczalnych soli, do wytwarzania leków, użytecznych w medycynie ludzkiej i/lub weterynaryjnej, do leczenia zaburzeń wywoływanych nadmiarem substancji P, a zwłaszcza zaburzeń ośrodkowego układu nerwowego, takich jak lęk, depresja, schizofrenia, psychoza maniakalno-depresyjna, dysfunkcje seksualne, uzależnienia od leków, zaburzenia pojmowania, choroba lokomocyjna i inne.
Tło wynalazku
Substancja P jest to peptyd tachykinina, który można wyizolować z tkanki mózgowej i z układu żołądkowo-jelitowego. W mózgu relatywnie wysokie stężenia substancji P zawierają istota czarna (substantia nigra) i zwoje podstawy mózgu.
Istnieją dowody sugerujące, że substancja P działa jako neuroprzekaźnik. W zwojach podstawy mózgu substancja P jest syntetyzowana w średnich neuronach prążkowia, a projekcja do pars reticulata istoty czarnej następuje poprzez rdzeń. Badania dystrybucji receptorów wskazują, że receptory NK1 występują w prążkowiu z relatywnie wysoką gęstością, lecz w żadnym zakresie ani do żadnego celu nie są obecne w istocie czarnej. Jednakże istota czarna zawiera jeden z najwyższych poziomów tkankowej substancji P w ośrodkowym układzie nerwowym. Chociaż wydaje się to wskazywać, że receptor i ligand nie są sparowane, to substancja P może oddziaływać z receptorami w prążkowiu poprzez uwalnianie z obocznych aksonów miejscowych neuronów istoty czarnej. Wykazano, że zakończenia zawierające substancję P tworzą kontakt synaptyczny z komórkowymi ciałami cholinergicznymi w prążkowiu. Wydaje się, że ekspresja receptorów NK1 w prążkowiu zachodzi głównie w interneuronach cholinergicznych, chociaż ekspresja tych receptorów może zachodzić także w niewielkiej populacji niecholinergicznych neuronów prążkowia. Ponadto, okazało się że stymulacja receptorów NK1 przez substancję P zwiększa uwalnianie acetylocholiny (Ach), zarówno in vitro i in vivo. W konsekwencji opisano obwód anatomiczny, w którym substancja P, uwalniana miejscowo w prążkowiu z obocznych aksonów neuronów prążkowia, może wiązać się z receptorami NK1 w cholinergicznych interneuronach prążkowia, stymulując uwalnianie acetylocholiny (J.J. Anderson, J. Pharmacol. Exp. Ther., 1995, 274, 928-936).
Substancja P jest także zaangażowana w patofizjologię szeregu zaburzeń neuropsychiatrycznych, takich jak schizofrenia, psychoza maniakalno-depresyjna, dysfunkcje seksualne, uzależnienia od leków, zaburzenia pojmowania, choroba lokomocyjna, oraz depresja (M. Bianchi, Inflamm. Res., 1995, 44 (11), 466-469). Podobnie, można wnioskować o istnieniu wyraźnego związku między stanami depresyjnymi a poziomem substancji P, ponieważ produkty działające jako inhibitory substancji P wykazują wyraźną komponentę antydepresyjną przy badaniu w różnych laboratoryjnych modelach zwierzęcych.
Z drugiej strony istnieje także związek między procesami lękowymi (anksjoliza/anksjogeneza) a poziomami substancji P. Wykazano, że produkty działające jako antagoniści receptora NK1 wykazują czynność anksjolityczną w teście interakcji socjalnych (S. File, Pharmacol. Biochem. Behav., 1997, 58(3), 747-752, z niewielką tendencją do rozwijania się tolerancji. Podobnie, podawanie substancji P stanowi czynnik anksjogenny w teście labiryntu (R.M.Teixeira, Eur. J. Pharmacol., 1996, 31(1), 7-14), a blokery receptora substancji P mają działanie odwrotne. Można zatem wywnioskować, że poziomy substancji P odgrywają ważną rolę w ekspresji lęku.
W publikacjach patentów EP 289380 i ES 9800793 zostały opisane pochodne karbinolu o wzorze ogólnym (I)
gdzie Ar oznacza pierścień benzenowy bądź podstawiony albo niepodstawiony pierścień tiofenowy; R1 oznacza atom wodoru lub niższą grupę alkilową C1 do C4; R2 oznacza dialkiloaminoalkil lub rodnik
PL 193 802 B1 azaheterocykloalkilowy, aHet oznacza azol, jak również ich fizjologicznie dopuszczalne sole. Związki te zastrzegano jako środki do leczenia bólu.
W publikacjach patentów PCT/EP96/05596, ES 9701538, ES 9701728 i ES 9800793 zostały również opisane różne sposoby wytwarzania enancjomerycznie czystych związków o wzorze ogólnym (l).
Obecnie stwierdziliśmy, że związki o wzorze ogólnym (l), jak również ich fizjologicznie dopuszczalne sole, są szczególnie przydatne do wytwarzania leków, użytecznych w medycynie ludzkiej i/lub weterynaryjnej, do leczenia zaburzeń wywoływanych nadmiarem substancji P, a zwłaszcza zaburzeń ośrodkowego układu nerwowego, takich jak lęk, depresja, schizofrenia, psychoza maniakalnodepresyjna, dysfunkcje seksualne, uzależnienia od leków, zaburzenia pojmowania, choroba lokomocyjna i inne.
Szczegółowy opis wynalazku
Wynalazek dotyczy zastosowania pochodnych arylo (lub heteroarylo) azolilokarbinoli o wzorze ogólnym (l)
w którym:
Ar oznacza rodnik fenylowy lub tienylowy, niepodstawiony albo ewentualnie podstawiony przez 1, 2 lub 3 takie same lub różne podstawniki, wybrane z grupy utworzonej przez fluor, chlor, brom, metyl, trifluorometyl i metoksyl;
R1 oznacza atom wodoru, grupę cykloheksylową, grupę N-metylopiperydylową, grupę fenylową, grupę winylową lub grupę alkilową C1-C4;
R2 oznacza atom wodoru, dialkilo(C1-C4)aminoalkil(C2-C3), alkilo(C1-C2)azaheterocykloalkil(C2-C3) lub azaheterocykloalkil(C2-C3); a
Het oznacza pięcioczłonowy azotowy heterocykliczny pierścień aromatyczny, zawierający od jednego do trzech atomów azotu, niepodstawiony lub ewentualnie podstawiony przez 1 lub 2 podstawniki, takie same lub różne, wybrane z grupy utworzonej z fluoru, chloru, bromu, grupy alkilowej C1-C12, rodnika benzylowego, rodnika cyjanoalkilowego (C2-C3), rodnika karboksyalkilowego (C2-C3), rodnika metoksykarbonyloalkilowego (C2-C3), rodnika hydroksyalkilowego (C2-C3), rodnika aminoalkilowego (C2-C3), rodnika dialkilo(C1-C4)aminoalkilowego(C2-C3) i rodnika azaheterocykloalkilowego (C2-C3);
lub jednej z ich fizjologicznie dopuszczalnych soli, do wytwarzania leku do leczenia zaburzeń wywoływanych nadmiarem substancji P, a zwłaszcza zaburzeń ośrodkowego układu nerwowego, w tym lęku, depresji, schizofrenii, psychozy maniakalno-depresyjnej, dysfunkcji seksualnych, uzależnienia od leków, zaburzenia pojmowania, choroby lokomocyjnej i innych, u ssaków, w tym człowieka.
Określenie „grupa alkilowa C1-C4” oznacza prosty lub rozgałęziony rodnik, wywodzący się spośród węglowodorów nasyconych zawierających 1 do 4 atomów węgla, taki jak na przykład metyl, etyl, propyl, izopropyl, butyl, izobutyl, sec-butyl i tert-butyl.
Określenie „dialkilo(C1-C4)aminoalkil(C2-C3), alkilo(C1-C2)azaheterocykloalkil(C2-C3) lub azaheterocykloalkil(C2-C3)” oznacza rodnik alkilowy o dwu lub trzech atomach węgla przyłączony do dialkilo(C1-C4)aminy lub do cyklicznej aminy, taki jak dimetyloaminoetyl, dimetyloaminopropyl, dietyloaminoetyl, piperydyloetyl, N-etylopiperydyloetyl, N-metylopirolidynyloetyl, morfolinylo-propyl, pirolidynoalkil i inne.
Określenie „alkilo(C1-C2)azaheterocykloalkil(C2-C3)” oznacza rodnik alkilowy o dwu lub trzech atomach węgla przyłączony do alkilo(C1-C2)azaheterocykloalkilu.
Określenie „cyjanoalkil (C2-C3)” oznacza rodnik alkilowy o dwu lub trzech atomach węgla przyłączony do cyjanowej grupy funkcyjnej.
Określenie „karboksyalkil (C2-C3)” oznacza rodnik alkilowy o dwu lub trzech atomach węgla przyłączony do karboksylowej grupy funkcyjnej.
Określenie „metoksykarbonyloalkil (C2-C3)” oznacza rodnik alkilowy o dwu lub trzech atomach węgla przyłączony do metoksykarbonylowej grupy funkcyjnej.
PL 193 802 B1
Określenie „hydroksyalkil (C2-C3)” oznacza rodnik alkilowy o dwu lub trzech atomach węgla przyłączony do hydroksylowej grupy funkcyjnej.
Określenie „aminoalkil (C2-C3)” oznacza rodnik alkilowy o dwu lub trzech atomach węgla przyłączony do aminowej grupy funkcyjnej.
Związki o wzorze ogólnym (l) można syntetyzować w sposób opisany w patentach EP 289380 lub ES 9800793. Związki o wzorze ogólnym (l) posiadają centrum stereogeniczne, a zatem wynalazek dotyczy zastosowania czystego enancjomeru jak również mieszaniny enancjomerów. Enancjomery można otrzymać w jeden ze sposobów opisanych w patentach PCT/EP96/05596, ES 9701538, ES 9701728 lub ES 9800793.
Przykłady kompozycji farmaceutycznych zawierających związki o wzorze ogólnym (l) są opisane w naszych zgłoszeniach patentowych EP 289380 i ES 9800793.
Ilustracyjne przykłady związków objętych wynalazkiem obejmują związki scharakteryzowane danymi przedstawionymi w tabelach 1 do 7.
T a b e l a 1
| Przykład Nr | R5 | R1 | R3 | Z1 | Z2 | R4 | R2 |
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 1 | H | H | Me | CH | N | H | DMA |
| 2 | 4-Cl | Me | Me | CH | N | H | DMA |
| 3 | 4-Cl | H | Me | CH | N | H | DMA |
| 4 | 3-Cl | H | Me | CH | N | H | DMA |
| 5 | 2-Cl | Me | Me | CH | N | H | DMA |
| 6 | 4-F | Me | Me | CH | N | H | DMA |
| 7 | 3-CF3 | Me | Me | CH | N | H | DMA |
| 8 | 3-Cl | Me | Me | CH | N | H | DMA |
| 9 | 3-Cl | n-But | Me | CH | N | H | DMA |
| 10 | 4-Cl | Me | n-But | CH | N | H | DMA |
| 11 | 4-OMe | Me | Me | CH | N | H | DMA |
| 12 | 3-Cl | Me | Me | CH | N | H | Pyr |
| 13 | 3,4,5-tri-OMe | n-But | C12H25- | CH | N | H | DMA |
| 14 | 4-CF3 | H | n-But | CH | N | H | DMA |
| 15 | 3-CF3 | Me | Me | CH | N | H | Pip |
| 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 |
PL 193 802 B1 cd. tabeli 1
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 19 | 3,4-di-Cl | H | Me | CH | N | H | DMA |
| 20 | 4-Cl | Me | CN-(CHA- | CH | N | H | DMA |
| 21 | 4-Cl | Me | Cn-(cha- | CH | N | H | DMA |
| 22 | 4-Cl | H | N=C-(CH2)3- | CH | N | H | DMA |
| 23 | 4-Cl | Me-f/ - | Me | CH | N | H | DMA |
| 24 | 4-Cl | H | -ch2-£J | CH | N | H | MBA |
| 25 | 4-Cl | Me | -(CH2)3-N(CHs)-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 | H | DMA |
| 41 | 4-Cl | H | Me | N | CCl | H | DMA |
| 42 | 4-Cl | H | Me | N | CH | H | DMA |
| 43 | 3-Cl | H | Me | N | CH | H | DMA |
| 44 | 4-Me | H | Me | N | CH | H | DMA |
| 45 | 2-Cl | H | Me | N | CH | H | DMA |
| 46 | H | H | Me | N | CH | H | Pip |
| 47 | H | H | Me | N | CH | H | Pr Z © |
| 48 | H | H | Me | N | CH | H | Et ά |
| 49 | H | H | Me | N | CH | H | Me / ty |
PL 193 802 B1 cd. tabeli 1
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 50 | H | H | Me | N | CH | H | DIPA |
| 51 | H | H | Me | N | CH | H | Me ά |
| 52 | 4-Cl | Me | Me | CH | N | H | DMAP |
| 53 | 3-Cl | H | Me | CH | N | H | DMAP |
| 54 | 4-Cl | Et | Me | CH | N | H | DMAP |
| 55 | 3-Cl | n-But | Me | CH | N | H | DMAP |
| 56 | 4-Cl | Θ | Me | CH | N | H | DMAP |
| 57 | 4-F | Me | Me | CH | N | H | DMAP |
| 58 | 3-CF3 | Me | Me | CH | N | H | DMAP |
| 59 | 2-Cl | Me | Me | CH | N | H | DMAP |
| 60 | 3-Cl | 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 | DMAP |
| 64 | 3,4,5-tri-OMe | H | Me | CH | N | H | DMAP |
| 65 | 4-CF3 | Me | Me | CH | N | H | DMAP |
| 66 | 3-CF3 | H | Me | CH | N | H | DMAP |
| 67 | 4-CF3 | H | Me | CH | N | H | DMAP |
| 68 | 4-OMe | H | Me | CH | N | H | DMAP |
| 69 | 3-CF3 | n-But | 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-Cl | n-But | n-But | CH | N | H | DMAP |
| 73 | 2,4-di-Cl | n-But | n-But | CH | N | H | DMAP |
| 74 | 4-CF3 | H | n-But | CH | N | H | DMAP |
| 75 | 4-Cl | H | Me | CH | N | H | PipP |
| 76 | 4-CF3 | Me | Me | CH | N | H | PipP |
| 77 | 2-Cl | n-But | Me | CH | N | H | DMAP |
| 78 | 3,4-di-Cl | n-But | Me | CH | N | H | DMAP |
| 79 | 3,4-di-Cl | Me | Me | CH | N | H | DMAP |
| 80 | 3,4-di-Cl | H | Me | CH | N | H | DMAP |
| 81 | 3,4-di-Cl | Θ | Me | CH | N | H | DMAP |
| 82 | 4-Cl | Me | CN'(CHĄ- | CH | N | H | DMAP |
| 83 | 4-Cl | Me | Cn-(ch3)- | CH | N | H | DMAP |
| 84 | 4-Cl | CHj-θ- | Me | CH | N | H | DMAP |
PL 193 802 B1 cd. tabeli 1
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 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 | H | DMAP |
| 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 | = dimetyloaminoetyl |
| Pyr | = pirolidynyloetyl |
| Pip | = piperydyloetyl |
| MBA | = (metylobenzyloamino)etyl |
| Mor | = morfolinylopropyl |
| DIPA | = diizopropyloaminoetyl |
| DMAP | = dimetyloaminopropyl |
| PipP | = piperydylopropyl |
| PirP | = pirolidynylopropyl |
T a b e l a 2
r2
| Przykład nr | R5 | R1 | R3 | R2 |
| 1 | 2 | 3 | 4 | 5 |
| 95 | 4-Cl | H | Me | DMA |
| 96 | 4-Cl | Me | Me | DMA |
| 97 | 4-Cl | H | Me | Pr / O |
| 98 | 4-Cl | H | Me | Me / Cr |
| 99 | 4-Cl | H | Me | Et / Cr |
PL 193 802 B1 cd. tabeli 2
| 1 | 2 | 3 | 4 | 5 |
| 100 | 4-Cl | H | Me | DIPA |
| 101 | 4-Cl | H | Me | Me / nN O |
| 102 | H | H | Me | DMAP |
| 103 | 4-Cl | H | Me | MorP |
| 104 | 4-Cl | H | Me | PirP |
DMA = dimetyloaminoetyl
DIPA = diizopropyloaminoetyl
DMAP = dimetyloaminopropyl
MorP = morfolinylopropyl
PirP = pirolidynylopropyl
T a b e l a 3
| Przykład Nr | R5 | R1 | R3 | Z1 | Z2 | R4 | t.t. |
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 105 | H | H | H | CH | N | H | 202-3°C |
| 106 | 4-Cl | H | H | CH | N | H | 196-7°C |
| 107 | 4-Cl | H | Me | CH | N | H | 137-9°C |
| 108 | 3-Cl | 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-Cl | H | Me | CH | N | H | 157-9°C |
| 114 | 4-CF3 | H | n-But | CH | N | H | 111-2°C |
| 115 | 2,4-di-Cl | H | n-But | CH | N | H | 94-7°C |
| 116 | 4-Cl | 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-Cl | n-But | Me | CH | N | H | 125-6°C |
| 120 | 3-Cl | Me | Me | CH | N | H | 180-1 °C |
| 121 | 4-Cl | Me | Me | CH | N | H | 191-2°C |
| 122 | 4-Cl | Me—N^J> | Me | CH | N | H | 183-4°C |
PL 193 802 B1 cd. tabeli 3
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 123 | 4-Cl | Et | Me | CH | N | H | 166-8°C |
| 124 | 4-Cl | n-But | Me | CH | N | H | 120-2°C |
| 125 | 4-Cl | 0 | Me | CH | N | H | 161-2°C |
| 126 | 2-Cl | Me | Me | CH | N | H | 181-2°C |
| 127 | 2-Cl | n-But | Me | CH | N | H | 138-41 °C |
| 128 | 3-CF3 | Me | Me | CH | N | H | 193-4°C |
| 129 | 3-CF3 | n-But | Me | CH | N | H | 140-1 °C |
| 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-Cl | Me | Me | CH | N | H | 207-8°C |
| 135 | 3,4-di-Cl | n-But | Me | CH | N | H | 142-4°C |
| 136 | 3,4-di-Cl | 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 | «<0 | 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-Cl | 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-Cl | n-But | n-But | CH | N | H | 142-3°C |
| 145 | 4-Cl | Me | CN“(CH^ | 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)2-CH | CH | N | H | 134-5°C |
| 151 | 4-Cl | H | -(CH2)2-NH2 | CH | N | H | 187-8°C |
| 152 | 3-Cl | H | -(CH2)2-CO2H | CH | N | H | 212-3°C |
| 153 | 4-Cl | H | -(CH2)2- CH2Me | CH | N | H | 121-2°C |
| 154 | 4-Cl | H | -(CH2)2- CO2OH | CH | N | H | 96-7°C |
| 155 | H | H | -(CH2)2- CO2OH | CH | N | H | 110-1 °C |
PL 193 802 B1 cd. tabeli 3
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 156 | 4-Me | Me | -(CH2)2- CO2OH | CH | N | H | 104-5°C |
| 157 | 4-OMe | H | -(CH2)2- CO2OH | CH | N | H | olej |
| 158 | 3,4-di-Cl | H | -(CH2)2- CH2OH | CH | N | H | 138-91 °C |
| 159 | H | H | -(CH2)2- CO2Me | CH | N | H | 93-6°C |
| 160 | 4-Cl | H | -(CH2)4-OH | CH | N | H | 131-2°C |
| 161 | 4-Cl | H | -(CH2)3-CN | CH | N | H | olej |
| 162 | 4-Cl | H | -(CH2)3-CO2H | CH | N | H | >300°C |
| 163 | 4-Cl | H | -(CH2)3- CO2Me | CH | N | H | 85-7°C |
| 164 | H | H | n-But | N | CH | H | 47-8°C |
| 165 | 4-Cl | H | Me | N | CH | H | 94-7°C |
| 166 | 3,4,5-tri-OMe | H | Me | N | CH | H | olej |
| 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-Cl | Ph | Me | N | CH | H | 167-8°C |
| 170 | 4-Cl | 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 | H | 137-8°C |
| 174 | H | CH2=CH- | Me | N | CH | H | 95-6°C |
| 175 | 4-Cl | CH2=CH- | n-But | N | CH | H | 84-5°C |
| 176 | H | H | Me | N | CCl | H | olej |
| 177 | 2-Me | H | Me | N | CH | H | 113-4°C |
| 178 | 3-Cl | H | Me | N | CH | H | 128-9°C |
| 179 | 4-Me | H | Me | N | CH | H | 123-6°C |
| 180 | 2-Cl | H | Me | N | CH | H | 96-8°C |
| 181 | 4-OMe | H | Me | N | CH | H | 129-30°C |
PL 193 802 B1
TABELA 4
| Przykład Nr | 1H NMR, δ (CDCIj) |
| 1 | 7.2 (s, 5H); 6.8 (d, 2H); 5.7 (s. 1H); 3.5 (m.2H); 3.35 <s, 3H); 2.6 (t, 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); 14-0.6 (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) |
PL 193 802 B1
| Przykład Nr | ’HNMR, 6 (CDCIj) ! i |
| 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 (tn, 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) „i |
| 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 (t, 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, 1h); 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 (t, 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, 2K); 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 (t, 2H); 2.15 (s, 9H) |
| 41 | 7.5-7.0 (m. 6H); 6.1 (s, 1H); 3.6 (m, 5H); 2.7 (t, 2H); 2.2 (s. 6H) |
| 42 | 7.3 (m, 5H); 5.9 (s, 1H); 5.5 (s, 1H); 3.8 (s, 3H); 3.5 (1, 2H); 2.5 (t, 2H): 2.2 (s, 6H) |
| 43 | 7.4-71 (m, 5H); 6.0 (s, 1H); 5.5 (s, 1H); 3.8 (s, 3H); 3.6 (t, 2H); 2.6 (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) |
PL 193 802 B1
| Przykład Nr | ’HNMR, δ (CDCI3) |
| 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 (t, 2H); 3.0 (m, 1H); 22-1.0 (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 (t, 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, I 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 | 7.3-67 (m, 6H); 3.6 (m, 1H); 3.3 (s, 3H); 3.1 (m. 1H); 2.4 (m, 2H); 2.25 (s, 6H); 1.9 (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); 2.8 (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) |
PL 193 802 B1
| Przykład Nr | ’Η NMR, 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); 3.45 (s. 3H); 2.4 (m, 2H); 2.25 (s, 6H); 1.8 (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); 2.4 (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- i 0.4 (m, 16H) ! |
| 72 | 7.9 (m, 1H); 7.15 (m, 3H); 6.8 (d, 2H); 3.45 (m, 2H); 30-2.2 (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), 1.90.5 (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 | 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) |
| 78 | 7.4-6.6 (m, 5H); 3.4 (m, 1H); 3.2 (s, 3H); 2.9 (1H); 2.3 (m, 4H); 2.15 (s, 6H); 1.9-0.5 (m, 2H) |
| 79 | 7.3 (m, 2H); 6.8 (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); 1.4 (m, 10H) |
| 84 | 7.2-6.6 <m, 6H); 3.4 (m, 1H); 3.1-2.5 (m, 8H); 2.15-1.5 (m, 14H); 1.0 (m, 4H) _ |
| 85 | 7,25 (m, 6H); 5.9 (m, 1H); 5.4 (s, 1H); 3.95 (t, 2H); 3.40 (t, 2H); 2.25 (t, 2H); 2.1 (s. 6H); 1.850.5 (m, 9H) |
| 86 | 7.45 (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, |
PL 193 802 B1
| Przykład Nr | ’HNMR, 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) |
| 88 | 7.4 (d, 1H); 7.2 (s, 5H); 6.35 (d. 1H); 3.55 (m, 2H); 3.4 (s, 3H); 2.35 (t, 2H); 2.2 (s, 6H); 1.951.6 (m. 5H) |
| 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) |
| 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) |
| 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, 2H) |
| 92 | 7.4-7.2 (m, 5H); 5.9 (s, 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); 2.1-1.0(m, 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) |
| 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); 15-0.5 (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); 2.3-1.6 (m. 4H) |
| 166 | 7.3 (d, 1H); 6.5 (s, 2H), 5.9 (s, 1H); 5.7 (s-1H), 3.6 (m, 12H) |
| 167 | 7.2 (d, 1H); 6.5 (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) |
PL 193 802 B1
TABELA 5
Μα
<
O-d
PL 193 802 B1
PL 193 802 B1
PL 193 802 B1
PL 193 802 B1
TABELA 6
PL 193 802 B1
| 121-122 | 121-122 | 130-131 | 130-131 | 130-131 | 129-131 |
| +2.8 (c=2.0 MeOH) | -2.3 (c=2.0 MeOH) | +87.5 (C=2 0 MeOH) | -85.4 (c=2.0 MeOH) | o CO Φ τ 2 II o | I o CM U csi V ° T— It u |
| 05 05 | 98.5 | 05 o | 98.5 | 99.1 | 0 66 |
| 3 | 3 | 2 | 3 | ||
| cytrynian | cytrynian | (D)-ditolui lowinian | (L)-ditoluilo- winian | cytrynian | cytrynian |
| X | I | X | I | X | I |
| 6 | d | d | d | d | |
| x z—o W | f^\ zT 2 — 0 w | d-f | d- | d-f | d-s' |
| (O 05 +“ | 197 | co 05 v- | 199 | 200 | 201 |
PL 193 802 B1
TABELA 7
PL 193 802 B1
PL 193 802 B1
Aktywność związków o wzorze ogólnym (I) w zastrzeganych zastosowaniach wykazano eksperymentalnie przez badanie wpływu na uwalnianie substancji P in vivo oraz w dwóch testach aktywności antydepresyjnej in vivo.
W poniższych przykładach wskazano pewne właściwości przedmiotu wynalazku na przykładzie cytrynianu (±)-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazolu (przykład 191).
W poniższych przykładach, przedstawionych dla ilustracji, opisano niektóre testy biologiczne, wi żadnym razie przykładów tych nie należy interpretować jako ograniczenia zakresu wynalazku.
Przykład 1
Wpływ na uwalnianie rdzeniowe substancji P u szczurów
Badanie przeprowadzono in vivo, na szczurach znieczulonych halotanem. Badanie polegało na dooponowej perfuzji sztucznym płynem mózgowo-rdzeniowym w celu zbierania peptydów uwalnianych z powierzchniowych warstw rdzenia kręgowego podczas miejscowego lub układowego podawania badanego produktu. Stosowano metodę opisaną przez E. Collin i in., (Naunyn-Schmiedeberg's Arch. Pharmacol, 1994, 349, 387-393).
Badano aktywność cytrynianu (±)-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazolu (przykład 191), podawanego dooponowo w płynie perfuzyjnym w stężeniu 1 mM. Jak zestawiono w tabeli 8, produkt hamował uwalnianie substancji P. Układowe podawanie produktu w dawce 46 mg/kg również zmniejszało uwalnianie substancji P.
Należy zauważyć, że wpływ układowego podawania produktu na rdzeniowe uwalnianie substancji P utrzymywał się dwie godziny, przy średnim hamowaniu w tym okresie równym 50%.
Przykład 2
Badanie aktywności antydepresyjnej
Aktywność antydepresyjną cytrynianu (±)-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazolu (przykład 191) badano i wykazano w dwóch różnych testach na myszach. W pierwszym teście badano hamowanie ptozy wywołanej przez rezerpinę, a w drugiej wpływ na ruchliwość w sytuacji odwrócenia.
2.1 Hamowanie ptozy wywołanej rezerpiną u myszy
Zastosowano metodę opisaną przez S.Garattini i współpr. (Med. Exp., 1960, 3, 315-320). Test polega na obserwowaniu ewentualnego hamowania ptozy wywołanej przez rezerpinę (25 mg/kg, ip: dootrzewnowo) u myszy po doustnym podaniu badanych produktów.
Oznaczano aktywność cytrynianu (±)-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazolu (przykład 191), podawanego doustnie w różnych dawkach. Jak zestawiono w tabeli 9, cytrynian (±)-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazolu (przykład 191), hamując działanie rezerpiny ma wyraźną aktywność antydepresyjną przy dobrej zależności dawka-odpowiedź.
2.2. Wpływ na ruchliwość w sytuacji odwrócenia
Zastosowano metodę R.D. Porsolt i współpr. (Arch. Int. Pharmacodyn., 1987, 288, 11-30). Test polegał na zawieszeniu myszy za ogony na sześć minut w aparacie ITEMATIC-TST, który mierzy ruchliwość i siłę ruchów zwierząt. Zwierzęta poddane tej sytuacji odwrócenia po początkowym okresie energicznej aktywności ulegają rezygnacji i na końcu pozostają spokojnie w bezruchu. Produkty o aktywności antydepresyjnej znacznie zmniejszają czas znieruchomienia.
Jak zestawiono w tabeli 10, cytrynian (±)-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazolu (przykład 191) okazał się wyraźnie aktywny w tym teście, znacznie skracając okres znieruchomienia w sposób zależny od dawki.
Przeprowadzone testy farmakologiczne wykazały, że cytrynian (±)-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazolu (przykład 191), jako przykład przedmiotu wynalazku, wykazuje wyraźną aktywność jako inhibitor substancji P, co stwarza możliwość stosowania go w leczeniu zaburzeń ośrodkowego układu nerwowego, wywoływanych nadmiarem substancji P. Ponadto, dla przykładu, wykazano aktywność przeciwdepresyjną w dwóch różnych testach na zwierzętach doświadczalnych.
PL 193 802 B1
Tabela 8.
Wpływ cytrynianu (±)-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazolu (przykład 191) na uwalnianie dooponowe substancji P
| Leczenie za pomocą związku z przykładu 191 | Hamowanie uwalniania dooponowego w porównaniu z grupą kontrolną, % |
| 1 mM, dooponowo | -58 |
| 46 mg/kg, i.p. | -50 |
Tabela 9.
Hamowanie ptozy wywołanej przez rezerpinę u myszy
| Produkt | Dawka* (mg/kg, doustnie) | % aktywności | ED-50 |
| Przykład 191 | 92 | 84 | |
| 80 | 75 | 38,5 mg/kg, | |
| 23 | 30 | doustnie | |
| 12 | 8 |
* Dawka wyrażona w mg/kg zasady związku z przykładu 191
Ta bela 10.
Zmniejszanie czasu znieruchomienia w sytuacji odwrócenia u myszy
| Produkt | Dawka* (mg/kg, doustnie ) | % czynności | ED-50 |
| Przykład 191 | 92 | 69 | |
| 46 | 41 | 50,5 mg/kg, | |
| 23 | 30 | doustnie | |
| 12 | 20 |
Zastrzeżenia patentowe
Claims (2)
- Zastrzeżenia patentowe1. Zastosowanie pochodnej arylo (lub heteroarylo) azolilokarbinolu o wzorze ogólnym (l) w którym:Ar oznacza rodnik fenylowy lub tienylowy, niepodstawiony albo ewentualnie podstawiony przez 1, 2 lub 3 takie same lub różne podstawniki, wybrane z grupy utworzonej przez fluor, chlor, brom, metyl, trifluorometyl i metoksyl;R1 oznacza atom wodoru, grupę cykloheksylową, grupę N-metylopiperydylową, grupę fenylową, grupę winylową lub grupę alkilową C1-C4;R2 oznacza atom wodoru, dialkilo(C1-C4)aminoalkil(C2-C3), alkilo(C1-C2)azaheterocykloalkil(C2-C3) lub azaheterocykloalkil(C2-C3); aHet oznacza pięcioczłonowy azotowy heterocykliczny pierścień aromatyczny, zawierający od jednego do trzech atomów azotu, niepodstawiony lub ewentualnie podstawiony przez 1 lub 2 podstawniki, takie same lub różne, wybrane z grupy utworzonej z fluoru, chloru, bromu, grupy alkilowejPL 193 802 B1C1-C12, rodnika benzylowego, rodnika cyjanoalkilowego (C2-C3), rodnika karboksyalkilowego (C2-C3), rodnika metoksykarbonyloalkilowego (C2-C3), rodnika hydroksyalkilowego (C2-C3), rodnika aminoalkilowego (C2-C3), rodnika dialkilo(C1-C4)aminoalkilowego (C2-C3) i rodnika azaheterocykloalkilowego (C2-C3);lub jednej z jej fizjologicznie dopuszczalnych soli, do wytwarzania leku do leczenia zaburzeń wywoływanych nadmiarem substancji P, w tym lęku, depresji, schizofrenii, psychozy maniakalnodepresyjnej, dysfunkcji seksualnych, uzależnienia od leków, zaburzenia pojmowania, choroby lokomocyjnej, itp., u ssaków, w tym człowieka.
- 2. Zastosowanie według zastrz. 1, w którym związek o wzorze ogólnym (l) jest wybrany z grupy następującej:[1] 2-{ a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-imidazol, [2] 2-{4-chloro-a-[2-(dimetyloamino)etoksy]-a-metylobenzylo}-1-metylo-1H-imidazol [3] 2-{4-chloro- a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-imidazol, [4] 2-{3-chloro- a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-imidazol, [5] 2-{4-chloro-a-[2-(dimetyloamino)etoksy]-a-metylobenzylo}-1-metylo-1H-imidazol, [6] 2-{4-fluoro-a-[2-(dimetyloamino)etoksy]-a-metylobenzylo}-1-metylo-1H-imidazol, [7] 2-{a-[2-(dimetyloamino)etoksy]-a-metylo-3-(trifluorometylo)benzylo}-1-metylo-1H-imidazol, [8] 2-{3-chloro-a-[2-(dimetyloamino)etoksy]-a-metylobenzylo}-1-metylo-1H-imidazol, [9] 2-{3-chloro- a-[2-(dimetyloamino)etoksy]- a-propylobenzylo}-1-metylo-1H-imidazol, [10] 1-butylo-2-{4-chloro-a-[2-(dimetyloamino)etoksy]-a-metylobenzylo}-1H-imidazol, [11] 2-{a-[2-(dimetyloamino)etoksy]-a-metylo-4-metoksybenzylo}-1-metylo-1H-imidazol, [12] 2-{3-chloro-a-metylo-a-[2-(N-pirolidylo)etoksy]benzylo}-1-metylo-1H-imidazol, [13] 2-{a-[2-(dimetyloamino)etoksy]-a-propylo-3,4,5-trimetoksybenzylo}-1-dodecylo-1H-imidazol, [14] 1-butylo-2-{a-[2-(dimetyloamino)etoksy]-4-(trifluorometylo)benzylo}-1H-imidazol, [15] 1-metylo-2-{a-metylo-a-[2-(N-piperydylo)etoksy]-3-(trifluorometylo)benzylo}-1H-imidazol, [16] 2-{a-cykloheksylo-3,4-dichloro-a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-imidazol, [17] 2-{3,4-dichloro-a-[2-(dimetyloamino)etoksy]-a-propylobenzylo}-1-metylo-1H-imidazol, [18] 2-{3,4-dichloro-a-[2-(dimetyloamino)etoksy]-a-metylobenzylo}-1-metylo-1H-imidazol, [19] 2-{3,4-dichloro-a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-imidazol, [20] 2-{4-chloro-a-[2-(dimetyloamino)etoksy]-a-metylobenzylo}-1-[2-(N-piperydylo)etylo-1H-imidazol, [21] 2-{4-chloro-a-[2-(dimetyloamino)etoksy]-a-metylobenzylo}-1-[2-(N-piperydylo)propylo]-1H-imidazol, [22] 1-(3-cyjanopropylo)-2-{4-chloro-a-[2-(dimetyloamino)etoksy]benzylo}-1H-imidazol, [23] 2-{4-chloro-a-[2-(dimetyloamino)etoksy]-a-(N-metylo-4-piperydylo)benzylo}-1-metylo-1H-imidazol, [24] 1-benzylo-2-{a-[2-(N-benzylo-N-metyloamino)etoksy]-4-chlorobenzylo}-1H-imidazol, [25] 2-{4-chloro-a-[2-(dimetyloamino)etoksy]-a-metylobenzylo}-7-metylo-6,7,8,9-tetrahydro-1H-imidazo[1,5-a][1,4]diazepina, [26] 2-{4-chloro-a-[2-(dimetyloamino)etoksy]benzylo}-7-metylo-6,7,8,9-tetrahydro-1H-imidazo[1,5-a][1,4]-diazepina, [27] 1-butylo-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1H-pirazol, [28] 5-{a-(4-chlorofenylo)-a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazol, [29] 1-butylo-5-{a-[2-(dimetyloamino)etoksy]-3,4,5-trimetoksybenzylo}-1H-pirazol, [30] 1-butylo-5-{4-chloro-a-[2-(dimetyloamino)etoksy]-a-metylobenzylo}-1H-pirazol, [31] 5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazol, [32] 5-{a-[2-(dimetyloamino)etoksy]-a-metylobenzyIo}-1-metylo-1H-pirazol, [33] 5-{a-[2-(dimetyloamino)etoksy]-3,4,5-trimetoksybenzylo}-1-metylo-1H-pirazol, [34] 1-metylo-5-{a-[2-(N-pirolidylo)etoksy]benzylo}-1H-pirazol, [35] 1-metylo-5-{a-[2-(N-morfolinylo)etoksy]benzylo}-1H-pirazol, [36] 5-{a-[2-(dimetyloamino)etoksy]-a-metylo-3,4,5-trimetoksybenzylo}-1-metylo-1H-pirazol, [37] 4-bromo-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H -pirazol, [38] 1,3-dimetylo-5-{a-[2-(dimetyloamino)etoksy]-a-metylobenzylo}-1H-pirazol, [39] 1,3-dimetylo-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1H-pirazol, [40] 5-{a-[2-(dimetyloamino)etoksy]-2-metylobenzylo}-1-metylo-1H-pirazol, [41] 4-chloro-5-{4-chloro-a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazol, [42] 5-{4-chloro-a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazol,PL 193 802 B1 [43] 5-{3-chloro-a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazol, [44] 5-{a-[2-(dimetyloamino)etoksy]-4-metylobenzylo}-1-metylo-1 H-pirazol, [45] 5-{2-chloro-a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazol, [46] 1 -metylo-5-{a-[2-(N-piperydylo)etoksy]benzylo}-1H-pirazol, [47] 1-metylo-5-{a-[2-(N-propylo-2-piperydylo)etoksy]benzylo}-1H-pirazol, [48] 5-{a-[2-(N-etylo-2-piperydylo)etoksy]benzylo}-1-metylo-1H-pirazol, [49] 1-metylo-5-{a-[2-(N-metylo-2-pirolidylo)etoksy]benzylo}-1H-pirazol, [50] 5-{a-[2-(diizopropyloamino)etoksy]benzylo}-1-metylo-1H-pirazol, [51] 1-metylo-5-{a-[2-(N-metylo-2-piperydylo)etoksy]benzylo}-1H-pirazol, [52] 2-{4-chloro-a-[3-(dimetyloamino)propoksy]-a-metylobenzylo}-1-metylo-1H-imidazol, [53] 2-{3-chloro-a-[3-(dimetyloamino)propoksy]benzylo}-1-metylo-1H-imidazol [54] 2-{4-chloro-a-[3-(dimetyloamino)propoksy]-a-etylobenzylo}-1-metylo-1H-imidazol, [55] 2-{a-butylo-3-chloro-a-[3-(dimetyloamino)propoksy]benzylo}-1-metylo-1H-imidazol, [56] 2-{a-cykloheksylo-4-chloro-a-[3-(dimetyloamino)propoksy]benzylo}-1-metylo-1H-imidazol, [57] 2-{a-[3-(dimetyloamino)propoksy]-4-fluoro-a-metylobenzylo}-1-metylo-1H-imidazol, [58] 2-{a-[3-(dimetyloamino)propoksy]-a-metylo-3-(trifluorometylo)benzylo}-1-metylo-1H-imidazol, [59] 2-{2-chloro-a-[3-(dimetyloamino)propoksy]-a-metylobenzylo}-1-metylo-1H-imidazol, [60] 2-{3-chloro-a-[3-(dimetyloamino)propoksy]-a-metylobenzylo}-1-metylo-1H-imidazol, [61] 2-{a-[3-(dimetyloamino)propoksy]-a-metylo-3,4,5-trimetoksybenzylo}-1-metylo-1H-imidazol, [62] 2-{a-[3-(dimetyloamino)propoksy]-a-metylo-4-metoksybenzylo}-1-metylo-1H-imidazol, [63] 2-{4-chloro-a-[3-(dimetyloamino)propoksy]benzylo}-1-metylo-1H-imidazol, [64] 2-{a-[3-(dimetyloamino)propoksy]-3,4,5-trimetoksybenzylo}-1-metylo-1H-imidazol, [65] 2-{a-[3-(dimetyloamino)propoksy]-a-metylo-4-(trifluorometylo)benzylo}-1-metylo-1H-imidazol, [66] 2-{a-[3-(dimetyloamino)propoksy]-3-(trifluorometylo)benzylo}-1-metylo-1H-imidazol, [67] 2-{a-[3-(dimetyloamino)propoksy]-4-(trifluorometylo)-benzylo}-1-metylo-1H-imidazol, [68] 2-{a-[3-(dimetyloamino)propoksy]-4-metoksybenzylo}-1-metylo-1H-imidazol, [69] 2-{a-butylo-a-[3-(dimetyloamino)propoksy]-3-(trifluorometylo)benzylo}-1-metylo-1H-imidazol, [70] 1-butylo-2-{4-chloro-a-[3-(dimetyloamino)propoksy]-a-metylobenzylo}-1H-imidazol, [71] 1-butylo-2-{a-butylo-a-[3-(dimetyloamino)propoksy]-3,4,5-trimetoksybenzylo}-1H-imidazol, [72] 1-butylo-2-{a-butylo-2-chloro-a-[3-(dimetyloamino)propoksy]benzylo}-1H-imidazol, [73] 1-butylo-2-{a-butylo-2,4-dichloro-a-[3-(dimetyloamino)propoksy]benzylo}-1H-imidazol, [74] 1-butylo-2-{a-[3-(dimetyloamino)propoksy]-4-(trifluorometylo)benzylo}-1H-imidazol, [75] 2-{4-chloro-a-[3-(N-piperydylo)propoksy]benzylo}-1-metylo-1H-imidazol, [76] 1-metylo-2-{a-metylo-a-[3-(N-piperydylo)propoksy]-4-(trifluorometylo)benzylo}-1H-imidazol, [77] 2-{a-butylo-2-chloro-a-[3-(dimetyloamino)propoksy]benzylo}-1-metylo-1H-imidazol, [78] 2-{a-butylo-3,4-dichloro-a-[3-(dimetyloamino)propoksy]benzylo}-1-metylo-1H-imidazol, [79] 2-{3,4-dichloro-a-[3-(dimetyloamino)propoksy]-a-metylobenzylo}-1-metylo-1H-imidazol, [80] 2-{3,4-dichloro-a-[3-(dimetyloamino)propoksy]benzylo}-1-metylo-1H-imidazol, [81] 2-{a-cykloheksylo]-3,4-dichloro-a-[3-(dimetyloamino)propoksy]benzylo}-1-metylo-1H-imidazol, [82] 2-{4-chloro-a-[3-(dimetyloamino)propoksy]-a-metylobenzylo}-a-[2-(N-piperydylo)etylo]-1H-imidazol, [83] 2-{4-chloro-a-[3-(dimetyloamino)propoksy]-a-metylobenzylo}-1-[2-(N-piperydylo)propylo]-1H-imidazol, [84] 2-{4-chloro-a-[3-(dimetyloamino)propoksy]-a-(N-metylo-4-piperydylo)benzylo}-1-metylo-1H-imidazol, [85] 1-butylo-5-{a-[3-(dimetyloamino)propoksy]benzylo}-1H-pirazol, [86] 1-butylo-5-{4-chloro-a-[3-(dimetyloamino)propoksy]-a-metylobenzylo}-1H-pirazol, [87] 5-{a-[3-(dimetyloamino)propoksy]benzylo}-1-metylo-1H-pirazol, [88] 5-{a-[3-(dimetyloamino)propoksy]-a-metylobenzylo}-1-metylo-1H-pirazol, [89] 1,3-dimetylo-5-{a-[3-(dimetyloamino)propoksy]-a-metylobenzylo}-1H-pirazol, [90] 1,3-dimetylo-5-{a-[3-dimetyloamino)propoksy]benzylo}-1H-pirazol, [91] 5-{a-[3-(dimetyloamino)propoksy]-2-metylobenzylo}-1-metylo-1H-pirazol, [92] 5-chloro-5-{4-chloro-a-[3-(dimetyloamino)propoksy]benzylo}-1-metylo-1H-pirazol, [93] 1-metylo-5-{a-[3-(N-piperydylo)propoksy]benzylo}-1H-pirazol, [94] 1-metylo-5-{a-[3-(N-pirolidylo)propoksy]benzylo}-1H-pirazol, [95] 4-{4-chloro-a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazol,PL 193 802 B1 [96] 4-{4-chloro-a-[2-(dimetyloamino)etoksy]-a-metylobenzylo}-1-metylo-1H-pirazol, [97] 4-{4-chloro-a-[2-(N-propylo-2-piperydylo)etoksy]benzylo}-1-metylo-1H-pirazol, [98] 4-{4-chloro-a-[2-(N-metylo-2-piperydylo)etoksy]benzylo}-1-metylo-1H-pirazol, [99] 4-{4-chloro-a-[2-(N-etylo-2-piperydylo)etoksy]benzylo}-1-metylo-1H-pirazol, [100] 4-{4-chloro-a-[2-(diizopropyloamino)etoksy]benzylo}-1-metylo-1H-pirazol, [101] 4-{4-chloro-a-[2-(N-metylo-2-pirolidylo)etoksy]benzylo}-1-metylo-1H-pirazol, [102] 4-{a-[3-(dimetyloamino)propoksy]benzylo}-1-metylo-1H-pirazol, [103] 4-{4-chloro-a-[3-(N-morfolinylo)propoksy]benzylo}-1-metylo-1H-pirazol, [104] 4-{4-chloro-a-[3-(N-pirolidylo)propoksy]benzylo}-1-metylo-1H-pirazol, [105] 2-(a-hydroksybenzylo)-1H-imidazol, [106] 2-(4-chloro-a-hydroksybenzylo)-1H-imidazol, [107] 2-(4-chloro-a-hydroksybenzylo)-1-metylo-1H-imidazol, [108] 2-(3-chloro-a-hydroksybenzylo)-1-metylo-1H-imidazol, [109] 2-(4-fluoro-a-hydroksybenzylo)-1-metylo-1H-imidazol, [110] 2-[a-hydroksy-3-(trifluorometylo)benzylo]-1-metylo-1H-imidazol, [111] 2-[a-hydroksy-4-(trifluorometylo)benzylo]-1-metylo-1H-imidazol, [112] 2-(a-hydroksy-3,4,5-trimetoksybenzylo)-1-metylo-1H-imidazol, [113] 2-(3,4-dichloro-a-hydroksybenzylo)-1-metylo-1H-imidazol, [114] 1-butylo-2-[a-hydroksy-4-(trifluorometylo)benzylo]-1H-imidazol, [115] 1-butylo-2-(3,4-dichloro-a-hydroksybenzylo)-1H-imidazol, [116] 1-butylo-2-(4-chloro-a-hydroksybenzylo)-1H-imidazol, [117] 1-butylo-2-(a-hydroksy-3,4,5-trimetoksybenzylo)-1H-imidazol, [118] 1-dodecylo-2-(a-hydroksy-3,4,5-trimetoksybenzylo)-1H-imidazol, [119] 2-(a-butylo-3-chloro-a-hydroksybenzylo)-1-metylo-1H-imidazol, [120] 2-(3-chloro-a-hydroksy-a-metylobenzylo)-1-metylo-1H-imidazol, [121] 2-(4-chloro-a-hydroksy-a-metylobenzylo)-1-metylo-1H-imidazol, [122] 2-[4-chloro-a-hydroksy-a-(N-metylo-4-piperydylo)benzylo]-1-metylo-1H-imidazol, [123] 2-(4-chloro-a-etylo-a-hydroksybenzylo)-1-metylo-1H-imidazol, [124] 2-(a-butylo-4-chloro-a-hydroksybenzylo)-1-metylo-1H-imidazol, [125] 2-(a-cykloheksylo-4-chloro-a-hydroksybenzylo)-1-metylo-1H-imidazol, [126] 2-(2-chloro-a-hydroksy-a-metylobenzylo)-1-metylo-1H-imidazol, [127] 2-(a-butylo-2-chloro-a-hydroksybenzylo)-1-metylo-1H-imidazol, [128] 2-[a-hydroksy-a-metylo-3-(trifluorometylo)benzylo]-1-metylo-1H-imidazol, [129] 2-[a-butylo-a-hydroksy-3-(trifluorometylo)benzylo]-1-metylo-1H-imidazol [130] 2-[a-cykloheksylo-a-hydroksy-3-(trifluorometylo)benzylo]-1-metylo-1H-imidazol, [131] 2-[a-hydroksy-a-metylo-4-(trifluorometylo)benzylo]-1-metylo-1H-imidazol, [132] 2-(4-fluoro-a-hydroksy-a-metylobenzylo)-1-metylo-1H-imidazol, [133] 2-(a-hydroksy-a-metylo-4-metoksybenzylo)-1-metylo-1H-imidazol, [134] 2-(3,4-dichloro-a-hydroksy-a-metylobenzylo)-1-metylo-1H-imidazol, [135] 2-(a-butylo-3,4-dichloro-a-hydroksybenzylo)-1-metylo-1H-imidazol, [136] 2-(a-cykloheksylo]-3,4-dichloro-a-hydroksybenzylo)-1-metylo-1H-imidazol, [137] 2-(a-hydroksy-a-metylo-3,4,5-trimetoksybenzylo)-1-metylo-1H-imidazol, [138] 1-butylo-2-(4-chloro-a-hydroksy-a-metylobenzylo)-1H-imidazol, [139] 1-butylo-2-(a-butylo-4-chloro-a-hydroksybenzylo]-1H-imidazol, [140] 1-butylo-2-[4-chloro-a-hydroksy-a-(N-metylo-4-piperydylo)benzylo]-1H-imidazol, [141] 1-butylo-2-(a-butylo-a-hydroksy-3,4,5-trimetoksybenzylo)-1H-imidazol, [142] 1-butylo-2-(a-butylo-2-chloro-a-hydroksybenzylo)-1H-imidazol, [143] 1-butylo-2-[a-etylo-a-hydroksy-3-(trifluorometylo)benzylo]-1H-imidazol, [144] 1-butylo-2-(a-butylo-2,4-dichloro-a-hydroksybenzylo)-1H-imidazol, [145] 2-(4-chloro-a-hydroksy-a-metylobenzylo)-1-[2-(N-piperydylo)etylo]-1H-imidazol, [146] 2-(4-chloro-a-hydroksy-a-metylobenzylo)-1-(3-dimetyloaminopropylo)-1H-imidazol, [147] 2-(a-butylo-a-hydroksy-3,4,5-trimetoksybenzylo)-1-dodecylo-1H-imidazol, [148] 1-benzylo-2-[a-butylo-a-hydroksy-3-(trifluorometylo)benzylo]-1H-imidazol, [149] 1-benzylo-2-(4-chloro-a-hydroksy-a-metylobenzylo)-1H-imidazol, [150] 1-(2-cyjanoetylo)-2-(4-chloro-a-hydroksybenzylo)-1H-imidazol, [151] 1-(3-aminopropylo)-2-(4-chloro-a-hydroksybenzylo)-1H-imidazol,PL 193 802 B1 [152] kwas 3-[2-(3-chloro-a-hydroksybenzylo)-1H-imidazol-1-ilo]propanowy, [153] 2-(4-chloro-a-hydroksybenzylo)-1-(3-hydroksypropylo)-1H-imidazol, [154] propanian 3-[2-(3-chloro-a-hydroksybenzylo)-1H-imidazol-1-ilo]metylu, [155] 2-(a-hydroksybenzylo)-1-(3-hydroksypropylo)-1H-imidazol, [156] 2-(a-hydroksy-4-metylobenzylo)-1-(3-hydroksypropylo)-1H-imidazol, [157] 2-(a-hydroksy-4-metoksybenzylo)-1-(3-hydroksypropylo)-1H-imidazol, [158] 2-(3,4-dichloro-a-hydroksybenzylo)-1-(3-hydroksypropylo)-1H-imidazol, [159] propanian 3-{2-(a-hydroksybenzylo)-1H-imidazol-1-ilo}metylu, [160] 2-(4-chloro-a-hydroksybenzylo)-1-(4-hydroksybutylo)-1H-imidazol, [161] 1-(3-cyjanopropylo)-2-(4-chloro-a-hydroksybenzylo)-1H-imidazol, [162] kwas 4-[2-(4-chloro-a-hydroksybenzylo)-1H-imidazol-1-ilo]butanowy, [163] butanian 4-[2-(4-chloro-a-hydroksybenzylo)-1H-imidazol-1-ilo]metylu, [164] 1-butylo-5-(a-hydroksybenzylo)-1H-pirazol, [165] 5-(4-chloro-a-hydroksybenzylo)-1-metylo-1H-pirazol, [166] 5-(a-hydroksy-3,4,5-trimetoksybenzylo)-1-metylo-1H-pirazol, [167] 1-butylo-5-(a-hydroksy-3,4,5-trimetoksybenzylo)-1H-pirazol, [168] 4-bromo-5-(1-hydroksybenzylo)-1-metylo-1H-pirazol, [169] 5-[a-(4-chlorofenylo)-a-hydroksybenzylo]-1-metylo-1H-pirazol, [170] 1-butylo-5-(4-chloro-a-hydroksy-a-metylobenzylo)-1H-pirazol, [171] 5-(a-hydroksy-a-metylobenzylo)-1-metylo-1H-pirazol, [172] 5-(a-hydroksy-a-metylo-3,4,5-trimetoksybenzylo)-1-metylo-1H-pirazol, [173] 1,3-dimetylo-5-(a-hydroksy-a-metylobenzylo)-1H-pirazol, [174] 1-butylo-5-(a-hydroksy-a-winylobenzylo)-1H-pirazol, [175] 1-butylo-5-(4-chloro-a-hydroksy-a-winylobenzylo)-1H-pirazol, [176] 4-chloro-5-(a-hydroksybenzylo)-1-metylo-1H-pirazol, [177] 5-(a-hydroksy-2-metylobenzylo)-1-metylo-1H-pirazol, [178] 5-(3-chloro-a-hydroksybenzylo)-1-metylo-1H-pirazol, [179] 5-(a-hydroksy-4-metylobenzylo)-1-metylo-1H-pirazol, [180] 5-(2-chloro-a-hydroksybenzylo)-1-metylo-1H-pirazol, [181] 5-(a-hydroksy-4-metoksybenzylo)-1-metylo-1H-pirazol, [182] 5-{a-[2-(dimetyloamino)etoksy]-2-tienylometylo}-1-metylo-1H- pirazol, [183] 5-{a-[2-(dimetyloamino)etoksy]-2-tienylometylo}-1-metylo-1H-pirazol, cytrynian, [184] 5-{a-[2-(dimetyloamino)etoksy]-3-tienylometylo}-1-metylo-1H-pirazol, [185] 2-{a-[2-(dimetyloamino)etoksy]-2-tienylometylo}-1-metylo-1H-imidazol, [186] 5-{a-[2-(dimetyloamino)etoksy]-3-metylo-2-tienylometylo}-1-metylo-1H-pirazol, [187] 5-{a-[2-(dimetyloamino)etoksy]-5-metylo-2-tienylometylo}-1-metylo-1H-pirazol, [188] 5-{5-bromo-a-[2-(dimetyloamino)etoksy]-2-tienylometylo}-1-metylo-1H-pirazol, [189] 5-{4-bromo-a-[2-(dimetyloamino)etoksy]-2-tienylometylo}-1-metylo-1H-pirazol, [190] 5-{a-[2-(dimetyloamino)etoksy]-a-metylo-2-tienylometylo}-1-metylo-1H-pirazol, [191] 5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazol, cytrynian, [192] (±)-5-{a-[2-(dimetyloamino)-1-(metylo)etoksy]benzylo}-1-metylo-1H-pirazol, [193] (±)-5-{a-[2-(dimetyloamino)-1-metylo)etoksy]benzylo}-1-metylo-1H-pirazol, [194] (+)-5-{a-[2-(dimetyloamino)etoksy]-2-tienylometylo}-1-metylo-1H-pirazol, [195] (-)-5-{a-[2-(dimetyloamino)etoksy]-2-tienylometylo}-1-metylo-1H-pirazol, [196] (+)-5-{a-[2-(dimetyloamino)etoksy]-2-tienylometylo}-1-metylo-1H-pirazol, cytrynian, [197] (-)-5-{a-[2-(dimetyloamino)etoksy]-2-tienylometylo}-1-metylo-1H-pirazol, cytrynian, [198] (+)-5-{a-[2-(dimetyloamino)etoksy]-2-tienylometylo}-1-metylo-1H-pirazol, D-ditoluilowinian, [199] (-)-5-{a-[2-(dimetyloamino)etoksy]-2-tienylometylo}-1-metylo-1H-pirazol, D-ditoluilowinian, [200] (+)-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazol, cytrynian, [201] (-)-5-{a-[2-(dimetyloamino)etoksy]benzylo}-1-metylo-1H-pirazol, cytrynian [202] 5-(a-hydroksy-2-tienylornetylo)-1-metylo-1H-pirazol, [203] 5-(a-hydroksy-3-metylo-2-tienylometylo)-1-metylo-1H-pirazol, [204] 5-(a-hydroksy-5-metylo-2-tienylometylo)-1-metylo-1H-pirazol, [205] 5-(5-bromo-a-hydroksy-2-tienylometylo)-1-metylo-1H-pirazol, [206] 5-(4-bromo-a-hydroksy-2-tienylometylo)-1-metylo-1H-pirazol, [207] 5-(a-hydroksy-a-metylo-2-tienylometylo)-1-metylo-1H-pirazol.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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. |
| PCT/ES1999/000255 WO2000007542A2 (es) | 1998-08-07 | 1999-08-05 | 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| PL346221A1 PL346221A1 (en) | 2002-01-28 |
| PL193802B1 true PL193802B1 (pl) | 2007-03-30 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL99346221A PL193802B1 (pl) | 1998-08-07 | 1999-08-05 | Zastosowanie pochodnych arylo (lub heteroarylo) azolilokarbinoli do wytwarzania leku do leczenia zaburzeń wywoływanych nadmiarem substancji P |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US6518295B1 (pl) |
| EP (1) | EP1103243B1 (pl) |
| JP (1) | JP2002522359A (pl) |
| KR (1) | KR100558506B1 (pl) |
| CN (1) | CN1151789C (pl) |
| AR (1) | AR019999A1 (pl) |
| AT (1) | ATE257379T1 (pl) |
| AU (1) | AU754124B2 (pl) |
| BR (1) | BR9912807A (pl) |
| CA (1) | CA2339661C (pl) |
| CO (1) | CO5080747A1 (pl) |
| CZ (1) | CZ292065B6 (pl) |
| DE (1) | DE69914085T8 (pl) |
| DK (1) | DK1103243T3 (pl) |
| ES (2) | ES2150378B1 (pl) |
| HU (1) | HUP0105428A3 (pl) |
| IL (1) | IL141295A0 (pl) |
| NO (1) | NO20010634L (pl) |
| NZ (1) | NZ509645A (pl) |
| PL (1) | PL193802B1 (pl) |
| PT (1) | PT1103243E (pl) |
| RU (1) | RU2223116C2 (pl) |
| TR (1) | TR200100378T2 (pl) |
| TW (1) | TW445259B (pl) |
| WO (1) | WO2000007542A2 (pl) |
| ZA (1) | ZA200100867B (pl) |
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| ES2174756B2 (es) * | 2001-04-06 | 2003-11-16 | Esteve Labor Dr | Derivados de aril (o heteroaril) azolilcarbinoles para el tratamiento de enfermedades respiratorias. |
| ES2180449B1 (es) * | 2001-07-06 | 2004-01-16 | Esteve Labor Dr | Derivados de aril (o heteroaril) azolilcarbinoles para el tratamiento de la incontinencia urinaria. |
| US20040142929A1 (en) * | 2001-07-06 | 2004-07-22 | Ramon Merce-Vidal | Derivatives of aryl (or heteroaryl) azolylcarbinoles for the treatment of urinary incontinence |
| DE10335566A1 (de) * | 2003-07-31 | 2005-02-24 | Grünenthal GmbH | Arzneimittel enthaltend Derivate von Aryl( oder Heteroaryl)azolylcarbinolen |
| EP1584335A3 (en) * | 2004-04-05 | 2006-02-22 | Laboratorios Del Dr. Esteve, S.A. | Active substance combination comprising a carbinol composition and an opioid |
| ES2244326B1 (es) * | 2004-04-05 | 2007-02-16 | Laboratorios Del Dr. Esteve, S.A. | Combinacion de substancias activas. |
| EP1784178A1 (en) * | 2004-07-30 | 2007-05-16 | 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 |
| EP1809104A4 (en) * | 2004-09-23 | 2009-04-29 | Alexander Michalow | METHODS FOR REGULATING NEUROTRANSMITTER SYSTEMS BY INDUCING COUNTER-ADAPTATIONS |
| 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. |
| 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 |
| 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 |
| WO2007085557A2 (en) * | 2006-01-27 | 2007-08-02 | F. Hoffmann-La Roche Ag | Use of substituted 2-imidazole of imidazoline derivatives |
| EP1820502A1 (en) * | 2006-02-10 | 2007-08-22 | Laboratorios Del Dr. Esteve, S.A. | Active substance combination comprising azolylcarbinol compounds |
| CN101528710B (zh) | 2006-10-19 | 2012-11-07 | 弗·哈夫曼-拉罗切有限公司 | 氨基甲基-4-咪唑类 |
| WO2008052907A1 (en) | 2006-11-02 | 2008-05-08 | F. Hoffmann-La Roche Ag | Substituted 2-imidazoles as modulators of the trace amine associated receptors |
| JP2010510184A (ja) | 2006-11-16 | 2010-04-02 | エフ．ホフマン−ラ ロシュ アーゲー | 置換４−イミダゾール類 |
| 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 |
| CN101557810B (zh) | 2006-12-13 | 2012-11-21 | 弗·哈夫曼-拉罗切有限公司 | 作为痕量胺相关受体（taar）的配体的新的2-咪唑类 |
| KR101174191B1 (ko) | 2007-02-02 | 2012-08-14 | 에프. 호프만-라 로슈 아게 | 중추 신경계 장애의 치료용 ｔａａｒ1 리간드로서 2-아미노옥사졸린 |
| WO2008098857A1 (en) | 2007-02-15 | 2008-08-21 | F. Hoffmann-La Roche Ag | 2-aminooxazolines as taar1 ligands |
| 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) |
| CA2691704A1 (en) | 2007-07-03 | 2009-01-08 | F. Hoffmann-La 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 |
| WO2009019149A1 (en) | 2007-08-03 | 2009-02-12 | F. Hoffmann-La 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 |
| WO2017157873A1 (en) | 2016-03-17 | 2017-09-21 | F. Hoffmann-La Roche Ag | 5-ethyl-4-methyl-pyrazole-3-carboxamide derivative having activity as agonist of taar |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| DE69732133T2 (de) * | 1996-12-02 | 2005-12-22 | Merck Sharp & Dohme Ltd., Hoddesdon | Verwendung von NK-1 Rezeptorantagonisten zur Behandlung von schweren Depressionen |
| JP2001508412A (ja) * | 1996-12-02 | 2001-06-26 | メルク シヤープ エンド ドーム リミテツド | 認識障害の治療のためのｎｋ−１受容体拮抗薬の使用 |
| AU729708B2 (en) * | 1996-12-02 | 2001-02-08 | Merck Sharp & Dohme Limited | Use of NK-1 receptor antagonists for treating severe anxiety disorders |
| CA2273807A1 (en) * | 1996-12-02 | 1998-06-11 | Merck Sharp & Dohme Limited | Use of nk-1 receptor antagonists for treating schizophrenic disorders |
| ES2150353B1 (es) * | 1998-04-15 | 2001-07-01 | Esteve Labor Dr | Tienilazolilalcoxietanaminas, su preparacion y su aplicacion como medicamentos. |
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- 1999-08-04 AR ARP990103870A patent/AR019999A1/es unknown
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- 1999-08-05 AT AT99940199T patent/ATE257379T1/de not_active IP Right Cessation
- 1999-08-05 DK DK99940199T patent/DK1103243T3/da active
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- 1999-08-05 CN CNB998109150A patent/CN1151789C/zh not_active Expired - Fee Related
- 1999-08-05 DE DE69914085T patent/DE69914085T8/de not_active Expired - Fee Related
- 1999-08-05 AU AU54229/99A patent/AU754124B2/en not_active Ceased
- 1999-08-05 TW TW088113353A patent/TW445259B/zh not_active IP Right Cessation
- 1999-08-05 PT PT99940199T patent/PT1103243E/pt unknown
- 1999-08-05 CZ CZ2001412A patent/CZ292065B6/cs not_active IP Right Cessation
- 1999-08-05 US US09/762,079 patent/US6518295B1/en not_active Expired - Fee Related
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- 1999-08-05 EP EP99940199A patent/EP1103243B1/en not_active Expired - Lifetime
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- 1999-08-05 WO PCT/ES1999/000255 patent/WO2000007542A2/es active IP Right Grant
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- 1999-08-05 ES ES99940199T patent/ES2213380T3/es not_active Expired - Lifetime
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- 1999-08-05 PL PL99346221A patent/PL193802B1/pl not_active IP Right Cessation
- 1999-08-05 JP JP2000563228A patent/JP2002522359A/ja active Pending
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