PL240473B1 - New N-6(4-arylpiperazine-1-yl)hexyl derivatives of cyclic 1,8-naphthyl/tetrahydroquinoline imides/amides/sulfonamides and method of preparing new N-6(4-arylpiperazine-1-yl)hexyl derivatives of cyclic 1,8-naphthyl/tetrahydroquinoline imides/amides/sulfonamides - Google Patents
New N-6(4-arylpiperazine-1-yl)hexyl derivatives of cyclic 1,8-naphthyl/tetrahydroquinoline imides/amides/sulfonamides and method of preparing new N-6(4-arylpiperazine-1-yl)hexyl derivatives of cyclic 1,8-naphthyl/tetrahydroquinoline imides/amides/sulfonamides Download PDFInfo
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- PL240473B1 PL240473B1 PL429473A PL42947319A PL240473B1 PL 240473 B1 PL240473 B1 PL 240473B1 PL 429473 A PL429473 A PL 429473A PL 42947319 A PL42947319 A PL 42947319A PL 240473 B1 PL240473 B1 PL 240473B1
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- Poland
- Prior art keywords
- hexyl
- piperazin
- rozc
- arh
- benzo
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- -1 tetrahydroquinoline imides Chemical class 0.000 title claims abstract description 86
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 title claims abstract description 77
- LBUJPTNKIBCYBY-UHFFFAOYSA-N tetrahydroquinoline Natural products C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 150000001408 amides Chemical class 0.000 title claims abstract description 17
- 229940124530 sulfonamide Drugs 0.000 title claims abstract description 16
- 150000003456 sulfonamides Chemical class 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims description 20
- 125000003118 aryl group Chemical group 0.000 claims abstract description 28
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 69
- 229910052739 hydrogen Inorganic materials 0.000 claims description 67
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 65
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- 239000000203 mixture Substances 0.000 claims description 56
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 31
- 239000003446 ligand Substances 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 29
- 238000003786 synthesis reaction Methods 0.000 claims description 25
- 230000015572 biosynthetic process Effects 0.000 claims description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 14
- 102000005962 receptors Human genes 0.000 claims description 13
- 108020003175 receptors Proteins 0.000 claims description 13
- 125000000524 functional group Chemical group 0.000 claims description 12
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 claims description 12
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 claims description 10
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 10
- 235000015320 potassium carbonate Nutrition 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 8
- 230000000144 pharmacologic effect Effects 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- 208000020925 Bipolar disease Diseases 0.000 claims description 5
- CIQZMHMOCHBPHK-UHFFFAOYSA-N 1-[6-(4-pyridin-2-ylpiperazin-1-yl)hexyl]benzo[cd]indol-2-one Chemical compound N1=C(C=CC=C1)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O CIQZMHMOCHBPHK-UHFFFAOYSA-N 0.000 claims description 4
- VJGYBRVHAUSTAR-UHFFFAOYSA-N 1-[6-(4-pyrimidin-2-ylpiperazin-1-yl)hexyl]benzo[cd]indol-2-one Chemical compound N1=C(N=CC=C1)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O VJGYBRVHAUSTAR-UHFFFAOYSA-N 0.000 claims description 4
- VRYRLEFYPRNMNK-UHFFFAOYSA-N 1-[6-[4-(3-chlorophenyl)piperazin-1-yl]hexyl]benzo[cd]indol-2-one Chemical compound ClC=1C=C(C=CC=1)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O VRYRLEFYPRNMNK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 4
- QGNQEODJYRGEJX-UHFFFAOYSA-N 4h-isoquinoline-1,3-dione Chemical compound C1=CC=C2C(=O)NC(=O)CC2=C1 QGNQEODJYRGEJX-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 230000002349 favourable effect Effects 0.000 claims description 4
- 239000012429 reaction media Substances 0.000 claims description 4
- 201000000980 schizophrenia Diseases 0.000 claims description 4
- UANZODATMICVSM-UHFFFAOYSA-N 1-[6-(4-quinolin-8-ylpiperazin-1-yl)hexyl]benzo[cd]indol-2-one Chemical compound N1=CC=CC2=CC=CC(=C12)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O UANZODATMICVSM-UHFFFAOYSA-N 0.000 claims description 3
- HGMFNQHREUMSGP-UHFFFAOYSA-N 1-[6-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]hexyl]benzo[cd]indol-2-one Chemical compound S1N=C(C2=C1C=CC=C2)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O HGMFNQHREUMSGP-UHFFFAOYSA-N 0.000 claims description 3
- HNKUJCOSNCIIKR-UHFFFAOYSA-N 1-[6-[4-(2,3-dichlorophenyl)piperazin-1-yl]hexyl]benzo[cd]indol-2-one Chemical compound ClC1=C(C=CC=C1Cl)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O HNKUJCOSNCIIKR-UHFFFAOYSA-N 0.000 claims description 3
- FJGNCKIPBKWGFB-UHFFFAOYSA-N 1-[6-[4-(2-ethoxyphenyl)piperazin-1-yl]hexyl]benzo[cd]indol-2-one Chemical compound C(C)OC1=C(C=CC=C1)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O FJGNCKIPBKWGFB-UHFFFAOYSA-N 0.000 claims description 3
- GYNZQBCSTGHPIZ-UHFFFAOYSA-N 1-[6-[4-(4-bromophenyl)piperazin-1-yl]hexyl]benzo[cd]indol-2-one Chemical compound BrC1=CC=C(C=C1)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O GYNZQBCSTGHPIZ-UHFFFAOYSA-N 0.000 claims description 3
- UPONGHYXDIIQIG-UHFFFAOYSA-N 1-[6-[4-(4-chlorophenyl)piperazin-1-yl]hexyl]benzo[cd]indol-2-one Chemical compound ClC1=CC=C(C=C1)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O UPONGHYXDIIQIG-UHFFFAOYSA-N 0.000 claims description 3
- RBRUKHRLEFHOEH-UHFFFAOYSA-N 1-[6-[4-[2-(trifluoromethyl)phenyl]piperazin-1-yl]hexyl]benzo[cd]indol-2-one Chemical compound FC(C1=C(C=CC=C1)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O)(F)F RBRUKHRLEFHOEH-UHFFFAOYSA-N 0.000 claims description 3
- JIKHUPCDDIJQPL-UHFFFAOYSA-N 2-[6-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]hexyl]benzo[de]isoquinoline-1,3-dione Chemical compound S1N=C(C2=C1C=CC=C2)N1CCN(CC1)CCCCCCN1C(C2=CC=CC=3C2=C(C1=O)C=CC=3)=O JIKHUPCDDIJQPL-UHFFFAOYSA-N 0.000 claims description 3
- VYUXTFBVDSGWAR-UHFFFAOYSA-N 2-[6-[4-(2-ethoxyphenyl)piperazin-1-yl]hexyl]benzo[de]isoquinoline-1,3-dione Chemical compound C(C)OC1=C(C=CC=C1)N1CCN(CC1)CCCCCCN1C(C2=CC=CC=3C2=C(C1=O)C=CC=3)=O VYUXTFBVDSGWAR-UHFFFAOYSA-N 0.000 claims description 3
- WPBPWIAMOQOWJZ-UHFFFAOYSA-N 2-[6-[4-(2-nitrophenyl)piperazin-1-yl]hexyl]benzo[de]isoquinoline-1,3-dione Chemical compound [N+](=O)([O-])C1=C(C=CC=C1)N1CCN(CC1)CCCCCCN1C(C2=CC=CC=3C2=C(C1=O)C=CC=3)=O WPBPWIAMOQOWJZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
- HKOFHLGKVUBWFI-UHFFFAOYSA-N 3-[6-[4-(2-methoxyphenyl)piperazin-1-yl]hexyl]-1,3-diazatricyclo[6.3.1.04,12]dodeca-4,6,8(12)-trien-2-one Chemical compound COC1=C(C=CC=C1)N1CCN(CC1)CCCCCCN1C(N2CCCC3=CC=CC1=C23)=O HKOFHLGKVUBWFI-UHFFFAOYSA-N 0.000 claims description 3
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- 101150049660 DRD2 gene Proteins 0.000 claims description 3
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- 230000009977 dual effect Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- UWHNOQYXXPSWSH-UHFFFAOYSA-N 1-[6-[4-(2-chlorophenyl)piperazin-1-yl]hexyl]benzo[cd]indol-2-one Chemical compound ClC1=C(C=CC=C1)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O UWHNOQYXXPSWSH-UHFFFAOYSA-N 0.000 claims description 2
- HKNMRMSDNAFOMI-UHFFFAOYSA-N 1-[6-[4-(2-fluorophenyl)piperazin-1-yl]hexyl]benzo[cd]indol-2-one Chemical compound FC1=C(C=CC=C1)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O HKNMRMSDNAFOMI-UHFFFAOYSA-N 0.000 claims description 2
- XPJNHBUTMFYRJT-UHFFFAOYSA-N 1-[6-[4-(4-methoxyphenyl)piperazin-1-yl]hexyl]benzo[cd]indol-2-one Chemical compound COC1=CC=C(C=C1)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O XPJNHBUTMFYRJT-UHFFFAOYSA-N 0.000 claims description 2
- ZAFMZQLZDHTXTI-UHFFFAOYSA-N 1-[6-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]hexyl]benzo[cd]indol-2-one Chemical compound FC(C=1C=C(C=CC=1)N1CCN(CC1)CCCCCCN1C(C2=C3C(C=CC=C13)=CC=C2)=O)(F)F ZAFMZQLZDHTXTI-UHFFFAOYSA-N 0.000 claims description 2
- UGOXZHALYQBPNO-UHFFFAOYSA-N 2-[6-[4-(4-methoxyphenyl)piperazin-1-yl]hexyl]benzo[de]isoquinoline-1,3-dione Chemical compound COC1=CC=C(C=C1)N1CCN(CC1)CCCCCCN1C(C2=CC=CC=3C2=C(C1=O)C=CC=3)=O UGOXZHALYQBPNO-UHFFFAOYSA-N 0.000 claims description 2
- LXNQXNYRRQSMER-UHFFFAOYSA-N 3-[6-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]hexyl]-1,3-diazatricyclo[6.3.1.04,12]dodeca-4,6,8(12)-trien-2-one Chemical compound S1N=C(C2=C1C=CC=C2)N1CCN(CC1)CCCCCCN1C(N2CCCC3=CC=CC1=C23)=O LXNQXNYRRQSMER-UHFFFAOYSA-N 0.000 claims description 2
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- 238000002425 crystallisation Methods 0.000 claims description 2
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- 150000001923 cyclic compounds Chemical class 0.000 claims description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
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Abstract
Przedmiotem zgłoszenia są nowe N-6(4-arylopiperazyno-1-ylo)heksylowe pochodne cyklicznych 1,8-naftylo / tetrahydrochinolino imidów / amidów / sulfonamidów określone wzorem ogólnym (I): gdzie: X oznacza N lub C; Z oznacza grupę CS, CO lub SO2; Y oznacza grupę CO z wyłączeniem pochodnej tertahydrochinoliny, lub Y oznacza - (puste); n oznacza długość łańcucha alkilowego od C5 do C8; R oznacza grupę arylową określoną wzorem ogólnym (IA) albo (IB) w którym: R1, R2, R3 oznacza H, OCH3, OC2H5, Cl, Br, F, CF3, NO2, C3H3N, OCONH, OCH3CONH, C6H5, E, F oznacza N lub C. Te nowe pochodne arylopiperazyny według wynalazku mogą znaleźć zastosowanie w leczeniu zaburzeń ośrodkowego układu nerwowego u ludzi. W niniejszym zgłoszeniu ujawniono także sposób wytwarzania wspomnianych wyżej nowych pochodnych arylopiperazyny.The subject of the application are new N-6(4-arylpiperazine-1-yl)hexyl derivatives of cyclic 1,8-naphthyl / tetrahydroquinoline imides / amides / sulfonamides defined by the general formula (I): where: X is N or C; Z represents the group CS, CO or SO2; Y represents a CO group excluding the tertahydroquinoline derivative, or Y represents - (empty); n is the length of the alkyl chain from C5 to C8; R is an aryl group represented by the general formula (IA) or (IB) in which: R1, R2, R3 is H, OCH3, OC2H5, Cl, Br, F, CF3, NO2, C3H3N, OCONH, OCH3CONH, C6H5, E, F means N or C. These new arylpiperazine derivatives according to the invention may find application in the treatment of central nervous system disorders in humans. The present application also discloses a process for preparing the above-mentioned new arylpiperazine derivatives.
Description
PL 240 473 B1
Opis wynalazku
Przedmiotem wynalazku jest grupa nowych pochodnych arylopiperazyny, obejmująca: N-6-(4-arylopiperazyn-1-ylo)heksylowe pochodne cyklicznych 1,8-naftylo imidów, N-6-(4-arylopiperazyn-1-ylo)heksylowe pochodne cyklicznych 1,8-naftylo amidów, N-6-(4-arylopiperazyn-1-ylo)heksylowe pochodne cyklicznych 1,8-naftylo sulfonamidów, N-6-(4-arylopiperazyn-1-ylo)heksylowe pochodne cyklicznych tetrahydrochinolino amidów, N-6-(4-arylopiperazyn-1-ylo)heksylowe pochodne cyklicznych tetrahydrochinolino sulfonamidów.
Przedmiotem wynalazku jest również sposób otrzymywania wspomnianych wyżej nowych pochodnych arylopiperazyny.
Te nowe związki, będące ligandami receptorów serotoninowych oraz dopaminowych, mogą znaleźć zastosowanie w leczeniu zaburzeń ośrodkowego układu nerwowego (OUN) u ludzi. Wiążą się one z wybranymi receptorami serotoninowymi (5-HTia, 5-HT2A, 5-Ht6, 5-Ht7) oraz dopaminowymi (D2), kluczowymi w leczeniu zaburzeń ośrodkowego układu nerwowego, takich jak depresja, zaburzenie afektywne dwubiegunowe, schizofrenia, zaburzenia lękowe lub zaburzenia snu. W celu uzyskania ich akceptowalnej farmaceutycznie formy, nowe związki mogą zostać przeprowadzone w znany sposób w sole kwasu chlorowodorowego, które wykazują dobrą rozpuszczalność w wodzie, metanolu oraz etanolu.
W wynalazku opisano aktywność biologiczną nowych związków, właściwości fizykochemiczne oraz sposób ich wytwarzania.
W poszukiwanie nowych leków działających na schorzenia ośrodkowego układu nerwowego, takie jak depresja, zaburzenie afektywne dwubiegunowe, schizofrenia, zaburzenia lękowe lub zaburzenia snu jako klasyczne cele receptorowe wymienia się: receptory serotoninowe 5-HT1a [J. Savitz, I. Lucki, W. C. Drevets, „5-HT(1A) receptor function in major depressive disorder”, Prog Neurobiol. 2009, 88(1), 17-31], i 5-HT2a [A. Wesołowska, Pharmacol Rep., „Potential role of the 5-HT6 receptor in depression and anxiety: an overview of preclinical data”, 2010, 62(4), 564-77], jak również receptory dopaminowe D2 [A. Etievant, C. Betry, N. Haddjeri, „Partial Dopamine D2/Serotonin 5-HTia Receptor Agonists as New Therapeutic Agents”, The Open Neuropsychopharmacology Journal 2010, 3, 1-12].
Nowsze cele receptorowe obejmują między innymi receptory 5-HT6 [M. Kołaczkowski, M. Marcinkowska, A. Bucki, M. Pawłowski, K. Mitka, J. Jaskowska, P. Kowalski i inni, „Novel Arylsulfonamide Derivatives with 5-HT6/5-HT7 Receptor Antagonism Targeting Behavioral and Psychological Symptoms of Dementia”, Journal of Medicinal Chemistry 2014, 57(11), 4543-4557] i 5-HT7 [L. N. Cates, A. J. Roberts, S. Huitron-Resendiz, P. B. Hedlund, „Effects of lurasidone in behavioral models of depression. Role of the 5-HT7 receptor subtype”. Neuropharmacology, 2013, 70, 211-217].
W ostatnich latach wykazano skuteczność leków działających jednocześnie na kilka celów receptorowych, zwanych dalej ligandami multifunkcyjnymi. Przykładem ligandów multifunkcyjnych są dualne ligandy receptorów 5-HTia / D2 w leczeniu depresji [A. Etievant, C. Betry, N. Haddjeri, „Partial Dopamine D2/Serotonin 5-HTia Receptor Agonists as New Therapeutic Agents”, The Open Neuropsychopharmacology Journal 2010, 3, 1-12].
Grupą szeroko stosowaną w leczeniu chorób ośrodkowego układu nerwowego są długołańcuchowe arylopiperazyny. Związki należące do długołańcuchowych arylopiperazyn są stosowane w lecznictwie od wielu lat, lecz zainteresowanie nimi wciąż nie gaśnie. W ostatnich latach nowe ligandy, wywodzące się z grupy długołańcuchowych arylopiperazyn (wilazodon, lurazydon, brekspiprazol, kariprazyna) zostały dopuszczone do użycia w leczeniu chorób OUN [T. J. Kreys, „The future of psychotropics: Did santa forget about mental illness?”, MentalHealth Clinician 2012, 2(6), 135-137] oraz [J. S. Frankel, T. L. Schwartz, „Brexpiprazole and cariprazine: distinguishing two new atypical antipsychotics from the original dopamine stabilizer aripiprazole”, Ther Adv Psychopharmacol. 2017, 7(1), 29-41]).
Znane są także długołańcuchowe arylopiperazyny, wśród których wymienić można ligandy zawierające w swojej strukturze fragment 1,8-naftyloamidu lub sulfonamidu [A. Lepailleur, R. Bureau, M. Paillet-Loilier, F. Fabis, N. Saettel, S. Lemaitre, F. Dauphin, A. Lesnard, J. C. Lancelot, S. Rault, „Molecular Modeling Studies Focused on 5-HT7 versus 5-HTia Selectivity. Discovery of Novel Phenylpyrrole Derivatives with High Affinity for 5-HT7 Receptors”, J. Med. Chem. 2005, 45, 1075], względnie imidu [P. Kowalski, T. Kowalska, A. J. Bojarski, B. Duszyńska, „Synthesis and biological properties of 1,8-naphthalimidebutylamines. Serotonin 5-HTia and 5-HT7 binding data and pass-assisted search”, Journal of Heterocyclic Chem. 2007, 44(4), 889-93]. W literaturze opisano niektóre związki należące do wyżej
PL 240 473 B1 wymienionej grupy jako mogące mieć powinowactwo do receptorów 5-HT? i 5-HTia. Jednakże w opublikowanej w powyższej literaturze grupie związków ujawniono niewiele ligandów. Co więcej, ligandy te nie posiadają scharakteryzowanego pełnego profilu powinowactwa do wspomnianych wcześniej receptorów 5-HTia‘ 5-HT2A, 5-HTs, 5-HT?, D2).
W literaturze naukowej i patentowej nie ujawniono dotąd pochodnych arylopiperazyny, zawierających fragment tetrahydrochinoliny zamiast naftalenu, które jak wykazano w niniejszym wynalazku charakteryzują się znacznie korzystniejszym profilem farmakologicznym w kontekście leczenia chorób OUN.
Niektóre publikacje opisują wzrost powinowactwa długołańcuchowych arylopiperazyn do wybranych receptorów serotoninowych, wraz ze wzrostem długości łańcucha alkilowego [E. Lacivita, M. Leopoldo, A. C. Masotti, C. lnglese, F. Berardi, R. Perrone, S. Ganguly, M. Jafurulla, A .B. Chattopadhyay, „Synthesis and Characterization of Environment-Sensitive Fluorescent Ligands for Human 5-HTia Receptors with 1-Arylpiperazine Structure”, J. Med. Chem. 2009, 52(23), 7892-6]. W związku z tym uzasadnione jest poszukiwanie nowych ligandów o wydłużonym łańcuchu alkilowym w stosunku do wcześniej ujawnionych związków.
W literaturze opisano do tej pory 11 związków należących do N-6-(4-arylopiperazyn-1-ylo)heksylowych pochodnych cyklicznych 1,8-naftylo/tetrahydrochinolino imidów/amidów/sulfonamidów, należących do związków o budowie podobnej do związków z grupy będącej przedmiotem niniejszego wynalazku, wśród których wymienia się: 1-{6-[4-(2-metoksyfenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on, {6-[4-(fenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on, {6-[4-(2-metoksyfenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dion, 2-{6-[4-(fenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dion [M. L. Lopez-Rodriguez, E. Porras, M. Morcillo, i inni, „Optimization of the pharmacophore model for 5-HT7R antagonism. Design and synthesis of new naphtholactam and naphthosultam derivatives”, Journal of Medicinal Chemistry 2003,46(26), 5638-5650].
2-{6-[4-(4-chlorofenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion, 2-{6-[4-(3-chlorofenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion, 2-{6-[4-(2-chlorofenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion, 2-{6-[4-(2-metylofenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion, 2-{6-[4-(fenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
[S. A. Andronati, T. A. Voronina, T. L. Karaseva i inni, „Affinity of 1-aryl-4-[(naphthalimido)alkyl]piperazines to 5-HT1A receptors and influence on anxiety of rats in the conflict situation test”, Dopovidi Natsional'noi Akademii Nauk Ukraini 2004, (4), 169-174].
W powyżej przywołanych publikacjach opisano długą i uciążliwą metodę syntezy związków należących do wspomnianej grupy, obejmującą dwie dwuetapowe ścieżki syntezy [M. Leopoldo, E. Lacivita, F. Berardi, R. Perrone, P. B. Hedlund, „Serotonin 5-HT? receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders”, Pharmacol Ther. 2011, 129(2), 120-148, C. Kikuchi, T. Ando, T. Watanabe, H. Nagaso, M. Okuno, T. Hiranuma, M. Koyama, „2a-[4-(Tetrahydropyridoindol-2-yl)butyl]tetrahydrobenzindole Derivatives: New Selective Antagonists of the 5-Hydroxytryptamine? Receptor”, J. Med. Chem. 2002, 45, 2197-2206, C. Kikuchi, H. Nagaso, T. Hiranuma, M. Koyama, „Tetrahydrobenzindoles: Selective Antagonists of the 5-HT? Receptor”, J. Med. Chem. 1999, 42, 533-535]. Pierwsza z nich polega na reakcji N-alkilowania arylopiperazyny dibromoalkanami, a następnie kondensacji produktu z 1,8-naftolaktamem / sultamem. Druga ścieżka obejmuje N-alkilowanie 1,8-naftolaktamu / sultamu, a następnie kondensację z wybraną arylopiperazyną. Reakcje prowadzono w atmosferze gazu obojętnego, w obecności NaH, z zastosowaniem dużych ilości toksycznych rozpuszczalników, takich jak acetonitryl lub dimetyloformamid (DMF). Czas reakcji wynosił 2-72 godziny.
Związki te nie wchodzą w przedmiotowy zakres niniejszego wynalazku.
Mając na uwadze nowe trendy syntezy organicznej i zasady dbałości o środowisko, uzasadnione jest więc poszukiwanie nowych, aktywnych biologicznie związków przydatnych w leczeniu schorzeń OUN oraz metod syntezy tych związków, ograniczających ilości używanych toksycznych odczynników i rozpuszczalników.
Celem tego wynalazku jest dostarczenie nowych związków, pochodnych arylopiperazyny, będących ligandami receptorów serotoninowych oraz dopaminowych, stanowiących grupę nowych N-6-(4-arylopipe
PL 240 473 BI razyn-1-ylo)heksylowych pochodnych cyklicznych 1,8-naftylo imidów/amidów/sulfonamidów i A/-6-(4-arylopiperazyn-1-ylo)heksylowych pochodnych cyklicznych tetrahydrochinolino amidów/sulfonamidów, użytecznych w leczeniu chorób ośrodkowego układu nerwowego.
Drugim celem wynalazku jest opracowanie takiego sposobu wytwarzania tego typu związków, w którym znacznie ogranicza się lub nawet eliminuje ilość szkodliwych rozpuszczalników, co udało się osiągnąć dzięki zastosowaniu syntezy w obecności pola promieniowania mikrofalowego.
Przedmiotem wynalazku jest grupa nowych związków, należących do grupy długołańcuchowych arylopiperazyn, mających strukturę przedstawioną wzorem ogólnym (I).
N- (CH2)n-N N-R
Ź V/ (i) gdzie:
X oznacza C, N,
Z oznacza CO, SO2, CS,
Y oznacza grupę CO z wyłączeniem pochodnych tetrahydrochinoliny, albo brak tego podstawnika (brak atomu, brak grupy funkcyjnej), oznacza wiązanie pojedyncze albo podwójne, n = 6,
R oznacza grupę arylową o wzorze ogólnym (la) albo (IB):
(IA) (IB) gdzie dla R o wzorze (IA):
R1 oznacza H, Cl, F, CF3, OC2H5, NO2, CsHs, OCH3,
R2 oznacza H, Cl, CF3, OCH3, CeHs, przy czym w związkach cyklicznych R1 = R2 i oznaczają C3H3N, OCONH, OCH2CONH,
R3 oznacza H, Cl, Br, CF3, OCH3, E, F oznacza N lub C.
Wynalazek obejmuje następujące związki, określone ogólnym wzorem (I):
- Związki należące do podgrupy W-6-(4-arylopiperazyn-1 -ylo)heksylowych pochodnych cyklicznych 1,8-naftyloamidów:
1) 1-{6-[4-(2-chlorofenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
2) 1-{6-[4-(3-chlorofenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
3) 1-{6-[4-(4-chlorofenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
4) 1-{6-[4-(3,4-dichlorofenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
5) 1-{6-[4-(2,3-dichlorofenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
6) 1-{6-[4-(4-bromofenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
7) 1-{6-[4-(2-fluorofenylo)piperazyn-1-yl]heksylo}-benzo[cd]indol-2(1H)-on,
8) 1-{6-[4-(2-trifluorometylofenylo)piperazyn-1-yl]heksylo}-benzo[cd]indol-2(1H)-on,
9) 1-{6-[4-(3-trifluorometylofenylo)piperazyn-1-yl]heksylo}-benzo[cd]indol-2(1H)-on,
10) 1-{6-[4-(4-trifluorometylofenylo)piperazyn-1-yl]heksylo}-benzo[cd]indol-2(1H)-on,
11) 1-{6-[4-(3-metoksyfenylo)piperazyn-1-ylo]heksylo}benzo[cd] indol-2(1H)-on,
12) 1-{6-[4-(4-metoksyfenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
13) 1-{6-[4-(2-etoksyfenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
14) 1-{6-[4-(2-pirydynylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
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15) 1-{6-[4-(2-pirymidynylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
16) 1-{6-[4-(2-nitrofenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
17) 1-{6-[4-(8-chinolinyl)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
18) 1-{6-[4-(1,2-benzizotiazol-3-ilo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on,
19) 1-{6-[4-(2-okso-2,3-dihydro-1,3-benzoksazol-7-ilo)piperazyn-1-ylo]heksylo}benzo[cd]indol2(1H)-on,
- Związki należące do podgrupy N-6-(4-arylopiperazyn-1 -ylo)heksylowych pochodnych cyklicznych 1,8-naftylosulfonamidów:
20) 2-{6-[4-(2-chlorofenylo)piperazyn-1 -ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1 (2H)-dion,
21) 2-{6-[4-(3-chlorofenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dion,
22) 2-{6-[4-(4-chlorofenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd] [1,2]tiazolo-1,1(2H)-dion,
23) 2-{6-[4-(2,3-dichlorofenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazol-1,1(2H)-dion,
24) 2-{6-[4-(3,4-dichlorofenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazol-1,1(2H)-dion,
25) 2-{6-[4-(3-trifluorometylofenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-
1,1(2H)-dion,
26) 2-{6-[4-(4-trifluorometylofenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dion,
27) 2-{6-[4-(2-fluorometylofenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dion,
28) 2-{6-[4-(2-etoksyfenylo)piperazyn-1 -ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1, 1 (2H)-dion,
29) 2-{6-[4-(2-pirydynylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dion,
30) 2-{6-[4-(2-nitrofenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dion,
31) 2-{6-[4-(1,2-benzizotiazol-3-ilo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazol-1,1(2H)-dion,
- Związki należące do podgrupy N-6-(4-arylopiperazyn-1 -ylo)heksylowych pochodnych cyklicznych 1,8-naftyloimidów:
32) 2-{6-[4-(2-metoksyfenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion,
33) 2-{6-[4-(3-metoksyfenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion,
34) 2-{6-[4-(4-metoksyfenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion,
35) 2-{6-[4-(2-etoksyfenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion,
36) 2-{6-[4-(2-pirydynylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion,
37) 2-{6-[4-(2-nitrofenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion,
38) 2-{6-[4-(2-fluorofenylo)piperazyn-1-ylo]heksylo}-2H-benzo[de]izochinotino-1,3(2H)-dion,
39) 2-{6-[4-(2-trifluorometylofenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion,
40) 2-{6-[4-(3-trifluorometylofenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion,
41) 2-{6-[4-(4-bromofenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion,
42) 2-{6-[4-(1,2-benzizotiazol-3-ilo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)- dion,
43) 2-{6-[4-{[1-okso-2,3-dihydro-1H-izoindol-2-ilo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion,
44) 2-[6-(4-{[1,1-bifenylo]-2-ylo}piperazyn-1-ylo)heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion,
- Związki należące do podgrupy N-6-(4-arylopiperazyn-1 -ylo)heksylowych pochodnych cyklicznych tetrahydrochinolino amidów:
45) 1-{6-[4-(2-metoksyfenylo)piperazyn-1-ylo]heksylo}-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin-2(1H)on,
46) 1-{6-[4-(3-chlorofenylo)piperazyn-1-ylo]heksylo}-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin-2(1H)-on,
47) 1-{6-[4-(1,2-benzizotiazol-3-ilo)piperazyn-1-ylo]heksylo}-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin2(1H)-on,
48) 1-{6-[4-(3-chlorofenylo)piperazyn-1-ylo]heksylo}-5,6-dihydro-4H-innidazo[4,5,1-ij]chinolin-2(1H)tion,
- Związek należący do podgrupy N-6-(4-arylopiperazyn-1-ylo)heksylowych pochodnych cyklicznych tetrahydrochinolino sulfonamidów:
49) 1-{6-[4-(3-chlorofenylo)piperazyn-1-ylo]heksylo}-1H,4H-[1,2,5]tiadiazolo[4,3,2-ij]chinolino-2,2ditlenek.
PL 240 473 BI
Pochodne arylopiperazyny o ogólnym wzorze (I) wykazują powinowactwo do wybranych receptorów, wymienionych jako cele terapeutyczne w leczeniu zaburzeń OUN, takich jak receptory dopaminergiczne D2 i serotoninergiczne, a w szczególności 5-HTia, 5-HT2A, 5-HTs, 5-HT?.
Związki według wynalazku znajdują zastosowanie w leczeniu i/lub zapobieganiu zaburzeń ośrodkowego układu nerwowego, takich jak schizofrenia, zaburzenie afektywne i dwubiegunowe, zaburzenia maniakalne, depresja, zaburzenia lękowe, delirium alkoholiczne, agresja, pobudzenie psychomotoryczne, zaburzenia snu o różnej etiologii, zespoły odstawienne o różnej etiologii, chorobie Alzheimera, objawy psychopatologicznych i zaburzeniach neurologiczne w przebiegu innych chorób centralnego i obwodowego układu nerwowego.
W trakcie badań ich właściwości, okazało się że najkorzystniejsze w zastosowaniach terapeutycznych do leczenia zaburzeń OUN są następujące związki:
- związek o nazwie chemicznej 1-{6-[4-(3-chlorofenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol2(1H)-on i o wzorze ogólnym (I), gdzie: X oznacza C, Z oznacza CO, Y oznacza brak atomu, brak grupy funkcyjnej, oznacza wiązanie podwójne, n wynosi 6, R oznacza grupę arylową o wzorze ogólnym (IA), w którym: R1 oznacza H, R2 oznacza Cl, R3 oznacza Η, E oznacza C, F oznacza C.
- związek o nazwie chemicznej 1-{6-[4-(2-pirydynylo)piperazyn-1-ylo]heksylo}benzo[cd]indol2(1H)-on i o wzorze ogólnym (I), gdzie: X oznacza C, Z oznacza CO, Y oznacza brak atomu, brak grupy funkcyjnej, oznacza wiązanie podwójne, n wynosi 6, R oznacza grupę arylową o wzorze ogólnym (IA), w którym: R1 oznacza H, R2 oznacza H, R3 oznacza Η, E oznacza N, F oznacza C.
- związek o nazwie chemicznej 1-{6-[4-(2-pirymidynylo)piperazyn-1-ylo]heksylo}benzo[cd]indol2(1H)-on i o wzorze ogólnym (I), gdzie: X oznacza C, Z oznacza CO, Y oznacza brak atomu, brak grupy funkcyjnej, oznacza wiązanie podwójne, n wynosi 6, R oznacza grupę arylową o wzorze ogólnym (IA), w którym: R1 oznacza H, R2 oznacza H, R3 oznacza Η, E oznacza N, F oznacza N.
- związek o nazwie chemicznej 2-[6-(4-{[1,1'-bifenylo]-2-ylo}piperazyn-1-ylo)heksylo]-1Hbenzo[de]izochinolino-1,3(2H)-dion i wzorze ogólnym (I), gdzie: X oznacza C, Z oznacza CO, Y oznacza CO, oznacza wiązanie podwójne, n wynosi 6, R oznacza grupę arylową o wzorze ogólnym (IA), w którym: R1 oznacza CsHs, R2 oznacza H, R3 oznacza Η, E oznacza C, F oznacza C.
- związek o nazwie chemicznej 1-{6-[4-(2-metoksyfenylo)piperazyn-1-ylo]heksylo}-5,6-dihydro4H-imidazo[4,5,1-ij]chinolin-2(1H)-on, i o wzorze ogólnym (I), gdzie: X oznacza N, Z oznacza CO, Y oznacza brak atomu, brak grupy funkcyjnej, oznacza wiązanie pojedyncze, n wynosi 6, R oznacza grupę arylową opisaną wzorem ogólnym (IA), w którym: R1 oznacza OCH3, R2 oznacza H, R3 oznacza Η, E oznacza C, F oznacza C.
- związek o nazwie chemicznej 1-{6-[4-(1,2-benzizotiazol-3-ilo)piperazyn-1-ylo]heksylo}-5,6dihydro-4H-imidazo[4,5,1-ij] chinolin-2(1H)-on i o wzorze ogólnym (I), gdzie: X oznacza N, Z oznacza CO, Y oznacza brak atomu, brak grupy funkcyjnej, oznacza wiązanie pojedyncze, n wynosi 6, R oznacza grupę arylowa opisana wzorem ogólnym (IB).
Związki opisane wzorem ogólnym (I) otrzymuje się według wynalazku w wyniku dwuetapowej syntezy, obejmującej N-alkilowanie dibromoalkanami 1,8-naftylo/tetrahydrochinolino imidów/amidów/sulfonamidów, w środowisku zasadowym, a następnie kondensację tak powstałego półproduktu z arylopiperazyną, zgodnie z przedstawionym poniżej dwuetapowym schematem syntezy:
PL 240 473 BI
Etap 1
(IV) (V) (I)
W pierwszym etapie syntezy związek opisany wzorem ogólnym (II), tzn. cykliczny 1,8-naftylo / tetrahydrochinolino imid / amid / sulfonamid poddaje się reakcji A/-alkilowania z dibromoalkanami - wzór ogólny (III) w obecności czynnika zasadowego, takiego jak K2CO3, Na2COs, KOH, NaOH, trietyloamina oraz katalizatora przeniesienia fazowego (PTC), takiego jak bromek tetra-n-butyloamoniowy (TBAB), chlorek tetraetyloamoniowy (TEAC), 1,4-diazabicyklo[2.2.2]oktan (DABCO) i rozpuszczalnika (stosowanego w relatywnie niewielkiej ilości), takiego jak A/,A/-dimetyloformamid (DMF), acetonitryl (ACN), woda albo bez rozpuszczalnika.
Po sporządzeniu mieszaniny, zawierającej na 1 mol cyklicznego 1,8-naftylo / tetra hydrach i nolino imidu / amidu / sulfonamidu 3 mole dibromoalkanów, 3 mole czynnika zasadowego, 0,1 mola katalizatora PCT i do 50 cm3 rozpuszczalnika, mieszaninę podaje się działaniu pola mikrofalowego przez 15-60 sekund w reaktorze mikrofalowym o mocy wyjściowej mikrofal 50-200 W. Tak otrzymany półprodukt, opisany wzorem ogólnym (IV) oddziela się od środowiska reakcji w znany sposób przez dodanie wody i ekstrakcję chlorkiem metylenu, a następnie po oddestylowaniu chlorku metylenu półprodukt maceruje się w heksanie i kieruje do drugiego etapu syntezy.
W drugim etapie syntezy, półprodukt otrzymany z pierwszego etapu (związek opisany wzorem IV), poddaje się reakcji kondensacji z arylopiperazyną o wzorze ogólnym (V) w obecności czynnika zasadowego, takiego jak K2CO3, Na2CO3, KOH, NaOH, trietyloamina, katalizatora przeniesienia fazowego PTC, takiego jak bromek tetra-n-butyloamoniowy (TBAB), chlorek tetraetyloamoniowy (TEAC), 1,4-diazabicyklo[2,2,2]oktan (DABCO) i rozpuszczalnika (stosowanego w relatywnie niewielkiej ilości), takiego jak A/,A/-dimetyloformamid (DMF), acetonitryl (ACN), woda albo bez rozpuszczalnika.
Po sporządzeniu mieszaniny, zawierającej na 1 mol półproduktu (wzór IV) 0,95 mola arylopiperazyny, 3 mole czynnika zasadowego, 0,1 mola katalizatora PCT i do 50 cm3 rozpuszczalnika, mieszaninę podaje się działaniu pola mikrofalowego przez 15-60 sekund w reaktorze mikrofalowym o mocy wyjściowej mikrofal 50-200 W. Tak otrzymany produkt, opisany wzorem ogólnym (I) oddziela się w znany sposób przez dodanie od środowiska reakcji wody i odsączenie, po czym surowy produkt oczyszcza się przez krystalizację z metanolu.
Związki wyjściowe o wzorach (II), (III) i (V) są znane oraz dostępne w handlu.
Otrzymane powyższym sposobem związki o wzorze ogólnym (I) mają charakter zasadowy, gdyż zawierają trzeciorzędową grupę aminową przy pierścieniu piperazyny. Mogą one tworzyć sole addycyjne z kwasami, przedstawione na wzorze (VI):
gdzie A oznacza dowolny anion kwasowy.
PL 240 473 B1
W celu określenia właściwości biologicznych nowych związków będących przedmiotem wynalazku, jako ligandów receptorów serotoninowych i dopaminowych, testowano je w postaci soli addycyjnych (chlorowodorków) otrzymanych przez rozpuszczenie wspomnianych zasadowych związków w eterze dietylowym lub acetonie i wytworzenie chlorowodorków przy użyciu roztworu HCI w dioksanie.
Nowe związki będące N-6(4-arylopiperazyno-1-ylo)heksylowymi pochodnymi cyklicznych 1,8naftylo / tetrahydrochinolino imidów / amidów / sulfonamidów mogą znaleźć zastosowanie w leczeniu wielu chorób ośrodkowego układu nerwowego, w tym zaburzeń psychiatrycznych oraz neurodegradacyjnych, co pokazuje ich profil farmakologiczny przedstawiony poniżej w formie tabeli, określony przez stałe powinowactwa względem wybranych receptorów (5-HTia, 5-HT2A, 5-HT6, 5-HT7, D2). Nowe związki będące przedmiotem wynalazku wytwarza się ekologiczną bezrozpuszczalnikową metodą, korzystną w kontekście ochrony środowiska naturalnego oraz minimalizacji kosztów produkcji.
Nowe pochodne arylopiperazyny, stanowiące przedmiot wynalazku oraz sposób ich syntezy przybliżono w poniższych przykładach.
Związki opisane wzorem (IV), będące półproduktami do syntezy nowych pochodnych arylopiperazyny, wytworzono zgodnie z procedurą opisaną w przykładach 1-12.
We wszystkich poniższych przykładach reakcje w warunkach mikrofalowych przeprowadzano w reaktorze mikrofalowym z regulowaną mocą mikrofal. Odczynniki do syntez zakupiono w firmie Sigma Aldrich. Wszystkie rozpuszczalniki stosowane w procesie syntezy i oczyszczania pochodziły z POCH (Polskie Odczynniki Chemiczne).
Analityczną chromatografię cienkowarstwową (TLC) wykonano przy zastosowaniu mieszaniny chloroform: metanol w stosunku 9 : 1 jako eluentu, stosując płytki z żelu krzemionkowego Sigma Aldrich na arkuszach aluminiowych ze wskaźnikiem fluorescencji 254 nm (grubość warstwy 200 μm, średnica porów 60 A, cząsteczka 8,0-12,0 μm rozmiar).
Dla poszczególnych substancji przedstawiono współczynniki retencji TLC Rf. Do analizy wykorzystano światło UV o długości fali 254 nm.
Analizę HPLC (wysokosprawna chromatografia cieczowa) wykonano za pomocą urządzenia HPLC Perkin Elmer Series 200 z kolumną XTerra RP C-18 (wielkość ziarna 3,5 μm, 4,6 x 150 mm) stosując jako eluent mieszaninę metanol : woda 1 : 1 zakwaszoną 0,1% kwasem mrówkowym, stosując detektor UV-VIS (detektor światła ultrafioletowego i widzialnego), przy długości fali 254 nm.
Dla poszczególnych substancji przedstawiono czasy retencji Rt.
Czystość otrzymanych produktów określono przy zastosowaniu techniki HPLC, stosując detekcję UV-VIS przy długości fali 254 nm.
Temperatury topnienia mierzono za pomocą aparatu Boetius.
Widma IR (podczerwieni) wykonano na spektrometrze FTS-165 (FTIR Biorad).
Widma 1H NMR (magnetycznego rezonansu jądrowego) rejestrowano na spektrometrze Bruker Avance 400 MHz, stosując TMS (tertametylosilan) jako wzorzec. Analizy UPLC-MS (ultrasprawna chromatografia cieczowa połączona ze spektrometrem mas) została przeprowadzona na aparacie Waters Acquity TQD z detektorem diodowym (DAD). Do spektrometrii mas zastosowano tryb jonizacji przez elektro rozpylanie (ESI). Wydajność otrzymanych związków obliczono na podstawie masy otrzymanego chlorowodorku związku określonego ogólnym wzorem (I).
Dla wszystkich półproduktów otrzymanych w przykładach 1-12 przedstawiono poniżej analizy potwierdzające strukturę, charakterystyczne właściwości fizykochemiczne i czystość otrzymanych połączeń. Przy prezentacji wyników analiz zastosowano anglosaski zapis liczbowy, według którego miejsca dziesiętne oddziela się kropką.
P R Z Y K Ł A D 1
Otrzymywanie półproduktu: 1-(6-bromoheksylo)benzo[cd]indol-2(1H)-onu, zwyczajowo nazywanego N-heksylo pochodną 1,8-naftyloamidu
W moździerzu roztarto 0,01 mola benzo[cd]indol-2(1H)-onu 0,03 mola NaOH oraz 0,001 mol TBAB. Mieszaninę przeniesiono do kolby okrągłodennej, po czym dodano 0,03 mola 1,6-dibromoheksanu i 0,1 cm3 ACN. Reakcję prowadzono przez 45 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 100 W. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i ekstrahowano chlorkiem metylenu. Po oddestylowaniu chlorku metylenu produkt reakcji macerowano w 20 cm3 heksanu, aby pozbyć się nadmiaru 1,6-dibromoheksanu.
PL 240 473 B1
-(6-bromoheksylobenzo[cd]indol-2(1 H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.08 (dd, J = 8.2, 4.9 Hz, 1H, ArH), 7.98 (dd, J = 7.2, 2.8 Hz, 1H, ArH), 7.77 (ddd, J = 8.1, 7.4, 3.5 Hz, 1H, ArH), 7.62 - 7.51 (m, 1H, ArH), 7.46 (t, J = 9.4 Hz, 1H, ArH), 6.75 (dd, J = 7.2, 3.1 Hz, 1H, ArH, 3.86 (t, J = 7.3 Hz, 2H, S(O)2N-CH), 3.44 (t, J = 6.7 Hz, 2H, BrCHAlif), 1.95 (ddd, J = 28.7, 14.1, 7.1 Hz, 4H, CHant), 1.61 (ddd, J = 23.6, 7.8, 3.7 Hz, 4H, CHat), Spektroskopia w podczerwieni: FT-IR 3055 (C-H Ar Rozc), 2932; 2857 (C-H Alif, Rozc), 1694 (C=O, Rozc), 1602; 1495 (C=C Ar, Rozc), 1373 (C-N, Rozc), 773 (C-Br, Rozc), Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.90, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt= 4.05 min, czystość = 88%, Wydajność = 78%.
P R Z Y K Ł A D 2
Otrzymywanie półproduktu: 1-(6-bromoheksylo)benzo[cd]indol-2(1H)-onu, zwyczajowo nazywanego N-heksylo pochodną 1,8-naftyloamidu
W moździerzu roztarto 0,01 mola benzo[cd]indol-2(1H)-onu 0,03 mola Na2CO3, oraz 0,001 mol TEAC. Mieszaninę przeniesiono do kolby okrągłodennej, po czym dodano 0,03 mola 1,6-dibromoheksanu. Reakcje prowadzono przez 60 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 50 W. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i ekstrahowano chlorkiem metylenu. Po oddestylowaniu chlorku metylenu produkt reakcji macerowano w 20 cm3 heksanu, aby pozbyć się nadmiaru 1,6-dibromoheksanu.
-(6-bromoheksylobenzo[cd]indol-2(1 H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.08 (dd, J = 8.2, 4.9 Hz, 1H, ArH), 7.98 (dd, J = 7.2, 2.8 Hz, 1H, ArH), 7.77 (ddd, J = 8.1, 7.4, 3.5 Hz, 1H, ArH), 7.62 - 7.51 (m, 1H, ArH), 7.46 (t, J = 9.4 Hz, 1H, ArH), 6.75 (dd, J = 7.2, 3.1 Hz, 1H, ArH, 3.86 (t, J = 7.3 Hz, 2H, S(O)2N-CH), 3.44 (t, J = 6.7 Hz, 2H, BrCHAlif), 1.95 (ddd, J = 28.7, 14.1, 7.1 Hz, 4H, CHat), 1.61 (ddd, J = 23.6, 7.8, 3.7 Hz, 4H, CHai»), Spektroskopia w podczerwieni: FT-IR 3055 (C-H Ar Rozc), 2932; 2857 (C-H Alif, Rozc), 1694 (C=O, Rozc), 1602; 1495 (C=C Ar, Rozc), 1373 (C-N, Rozc), 773 (C-Br, Rozc), Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.90, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 4.05 min, czystość = 88%, Wydajność = 62%.
P R Z Y K Ł A D 3
Otrzymywanie półproduktu: 2-(6-bromoheksylo)-2H-naft[1,8-cd]izotiazolo-1,1(2H)-dionu, zwyczajowo nazywanego N-heksylo pochodną 1,8-naftytosulfonamidu
W moździeżu roztarto 0,01 mola(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dionu, 0,03 mola KOH oraz 0,001 mola TBAB. Mieszaninę przeniesiono do kolby okrągłodennej, po czym dodano 0,03 mola 1,6-dibromoheksanu i 0,2 cm3 wody. Reakcje prowadzono przez 40 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 80 W. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i ekstrahowano chlorkiem metylenu. Po oddestylowaniu chlorku metylenu produkt reakcji macerowano w 20 cm3 heksanu, aby pozbyć się nadmiaru 1,6-dibromoheksanu. Surowy produkt krystalizowano z metanolu.
2-(6-bromoheksylo)-2H-naft[1,8-cd]izotiazolo-1,1(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.09 (d, J = 7.0 Hz, 1H, ArH), 8.07 - 8.01 (m, 1H, ArH), 7.76 - 7.72 (m, 1H, ArH), 7.56 (d, J = 8.4 Hz, 1H, ArH), 7.52 - 7.46 (m, 1H, ArH), 6.94 (d, J = 6.9 Hz, 1H, ArH), 3.99 - 3.93 (m, 2H, SONCH), 3.44 - 3.40 (m, 2H, BrCHAlif), 1.89 - 1.80 (m, 4H, CHai»), 1.50 (ddd, J = 13.7, 8.7, 5.6 Hz, 4H, CHaj»), Spektroskopia w podczerwieni: FT-IR 3060, (C-H Ar, Rozc), 2933, 2856 (C-H, Alif, Rozc), 1591, 1492 (C=C Ar, Rozc), 1371 (C-N, Rozc), 1348 (S=O, Rozc), 851 (N-S, Rozc), 756 (C-Br, Rozc), Chromatografia cienkowarstwowa TLC; współczynnik retencji R/= 0.90, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 4.12 min, czystość = 95%, Wydajność = 65%.
PL 240 473 B1
P R Z Y K Ł A D 4
Otrzymywanie półproduktu: 2-(6-bromoheksylo)-2H-naft[1,8-cd]izotiazolo-1,1(2H)-dionu, zwyczajowo nazywanego N-heksylo pochodną 1,8-naftylosulfonamidu
W moździerzu roztarto 0,01 mola(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dionu 0,03 mola Na2CO3 oraz 0,001 mola TEAC. Mieszaninę przeniesiono do kolby okrągłodennej, po czym dodano 0,003 mola 1,6-dibromoheksanu. Reakcje prowadzono przez 20 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 100 W. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i ekstrahowano chlorkiem metylenu. Po oddestylowaniu chlorku metylenu produkt reakcji macerowano w 20 cm3 heksanu, aby pozbyć się nadmiaru 1,6-dibromoheksanu. Surowy produkt krystalizowano z metanolu.
2-(6-bromoheksylo)-2H-naft[1,8-cd]izotiazolo-1,1(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.09 (d, J = 7.0 Hz, 1H, ArH), 8.07 - 8.01 (m, 1H, ArH), 7.76 - 7.72 (m, 1H, ArH), 7.56 (d, J = 8.4 Hz, 1H, ArH), 7.52 - 7.46 (m, 1H, ArH), 6.94 (d, J = 6.9 Hz, 1H, ArH), 3.99 - 3.93 (m, 2H, SONCH), 3.44 - 3.40 (m, 2H, BrCHAlif), 1.89 - 1.80 (m, 4H, CHaj»), 1.50 (ddd, J = 13.7, 8.7, 5,6 Hz, 4H, CHaj»),
Spektroskopia w podczerwieni: FT-IR 3060, (C-H Ar, Rozc), 2933, 2856 (C-H, Alif, Rozc), 1591, 1492 (C=C Ar, Rozc), 1371 (C-N, Rozc), 1348 (S=O, Rozc), 851 (N-S, Rozc), 756 (C-Br, Rozc), Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.90,
Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 4.12 min, czystość = 95%, Wydajność = 67%.
P R Z Y K Ł A D 5
Otrzymywanie półproduktu: 2-(6-bromoheksylo)-1H-benzo[de]izochinolino-1,3(2H)-dionu, zwyczajowo nazywanego N-heksylo pochodną 1,8-naftyloimidu
W kolbie okrągłodennej zmieszano 0,01 mola 1 H-benzo[de]izochinolino-1,3(2H)-dionu, 0,03 mola trietyloaminy, 0,001 mola DABCO, 0,03 mola 1,6-dibromoheksanu i 0,05 DMF. Reakcje prowadzono przez 15 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 200 W. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i produkt reakcji odsączono. Surowy produkt krystalizowano z metanolu.
2-(6-bromoheksylo)-1 H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.48 (ddd, J = 9.1,7.8, 0.9 Hz, 4H, ArH), 7.91 - 7.79 (m, 2H, ArH), 4.07 - 4.01 (m, 2H, CONCH), 3.53 (t, J = 6.7 Hz, 2H, BrCHAlif), 1.87 - 1.75 (m, 2H, CHaj»), 1.64 (dd, J = 14.7, 7.3 Hz, 2H, CHaj»), 1.40 (ddd, J = 15.2, 8.2, 3.4 Hz, 4H, CHAiif),
Spektroskopia w podczerwieni FT-IR: 3061 (C-H Ar Rozc), 2933; 2855 (C-H Alif, Rozc), 1692 (C=O, Rozc), 1587; 1461 (C=C Ar, Rozc), 1361 (C-N, Rozc), 779 (C-Br, Rozc), Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.90,
Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.85 min, czystość = 99%, Wydajność = 75%.
P R Z Y K Ł A D 6
Otrzymywanie półproduktu: 2-(6-bromoheksylo)-1H-benzo[de]izochinolino-1,3(2H)-dionu, zwyczajowo nazywanego N-heksylo pochodną 1,8-naftyloimidu
W moździerzu roztarto 0,01 mola 1H-benzo[de]izochinolino-1,3(2H)-dionu 0,03 mola oraz 0,001 mola TBAB. Mieszaninę przeniesiono do kolby okrągłodennej, po czym dodano 0,03 mola 1,6-dibromoheksanu. Reakcje prowadzono przez 20 sekund w reaktorze przy mocy wyjściowej mikrofal 180 W. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i produkt reakcji odsączono. Surowy produkt krystalizowano z metanolu.
2-(6-bromoheksylo)-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.48 (ddd, J = 9.1,7.8, 0.9 Hz, 4H, ArH), 7.91 - 7.79 (m, 2H, ArH), 4.07 - 4.01 (m, 2H, CONCH), 3.53 (t, J = 6.7 Hz, 2H, BrCHAlif, 1.87 - 1.75 (m, 2H, CHAiif), 1.64 (dd, J = 14.7, 7.3 Hz, 2H, CHAiif), 1.40 (ddd, J = 15.2, 8.2, 3.4 Hz, 4H, CHAiif),
PL 240 473 B1
Spektroskopia w podczerwieni FT-IR: 3061 (C-H Ar Rozc), 2933; 2855 (C-H Alif, Rozc), 1692 (C=O, Rozc), 1587; 1461 (C=C Ar, Rozc), 1361 (C-N, Rozc), 779 (C-Br, Rozc), Chromatografia cienkowarstwowa TLC: współczynnik retencji Rf = 0.90, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.85 min, czystość = 99%, Wydajność = 87%.
P R Z Y K Ł A D 7
Otrzymywanie półproduktu: 1-(6-bromoheksylo)-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin2(1H)-onu, zwyczajowo nazywanego N-heksylo pochodną tetrahydrochinolinoamidu
W moździerzu roztarto 0,01 mola 5,6-dihydro-4H-imidazo[4,5,1-jj]chinolin-2(1H)-onu 0,03 mola K2CO3 oraz 0,001 mola TBAB. Mieszaninę przeniesiono do kolby okrągłodennej, po czym dodano 0,03 mola 1,6-dibromoheksanu i 0,3 cm3 ACN. Reakcje prowadzono przez 45 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 90 W. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i ekstrahowano chlorkiem metylenu. Po odparowaniu chlorku metylenu produkt reakcji macerowano w 20 cm3 heksanu, aby pozbyć się nadmiaru 1,6-dibromoheksanu.
-(6-bromoheksylo)-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin-2(1 H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 7.00 - 6.91 (m, 2H, ArH), 6.85 (dd, J = 6.5, 1.9 Hz, 1H, ArH), 4.39 (d, J = 12.4 Hz, 2H, CONCH), 3.44 - 3.40 (m, 2H, BrCHAlif), 3.15 (s, 2H, CHai»), 2.84 (t, J = 6.0 Hz, 2H, CHAlif), 2.12 (dd, J = 11.8, 6.1 Hz, 2H, CHai»), 1.90 (s, 2H, CHAlif), 1.84 - 1.74 (m, 2H, CHAlif), 1.40 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3059 (C-H Ar Rozc), 2928; 2852 (C-H Alif, Rozc), 1703 (C=O, Rozc), 1599; 1486 (C=C Ar, Rozc), 1373 (C-N, Rozc), 780 (C-Br, Rozc), Chromatografia cienkowarstwowa TLC: współczynnik retencji Rf = 0.90, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 4.17 min, czystość = 96%, Wydajność = 79%.
P R Z Y K Ł A D 8
Otrzymywanie półproduktu: 1-(6-bromoheksylo)-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin-2(1H)-onu, zwyczajowo nazywanego N-heksylo pochodną tetrahydrochinolinoamidu
W moździerzu utarto 0,01 mola 5,6-dihydro-4H-imidazo[4,5,1-jj]chinolin-2(1H)-onu, 0,03 mola NaOH oraz 0,001 mola TBAB. Mieszaninę przeniesiono do kolby okrągłodennej, po czym dodano 0,03 mola 1,6-dibromoheksanu. Reakcje prowadzono przez 40 sekund w reaktorze mikrofalowym. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i ekstrahowano chlorkiem metylenu, przy mocy wyjściowej mikrofal 150 W. Po odparowaniu chlorku metylenu produkt reakcji macerowano w 20 cm3 heksanu, aby pozbyć się nadmiaru 1,6-dibromoheksanu.
-(6-bromoheksylo)-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin-2(1 H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 7.00 - 6.91 (m, 2H, ArH), 6.85 (dd, J = 6.5, 1.9 Hz, 1H, ArH), 4.39 (d, J = 12.4 Hz, 2H, CONCH), 3.44 - 3.40 (m, 2H, BrCHAlif), 3.15 (s, 2H, CHAlif), 2.84 (t, J = 6.0 Hz, 2H, CHAlif), 2.12 (dd, J = 11.8, 6.1 Hz, 2H, CHAlif), 1.90 (s, 2H, CHAlif), 1.84 - 1.74 (m, 2H, CHAlif), 1.40 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3059 (C-H Ar Rozc), 2928; 2852 (C-H Alif, Rozc), 1703 (C=O, Rozc), 1599; 1486 (C=C Ar, Rozc), 1373 (C-N, Rozc), 780 (C-Br, Rozc), Chromatografia cienkowarstwowa TLC: współczynnik retencji Rf = 0.90, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt= 4.17 min, czystość = 96%, Wydajność = 79%.
P R Z Y K Ł A D 9
Otrzymywanie półproduktu: 1-(6-bromoheksylo)-5,6-dihydro-4H-imidazo[4,5,1-jj]chinolin-2(1H)-tionu, zwyczajowo nazywanego N-heksylo pochodną tetrahydrochinolinoamidu
W moździerzu utarto 0,01 mola 5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin-2(1H)-thionu, 0,03 mola NaOH oraz 0,001 mola TBAB. Mieszaninę przeniesiono do kolby okrągłodennej, po czym dodano 0,03 mola 1,6-dibromoheksanu i 2 cm3 wody. Reakcje prowadzono przez 15 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 170 W. Po zakończeniu reakcji do mieszaniny dodano 40 cm3
PL 240 473 B1 wody i ekstrahowano chlorkiem metylenu. Po oddestylowaniu chlorku metylenu produkt reakcji macerowano w 20 cm3 heksanu, aby pozbyć się nadmiaru 1,6-dibromoheksanu.
-(6-bromoheksylo)-5,6-dihydro-4H-imidazo[4,5,1-jj]chinolin-2(1 H)-tion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 7.31 - 7.23 (m, 2H, ArH), 6.89 (dd, J = 6.6, 1.9 Hz, 1H, ArH, 4.44 (d, J = 12.4 Hz, 2H, CONCH), 3.54 - 3.45 (m, 2H, BrCHAlif), 3.00 (t, J = 5.9 Hz, 2H, CHAlf), 2.40 - 2.27 (m, 2H, CHAlf), 1.87 - 1.69 (m, 6H, CHAlf), 1.48 (m, 2H, CHAlf), 1.40 - 1.34 (m, 2H, CHAlf), Spektroskopia w podczerwieni FT-IR: 3046 (C-H Ar Rozc), 2943; 2852 (C-H Alif, Rozc), 1600; 1491 (C=C Ar, Rozc), 1372 (C-N, Rozc), 762 (C-Br, Rozc), Chromatografia cienkowarstwowa TLC; współczynnik retencji R/ = 0.90, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.02 min, czystość = 95%, Wydajność = 79%.
P R Z Y K Ł A D 10
Otrzymywanie półproduktu: 1-(6-bromoheksylo)-5,6-dihydro-4H-imidazo[4,5,1-jj]chinolin-2(1H)-tionu, zwyczajowo nazywanego N-heksylo pochodną tetrahydrochinolinoamidu
W moździerzu roztarto 0,01 mola 5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin-2(1H)-thionu, 0,03 mola NaOH oraz 0,001 mola TBAB. Mieszaninę przeniesiono do kolby okrągłodennej, po czym dodano 0,03 mola 1,6-dibromoheksanu. Reakcje prowadzono przez 60 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 100 W. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i ekstrahowano chlorkiem metylenu. Po oddestylowaniu chlorku metylenu produkt reakcji macerowano w 20 cm3 heksanu, aby pozbyć się nadmiaru 1,6-dibromoheksanu.
-(6-bromoheksylo)-5,6-dihydro-4H-imidazo[4,5,1-jj]chinolin-2(1 H)-tion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 7.31 - 7.23 (m, 2H, ArH), 6.89 (dd, J = 6.6, 1.9 Hz, 1H, ArH, 4.44 (d, J = 12.4 Hz, 2H, CONCH), 3.54 - 3.45 (m, 2H, BrCHAlif), 3.00 (t, J = 5.9 Hz, 2H, CHAlif), 2.40 - 2.27 (m, 2H, CHAlf), 1.87 - 1.69 (m, 6H, CHAlif), 1.48 (m, 2H, CHAlif), 1.40 - 1.34 (m, 2H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3046 (C-H Ar Rozc), 2943; 2852 (C-H Alif, Rozc), 1600; 1491 (C=C Ar, Rozc), 1372 (C-N, Rozc), 762 (C-Br, Rozc), Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.90, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt= 3.02 min, czystość = 95%, Wydajność = 71%.
P R Z Y K Ł A D 11
Otrzymywanie półproduktu: 1-(6-bromoheksylo)-1H,4H-[1,2,5]tiadiazolo[4,3,2-ij]chinoliny,2,2ditlenku zwyczajowo nazywanego N-heksylo pochodną tetrahydrochinolino sulfonamidu
W moździerzu utarto 0,01 mola 1H,4H-[1,2,5]tiadiazolo[4,3,2-ij]chinoliny, 2,2-ditlenku, 0,03 mola NaOH oraz 0,001 mola TBAB. Mieszaninę przeniesiono do kolby okrągłodennej, po czym dodano 0,03 mola 1,6-dibromoheksanu i 0,2 cm3 ACN. Reakcję prowadzono przez 45 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 80 W. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i ekstrahowano chlorkiem metylenu. Po oddestylowaniu chlorku metylenu produkt reakcji macerowano w 20 cm3 heksanu, aby pozbyć się nadmiaru 1,6-dibromoheksanu.
-(6-bromoheksylo)-1H,4H-[1,2,5]tiadiazolo[4,3,2-ij]chinoliny-2,2-ditlenek
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCh) δ 7.21 - 6.90 (m, 2H, ArH), δ 6.85 - 6.80 (m, J = 6.5, 1.9 Hz, 1H, ArH), 3.86 - 3.70 (m, 2H, S(O)2N-CH), 3.40 - 3.33 (m, 2H, BrCHAlif), 3.20 (s, 2H, CHAlif), 2.35 - 2.31 (m, 2H, CHAlif), 2.17 (dd, J = 11.8, 6.1 Hz, 2H, CHAlif), 2.00 (s, 2H, CHAlif, 1.90 - 1.84 (m, 2H, CHAlif), 1.40 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3059 (C-H Ar Rozc), 2998; 2845 (C-H Alif, Rozc), 1599; 1478 (C=C Ar, Rozc), 1372 (C-N, Rozc), 1298 (S=O, Rozc), 685 (S-N, Rozc), 771 (C-Br, Rozc), Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.90, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 2.82 min, czystość = 85%, Wydajność = 64%.
PL 240 473 B1
P R Z Y K Ł A D 12
Otrzymywanie półproduktu: 1-(6-bromoheksylo)-1H,4H-[1,2,5]tiadiazolo[4,3,2-ij]chinoliny-2,2ditlenku, zwyczajowo nazywanego N-heksylo pochodną tetrahydrochinolino sulfonamidu, zwyczajowo nazywanego N-heksylo pochodną tetrahydrochinolino sulfonamidu
W moździerzu utarto 0,01 mola 1H,4H-[1,2,5]tiadiazolo[4,3,2-ij]chinoliny, 2,2-ditlenku, 0,03 mola K2CO3 oraz 0,001 mola TBAB. Mieszaninę przeniesiono do kolby okrągłodennej, po czym dodano 0,03 mola 1,6-dibromoheksanu. Reakcję prowadzono przez 60 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 100 W. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i ekstrahowano chlorkiem metylenu. Po oddestylowaniu chlorku metylenu produkt reakcji macerowano w 20 cm3 heksanu, aby pozbyć się nadmiaru 1,6-dibromoheksanu.
-(6-bromoheksylo)-1H,4H-[1,2,5]tiadiazolo[4,3,2-ij]chinolin-2,2-ditlenek
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 7.21 - 6.90 (m, 2H, ArH), δ 6.85 - 6.80 (m, J = 6.5, 1.9 Hz, 1H,, ArH), 3.86 - 3.70 (m, 2H, S(O)2N-CH), 3.40 - 3.33 (m, 2H, BrCHAlif), 3.20 (s, 2H, CHant), 2.35 - 2.31 (m, 2H, CHant), 2.17 (dd, J = 11.8, 6.1 Hz, 2H, CHAlif), 2.00 (s, 2H, CHAlif), 1.90 - 1.84 (m, 2H, CHat), 1.40 (s, 4H, CHat), Spektroskopia w podczerwieni FT-IR: 3059 (C-H Ar Rozc), 2998; 2845 (C-H Alif, Rozc), 1599; 1478 (C=C Ar, Rozc), 1372 (C-N, Rozc), 1298 (S=O, Rozc), 685 (S-N, Rozc), 771 (C-Br, Rozc), Chromatografia cienkowarstwowa TLC; współczynnik retencji Rf = 0.90, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 2.82 min, czystość = 85%, Wydajność = 42%.
Związki opisane wzorem (I) wytworzono zgodnie z procedurą opisaną w przykładach 13-24, stosując w syntezie półprodukty otrzymane w przykładach 1-12.
Dla związków (produktów) otrzymanych w przykładach 13-24 przedstawiono, po opisie ich przykładowej syntezy, analizy potwierdzające strukturę i czystość otrzymanych połączeń. W poniższych przykładach zastosowano anglosaski zapis liczbowy, według którego miejsca dziesiętne oddziela się kropką.
Związki opisane numerami 1-19 otrzymano zgodnie z procedurą opisaną w przykładach 13 i 14, stosując w syntezie półprodukty otrzymane w przykładach 1 i 2.
P R Z Y K Ł A D 13
Otrzymywanie 1-{6-[4-(arylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-onów
W moździerzu utarto 0,001 mola 1-(6-bromoheksylo)benzo[cd]indol-2(1H)-onu, 0,00095 mola arylopiperazyny opisanej wzorem (V) dobranej odpowiednio do syntezowanego związku, 0,003 mola K2CO3 oraz 0,0001 mola TBAB. Roztartą mieszaninę przeniesiono do kolby okrągłodennej i do mieszaniny reakcyjnej dodano 2 cm3 ACN. Reakcje prowadzono przez 50 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 100 W. Postęp reakcji monitorowano za pomocą TLC. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i umieszczono w lodówce (temp. 4°C) na 12 godzin. Po ochłodzeniu produkt odsączono. Surowy produkt krystalizowano z metanolu. Ligand rozpuszczono w acetonie, następnie przekształcono w chlorowodorki z 4 M HCI w dioksanie.
P R Z Y K Ł A D 14
Otrzymywanie 1-{6-[4-(arylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-onów
W moździerzu utarto 0,001 mola 1-(6-bromoheksylo)benzo[cd]indol-2(1H)-onu, 0,00095 mola arylopiperazyny opisanej wzorem (V) dobranej odpowiednio do syntezowanego związku, 0,003 mola Na2CO3 oraz 0,0001 mola TEAC. Roztartą mieszaninę przeniesiono do kolby okrągłodennej. Reakcje prowadzono przez 60 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 50 W. Postęp reakcji monitorowano za pomocą TLC. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i umieszczono w lodówce (temp. 4°C) na 12 godzin. Po ochłodzeniu produkt odsączono. Surowy produkt krystalizowano z metanolu. Ligand rozpuszczono w acetonie, następnie przekształcono w chlorowodorki z 4 M HCI w dioksanie.
Związek nr 1
1-{6-(4-(2-chlorofenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on
PL 240 473 B1
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H, ArH), 8.06 (d, J = 7.0 Hz, 1H, ArH), 7.86 - 7.76 (m, 1H, ArH), 7.65 (d, J = 8.3 Hz, 1H, ArH), 7.62 - 7.52 (m, 1H, ArH), 7.45 (d, J = 7.8 Hz, 1H, ArH), 7.34 (t, J = 7.8 Hz, 1H, ArH), 7.21 (t, J = 7.5 Hz, 2H ArH), 7.11 (t, J = 7.8 Hz, 1H, ArH), 3.92 (t, J = 6.9 Hz, 2H, C(O)N-CH), 3,57 (s, 2H, CHPiperazyna), 3.41 (s, 2H, CHPiperazyna), 3.12 (s, 6H, CHPiperazyna, N-CHAlf), 1.74 (s, 4H, CHAlif), 1.37 (s, 4H, CHAlf), Spektroskopia w podczerwieni FT-IR: 2998 (C-H Ar, Rozc), 2937; 2859 (C-H Alif, Rozc), 1699 (C=O, Rozc), 1590; 1493 (C=C Ar, Rozc), 1366 (C-N, Rozc), 775 (C-CI, Rozc), Temperatura topnienia: mp = 107-110°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.52, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 2.97 min, czystość = 95%, Wydajność = 60%,
Związek nr 2
1-{6-[4-(3-chlorofenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.19 (d, J = 8.2 Hz, 1H, ArH), 8.05 (d, J = 7.0 Hz, 1H, ArH), 7.86 - 7.76 (m, 1H, ArH), 7.65 (d, J = 8.5 Hz, 1H, ArH), 7.60 - 7.51 (m, 1H, ArH), 7.32 - 7.18 (m, 2H, ArH), 7.03 (d, J = 2.1 Hz, 1H, ArH), 6.94 (d, J = 8.4 Hz, 1H, ArH), 6.86 (d, J = 7.8 Hz, 1H, ArH), 3.93 - 3.79 (m, 2H, C(O)N-CH), 3.57 - 3.32 (m, 4H, CHpperazyna), 3.21 (d, J = 24.0 Hz, 4H, CHPiperazyna), 3.07 (d, J = 8.9 Hz, 2H, N-CHAlf), 1.73 (s, 4H, CHAlif), 1.29 (d, J = 39.7 Hz, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3005 (C-H Ar, Rozc), 2934; 2856 (C-H Alif, Rozc), 1696 (C=O Rozc), 1593; 1493 (C=C Ar, Rozc), 1360 (C-N, Rozc), 768 (C-Cl, Rozc), Temperatura topnienia: mp = 105-108°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.68, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.10 min, czystość = 91%, Wydajność = 32%,
Związek nr 3
1-(6-[4-(4-chlorofenylo)piperazyn-1-ylo]heksylo)benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.05 (t, J = 7.8 Hz, 2H, ArH), 7.80 (d, J = 9.0 Hz, 2H, ArH), 7.77 - 7.69 (m, 1H, ArH), 7.57 (d, J = 8.1 Hz, 1H, ArH), 7.53 - 7.44 (m, 3H, ArH), 6.94 (d, J = 6.9 Hz, 1H, ArH), 4.73 (s, 2H, C(O)N-CH), 3.97 (t, J = 6.8 Hz, 4H, CHPiperazyna), 3.67 (dd, J = 20.4, 9.6 Hz, 4H, CHPiperazyna), 3.14 (s, 2H, N-CHAlf), 1.87 (dd, J = 18.7, 11.3 Hz, 4H, CHAlif), 1.50 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3013 (C-H Ar, Rozc), 2937; 2860 (C-H Alif, Rozc), 1738 (C=O, Rozc), 1603; 1491 (C=C Ar, Rozc), 1366 (C-N, Rozc), 772 (C-CI, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 448.20, czas retencji Rt = 5.75 min, czystość = 93%, Temperatura topnienia: mp = 127-130°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.66, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt= 3.03 min, czystość = 93%, Wydajność = 61%,
Związek nr 4
1-(6-[4-(3,4-dichlorofenylo)piperazyn-1-ylo]heksylo)benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.19 (d, J = 8.1 Hz, 1H, ArH), 8.05 (d, J = 6.9 Hz, 1H, ArH), 7.86 - 7.78 (m, 1H, ArH), 7.65 (d, J = 8.4 Hz, 1H, ArH), 7.61 - 7.53 (m, 1H, ArH), 7.45 (d, J = 9.0 Hz, 1H, ArH), 7.26 - 7.20 (m, 2H, ArH), 6,99 (dd, J = 8.9, 2.8 Hz, 1H, ArH), 3.49 (d, J = 10.8 Hz, 2H, C(O)N-CH), 3.17 (d, J = 11.9 Hz, 4H, CHPiperazyna), 3.05 (s, 4H, CHPiperazyna), 2.08 (s, 2H, N-CHAlf), 1.73 (s, 4H, CHAlif), 1.36 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 2970 (C-H Ar, Rozc), 2938; 2861 (C-H Alif, Rozc), 1699 (C=O, Rozc), 1604; 1494, (C=C Ar, Rozc), 1374 (C-N Rozc), 770 (C-CI, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 482.16, czas retencji Rt = 6.02 min, czystość = 90%, Temperatura topnienia: mp = 115-118°C,
PL 240 473 B1
Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.64, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 4.23 min, czystość = 90%, Wydajność = 43%,
Związek nr 5
1-{6-[4-(2,3-dichlorofenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H, ArH), 8.06 (d, J = 6.9 Hz, 1H, ArH), 7.82 (t, J = 7.5 Hz, 1H, ArH), 7.66 (d, J = 8.4 Hz, 1H, ArH), 7.57 (t, J = 7.7 Hz, 1H, ArH), 7.40 - 7.33 (m, 2H, ArH), 7.22 (dd, J = 10.6, 7.3 Hz, 2H, ArH), 3.92 (t, J = 6.8 Hz, 2H, C(O)N-CH), 3.56 (d, J = 8.8 Hz, 2H, CHPiperazyna), 3.13 (d, J = 8.9 Hz, 6H, CHPiperazyna), 1.78 - 1.65 (m, 4H, CHAlif), 1.40 (d, J = 17.4 Hz, 4H, CHaj»), Spektroskopia w podczerwieni FT-IR: 2999 (C-H Ar, Rozc), 2930; 2857 (C-H Alif, Rozc), 1698 (C=O, Rozc), 1604; 1495, (C=C Ar, Rozc), 1371 (C-N Rozc), 768 (C-CI, Rozc), Temperatura topnienia: mp = 188-190°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.73, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.27 min, czystość = 91%, Wydajność = 36%,
Związek nr 6
1-{6-[4-(4-bromofenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.20 (dd, J = 8.1, 5.8 Hz, 1H, ArH), 8.05 (dd, J = 8.9, 7.0 Hz, 1H, ArH), 7.86 - 7.79 (m, 1H, ArH), 7.65 (t, J = 8.0 Hz, 1H, ArH), 7.60 - 7.52 (m, 1H, ArH), 7.28 - 7.22 (m, 1H, ArH), 7.18 (d, J = 7.0 Hz, 1H, ArH), 7.12 (dd, J = 13.4, 5.3 Hz, 1H, ArH), 6.88 (d, J = 7.7 Hz, 1H, ArH), 6.73 (d, J = 7.9 Hz, 1H, ArH), 3.90 (dt, J = 19.9, 7.0 Hz, 2H, CHPiperazyna), 3.76 (t, J = 7.1 Hz, 2H, C(O)N-CH), 3.55 (s, 2H, CHPiperazyna), 3.14 (d, J = 8.9 Hz, 4H, CHPiperazyna), 1.76 - 1.64 (m, 4H, CHAlif), 1.37 (d, J = 3.8 Hz, 4H, CHaj»), Spektroskopia w podczerwieni FT-IR: 3010(C-H Ar, Rozc), 2938; 2857 (C-H Alif, Rozc), 1677 (C=O, Rozc), 1609; 1498, (C=C Ar, Rozc), 1370 (C-N Rozc), 745 (C-Br, Rozc), Temperatura topnienia: mp = 100-104 °C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.87, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.04 min, czystość = 93%, Wydajność = 19%,
Związek nr 7
1-(6-[4-(2-fluorofenylo)piperazyn-1-yl]heksylo}-benzo[cd]indo1-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.19 (d, J = 8.0 Hz, 1H, ArH), 8.05 (d, J = 6.9 Hz 1H, ArH), 7.85 - 7.75 (m, 1H, ArH), 7.65 (d, J = 8.5 Hz, 1H, ArH), 7.60 - 7.51 (m, 1H, ArH), 7.25 - 7.01 (m, 5H, ArH), 3.91 (t, J = 7.0 Hz, 2H, C(O)N-CH), 3.59 - 3.41 (m, 4H, CHPiperazyna), 3.15 (d, J = 8.3 Hz, 6H, CHPiperazyna, N-CHAlif), 1.72 (s, 4H, CHAlif), 1.37 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3001 (C-H Ar, Rozc), 2942; 2869 (C-H Alif, Rozc), 1720 (C=O, Rozc), 1620 (C=N, Rozc), 1554; 1500 (C=C, Ar, Rozc), 1370 (C-N, Rozc), Temperatura topnienia: mp = 179-181°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.74, TLC Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 1.68 min, czystość = 95%, Wydajność = 52%,
Związek nr 8
1-{6-[4-(2-trifluorometylofenylo)piperazyn-1-yl]heksylo}-benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.05 (dd, J = 11.0, 7.6 Hz, 2H, ArH), 7.76 - 7.69 (m, 1H, ArH), 7.65 (d, J = 7.7 Hz, 1H, ArH), 7.53 (dd, J = 15.0, 7.7 Hz, 4H, ArH), 7.37 - 7.29 (m, 1H, ArH), 6.95 (d, J = 6.8 Hz, 1H, ArH), 3.95 (t, J = 6.9 Hz, 2H, C(O)NCH), 3.80 (t, J = 12.1 Hz, 2H, CHiperazine), 3.55 (d, J = 12.6 Hz, 2H, CHiperazine), 3.04 - 2.93 (m, 4H, CHiperazine), 1.97 (s, 2H, NCHAiif), 1.81 (d, J = 17.4 Hz, 4H, CHai»), 1.48 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 2985 (C-H Ar, Rozc), 2938; 2858 (C-H Alif, Rozc), 1699 (C=O, Rozc), 1602; 1473, (C=C Ar, Rozc), 1374 (C-N, Rozc), 1175 (C-F, Rozc),
PL 240 473 B1
Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 482.23, czas retencji Rt = 6.02 min, czystość = 94%, Temperatura topnienia: mp = 162-164°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.52, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 2.62 min, czystość = 94%, Wydajność = 18%,
Związek nr 9
1-{6-(4-(3-trifluorometylofenylo)piperazyn-1-yl]heksylo}-benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.19 (d, J = 8.1 Hz, 1H, ArH), 8.05 (d, J = 7.0 Hz, 1H, ArH), 7.86 - 7.75 (m, 1H, ArH), 7.65 (d, J = 8.4 Hz, 1H, ArH), 7.61 - 7.52 (m, 1H, ArH), 7.47 (t, J = 7.8 Hz, 1H, ArH), 7.25 (dd, J = 14.7, 8.5 Hz, 3H, ArH), 7.15 (d, J = 7.5 Hz, 1H, ArH), 3.91 (t, J = 7.0 Hz, 2H, C(O)N-CH), 3.60 - 3.42 (m, 4H, CHPiperazyna), 3.17 (d, J = 12.4 Hz, 4H, CHPiperazyna), 3.07 (d, J = 7.9 Hz, 2H, N-CHAlif), 1.73 (d, J = 6.2 Hz, 4H, CHant), 1.37 (s, 4H, CHAiif), Spektroskopia w podczerwieni FT-IR: 2970 (C-H Ar, Rozc), 2938; 2865 (C-H Alif, Rozc), 1706 (C=O, Rozc), 1602; 1509 (C=C Ar, Rozc), 1366 (C-N, Rozc), 1122 (C-F, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 482.3, czas retencji Rt = 5.79 min, czystość = 91%, Temperatura topnienia: mp = 120-124°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.64, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.28 min, czystość = 90%, Wydajność = 38%,
Związek nr 10
1-{6-[4-(4-trifluorometylofenylo)piperazyn-1-yl]heksylo}-benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H, ArH), 8.05 (dd, J = 9.7, 6.9 Hz, 1H, ArH), 7.82 (dd, J = 8.0, 7.1 Hz, 1H, ArH), 7.65(t,
J = 6.0 Hz, 1H, ArH), 7.56 (ddd, J = 11.6, 7.5, 4.0 Hz, 3H, ArH), 7.23 (d, J = 7.0 Hz, 1H, ArH), 7.15(t,
J = 6.1 Hz, 2H, ArH), 4.01 - 3.86 (m, 4H, CHPiperazyna), 3.53 (d, J = 11.8 Hz, 2H, C(O)N-CH), 3.24(t,
J = 12.1 Hz, 2H, CHPiperazyna), 3.08 (s, 4H, CHPiperazyna), 1.73 (dd, J = 13.8, 7.0 Hz, 4H, CHAiif), 1.37 (s,
4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3060(C-H Ar, Rozc), 2943; 2860 (C-H Alif, Rozc), 1677 (C=O, Rozc), 1615; 1493, (C=C Ar, Rozc), 1373 (C-N Rozc), 1112 (C-F, Rozc), Temperatura topnienia: mp = 203-205°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.67, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.32 min, czystość = 91%, Wydajność = 40%,
Związek nr 11
1-{6-[4-(3-metoksyfenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.10 - 8.01 (m, 2H, ArH), 7.78 - 7.68 (m, 1H, ArH), 7.54 (dd, J = 16.7, 7.7 Hz, 3H, ArH), 7.43 (s, 2H, ArH), 7.02 (s, 1H, ArH), 6.94 (d, J = 6.6 Hz, 1H, ArH), 4.83 (s, 3H, OCH), 4.35 - 4.26 (m, 2H, CONCH), 3.87 (s, 4H, CHPiperazyna), 3.72 - 3.61 (m, 4H CHPiperazyna), 3.15 (s, 2H, NCHAlif), 1.86 (m, 4H, CHAlif), 1.52 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 2970 (C-H Ar, Rozc), 2936; 2863 (C-H Alif, Rozc), 1703 (C=O, Rozc), 1616; 1455 (C=C Ar, Rozc), 1365 (C-N, Rozc), 1263; 1026 (C-O, Rozc), Temperatura topnienia: mp = 141-145°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.46, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt,= 2.90 min, czystość = 92%, Wydajność = 51%,
Związek nr 12
-{6-[4-(4-metoksyfenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1 H)-on
PL 240 473 B1
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.09 - 8.00 (m, 2H, ArH), 7.86 (d, J = 9.0 Hz, 2H, ArH), 7.77 - 7.69 (m, 1H, ArH), 7.55 (d, J = 8.4 Hz, 2H, ArH), 7.52 - 7.46 (m, 1H, ArH), 6.99 (d, J = 9.0 Hz, 1H, ArH), 6.93 (d, J = 6.8 Hz, 1H, ArH), 4.79 (m, 3H, OCH), 4.33 (s, 2H, CONCH), 3.84 (s, 4H, CHPiperazyna), 3.65 (t, J = 15.4 Hz, 4H, CHPiperazyna), 3.15 (s, 2H, NCHAlif), 1.86 (dd, J = 18.7,11.3 Hz, 4H, CHAlif), 1.51 (s, 4H, CHant), Spektroskopia w podczerwieni FT-IR: 3060 (C-H Ar Rozc), 2936; 2858 (C-H Aj», Rozc), 1700 (C=O, Rozc), 1568; 1397 (C=C Ar, Rozc), 1366 (C-N, Rozc), 1261; 1025 (C-O, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 444.28, czas retencji Rt = 5.08 min, czystość = 92%, Temperatura topnienia: mp = 150-153°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.52, HPLC Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 2.93 min, czystość = 93%, Wydajność = 78%,
Związek nr 13
1-{6-[4-(2-etoksyfenylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H, ArH), 8.06 (d, J = 6.9 Hz, 1H, ArH), 7.82 (dd, J = 8.1, 7.1 Hz, 1H, ArH), 7.66 (d, J = 8.4 Hz, 1H, ArH), 7.60 - 7.54 (m, 1H, ArH), 7.23 (d, J = 7.0 Hz, 1H, ArH), 6.98 (dd, J = 6.3,4.4 Hz, 2H, ArH), 6.91 (t, J = 4.2 Hz, 2H, ArH), 4.05 - 4.02 (m, 2H, OCH), 3.92 (t, J = 6.3 Hz, 2H, CONCH), 3.53 (d, J = 10.2 Hz, 4H, CHPiperazyna), 3.14 - 3.10 (m, 4H, CHPiperazyna), 2.98 (d, J = 11.1 Hz, 2H, NCHAlif), 1.72 (d, J = 24.4 Hz, 4H, CHAlif), 1.37 (d, J = 1.5 Hz, 4H, CHaj»), 1.34 (d, J = 7.0 Hz, 3H, CHaj»), Spektroskopia w podczerwieni FT-IR: 3060 (C-H Ar Rozc), 2934; 2858 (C-H Alif, Rozc), 1695 (C=O, Rozc), 1604; 1496 (C=C Ar, Rozc), 1371 (C-N, Rozc), 1242; 1036 (C-O, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 458.37, czas retencji Rt = 5.63 min, czystość 90%, Temperatura topnienia: mp = 132-134°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.52, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt= 2.81 min, czystość = 90%, Wydajność = 82%,
Związek nr 14
1-{6-[4-(2-pirydynylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.19 (d, J = 8.1 Hz, 1H, ArH), 8.12 (s, 1H, ArH), 8.05 (d, J = 7Ό Hz, 1H, ArH), 7.87 (s, 1H, ArH), 7.84 - 7.77 (m, 1H, ArH), 7.65 (d, J = 8.5 Hz, 1H, ArH), 7.60 - 7.52 (m, 1H, ArH), 7.23 (d, J = 6.9 Hz, 2H, ArH), 6.92 (s, 1H, ArH), 4.42 (d, J = 13.6 Hz, 2H, CONCH), 3.91 (t, J = 6.9 Hz, 4H, CHPiperazyna), 3.61 - 3.45 (m, 4H, CHPiperazyna), 3.07 (s, 2H, NCAlif), 1.74 (s, 4H, CHAlif), 1.36 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3002 (C-H Ar Rozc), 2938; 2858 (C-H Alif, Rozc), 1738 (C=O, Rozc), 1619 (C=N, Rozc), 1537; 1494 (C=C Ar, Rozc), 1373 (C-N, Rozc), Temperatura topnienia: mp = 106-109°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.4, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 1.65 min, czystość = 94%, Wydajność = 56%,
Związek nr 15
1-(6-[4-(2-pirymidynylo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.44 (d, J = 4.7 Hz, 2H, ArH), 8.19 (d, J = 8.1 Hz, 1H, ArH), 8.05 (d, J = 6.9 Hz, 1H, ArH), 7.80 (d, J = 7.4 Hz, 1H, ArH), 7.65 (d, J = 8.5 Hz, 1H, ArH), 7.59 - 7.52 (m, 1H, ArH), 7.22 (d, J = 7.0 Hz, 1H, ArH), 6.76 (t, J = 4.8 Hz, 1H, ArH), 3.90 (t, J = 6.8 Hz, 2H, CONCh), 3.45 (d, J = 41.9 Hz, 4H, CHPiperazyna), 3.03 (s, 4H, CHPiperazyna), 2.11 (d, J = 15.5 Hz, 2H, NCHAlif), 1.73 (s, 4H, CHaj»), 1.36 (s, 4H, CHant), Spektroskopia w podczerwieni FT-IR: 3001 (C-H Ar, Rozc), 2942; 2869 (C-H Alif, Rozc), 1720 (C=O, Rozc), 1604 (C=N, Rozc), 1554; 1500 (C=C, Ar, Rozc), 1370 (C-N, Rozc), mp = 179-181eC, Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 416,23, czas retencji - Rt = 4.67 min, czystość 89%,
PL 240 473 B1
Temperatura topnienia: mp = 121-124°C,
Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.74, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 1.68 min, czystość = 88%, Wydajność = 38%,
Związek nr 16
-{6-[4-(2-nitrofenylo)piperazyn-1 -ylo]heksylo}benzo[cd]indol-2(1 H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.19 (t, J = 7.9 Hz, 2H, ArH), 8.06 (d, J = 6.9 Hz, 1H, ArH), 7.82 (dd, J = 8.0, 7.1 Hz, 2H, ArH), 7.66 (d, J = 8.3 Hz, 2H, ArH), 7.60 - 7.53 (m, 2H, ArH), 7.23 (d, J = 6.9 Hz, 1H, ArH), 3.90 (dd, J = 15.7, 8.8 Hz, 2H, CONCH), 3.77 (s, 8H, CHpiperazyna), 3.09 (s, 2H, NCHAlif), 1.73 (s, 4H, CHAlif), 1.36 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 2990(C-H Ar, Rozc), 2937; 2864 (C-H Alif, Rozc), 1686 (C=O, Rozc), 1631; 1310 (NO2, Rozc), 1604; 1495, (C=C Ar, Rozc), 1374 (C-N Rozc), Temperatura topnienia: mp = 188-191°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.68, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 5.60 min, czystość = 92%, Wydajność = 36%,
Związek nr 17
1-{6-[4-(8-chinolinyl)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.19 (dd, J = 12.6, 8.1 Hz, 1H, ArH), 8.05 (dd, J = 13.2, 8.0 Hz, 1H, ArH), 7.70 (dddd, J = 21.6, 14.6, 10.7, 6.6 Hz, 7H, ArH), 7.40 (d, J = 7.8 Hz, 1H, ArH), 7.28 - 7.01 (m, 2H, ArH), 3.92 (dd, J = 14.5, 7.4 Hz, 4H, CH, CONCH), 3.39 (d, J = 11.4 Hz, 4H, CHpiperazyna), 3.26 (d, J = 11.5 Hz, 2H, CHpiperazyna), 3.15 (s, 2H, NCHAlif), 1.77 (t, J = 10.4 Hz, 4H, CHAlif), 1.40 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3061 (C-H Ar, Rozc), 2934; 2856 (C-H Alif, Rozc), 1694 (C=O, Rozc), 1630 (C=N, Rozc), 1593; 1493 (C=C, Ar, Rozc), 1377 (C-N, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 465.35, czas retencji - Rt = 4.30 min, czystość 91%, Temperatura topnienia: mp = (olej), Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.70, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 5.90 min, czystość = 91%, Wydajność = 38%,
Związek nr 18
1-{6-[4-(1,2-benzizotiazol-3-ilo)piperazyn-1-ylo]heksylo}benzo[cd]indol-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H, ArH), 8.13 (d, J = 8.2 Hz, 2H, ArH), 8.07 (d, J = 6.9 Hz, 1H, ArH), 7.82 (dd, J = 8.0, 7.1 Hz, 1H, ArH), 7.66 (d, J = 8.4 Hz, 1H, ArH), 7.59 (dd, J = 7.5, 3.6 Hz, 2H, ArH), 7.49 (d, J = 8.0 Hz, 1H ArH), 7.24 (d, J = 7.0 Hz, 1H ArH), 4.05 (s, 2H, CONCH), 3.93 (t, J = 6.9 Hz, 2H, CHpiperazyna), 3,58 (d, J = 10.9 Hz, 2H, CHpiperazyna), 3.45 - 3.36 (m, 4H, CHpiperazyna), 3.16 (s, 2H, NCHAlif), 1.73 (d, J = 22.7 Hz, 4H, CHAiif), 1.39 (s, 4H, CHAiif), Spektroskopia w podczerwieni FT-IR: 3037 (C-H Ar, Rozc), 2945; 2842 (C-H Alif, Rozc), 1708 (C=O, Rozc), 1642 (C=N, Rozc), 1540; 1471 (C=C, Rozc), 1371 (C-N, Rozc), 692 (S-N, Rozc), 660 (C-S, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 471.20, czas retencji - Rt = 5.82 min, czystość 93%, Temperatura topnienia: mp = 193-194°C Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0,82, Wysokosprawna chromatografia cieczowa HpLC: czas retencji Rt= 11.16 min, czystość = 95%, Wydajność = 36%,
Związek nr 19
1-{6-[4-(2-okso-2,3-dihydro-1,3-benzoksazol-7-ilo)piperazyn-1-ylo]heksylo}benzo[cd]indol2(1H)-on
PL 240 473 B1
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H, ArH), 8.06 (d, J = 6.9 Hz, 1H, ArH), 7.82 (dd, J = 8.1, 7.1 Hz, 1H, ArH), 7.66 (d, J = 8.4 Hz, 1H, ArH), 7.57 (dd, J = 8.4, 7.1 Hz, 1H, ArH), 7.40 (d, J = 9.0 Hz, 2H, ArH), 7.23 (d, J = 7.0 Hz, 1H, ArH), 6.95 (s, 2H, ArH), 3.91 (t, J = 7.0 Hz, 2H), 3.78 (d, J = 12.3 Hz, 2H), 3.51 (d, J = 11.1 Hz, 2H, CONCH), 3.14 - 3.00 (m, 6H, CHPiperazyna), 3.02 - 2.98 (m, 4H, CHPiperazyna), 1.73 (d, J = 6.8 Hz, 4H, CHAlif), 1.36 (s, 4H, CHai»), Spektroskopia w podczerwieni FT-IR: 2980(C-H Ar, Rozc), 2936; 2858 (C-H Alif, Rozc), 1698 (C=O, Rozc), 1603; 1488, (C=C Ar, Rozc), 1373 (C-N Rozc), 1266; 1026 (C-O, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 470.11, czas retencji - Rt = 5.83 min, czystość 93%, Temperatura topnienia: mp = 167-169°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0,80, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt= 5,83 min, czystość = 93%, Wydajność = 44%,
Związki opisane numerami 20-31 otrzymano zgodnie z procedurą opisaną w przykładach 15 i 16, stosując w syntezie półprodukty otrzymane w przykładach 3 i 4.
P R Z Y K Ł A D 15
Otrzymywanie 2-{6-[4-(arylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1, 1 (2H)-dionów
W moździerzu utarto 0,001 mola 2-(6-bromoheksyto)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dionu, 0,00095 mola arylopiperazyny opisanej wzorem (V) dobranej odpowiednio do syntezowanego związku, 0,003 NaOH oraz 0,0001 mola DABCO. Roztartą mieszaninę przeniesiono do kolby okrągłodennej i do mieszaniny reakcyjnej dodano 1 cm3 DMF. Reakcje prowadzono przez 50 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 120 W. Postęp reakcji monitorowano za pomocą TLC. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i umieszczono w lodówce (temp. 4°C) na 12 godzin. Po ochłodzeniu produkt odsączono. Surowy produkt krystalizowano z metanolu. Ligand rozpuszczono w acetonie, następnie przekształcono w chlorowodorki z 4 M HCI w dioksanie.
P R Z Y K Ł A D 16
Otrzymywanie 2-{6-[4-(arylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dionów
W moździerzu roztarto 0,001 mola 2-(6-bromoheksylo)nafto[1,8-cd]1,2]tiazolo-1,1(2H)-dionu, 0,00095 mola arylopiperazyny opisanej wzorem (V) dobranej odpowiednio do syntezowanego związku, oraz 0,0001 mola TBAB. Roztartą mieszaninę przeniesiono do kolby okrągłodennej, po czym dodano 0,003 mola trietyloaminy. Reakcje prowadzono przez 15 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 200 W. Postęp reakcji monitorowano za pomocą TLC. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i umieszczono w lodówce (temp. 4°C) na 12 godzin. Po ochłodzeniu produkt odsączono. Surowy produkt krystalizowano z metanolu. Ligand rozpuszczono w acetonie, następnie przekształcono w chlorowodorki z 4 M HCI w dioksanie.
Związek nr 20
2-{6-[4-(2-chiorofenyio)piperazyn-1-yio]heksyio}-(2H)nafto[1,8-cd][1,2]tiazoio-1,1(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.30 (d, J = 8.2 Hz, 1H, ArH), 8.25 (d, J = 7.2 Hz, 1H, ArH), 7.94 - 7.83 (m, 1H, ArH), 7.64 (dd, J = 15.0, 7.5 Hz, 2H, ArH), 7.45 (d, J = 7.9 Hz, 1H, ArH), 7.36 - 7.31 (m, 1H, ArH), 7.20 (d, J = 6.0 Hz, 1H, ArH), 7.14 - 7.08 (m, 2H, ArH), 3.86 (t, J = 7.3 Hz, 2H, S(O)2N-CH), 3.63 - 3.49 (m, 2H, CHPiperazyna), 3.40 (d, J = 11.3 Hz, 2H, CHPiperazyna), 3.21 (S, 4H, CHPiperazyna), 3.13 (s, 2H, NCHAiif), 1.80 (ddd, J = 32.8, 15,2, 7.8 Hz, 4H, CHAiif), 1.54 - 1.35 (m, 4H, CHAiif), Spektroskopia w podczerwieni FT-IR: 2987 (C-H Ar, Rozc), 2937, 2818 (C-H, Alif, Rozc), 1589, 1481 (C=C Ar, Rozc), 1374 (C-N, Rozc), 1309 (S=O, Rozc), 805 (N-S, Rozc), 758 (C-Cl, Rozc), Temperatura topnienia: mp = 199-211°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.64, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.81 min, czystość = 89%, Wydajność = 71%,
PL 240 473 B1
Związek nr 21
2-{6-[4-(3-chlorofenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.05 (dd, J = 11.0, 7.6 Hz, 2H, ArH), 7.76 - 7.69 (m, 1H, ArH), 7.65 (d, J = 7.7 Hz, 1H, ArH), 7.53 (dd, J = 15.0, 7.7 Hz, 4H, ArH), 7.37 - 7.29 (m, 1H, ArH), 6.95 (d, J = 6.8 Hz, 1H, ArH), 3.95 (t, J = 6.9 Hz, 2H, S(O>N-CH), 3.80 (t, J = 12.1 Hz, 2H, CHPiperazyna), 3.55 (d, J = 12.6 Hz, 2H, CHPiperazyna), 3.04 - 2.93 (m, 4H, CHPiperazyna), 1.97 (s, 2H, N-CHAlif), 1.81 (d, J = 17.4 Hz, 4H, CHAlif), 1.48 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 2990 (C-H Ar, Rozc), 2933; 2860 (C-H Alif, Rozc), 1594, 1487 (C=C Ar, Rozc), 1374 (C-N, Rozc), 1308 (S=O, Rozc), 852 (N-S, Rozc), 772 (C-CI, Rozc), Temperatura topnienia: mp = 162-165°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.74, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.79 min, czystość = 88%, Wydajność = 71%,
Związek nr 22
2-{6-[4-(4-chlorofenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd] [1,2]tiazolo-1,1(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.09 (d, J = 8.2 Hz, 1H, ArH), 7.97 (d, J = 7.4 Hz, 1H, ArH), 7.8o (d, J = 8.9 Hz, 3H, ArH), 7.56 (d, J = 7.2 Hz, 1H, ArH), 7.53 - 7.45 (m, 3H, ArH), 6.77 (d, J = 7.4 Hz, 1H, ArH), 4.72 (s, 2H, S(O)2N-CH), 4.09 (s, 4H, CHPiperazyna), 3.68 (d, J = 17.7 Hz, 4H, CHPiperazyna), 3.18 (s, 2H, N-CHAlif), 1.98 (s, 4H, CHAlif), 1.60 (s, 4H, CHalif), Spektroskopia w podczerwieni FT-1R : 2970 (C-H Ar, Rozc), 2941, 2860 (C-H Alif, Rozc), 1590, 1490 (C=C Ar, Rozc), 1372 (C-N, Rozc), 1308 (S=O, Rozc), 827 (N-S, Rozc), 771 (C-CI, Rozc), Temperatura topnienia: mp = 150-152°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.66, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.14 min, czystość = 90%, Wydajność = 66%,
Związek nr 23
2-{6-[4-(2,3-dichlorofenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazol-1,1(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.08 (s, 1H, ArH), 7.96 (s, 1H, ArH), 7.78 (d, J = 7.4 Hz, 1H, ArH), 7.57 (d, J = 7.4 Hz, 1H, ArH), 7.48 (d, J = 8.5 Hz, 1H, ArH), 7.21 (s, 2H, ArH), 7.05 (s, 1H, ArH), 6.78 (m, 1H, ArH), 3.86 (m, 2H, S(O)2N-CH), 3.64 (m, 4H, CHPiperazyna), 3.39 (s, 4H, CHPiperazyna), 3.07 (s, 2H, N-CHAlif), 1.98 (s, 4H, CHAlif), 1.57 (s, 4H, CHalif), Spektroskopia w podczerwieni FT-IR: 3014 (C-H Ar, Rozc), 2940, 2853 (C-H, Alif, Rozc), 1589, 1494 (C=C Ar, Rozc), 1376 (C-N, Rozc), 1304 (S=O, Rozc), 826 (N-S, Rozc), 777 (C-CI, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 518.12, czas retencji - Rt = 6.21 min, czystość 91%, Temperatura topnienia: mp = 158-160°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.70, Wysokosprawna chromatografia cieczowa HPLC: czas retencji 3.88 min, czystość = 96%, Wydajność = 72%,
Związek nr 24
2-{6-[4-(3,4-dichlorofenylo)piperazyn-1-ylo)heksylo}-(2H)nafto[1,8-cd][1,2]tiazol-1,1(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.30 (d, J = 8.1 Hz, 1H, ArH), 8.24 (d, J = 7.1 Hz, 1H, ArH), 7.89 (dd, J = 8.1,7.4 Hz, 1H, ArH), 7.65 (dt, J = 22.2, 7.5 Hz, 2H, ArH), 7.45 (d, J = 9.0 Hz, 1H, ArH), 7.23 (dd, J = 7.1,2.9 Hz, 1H, ArH), 7.11 (d, J = 6.6 Hz, 1H, ArH), 7.00 (dd, J = 9.0, 2,9 Hz, 1H, ArH), 3.86 (dd, J = 14.8, 7.8 Hz, 4H, CHPiperazyna), 3.51 (d, J = 11.6 Hz, 2H, S(O)2N-CH), 3.23 (dd, J = 22.9, 11.2 Hz, 2H, CHPiperazyna), 3.12 - 3.03 (m, 4H, CHPiperazyna), 1.88 - 1.72 (m, 4H, CHAlif), 1.43 (ddd, J = 21.4, 14.7, 7.4 Hz, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3008 (C-H Ar, Rozc), 2942, 2858 (C-H, Alif, Rozc), 1590, 1495 (C=C Ar, Rozc), 1373 (C-N, Rozc), 1308 (S=O, Rozc), 829 (N-S, Rozc), 777 (C-Cl, Rozc), Temperatura topnienia: mp = 130-132°C,
PL 240 473 B1
Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.87, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.47 min, czystość = 93%, Wydajność = 75%,
Związek nr 25
2-{6-[4-(3-trifIuorometyIofenyIo)piperazyn-1-yIo]heksyIo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.30 (d, J = 8.1 Hz, 1H, ArH), 8.24 (d, J = 7.1 Hz, 1H, ArH), 7.90 (dd, J = 8.1,7.4 Hz, 1H, ArH), 7.65 (dt, J = 22.4, 7.5 Hz, 2H, ArH), 7.47 (t, J = 7.9 Hz, 1H, ArH), 7.30 - 7.24 (m, 2H, ArH), 7.16 (d, J = 5.4 Hz, 1H, ArH), 7.11 (d, J = 6.9 Hz, 1H, ArH), 3.86 (t, J = 7.3 Hz, 2H, S(O)2N-CH), 3.55 (d, J = 13.5 Hz, 2H, CHPiperazin), 3.52 - 3.45 (m, 2H, CHPiperazin), 3.22 (d, J = 9.6 Hz, 2H, CHPiperazin), 3.10 (dd, J = 21.2, 10.1 Hz, 4H, CHpiperazin), 1.80 (ddd, J = 23.2, 15.0, 7.6 Hz, 4H, CHAlif), 1.54 - 1.37 (m, 4H, CHa»), Spektroskopia w podczerwieni FT-IR: 2984 (C-H Ar, Rozc), 2940, 2867 (C-H, Alif, Rozc), 1591, 1494 (C=C Ar, Rozc), 1374 (C-N, Rozc), 1313 (S=O, Rozc), 1228 (C-F, Rozc), 822 (n-S, Rozc), Temperatura topnienia: mp = 124-125°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.71, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.68 min, czystość = 99%, Wydajność = 89%,
Związek nr 26
2-{6-[4-(4-trifIuorometyIofenyIo)piperazyn-1-yIo]heksyIo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.29 (d, J = 8.2 Hz, 1H, ArH), 8.24 (d, J = 7.2 Hz, 1H, ArH), 7.92 - 7.85 (m, 1H, ArH), 7.69 - 7.59 (m, 2H, ArH), 7.56 (d, J = 8.8 Hz, 2H, ArH), 7.12 (dd, J = 13.3, 7.9 Hz, 3H, ArH), 3.98 (d, J = 13.4 Hz, 2H, S(O)2NCH), 3.85 (t, J = 7.3 Hz, 2H, CHPiperazin), 3.55 (d, J = 12.9 Hz, 2H, CHPiperazin), 3.33 (t, J = 11.9 Hz, 2H, CHPiperazin), 3.08 (dd, J = 21.1, 10.0 Hz, 4H, CHPiperazin), 1.86 - 1.76 (m, 4H, CHaj»), 1.43 (ddd, J = 21.1, 14.7, 7.3 Hz, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3065 (C-H Ar, Rozc), 2933, 2855 (C-H, Alif, Rozc), 1588, 1499 (C=C Ar, Rozc), 1361 (C-N, Rozc), 1340 (S=O, Rozc), 1234 (C-F, Rozc), 848 (N-S, Rozc), Temperatura topnienia: mp = 204-206°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.85, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.76 min, czystość = 100%, Wydajność = 46%,
Związek nr 27
2-{6-[4-(2-fIuorofenyIo)piperazyn-1 -ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1, 1 (2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.08 (d, J = 7.8 Hz, 1H, ArH), 7.96 (d, J = 6.7 Hz, 1H, ArH), 7.79 - 7.71 (m, 1H, ArH), 7.56 (d, J = 7.3 Hz, 1H, ArH), 7.47 (d, J = 8.6 Hz, 1H, ArH), 7.09 - 7.01 (m, 4H, ArH), 6.77 (d, J = 7.3 Hz, 1H, ArH), 3.85 (t, J = 6.9 Hz, 2H, S(O)2N-CH), 3.73 (s, 2H, CHPiperazin), 3.58 (s, 2H, CHPiperazin), 3.45 (d, J = 11.3 Hz, 4H, CHPiperazin), 3.05 (s, 2H, NCHAlif), 1.97 (s, 4H, CHAlif), 1.66 (s ,4H, CHaj»), Spektroskopia w podczerwieni FT-IR: 2993 (C-H Ar, Rozc), 2940, 2869 (C-H, Alif, Rozc), 1591, 1485 (C=C Ar, Rozc), 1372 (C-N, Rozc), 1310 (S=O, Rozc), 1236 (C-F, Rozc), 811 (N-S, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 468.21, czas retencji - Rt = 5.69 min, czystość 100%, Temperatura topnienia: mp = 113-114°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.71, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 1.82 min, czystość = 100%, Wydajność = 71%,
Związek nr 28
2-{6-[4-(2-etoksyfenylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.23 (d, J = 8.2 Hz, 1H, ArH), 8.07 (d, J = 8.1 Hz, 1H, ArH), 7.96 (d, J = 7.2 Hz, 1H, ArH), 7.80 - 7.72 (m, 1H,
PL 240 473 B1
ArH), 7.62 - 7.51 (m, 1H, ArH), 7.49 - 7.39 (m, 2H, ArH), 7.05 (dd, J = 15.7, 7.8 Hz, 2H, ArH), 6.75 (d, J = 7.4 Hz, 1H, ArH), 5.02 (m, 2H, OCH), 4.51 (d, J = 12.5 Hz, 2H, SO2NCH), 4.35 (dd, J = 14.2, 7.1 Hz, 4H, CHPiperazyna), 3.61 (t, J = 12.5 Hz, 4H, CHPiperazyna), 3.16 (s, 2H, NCHAlif), 1.96 (s, 4H, CHAlif), 1.63 (t, J = 7.0 Hz, 4H, CHAlif), 1.56 (s, 3H, CHai»), Spektroskopia w podczerwieni FT-IR: 2981 (C-H Ar, Rozc), 2936, 2867 (C-H, Alif, Rozc), 1610, 1491 (C=C Ar, Rozc), 1370 (C-N, Rozc), 1309 (S=O, Rozc), 1255; 1033 (C-O, Rozc), 815 (N-S, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 494.25, czas retencji - Rt = 5.83 min, czystość 88%, Temperatura topnienia: mp = 140-143°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.67, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 1.82 min, czystość = 90%, Wydajność = 39%,
Związek nr 29
2-{6-[4-(2-pirydynylo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1,1(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.30 (dd, J = 8.2, 3.2 Hz, 1H, ArH), 8.25 (dd, J = 7.2, 1.8 Hz, iH, ArH), 8.15 (dd, J = 5.3, 1.4 Hz, 1H, ArH), 7.90 (ddd, J = 10.2, 7.7, 2.8 Hz, 1H, ArH), 7.78 (s, 1H, ArH), 7.68 - 7.60 (m, 2H, ArH), 7.15 - 7.03 (m, 2H, ArH), 6.89 - 6.79 (m, 1H, ArH), 4.40 (d, J = 14.2 Hz, 2H, SO2NCH), 3.85 (dd, J = 14.8, 7.5 Hz, 2H, CHPiperazyna), 3.33 (d, J = 13.0 Hz, 2H, CHPiperazyna), 3.09 (dd, J = 13.6, 8.8 Hz, 4H, CHPiperazyna), 1.87 - 1.71 (m, 4H, CHAlif), 1.54 - 1.38 (m, 4H, CHaw), Spektroskopia w podczerwieni FT-IR: 3060 (C-H Ar, Rozc), 2932, 2854 (C-H, Alif, Rozc), 1640 (C=N, Rozc), 1604, 1497 (C=C Ar, Rozc), 1373 (C-N, Rozc), 1305 (S=O, Rozc), 1256; 1028 (C-O, Rozc), 817 (N-S, Rozc), Temperatura topnienia: mp = 119-121 °C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.65, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.06 min, czystość = 89%, Wydajność = 10%,
Związek nr 30
2-{6-[4-(2-nitrofenylo)piperazyn-1 -ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazolo-1, 1 (2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.29 (d, J = 8.1 Hz, 1H, ArH), 8.24 (d, J = 7.2 Hz, 1H, ArH), 7.92 - 7.85 (m, 1H, ArH), 7.78 (dd, J = 8.1, 1.6 Hz, 1H, ArH), 7.65 (dd, J = 15.3, 8.3 Hz, 2H, ArH), 7.60 - 7.54 (m, 1H, ArH), 7.29 (d, J = 7.3 Hz, 1H, ArH), 7.15 - 7.06 (m, 2H, ArH), 3.84 (t, J = 7.3 Hz, 2H, SO2NCH), 3.44 (s, 4H, CHPiperazyna), 3.34 - 3.26 (m, 4H, CHPiperazyna), 2.34 - 2.29 (m, 2H, NCHAlif), 1.93 - 1.74 (m, 4H, CHAlif), 1.45 (d, J = 6.5 Hz, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3061 (C-H Ar, Rozc), 2932, 2865 (C-H, Alif, Rozc), 1656; 1342 (NO2, Rozc), 1591, 1492 (C=C Ar, Rozc), 1389 (C-N, Rozc), 1343 (S=O, Rozc), 851 (N-S, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 495.32, czas retencji - Rt = 5.49 min, czystość 100%, Temperatura topnienia: mp = 238-240°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.71, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 4.20 min, czystość = 100%, Wydajność = 43%,
Związek nr 31
2-{6-[4-(1,2-benzizotiazol-3-ilo)piperazyn-1-ylo]heksylo}-(2H)nafto[1,8-cd][1,2]tiazol-1,1 (2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.31 (d, J = 8.1 Hz, 1H, ArH), 8.25 (d, J = 7.2 Hz, 1H, ArH), 8.17 - 8.10 (m, 2H, ArH), 7.93 - 7.88 (m, 1H, ArH), .64 (ddd, J = 15.9, 14.4, 8.3 Hz, 3H, ArH), 7.48 (t, J = 7.2 Hz, 1H, ArH), 7.11 (d, J = 6.6 Hz, 1H, ArH), .09 (d, J = 12.8 Hz, 2H, SO2NCH), 3.87 (t, J = 7.3 Hz, 2H, CHPiperazyna), 3.61 (d, J = 11.4 Hz, 2H,
CHPiperazyna), 3.39 (d, J = 7.7 Hz, 2H, CHPiperazyna), 3.27 (s, 2H, CHPiperazyna), 3.19 (s, 2H, NCHAlif), 1.90
- 1.85 (m, 2H, CHai»), 1.73 (s, 2H, CHAlif), 1.55 - 1.47 (m, 2H, CHAlif), 1.43 (d, J = 7.3 Hz, 2H, CHAlif). Spektroskopia w podczerwieni FT-1R : 2978 (C-H Ar, Rozc), 2939, 2884 (C-H, Alif, Rozc), 1639 (C=N, Rozc), 1594,1476 (C=C Ar, Rozc), 1376 (C-N, Rozc), 1298 (S=O, Rozc), 687 (s-N, Rozc), Temperatura topnienia: mp = 117-121 °C,
PL 240 473 B1
Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.87, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 8,97 min, czystość = 100%, Wydajność = 45%,
Związki opisane numerami 32-44 otrzymano zgodnie z procedurą opisaną w przykładach 17 i 18, stosując w syntezie półprodukty otrzymane w przykładach 5 i 6.
P R Z Y K Ł A D 17
Otrzymywanie 2-{6-[4-(arylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dionów
W moździerzu utarto 0,001 mola 2-(6-bromoheksylo)-1H-benzo[de]izochinolino-1,3(2H)-dionu, 0,00095 mola arylopiperazyny opisanej wzorem (V) dobranej odpowiednio do syntezowanego związku, 0,003 mola K2CO3 oraz 0,0001 mola TEAC. Roztartą mieszaninę przeniesiono do kolby okrągłodennej i do mieszaniny reakcyjnej dodano 5 cm3 DMF. Reakcje prowadzono przez 50 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 90 W. Postęp reakcji monitorowano za pomocą TLC. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i umieszczono w lodówce (temp. 4°C) na 12 godzin. Po ochłodzeniu surowy produkt odsączono. Surowy produkt krystalizowano z metanolu, Ligand rozpuszczono w acetonie, następnie przekształcono w chlorowodorki z 4 M HCI w dioksanie.
P R Z Y K Ł A D 18
Otrzymywanie 2-{6-[4-(arylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dionów
W moździerzu utarto 0,001 mola 2-(6-bromoheksylo)-1H-benzo[de]izochinolino-1,3(2H)-dionu, 0,00095 mola arylopiperazyny opisanej wzorem (V) dobranej odpowiednio do syntezowanego związku, 0,003 mola Na2CO3 oraz 0,0001 DABCO. Roztartą mieszaninę przeniesiono do kolby okrągłodennej. Reakcje prowadzono przez 50 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 100 W. Postęp reakcji monitorowano za pomocą TLC. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i umieszczono w lodówce (temp. 4°C) na 12 godzin. Po ochłodzeniu surowy produkt odsączono. Surowy produkt krystalizowano z metanolu. Ligand rozpuszczono w acetonie, następnie przekształcono w chlorowodorki z 4 M HCI w dioksanie.
Związek nr 32
2-{6-[4-(2-metoksyfenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.61 (d, J = 7.3 Hz, 2H, ArH), 8.22 (d, J = 7.7 Hz, 2H, ArH), 7.82 - 7.71 (m, 2H, ArH), 7.28 (d, J = 10.5 Hz, 2H, ArH), 7.01 (t, J = 7.2 Hz, 2H, ArH), 4.46 (s, 3H, OCH), 4.23 - 4.15 (m, 2H, CONCH), 3.90 (d, J = 54.3 Hz, 4H, CHpiperazyna), 3.58 (t, J = 13.2 Hz, 4H, CHpiperazyna), 3.07 (s, 2H, NCHAlif), 1.99 (s, 2H, CHAlif), 1.78 (s, 2H, CHAlif), 1.50 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3060 (C-H Ar, Rozc), 2932; 2859 (C-H Alif, Rozc), 1694 (C=O, Rozc), 1590; 1492 (C=C Ar, Rozc), 1361 (C-N, Rozc), 1242; 1026 (C-O, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 472.26, czas retencji - Rt = 5.43 min, czystość 92%, Temperatura topnienia: mp = 245-248°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.70, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 2.73 min, czystość = 92%, Wydajność = 47%,
Związek nr 33
2-{6-[4-(3-metoksyfenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.52 - 8.43 (m, 4H, ArH), 7.90 - 7.84 (m, 2H, ArH), 7.16 (td,‘J = 8.2, 2.6 Hz, 1H, ArH), 6.60 - 6.56 (m, 1H, ArH), 6.53 (dt, J = 4.5, 2.3 Hz, 1H, ArH), 6,48 - 6.41 (m, 1H, ArH), 4.04 (dd, J = 15.1, 7.8 Hz, 2H, CONCH), 3.84 - 3.76 (m, 2H, CHpiperazyna), 3.58 - 3.46 (m, 2H, CHpiperazyna, 3.38 (dd, J = 12.4, 7.0 Hz, 2H, CHpiperazyna), 3.18 (d, J = 11.2 Hz, 2H, CHpiperazyna), 3.08 (d, J = 9.9 Hz, 2H, NCHAlif), 1.79 - 1.61 (m, 4H, CHAlif), 1.43 - 1.33 (m, 4H, CHAlif), Spektroskopia w podczerwieni FT-iR: 3060 (C-H Ar, Rozc), 2938; 2864 (C-H Alif, Rozc), 1686 (C=O, Rozc), 1590; 1494 (C=C Ar, Rozc), 1371 (C-N, Rozc), 1233; 1027 (C-O, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 472,26, czas retencji - Rt = 5.56 min, czystość = 90%,
PL 240 473 B1
Temperatura topnienia: mp = 240-243°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.67, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 4.20 min, czystość = 89%, Wydajność = 43%,
Związek nr 34
22-{6-[4-(4-metoksyfenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.50 (ddd, J = 9.3, 7.8, 1.0 Hz, 4H, ArH), 7.90 (dd, J = 8.1,7.4 Hz, 2H, ArH), 7.58 (d, J = 8.8 Hz, 2H, ArH), 7.15 (d, J = 8.8 Hz, 2H, ArH), 4.11 - 4.05 (m, 2H, ArH, CONCH), 4.00 (d, J = 13.1 Hz, 2H CHPiperazyna), 3.56 (s, 2H, NCHAlif), 3.15 (dt, J = 23.1,12.3 Hz, 6H CHPiperazyna), 1.69 (dd, J = 14.3, 6.9 Hz, 4H, CHa»), 1.40 (d, J = 3.2 Hz, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3064 (C-H Ar, Rozc), 2937; 2863 (C-H Alif, Rozc), 1696 (C=O, Rozc), 1590; 1439 (C=C Ar, Rozc), 1346 (C-N, Rozc), 1236; 1071 (C-O, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 472.26, czas retencji - Rt = 5.99 min, czystość 100%, Temperatura topnienia: mp = 147-150°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.69, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.80 min, czystość = 99%, Wydajność = 16%,
Związek nr 35
2-{6-[4-(2-etoksyfenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.61 (d, J = 7.2 Hz, 2H, ArH), 8.23 (t, J = 7.4 Hz, 3H, ArH), 7.80 - 7.72 (m, 2H, ArH), 7.45 (t, J = 7.9 Hz, 1H, ArH), 7.05 (dd, J = 15.6, 7.5 Hz, 2H, ArH), 5.03 (d, J = 12.3 Hz, 3H, OCH), 4.54 (s, 2H, CONCH), 4.35 (dd, J = 13.9, 6.9 Hz, 2H, CHPiperazyna), 4.23 - 4.14 (m, 2H, CHPiperazyna), 3.66 (s, 4H, CHPiperazyna), 3.14 (s, 2H, NCHAlif), 1.98 (s, 2H, CHAlif), 1.78 (s, 2H, CHAlif), 1.64 (t, J = 7.0 Hz, 3H, CHaj»), 1.50 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3063 (C-H Ar, Rozc), 2936; 2867 (C-H Alif, Rozc), 1694 (C=O, Rozc), 1599; 1500 (C=C Ar, Rozc), 1347 (C-N, Rozc), 1240; 1029 (C-O, Rozc), Temperatura topnienia: mp = 240-243°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.65, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.12 min, czystość = 89%, Wydajność = 19%,
Związek nr 36
2-{6-[4-(2-pirydynylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.62 (t, J = 8.1 Hz, 2H, ArH), 8.24 (t, J = 7.6 Hz, 2H, ArH), 8.0Ϊ (s, 2H, ArH), 7.83 - 7.74 (m, 2H, ArH), 7.05 (d, J = 26.7 Hz, 2H, ArH), 4.57 (s, 2H, CONCH), 4.32 (s, 2H, CHPiperazyna), 4.25 - 4.15 (m, 2H, CHPiperazyna), 3.73 (s, 2H, CHPiperazyna), 3.18 (s, 2H, CHPiperazyna), 3.08 (s, 2H, NCHAlif), 2.00 (s, 4H, CHAlif, 1.79 (s, 4H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3061 (C-H Ar, Rozc), 2933; 2855 (C-H Alif, Rozc), 1692 (C=O, Rozc), 1658 (C=N, Rozc), 1587; 1513 (C=C Ar, Rozc), 1340 (C-N, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 443.22, czas retencji - Rt = 4.25 min, czystość 90%, Temperatura topnienia: mp = 176-179°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.54, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 3.73 min, czystość = 89%, Wydajność = 50%,
Związek nr 37
2-{6-[4-(2-nitrofenylo)piperazyn-1 -ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.63 (dd, J = 7.3, 0.9 Hz, 2H, ArH), 8.25 (dd, J = 8.3, 0.9 Hz, 2H, ArH), 7.87 (dd, J = 8.1, 1.5 Hz, 1H, ArH), 7.83 - 7.74 (m, 2H, ArH), 7.64 - 7.57 (m, 1H, ArH), 7.36 (dd, J = 8.2, 1.1 Hz, 1H, ArH), 7.28 - 7.24 (m, 1H,
PL 240 473 B1
ArH), 4.26 - 4.18 (m, 2H, CONCH), 3.89 (t, J = 11.3 Hz, 2H, CHPiperazyna), 3.60 (t, J = 9.5 Hz, 2H, CHpperazyna), 3.32 (d, J = 12.9 Hz, 2H, NCHant), 3.15 - 2.99 (m, 4H, CHPiperazyna), 2.01 (s, 2H, CHant), 1.83 - 1.76 (m, 2H, CHant), 1.52 (s, 4H, CHant), Spektroskopia w podczerwieni FT-IR: 3060 (C-H Ar, Rozc), 2934; 2856 (C-H Alif, Rozc), 1693 (C=O, Rozc), 1656; 1308 (NO2, Rozc), 1589; 1513, (C=C Ar, Rozc), 1361 (C-N Rozc), Temperatura topnienia: mp = 230-231°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.66, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 5.82 min, czystość = 96%, Wydajność = 19%,
Związek nr 38
2-{6-[4-(2-fluorofenylo)piperazyn-1 -ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.55 - 8.44 (m, 4H, ArH), 7.92 - 7.86 (m, 2H, ArH), 7.80 - 7.71 (m, 4H, ArH), 4.07 (dd, J = 16.2, 8.8 Hz, 2H, CONCH), 3.57 - 3.48 (m, 2H, CHPiperazyna), 3.44 (s, 8H, CHPiperazyna), 1.81 (dd, J = 14.4, 6.9 Hz, 2H, CHAiif), 1.65 (dt, J = 14.8, 7.4 Hz, 2H, CHant), 1.47 - 1.35 (m, 4H, CHant), Spektroskopia w podczerwieni FT-IR: 3002 (C-H Ar, Rozc), 2944; 2866 (C-H Alif, Rozc), 1698 (C=O, Rozc), 1587; 1500 (C=C Ar, Rozc), 1337 (C-N, Rozc), 1234 (C-F, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 460.23 czas retencji - Rt = 5.61 min, czystość = 97%, Temperatura topnienia: mp = 111-113°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.63, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 5.61 min, czystość = 97%, Wydajność = 43%,
Związek nr 39
2-{6-[4-(2-trifluorometylofenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.62 (dd, J = 7.3, 0.9 Hz, 2H, ArH), 8.24 (dd, J = 8.3, 0,9 Hz, 2H, ArH), 7.78 (dd, J = 8.1, 7.4 Hz, 2H, ArH), 7.66 (d, J = 7.7 Hz, 1H, ArH), 7.61 - 7.52 (m, 2H, ArH), 7.33 (t, J = 7.5 Hz, 1H, ArH), 4.24 - 4.17 (m, 2H, CONCH), 3.81 (t, J = 10.8 Hz, 2H, CHPiperazyna), 3.57 (t, J = 10.5 Hz, 2H, CHPiperazyna), 3.04 (dd, J = 12.9, 4.0 Hz, 4H, CHPiperazyna), 2.01 (s, 2H, NCHant), 1.78 (d, J = 9.6 Hz, 4H, CHant), 1.54 - 1.46 (m,4H,CHAiif). Spektroskopia w podczerwieni FT-IR: 3055(C-H Ar, Rozc), 2945; 2869 (C-H Alif, Rozc), 1696 (C=O, Rozc), 1590; 1493 (C=C Ar, Rozc), 1343 (C-N, Rozc), 1233 (C-F, Rozc), Temperatura topnienia: mp = 167-169°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.76, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 5.81 min, czystość = 98%, Wydajność = 52%,
Związek nr 40
2-{6-[4-(3-trifluorometylofenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.62 (t, J = 6.0 Hz, 2H, ArH), 8.24 (d, J = 8.2 Hz, 4H, ArH), 7.84 - 7.72 (m, 2H, ArH), 7,64 - 7.54 (m, 2H, ArH), 4.46 (t, J = 11.4 Hz, 2H, CONCH), 4.24 - 4.18 (m, 2H, CHplperazyna), 3.78 - 3.69 (m, 6H, CHPiperazyna), 3.16 (s, 2H, NCHant), 2.00 (s, 2H, CHant), 1.86 - 1.74 (m, 2H, CHant), 1.54 (s, 4H, CHant), Spektroskopia w podczerwieni FT-IR: 3064(C-H Ar, Rozc), 2936; 2865 (C-H Alif, Rozc), 1696 (C=O, Rozc), 1591; 1440 (C=C Ar, Rozc), 1348 (C-N, Rozc), 1239 (C-F, Rozc), Temperatura topnienia: mp = 112-116°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.84, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt= 6.22 min, czystość = 100%, Wydajność = 29%,
Związek nr 41
2-{6-[4-(4-bromofenylo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.66 - 8.59 (m, 2H, ArH), 8.25 (dd, J = 8.0, 3.0 Hz, 2H, ArH), 7.83 - 7.76 (m, 2H, ArH), 7.56 (d, J = 7.7 Hz,
PL 240 473 B1
2H, ArH), 7.37 (s, 2H, ArH), 4.35 (s, 2H, CONCH), 4.25 - 4.17 (m, 2H, , CHPiperazyna), 3.68 (s, 4H, CHpiperazyna), 3.12 (s, 2H, CHPiperazyna), 2.00 (s, 2H, NCHAlf), 1.79 (d, J = 7.3 Hz, 4H, CHAlif), 1.54 (s, 4H, CHAlif). Spektroskopia w podczerwieni FT-IR: 2983 (C-H Ar, Rozc), 2939; 2870 (C-H Alif, Rozc), 1696 (C=O, Rozc), 1592; 1437 (C=C, Rozc), 1377 (C-N, Rozc), 746 (C-Br, Rozc), Temperatura topnienia: mp = 188-189°C,
Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.71,
Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 7.22 min, czystość = 99%, Wydajność = 12%,
Związek nr 42
2-{6-[4-(1,2-benzizotiazol-3-ilo)piperazyn-1-ylo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.50 (dd, J = 14.4, 7.6 Hz, 4H, ArH), 8.16 - 8.08 (m, 2H, ArH), 7.88 (d, J = 7.7 Hz, 2H, ArH), 7.60 (t, J = 7.6 Hz, 1H, ArH), 7.47 (t, J = 7.4 Hz, 1H, ArH), 3.64 (d, J = 19.2 Hz, 2H, CONCH), 3.59 (d, J = 12.1 Hz, 2H, CHPiperazyna), 3.47 (t, J = 12.3 Hz, 2H, CHPiperazyna), 3.37 - 3.20 (m, 4H, CHPiperazyna), 3.16 (s, 2H, NCHAlif), 1.73 (d,J= 19.2 Hz, 2H, CHAlif), 1.69 (s, 2H, CHAlif), 1.41 (s, 4H, CHAlif).
Spektroskopia w podczerwieni FT-IR: 3062 (C-H Ar, Rozc), 2942, 2874 (C-H, Alif, Rozc), 1693 (C=O, Rozc), 1656 (C=N, Rozc), 1589,1493 (C=C Ar, Rozc), 1354 (C-N, Rozc), 697 (S-N, Rozc), Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.47,
Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 5.83 min, czystość = 100%, Wydajność = 47%,
Związek nr 43
2-{6-[4-{[1-okso-2,3-dihydro-1H-izoindol-2-ilo]heksylo}-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.55 - 8.43 (m, 4H, ArH), 7.87 (dt, J = 14.4, 7.2 Hz, 2H, ArH),6 7.75 - 7.43 (m, 3H, ArH) 4.09 - 4.01 (m, 2H, CONCH), 3.53 (t, J = 6.7 Hz, 2H, CONCH), 3.37 (s, 10H, CHPiperazyna), 1.85 - 1.76 (m, 2H, CHAlif), 1.65 (dt, J = 14.7, 7.4 Hz, 2H, CHAlif), 1.45 - 1.32 (m, 4H, CHAlif).
Spektroskopia w podczerwieni FT-IR: 3058 (C-H Ar, Rozc), 2934; 2854 (C-H Alif, Rozc), 1693 (C=O, Rozc), 1590; 1436 (C=C Ar, Rozc), 1341 (C-N, Rozc), 1246; 1066 (C-O, Rozc), Temperatura topnienia: mp = 111-112°C,
Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.63,
Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 4,38 min, czystość = 91%, Wydajność = 12%,
Związek nr 44
2-[6-(4-{[1,1'-bifenylo]-2-ylo}piperazyn-1-ylo)heksylo]-1H-benzo[de]izochinolino-1,3(2H)-dion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.49 (ddd, J = 9.2, 7.8, 0.9 Hz, 6H, ArH), δ 7.76 (d, J = 7.2 Hz, 2H, ArH), 7.52 (d, J = 7.2 Hz, 2H, ArH), 7.42 (t, J = 7.5 Hz, 2H, ArH), 7.88 (dd, J = 8.1, 7.4 Hz, 3H, ArH), 4.10 - 4.01 (m, 2H, CONCH), 3.59 - 3.48 (m, 2H, CHPiperazyna), 3.36 - 3.01 (s, 8H, CHPiperazyna), 1.87 - 1.76 (m, 2H, CHAlif), 1.65 (dt, J = 14.7, 7.4 Hz, 2H, CHAlif), 1.49 - 1.34 (m, 4H, CHAlif).
Spektroskopia w podczerwieni FT-IR: 3023 (C-H Ar, Rozc), 2942, 2874 (C-H, Alif, Rozc), 1693 (C=O, Rozc), 1590,1436 (C=C Ar, Rozc), 1345 (C-N, Rozc),
Temperatura topnienia: mp = 118-122°C,
Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.72,
Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 6.50 min, czystość = 100%, Wydajność = 19%,
Związki opisane numerami 45-47 otrzymano zgodnie z procedurą opisaną w przykładach 19-20, stosując w syntezie półprodukty otrzymane w przykładach 7-8.
P R Z Y K Ł A D 19
Otrzymywanie 1-{6-[4-(arylo)piperazyn-1-ylo]heksylo}-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin2(1H)-onów
PL 240 473 B1
W moździerzu utarto 0,001 mola 1-(6-bromoheksylo)-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin2(1H)-onu, 0,00095 mola arylopiperazyny opisanej wzorem (V) dobranej odpowiednio do syntezowanego związku, 0,003 mola NaOH oraz 0,0001 mola TBAB. Roztartą mieszaniną przeniesiono do kolby okrągłodennej i do mieszaniny reakcyjnej dodano 1 cm3 ACN. Reakcje prowadzono przez 30 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 130 W. Postęp reakcji monitorowano za pomocą TLC. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i umieszczono w lodówce (temp. 4°C) na 12 godzin. Po ochłodzeniu surowy produkt odsączono. Surowy produkt krystalizowano z metanolu. Ligand rozpuszczono w acetonie, następnie przekształcono w chlorowodorki z 4 M HCI w dioksanie.
P R Z Y K Ł A D 20
Otrzymywanie 1-(6-[4-(arylo)piperazyn-1-ylo]heksylo}-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin2(1H)-onów
W moździerzu roztarto 0,001 mola 1-(6-bromoheksylo)-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin2(1H)-onu, 0,00095 mola arylopiperazyny opisanej wzorem (V) dobranej odpowiednio do syntezowanego związku, 0,003 mola K2CO3 oraz 0,0001 mola TEAC. Roztartą mieszaninę przeniesiono do kolby okrągłodennej. Reakcje prowadzono przez 50 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 100 W. Postęp reakcji monitorowano za pomocą TLC. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i umieszczono w lodówce (temp. 4°C) na 12 godzin. Po ochłodzeniu surowy produkt odsączono. Surowy produkt krystalizowano z metanolu. Ligand rozpuszczono w acetonie, następnie przekształcono w chlorowodorki z 4 M HCI w dioksanie.
Związek nr 45
1-{6-[4-(2-metoksyfenylo)piperazyn-1-ylo]heksylo}-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, CDCI3) δ 8.27 (d, J = 7.6 Hz, 1H, ArH), 7.49 (t, J = 7.9 Hz, 1H, ArH), 7.08 (dd, J = 8.0, 3.2 Hz, 2H, ArH), 6.99 (t, J = 7.7 Hz, 1H, ArH), 6.84 (dd, J = 12.1, 7.7 Hz, 2H, ArH), 5.18 (t, J = 11.4 Hz, 3H, OCH), 4.45 (d, J = 12.6 Hz, 2H, CONCH), 4.08 (d, J = 7.8 Hz, 4H, CHPiperazyna), 3.88 (t, J = 5.6 Hz, 4H, CHPiperazyna), 3.59 (d, J = 11.2 Hz, 2H, NCHAlif), 3.10 (s, 2H, NCHAlif), 2.87 (t, J = 6.0 Hz, 2H, CHant), 2.14 (dd, J = 11.8, 6.1 Hz, 2H, CHAlif), 1.93 (s, 2H, CHAlif), 1.84 - 1.74 (m, 2H, CHat), 1.45 (s, 4H, CHat), Spektroskopia w podczerwieni FT-IR: 3017 (C-H Ar, Rozc), 2939; 2860 (C-H Alif, Rozc), 1676 (C=O Rozc), 1609; 1499 (C=C Ar, Rozc), 1369 (C-N, Rozc), 1264; 1016 (C-O, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 449.33, czas retencji - Rt = 5.03 min, czystość 91%, Temperatura topnienia: mp = 115-117°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.85, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 4.16 min, czystość = 91%, Wydajność = 84%,
Związek nr 46
1-{6-[4-(3-chlorofenylo)piperazyn-1-ylo]heksylo}-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (300 MHz, cdcl3) δ 7.54 (s, 1H, ArH), 7.39 (d, J = 7.9 Hz, 2H, ArH), 7.25 (s, 1H, ArH),‘ 6.99 (t, J = 7.7 Hz, 1H, ArH), 6.84 (dd, J = 12.5, 7.6 Hz, 2H, ArH), 4.37 (s, 2H, CONCH), 3.86 (dt, J = 14.2, 6.9 Hz, 4H, CHPiperazyna), 3.65 (d, J = 11.8 Hz, 6H, CHPiperazyna), 3.10 (s, 2H, NCHAlif), 2,86 (t, J = 5.7 Hz, 2H, CHAlif), 2.20 - 2.08 (m, 2H, CHAlif), 1.93 (s, 2H, CHAlif), 1.85 - 1.71 (m, 2H, CHAlif), 1.46 (s, 4H, CHAlif). Spektroskopia w podczerwieni FT-IR: 3060 (C-H Ar, Rozc), 2937; 2861 (C-H Alif, Rozc), 1700 (C=O Rozc), 1594; 1498 (C=C Ar, Rozc), 1374 (C-N, Rozc), 763 (C-CI, Rozc), Temperatura topnienia: mp = 165-168°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.66, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt= 4.98 min, czystość = 91%, Wydajność = 53%,
PL 240 473 B1
Związek nr 47
1-{6-[4-(1,2-benzizotiazol-3-ilo)piperazyn-1-ylo]heksylo}-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin-2(1H)-on
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 8.12 (t, J = 8.6 Hz, 2H, ArH), 7.60 (t, J = 7.6 Hz, 1H, ArH), 7.48 (t, J = 7.2 Hz, 1H, ArH), 7.00 (d, J = 7.6 Hz, 1H, ArH), 6.93 (dd, J = 9.5, 5.8 Hz, 1H, ArH), 6.83 (d, J = 7.4 Hz, 1H, ArH), 4.05 (d, J = 13.7 Hz, 2H, CONCH), 3.78 (dt, J = 11.4, 6.4 Hz, 4H, CHpiperazyna), 3.58 — 3.44 (m, 4H, CHpiperazyna), 3.31 - 3.21 (m, 2H, NCHAlif), 3.11 (dt, J = 10.5, 5.1 Hz, 2H, NCHa»), 2.79 (t, J = 5.8 Hz, 2H, CHAiif), 2.02 (dd, J = 11.4, 5.8 Hz, 2H, CHAlif), 1.69 (dd, J = 13.7, 6.9 Hz, 4H, CHat), 1.35 (d, J = 3.6 Hz, 4H, CHat). Spektroskopia w podczerwieni FT-IR: 3067 (C-H Ar, Rozc), 2935; 2859 (C-H Alif, Rozc), 1672 (C=O Rozc), 1642 (C=N, Rozc), 1589; 1498 (C=C Ar, Rozc), 1379 (C-N, Rozc), 677 (S-N, Rozc), 656 (C-S, Rozc), Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.80, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt= 4.54 min, czystość = 89%, Wydajność = 67%,
Związek opisany numerem 48 otrzymano zgodnie z procedurą opisaną w przykładach 21-22, stosując w syntezie półprodukty otrzymane w przykładach 9-10.
P R Z Y K Ł A D 21
Otrzymywanie 1-(6-[4-(arylo)piperazyn-1-ylo]heksylo}-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin2(1H)-tionu
W moździerzu utarto 0,001 mola 1-(6-bromoheksylo)-5,6-dihydro-4H-imidazo[4,5,1-ij]chinotin2(1H)-tionu, 0,00095 mola arylopiperazyny opisanej wzorem (V) dobranej odpowiednio do syntezowanego związku, 0,003 mola NaOH oraz 0,0001 mola TEAC. Roztartą mieszaninę przeniesiono do kolby okrągłodennej i do mieszaniny reakcyjnej dodano 5 cm3 wody. Reakcje prowadzono przez 50 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 80 W. Postęp reakcji monitorowano za pomocą TLC. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i umieszczono w lodówce (temp. 4°C) na 12 godzin. Po ochłodzeniu produkt odsączono. Surowy produkt krystalizowano z metanolu. Ligand rozpuszczono w acetonie, następnie przekształcono w chlorowodorki z 4 M HCI w dioksanie.
P R Z Y K Ł A D 22
Otrzymywanie 1-{6-[4-(arylo)piperazyn-1-ylo]heksylo}-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin2(1H)-tionu
W moździerzu utarto 0,001 mola 1-(6-bromoheksylo)-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin2(1H)-tionu, 0,00095 mola arylopiperazyny opisanej wzorem (V) dobranej odpowiednio do syntezowanego związku, 0,003 mola K2CO3 oraz 0,0001 mola TBAB. Roztartą mieszaninę przeniesiono do kolby okrągłodennej. Reakcje prowadzono przez 15 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 180 W. Postęp reakcji monitorowano za pomocą TLC. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i umieszczono w lodówce (temp. 4°C) na 12 godzin. Po ochłodzeniu produkt odsączono. Surowy produkt krystalizowano z metanolu. Ligand rozpuszczono w acetonie, następnie przekształcono w chlorowodorki z 4 M HCI w dioksanie.
Związek nr 48
1-{6-[4-(3-chlorofenylo)piperazyn-1-ylo]heksylo}-5,6-dihydro-4H-imidazo[4,5,1-ij]chinolin-2(1H)-tion
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 7.48 (d, J = 8.2 Hz, 1H, ArH), 7.33 - 7.24 (m, 2H, ArH), 7.17 (d, J = 6.6 Hz, 1H, ArH), 7.06 (t, J = 2.1 Hz, 1H, ArH), 6.97 (dd, J = 8.4, 2.0 Hz, 1H, ArH), 6.88 (dd, J = 7.8, 1.4 Hz, 1H, ArH), 4.22 - 4.13 (m, 2H), 3.87 (d, J = 12.6 Hz, 2H, CHpiperazyna), 3.23 - 2.99 (m, 8H, CHpiperazyna), 2.96 (t, J = 5.9 Hz, 2H, CHAlif), 2.23 - 2.17 (m, 2H, CHaj»), 1.81 - 1.69 (m, 6H, CHAlif), 1.48 (dt, J = 14.3, 7.2 Hz, 2H, CHAiif), 1.39 - 1.30 (m, 2H, CHAlif), Spektroskopia w podczerwieni FT-IR: 3057 (C-H Ar, Rozc), 2937; 2861 (C-H Alif, Rozc), 1590; 1491 (C=C Ar, Rozc), 1386(C-N, Rozc), 767 (C-CI, Rozc) 654 (C-S, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 469.27, czas retencji - Rt = 4.43 min, czystość 93%, Temperatura topnienia: mp = 112-113°C, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.78,
PL 240 473 B1
Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt = 4.46 min, czystość = 93%, Wydajność = 43%,
Związek opisany numerem 49 otrzymano zgodnie z procedurą opisaną w przykładach 23 i 24, stosując w syntezie półprodukty otrzymane w przykładach 11 i 12.
P R Z Y K Ł A D 23
Otrzymywanie 1-{6-[4-(arylo)piperazyn-1-ylo]heksylo}-1H,4H-[1,2,5]tiadiazolo[4,3,2-ij]chinoliny2,2-ditlenku
W moździerzu roztarto 0,001 mola 2,2-ditlenku 1-(6-bromoheksylo)-1H,4H-[1,2,5]tiadiazolo[4,3,2-ij]chinoliny, 0,00095 mola arylopiperazyny opisanej wzorem (V) dobranej odpowiednio do syntezowanego związku, 0,003 mola NaOH oraz 0,0001 mola TBAB. Roztartą mieszaninę przeniesiono do kolby okrągłodennej i do mieszaniny reakcyjnej dodano 2 cm3 ACN. Reakcje prowadzono przez 45 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 100 W. Postęp reakcji monitorowano za pomocą TLC. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i umieszczono w lodówce (temp. 4°C) na 12 godzin. Po ochłodzeniu surowy produkt odsączono. Surowy produkt krystalizowano z metanolu. Ligand rozpuszczono w acetonie, następnie przekształcono w chlorowodorki z 4 M HCI w dioksanie.
P R Z Y K Ł A D 24
Otrzymywanie 1-{6-[4-(arylo)piperazyn-1-ylo]heksylo}-1H,4H-[1,2,5]tiadiazolo[4,3,2-ij]chinoliny2,2-ditlenku
W moździerzu utarto 0,001 mola 2,2-ditlenku 1-(6-bromoheksylo)-1H,4H-[1,2,5]tiadiazolo[4,3,2ij]chinoliny, 0,00095 mola arylopiperazyny opisanej wzorem (V) dobranej odpowiednio do syntezowanego związku, 0,003 mola NaOH oraz 0,0001 mola DABCO. Roztartą mieszaninę przeniesiono do kolby okrągłodennej. Reakcje prowadzono przez 60 sekund w reaktorze mikrofalowym przy mocy wyjściowej mikrofal 60 W. Postęp reakcji monitorowano za pomocą TLC. Po zakończeniu reakcji do mieszaniny dodano 40 cm3 wody i umieszczono w lodówce (temp. 4°C) na 12 godzin. Po ochłodzeniu surowy produkt odsączono. Surowy produkt krystalizowano z metanolu. Ligand rozpuszczono w acetonie, następnie przekształcono w chlorowodorki z 4 M HCI w dioksanie.
Związek nr 49
1-{6-[4-(3-chlorofenylo)piperazyn-1-ylo]heksylo}-1H,4H-[1,2,5] tiadiazolo[4,3,2-ij]chinolino-2,2-ditlenek
Widmo wodorowe magnetycznego rezonansu jądrowego 1H NMR (400 MHz, DMSO) δ 7.42 - 7.21 (m, 3H, ArH), 6 7.11 - 6.90 (m, 2H, ArH), 7.17 (d, J = 6.6 Hz, 1H, ArH), δ 6.81 - 6.78 (m, 1H, ArH), 4.22 - 4.13 (m, 2H, S(O)2N-CH), 3.87 (d, J = 12.6 Hz, 2H, CHPiperazyna), 3.21 — 2.95 (m, 8H, CHPiperazyna), 2.96 - 2.85 (m, 2H, CHai»), 2.13 - 2.10 (m, 2H, CHAlif), 1.80 - 1.62 (m, 6H, CHAlif), 1.48 - 1.43 (m, 2H, CHAiif), 1.39 - 1.30 (m, 2H, CHAiif), Spektroskopia w podczerwieni FT-1R : 3051 (C-H Ar, Rozc), 2943; 2844 (C-H Alif, Rozc), 1575; 1499 (C=C Ar, Rozc), 1367 (C-N, Rozc), 771 (C-CI, Rozc), Wysokosprawna chromatografia cieczowa połączona ze spektrometrem mas UPLC-MS: m/z = 489.28, czas retencji - Rt = 5.19 min, czystość 94%, Temperatura topnienia: mp = olej, Chromatografia cienkowarstwowa TLC: współczynnik retencji R/ = 0.65, Wysokosprawna chromatografia cieczowa HPLC: czas retencji Rt= 6.05 min, czystość = 99%, Wydajność = 32%,
Powinowactwo zsyntezowanych związków, o wskazanych wyżej numerach 1 do 49 oraz opisanych wzorem ogólnym (I), do wybranych receptorów serotoninowych i dopaminowych zbadano zgodnie ze standardową procedurą oceny aktywności do receptorów D2, 5-HT1A, 5-HT2A, 5-HTs, 5-HT? (Y. Cheng, W. Prusoff, „Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (150) of an enzymatic reaction”, Biochem. Pharmacol., 1973), (M. Kołaczkowski, M. Marcinkowska, i inni, „Novel Arylsulfonamide Derivatives with 5-HTs/5-HT7 Receptor Antagonism Targeting Behavioral and Psychological Symptoms of Dementia”, Journal of Medicinal Chemistry 2014), co opisano poniżej w przykładach 25 oraz 26 i przedstawiono w tabeli zawierającej ich profil farmakologiczny.
PL 240 473 B1
P R Z Y K Ł A D 25
Hodowla komórkowa oraz wytwarzanie błon komórkowych do testów in-vitro
Komórki HEK293 o stabilnej ekspresji ludzkich receptorów serotoninowych oraz dopaminowych (5-HTia, 5-HT6, 5-HT/b, D2l) przygotowano z użyciem Lipofectamine 2000 lub CHO-K1 z plazmidem zawierającym sekwencję kodującą ludzką serotoninę. Receptor 5-HT2a (utrzymywany w 37°C w wilgotnej atmosferze, 5% CO2, hodowany na podłożu Eagle Dulbecco, 10% dializowana płodowa surowica bydlęca i 500 μg / ml siarczanu G418). Preparat błonowy - komórki hodowano w kolbach o pojemności 150 cm2 i hodowano do konfluencji 90%, przemywano dwukrotnie solą fizjologiczną buforowaną fosforanem (PBS) w 37°C i osadzano przez odwirowanie (200 g) w PBS zawierającym 0,1 mM EDTA i 1 mM ditiotreitol. Przed przygotowaniem membrany peletki przechowywano w temperaturze -80°C.
P R Z Y K Ł A D 26
Testy wiązania radioliganda
Rozmrożone i homogenizowane (20 objętości buforu testowego, homogenizator tkanek Ultra Turrax) wirowano dwukrotnie (35 G przez 20 min w 4°C, z inkubacją przez 15 minut w 37°C pomiędzy rundami wirowania). Skład buforów testowych: 5-HTia: 50 mM Tris-HCl, 0,1 mM EDTA, 4 mM MgCb, 10 μM pargiliny, 0,1% askorbinianu, 5-HT2a: 50 mM Tris-HCl, 0,1 mM EDTA, 4 mM MgCb 0,1% askorbinianu; 5-HTs: 50 mM Tris-HCl, 0,5 mM EDTA i 4 mM MgCb; 5-HT7: 50 mM Tris-HCl, 4 mM MgCb, 10 μM pargiliny, 0,1% askorbinianu; D2: 50 mM Tris HCl, 1 mM EDTA, 4 mM MgCb,120 mM NaCl, 5 mM KCI, 1,5 mM CaCI2, 0,1% askorbinianu. Wszystkie testy inkubowano w całkowitej objętości 200 μl na 96-studzienkowych płytkach do mikromiareczkowania przez 1 godz. w 37°C, z wyjątkiem 5-HTia i 5-HT2a, które inkubowano w temperaturze pokojowej. Stan równowagi utrwalono przez filtrację (płytki Unifilter z 96-dołkowym aparatem do zbierania komórek (PerkinElmer)). Zawartość radioligandów zatrzymanych na filtrach oznaczono ilościowo na czytniku płytek Microbeta (PerkinElmer). W przypadku badań wypierania, próbki do testu zawierały jako radioligandy: 2,5 nM [3H]-8-OHDPAT (187 Ci / mmol) - 5-HTia, 1 nM [3H]-Ketanserin (53,4 Ci / mmol) - 5-HT2A , 2 nM [3H]-LSD (85,2 Ci / mmol - 5-HT6, 0,8 nM [3H]5-CT (39,2 Ci / mmol) - 5-HT7 lub 2,5 nM (3H)-raclopride (76,0 Ci / mmol ) - D2. Nieswoiste wiązanie zdefiniowano za pomocą 10 μM 5-HT w próbach wiązania 5-HTia i 5-HT7, podczas gdy 10 μM chlorpromazyny lub 10 μM metiothepiny zastosowano w testach 5-HT2A / D2 i 5-HT6. Odpowiednio każdy związek badano w trzech powtórzeniach w 7 do 8 różnych stężeniach (10^-10-11 M.) Stałe wypierania (Ki) obliczono z równania Chenga-Prusoffa (Y. Cheng, W. Prusoff „Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (150) of an enzymatic reaction”, Biochem. Pharmacol., 1973).
PL 240 473 BI
Tabela. Profil farmakologiczny nowych pochodnych arylopiperazyny
Nr związku d2 5HT1A 5-HTm 5-HT6 5-HT, 1 58 66 540 1681 336 2 75 43 429 480 53 3 197 181 423 689 124 4 246 161 493 1860 166 5 94 122 406 918 5095 6 204 688 1490 3187 1833 7 320 64 524 1726 420 8 161 599 1766 1128 17780 9 496 54 773 2214 291 10 945 536 4354 2045 48960 11 114 47 652 1699 366 12 180 291 1927 3666 3743 13 11 22 717 1916 84 14 867 32 892 1461 184 15 188 94 43 5253 475 16 431 9473 3983 952 696 17 82 22 222 999 119 18 56 71 55 568 36 19 2852 681 1913 1558 595 20 142 106 548 507 286 21 121 46 322 624 432 22 336 197 147 433 280 23 220 149 177 237 140 24 254 79 251 225 404 25 304 132 596 374 167 26 927 989 1526 937 5996 27 90 81 376 710 203 28 30 48 578 476 34 29 118 35 443 182 344 30 264 482 533 494 822 31 18 63 32 158 105 32 10 20 337 671 266 33 271 47 334 347 371 34 40040 35690 60100 5765 116S00 35 27 28 461 246 73 36 1302 172 563 1965 1200 37 141 373 1918 1410 710 38 393 98 812 1142 605 39 344 1674 4784 3253 3750 40 319 187 629 392 405 41 1620 20330 5477 8757 2033 42 59 86 53 110 118 43 108 219 538 1075 509 44 337 251 1903 1672 47 45 2 19 456 3270 291 46 18 74 66 1139 61 47 1 44 12 379 16 48 85 206 258 582 171 49 253 70 282 1694 162PL 240 473 B1
Description of the invention
The subject of the invention is a group of new arylpiperazine derivatives, including: N-6- (4-arylpiperazin-1-yl) hexyl cyclic derivatives of 1,8-naphthylimides, N-6- (4-aryl piperazin-1-yl) hexyl cyclic derivatives 1 , 8-naphthylamides, N-6- (4-arylpiperazin-1-yl) hexyl derivatives of cyclic 1,8-naphthylsulfonamides, N-6- (4-arylpiperazin-1-yl) hexyl derivatives of cyclic tetrahydroquinoline amides, N- 6- (4-arylpiperazin-1-yl) hexyl derivatives of cyclic tetrahydroquinoline sulfonamides.
The invention also relates to a process for the preparation of the above-mentioned novel arylpiperazine derivatives.
These new compounds, ligands for serotonin and dopamine receptors, could find application in the treatment of central nervous system (CNS) disorders in humans. They bind to selected serotonin receptors (5-HTia, 5-HT2A, 5-Ht6, 5-Ht7) and dopamine (D2) receptors, key in the treatment of central nervous system disorders such as depression, bipolar disorder, schizophrenia, anxiety disorders or sleep disturbance. In order to obtain their pharmaceutically acceptable form, the new compounds can be converted in a known manner into salts of hydrochloric acid which show good solubility in water, methanol and ethanol.
The invention describes the biological activity of the new compounds, their physicochemical properties and the method of their preparation.
In the search for new drugs acting on diseases of the central nervous system, such as depression, bipolar disorder, schizophrenia, anxiety disorders or sleep disorders, the classic receptor targets include: 5-HT1a serotonin receptors [J. Savitz, I. Lucki, WC Drevets, "5-HT (1A) receptor function in major depressive disorder", Prog Neurobiol. 2009, 88 (1), 17-31], and 5-HT2a [A. Wesołowska, Pharmacol Rep., "Potential role of the 5-HT6 receptor in depression and anxiety: an overview of preclinical data", 2010, 62 (4), 564-77], as well as dopamine D2 receptors [A. Etievant, C. Betry, N. Haddjeri, "Partial Dopamine D2 / Serotonin 5-HTia Receptor Agonists as New Therapeutic Agents", The Open Neuropsychopharmacology Journal 2010, 3, 1-12].
Newer receptor targets include, but are not limited to, 5-HT6 receptors [M. Kołaczkowski, M. Marcinkowska, A. Bucki, M. Pawłowski, K. Mitka, J. Jaskowska, P. Kowalski and others, "Novel Arylsulfonamide Derivatives with 5-HT6 / 5-HT7 Receptor Antagonism Targeting Behavioral and Psychological Symptoms of Dementia" , Journal of Medicinal Chemistry 2014, 57 (11), 4543-4557] and 5-HT7 [LN Cates, AJ Roberts, S. Huitron-Resendiz, PB Hedlund, "Effects of lurasidone in behavioral models of depression. Role of the 5-HT7 receptor subtype ”. Neuropharmacology, 2013, 70, 211-217].
In recent years, the effectiveness of drugs acting simultaneously on several receptor targets, hereinafter referred to as multifunctional ligands, has been shown to be effective. An example of multifunctional ligands are the dual ligands of 5-HTia / D2 receptors in the treatment of depression [A. Etievant, C. Betry, N. Haddjeri, "Partial Dopamine D2 / Serotonin 5-HTia Receptor Agonists as New Therapeutic Agents", The Open Neuropsychopharmacology Journal 2010, 3, 1-12].
A group widely used in the treatment of diseases of the central nervous system is the long-chain arylpiperazines. Compounds belonging to long-chain arylpiperazines have been used in medicine for many years, but the interest in them is still not waning. In recent years, new ligands derived from the group of long-chain arylpiperazines (vilazodone, lurasidone, brecspiprazole, cariprazine) have been approved for use in the treatment of CNS diseases [TJ Kreys, "The future of psychotropics: Did santa forget about mental illness?", MentalHealth Clinician 2012, 2 (6), 135-137] and [JS Frankel, TL Schwartz, "Brexpiprazole and cariprazine: distinguishing two new atypical antipsychotics from the original dopamine stabilizer aripiprazole", Ther Adv Psychopharmacol. 2017, 7 (1), 29-41]).
Long-chain aryl piperazines are also known, among which ligands containing a 1,8-naphthylamide or sulfonamide fragment in their structure [A. Lepailleur, R. Bureau, M. Paillet-Loilier, F. Fabis, N. Saettel, S. Lemaitre, F. Dauphin, A. Lesnard, JC Lancelot, S. Rault, "Molecular Modeling Studies Focused on 5-HT7 versus 5 -HTia Selectivity. Discovery of Novel Phenylpyrrole Derivatives with High Affinity for 5-HT7 Receptors ", J. Med. Chem. 2005, 45, 1075], or imide [P. Kowalski, T. Kowalska, AJ Bojarski, B. Duszyńska, "Synthesis and biological properties of 1,8-naphthalimidebutylamines. Serotonin 5-HTia and 5-HT7 binding data and pass-assisted search ”, Journal of Heterocyclic Chem. 2007, 44 (4), 889-93]. Some compounds belonging to the above have been described in the literature
Of said group as likely to have affinity for 5-HT receptors? and 5-HTia. However, few ligands are disclosed in the group of compounds published in the above literature. Moreover, these ligands do not have a fully characterized affinity profile for the aforementioned 5-HTia '5-HT2A, 5-HTs, 5-HT®, D2 receptors).
No arylpiperazine derivatives containing a tetrahydroquinoline fragment in place of naphthalene have been disclosed in the scientific and patent literature so far, which have been shown in the present invention to have a much more favorable pharmacological profile in the context of the treatment of CNS diseases.
Some publications describe an increase in the affinity of long-chain aryl piperazines for selected serotonin receptors with an increase in the length of the alkyl chain [E. Lacivita, M. Leopoldo, AC Masotti, C. Inglese, F. Berardi, R. Perrone, S. Ganguly, M. Jafurulla, A .B. Chattopadhyay, "Synthesis and Characterization of Environment-Sensitive Fluorescent Ligands for Human 5-HTia Receptors with 1-Arylpiperazine Structure", J. Med. Chem. 2009, 52 (23), 7892-6]. Therefore, it is reasonable to search for new alkyl chain-extended ligands with respect to the previously disclosed compounds.
So far, 11 compounds belonging to N-6- (4-arylpiperazin-1-yl) hexyl cyclic derivatives of 1,8-naphthyl / tetrahydroquinoline imides / amides / sulfonamides have been described in the literature, which belong to compounds with a structure similar to the compounds of the group consisting of the present invention includes: 1- {6- [4- (2-methoxyphenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one, {6- [4- ( phenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one, {6- [4- (2-methoxyphenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1, 8-cd] [1,2] thiazole-1,1 (2H) -dione, 2- {6- [4- (phenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd ] [1,2] thiazole-1,1 (2H) -dione [ML Lopez-Rodriguez, E. Porras, M. Morcillo, et al., "Optimization of the pharmacophore model for 5-HT7R antagonism. Design and synthesis of new naphtholactam and naphthosultam derivatives ”, Journal of Medicinal Chemistry 2003, 46 (26), 5638-5650].
2- {6- [4- (4-chlorophenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione, 2- {6- [4- (3- chlorophenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione, 2- {6- [4- (2-chlorophenyl) piperazin-1-yl] hexyl} - 1H-benzo [de] isoquinoline-1,3 (2H) -dione, 2- {6- [4- (2-methylphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione, 2- {6- [4- (phenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
[SA Andronati, TA Voronina, TL Karaseva et al., "Affinity of 1-aryl-4 - [(naphthalimido) alkyl] piperazines to 5-HT1A receptors and influence on anxiety of rats in the conflict situation test", Dopovidi Natsional'noi Academy of Sciences of Ukraine 2004, (4), 169-174].
The above-cited publications describe a long and cumbersome method of synthesizing compounds belonging to the aforementioned group, involving two two-step synthetic pathways [M. Leopoldo, E. Lacivita, F. Berardi, R. Perrone, PB Hedlund, "Serotonin 5-HT? receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders ”, Pharmacol Ther. 2011, 129 (2), 120-148, C. Kikuchi, T. Ando, T. Watanabe, H. Nagaso, M. Okuno, T. Hiranuma, M. Koyama, "2a- [4- (Tetrahydropyridoindol-2- yl) butyl] tetrahydrobenzindole Derivatives: New Selective Antagonists of the 5-Hydroxytryptamine? Receptor ”, J. Med. Chem. 2002, 45, 2197-2206, C. Kikuchi, H. Nagaso, T. Hiranuma, M. Koyama, "Tetrahydrobenzindoles: Selective Antagonists of the 5-HT? Receptor ”, J. Med. Chem. 1999, 42, 533-535]. The first is the N-alkylation of arylpiperazine with dibromoalkanes followed by condensation of the product with 1,8-naphtholactam / sultam. The second route involves the N-alkylation of 1,8-naphtholactam / sultam followed by condensation with the selected aryl piperazine. Reactions were carried out under an inert gas atmosphere in the presence of NaH with the use of large amounts of toxic solvents such as acetonitrile or dimethylformamide (DMF). The reaction time was 2-72 hours.
These compounds do not fall within the scope of the present invention.
Taking into account the new trends in organic synthesis and the principles of care for the environment, it is justified to search for new, biologically active compounds useful in the treatment of CNS diseases and methods of synthesizing these compounds, limiting the amounts of toxic reagents and solvents used.
The aim of this invention is to provide new compounds, arylpiperazine derivatives, ligands for serotonin and dopamine receptors, which constitute a group of new N-6- (4-arylpipe)
PL 240 473 BI razin-1-yl) hexyl cyclic derivatives of 1,8-naphthylimides / amides / sulfonamides and N -6- (4-arylpiperazin-1-yl) hexyl cyclic tetrahydroquinoline amides / sulfonamides, useful in the treatment of diseases central nervous system.
The second object of the invention is to develop such a method for the production of this type of compounds, in which the amount of harmful solvents is significantly reduced or even eliminated, which was achieved thanks to the use of synthesis in the presence of a microwave radiation field.
The present invention relates to a group of novel compounds belonging to the group of long-chain arylpiperazines having the structure represented by the general formula (I).
N- (CH2 ) n -N NO
Ź V / (i) where:
X is C, N,
Z stands for CO, SO2, CS,
Y is a CO group with the exception of tetrahydroquinoline derivatives, or the absence of this substituent (no atom, no functional group), means a single or double bond, n = 6,
R represents an aryl group of the general formula (Ia) or (IB):
(IA) (IB) where for R of formula (IA):
R1 is H, Cl, F, CF3, OC2H5, NO2, CsHs, OCH3,
R2 is H, Cl, CF3, OCH3, CeHs, where in cyclic compounds R1 = R2 and are C3H3N, OCONH, OCH2CONH,
R3 is H, Cl, Br, CF3, OCH3, E, F is N or C.
The invention includes the following compounds represented by general formula (I):
- Compounds belonging to the subgroup W-6- (4-arylpiperazin-1-yl) hexyl cyclic derivatives of 1,8-naphthylamides:
1) 1- {6- [4- (2-chlorophenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
2) 1- {6- [4- (3-chlorophenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
3) 1- {6- [4- (4-chlorophenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
4) 1- {6- [4- (3,4-dichlorophenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
5) 1- {6- [4- (2,3-dichlorophenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
6) 1- {6- [4- (4-bromophenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
7) 1- {6- [4- (2-fluorophenyl) piperazin-1-yl] hexyl} -benzo [cd] indol-2 (1H) -one,
8) 1- {6- [4- (2-trifluoromethylphenyl) piperazin-1-yl] hexyl} -benzo [cd] indol-2 (1H) -one,
9) 1- {6- [4- (3-trifluoromethylphenyl) piperazin-1-yl] hexyl} -benzo [cd] indol-2 (1H) -one,
10) 1- {6- [4- (4-trifluoromethylphenyl) piperazin-1-yl] hexyl} -benzo [cd] indol-2 (1H) -one,
11) 1- {6- [4- (3-methoxyphenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
12) 1- {6- [4- (4-methoxyphenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
13) 1- {6- [4- (2-ethoxyphenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
14) 1- {6- [4- (2-pyridinyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
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15) 1- {6- [4- (2-pyrimidinyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
16) 1- {6- [4- (2-nitrophenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
17) 1- {6- [4- (8-quinolinyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
18) 1- {6- [4- (1,2-benzisothiazol-3-yl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one,
19) 1- {6- [4- (2-oxo-2,3-dihydro-1,3-benzoxazol-7-yl) piperazin-1-yl] hexyl} benzo [cd] indol 2 (1H) -one,
- Compounds belonging to the subgroup of N-6- (4-arylpiperazin-1-yl) hexyl cyclic derivatives of 1,8-naphthylsulfonamides:
20) 2- {6- [4- (2-chlorophenyl) piperazin-1-yl] hexyl} - (2H) naphtha [1,8-cd] [1,2] thiazole-1,1 (2H) -dione ,
21) 2- {6- [4- (3-chlorophenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione ,
22) 2- {6- [4- (4-chlorophenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione ,
23) 2- {6- [4- (2,3-dichlorophenyl) piperazin-1-yl] hexyl} - (2H) naphtha [1,8-cd] [1,2] thiazol-1,1 (2H) -dion,
24) 2- {6- [4- (3,4-dichlorophenyl) piperazin-1-yl] hexyl} - (2H) naphtha [1,8-cd] [1,2] thiazol-1,1 (2H) -dion,
25) 2- {6- [4- (3-trifluoromethylphenyl) piperazin-1-yl] hexyl} - (2H) naphtha [1,8-cd] [1,2] thiazole
1,1 (2H) -dione,
26) 2- {6- [4- (4-trifluoromethylphenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione ,
27) 2- {6- [4- (2-fluoromethylphenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione ,
28) 2- {6- [4- (2-ethoxyphenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione ,
29) 2- {6- [4- (2-pyridinyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione ,
30) 2- {6- [4- (2-nitrophenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione ,
31) 2- {6- [4- (1,2-benzisothiazol-3-yl) piperazin-1-yl] hexyl} - (2H) naphtha [1,8-cd] [1,2] thiazol-1, 1 (2H) -dione,
- Compounds belonging to the subgroup N-6- (4-arylpiperazin-1-yl) hexyl 1,8-naphthylimide cyclic derivatives:
32) 2- {6- [4- (2-methoxyphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione,
33) 2- {6- [4- (3-methoxyphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione,
34) 2- {6- [4- (4-methoxyphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione,
35) 2- {6- [4- (2-ethoxyphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione,
36) 2- {6- [4- (2-pyridinyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione,
37) 2- {6- [4- (2-nitrophenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione,
38) 2- {6- [4- (2-fluorophenyl) piperazin-1-yl] hexyl} -2H-benzo [de] isoquinotino-1,3 (2H) -dione,
39) 2- {6- [4- (2-trifluoromethylphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione,
40) 2- {6- [4- (3-trifluoromethylphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione,
41) 2- {6- [4- (4-bromophenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione,
42) 2- {6- [4- (1,2-benzisothiazol-3-yl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione,
43) 2- {6- [4 - {[1-oxo-2,3-dihydro-1H-isoindol-2-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione,
44) 2- [6- (4 - {[1,1-biphenyl] -2-yl} piperazin-1-yl) hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione,
- Compounds belonging to the subgroup of N-6- (4-arylpiperazin-1-yl) hexyl derivatives of cyclic tetrahydroquinoline amides:
45) 1- {6- [4- (2-methoxyphenyl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) one,
46) 1- {6- [4- (3-chlorophenyl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) -one ,
47) 1- {6- [4- (1,2-benzisothiazol-3-yl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin2 ( 1H) -on,
48) 1- {6- [4- (3-chlorophenyl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-innidazo [4,5,1-ij] quinolin-2 (1H) thion,
- A compound belonging to the subgroup of N-6- (4-arylpiperazin-1-yl) hexyl cyclic tetrahydroquinoline sulfonamides:
49) 1- {6- [4- (3-chlorophenyl) piperazin-1-yl] hexyl} -1H, 4H- [1,2,5] thiadiazolo [4,3,2-ij] quinoline-2,2 dioxide .
PL 240 473 BI
The arylpiperazine derivatives of general formula (I) show affinity for selected receptors mentioned as therapeutic targets for the treatment of CNS disorders such as dopaminergic D2 and serotonergic receptors, in particular 5-HTia, 5-HT2A, 5-HTs, 5-HTβ.
The compounds according to the invention are useful in the treatment and / or prevention of central nervous system disorders such as schizophrenia, bipolar and affective disorders, manic disorders, depression, anxiety disorders, alcoholic delirium, aggression, psychomotor agitation, sleep disorders of various etiologies, withdrawal syndromes various etiologies, Alzheimer's disease, psychopathological symptoms and neurological disorders in the course of other diseases of the central and peripheral nervous system.
In the course of research on their properties, it turned out that the following compounds are the most advantageous in therapeutic applications for the treatment of CNS disorders:
- a compound with the chemical name 1- {6- [4- (3-chlorophenyl) piperazin-1-yl] hexyl} benzo [cd] indol2 (1H) -one and the general formula (I), where: X is C, Z is CO, Y is no atom, no functional group, is a double bond, n is 6, R is an aryl group of the general formula (IA), in which: R1 is H, R2 is Cl, R3 is Η, E is C, F is C.
- a compound with the chemical name 1- {6- [4- (2-pyridinyl) piperazin-1-yl] hexyl} benzo [cd] indole 2 (1H) -one and with the general formula (I), where: X is C, Z is CO, Y means no atom, no functional group, means a double bond, n is 6, R is an aryl group of the general formula (IA) in which: R1 is H, R2 is H, R3 is Η, E is N, F is C.
- a compound with the chemical name 1- {6- [4- (2-pyrimidinyl) piperazin-1-yl] hexyl} benzo [cd] indole 2 (1H) -one and with the general formula (I), where: X is C, Z is CO, Y means no atom, no functional group, means a double bond, n is 6, R is an aryl group of the general formula (IA) in which: R1 is H, R2 is H, R3 is Η, E is N, F is N.
- compound with chemical name 2- [6- (4 - {[1,1'-biphenyl] -2-yl} piperazin-1-yl) hexyl] -1H-benzo [de] isoquinoline-1,3 (2H) -dione and the general formula (I), where: X is C, Z is CO, Y is CO, is a double bond, n is 6, R is an aryl group of the general formula (IA), in which: R1 is CsHs, R2 is H , R3 is Η, E is C, F is C.
- a compound with a chemical name 1- {6- [4- (2-methoxyphenyl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) - on, with the general formula (I), where: X is N, Z is CO, Y is no atom, no functional group, is a single bond, n is 6, R is an aryl group represented by the general formula (IA), in which: R1 is OCH3, R2 is H, R3 is Η, E is C, F is C.
- compound with chemical name 1- {6- [4- (1,2-benzisothiazol-3-yl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinoline -2 (1H) -one of the general formula (I), where: X is N, Z is CO, Y is no atom, no functional group, is a single bond, n is 6, R is an aryl group described by the general formula (IB ).
The compounds described by the general formula (I) are obtained according to the invention by a two-step synthesis involving N-alkylation of 1,8-naphthyl / tetrahydroquinoline imides / amides / sulfonamides with dibromoalkanes in basic medium and then condensation of the thus obtained intermediate with arylpiperazine according to the presented below is a two-step synthesis scheme:
PL 240 473 BI
Level 1
(IV) (V) (I)
In the first stage of the synthesis, the compound described by the general formula (II), i.e. cyclic 1,8-naphthyl / tetrahydroquinoline imide / amide / sulfonamide, is subjected to the N -alkylation reaction with dibromoalkanes - general formula (III) in the presence of a basic agent such as K2CO3 , Na2COs, KOH, NaOH, triethylamine, and a phase transfer catalyst (PTC) such as tetra-n-butylammonium bromide (TBAB), tetraethylammonium chloride (TEAC), 1,4-diazabicyclo [2.2.2] octane (DABCO) and solvent (used at a relatively low level) such as N, N-dimethylformamide (DMF), acetonitrile (ACN), water, or no solvent.
After preparing a mixture containing 3 moles of dibromoalkanes, 3 moles of basic agent, 0.1 mole of PCT catalyst and up to 50 cm 3 of solvent per 1 mole of cyclic 1,8-naphthyl / tetrahydrate and nolinimide / amide / sulfonamide, the mixture is treated with microwave field for 15-60 seconds in a microwave reactor with a microwave output of 50-200 W. The thus obtained intermediate, described by the general formula (IV), is separated from the reaction medium in a known manner by adding water and extraction with methylene chloride, followed by distilling off the chloride the methylene intermediate is macerated in hexane and sent to the second stage of the synthesis.
In the second stage of the synthesis, the intermediate obtained from the first stage (a compound described by formula IV) is subjected to a condensation reaction with an arylpiperazine of general formula (V) in the presence of a basic agent such as K2CO3, Na2CO3, KOH, NaOH, triethylamine, PTC phase transfer catalyst such as tetra-n-butylammonium bromide (TBAB), tetraethylammonium chloride (TEAC), 1,4-diazabicyclo [2.2.2] octane (DABCO) and a solvent (relatively small amount used) such as A /, N-dimethylformamide (DMF), acetonitrile (ACN), water or no solvent.
After preparing a mixture containing per 1 mole of intermediate (formula IV) 0.95 moles of arylpiperazine, 3 moles of basic agent, 0.1 mole of PCT catalyst and up to 50 cm 3 of solvent, the mixture is exposed to the microwave field for 15-60 seconds in a reactor. In a microwave oven with a microwave output of 50-200 W. The product thus obtained, described by the general formula (I), is separated in a known manner by adding water from the reaction medium and filtering, and the crude product is purified by crystallization from methanol.
The starting compounds of the formulas (II), (III) and (V) are known and commercially available.
The compounds of general formula (I) obtained by the above process are basic in nature as they contain a tertiary amine group on the piperazine ring. They can form the acid addition salts shown in formula (VI):
where A is any acid anion.
PL 240 473 B1
In order to determine the biological properties of the novel compounds of the invention as ligands for serotonin and dopamine receptors, they were tested in the form of addition salts (hydrochlorides) obtained by dissolving said basic compounds in diethyl ether or acetone and producing the hydrochlorides using a solution of HCl in dioxane.
The new compounds, which are N-6 (4-arylpiperazine-1-yl) hexyl derivatives of cyclic 1,8-naphthyl / tetrahydroquinoline imides / amides / sulfonamides, can be used in the treatment of many diseases of the central nervous system, including psychiatric and neurodegenerative disorders, which shows their profile the pharmacology is shown below in tabular form, determined by the affinity constants for selected receptors (5-HTia, 5-HT2A, 5-HT6, 5-HT7, D2). The new compounds, which are the subject of the invention, are produced by an ecological, solvent-free method, which is advantageous in the context of environmental protection and minimization of production costs.
The novel arylpiperazine derivatives according to the invention and the method of their synthesis are presented in the following examples.
The compounds described by the formula (IV), which are intermediates for the synthesis of the new arylpiperazine derivatives, were prepared according to the procedure described in Examples 1-12.
In all of the following examples, microwave reactions were performed in a microwave reactor with controlled microwave power. Reagents for syntheses were purchased from Sigma Aldrich. All solvents used in the synthesis and purification process came from POCH (Polish Chemical Reagents).
Analytical thin layer chromatography (TLC) was performed using a 9: 1 mixture of chloroform: methanol as the eluent, using Sigma Aldrich silica gel plates on aluminum sheets with a fluorescence index of 254 nm (layer thickness 200 μm, pore diameter 60 A, particle 8, 0-12.0 μm size).
TLC Rf retention coefficients are presented for individual substances. UV light with a wavelength of 254 nm was used for the analysis.
HPLC analysis (high performance liquid chromatography) was performed on a Perkin Elmer Series 200 HPLC device with an XTerra RP C-18 column (grain size 3.5 μm, 4.6 x 150 mm) using methanol: water 1: 1 acidified with 0 as eluent. , 1% formic acid, using a UV-VIS detector (ultraviolet and visible light detector) at 254 nm.
Retention times Rt are presented for individual substances.
The purity of the products obtained was determined by means of the HPLC technique, using UV-VIS detection at a wavelength of 254 nm.
Melting points were measured with a Boetius apparatus.
IR (infrared) spectra were made on an FTS-165 (FTIR Biorad) spectrometer.
1H NMR (nuclear magnetic resonance) spectra were recorded on a Bruker Avance 400 MHz spectrometer using TMS (tertamethylsilane) as a reference. UPLC-MS analyzes (ultra-efficient liquid chromatography combined with a mass spectrometer) were performed on a Waters Acquity TQD apparatus with a diode array detector (DAD). The electrospray ionization (ESI) mode was used for mass spectrometry. The yield of the compounds obtained was calculated based on the mass of the obtained hydrochloride of the compound represented by the general formula (I).
For all intermediates obtained in Examples 1-12, the analyzes confirming the structure, characteristic physicochemical properties and purity of the obtained combinations are presented below. When presenting the results of the analyzes, the Anglo-Saxon numerical notation was used, according to which the decimal places are separated with a dot.
EXAMPLE 1
Preparation of the intermediate: 1- (6-bromohexyl) benzo [cd] indol-2 (1H) -one, commonly called N-hexyl derivative of 1,8-naphthylamide
0.01 mol of benzo [cd] indol-2 (1H) -one, 0.03 mol of NaOH and 0.001 mol of TBAB were triturated in a mortar. The mixture was transferred to a round bottom flask, then 0.03 mol of 1,6-dibromohexane and 0.1 ml of ACN were added. The reaction was carried out for 45 seconds in a microwave reactor with a microwave output of 100 W. After the reaction was completed, 40 cm 3 of water were added to the mixture and extracted with methylene chloride. After distilling off the methylene chloride, the reaction product was macerated in 20 cm 3 of hexane to get rid of the excess 1,6-dibromohexane.
PL 240 473 B1
- (6-Bromohexylbenzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.08 (dd, J = 8.2, 4.9 Hz, 1H, ArH), 7.98 (dd, J = 7.2, 2.8 Hz, 1H, ArH), 7.77 (ddd , J = 8.1, 7.4, 3.5 Hz, 1H, ArH), 7.62 - 7.51 (m, 1H, ArH), 7.46 (t, J = 9.4 Hz, 1H, ArH), 6.75 (dd, J = 7.2, 3.1 Hz , 1H, ArH, 3.86 (t, J = 7.3 Hz, 2H, S (O) 2N-CH), 3.44 (t, J = 6.7 Hz, 2H, BrCHAlif), 1.95 (ddd, J = 28.7, 14.1, 7.1 Hz, 4H, CHant), 1.61 (ddd, J = 23.6, 7.8, 3.7 Hz, 4H, CHat), Infrared spectroscopy: FT-IR 3055 (CH Ar Rozc), 2932; 2857 (CH Alif, Rozc), 1694 (C = O, Rozc), 1602; 1495 (C = C Ar, Rozc), 1373 (CN, Rozc), 773 (C-Br, Rozc), Thin layer chromatography TLC: retention coefficient R / = 0.90, High performance liquid chromatography HPLC: retention time Rt = 4.05 min, purity = 88%, Yield = 78%.
EXAMPLE 2
Preparation of the intermediate: 1- (6-bromohexyl) benzo [cd] indol-2 (1H) -one, commonly called N-hexyl derivative of 1,8-naphthylamide
0.01 mole of benzo [cd] indol-2 (1H) -one, 0.03 mole of Na2CO3, and 0.001 mole of TEAC were triturated in a mortar. The mixture was transferred to a round bottom flask and then 0.03 mol of 1,6-dibromohexane was added. Reactions were carried out for 60 seconds in a microwave reactor with a microwave output of 50 W. After the reaction was completed, 40 cm 3 of water were added to the mixture and extracted with methylene chloride. After distilling off the methylene chloride, the reaction product was macerated in 20 cm 3 of hexane to get rid of the excess 1,6-dibromohexane.
- (6-Bromohexylbenzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.08 (dd, J = 8.2, 4.9 Hz, 1H, ArH), 7.98 (dd, J = 7.2, 2.8 Hz, 1H, ArH), 7.77 (ddd, J = 8.1, 7.4, 3.5 Hz, 1H, ArH), 7.62 - 7.51 (m, 1H, ArH), 7.46 (t, J = 9.4 Hz, 1H, ArH), 6.75 (dd, J = 7.2, 3.1 Hz, 1H, ArH, 3.86 (t, J = 7.3 Hz, 2H, S (O) 2N-CH), 3.44 (t, J = 6.7 Hz, 2H, BrCHAlif), 1.95 (ddd, J = 28.7, 14.1, 7.1 Hz , 4H, CHat), 1.61 (ddd, J = 23.6, 7.8, 3.7 Hz, 4H, CHai »), Infrared spectroscopy: FT-IR 3055 (CH Ar Rozc), 2932; 2857 (CH Alif, Rozc), 1694 (C = O, Rozc), 1602; 1495 (C = C Ar, Rozc), 1373 (CN, Rozc), 773 (C-Br, Rozc), Thin layer chromatography TLC: retention coefficient R / = 0.90, High performance liquid chromatography HPLC: retention time Rt = 4.05 min, purity = 88%, Yield = 62%.
EXAMPLE 3
Preparation of intermediate: 2- (6-bromohexyl) -2H-naphtha [1,8-cd] isothiazole-1,1 (2H) -dione, commonly called N-hexyl derivative of 1,8-naphthytosulfonamide
0.01 mole (2H) naphtha [1,8-cd] [1,2] thiazole-1,1 (2H) -dione, 0.03 mole KOH and 0.001 mole TBAB were triturated in a mortar. The mixture was transferred to a round bottom flask, then 0.03 mol of 1,6-dibromohexane and 0.2 ml of water were added. Reactions were carried out for 40 seconds in a microwave reactor with a microwave output of 80 W. After the reaction was completed, 40 cm 3 of water were added to the mixture and extracted with methylene chloride. After distilling off the methylene chloride, the reaction product was macerated in 20 cm 3 of hexane to get rid of the excess 1,6-dibromohexane. The crude product was crystallized from methanol.
2- (6-bromohexyl) -2H-naphtha [1,8-cd] isothiazole-1,1 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.09 (d, J = 7.0 Hz, 1H, ArH), 8.07 - 8.01 (m, 1H, ArH), 7.76 - 7.72 (m, 1H, ArH), 7.56 (d, J = 8.4 Hz, 1H, ArH), 7.52 - 7.46 (m, 1H, ArH), 6.94 (d, J = 6.9 Hz, 1H, ArH), 3.99 - 3.93 (m, 2H, SONCH), 3.44 - 3.40 (m, 2H, BrCHAlif), 1.89 - 1.80 (m, 4H, CHai »), 1.50 (ddd, J = 13.7, 8.7, 5.6 Hz, 4H, CHaj»), Infrared spectroscopy: FT-IR 3060 , (CH Ar, Rozc), 2933, 2856 (CH, Alif, Rozc), 1591, 1492 (C = C Ar, Rozc), 1371 (CN, Rozc), 1348 (S = O, Rozc), 851 (NS , Rozc), 756 (C-Br, Rozc), TLC thin layer chromatography; retention factor R f = 0.90, HPLC high performance liquid chromatography: retention time Rt = 4.12 min, purity = 95%, Yield = 65%.
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EXAMPLE 4
Preparation of intermediate: 2- (6-bromohexyl) -2H-naphtha [1,8-cd] isothiazole-1,1 (2H) -dione, commonly called N-hexyl derivative of 1,8-naphthylsulfonamide
0.01 mole (2H) naphtha [1,8-cd] [1,2] thiazole-1,1 (2H) -dione, 0.03 mole Na2CO3 and 0.001 mole TEAC were triturated in a mortar. The mixture was transferred to a round bottom flask and then 0.003 mol of 1,6-dibromohexane was added. Reactions were carried out for 20 seconds in a microwave reactor with a microwave output of 100 W. After the reaction was completed, 40 cm 3 of water were added to the mixture and extracted with methylene chloride. After distilling off the methylene chloride, the reaction product was macerated in 20 cm 3 of hexane to get rid of the excess 1,6-dibromohexane. The crude product was crystallized from methanol.
2- (6-bromohexyl) -2H-naphtha [1,8-cd] isothiazole-1,1 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.09 (d, J = 7.0 Hz, 1H, ArH), 8.07 - 8.01 (m, 1H, ArH), 7.76 - 7.72 (m, 1H, ArH), 7.56 (d, J = 8.4 Hz, 1H, ArH), 7.52 - 7.46 (m, 1H, ArH), 6.94 (d, J = 6.9 Hz, 1H, ArH), 3.99 - 3.93 (m, 2H, SONCH), 3.44 - 3.40 (m, 2H, BrCHAlif), 1.89 - 1.80 (m, 4H, CHaj »), 1.50 (ddd, J = 13.7, 8.7, 5.6 Hz, 4H, CHaj»),
Infrared spectroscopy: FT-IR 3060, (CH Ar, Rozc), 2933, 2856 (CH, Alif, Rozc), 1591, 1492 (C = C Ar, Rozc), 1371 (CN, Rozc), 1348 (S = O, Rozc), 851 (NS, Rozc), 756 (C-Br, Rozc), TLC thin layer chromatography: retention coefficient R / = 0.90,
HPLC high performance liquid chromatography: retention time Rt = 4.12 min, purity = 95%, Yield = 67%.
EXAMPLE 5
Preparation of the intermediate: 2- (6-bromohexyl) -1H-benzo [de] isoquinoline-1,3 (2H) -dione, commonly called N-hexyl derivative of 1,8-naphthylimide
In a round bottom flask, 0.01 mol of 1H-benzo [de] isoquinoline-1,3 (2H) -dione, 0.03 mol of triethylamine, 0.001 mol of DABCO, 0.03 mol of 1,6-dibromohexane and 0.05 DMF were mixed. . Reactions were carried out for 15 seconds in a microwave reactor with a microwave output of 200 W. After the reaction was completed, 40 cm 3 of water was added to the mixture and the reaction product was filtered off. The crude product was crystallized from methanol.
2- (6-bromohexyl) -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.48 (ddd, J = 9.1.7.8, 0.9 Hz, 4H, ArH), 7.91 - 7.79 (m, 2H, ArH), 4.07 - 4.01 (m, 2H , CONCH), 3.53 (t, J = 6.7 Hz, 2H, BrCHAlif), 1.87 - 1.75 (m, 2H, CHaj »), 1.64 (dd, J = 14.7, 7.3 Hz, 2H, CHaj»), 1.40 (ddd , J = 15.2, 8.2, 3.4 Hz, 4H, CHAiif),
Infrared spectroscopy FT-IR: 3061 (CH Ar Rozc), 2933; 2855 (CH Alif, Rozc), 1692 (C = O, Rozc), 1587; 1461 (C = C Ar, Rozc), 1361 (CN, Rozc), 779 (C-Br, Rozc), TLC thin layer chromatography: retention coefficient R / = 0.90,
HPLC high performance liquid chromatography: retention time Rt = 3.85 min, purity = 99%, Yield = 75%.
EXAMPLE 6
Preparation of the intermediate: 2- (6-bromohexyl) -1H-benzo [de] isoquinoline-1,3 (2H) -dione, commonly called N-hexyl derivative of 1,8-naphthylimide
0.01 mol of 1H-benzo [de] isoquinoline-1,3 (2H) -dione, 0.03 mol and 0.001 mol of TBAB were triturated in a mortar. The mixture was transferred to a round bottom flask and then 0.03 mol of 1,6-dibromohexane was added. Reactions were carried out for 20 seconds in the reactor with a microwave output of 180 W. After the reaction was completed, 40 cm 3 of water was added to the mixture and the reaction product was filtered off. The crude product was crystallized from methanol.
2- (6-bromohexyl) -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.48 (ddd, J = 9.1.7.8, 0.9 Hz, 4H, ArH), 7.91 - 7.79 (m, 2H, ArH), 4.07 - 4.01 (m, 2H , CONCH), 3.53 (t, J = 6.7 Hz, 2H, BrCHAlif, 1.87 - 1.75 (m, 2H, CHAiif), 1.64 (dd, J = 14.7, 7.3 Hz, 2H, CHAiif), 1.40 (ddd, J = 15.2, 8.2, 3.4 Hz, 4H, CHAiif),
PL 240 473 B1
Infrared spectroscopy FT-IR: 3061 (CH Ar Rozc), 2933; 2855 (CH Alif, Rozc), 1692 (C = O, Rozc), 1587; 1461 (C = C Ar, Rozc), 1361 (CN, Rozc), 779 (C-Br, Rozc), TLC thin layer chromatography: retention factor Rf = 0.90, HPLC high performance liquid chromatography: retention time Rt = 3.85 min, purity = 99%, Yield = 87%.
EXAMPLE 7
Preparation of the intermediate: 1- (6-bromohexyl) -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin2 (1H) -one, commonly called N-hexyl derivative of tetrahydroquinoline amide
0.01 mole of 5,6-dihydro-4H-imidazo [4,5,1-[mu]] quinolin-2 (1H) -one, 0.03 mole of K2CO3 and 0.001 mole of TBAB were triturated in a mortar. The mixture was transferred to a round bottom flask, then 0.03 mol of 1,6-dibromohexane and 0.3 ml of ACN were added. Reactions were carried out for 45 seconds in a microwave reactor with a microwave output of 90 W. After the reaction was completed, 40 cm 3 of water were added to the mixture and extracted with methylene chloride. After evaporating off the methylene chloride, the reaction product was macerated in 20 cm 3 of hexane to get rid of the excess 1,6-dibromohexane.
- (6-bromohexyl) -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 7.00 - 6.91 (m, 2H, ArH), 6.85 (dd, J = 6.5, 1.9 Hz, 1H, ArH), 4.39 (d, J = 12.4 Hz, 2H, CONCH), 3.44 - 3.40 (m, 2H, BrCHAlif), 3.15 (s, 2H, CHai »), 2.84 (t, J = 6.0 Hz, 2H, CHAlif), 2.12 (dd, J = 11.8, 6.1 Hz , 2H, CHAlif »), 1.90 (s, 2H, CHAlif), 1.84 - 1.74 (m, 2H, CHAlif), 1.40 (s, 4H, CHAlif), Infrared spectroscopy FT-IR: 3059 (CH Ar Rozc), 2928; 2852 (CH Alif, Rozc), 1703 (C = O, Rozc), 1599; 1486 (C = C Ar, Rozc), 1373 (CN, Rozc), 780 (C-Br, Rozc), TLC thin layer chromatography: retention factor Rf = 0.90, HPLC high performance liquid chromatography: retention time Rt = 4.17 min, purity = 96%, Yield = 79%.
EXAMPLE 8
Preparation of the intermediate: 1- (6-bromohexyl) -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) -one, commonly called N-hexyl derivative of tetrahydroquinoline amide
0.01 mol of 5,6-dihydro-4H-imidazo [4,5,1-µ] quinolin-2 (1H) -one, 0.03 mol of NaOH and 0.001 mol of TBAB were triturated in a mortar. The mixture was transferred to a round bottom flask and then 0.03 mol of 1,6-dibromohexane was added. Reactions were carried out for 40 seconds in a microwave reactor. After the completion of the reaction, 40 ml of water were added to the mixture and the mixture was extracted with methylene chloride, using a microwave output of 150 W. After evaporating off the methylene chloride, the reaction product was triturated in 20 ml of hexane to get rid of the excess 1,6-dibromohexane.
- (6-bromohexyl) -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 7.00 - 6.91 (m, 2H, ArH), 6.85 (dd, J = 6.5, 1.9 Hz, 1H, ArH), 4.39 (d, J = 12.4 Hz, 2H, CONCH), 3.44 - 3.40 (m, 2H, BrCHAlif), 3.15 (s, 2H, CHAlif), 2.84 (t, J = 6.0 Hz, 2H, CHAlif), 2.12 (dd, J = 11.8, 6.1 Hz, 2H, CHAlif), 1.90 (s, 2H, CHAlif), 1.84 - 1.74 (m, 2H, CHAlif), 1.40 (s, 4H, CHAlif), FT-IR infrared spectroscopy: 3059 (CH Ar Rozc), 2928; 2852 (CH Alif, Rozc), 1703 (C = O, Rozc), 1599; 1486 (C = C Ar, Rozc), 1373 (CN, Rozc), 780 (C-Br, Rozc), TLC thin layer chromatography: retention factor Rf = 0.90, HPLC high performance liquid chromatography: retention time Rt = 4.17 min, purity = 96%, Yield = 79%.
EXAMPLE 9
Preparation of the intermediate: 1- (6-bromohexyl) -5,6-dihydro-4H-imidazo [4,5,1-j] quinolin-2 (1H) -thion, commonly called N-hexyl derivative of tetrahydroquinoline amide
0.01 mol of 5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) -thione, 0.03 mol of NaOH and 0.001 mol of TBAB were triturated in a mortar. The mixture was transferred to a round bottom flask, then 0.03 mol of 1,6-dibromohexane and 2 cm 3 of water were added. Reactions were carried out for 15 seconds in a microwave reactor with a microwave output of 170 W. After completion of the reaction, 40 cm3 was added to the mixture .
Of water and extracted with methylene chloride. After distilling off the methylene chloride, the reaction product was macerated in 20 cm 3 of hexane to get rid of the excess 1,6-dibromohexane.
- (6-bromohexyl) -5,6-dihydro-4H-imidazo [4,5,1-j] quinolin-2 (1H) -thion
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 7.31 - 7.23 (m, 2H, ArH), 6.89 (dd, J = 6.6, 1.9 Hz, 1H, ArH, 4.44 (d, J = 12.4 Hz, 2H , CONCH), 3.54 - 3.45 (m, 2H, BrCHAlif), 3.00 (t, J = 5.9 Hz, 2H, CHAlf), 2.40 - 2.27 (m, 2H, CHAlf), 1.87 - 1.69 (m, 6H, CHAlf) , 1.48 (m, 2H, CHAlf), 1.40 - 1.34 (m, 2H, CHAlf), FT-IR infrared spectroscopy: 3046 (CH Ar Rozc), 2943; 2852 (CH Alif, Rozc), 1600; 1491 (C = C Ar, Rozc), 1372 (CN, Rozc), 762 (C-Br, Rozc), TLC thin layer chromatography; retention coefficient R / = 0.90, HPLC high performance liquid chromatography: retention time Rt = 3.02 min, purity = 95% . Yield = 79%.
EXAMPLE 10
Preparation of the intermediate: 1- (6-bromohexyl) -5,6-dihydro-4H-imidazo [4,5,1-j] quinolin-2 (1H) -thion, commonly called N-hexyl derivative of tetrahydroquinoline amide
0.01 mol of 5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) -thione, 0.03 mol of NaOH and 0.001 mol of TBAB were triturated in a mortar. The mixture was transferred to a round bottom flask and then 0.03 mol of 1,6-dibromohexane was added. Reactions were carried out for 60 seconds in a microwave reactor with a microwave output of 100 W. After the reaction was completed, 40 cm 3 of water were added to the mixture and extracted with methylene chloride. After distilling off the methylene chloride, the reaction product was macerated in 20 cm 3 of hexane to get rid of the excess 1,6-dibromohexane.
- (6-bromohexyl) -5,6-dihydro-4H-imidazo [4,5,1-j] quinolin-2 (1H) -thion
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 7.31 - 7.23 (m, 2H, ArH), 6.89 (dd, J = 6.6, 1.9 Hz, 1H, ArH, 4.44 (d, J = 12.4 Hz, 2H , CONCH), 3.54 - 3.45 (m, 2H, BrCHAlif), 3.00 (t, J = 5.9 Hz, 2H, CHAlif), 2.40 - 2.27 (m, 2H, CHAlf), 1.87 - 1.69 (m, 6H, CHAlif) , 1.48 (m, 2H, CHAlif), 1.40 - 1.34 (m, 2H, CHAlif), FT-IR infrared spectroscopy: 3046 (CH Ar Rozc), 2943; 2852 (CH Alif, Rozc), 1600; 1491 (C = C Ar, Rozc), 1372 (CN, Rozc), 762 (C-Br, Rozc), TLC thin layer chromatography: retention factor R / = 0.90, HPLC high performance liquid chromatography: retention time Rt = 3.02 min, purity = 95% . Yield = 71%.
EXAMPLE 11
Preparation of the intermediate: 1- (6-bromohexyl) -1H, 4H- [1,2,5] thiadiazolo [4,3,2-ij] quinoline, 2,2 dioxide, commonly known as N-hexyl derivative of tetrahydroquinoline sulfonamide
0.01 mol of 1H, 4H- [1,2,5] thiadiazolo [4,3,2-ij] quinoline, 2,2-dioxide, 0.03 mol of NaOH and 0.001 mol of TBAB were triturated in a mortar. The mixture was transferred to a round bottom flask, then 0.03 mol of 1,6-dibromohexane and 0.2 ml of ACN were added. The reaction was carried out for 45 seconds in a microwave reactor with a microwave output of 80 W. After the reaction was completed, 40 cm 3 of water were added to the mixture and extracted with methylene chloride. After distilling off the methylene chloride, the reaction product was macerated in 20 cm 3 of hexane to get rid of the excess 1,6-dibromohexane.
- (6-bromohexyl) -1H, 4H- [1,2,5] thiadiazolo [4,3,2-ij] quinoline-2,2-dioxide
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCh) δ 7.21 - 6.90 (m, 2H, ArH), δ 6.85 - 6.80 (m, J = 6.5, 1.9 Hz, 1H, ArH), 3.86 - 3.70 (m, 2H, S (O) 2N-CH), 3.40 - 3.33 (m, 2H, BrCHAlif), 3.20 (s, 2H, CHAlif), 2.35 - 2.31 (m, 2H, CHAlif), 2.17 (dd, J = 11.8, 6.1 Hz, 2H, CHAlif), 2.00 (s, 2H, CHAlif, 1.90 - 1.84 (m, 2H, CHAlif), 1.40 (s, 4H, CHAlif), Infrared spectroscopy FT-IR: 3059 (CH Ar Rozc), 2998; 2845 (CH Alif, Rozc), 1599; 1478 (C = C Ar, Rozc), 1372 (CN, Rozc), 1298 (S = O, Rozc), 685 (SN, Rozc), 771 (C-Br , Dilution), TLC thin layer chromatography: retention coefficient R f = 0.90, HPLC high performance liquid chromatography: retention time Rt = 2.82 min, purity = 85%, Yield = 64%.
PL 240 473 B1
EXAMPLE 12
Preparation of the intermediate: 1- (6-bromohexyl) -1H, 4H- [1,2,5] thiadiazolo [4,3,2-ij] quinoline-2,2-dioxide, commonly called N-hexyl derivative of tetrahydroquinoline sulfonamide, commonly called N -hexyl derivative of a tetrahydroquinoline sulfonamide
0.01 mole of 1H, 4H- [1,2,5] thiadiazolo [4,3,2-ij] quinoline, 2,2-dioxide, 0.03 mole of K2CO3 and 0.001 mole of TBAB were triturated in a mortar. The mixture was transferred to a round bottom flask and then 0.03 mol of 1,6-dibromohexane was added. The reaction was carried out for 60 seconds in a microwave reactor with a microwave output of 100 W. After the reaction was completed, 40 cm 3 of water were added to the mixture and extracted with methylene chloride. After distilling off the methylene chloride, the reaction product was macerated in 20 cm 3 of hexane to get rid of the excess 1,6-dibromohexane.
- (6-bromohexyl) -1H, 4H- [1,2,5] thiadiazolo [4,3,2-ij] quinolin-2,2-dioxide
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 7.21 - 6.90 (m, 2H, ArH), δ 6.85 - 6.80 (m, J = 6.5, 1.9 Hz, 1H, ArH), 3.86 - 3.70 (m , 2H, S (O) 2N-CH), 3.40 - 3.33 (m, 2H, BrCHAlif), 3.20 (s, 2H, CHant), 2.35 - 2.31 (m, 2H, CHant), 2.17 (dd, J = 11.8 , 6.1 Hz, 2H, CHAlif), 2.00 (s, 2H, CHAlif), 1.90 - 1.84 (m, 2H, CHat), 1.40 (s, 4H, CHat), FT-IR spectroscopy: 3059 (CH Ar Rozc ), 2998; 2845 (CH Alif, Rozc), 1599; 1478 (C = C Ar, Rozc), 1372 (CN, Rozc), 1298 (S = O, Rozc), 685 (SN, Rozc), 771 (C-Br, Rozc), TLC thin layer chromatography; retention factor Rf = 0.90, HPLC high performance liquid chromatography: retention time Rt = 2.82 min, purity = 85%, Yield = 42%.
The compounds described by the formula (I) were prepared according to the procedure described in Examples 13-24, using in the synthesis the intermediates obtained in Examples 1-12.
For the compounds (products) obtained in Examples 13-24, after the description of their exemplary synthesis, analyzes were presented to confirm the structure and purity of the obtained combinations. The following examples use the Anglo-Saxon numeric notation that separates the decimal places with a period.
The compounds described with Nos. 1-19 were prepared according to the procedure described in Examples 13 and 14, using in the synthesis the intermediates obtained in Examples 1 and 2.
EXAMPLE 13
Preparation of 1- {6- [4- (aryl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -ones
0.001 mol of 1- (6-bromohexyl) benzo [cd] indol-2 (1H) -one, 0.00095 mol of arylpiperazine described by the formula (V) selected appropriately for the synthesized compound, 0.003 mol of K2CO3 and 0.0001 mol of TBAB were triturated in a mortar. . The triturated mixture was transferred to a round bottom flask and 2 ml of ACN was added to the reaction mixture. Reactions were carried out for 50 seconds in a microwave reactor with a microwave output of 100 W. The progress of the reaction was monitored by TLC. After completion of the reaction, 40 cm 3 of water was added to the mixture and placed in a refrigerator (temperature 4 ° C) for 12 hours. After cooling, the product was filtered off. The crude product was crystallized from methanol. The ligand was dissolved in acetone then converted to the hydrochloride salt with 4M HCl in dioxane.
EXAMPLE 14
Preparation of 1- {6- [4- (aryl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -ones
0.001 mol of 1- (6-bromohexyl) benzo [cd] indol-2 (1H) -one, 0.00095 mol of arylpiperazine described by the formula (V) selected appropriately for the synthesized compound, 0.003 mol of Na2CO3 and 0.0001 mol of TEAC were triturated in a mortar. . The triturated mixture was transferred to a round bottom flask. Reactions were carried out for 60 seconds in a microwave reactor with a microwave output of 50 W. The progress of the reaction was monitored by TLC. After completion of the reaction, 40 cm 3 of water was added to the mixture and placed in a refrigerator (temperature 4 ° C) for 12 hours. After cooling, the product was filtered off. The crude product was crystallized from methanol. The ligand was dissolved in acetone then converted to the hydrochloride salt with 4M HCl in dioxane.
Compound No. 1
1- {6- (4- (2-chlorophenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one
PL 240 473 B1
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H, ArH), 8.06 (d, J = 7.0 Hz, 1H, ArH), 7.86 - 7.76 (m, 1H , ArH), 7.65 (d, J = 8.3 Hz, 1H, ArH), 7.62 - 7.52 (m, 1H, ArH), 7.45 (d, J = 7.8 Hz, 1H, ArH), 7.34 (t, J = 7.8 Hz, 1H, ArH), 7.21 (t, J = 7.5 Hz, 2H ArH), 7.11 (t, J = 7.8 Hz, 1H, ArH), 3.92 (t, J = 6.9 Hz, 2H, C (O) N -CH), 3.57 (s, 2H, CHPiperazine), 3.41 (s, 2H, CHPiperazine), 3.12 (s, 6H, CHPiperazine, N-CHAlf), 1.74 (s, 4H, CHAlif), 1.37 (s, 4H, CHAlf), FT-IR infrared spectroscopy: 2998 (CHAr, Rozc), 2937; 2859 (CH Alif, Rozc), 1699 (C = O, Rozc), 1590; 1493 (C = C Ar, Rozc), 1366 (CN, Rozc), 775 (C-CI, Rozc), Melting point: mp = 107-110 ° C, TLC thin layer chromatography: retention coefficient R / = 0.52, High performance chromatography liquid HPLC: retention time Rt = 2.97 min, purity = 95%, Yield = 60%,
Compound No. 2
1- {6- [4- (3-chlorophenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.19 (d, J = 8.2 Hz, 1H, ArH), 8.05 (d, J = 7.0 Hz, 1H, ArH), 7.86 - 7.76 (m, 1H, ArH), 7.65 (d, J = 8.5 Hz, 1H, ArH), 7.60 - 7.51 (m, 1H, ArH), 7.32 - 7.18 (m, 2H, ArH), 7.03 (d, J = 2.1 Hz, 1H, ArH), 6.94 (d, J = 8.4 Hz, 1H, ArH), 6.86 (d, J = 7.8 Hz, 1H, ArH), 3.93 - 3.79 (m, 2H, C (O) N-CH), 3.57 - 3.32 (m, 4H, CHpperazine), 3.21 (d, J = 24.0 Hz, 4H, CHPiperazine), 3.07 (d, J = 8.9 Hz, 2H, N-CHAlf), 1.73 (s, 4H, CHAlif), 1.29 ( d, J = 39.7 Hz, 4H, CHAlif), FT-IR infrared spectroscopy: 3005 (CH Ar, Rozc), 2934; 2856 (CH Alif, Rozc), 1696 (C = Rozc), 1593; 1493 (C = C Ar, Rozc), 1360 (CN, Rozc), 768 (C-Cl, Rozc), Melting point: mp = 105-108 ° C, TLC thin layer chromatography: retention coefficient R / = 0.68, High performance chromatography liquid HPLC: retention time Rt = 3.10 min, purity = 91%, Yield = 32%,
Compound No. 3
1- (6- [4- (4-chlorophenyl) piperazin-1-yl] hexyl) benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.05 (t, J = 7.8 Hz, 2H, ArH), 7.80 (d, J = 9.0 Hz, 2H, ArH), 7.77 - 7.69 (m, 1H, ArH), 7.57 (d, J = 8.1 Hz, 1H, ArH), 7.53 - 7.44 (m, 3H, ArH), 6.94 (d, J = 6.9 Hz, 1H, ArH), 4.73 (s, 2H, C ( O) N-CH), 3.97 (t, J = 6.8 Hz, 4H, CHPiperazine), 3.67 (dd, J = 20.4, 9.6 Hz, 4H, CHPiperazine), 3.14 (s, 2H, N-CHAlf), 1.87 ( dd, J = 18.7, 11.3 Hz, 4H, CHAlif), 1.50 (s, 4H, CHAlif), FT-IR infrared spectroscopy: 3013 (CH Ar, Rozc), 2937; 2860 (CH Alif, Rozc), 1738 (C = O, Rozc), 1603; 1491 (C = C Ar, Rozc), 1366 (CN, Rozc), 772 (C-CI, Rozc), High performance liquid chromatography combined with UPLC-MS mass spectrometer: m / z = 448.20, retention time Rt = 5.75 min, purity = 93%, Melting point: mp = 127-130 ° C, TLC thin layer chromatography: retention coefficient R / = 0.66, High performance liquid chromatography HPLC: retention time Rt = 3.03 min, purity = 93%, Yield = 61%,
Compound No. 4
1- (6- [4- (3,4-dichlorophenyl) piperazin-1-yl] hexyl) benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.19 (d, J = 8.1 Hz, 1H, ArH), 8.05 (d, J = 6.9 Hz, 1H, ArH), 7.86 - 7.78 (m, 1H, ArH), 7.65 (d, J = 8.4 Hz, 1H, ArH), 7.61 - 7.53 (m, 1H, ArH), 7.45 (d, J = 9.0 Hz, 1H, ArH), 7.26 - 7.20 (m, 2H, ArH), 6.99 (dd, J = 8.9, 2.8 Hz, 1H, ArH), 3.49 (d, J = 10.8 Hz, 2H, C (O) N-CH), 3.17 (d, J = 11.9 Hz, 4H, CHPiperazine), 3.05 (s, 4H, CHPiperazine), 2.08 (s, 2H, N-CHAlf), 1.73 (s, 4H, CHAlif), 1.36 (s, 4H, CHAlif), FT-IR infrared spectroscopy: 2970 (CH, Ar, Rozc), 2938; 2861 (CH Alif, Rozc), 1699 (C = O, Rozc), 1604; 1494, (C = C Ar, Rozc), 1374 (CN Rozc), 770 (C-CI, Rozc), High performance liquid chromatography combined with UPLC-MS mass spectrometer: m / z = 482.16, retention time Rt = 6.02 min, purity = 90%, Melting point: mp = 115-118 ° C,
PL 240 473 B1
TLC thin layer chromatography: retention factor R / = 0.64, High performance liquid chromatography HPLC: retention time Rt = 4.23 min, purity = 90%, Yield = 43%,
Compound No. 5
1- {6- [4- (2,3-dichlorophenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H, ArH), 8.06 (d, J = 6.9 Hz, 1H, ArH), 7.82 (t, J = 7.5 Hz , 1H, ArH), 7.66 (d, J = 8.4 Hz, 1H, ArH), 7.57 (t, J = 7.7 Hz, 1H, ArH), 7.40 - 7.33 (m, 2H, ArH), 7.22 (dd, J = 10.6, 7.3 Hz, 2H, ArH), 3.92 (t, J = 6.8 Hz, 2H, C (O) N-CH), 3.56 (d, J = 8.8 Hz, 2H, CHPiperazine), 3.13 (d, J = 8.9 Hz, 6H, CHPiperazine), 1.78 - 1.65 (m, 4H, CHAlif), 1.40 (d, J = 17.4 Hz, 4H, CHaj »), FT-IR infrared spectroscopy: 2999 (CH Ar, Rozc), 2930; 2857 (CH Alif, Rozc), 1698 (C = O, Rozc), 1604; 1495, (C = C Ar, Rozc), 1371 (CN Rozc), 768 (C-CI, Rozc), Melting point: mp = 188-190 ° C, Thin layer chromatography TLC: retention coefficient R / = 0.73, High performance chromatography liquid HPLC: retention time Rt = 3.27 min, purity = 91%, Yield = 36%,
Compound No. 6
1- {6- [4- (4-bromophenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.20 (dd, J = 8.1, 5.8 Hz, 1H, ArH), 8.05 (dd, J = 8.9, 7.0 Hz, 1H, ArH), 7.86 - 7.79 ( m, 1H, ArH), 7.65 (t, J = 8.0 Hz, 1H, ArH), 7.60 - 7.52 (m, 1H, ArH), 7.28 - 7.22 (m, 1H, ArH), 7.18 (d, J = 7.0 Hz, 1H, ArH), 7.12 (dd, J = 13.4, 5.3 Hz, 1H, ArH), 6.88 (d, J = 7.7 Hz, 1H, ArH), 6.73 (d, J = 7.9 Hz, 1H, ArH) , 3.90 (dt, J = 19.9, 7.0 Hz, 2H, CHPiperazine), 3.76 (t, J = 7.1 Hz, 2H, C (O) N-CH), 3.55 (s, 2H, CHPiperazine), 3.14 (d, J = 8.9 Hz, 4H, CHPiperazine), 1.76 - 1.64 (m, 4H, CHAlif), 1.37 (d, J = 3.8 Hz, 4H, CHaj »), FT-IR infrared spectroscopy: 3010 (CH Ar, Rozc) , 2938; 2857 (CH Alif, Rozc), 1677 (C = O, Rozc), 1609; 1498, (C = C Ar, Rozc), 1370 (CN Rozc), 745 (C-Br, Rozc), Melting point: mp = 100-104 ° C, TLC thin layer chromatography: retention coefficient R / = 0.87, High performance chromatography liquid HPLC: retention time Rt = 3.04 min, purity = 93%, Yield = 19%,
Relationship No. 7
1- (6- [4- (2-fluorophenyl) piperazin-1-yl] hexyl} -benzo [cd] indo1-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.19 (d, J = 8.0 Hz, 1H, ArH), 8.05 (d, J = 6.9 Hz 1H, ArH), 7.85 - 7.75 (m, 1H, ArH ), 7.65 (d, J = 8.5 Hz, 1H, ArH), 7.60 - 7.51 (m, 1H, ArH), 7.25 - 7.01 (m, 5H, ArH), 3.91 (t, J = 7.0 Hz, 2H, C (O) N-CH), 3.59 - 3.41 (m, 4H, CHPiperazine), 3.15 (d, J = 8.3 Hz, 6H, CHPiperazine, N-CHAlif), 1.72 (s, 4H, CHAlif), 1.37 (s, 4H, CHAlif), FT-IR infrared spectroscopy: 3001 (CH Ar, Rozc), 2942; 2869 (CH Alif, Rozc), 1720 (C = O, Rozc), 1620 (C = N, Rozc), 1554; 1500 (C = C, Ar, Rozc), 1370 (CN, Rozc), Melting point: mp = 179-181 ° C, TLC thin layer chromatography: retention factor R / = 0.74, TLC HPLC high performance liquid chromatography: retention time Rt = 1.68 min, purity = 95%, Efficiency = 52%,
Compound No. 8
1- {6- [4- (2-trifluoromethylphenyl) piperazin-1-yl] hexyl} -benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.05 (dd, J = 11.0, 7.6 Hz, 2H, ArH), 7.76 - 7.69 (m, 1H, ArH), 7.65 (d, J = 7.7 Hz, 1H, ArH), 7.53 (dd, J = 15.0, 7.7 Hz, 4H, ArH), 7.37 - 7.29 (m, 1H, ArH), 6.95 (d, J = 6.8 Hz, 1H, ArH), 3.95 (t, J = 6.9 Hz, 2H, C (O) NCH), 3.80 (t, J = 12.1 Hz, 2H, CHiperazine), 3.55 (d, J = 12.6 Hz, 2H, CHiperazine), 3.04 - 2.93 (m, 4H, CHiperazine), 1.97 (s, 2H, NCHAiif), 1.81 (d, J = 17.4 Hz, 4H, CHai »), 1.48 (s, 4H, CHAlif), Infrared spectroscopy FT-IR: 2985 (CH Ar, Rozc) , 2938; 2858 (CH Alif, Rozc), 1699 (C = O, Rozc), 1602; 1473, (C = C Ar, Rozc), 1374 (CN, Rozc), 1175 (CF, Rozc),
PL 240 473 B1
High performance liquid chromatography combined with a UPLC-MS mass spectrometer: m / z = 482.23, retention time Rt = 6.02 min, purity = 94%, Melting point: mp = 162-164 ° C, TLC thin layer chromatography: retention coefficient R / = 0.52 . High performance liquid chromatography HPLC: retention time Rt = 2.62 min, purity = 94%, Yield = 18%,
Relationship No. 9
1- {6- (4- (3-trifluoromethylphenyl) piperazin-1-yl] hexyl} -benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.19 (d, J = 8.1 Hz, 1H, ArH), 8.05 (d, J = 7.0 Hz, 1H, ArH), 7.86 - 7.75 (m, 1H, ArH), 7.65 (d, J = 8.4 Hz, 1H, ArH), 7.61 - 7.52 (m, 1H, ArH), 7.47 (t, J = 7.8 Hz, 1H, ArH), 7.25 (dd, J = 14.7, 8.5 Hz, 3H, ArH), 7.15 (d, J = 7.5 Hz, 1H, ArH), 3.91 (t, J = 7.0 Hz, 2H, C (O) N-CH), 3.60 - 3.42 (m, 4H, CHPiperazine), 3.17 (d, J = 12.4 Hz, 4H, CHPiperazine), 3.07 (d, J = 7.9 Hz, 2H, N-CHAlif), 1.73 (d, J = 6.2 Hz, 4H, CHant), 1.37 (s , 4H, CHAiif), FT-IR infrared spectroscopy: 2970 (CH Ar, Rozc), 2938; 2865 (CH Alif, Rozc), 1706 (C = O, Rozc), 1602; 1509 (C = C Ar, Rozc), 1366 (CN, Rozc), 1122 (CF, Rozc), High performance liquid chromatography combined with UPLC-MS mass spectrometer: m / z = 482.3, retention time Rt = 5.79 min, purity = 91%, Melting point: mp = 120-124 ° C, TLC thin layer chromatography: retention coefficient R / = 0.64, High performance liquid chromatography HPLC: retention time Rt = 3.28 min, purity = 90%, Yield = 38%,
Compound No. 10
1- {6- [4- (4-trifluoromethylphenyl) piperazin-1-yl] hexyl} -benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H, ArH), 8.05 (dd, J = 9.7, 6.9 Hz, 1H, ArH), 7.82 (dd, J = 8.0, 7.1 Hz, 1H, ArH), 7.65 (t,
J = 6.0 Hz, 1H, ArH), 7.56 (ddd, J = 11.6, 7.5, 4.0 Hz, 3H, ArH), 7.23 (d, J = 7.0 Hz, 1H, ArH), 7.15 (t,
J = 6.1 Hz, 2H, ArH), 4.01 - 3.86 (m, 4H, CHPiperazine), 3.53 (d, J = 11.8 Hz, 2H, C (O) N-CH), 3.24 (t,
J = 12.1 Hz, 2H, CHPiperazine), 3.08 (s, 4H, CHPiperazine), 1.73 (dd, J = 13.8, 7.0 Hz, 4H, CHAiif), 1.37 (s,
4H, CHAlif), FT-IR infrared spectroscopy: 3060 (CH Ar, Rozc), 2943; 2860 (CH Alif, Rozc), 1677 (C = O, Rozc), 1615; 1493, (C = C Ar, Rozc), 1373 (CN Rozc), 1112 (CF, Rozc), Melting point: mp = 203-205 ° C, TLC thin layer chromatography: retention coefficient R / = 0.67, High performance liquid chromatography HPLC : retention time Rt = 3.32 min, purity = 91%, Yield = 40%,
Relationship No. 11
1- {6- [4- (3-methoxyphenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.10 - 8.01 (m, 2H, ArH), 7.78 - 7.68 (m, 1H, ArH), 7.54 (dd, J = 16.7, 7.7 Hz, 3H, ArH ), 7.43 (s, 2H, ArH), 7.02 (s, 1H, ArH), 6.94 (d, J = 6.6 Hz, 1H, ArH), 4.83 (s, 3H, OCH), 4.35 - 4.26 (m, 2H , CONCH), 3.87 (s, 4H, CHPiperazine), 3.72 - 3.61 (m, 4H CHPiperazine), 3.15 (s, 2H, NCHAlif), 1.86 (m, 4H, CHAlif), 1.52 (s, 4H, CHAlif), FT-IR infrared spectroscopy: 2970 (CH Ar, Rozc), 2936; 2863 (CH Alif, Rozc), 1703 (C = O, Rozc), 1616; 1455 (C = C Ar, Rozc), 1365 (CN, Rozc), 1263; 1026 (CO, Diff), Melting point: mp = 141-145 ° C, TLC thin layer chromatography: retention factor R / = 0.46, High performance liquid chromatography HPLC: retention time Rt = 2.90 min, purity = 92%, Yield = 51 %,
Relationship No. 12
- {6- [4- (4-methoxyphenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one
PL 240 473 B1
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.09 - 8.00 (m, 2H, ArH), 7.86 (d, J = 9.0 Hz, 2H, ArH), 7.77 - 7.69 (m, 1H, ArH) , 7.55 (d, J = 8.4 Hz, 2H, ArH), 7.52 - 7.46 (m, 1H, ArH), 6.99 (d, J = 9.0 Hz, 1H, ArH), 6.93 (d, J = 6.8 Hz, 1H , ArH), 4.79 (m, 3H, OCH), 4.33 (s, 2H, CONCH), 3.84 (s, 4H, CHPiperazine), 3.65 (t, J = 15.4 Hz, 4H, CHPiperazine), 3.15 (s, 2H , NCHAlif), 1.86 (dd, J = 18.7.11.3 Hz, 4H, CHAlif), 1.51 (s, 4H, CHant), FT-IR spectroscopy: 3060 (CH Ar Rozc), 2936; 2858 (CH Aj », Rozc), 1700 (C = O, Rozc), 1568; 1397 (C = C Ar, Rozc), 1366 (CN, Rozc), 1261; 1025 (CO, Dilution), High performance liquid chromatography combined with a UPLC-MS mass spectrometer: m / z = 444.28, retention time Rt = 5.08 min, purity = 92%, Melting point: mp = 150-153 ° C, TLC thin layer chromatography : retention ratio R f = 0.52, HPLC High performance liquid chromatography HPLC: retention time Rt = 2.93 min, purity = 93%, Yield = 78%,
Relationship No. 13
1- {6- [4- (2-ethoxyphenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H, ArH), 8.06 (d, J = 6.9 Hz, 1H, ArH), 7.82 (dd, J = 8.1, 7.1 Hz, 1H, ArH), 7.66 (d, J = 8.4 Hz, 1H, ArH), 7.60 - 7.54 (m, 1H, ArH), 7.23 (d, J = 7.0 Hz, 1H, ArH), 6.98 (dd , J = 6.3, 4.4 Hz, 2H, ArH), 6.91 (t, J = 4.2 Hz, 2H, ArH), 4.05 - 4.02 (m, 2H, OCH), 3.92 (t, J = 6.3 Hz, 2H, CONCH ), 3.53 (d, J = 10.2 Hz, 4H, CHPiperazine), 3.14 - 3.10 (m, 4H, CHPiperazine), 2.98 (d, J = 11.1 Hz, 2H, NCHAlif), 1.72 (d, J = 24.4 Hz, 4H, CHAlif), 1.37 (d, J = 1.5 Hz, 4H, CHaj »), 1.34 (d, J = 7.0 Hz, 3H, CHaj»), FT-IR spectroscopy: 3060 (CH Ar Rozc), 2934 ; 2858 (CH Alif, Rozc), 1695 (C = O, Rozc), 1604; 1496 (C = C Ar, Rozc), 1371 (CN, Rozc), 1242; 1036 (CO, Diff), High performance liquid chromatography combined with a UPLC-MS mass spectrometer: m / z = 458.37, retention time Rt = 5.63 min, purity 90%, Melting point: mp = 132-134 ° C, TLC thin layer chromatography: retention factor R / = 0.52, HPLC high performance liquid chromatography: retention time Rt = 2.81 min, purity = 90%, Yield = 82%,
Relationship No. 14
1- {6- [4- (2-pyridinyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.19 (d, J = 8.1 Hz, 1H, ArH), 8.12 (s, 1H, ArH), 8.05 (d, J = 7Ό Hz, 1H, ArH) , 7.87 (s, 1H, ArH), 7.84 - 7.77 (m, 1H, ArH), 7.65 (d, J = 8.5 Hz, 1H, ArH), 7.60 - 7.52 (m, 1H, ArH), 7.23 (d, J = 6.9 Hz, 2H, ArH), 6.92 (s, 1H, ArH), 4.42 (d, J = 13.6 Hz, 2H, CONCH), 3.91 (t, J = 6.9 Hz, 4H, CHPiperazine), 3.61 - 3.45 (m, 4H, CHPiperazine), 3.07 (s, 2H, NCAlif), 1.74 (s, 4H, CHAlif), 1.36 (s, 4H, CHAlif), FT-IR infrared spectroscopy: 3002 (CH Ar Rozc), 2938 ; 2858 (CH Alif, Rozc), 1738 (C = O, Rozc), 1619 (C = N, Rozc), 1537; 1494 (C = C Ar, Rozc), 1373 (CN, Rozc), Melting point: mp = 106-109 ° C, TLC thin layer chromatography: retention coefficient R / = 0.4, HPLC high performance liquid chromatography: retention time Rt = 1.65 min , Purity = 94%, Yield = 56%,
Relationship No. 15
1- (6- [4- (2-pyrimidinyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.44 (d, J = 4.7 Hz, 2H, ArH), 8.19 (d, J = 8.1 Hz, 1H, ArH), 8.05 (d, J = 6.9 Hz , 1H, ArH), 7.80 (d, J = 7.4 Hz, 1H, ArH), 7.65 (d, J = 8.5 Hz, 1H, ArH), 7.59 - 7.52 (m, 1H, ArH), 7.22 (d, J = 7.0 Hz, 1H, ArH), 6.76 (t, J = 4.8 Hz, 1H, ArH), 3.90 (t, J = 6.8 Hz, 2H, CONCh), 3.45 (d, J = 41.9 Hz, 4H, CHPiperazine) , 3.03 (s, 4H, CHPiperazine), 2.11 (d, J = 15.5 Hz, 2H, NCHAlif), 1.73 (s, 4H, CHaj "), 1.36 (s, 4H, CHant), FT-IR infrared spectroscopy: 3001 (CH, Ar, Rozc), 2942; 2869 (CH Alif, Rozc), 1720 (C = O, Rozc), 1604 (C = N, Rozc), 1554; 1500 (C = C, Ar, Rozc), 1370 (CN, Rozc), mp = 179-181 e C, High performance liquid chromatography combined with UPLC-MS mass spectrometer: m / z = 416.23, retention time - Rt = 4.67 min, purity 89%,
PL 240 473 B1
Melting point: mp = 121-124 ° C,
TLC thin layer chromatography: retention factor R / = 0.74, High performance liquid chromatography HPLC: retention time Rt = 1.68 min, purity = 88%, Yield = 38%,
Relationship No. 16
- {6- [4- (2-nitrophenyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.19 (t, J = 7.9 Hz, 2H, ArH), 8.06 (d, J = 6.9 Hz, 1H, ArH), 7.82 (dd, J = 8.0, 7.1 Hz, 2H, ArH), 7.66 (d, J = 8.3 Hz, 2H, ArH), 7.60 - 7.53 (m, 2H, ArH), 7.23 (d, J = 6.9 Hz, 1H, ArH), 3.90 (dd , J = 15.7, 8.8 Hz, 2H, CONCH), 3.77 (s, 8H, CH-piperazine), 3.09 (s, 2H, NCHAlif), 1.73 (s, 4H, CHAlif), 1.36 (s, 4H, CHAlif), Spectroscopy infrared FT-IR: 2990 (CH Ar, Rozc), 2937; 2864 (CH Alif, Rozc), 1686 (C = O, Rozc), 1631; 1310 (NO2, Rozc), 1604; 1495, (C = C Ar, Rozc), 1374 (CN Rozc), Melting point: mp = 188-191 ° C, TLC thin layer chromatography: retention factor R / = 0.68, High performance liquid chromatography HPLC: retention time Rt = 5.60 min , Purity = 92%, Yield = 36%,
Relationship No. 17
1- {6- [4- (8-quinolinyl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.19 (dd, J = 12.6, 8.1 Hz, 1H, ArH), 8.05 (dd, J = 13.2, 8.0 Hz, 1H, ArH), 7.70 (dddd, J = 21.6, 14.6, 10.7, 6.6 Hz, 7H, ArH), 7.40 (d, J = 7.8 Hz, 1H, ArH), 7.28 - 7.01 (m, 2H, ArH), 3.92 (dd, J = 14.5, 7.4 Hz, 4H, CH, CONCH), 3.39 (d, J = 11.4 Hz, 4H, CH-piperazine), 3.26 (d, J = 11.5 Hz, 2H, CH-piperazine), 3.15 (s, 2H, NCHAlif), 1.77 (t, J = 10.4 Hz, 4H, CHAlif), 1.40 (s, 4H, CHAlif), FT-IR infrared spectroscopy: 3061 (CH Ar, Rozc), 2934; 2856 (CH Alif, Rozc), 1694 (C = O, Rozc), 1630 (C = N, Rozc), 1593; 1493 (C = C, Ar, Rozc), 1377 (CN, Rozc), High performance liquid chromatography combined with UPLC-MS mass spectrometer: m / z = 465.35, retention time - Rt = 4.30 min, 91% purity, Melting point: mp = (oil), TLC thin layer chromatography: retention coefficient R / = 0.70, HPLC high performance liquid chromatography: retention time Rt = 5.90 min, purity = 91%, Yield = 38%,
Compound No. 18
1- {6- [4- (1,2-benzisothiazol-3-yl) piperazin-1-yl] hexyl} benzo [cd] indol-2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H, ArH), 8.13 (d, J = 8.2 Hz, 2H, ArH), 8.07 (d, J = 6.9 Hz , 1H, ArH), 7.82 (dd, J = 8.0, 7.1 Hz, 1H, ArH), 7.66 (d, J = 8.4 Hz, 1H, ArH), 7.59 (dd, J = 7.5, 3.6 Hz, 2H, ArH ), 7.49 (d, J = 8.0 Hz, 1H ArH), 7.24 (d, J = 7.0 Hz, 1H ArH), 4.05 (s, 2H, CONCH), 3.93 (t, J = 6.9 Hz, 2H, CH-piperazine) , 3.58 (d, J = 10.9 Hz, 2H, CH-piperazine), 3.45 - 3.36 (m, 4H, CH-piperazine), 3.16 (s, 2H, NCHAlif), 1.73 (d, J = 22.7 Hz, 4H, CHAiif) , 1.39 (s, 4H, CHAiif), FT-IR infrared spectroscopy: 3037 (CH Ar, Rozc), 2945; 2842 (CH Alif, Rozc), 1708 (C = O, Rozc), 1642 (C = N, Rozc), 1540; 1471 (C = C, Rozc), 1371 (CN, Rozc), 692 (SN, Rozc), 660 (CS, Rozc), High performance liquid chromatography combined with UPLC-MS mass spectrometer: m / z = 471.20, retention time - Rt = 5.82 min, purity 93%, Melting point: mp = 193-194 ° C. TLC thin layer chromatography: retention factor R / = 0.82, High performance liquid chromatography HpLC: retention time Rt = 11.16 min, purity = 95%, Yield = 36%,
Relationship No. 19
1- {6- [4- (2-oxo-2,3-dihydro-1,3-benzoxazol-7-yl) piperazin-1-yl] hexyl} benzo [cd] indol2 (1H) -one
PL 240 473 B1
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H, ArH), 8.06 (d, J = 6.9 Hz, 1H, ArH), 7.82 (dd, J = 8.1 , 7.1 Hz, 1H, ArH), 7.66 (d, J = 8.4 Hz, 1H, ArH), 7.57 (dd, J = 8.4, 7.1 Hz, 1H, ArH), 7.40 (d, J = 9.0 Hz, 2H, ArH), 7.23 (d, J = 7.0 Hz, 1H, ArH), 6.95 (s, 2H, ArH), 3.91 (t, J = 7.0 Hz, 2H), 3.78 (d, J = 12.3 Hz, 2H), 3.51 (d, J = 11.1 Hz, 2H, CONCH), 3.14 - 3.00 (m, 6H, CHPiperazine), 3.02 - 2.98 (m, 4H, CHPiperazine), 1.73 (d, J = 6.8 Hz, 4H, CHAlif), 1.36 (s, 4H, CHai "), FT-IR infrared spectroscopy: 2980 (CH Ar, Rozc), 2936; 2858 (CH Alif, Rozc), 1698 (C = O, Rozc), 1603; 1488, (C = C Ar, Rozc), 1373 (CN Rozc), 1266; 1026 (CO, Dilution), High performance liquid chromatography combined with a UPLC-MS mass spectrometer: m / z = 470.11, retention time - Rt = 5.83 min, purity 93%, Melting point: mp = 167-169 ° C, TLC thin layer chromatography : retention coefficient R f = 0.80, HPLC high performance liquid chromatography: retention time Rt = 5.83 min, purity = 93%, Yield = 44%,
The compounds described with Nos. 20-31 were prepared according to the procedure described in Examples 15 and 16, using in the synthesis the intermediates obtained in Examples 3 and 4.
EXAMPLE 15
Preparation of 2- {6- [4- (aryl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -diones
0.001 moles of 2- (6-bromohexyl) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione were triturated in a mortar, 0.00095 moles of arylpiperazine described by the formula (V) selected appropriately for the synthesized compound, 0.003 NaOH and 0.0001 mol DABCO. The triturated mixture was transferred to a round bottom flask and 1 cm 3 of DMF was added to the reaction mixture. Reactions were carried out for 50 seconds in a microwave reactor with a microwave output of 120 W. The progress of the reaction was monitored by TLC. After completion of the reaction, 40 cm 3 of water was added to the mixture and placed in a refrigerator (temperature 4 ° C) for 12 hours. After cooling, the product was filtered off. The crude product was crystallized from methanol. The ligand was dissolved in acetone then converted to the hydrochloride salt with 4M HCl in dioxane.
EXAMPLE 16
Preparation of 2- {6- [4- (aryl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -diones
0.001 moles of 2- (6-bromohexyl) naphtho [1,8-cd] 1,2] thiazole-1,1 (2H) -dione, 0.00095 moles of arylpiperazine described by the formula (V) selected appropriately for the synthesized compound were triturated in a mortar. , and 0.0001 moles of TBAB. The triturated mixture was transferred to a round bottom flask, and then 0.003 mol of triethylamine was added. Reactions were carried out for 15 seconds in a microwave reactor with a microwave output of 200 W. The progress of the reaction was monitored by TLC. After completion of the reaction, 40 cm 3 of water was added to the mixture and placed in a refrigerator (temperature 4 ° C) for 12 hours. After cooling, the product was filtered off. The crude product was crystallized from methanol. The ligand was dissolved in acetone then converted to the hydrochloride salt with 4M HCl in dioxane.
Compound No. 20
2- {6- [4- (2-chiorofenyio) piperazin-1-yio] hexyio} - (2H) naphtho [1,8-cd] [1,2] thiazoio-1,1 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.30 (d, J = 8.2 Hz, 1H, ArH), 8.25 (d, J = 7.2 Hz, 1H, ArH), 7.94 - 7.83 (m, 1H, ArH), 7.64 (dd, J = 15.0, 7.5 Hz, 2H, ArH), 7.45 (d, J = 7.9 Hz, 1H, ArH), 7.36 - 7.31 (m, 1H, ArH), 7.20 (d, J = 6.0 Hz, 1H, ArH), 7.14 - 7.08 (m, 2H, ArH), 3.86 (t, J = 7.3 Hz, 2H, S (O) 2N-CH), 3.63 - 3.49 (m, 2H, CHPiperazine), 3.40 (d, J = 11.3Hz, 2H, CHPiperazine), 3.21 (S, 4H, CHPiperazine), 3.13 (s, 2H, NCHAiif), 1.80 (ddd, J = 32.8, 15.2, 7.8Hz, 4H, CHAiif ), 1.54 - 1.35 (m, 4H, CHAiif), FT-IR infrared spectroscopy: 2987 (CH Ar, Rozc), 2937, 2818 (CH, Alif, Rozc), 1589, 1481 (C = C Ar, Rozc) , 1374 (CN, Rozc), 1309 (S = O, Rozc), 805 (NS, Rozc), 758 (C-Cl, Rozc), Melting point: mp = 199-211 ° C, TLC thin layer chromatography: retention factor R f = 0.64, HPLC high performance liquid chromatography: retention time Rt = 3.81 min, purity = 89%, Yield = 71%,
PL 240 473 B1
Relationship No. 21
2- {6- [4- (3-chlorophenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.05 (dd, J = 11.0, 7.6 Hz, 2H, ArH), 7.76 - 7.69 (m, 1H, ArH), 7.65 (d, J = 7.7 Hz, 1H, ArH), 7.53 (dd, J = 15.0, 7.7 Hz, 4H, ArH), 7.37 - 7.29 (m, 1H, ArH), 6.95 (d, J = 6.8 Hz, 1H, ArH), 3.95 (t, J = 6.9 Hz, 2H, S (O> N-CH), 3.80 (t, J = 12.1 Hz, 2H, CHPiperazine), 3.55 (d, J = 12.6 Hz, 2H, CHPiperazine), 3.04 - 2.93 (m, 4H, CHPiperazine), 1.97 (s, 2H, N-CHAlif), 1.81 (d, J = 17.4 Hz, 4H, CHAlif), 1.48 (s, 4H, CHAlif), FT-IR infrared spectroscopy: 2990 (CH Ar , Rozc), 2933; 2860 (CH Alif, Rozc), 1594, 1487 (C = C Ar, Rozc), 1374 (CN, Rozc), 1308 (S = O, Rozc), 852 (NS, Rozc), 772 (C-Cl, Diff), Melting point: mp = 162-165 ° C, TLC thin layer chromatography: retention coefficient R / = 0.74, High performance liquid chromatography HPLC: retention time Rt = 3.79 min, purity = 88%, Yield = 71 %,
Relationship No. 22
2- {6- [4- (4-chlorophenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.09 (d, J = 8.2 Hz, 1H, ArH), 7.97 (d, J = 7.4 Hz, 1H, ArH), 7.8o (d, J = 8.9 Hz, 3H, ArH), 7.56 (d, J = 7.2 Hz, 1H, ArH), 7.53 - 7.45 (m, 3H, ArH), 6.77 (d, J = 7.4 Hz, 1H, ArH), 4.72 (s, 2H, S (O) 2N-CH), 4.09 (s, 4H, CHPiperazine), 3.68 (d, J = 17.7 Hz, 4H, CHPiperazine), 3.18 (s, 2H, N-CHAlif), 1.98 (s, 4H , CHAlif), 1.60 (s, 4H, CHalif), FT-1R infrared spectroscopy: 2970 (CH Ar, Rozc), 2941, 2860 (CH Alif, Rozc), 1590, 1490 (C = C Ar, Rozc), 1372 (CN, Rozc), 1308 (S = O, Rozc), 827 (NS, Rozc), 771 (C-CI, Rozc), Melting point: mp = 150-152 ° C, TLC thin layer chromatography: retention factor R F = 0.66, HPLC high performance liquid chromatography: retention time Rt = 3.14 min, purity = 90%, Yield = 66%,
Relationship No. 23
2- {6- [4- (2,3-dichlorophenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazol-1,1 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.08 (s, 1H, ArH), 7.96 (s, 1H, ArH), 7.78 (d, J = 7.4Hz, 1H, ArH), 7.57 (d, J = 7.4 Hz, 1H, ArH), 7.48 (d, J = 8.5 Hz, 1H, ArH), 7.21 (s, 2H, ArH), 7.05 (s, 1H, ArH), 6.78 (m, 1H, ArH) , 3.86 (m, 2H, S (O) 2N-CH), 3.64 (m, 4H, CHPiperazine), 3.39 (s, 4H, CHPiperazine), 3.07 (s, 2H, N-CHAlif), 1.98 (s, 4H , CHAlif), 1.57 (s, 4H, CHalif), FT-IR infrared spectroscopy: 3014 (CH Ar, Rozc), 2940, 2853 (CH, Alif, Rozc), 1589, 1494 (C = C Ar, Rozc) , 1376 (CN, Rozc), 1304 (S = O, Rozc), 826 (NS, Rozc), 777 (C-CI, Rozc), High performance liquid chromatography combined with UPLC-MS mass spectrometer: m / z = 518.12, retention time - Rt = 6.21 min, purity 91%, Melting point: mp = 158-160 ° C, TLC thin layer chromatography: retention coefficient R / = 0.70, HPLC high performance liquid chromatography: retention time 3.88 min, purity = 96%, Yield = 72%,
Relationship No. 24
2- {6- [4- (3,4-dichlorophenyl) piperazin-1-yl) hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazol-1,1 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.30 (d, J = 8.1 Hz, 1H, ArH), 8.24 (d, J = 7.1 Hz, 1H, ArH), 7.89 (dd, J = 8.1, 7.4 Hz, 1H, ArH), 7.65 (dt, J = 22.2, 7.5 Hz, 2H, ArH), 7.45 (d, J = 9.0 Hz, 1H, ArH), 7.23 (dd, J = 7.1, 2.9 Hz, 1H , ArH), 7.11 (d, J = 6.6 Hz, 1H, ArH), 7.00 (dd, J = 9.0, 2.9 Hz, 1H, ArH), 3.86 (dd, J = 14.8, 7.8 Hz, 4H, CHPiperazine ), 3.51 (d, J = 11.6 Hz, 2H, S (O) 2N-CH), 3.23 (dd, J = 22.9, 11.2 Hz, 2H, CHPiperazine), 3.12-3.03 (m, 4H, CHPiperazine), 1.88 - 1.72 (m, 4H, CHAlif), 1.43 (ddd, J = 21.4, 14.7, 7.4 Hz, 4H, CHAlif), FT-IR infrared spectroscopy: 3008 (CH Ar, Rozc), 2942, 2858 (CH, Alif , Rozc), 1590, 1495 (C = C Ar, Rozc), 1373 (CN, Rozc), 1308 (S = O, Rozc), 829 (NS, Rozc), 777 (C-Cl, Rozc), Melting point : mp = 130-132 ° C,
PL 240 473 B1
TLC thin layer chromatography: retention ratio R / = 0.87, High performance liquid chromatography HPLC: retention time Rt = 3.47 min, purity = 93%, Yield = 75%,
Compound No. 25
2- {6- [4- (3-trifluoromethylphenyl) piperazin-1-yl] hexyIo} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.30 (d, J = 8.1 Hz, 1H, ArH), 8.24 (d, J = 7.1 Hz, 1H, ArH), 7.90 (dd, J = 8.1, 7.4 Hz, 1H, ArH), 7.65 (dt, J = 22.4, 7.5 Hz, 2H, ArH), 7.47 (t, J = 7.9 Hz, 1H, ArH), 7.30 - 7.24 (m, 2H, ArH), 7.16 (d, J = 5.4 Hz, 1H, ArH), 7.11 (d, J = 6.9 Hz, 1H, ArH), 3.86 (t, J = 7.3 Hz, 2H, S (O) 2N-CH), 3.55 (d , J = 13.5 Hz, 2H, CHPiperazin), 3.52 - 3.45 (m, 2H, CHPiperazin), 3.22 (d, J = 9.6 Hz, 2H, CHPiperazin), 3.10 (dd, J = 21.2, 10.1 Hz, 4H, CHpiperazin ), 1.80 (ddd, J = 23.2, 15.0, 7.6 Hz, 4H, CHAlif), 1.54 - 1.37 (m, 4H, CHa »), FT-IR spectroscopy: 2984 (CH Ar, Rozc), 2940, 2867 (CH, Alif, Rozc), 1591, 1494 (C = C Ar, Rozc), 1374 (CN, Rozc), 1313 (S = O, Rozc), 1228 (CF, Rozc), 822 (nS, Rozc), Melting point: mp = 124-125 ° C, TLC thin layer chromatography: retention factor R / = 0.71, High performance liquid chromatography HPLC: retention time Rt = 3.68 min, purity = 99%, Yield = 89%,
Relationship No. 26
2- {6- [4- (4-trifluoromethylphenyl) piperazin-1-yl] hexyIo} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.29 (d, J = 8.2 Hz, 1H, ArH), 8.24 (d, J = 7.2 Hz, 1H, ArH), 7.92 - 7.85 (m, 1H, ArH), 7.69 - 7.59 (m, 2H, ArH), 7.56 (d, J = 8.8 Hz, 2H, ArH), 7.12 (dd, J = 13.3, 7.9 Hz, 3H, ArH), 3.98 (d, J = 13.4 Hz, 2H, S (O) 2NCH), 3.85 (t, J = 7.3 Hz, 2H, CHPiperazin), 3.55 (d, J = 12.9 Hz, 2H, CHPiperazin), 3.33 (t, J = 11.9 Hz, 2H , CHPiperazin), 3.08 (dd, J = 21.1, 10.0 Hz, 4H, CHPiperazin), 1.86 - 1.76 (m, 4H, CHaj »), 1.43 (ddd, J = 21.1, 14.7, 7.3 Hz, 4H, CHAlif), FT-IR infrared spectroscopy: 3065 (CH Ar, Rozc), 2933, 2855 (CH, Alif, Rozc), 1588, 1499 (C = C Ar, Rozc), 1361 (CN, Rozc), 1340 (S = O , Rozc), 1234 (CF, Rozc), 848 (NS, Rozc), Melting point: mp = 204-206 ° C, TLC thin layer chromatography: retention factor R / = 0.85, HPLC high performance liquid chromatography: retention time Rt = 3.76 min, Purity = 100%, Yield = 46%,
Relationship No. 27
2- {6- [4- (2-fluorophenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.08 (d, J = 7.8 Hz, 1H, ArH), 7.96 (d, J = 6.7 Hz, 1H, ArH), 7.79 - 7.71 (m, 1H, ArH), 7.56 (d, J = 7.3 Hz, 1H, ArH), 7.47 (d, J = 8.6 Hz, 1H, ArH), 7.09 - 7.01 (m, 4H, ArH), 6.77 (d, J = 7.3 Hz , 1H, ArH), 3.85 (t, J = 6.9Hz, 2H, S (O) 2N-CH), 3.73 (s, 2H, CHPiperazin), 3.58 (s, 2H, CHPiperazin), 3.45 (d, J = 11.3 Hz, 4H, CHPiperazin), 3.05 (s, 2H, NCHAlif), 1.97 (s, 4H, CHAlif), 1.66 (s, 4H, CHaj »), FT-IR spectroscopy: 2993 (CH Ar, Rozc) , 2940, 2869 (CH, Alif, Rozc), 1591, 1485 (C = C Ar, Rozc), 1372 (CN, Rozc), 1310 (S = O, Rozc), 1236 (CF, Rozc), 811 (NS , Rozc), High performance liquid chromatography combined with a UPLC-MS mass spectrometer: m / z = 468.21, retention time - Rt = 5.69 min, 100% purity, Melting point: mp = 113-114 ° C, TLC thin layer chromatography: retention factor R f = 0.71, HPLC high performance liquid chromatography: retention time Rt = 1.82 min, purity = 100%, yield rate = 71%,
Relationship No. 28
2- {6- [4- (2-ethoxyphenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.23 (d, J = 8.2 Hz, 1H, ArH), 8.07 (d, J = 8.1 Hz, 1H, ArH), 7.96 (d, J = 7.2 Hz , 1H, ArH), 7.80 - 7.72 (m, 1H,
PL 240 473 B1
ArH), 7.62 - 7.51 (m, 1H, ArH), 7.49 - 7.39 (m, 2H, ArH), 7.05 (dd, J = 15.7, 7.8 Hz, 2H, ArH), 6.75 (d, J = 7.4 Hz, 1H, ArH), 5.02 (m, 2H, OCH), 4.51 (d, J = 12.5 Hz, 2H, SO2NCH), 4.35 (dd, J = 14.2, 7.1 Hz, 4H, CHPiperazine), 3.61 (t, J = 12.5 Hz, 4H, CHPiperazine), 3.16 (s, 2H, NCHAlif), 1.96 (s, 4H, CHAlif), 1.63 (t, J = 7.0 Hz, 4H, CHAlif), 1.56 (s, 3H, CHai »), FT-IR infrared spectroscopy: 2981 (CH Ar, Rozc), 2936, 2867 (CH, Alif, Rozc), 1610, 1491 (C = C Ar, Rozc), 1370 (CN, Rozc), 1309 (S = O , Rozc), 1255; 1033 (CO, Rozc), 815 (NS, Rozc), High performance liquid chromatography combined with UPLC-MS mass spectrometer: m / z = 494.25, retention time - Rt = 5.83 min, purity 88%, Melting point: mp = 140- 143 ° C, TLC thin layer chromatography: retention factor R / = 0.67, High performance liquid chromatography HPLC: retention time Rt = 1.82 min, purity = 90%, Yield = 39%,
Relationship No. 29
2- {6- [4- (2-pyridinyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.30 (dd, J = 8.2, 3.2 Hz, 1H, ArH), 8.25 (dd, J = 7.2, 1.8 Hz, iH, ArH), 8.15 (dd, J = 5.3, 1.4 Hz, 1H, ArH), 7.90 (ddd, J = 10.2, 7.7, 2.8 Hz, 1H, ArH), 7.78 (s, 1H, ArH), 7.68 - 7.60 (m, 2H, ArH), 7.15 - 7.03 (m, 2H, ArH), 6.89 - 6.79 (m, 1H, ArH), 4.40 (d, J = 14.2 Hz, 2H, SO2NCH), 3.85 (dd, J = 14.8, 7.5 Hz, 2H, CHPiperazine ), 3.33 (d, J = 13.0 Hz, 2H, CHPiperazine), 3.09 (dd, J = 13.6, 8.8 Hz, 4H, CHPiperazine), 1.87 - 1.71 (m, 4H, CHAlif), 1.54 - 1.38 (m, 4H , CHaw), FT-IR infrared spectroscopy: 3060 (CH Ar, Rozc), 2932, 2854 (CH, Alif, Rozc), 1640 (C = N, Rozc), 1604, 1497 (C = C Ar, Rozc) , 1373 (CN, Rozc), 1305 (S = O, Rozc), 1256; 1028 (CO, Diff), 817 (NS, Diff), Melting point: mp = 119-121 ° C, TLC thin layer chromatography: retention factor R / = 0.65, HPLC high performance liquid chromatography: retention time Rt = 3.06 min, purity = 89%, Efficiency = 10%,
Relationship No. 30
2- {6- [4- (2-nitrophenyl) piperazin-1-yl] hexyl} - (2H) naphtho [1,8-cd] [1,2] thiazole-1,1 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.29 (d, J = 8.1 Hz, 1H, ArH), 8.24 (d, J = 7.2 Hz, 1H, ArH), 7.92 - 7.85 (m, 1H, ArH), 7.78 (dd, J = 8.1, 1.6 Hz, 1H, ArH), 7.65 (dd, J = 15.3, 8.3 Hz, 2H, ArH), 7.60 - 7.54 (m, 1H, ArH), 7.29 (d, J = 7.3 Hz, 1H, ArH), 7.15 - 7.06 (m, 2H, ArH), 3.84 (t, J = 7.3 Hz, 2H, SO2NCH), 3.44 (s, 4H, CHPiperazine), 3.34 - 3.26 (m, 4H, CHPiperazine), 2.34 - 2.29 (m, 2H, NCHAlif), 1.93 - 1.74 (m, 4H, CHAlif), 1.45 (d, J = 6.5 Hz, 4H, CHAlif), FT-IR infrared spectroscopy: 3061 ( CH Ar, Rozc), 2932, 2865 (CH, Alif, Rozc), 1656; 1342 (NO2, Rozc), 1591, 1492 (C = C Ar, Rozc), 1389 (CN, Rozc), 1343 (S = O, Rozc), 851 (NS, Rozc), High performance liquid chromatography combined with a UPLC mass spectrometer -MS: m / z = 495.32, retention time - Rt = 5.49 min, purity 100%, Melting point: mp = 238-240 ° C, TLC thin layer chromatography: retention coefficient R / = 0.71, High performance liquid chromatography HPLC: retention time Rt = 4.20 min, Purity = 100%, Yield = 43%,
Relationship No. 31
2- {6- [4- (1,2-benzisothiazol-3-yl) piperazin-1-yl] hexyl} - (2H) naphtha [1,8-cd] [1,2] thiazol-1,1 ( 2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.31 (d, J = 8.1 Hz, 1H, ArH), 8.25 (d, J = 7.2 Hz, 1H, ArH), 8.17 - 8.10 (m, 2H, ArH), 7.93 - 7.88 (m, 1H, ArH), .64 (ddd, J = 15.9, 14.4, 8.3 Hz, 3H, ArH), 7.48 (t, J = 7.2 Hz, 1H, ArH), 7.11 (d , J = 6.6 Hz, 1H, ArH), .09 (d, J = 12.8 Hz, 2H, SO2NCH), 3.87 (t, J = 7.3 Hz, 2H, CHPiperazine), 3.61 (d, J = 11.4 Hz, 2H ,
CHPiperazine), 3.39 (d, J = 7.7Hz, 2H, CHPiperazine), 3.27 (s, 2H, CHPiperazine), 3.19 (s, 2H, NCHAlif), 1.90
- 1.85 (m, 2H, CHai "), 1.73 (s, 2H, CHAlif), 1.55 - 1.47 (m, 2H, CHAlif), 1.43 (d, J = 7.3 Hz, 2H, CHAlif). FT-1R infrared spectroscopy: 2978 (CH Ar, Rozc), 2939, 2884 (CH, Alif, Rozc), 1639 (C = N, Rozc), 1594.1476 (C = C Ar, Rozc), 1376 (CN , Rozc), 1298 (S = O, Rozc), 687 (sN, Rozc), Melting point: mp = 117-121 ° C,
PL 240 473 B1
TLC thin layer chromatography: retention ratio R / = 0.87, High performance liquid chromatography HPLC: retention time Rt = 8.97 min, purity = 100%, Yield = 45%,
The compounds described with Nos. 32-44 were prepared according to the procedure described in Examples 17 and 18, using in the synthesis the intermediates obtained in Examples 5 and 6.
EXAMPLE 17
Preparation of 2- {6- [4- (aryl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -diones
0.001 mol of 2- (6-bromohexyl) -1H-benzo [de] isoquinoline-1,3 (2H) -dione, 0.00095 mol of arylpiperazine described by the formula (V) selected appropriately for the synthesized compound, 0.003 mol of K2CO3 and 0.0001 moles of TEAC. The triturated mixture was transferred to a round bottom flask and 5 ml of DMF was added to the reaction mixture. Reactions were carried out for 50 seconds in a microwave reactor with a microwave output of 90 W. The progress of the reaction was monitored by TLC. After completion of the reaction, 40 cm 3 of water was added to the mixture and placed in a refrigerator (temperature 4 ° C) for 12 hours. After cooling, the crude product was filtered off. The crude product was crystallized from methanol, the Ligand was dissolved in acetone then converted to the hydrochloride salt with 4M HCl in dioxane.
EXAMPLE 18
Preparation of 2- {6- [4- (aryl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -diones
0.001 mol of 2- (6-bromohexyl) -1H-benzo [de] isoquinoline-1,3 (2H) -dione, 0.00095 mol of arylpiperazine described by the formula (V) selected appropriately for the synthesized compound, 0.003 mol of Na2CO3 and 0.0001 DABCO. The triturated mixture was transferred to a round bottom flask. Reactions were carried out for 50 seconds in a microwave reactor with a microwave output of 100 W. The progress of the reaction was monitored by TLC. After completion of the reaction, 40 cm 3 of water was added to the mixture and placed in a refrigerator (temperature 4 ° C) for 12 hours. After cooling, the crude product was filtered off. The crude product was crystallized from methanol. The ligand was dissolved in acetone then converted to the hydrochloride salt with 4M HCl in dioxane.
Relationship No. 32
2- {6- [4- (2-methoxyphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.61 (d, J = 7.3 Hz, 2H, ArH), 8.22 (d, J = 7.7 Hz, 2H, ArH), 7.82 - 7.71 (m, 2H, ArH), 7.28 (d, J = 10.5 Hz, 2H, ArH), 7.01 (t, J = 7.2 Hz, 2H, ArH), 4.46 (s, 3H, OCH), 4.23-4.15 (m, 2H, CONCH) , 3.90 (d, J = 54.3 Hz, 4H, CH-piperazine), 3.58 (t, J = 13.2 Hz, 4H, CH-piperazine), 3.07 (s, 2H, NCHAlif), 1.99 (s, 2H, CHAlif), 1.78 (s , 2H, CHAlif), 1.50 (s, 4H, CHAlif), FT-IR infrared spectroscopy: 3060 (CH Ar, Rozc), 2932; 2859 (CH Alif, Rozc), 1694 (C = O, Rozc), 1590; 1492 (C = C Ar, Rozc), 1361 (CN, Rozc), 1242; 1026 (CO, Diff), High performance liquid chromatography combined with a UPLC-MS mass spectrometer: m / z = 472.26, retention time - Rt = 5.43 min, 92% purity, Melting point: mp = 245-248 ° C, TLC thin layer chromatography : retention factor R / = 0.70, High performance liquid chromatography HPLC: retention time Rt = 2.73 min, purity = 92%, Yield = 47%,
Relationship No. 33
2- {6- [4- (3-methoxyphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.52 - 8.43 (m, 4H, ArH), 7.90 - 7.84 (m, 2H, ArH), 7.16 (td, 'J = 8.2, 2.6 Hz, 1H, ArH), 6.60 - 6.56 (m, 1H, ArH), 6.53 (dt, J = 4.5, 2.3 Hz, 1H, ArH), 6.48 - 6.41 (m, 1H, ArH), 4.04 (dd, J = 15.1 , 7.8 Hz, 2H, CONCH), 3.84 - 3.76 (m, 2H, CH-piperazine), 3.58 - 3.46 (m, 2H, CH-piperazine, 3.38 (dd, J = 12.4, 7.0 Hz, 2H, CH-piperazine), 3.18 (d, J = 11.2 Hz, 2H, CH-piperazine), 3.08 (d, J = 9.9 Hz, 2H, NCHAlif), 1.79 - 1.61 (m, 4H, CHAlif), 1.43 - 1.33 (m, 4H, CHAlif), FT infrared spectroscopy -iR: 3060 (CH Ar, Rozc), 2938; 2864 (CH Alif, Rozc), 1686 (C = O, Rozc), 1590; 1494 (C = C Ar, Rozc), 1371 (CN, Rozc), 1233 1027 (CO, Rozc), High performance liquid chromatography combined with a UPLC-MS mass spectrometer: m / z = 472.26, retention time - Rt = 5.56 min, purity = 90%,
PL 240 473 B1
Melting point: mp = 240-243 ° C, TLC thin layer chromatography: retention factor R / = 0.67, High performance liquid chromatography HPLC: retention time Rt = 4.20 min, purity = 89%, Yield = 43%,
Relationship No. 34
22- {6- [4- (4-methoxyphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.50 (ddd, J = 9.3, 7.8, 1.0 Hz, 4H, ArH), 7.90 (dd, J = 8.1,7.4 Hz, 2H, ArH), 7.58 ( d, J = 8.8 Hz, 2H, ArH), 7.15 (d, J = 8.8 Hz, 2H, ArH), 4.11 - 4.05 (m, 2H, ArH, CONCH), 4.00 (d, J = 13.1 Hz, 2H CHPiperazine ), 3.56 (s, 2H, NCHAlif), 3.15 (dt, J = 23.1, 12.3 Hz, 6H CHPiperazine), 1.69 (dd, J = 14.3, 6.9 Hz, 4H, CHa »), 1.40 (d, J = 3.2 Hz, 4H, CHAlif), FT-IR Infrared Spectroscopy: 3064 (CH Ar, Rozc), 2937; 2863 (CH Alif, Rozc), 1696 (C = O, Rozc), 1590; 1439 (C = C Ar, Rozc), 1346 (CN, Rozc), 1236; 1071 (CO, Rozc), High performance liquid chromatography combined with a UPLC-MS mass spectrometer: m / z = 472.26, retention time - Rt = 5.99 min, 100% purity, Melting point: mp = 147-150 ° C, TLC thin layer chromatography : retention factor R / = 0.69, High performance liquid chromatography HPLC: retention time Rt = 3.80 min, purity = 99%, Yield = 16%,
Compound No. 35
2- {6- [4- (2-ethoxyphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.61 (d, J = 7.2 Hz, 2H, ArH), 8.23 (t, J = 7.4 Hz, 3H, ArH), 7.80 - 7.72 (m, 2H, ArH), 7.45 (t, J = 7.9 Hz, 1H, ArH), 7.05 (dd, J = 15.6, 7.5 Hz, 2H, ArH), 5.03 (d, J = 12.3 Hz, 3H, OCH), 4.54 (s , 2H, CONCH), 4.35 (dd, J = 13.9, 6.9 Hz, 2H, CHPiperazine), 4.23 - 4.14 (m, 2H, CHPiperazine), 3.66 (s, 4H, CHPiperazine), 3.14 (s, 2H, NCHAlif) , 1.98 (s, 2H, CHAlif), 1.78 (s, 2H, CHAlif), 1.64 (t, J = 7.0 Hz, 3H, CHAlif), 1.50 (s, 4H, CHAlif), FT-IR infrared spectroscopy: 3063 (CH, Ar, Rozc), 2936; 2867 (CH Alif, Rozc), 1694 (C = O, Rozc), 1599; 1500 (C = C Ar, Rozc), 1347 (CN, Rozc), 1240; 1029 (CO, Dilute), Melting point: mp = 240-243 ° C, TLC thin layer chromatography: retention factor R / = 0.65, High performance liquid chromatography HPLC: retention time Rt = 3.12 min, purity = 89%, Yield = 19% ,
Relationship No. 36
2- {6- [4- (2-pyridinyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.62 (t, J = 8.1 Hz, 2H, ArH), 8.24 (t, J = 7.6 Hz, 2H, ArH), 8.0Ϊ (s, 2H, ArH ), 7.83 - 7.74 (m, 2H, ArH), 7.05 (d, J = 26.7 Hz, 2H, ArH), 4.57 (s, 2H, CONCH), 4.32 (s, 2H, CHPiperazine), 4.25 - 4.15 (m , 2H, CHPiperazine), 3.73 (s, 2H, CHPiperazine), 3.18 (s, 2H, CHPiperazine), 3.08 (s, 2H, NCHAlif), 2.00 (s, 4H, CHAlif, 1.79 (s, 4H, CHAlif), FT-IR infrared spectroscopy: 3061 (CH Ar, Rozc), 2933; 2855 (CH Alif, Rozc), 1692 (C = O, Rozc), 1658 (C = N, Rozc), 1587; 1513 (C = C Ar, Rozc), 1340 (CN, Rozc), High performance liquid chromatography combined with a UPLC-MS mass spectrometer: m / z = 443.22, retention time - Rt = 4.25 min, 90% purity, Melting point: mp = 176-179 ° C, TLC thin layer chromatography: retention factor R / = 0.54, High performance liquid chromatography HPLC: retention time Rt = 3.73 min, purity = 89%, Yield = 50%,
Relationship No. 37
2- {6- [4- (2-nitrophenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.63 (dd, J = 7.3, 0.9 Hz, 2H, ArH), 8.25 (dd, J = 8.3, 0.9 Hz, 2H, ArH), 7.87 (dd, J = 8.1, 1.5 Hz, 1H, ArH), 7.83 - 7.74 (m, 2H, ArH), 7.64 - 7.57 (m, 1H, ArH), 7.36 (dd, J = 8.2, 1.1 Hz, 1H, ArH), 7.28 - 7.24 (m, 1H,
PL 240 473 B1
ArH), 4.26-4.18 (m, 2H, CONCH), 3.89 (t, J = 11.3 Hz, 2H, CHPiperazine), 3.60 (t, J = 9.5 Hz, 2H, CH-pperazine), 3.32 (d, J = 12.9 Hz , 2H, NCHant), 3.15 - 2.99 (m, 4H, CHPiperazine), 2.01 (s, 2H, CHant), 1.83 - 1.76 (m, 2H, CHant), 1.52 (s, 4H, CHant), FT infrared spectroscopy -IR: 3060 (CH Ar, Rozc), 2934; 2856 (CH Alif, Rozc), 1693 (C = O, Rozc), 1656; 1308 (NO2, Rozc), 1589; 1513, (C = C Ar, Rozc), 1361 (CN Rozc), Melting point: mp = 230-231 ° C, TLC thin layer chromatography: retention factor R / = 0.66, High performance liquid chromatography HPLC: retention time Rt = 5.82 min , Purity = 96%, Yield = 19%,
Relationship No. 38
2- {6- [4- (2-fluorophenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.55 - 8.44 (m, 4H, ArH), 7.92 - 7.86 (m, 2H, ArH), 7.80 - 7.71 (m, 4H, ArH), 4.07 (dd , J = 16.2, 8.8 Hz, 2H, CONCH), 3.57 - 3.48 (m, 2H, CHPiperazine), 3.44 (s, 8H, CHPiperazine), 1.81 (dd, J = 14.4, 6.9 Hz, 2H, CHAiif), 1.65 (dt, J = 14.8, 7.4 Hz, 2H, CHant), 1.47 - 1.35 (m, 4H, CHant), FT-IR infrared spectroscopy: 3002 (CH Ar, Rozc), 2944; 2866 (CH Alif, Rozc), 1698 (C = O, Rozc), 1587; 1500 (C = C Ar, Rozc), 1337 (CN, Rozc), 1234 (CF, Rozc), High performance liquid chromatography combined with UPLC-MS mass spectrometer: m / z = 460.23 retention time - Rt = 5.61 min, purity = 97%, Melting point: mp = 111-113 ° C, TLC thin layer chromatography: retention factor R / = 0.63, High performance liquid chromatography HPLC: retention time Rt = 5.61 min, purity = 97%, Yield = 43%,
Relationship No. 39
2- {6- [4- (2-trifluoromethylphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.62 (dd, J = 7.3, 0.9 Hz, 2H, ArH), 8.24 (dd, J = 8.3, 0.9 Hz, 2H, ArH), 7.78 ( dd, J = 8.1, 7.4 Hz, 2H, ArH), 7.66 (d, J = 7.7 Hz, 1H, ArH), 7.61 - 7.52 (m, 2H, ArH), 7.33 (t, J = 7.5 Hz, 1H, ArH), 4.24-4.17 (m, 2H, CONCH), 3.81 (t, J = 10.8 Hz, 2H, CHPiperazine), 3.57 (t, J = 10.5 Hz, 2H, CHPiperazine), 3.04 (dd, J = 12.9, 4.0 Hz, 4H, CHPiperazine), 2.01 (s, 2H, NCHant), 1.78 (d, J = 9.6 Hz, 4H, CHant), 1.54 - 1.46 (m, 4H, CHAiif). Infrared spectroscopy FT-IR: 3055 (CH Ar, Rozc), 2945; 2869 (CH Alif, Rozc), 1696 (C = O, Rozc), 1590; 1493 (C = C Ar, Rozc), 1343 (CN, Rozc), 1233 (CF, Rozc), Melting point: mp = 167-169 ° C, TLC thin layer chromatography: retention factor R / = 0.76, HPLC high performance liquid chromatography : retention time Rt = 5.81 min, purity = 98%, Yield = 52%,
Compound No. 40
2- {6- [4- (3-trifluoromethylphenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.62 (t, J = 6.0 Hz, 2H, ArH), 8.24 (d, J = 8.2 Hz, 4H, ArH), 7.84 - 7.72 (m, 2H, ArH), 7.64 - 7.54 (m, 2H, ArH), 4.46 (t, J = 11.4 Hz, 2H, CONCH), 4.24 - 4.18 (m, 2H, CHplperazine), 3.78 - 3.69 (m, 6H, CHPiperazine ), 3.16 (s, 2H, NCHant), 2.00 (s, 2H, CHant), 1.86 - 1.74 (m, 2H, CHant), 1.54 (s, 4H, CHant), FT-IR spectroscopy: 3064 (CH Ar, Rozc), 2936; 2865 (CH Alif, Rozc), 1696 (C = O, Rozc), 1591; 1440 (C = C Ar, Rozc), 1348 (CN, Rozc), 1239 (CF, Rozc), Melting point: mp = 112-116 ° C, TLC thin layer chromatography: retention coefficient R / = 0.84, High performance liquid chromatography HPLC : retention time Rt = 6.22 min, purity = 100%, Yield = 29%,
Relationship No. 41
2- {6- [4- (4-bromophenyl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.66 - 8.59 (m, 2H, ArH), 8.25 (dd, J = 8.0, 3.0 Hz, 2H, ArH), 7.83 - 7.76 (m, 2H, ArH ), 7.56 (d, J = 7.7 Hz,
PL 240 473 B1
2H, ArH), 7.37 (s, 2H, ArH), 4.35 (s, 2H, CONCH), 4.25-4.17 (m, 2H, CHPiperazine), 3.68 (s, 4H, CH-piperazine), 3.12 (s, 2H, CHPiperazine), 2.00 (s, 2H, NCHAlf), 1.79 (d, J = 7.3 Hz, 4H, CHAlif), 1.54 (s, 4H, CHAlif). FT-IR infrared spectroscopy: 2983 (CH Ar, Rozc), 2939; 2870 (CH Alif, Rozc), 1696 (C = O, Rozc), 1592; 1437 (C = C, Rozc), 1377 (CN, Rozc), 746 (C-Br, Rozc), Melting point: mp = 188-189 ° C,
TLC thin layer chromatography: retention factor R / = 0.71,
HPLC high performance liquid chromatography: retention time Rt = 7.22 min, purity = 99%, Yield = 12%,
Relationship No. 42
2- {6- [4- (1,2-benzisothiazol-3-yl) piperazin-1-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.50 (dd, J = 14.4, 7.6 Hz, 4H, ArH), 8.16 - 8.08 (m, 2H, ArH), 7.88 (d, J = 7.7 Hz, 2H, ArH), 7.60 (t, J = 7.6 Hz, 1H, ArH), 7.47 (t, J = 7.4 Hz, 1H, ArH), 3.64 (d, J = 19.2 Hz, 2H, CONCH), 3.59 (d , J = 12.1 Hz, 2H, CHPiperazine), 3.47 (t, J = 12.3 Hz, 2H, CHPiperazine), 3.37 - 3.20 (m, 4H, CHPiperazine), 3.16 (s, 2H, NCHAlif), 1.73 (d, J = 19.2 Hz, 2H, CHAlif), 1.69 (s, 2H, CHAlif), 1.41 (s, 4H, CHAlif).
FT-IR infrared spectroscopy: 3062 (CH Ar, Rozc), 2942, 2874 (CH, Alif, Rozc), 1693 (C = O, Rozc), 1656 (C = N, Rozc), 1589.1493 (C = C Ar, Rozc), 1354 (CN, Rozc), 697 (SN, Rozc), TLC thin layer chromatography: retention coefficient R / = 0.47,
HPLC high performance liquid chromatography: retention time Rt = 5.83 min, purity = 100%, Yield = 47%,
Relationship No. 43
2- {6- [4 - {[1-oxo-2,3-dihydro-1H-isoindol-2-yl] hexyl} -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.55 - 8.43 (m, 4H, ArH), 7.87 (dt, J = 14.4, 7.2 Hz, 2H, ArH), 6 7.75 - 7.43 (m, 3H, ArH) 4.09 - 4.01 (m, 2H, CONCH), 3.53 (t, J = 6.7 Hz, 2H, CONCH), 3.37 (s, 10H, CHPiperazine), 1.85 - 1.76 (m, 2H, CHAlif), 1.65 (dt , J = 14.7, 7.4 Hz, 2H, CHAlif), 1.45 - 1.32 (m, 4H, CHAlif).
FT-IR infrared spectroscopy: 3058 (CH Ar, Rozc), 2934; 2854 (CH Alif, Rozc), 1693 (C = O, Rozc), 1590; 1436 (C = C Ar, Rozc), 1341 (CN, Rozc), 1246; 1066 (CO, Diff), Melting point: mp = 111-112 ° C,
TLC thin layer chromatography: retention factor R / = 0.63,
HPLC high performance liquid chromatography: retention time Rt = 4.38 min, purity = 91%, Yield = 12%,
Compound No. 44
2- [6- (4 - {[1,1'-biphenyl] -2-yl} piperazin-1-yl) hexyl] -1H-benzo [de] isoquinoline-1,3 (2H) -dione
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.49 (ddd, J = 9.2, 7.8, 0.9 Hz, 6H, ArH), δ 7.76 (d, J = 7.2 Hz, 2H, ArH), 7.52 (d , J = 7.2 Hz, 2H, ArH), 7.42 (t, J = 7.5 Hz, 2H, ArH), 7.88 (dd, J = 8.1, 7.4 Hz, 3H, ArH), 4.10 - 4.01 (m, 2H, CONCH ), 3.59 - 3.48 (m, 2H, CHPiperazine), 3.36 - 3.01 (s, 8H, CHPiperazine), 1.87 - 1.76 (m, 2H, CHAlif), 1.65 (dt, J = 14.7, 7.4 Hz, 2H, CHAlif) , 1.49 - 1.34 (m, 4H, CHAlif).
FT-IR infrared spectroscopy: 3023 (CH Ar, Rozc), 2942, 2874 (CH, Alif, Rozc), 1693 (C = O, Rozc), 1590.1436 (C = C Ar, Rozc), 1345 (CN , Rozc),
Melting point: mp = 118-122 ° C,
TLC thin layer chromatography: retention factor R / = 0.72,
HPLC high performance liquid chromatography: retention time Rt = 6.50 min, purity = 100%, Yield = 19%,
Compounds described in Nos. 45-47 were prepared according to the procedure described in Examples 19-20, using the intermediates obtained in Examples 7-8 in the synthesis.
EXAMPLE 19
Preparation of 1- {6- [4- (aryl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) -ones
PL 240 473 B1
0.001 mol of 1- (6-bromohexyl) -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin2 (1H) -one, 0.00095 mol of arylpiperazine described by the formula (V) was triturated in a mortar. to the synthesized compound, 0.003 mol of NaOH and 0.0001 mol of TBAB. The triturated mixture was transferred to a round bottom flask and 1 cm 3 of ACN was added to the reaction mixture. Reactions were carried out for 30 seconds in a microwave reactor with a microwave output of 130 W. The progress of the reaction was monitored by TLC. After completion of the reaction, 40 cm 3 of water was added to the mixture and placed in a refrigerator (temperature 4 ° C) for 12 hours. After cooling, the crude product was filtered off. The crude product was crystallized from methanol. The ligand was dissolved in acetone then converted to the hydrochloride salt with 4M HCl in dioxane.
EXAMPLE 20
Preparation of 1- (6- [4- (aryl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) -ones
0.001 mol of 1- (6-bromohexyl) -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin2 (1H) -one, 0.00095 mol of arylpiperazine described by the formula (V) was triturated in a mortar. to the synthesized compound, 0.003 mol K2CO3 and 0.0001 mol TEAC. The triturated mixture was transferred to a round bottom flask. Reactions were carried out for 50 seconds in a microwave reactor with a microwave output of 100 W. The progress of the reaction was monitored by TLC. After completion of the reaction, 40 cm 3 of water was added to the mixture and placed in a refrigerator (temperature 4 ° C) for 12 hours. After cooling, the crude product was filtered off. The crude product was crystallized from methanol. The ligand was dissolved in acetone then converted to the hydrochloride salt with 4M HCl in dioxane.
Compound No. 45
1- {6- [4- (2-methoxyphenyl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin 2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (400 MHz, CDCl3) δ 8.27 (d, J = 7.6 Hz, 1H, ArH), 7.49 (t, J = 7.9 Hz, 1H, ArH), 7.08 (dd, J = 8.0, 3.2 Hz, 2H, ArH), 6.99 (t, J = 7.7 Hz, 1H, ArH), 6.84 (dd, J = 12.1, 7.7 Hz, 2H, ArH), 5.18 (t, J = 11.4 Hz, 3H, OCH ), 4.45 (d, J = 12.6 Hz, 2H, CONCH), 4.08 (d, J = 7.8 Hz, 4H, CHPiperazine), 3.88 (t, J = 5.6 Hz, 4H, CHPiperazine), 3.59 (d, J = 11.2 Hz, 2H, NCHAlif), 3.10 (s, 2H, NCHAlif), 2.87 (t, J = 6.0 Hz, 2H, CHant), 2.14 (dd, J = 11.8, 6.1 Hz, 2H, CHAlif), 1.93 (s , 2H, CHAlif), 1.84 - 1.74 (m, 2H, CHat), 1.45 (s, 4H, CHat), FT-IR spectroscopy: 3017 (CH Ar, Rozc), 2939; 2860 (CH Alif, Rozc), 1676 (C = O Rozc), 1609; 1499 (C = C Ar, Rozc), 1369 (CN, Rozc), 1264; 1016 (CO, Dilution), High performance liquid chromatography combined with a UPLC-MS mass spectrometer: m / z = 449.33, retention time - Rt = 5.03 min, purity 91%, Melting point: mp = 115-117 ° C, TLC thin layer chromatography : retention coefficient R f = 0.85, High performance liquid chromatography HPLC: retention time Rt = 4.16 min, purity = 91%, Yield = 84%,
Relationship No. 46
1- {6- [4- (3-chlorophenyl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin2 (1H) -one
1H NMR hydrogen magnetic resonance spectrum (300 MHz, cdcl3) δ 7.54 (s, 1H, ArH), 7.39 (d, J = 7.9 Hz, 2H, ArH), 7.25 (s, 1H, ArH), '6.99 (t , J = 7.7 Hz, 1H, ArH), 6.84 (dd, J = 12.5, 7.6 Hz, 2H, ArH), 4.37 (s, 2H, CONCH), 3.86 (dt, J = 14.2, 6.9 Hz, 4H, CHPiperazine ), 3.65 (d, J = 11.8 Hz, 6H, CHPiperazine), 3.10 (s, 2H, NCHAlif), 2.86 (t, J = 5.7 Hz, 2H, CHAlif), 2.20 - 2.08 (m, 2H, CHAlif ), 1.93 (s, 2H, CHAlif), 1.85 - 1.71 (m, 2H, CHAlif), 1.46 (s, 4H, CHAlif). Infrared spectroscopy FT-IR: 3060 (CH Ar, Rozc), 2937; 2861 (CH Alif, Rozc), 1700 (C = O Rozc), 1594; 1498 (C = C Ar, Rozc), 1374 (CN, Rozc), 763 (C-CI, Rozc), Melting point: mp = 165-168 ° C, TLC thin layer chromatography: retention coefficient R f = 0.66, High performance chromatography liquid HPLC: retention time Rt = 4.98 min, purity = 91%, Yield = 53%,
PL 240 473 B1
Relationship No. 47
1- {6- [4- (1,2-benzisothiazol-3-yl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 ( 1H) -on
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 8.12 (t, J = 8.6 Hz, 2H, ArH), 7.60 (t, J = 7.6 Hz, 1H, ArH), 7.48 (t, J = 7.2 Hz , 1H, ArH), 7.00 (d, J = 7.6 Hz, 1H, ArH), 6.93 (dd, J = 9.5, 5.8 Hz, 1H, ArH), 6.83 (d, J = 7.4 Hz, 1H, ArH), 4.05 (d, J = 13.7 Hz, 2H, CONCH), 3.78 (dt, J = 11.4, 6.4 Hz, 4H, CH-piperazine), 3.58 - 3.44 (m, 4H, CH-piperazine), 3.31 - 3.21 (m, 2H, NCHAlif ), 3.11 (dt, J = 10.5, 5.1 Hz, 2H, NCHa »), 2.79 (t, J = 5.8 Hz, 2H, CHAiif), 2.02 (dd, J = 11.4, 5.8 Hz, 2H, CHAlif), 1.69 (dd, J = 13.7, 6.9 Hz, 4H, CHat), 1.35 (d, J = 3.6 Hz, 4H, CHat). FT-IR infrared spectroscopy: 3067 (CH Ar, Rozc), 2935; 2859 (CH Alif, Rozc), 1672 (C = O Rozc), 1642 (C = N, Rozc), 1589; 1498 (C = C Ar, Rozc), 1379 (CN, Rozc), 677 (SN, Rozc), 656 (CS, Rozc), TLC thin layer chromatography: retention coefficient R / = 0.80, HPLC high performance liquid chromatography: retention time Rt = 4.54 min, purity = 89%, Yield = 67%,
The compound described by number 48 was prepared according to the procedure described in examples 21-22, using in the synthesis the intermediates obtained in examples 9-10.
EXAMPLE 21
Preparation of 1- (6- [4- (aryl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) -thion
0.001 mol of 1- (6-bromohexyl) -5,6-dihydro-4H-imidazo [4,5,1-ij] quinotin2 (1H) -thione, 0.00095 mol of arylpiperazine described by the formula (V) was triturated in a mortar. to the synthesized compound, 0.003 mol of NaOH and 0.0001 mol of TEAC. The triturated mixture was transferred to a round bottom flask and 5 cm 3 of water was added to the reaction mixture. Reactions were carried out for 50 seconds in a microwave reactor with a microwave output of 80 W. The progress of the reaction was monitored by TLC. After completion of the reaction, 40 cm 3 of water was added to the mixture and placed in a refrigerator (temperature 4 ° C) for 12 hours. After cooling, the product was filtered off. The crude product was crystallized from methanol. The ligand was dissolved in acetone then converted to the hydrochloride salt with 4M HCl in dioxane.
EXAMPLE 22
Preparation of 1- {6- [4- (aryl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) -thion
0.001 mol of 1- (6-bromohexyl) -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin2 (1H) -thione, 0.00095 mol of arylpiperazine described by the formula (V) was triturated in a mortar. to the synthesized compound, 0.003 mol K2CO3 and 0.0001 mol TBAB. The triturated mixture was transferred to a round bottom flask. Reactions were carried out for 15 seconds in a microwave reactor with a microwave output of 180 W. The progress of the reaction was monitored by TLC. After completion of the reaction, 40 cm 3 of water was added to the mixture and placed in a refrigerator (temperature 4 ° C) for 12 hours. After cooling, the product was filtered off. The crude product was crystallized from methanol. The ligand was dissolved in acetone then converted to the hydrochloride salt with 4M HCl in dioxane.
Relationship No. 48
1- {6- [4- (3-chlorophenyl) piperazin-1-yl] hexyl} -5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2 (1H) -thion
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 7.48 (d, J = 8.2 Hz, 1H, ArH), 7.33 - 7.24 (m, 2H, ArH), 7.17 (d, J = 6.6 Hz, 1H, ArH), 7.06 (t, J = 2.1 Hz, 1H, ArH), 6.97 (dd, J = 8.4, 2.0 Hz, 1H, ArH), 6.88 (dd, J = 7.8, 1.4 Hz, 1H, ArH), 4.22 - 4.13 (m, 2H), 3.87 (d, J = 12.6 Hz, 2H, CH-piperazine), 3.23 - 2.99 (m, 8H, CH-piperazine), 2.96 (t, J = 5.9 Hz, 2H, CHAlif), 2.23 - 2.17 (m, 2H, CHaj »), 1.81 - 1.69 (m, 6H, CHAlif), 1.48 (dt, J = 14.3, 7.2 Hz, 2H, CHAiif), 1.39 - 1.30 (m, 2H, CHAlif), Infrared spectroscopy FT-IR: 3057 (CH Ar, Rozc), 2937; 2861 (CH Alif, Rozc), 1590; 1491 (C = C Ar, Rozc), 1386 (CN, Rozc), 767 (C-CI, Rozc) 654 (CS, Rozc), High performance liquid chromatography combined with UPLC-MS mass spectrometer: m / z = 469.27, time retention - Rt = 4.43 min, purity 93%, Melting point: mp = 112-113 ° C, TLC thin layer chromatography: retention coefficient R / = 0.78,
PL 240 473 B1
HPLC high performance liquid chromatography: retention time Rt = 4.46 min, purity = 93%, Yield = 43%,
The compound described by number 49 was prepared according to the procedure described in examples 23 and 24, using in the synthesis the intermediates obtained in examples 11 and 12.
EXAMPLE 23
Preparation of 1- {6- [4- (aryl) piperazin-1-yl] hexyl} -1H, 4H- [1,2,5] thiadiazolo [4,3,2-ij] quinoline-2,2-dioxide
0.001 mol of 1- (6-bromohexyl) -1H, 4H- [1,2,5] thiadiazolo [4,3,2-ij] quinoline, 0.00095 mol of arylpiperazine described by the formula (V ) selected appropriately for the synthesized compound, 0.003 mol of NaOH and 0.0001 mol of TBAB. The triturated mixture was transferred to a round bottom flask and 2 ml of ACN was added to the reaction mixture. Reactions were carried out for 45 seconds in a microwave reactor with a microwave output of 100 W. The progress of the reaction was monitored by TLC. After completion of the reaction, 40 cm 3 of water was added to the mixture and placed in a refrigerator (temperature 4 ° C) for 12 hours. After cooling, the crude product was filtered off. The crude product was crystallized from methanol. The ligand was dissolved in acetone then converted to the hydrochloride salt with 4 M HCl in dioxane.
EXAMPLE 24
Preparation of 1- {6- [4- (aryl) piperazin-1-yl] hexyl} -1H, 4H- [1,2,5] thiadiazolo [4,3,2-ij] quinoline-2,2-dioxide
0.001 mol of 1- (6-bromohexyl) -1H, 4H- [1,2,5] thiadiazolo [4.3.2ij] quinoline, 0.00095 mol of arylpiperazine described by the formula (V) was triturated in a mortar According to the synthesized compound, 0.003 mol of NaOH and 0.0001 mol of DABCO, respectively. The triturated mixture was transferred to a round bottom flask. Reactions were carried out for 60 seconds in a microwave reactor with a microwave output of 60 W. The progress of the reaction was monitored by TLC. After completion of the reaction, 40 cm 3 of water was added to the mixture and placed in a refrigerator (temperature 4 ° C) for 12 hours. After cooling, the crude product was filtered off. The crude product was crystallized from methanol. The ligand was dissolved in acetone then converted to the hydrochloride salt with 4M HCl in dioxane.
Relationship No. 49
1- {6- [4- (3-chlorophenyl) piperazin-1-yl] hexyl} -1H, 4H- [1,2,5] thiadiazolo [4,3,2-ij] quinoline-2,2-dioxide
1H NMR hydrogen magnetic resonance spectrum (400 MHz, DMSO) δ 7.42 - 7.21 (m, 3H, ArH), 6 7.11 - 6.90 (m, 2H, ArH), 7.17 (d, J = 6.6 Hz, 1H, ArH) , δ 6.81 - 6.78 (m, 1H, ArH), 4.22 - 4.13 (m, 2H, S (O) 2N-CH), 3.87 (d, J = 12.6 Hz, 2H, CHPiperazine), 3.21 - 2.95 (m, 8H, CHPiperazine), 2.96 - 2.85 (m, 2H, CHai »), 2.13 - 2.10 (m, 2H, CHAlif), 1.80 - 1.62 (m, 6H, CHAlif), 1.48 - 1.43 (m, 2H, CHAiif), 1.39-1.30 (m, 2H, CHAiif), FT-1R infrared spectroscopy: 3051 (CH Ar, Rozc), 2943; 2844 (CH Alif, Rozc), 1575; 1499 (C = C Ar, Rozc), 1367 (CN, Rozc), 771 (C-CI, Rozc), High performance liquid chromatography combined with UPLC-MS mass spectrometer: m / z = 489.28, retention time - Rt = 5.19 min , purity 94%, Melting point: mp = oil, TLC thin layer chromatography: retention factor R / = 0.65, High performance liquid chromatography HPLC: retention time Rt = 6.05 min, purity = 99%, Yield = 32%,
The affinity of the synthesized compounds, numbered 1 to 49 above and described by the general formula (I), for selected serotonin and dopamine receptors was tested according to standard activity evaluation procedure for D2, 5-HT1A, 5-HT2A, 5-HTs, 5- receptors. HT? (Y. Cheng, W. Prusoff, "Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (150) of an enzymatic reaction", Biochem. Pharmacol., 1973), (M. Kołaczkowski , M. Marcinkowska, et al., "Novel Arylsulfonamide Derivatives with 5-HTs / 5-HT7 Receptor Antagonism Targeting Behavioral and Psychological Symptoms of Dementia", Journal of Medicinal Chemistry 2014) as described below in Examples 25 and 26 and shown in Table containing their pharmacological profile.
PL 240 473 B1
EXAMPLE 25
Cell culture and production of cell membranes for in-vitro tests
HEK293 cells stably expressing human serotonin and dopamine receptors (5-HTia, 5-HT6, 5-HT / b, D2l) were prepared with Lipofectamine 2000 or CHO-K1 with a plasmid containing the human serotonin coding sequence. 5-HT2a receptor (maintained at 37 ° C in a humidified atmosphere, 5% CO2, cultured in Eagle Dulbecco Medium, 10% dialyzed fetal bovine serum and 500 µg / ml G418 sulfate). Membrane preparation - cells were grown in 150 cm 2 flasks and grown to 90% confluency, washed twice with phosphate buffered saline (PBS) at 37 ° C and pelleted by centrifugation (200 g) in PBS containing 0.1 mM EDTA and 1 mM dithiothreitol. Prior to membrane preparation, the pellets were stored at -80 ° C.
EXAMPLE 26
Radioligand Binding Assays
Thawed and homogenized (20 volumes of assay buffer, Ultra Turrax tissue homogenizer) were centrifuged twice (35 G for 20 min at 4 ° C, incubating for 15 minutes at 37 ° C between rounds of centrifugation). Composition of the test buffers: 5-HTia: 50 mM Tris-HCl, 0.1 mM EDTA, 4 mM MgCb, 10 μM pargilline, 0.1% ascorbate, 5-HT2a: 50 mM Tris-HCl, 0.1 mM EDTA, 4 mM MgClb 0.1% ascorbate; 5-HT s : 50 mM Tris-HCl, 0.5 mM EDTA and 4 mM MgCl 2; 5-HT7: 50 mM Tris-HCl, 4 mM MgCl 2, 10 µM pargilline, 0.1% ascorbate; D2: 50 mM Tris HCl, 1 mM EDTA, 4 mM MgCl 2, 120 mM NaCl, 5 mM KCl, 1.5 mM CaCl 2, 0.1% ascorbate. All assays were incubated in a total volume of 200 µl in 96-well microtiter plates for 1 hour. at 37 ° C, except for 5-HTia and 5-HT2a which were incubated at room temperature. The equilibrium state was fixed by filtration (Unifilter plates with a 96-well cell harvester (PerkinElmer)). The content of radioligands retained on the filters was quantified on a Microbeta plate reader (PerkinElmer). In the case of displacement studies, the test samples contained as radioligands: 2.5 nM [3H] -8-OHDPAT (187 Ci / mmol) - 5-HTia, 1 nM [3H] -Ketanserin (53.4 Ci / mmol) - 5-HT2A, 2 nM [3H] -LSD (85.2 Ci / mmol - 5-HT6, 0.8 nM [3H] 5-CT (39.2 Ci / mmol) - 5-HT7 or 2.5 nM (3H) -raclopride (76.0 Ci / mmol) - D2 Nonspecific binding was defined by 10 μM 5-HT in the 5-HTia and 5-HT7 binding assays, while 10 μM chlorpromazine or 10 μM metiothepine was used in the 5-HTIA binding assays. -HT2A / D2 and 5-HT6 Each compound was respectively tested in triplicate at 7 to 8 different concentrations (10 ^ -10 -11 M.) The displacement constants (Ki) were calculated from the Cheng-Prusoff equation (Y. Cheng, W. Prusoff "Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (150) of an enzymatic reaction", Biochem. Pharmacol., 1973).
PL 240 473 BI
Table. Pharmacological profile of new arylpiperazine derivatives
Relationship no d2 5HT1A 5-HTm 5-HT6 5-HT, 1 58 66 540 1681 336 2 75 43 429 480 53 3 197 181 423 689 124 4 246 161 493 1860 166 5 94 122 406 918 5095 6 204 688 1490 3187 1833 7 320 64 524 1726 420 8 161 599 1766 1128 17780 9 496 54 773 2214 291 10 945 536 4354 2045 48960 11 114 47 652 1699 366 12 180 291 1927 3666 3743 13 11 22 717 1916 84 14 867 32 892 1461 184 15 188 94 43 5253 475 16 431 9473 3983 952 696 17 82 22 222 999 119 18 56 71 55 568 36 19 2852 681 1913 1558 595 twenty 142 106 548 507 286 21 121 46 322 624 432 22 336 197 147 433 280 23 220 149 177 237 140 24 254 79 251 225 404 25 304 132 596 374 167 26 927 989 1526 937 5996 27 90 81 376 710 203 28 thirty 48 578 476 34 29 118 35 443 182 344 thirty 264 482 533 494 822 31 18 63 32 158 105 32 10 twenty 337 671 266 33 271 47 334 347 371 34 40040 35690 60100 5765 116S00 35 27 28 461 246 73 36 1302 172 563 1965 1200 37 141 373 1918 1410 710 38 393 98 812 1142 605 39 344 1674 4784 3253 3750 40 319 187 629 392 405 41 1620 20330 5477 8757 2033 42 59 86 53 110 118 43 108 219 538 1075 509 44 337 251 1903 1672 47 45 2 19 456 3270 291 46 18 74 66 1139 61 47 1 44 12 379 16 48 85 206 258 582 171 49 253 70 282 1694 162Claims (9)
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