HRP20010167A2 - 4,4-biarylpiperidine derivatives with opioid receptor activity - Google Patents
4,4-biarylpiperidine derivatives with opioid receptor activity Download PDFInfo
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- HRP20010167A2 HRP20010167A2 HR20010167A HRP20010167A HRP20010167A2 HR P20010167 A2 HRP20010167 A2 HR P20010167A2 HR 20010167 A HR20010167 A HR 20010167A HR P20010167 A HRP20010167 A HR P20010167A HR P20010167 A2 HRP20010167 A2 HR P20010167A2
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- Prior art keywords
- alkyl
- comp
- phenyl
- pain
- addiction
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- 102000003840 Opioid Receptors Human genes 0.000 title claims description 22
- 108090000137 Opioid Receptors Proteins 0.000 title claims description 22
- 230000000694 effects Effects 0.000 title description 8
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 60
- -1 aryl-(C1-C8) alkyl- Chemical group 0.000 claims description 54
- 208000035475 disorder Diseases 0.000 claims description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 34
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- 238000009739 binding Methods 0.000 claims description 22
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- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- XOLBLPGZBRYERU-UHFFFAOYSA-N tin dioxide Chemical compound O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 description 1
- 229910001887 tin oxide Inorganic materials 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
Classifications
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- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
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- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Description
Pozadina izuma
Ovaj izum se odnosi na 4,4-biarilpiperidinske derivate koji se upotrebljavaju kao ligandi opioidnih receptora.
U proučavanju kemije opioida, identificirani su razni endogeni i neendogeni opioidni spojevi. U tom pogledu značajno istraživanje je usmjereno na razumijevanje mehanizma djelovanja opioidnih lijekova, pogotovo jer se to odnosi opioidne receptore na stanicama i izdiferenciranom tkivu.
Opioidni lijekovi se tipično klasificiraju prema njihovoj selektivnosti vezanja na receptore na stanicama i izdiferenciranom tkivu, na koje se specifični lijek veže kao ligand. Ovi receptori uključuju mi (µ), delta (δ) i kapa (κ) receptore.
U znanstvenoj literaturi opisano je i dokumentirano najmanje 3 podvrste opioidnih receptora (μ, δ i κ). Sva 3 receptora su prisutna u središnjem i perifernom živčanom sustavu mnogih vrsta, uključujući čovjeka. Aktiviranje δ receptora uzrokuje antinocicepciju kod glodavaca, a može uzrokovati analgeziju kod čovjeka, pored utjecaja na motilitet gastrointestinalnog trakta. (vidjeti Burks, T.F.: "The Pharmacology of Opioid Peptides", izdanje L.F. Tseng, Harwood Academic Publishers).
Dobro poznati narkotički opijati, npr. morfin i njegovi analozi, su selektivni prema μ opioidnom receptoru. μ-receptori posreduju u analgeziji, respiratornoj depresiji i inhibiciji gastrointestinalnog prometa. κ-receptori posreduju u analgeziji i sedaciji.
Postojanje opioidnih δ-receptora je otkriveno relativno nedavno, a uslijedilo je poslije izoliranja i karakteriziranja endogenih enkefalinskih peptida, koji su ligandi δ-receptora. Istraživanja u prošloj dekadi su dala značajne informacije o δ-receptoru, ali jasna slika njegovog funkcioniranja još nije dostignuta. δ-receptori posreduju u analgeziji, ali izgleda da ne inhibiraju crijevni promet na način karakterističan za μ-receptore.
US patent br. 4,816,586, objavljen 28. ožujka 1989., od P.S. Porthogese, odnosi se na različite antagoniste δ opioidnih receptora. Opisano je da ovi spojevi posjeduju jedinstven antagonistički profil prema opioidnim receptorima, kao spojevi visoko selektivni prema δ opioidnom receptoru.
US patent br. 4,518,711, objavljen 21. svibnja 1985., od V.J. Hruby i drugi, opisuje cikličke, konformacijski oblikovane analoge enkefalina. Ovi spojevi uključuju i agoniste i antagoniste δ receptora i kaže se da uzrokuju farmakološke i terapeutske učinke, poput analgezije, u slučaju kada ti spojevi pripadaju agonističkoj grupi. Antagonističke grupe opisanih spojeva se navode kao pogodne u tretiranju shizofrenije, Alzheimer-ove bolesti i dišnih i kardiovaskularnim funkcija.
S. Goenechea drugi: "Investigation of the Biotransformation of Meclozine in the Human Body", "J. Clin. Chem. Clin. Biochem.", 26(2), 105-15, (1988.) opisuju oralno davanje poliarilpiperazinskog spoja u proučavanju metabolizma meklozina kod ljudi.
Članak Meuldermans W. i drugi: "Plasma Levels, Biotransformation and Excretion of Oxatomide in Rats, Dogs and Man", "Xenobiotica", 15(6), 445-62, (1984.), odnosi se na metaboličko proučavanje razine u plazmi, na biotransformaciju i izlučivanje oksatomida.
T. Iwamoto i drugi: "Effects of KB-2796. A New Calcium Antagonist and Other Diphenilpiperazines on [3H]nitrendipin Binding", "Jpn. J. Pharmacol.", 48(2), 241-7, (1988.) opisuju učinak poliarilpiperazina kao antagonista kalcija.
K. Natsuka i drugi: "Synthesis and Structure-Activity Relationships of 1-Substituted 4-(1,2-Diphenylethyl)piperazine Derivatives Having Narcotic Agonist and Antagonist Activity", "J. Med. Chem.", 30(10), 1779-1787, (1987.), opisuju racemate i enantiomere derivata 1-supstituiranih 4-[2-(3-hidroksifenil)-1-feniletil]piperazina.
Evropska patentna prijava br. 458.160, objavljena 27. studenog 1991. odnosi se na neke derivate supstituiranog difenilmetana, kao analgetike i antiflogistike, uključujući spojeve u kojima je metilenski most (koji povezuje 2 fenilna ostatka) supstituiran na metilenskom ugljiku piperidinilnom ili piperazinilnom grupom.
Južnoafrička patentna prijava br. 8.604.522, objavljena 12. prosinca 1986. odnosi se na neke N-supstituirane arilalkilne i aril-alkilenski supstituirane amino-heterocikličke spojeve, uključujući derivate piperidina, kao kardiovaskularne, antihistaminske i antisekrecijske tvari.
Evropska patentna prijava br. 133.323, objavljena 20. veljače 1985. odnosi se na neke spojeve difenilmetilpiperazina, kao nesedativne antihistaminike.
Postoji stalna potreba u tom području tehnike za poboljšanim opioidnim spojevima, osobito spojevima koji nemaju karakter stvaranja ovisnosti i druge štetne sporedne učinke konvencionalnih opijata, poput morfina i petidina.
Ovaj izumitelj je otkrio novu klasu derivata 4,4-biarilpiperidina koji su snažni i selektivni δ opioidni ligandi i pogodni u tretmanu odbacivanja organskih transplantata i presadaka kože, epilepsije, kronične boli, neurogene boli, nesomatske boli, moždanog udara, cerebralne ishemije, šoka, povrede glave, povrede kralježnične moždine, edema mozga, Hodgkin-ove bolesti, Sjogren-ove bolesti, sistemskog lupus eritematozusa, gastrointestinalnih poremetnji poput gastritisa, funkcionalne bolesti utrobe, sindroma nadražljive utrobe, funkcionalne dijareja, funkcionalna nadutosti, neulcerogene dispepsije i drugih poremećaja motiliteta ili lučenja, i kod povraćanja, akutne boli, kronične boli, neurogene boli, nesomatske boli, alergije, dišnih poremetnji poput astme, kašlja i apneje, upalnih poremetnji poput reumatoidnog artritisa, osteoartritisa, psorijaze i upalne bolesti utrobe, poremetnji urogenitalnog trakta poput inkontinencije mokraće, hipoksije (npr. perinatalne hipoksije), hipoglikemičkog neuronskog oštećenja, ovisnosti i navike o kemijskim sredstvima (npr. ovisnosti ili navike na opijate, benzodiazepine, kokain, nikotin ili etanol), simptoma ustezanja od droga ili alkohola i cerebralnih deficijencija nakon kirurgije srčane premosnice i presađivanja.
Bit izuma
Ovaj izum se odnosi na spojeve formule
[image]
gdje:
R1 je vodik, (C0-C8)alkoksi-(C0-C8)alkil-, gdje je ukupni broj atoma ugljika 8 ili manji, aril, aril-(C1-C8)alkil-, heteroaril, heteroaril-(C1-C8)alkil-, heterocikl, heterocikl-(C1-C8)alkil, (C3-C7)cikloalkil ili (C3-C7)cikloalkil-(C1-C8)alkil, gdje se spomenuti aril i arilni ostaci spomenutih aril-(C1-C8)alkil- neovisno biraju između fenila i naftila, a gdje se spomenuti heteroaril ili heteroarilni ostatak u spomenutom heteroaril-(C1-C8)alkil- neovisno biraju između pirazinila, benzofuranila, kinolila, izokinolila, benzotienila, izobenzofurila, pirazolila, indolila, izoindolila, benzimidazolila, purinila, karbazolila, 1,2,5-tiadiazolila, kinazolinila, piridazinila, pirazinila, cinolinila, ftalazinila, kinoksalinila, ksantinila, hipoksantinila, pteridinila, 5-azacitidinila, 5-azauracila, triazolopiridinila, imidazolopiridinila, pirolopirimidinila, pirazolopirimidinila, oksazolila, oksadiazolila, izoksazolila, tiazolila, izotiazolila, furanila, pirazolila, pirolila, tetrazolila, triazolila, tienila, imidazolila, piridinila i pirimidinila; i gdje se spomenuti heterocikl ili heterociklički ostatak spomenutog heterocikl-(C1-C8)alkil- bira između zasićenih i nezasićenih nearomatskih monocikličkih i bicikličkih sustava prstenova, u kojim spomenuti monociklički sustavi prstenova sadrže 4 do 7 atoma ugljika, a 1 do 3 od njih se mogu izborno supstituirati s O, N ili S, i gdje spomenuti biciklički sustavi prstenova sadrže od 7 do 12 atoma ugljika u prstenu, od kojih 1 do 4 se mogu izborno supstituirati s O, N ili S; i pri čemu bilo koji od arilnih, heteroarilnih ili heterocikličkih ostataka R1 može izborno biti supstituiran s 1 do 3 supstituenta, po mogućnosti s 1 ili 2 supstituenta, koji se neovisno biraju između halo (tj. klor, fluor, brom i jod), (C1-C6)alkila, izborno supstituiranog s 1 do 7 (po mogućnosti s 0 do 4) atoma fluora, fenila, benzila, hidroksi, acetila, amino, cijano, nitro, (C1-C6)alkoksi, (C1-C6)alkilamino i [(C1-C6) alkil]2amino, pri čemu se bilo koji od alkilnih ostataka u R1 (npr. alkilni ostatak iz alkila, alkoksi ili alkilamino grupa) može izborno supstituirati s 1 do 7 (po mogućnosti od 0 do 4) atoma fluora;
R2 je vodik, aril, heteroaril, heterocikl, SO2R4, COR4, CONR5R6, COOR4 ili C(OH)R5R6, gdje je svaki od R4, R5 i R6 neovisno, definiran kao R1 koji je definiran gore, ili R5 i R6 uzeti zajedno s ugljikom ili dušikom uz koji su oba spojeni, formiraju 3- do 7-eročlani zasićeni prsten koji sadrži od 0 do 3 heteroatoma koji se biraju, neovisno, između O, N i S, i pri čemu su aril, heteroaril i heterocikl definirani gore, u definiciji za R1, i pri čemu bilo koji arilni, heteroarilni i heterociklički ostatak u R2 može izborno biti supstituiran s 1 do 3 supstituenta, po mogućnosti s 1 do 2 supstituenta, koji se neovisno biraju između halo (tj. klor, fluor, brom ili jod), (C1-C6)alkila izborno supstituiranog s 1 do 7 (po mogućnosti od 0 do 4) atoma fluora, fenila, benzila, hidroksi, acetila, amino, cijano, nitro, (C1-C6)alkoksi izborno supstituiranog s 1 do 7 (poželjno 0 do 4) atoma fluora, (C1-C6)alkilamino i [(C1-C6)alkil]2amino;
R3 je hidroksi, NHSO2R7, C(OH)R7R8, fluor ili CONHR7, pri čemu su R7 i R8 isti ili različiti, a biraju se između vodika, (C1-C4)alkila, (C1-C4)alkoksi i (C1-C4)alkoksi-(C1-C4)alkila koji ima ukupno 4 ili manje atoma ugljika, pri čemu bio koji od alkilnih ostataka u R7 i R8 može izborno biti supstituiran s 1 do 7 (poželjno 0 do 4) atoma fluora; a
Z1 i Z2 se neovisno biraju između vodika, halo i (C1-C5)alkila;
pod uvjetom da u prstenu ne postoje 2 susjedna atoma kisika i da ni 1 atom kisika u prstenu nije u susjedstvu s bilo kojim od atoma dušika u prstenu ili atoma sumpora u prstenu, bilo kog od heterocikličkih ili heteroarilnih ostataka u formuli 1;
i farmaceutski prihvatljive soli ovih spojeva.
Pogodni spojevi formule 1 su oni u kojima R1 je ciklopropilmetil, 3-cikloheksilpropil, 2-feniletil, 2-metilpentil, p-metilbenzil, 2,2,2-trifluoretil ili 1-metilpentil.
Drugi primjeri pogodnih spojeva formule 1 su oni u kojima R2 je dietilamid, metiletilamid, dietilkarbinol, tetrazol ili pirazol.
Drugi primjeri pogodnih spojeva formule 1 su oni u kojima R3 je hidroksi, fluor, CONH2, NHSO2CH3 ili metoksi.
Spojevi formule 1 i njihove farmaceutski prihvatljive soli su ligandi opioidnih receptora i pogodni su u tretiranju raznih neuroloških i gastrointestinalnih poremetnji. Primjeri poremetnji koje se mogu tretirati spojevima formule 1 i njihovim farmaceutski prihvatljivim solima su odbacivanje organskih transplantata i presadaka kože, epilepsije, kronične boli, neurogene boli, nesomatske bola, moždanog udara, cerebralne ishemije, šoka, povreda glave, povreda kralježnične moždine, edem mozga, Hodgkin-ova bolest, Sjogren-ova bolest, sistemski lupus eritematozusa, gastrointestinalne poremetnje poput gastritisa, funkcionalne bolesti utrobe, sindroma nadražljive utrobe, funkcionalne dijareje, funkcionalne nadutosti, neulcerogene dispepsije i drugih poremetnji motiliteta ili lučenja i povraćanja, akutne boli, kronični boli, neurogene boli, nesomatske boli, alergije, dišnih poremetnji poput astme, kašlja i apneje, upalnih poremetnji poput reumatoidnog artritisa, osteoartritisa, psorijaze i upalne bolesti utrobe, poremetnje urogenitalnog trakta poput inkontinencije mokraće, hipoksije (npr. perinatalne hipoksije), hipoglikemičkog neuronskog oštećenja, ovisnosti i navika o kemijskim sredstvima (npr. ovisnosti ili navika na opijate, benzodiazepine, kokain, nikotin ili etanol), simptoma ustezanja od droga ili alkohola i cerebralnih deficijencija nakon kirurgije srčane premosnice i presađivanja.
Ovaj izum se također odnosi na farmaceutski prihvatljive kisele i alkalne adicijske soli spojeva formule 1. Kiseline koje se koriste za dobivanje farmaceutski prihvatljivih kiselih adicijskih soli gore navedenih alkalnih spojeva ovog izuma su od onih koje formiraju neotrovne kisele adicijske soli, tj. soli koje sadrže farmakološki prihvatljive anione, poput hidroklorida, hidrobromida, hidrojodida, nitrata, sulfata, bisulfata, fosfata, kiselih fosfata, acetata, laktata, citrata i kiselih citrata, tartarata, bitartarata, sukcinata, maleata, fumarata, glukonata, saharata, benzoata, metansulfonata, etansulfonata, benzensulfonata, p-toluensulfonata i pamoata (tj. 1,1'-metilen-bis-(2-hidroksi-3-naftoata)). Kemijske baze koje se koriste kao reagensi u dobivanju farmaceutski prihvatljivih alkalnih soli ovog izuma su od onih koje tvore neotrovne alkalne soli s kiselim spojevima formule 1. Te neotrovne alkalne soli su od onih koje se izvode iz farmakološki prihvatljivih kationa, poput natrija, kalija, kalcija, magnezija itd.
Ovaj izum se također odnosi na farmaceutski prihvatljive alkalne adicijske soli spojeva formule 1. Ove soli se dobivaju konvencionalnim tehnikama. Kemijske alkalije koje se koriste kao reagensi za dobivanje farmaceutski prihvatljivih alkalnih soli iz ovog izuma su od onih koje tvore neotrovne alkalne soli s kiselim spojevima formule 1. Te neotrovne alkalne soli su one koje se deriviraju iz farmakološki prihvatljivih kationa, poput natrija, kalija, kalcija i magnezija itd.
Za pregled farmaceutski prihvatljivih soli vidjeti Berge, i drugi: "J. Pharm. Sci.", 66, 1-19, (1977.).
Ovaj izum se također odnosi na farmaceutski pripravak za tretiranje poremetnje ili stanja, na čiji tretman ili prevenciju se može djelovati ili ih olakšati moduliranjem (tj. povećavanjem ili smanjivanjem) vezanja na opioidne receptore kod sisavca, uključujući čovjeka, koji sadrži količinu spoja formule 1 ili njegove farmaceutski aktivne soli, djelotvornu u tretiranju takve poremetnje ili stanja i farmaceutski prihvatljivu podlogu.
Ovaj izum se također odnosi na postupak tretiranja poremetnje ili stanja, na čiji tretman se može djelovati ili ga olakšati moduliranjem vezanja na opioidne receptore, a taj postupak se sastoji u davanju sisavcu, kome je takav tretman nužan, količine spoja formule 1, ili njegove farmaceutski aktivne soli, djelotvorne u tretiranju takve poremetnje ili stanja.
Ovaj izum se također odnosi na pripravak za tretiranje poremetnje ili stanja koje se bira između upalnih bolesti poput artritisa (npr. reumatoidnog artritisa i osteoartritisa), psorijaze, astme ili upalne bolesti utrobe, poremetnje dišne funkcije poput kašlja, apneje, alergije, gastrointestinalnih poremetnji poput gastritisa, funkcionalne bolesti utrobe, sindroma nadražljive utrobe, funkcionalne dijareje, funkcionalna nadutosti, funkcionalne boli, neulcerogene dispepsije i drugih poremetnji motiliteta ili lučenja i povraćanja, moždanog udara, šoka, edema mozga, oštećenja glave, oštećenja kralježnične moždine, cerebralne ishemije, cerebralnih deficijencija nakon kirurgije srčane premosnice i presađivanja, poremetnji urogenitalnog trakta poput inkontinencije mokraće, ovisnosti i navike na kemijska sredstva (npr. navike na ili ovisnosti o alkoholu, opijatima, benzodiazepinima, nikotinu, heroinu ili kokainu), kronične boli, nesomatske boli, akutne boli i neurogene boli, sistemskog lupus eritematozusa, Hodgkin-ova bolesti, Sjogren-ove bolesti, epilepsije i odbacivanja organskih transplantata i presadaka kože kod sisavca, uključujući čovjeka, koji sadrži količinu spoja formule 1 ili njegove farmaceutske soli, djelotvornu u moduliranju neurotransmisije glutamata, i farmaceutski prihvatljivu podlogu.
Ovaj izum se odnosi također na postupak tretiranja stanja koja se biraju između upalnih bolesti poput artritisa, psorijaze, astme ili upalne bolesti utrobe, poremetnje dišne funkcije poput astme, kašlja, apneje, alergije, gastrointestinalnih poremećaja poput gastritisa, funkcionalne bolesti utrobe, sindroma nadražljive utrobe, funkcionalne dijareje, funkcionalna nadutosti, funkcionalne boli, neulcerogene dispepsije i drugih poremetnji motiliteta ili lučenja i povraćanja, moždanog udara, šoka, edema mozga, povrede glave, povrede kralježnične moždine, cerebralne ishemije, cerebralnih deficijencija nakon kirurgije srčane premosnice i presađivanja, poremetnji urogenitalnog trakta poput inkontinencije mokraće, ovisnosti i navike o kemijskim sredstvima (npr. navike na ili ovisnosti o alkoholu, opijatima, benzodiazepinima, nikotinu, heroinu ili kokainu), kronične boli, nesomatske boli, akutne boli i neurogene boli, sistemskog lupus eritematozusa, Hodgkin-ove bolesti, Sjogren-ove bolesti, epilepsije i odbacivanje organskih transplantata i presadaka kože kod sisavca, uključujući čovjeka, koji se sastoji u davanju tom sisavcu, uključujući čovjeku, količine spoja formule 1, ili njegove farmaceutski prihvatljive soli, djelotvorne u moduliranju vezanja na opioidni receptor.
Ovaj izum se također odnosi na farmaceutski pripravak za tretiranje poremetnje ili stanja, a taj se tretman može biti provesti ili olakšati moduliranjem vezanja za opioidne receptore kod sisavca, uključujući čovjeka, koji sadrži količinu spoja formule 1, ili njegove farmaceutski prihvatljive soli, djelotvorne u moduliranju vezanja na opioidni receptor, i farmaceutski prihvatljivu podlogu.
Ovaj izum se također odnosi na postupak tretiranja poremetnje ili stanja, a taj tretman se može ostvariti ili olakšati moduliranjem kod sisavca, uključujući čovjeka, koji se sastoji u davanju tom sisavcu količinu spoja formule 1, ili njegove farmaceutski prihvatljive soli, djelotvorne u moduliranju vezanja na opioidni receptor.
Ovaj izum se također odnosi na postupak tretiranja stanja koje se bira između upalnih bolesti poput artritisa, psorijaze, astme ili upalne bolesti utrobe, poremetnje dišne funkcije poput astme, kašlja, apneje, alergije, gastrointestinalnih poremetnji poput gastritisa, funkcionalne bolesti utrobe, sindroma nadražljive utrobe, funkcionalne dijareje, funkcionalne nadutosti, funkcionalne boli, neulcerogene dispepsije i drugih poremetnji motiliteta ili lučenja i povraćanja, moždanog udara, šoka, edema mozga, povrede glave, povrede kralježnične moždine, cerebralne ishemije, cerebralnih deficijencija nakon kirurgije srčane premosnice i presađivanja, poremetnji urogenitalnog trakta, poput inkontinencije mokraće, ovisnosti i navikavanja na kemijska sredstva (npr. navike na ili ovisnosti o alkoholu, opijatima, benzodiazepinima, nikotinu, heroinu ili kokainu), kronične boli, nesomatske boli, akutne boli i neurogene boli, sistemskog lupus eritematozusa, Hodgkin-ove bolesti, Sjogren-ove bolesti, epilepsije i odbacivanja organskih transplantata i presadaka kože kod sisavca, uključujući čovjeka, koji se sastoji u davanju sisavcu, kome je takav tretman nužan, količine spoja formule 1, djelotvorne u tretiranju takvog stanja.
Ovaj izum se odnosi također na farmaceutski pripravak za tretiranje stanja koja se biraju između upalnih bolesti poput artritisa, psorijaze, astme ili upalne bolesti utrobe, poremetnje dišne funkcije poput astme, kašlja, apneje, alergije, gastrointestinalnih poremetnji poput gastritisa, funkcionalne bolesti utrobe, sindroma nadražljive utrobe, funkcionalne dijareje, funkcionalne nadutosti, funkcionalne boli, neulcerogene dispepsije i drugih poremetnji motiliteta ili lučenja i povraćanja, moždanog udara, šoka, edema mozga, povrede glave, povrede kralježnične moždine, cerebralne ishemije, cerebralnih deficijencija nakon kirurgije srčane premosnice i presađivanja, poremetnji urogenitalnog trakta, poput inkontinencije mokraće, ovisnosti i navikavanja na kemijska sredstva (npr. navike na ili ovisnosti o alkoholu, opijatima, benzodiazepinima, nikotinu, heroinu ili kokainu), kronične boli, nesomatske boli, akutne boli i neurogene boli, sistemskog lupus eritematozusa, Hodgkin-ove bolesti, Sjogren-ove bolesti, epilepsije i odbacivanja organskih transplantata i presadaka kože kod sisavca, koji sadrži količinu spoja formule 1, djelotvorne u tretiranju takvog stanja, i farmaceutski prihvatljivu podlogu.
Ukoliko drugačije nije rečeno, alkilne grupe koje se ovdje navode, kao i alkilni ostaci ostalih grupa koje se ovdje navode (npr. alkoksi), mogu biti ravnolančane ili razgranate, a mogu biti također cikličke (npr. ciklopropil, ciklobutil, ciklopentil ili cikloheksil) ili ravnolančane ili razgranate s vezanim cikličkim ostacima.
Naziv "alkoksi", kako se ovdje koristi, označava "-O-alkil", gdje je "alkil" definiran gore.
Naziv "alkilen", kako se ovdje koristi, označava alkilnu grupu koja ima 2 dostupna mjesta za vezanje (tj. -alkil-, gdje je alkil definiran gore).
Naziv "tretiranje", kako se ovdje koristi, odnosi se na remisiju, olakšavanje i inhibiranje napredovanja, ili na prevenciju poremetnje ili stanja na koja se taj naziv odnosi, ili na 1 ili više simptoma takve poremetnje ili stanja. Naziv "tretman", kako se ovdje koristi, označava sam čin tretiranja, a "tretiranje" je definirano neposredno gore.
Ukoliko se drugačije ne ukaže "halo" ili "halogen" se ovdje koristi u značenju fluor, klor, brom ili jod.
Spojevi formule 1 mogu imati kiralne centre, pa stoga mogu postojati u različitim enantiomernim i dijastereomernim oblicima. Ovaj izum se odnosi na sve optičke izomere i sve druge izomere spojeva formule 1 i na sve njihove racemske i druge smjese i na sve gore definirane farmaceutske pripravke i postupke tretiranja, a koji sadrže ili koriste te izomere ili smjese.
Gornja formula 1 obuhvaća spojeve identične opisanima, uz činjenicu da 1 ili više vodika ili ugljika mogu biti supstituirani njihovim izotopima. Takvi spojevi su pogodni kao istraživačka i dijagnostička sredstva u farmakokinetičkim proučavanjima metabolizma i u testovima vezanja. Specifične primjene u istraživanju obuhvaćaju testove vezanja radioliganada, proučavanje autoradiografije i proučavanja vezanja in vivo.
Detaljni opis izuma
Spojevi formule 1 mogu se dobiti u skladu s postupcima prikazanim u Shemama 1-9, i razmatranim u nastavku. U reakcijskim shemama i razmatranju koje slijedi, ukoliko se drugačije ne ukaže, Z1, Z2, R1, R2 i R3 i strukturna formula 1 odgovaraju gornjoj definiciji.
Shema 1 ilustrira postupak dobivanja spojeva opće formule 1, u kojima R3 predstavlja (C1-C6)alkoksi ili fluor, R2 je CONR5R6, a R1 je definiran gore, pod uvjetom da nije vezan za dušik u piperidinu, za sekundarni alkilni ugljik ili za arilnu grupu. Pozivajući se na Shemu 1, derivat brombenzena formule 0, gdje R3 predstavlja metoksi ili fluor, ohladi se u suhom ledu na –70 °C u suhom tetrahidrofuranu, pa mu se zatim doda otopina n-butillitija. Nastala otopina zatim reagira s N-benzilpiperidinonom, pa se otopinu pusti da se zagrije do sobne temperature, dajući odgovarajući spoj formule 1.
Alternativno, derivat benzena formule 0 u tetrahidrofuranu može reagirati s magnezijem na temperaturi od oko 0 °C do temperature refluksa, po mogućnosti počevši od sobne temperature, tijekom oko 3 sata, a zatim grijanjem pod refluksom, puštajući da reakcija napreduje slijedećih sat vremena. Nakon toga u smjesu se doda N-benzilpiperidinon. Nastalu otopinu se zatim miješa na temperaturi raspona od oko 0 °C pa do temperature refluksa, po mogućnosti oko sobne temperature, dajući odgovarajući spoj formule 1.
Spoj formule 1 dobiven bilo kojim od navedenih postupaka, reagira zatim u dikloretanu s fenolom i aluminij-kloridom ili kojom drugom Lewis-ovom bazom (npr. bor-trifluorid eteratom), pa se dobivenu otopinu miješa na temperaturi raspona od oko 0 °C do temperature refluksa, po mogućnosti oko temperature refluksa, dajući odgovarajući fenolski derivat formule 2. Spoj formule 2 zatim reagira s trifluor-metansulfonskim anhidridom ili drugim pogodnim reagensom, npr. N-feniltrifluormetansulfonimidom, u prisustvu alkalije, npr. piridina, trietilamina, nekog drugog trialkilamina, hidrida ili karbonata alkalnog metala, kako bi se dobio trifluormetilsulfonatni ester formule 3. Ova reakcija se tipično obavlja i diklormetanu, na temperaturi raspona od oko 0 °C do temperature refluksa, po mogućnosti na sobnoj temperaturi.
Spoj formule 3 se stavi u atmosferu ugljik-monoksida, pod tlakom raspona od oko 0,97 do 6,9 bar, u otopinu dimetilsulfoksida i nižeg alkanola, poput metanola ili etanola, s pogodnom trialkilaminskom alkalijom (npr. trietilaminom) i paladij-acetatom s 1,3-bis(difenilfosfino)propanom (DPPP) ili drugim pogodnim paladijevim ligandom. Može se upotrijebiti i neki drugi pogodan paladijev katalizator, npr. bis(trifenilfosfin)paladij-diklorid. Ova reakcija se provodi na temperaturi raspona od 20 °C do 100 °C.
Reakcija estera formule 4 s aluminij-amidom primarnog ili sekundarnog amina, npr. dietilamina, u otapalu poput dikloretana ili toluena, na temperaturi raspona od oko 20 °C do oko temperature refluksa, po mogućnosti oko temperature refluksa, daje odgovarajući amid formule 5. Promjena prirode grupe R1 na dušiku piperidina može se ostvariti na slijedeći način, kao što prikazuju koraci postupka (5 → 6 → 7) u Shemi 1. Spoj formule 5 se stavi u atmosferu vodika, pod tlakom raspona od 0,97 do 6,9 bar, u etanolu ili drugom otapalu, poput octene kiseline ili metanola, dajući odgovarajući spoj formule 6. Ova reakcija se tipično provodi na temperaturi od oko 0 °C do oko temperature refluksa, po mogućnosti oko sobne temperature.
Reakcija spoja formule 6 s aldehidom i natrij-triacetoksiborhidridom, ili drugim reducensom (npr. natrij-borhidridom ili natrij-cijanborhidridom) u diklormetanu, 1,2-dikloretanu ili drugom pogodnom otapalu, poput metanola, etanola, toluena, na temperaturi raspona od oko 0 °C do 100 °C, po mogućnosti oko sobne temperature, daje traženi spoj formule 7.
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Spojevi formule I, u kojima R1 je grupa spojena s piperidinskim dušikom preko arilnog ostatka ili primarnog ili sekundarnog alkilnog ostatka, mogu se dobiti reakcijom odgovarajućeg spoja formule 6 s alkilirajućim ili arilirajućim agensom formule R1X, gdje X je izlazna grupa, npr. klor, brom, jod, triflat (OTf), mezilat (OMs) ili tosilat (OTs), i natrij- ili kalij-karbonatom ili drugim karbonatom ili bikarbonatom alkalnog metala, u otapalu poput dimetilformamida, dikloretana ili 1,2-dikloretana, na temperaturi raspona od oko 20 ° do 100 °C, kao što je navedeno niže, u Shemi 2.
U vezi s definicijom formule R1X, u slučaju kada X je aldehidni ostatak (CHO), treba uočiti da se aldehidni ugljik veže na piperidinski dušik, tako da u R1 ulazi dodatni atom ugljika, činjenica koja navedena u Primjeru 16 (reaktant F → reaktant G), gdje se upotrebljava oznaka RxCHO.
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Spojevi opće formule 1, u kojima R1 je hidroksi, mogu se dobiti skidanjem zaštite s odgovarajućeg alkil etera formule 7 (gdje R10 je (C1-C6)alkil) bor-tribromidom u diklormetanu, ili vodenom bromovodičnom kiselinom i octenom kiselinom, ili natrij-etantiolatom u dimetilformamidu, na temperaturi raspona od oko 0 °C do temperature refluksa, kao što je prikazano u Shemi 3. Poželjna je sobna temperatura, kada se koristi bor-tribromid, a temperatura refluksa je poželjna kada se koriste bromovodična i octena kiselina, a od oko 100 ° do oko 120 °C je poželjno kada se koristi natrij-etanmetiolat.
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Spojevi opće formule I, u kojima R3 = CONHR, mogu se dobiti iz odgovarajućih fenola formule 9, kao što prikazuje Shema 4, niže. Ovo se može provesti dobivanjem triflata formule 10, uz uvjete identične onima upotrijebljenim pri dobivanju spojeva formule 3 (Shema 1). Spoj formule 10 se zatim prevede u odgovarajući ester formule 11, uz uvjete identične onima upotrijebljenim pri dobivanju estera formule 4 (Shema 1). Reakcija spoja formule 11 s aluminij-amidom amina, u otapalu poput toluena ili 1,2-dikloretana, na temperaturi raspona od oko 0 °C do oko temperature refluksa, po mogućnosti oko temperature refluksa, ili reakcijom istog s litij-amidom u eteru ili tetrahidrofuranu, na temperaturi raspona od oko –78 °C do temperature refluksa, po mogućnosti na oko –78 °C, daje traženi spoj formule I, u kome R3 = CONHR4, a R4 ima formulu 12, niže.
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Alternativno, karboksamid formule 12 se može dobiti prevođenjem triflatnog estera formule 10 u nitril formule 13, reakcijom s cink-cijanidom i paladijevim katalizatorom, poput tetrakis-trifenilfosfin-paladija, u otapalu poput dimetilformamida ili toluena, na temperaturi od oko 0 °C do oko temperature refluksa, po mogućnosti oko temperature refluksa. Nitril formule 13 se može prevesti u karboksamid formule 12 reakcijom s vodik-peroksidom i natrij-karbonatom u etanolu, na temperaturi raspona od oko 0 °C do oko temperature refluksa, po mogućnosti oko sobne temperature.
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Spojevi opće formule I, u kojoj R3 je NHSO2R5, može se dobiti prema prikazu u Shemi 5, hidrolizom estera formule 11 u karboksilnu kiselinu formule 14, reakcijom s litij-hidroksidom ili drugim hidroksidom alkalnog metala, u smjesi tetrahidrofurana (THF) i vode, na temperaturi od oko sobne temperature do oko temperature refluksa. Spoj formule 14 se zatim prevede u anilin formule 15, reakcijom s difenilfosforil-azidom, u prisustvu trietilamina ili druge trialkilaminske alkalije, u t-butanolu, na temperaturi refluksa, nakon čega slijedi kisela hidroliza vodenom klorovodičnom kiselinom u etil acetatu ili s trifluoroctenom kiselinom u metilenkloridu. Spoj formule 15 se zatim sulfonilira kako bi se dobio traženi spoj formule 16, s aril- ili alkilsulfonil-kloridom i piridintrietilaminom ili drugom trialkilaminskom bazom, u diklormetanu, dikloretanu ili toluenu, na temperaturi od oko 0 °C do oko temperature refluksa, po mogućnosti oko sobne temperature.
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Spojevi opće formule I, u kojima R3 je metoksi, hidroksi ili fluor, a R2 je aromatski ili heteroaromatski ostatak (navedeni u Shemi 6 kao spojevi formule 17), mogu se dobiti vezanjem organometala formule 3 s aril ili heteroaril boronskom kiselinom, gdje su aril i heteroaril definirani u definicijama za R1 i R2, u otapalu poput etanola ili toluena, u prisustvu paladijevog katalizatora, poput tetrakis-trifenilfosfin-paladija i trialkilaminske alkalije (npr. trietilamina) i karbonata alkalnog metala kao alkalije, kao što je prikazano niže u Shemi 6. Obično se ova reakcija vodi na temperaturi od oko sobne temperature do oko temperature refluksa, po mogućnosti oko temperature refluksa.
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Spojevi formule 1, u kojima R2 je triazolil, mogu se dobiti prema prikazu u Shemi 7, niže, prevođenjem odgovarajućeg triflata, formule 3, u odgovarajući nitril formule 18. Ovo se može obaviti reakcijom spoja triflata s cink-cijanidom i paladijevim katalizatorom, poput tetrakis-trifenilfosfin-paladija, u otapalu poput dimetilformamida, na temperaturi raspona od oko 0 °C do oko 100 °C, po mogućnosti oko temperature refluksa. Stvaranje tetrazola dolazi nakon reakcije nastalog nitrila s natrij- ili trimetilsilil azidom i katalitičkom količinom kositar-oksida, u otapalu poput dimetilformamida, po mogućnosti oko temperature refluksa, ili u toluenu na temperaturi raspona od oko 20 °C do oko temperature refluksa. Alkiliranje tetrazola se obavlja reakcijom s trietilaminom ili drugom trialkilaminskom alkalijom, ili hidridom, alkoksidom ili karbonatom alkalnog metala i odgovarajućim spojem formule R6X, gdje X je izlazna grupa, npr. klor, brom, jod, triflat, mezilat ili tosilat, u otapalu poput metanola, etanola ili tetrahidrofurana, na temperaturi raspona od oko 0 °C, do oko temperature refluksa, po mogućnosti oko sobne temperature.
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Spojevi opće formule 1, u kojima R3 je fluor ili metoksi, a R2 je heterocikl, poput oksazolina ili tiazolina, mogu se dobiti prema prikazu u Shemi 8, iz odgovarajuće karboksilne kiseline formule 20, koja se može dobiti uz uvjete identične onima za dobivanje karboksilnih kiselina formule 12 (Shema 5). Karboksilna kiselina formule 20 se prvo prevede u odgovarajući kiselinski klorid, reakcijom s oksalil kloridom ili tionil kloridom, a zatim reagira s odgovarajućim amino alkoholom formule NH2C(R5)(R6)CH2OH ili aminotiolom formule NH2C(R5)(R6)CH2S. Kiselinski klorid obično reagira kao čista tvari ili u otapalu poput diklormetana ili dikloretana, na temperaturi od oko 0 °C do oko temperature refluksa, po mogućnosti oko temperature refluksa. Reakcija s odgovarajućim aminoalkoholom ili aminotiolom obično se obavlja na sličnim temperaturama, u otapalu poput diklormetana ili dikloretana. Dehidrativna ciklizacija, uz tionil klorid, čist ili u diklormetanu, oko temperature refluksa, ili upotrebljavajući triflički anhidrid i piridin ili trialkiamin, npr. trietilamin, u diklormetanu, dikloretanu ili tetrahidrofuranu, na temperaturi raspona oko –78 °C, uz stupnjevito grijanje do sobne temperature, daje traženi spoj formule I. Ovaj niz reakcija je prikazan u Shemi 8 dobivanja spoja formule I u kome R3 je fluor ili metoksi, a R2 je 4,4-dimetiloksazolil (formula 23 u Shemi 8).
Alternativno, spojevi formule 23 se mogu dobiti prema prikazu u Shemi 8a, reakcijom odgovarajućeg amida formule 7 (Shema 1) s trifličkim anhidridom, piridinom ili trialkilaminskom alkalijom poput trietilamina, i odgovarajućim aminoalkoholom ili aminotiolom, kao što je navedeno u prethodnom paragrafu, u otapalu poput diklormetana ili dikloretana, na temperaturi od oko –78 °C do oko sobne temperature, po mogućnosti počevši od –78 °C pa uz lagano grijanje reakcijske smjese do sobne temperature.
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Spojevi opće formule I, u kojima R3 je fluor ili metoksi, a R2 je karbinol, npr. dietilkarbinol (naveden u Shemi 9 kao spoj formule 24), može se dobiti prema prikazu u Shemi 9, reakcijom estera formule 4 s alkil Grignard-ovim reagensom ili alkillitijem, u otapalu poput etera ili tetrahidrofurana, na temperaturi raspona od oko –78 °C do oko temperature refluksa, po mogućnosti polazeći od sobne temperature, pa uz grijanje do temperature refluksa.
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Spojevi opće formule I, u kojima R2 je diazaoksazolski prsten (npr. spojevi formule 27 u Shemi 10), mogu se dobiti prema prikazu u Shemi 10, reakcijom metil estera formule 4 s hidrazinskim hidratom, u metanolu, na temperaturi od oko 0 °C do oko temperature refluksa, po mogućnosti oko temperature refluksa, što daje hidrazid formule 25. Naknadno aciliranje s kiselinskim kloridom i piridinom, trietilaminom ili drugim trialkilaminom, u otapalu poput diklormetana, dikloretana ili toluena, na temperaturi od oko 0 °C do oko temperature refluksa, po mogućnosti oko sobne temperature, daje odgovarajuće spoj formule 26. Ciklizacija se može obaviti kombinacijom reagensa, npr. trifenilfosfin/joda i trietilamina ili drugog trialkilamina, u otapalu poput tetrahidrofurana ili toluena, na temperaturi od oko 0 °C do oko temperature refluksa, po mogućnosti oko sobne temperature, ili trifličkim anhidridom i piridinom ili trialkilaminom, u diklormetanu ili tetrahidrofuranu, na temperaturi od oko –78 °C do oko sobne temperature, po mogućnosti polazeći od –78 °C, pa stupnjevitim grijanjem do oko sobne temperature, ili tionil kloridom u diklormetanu ili čistim, na temperaturi od oko sobne temperature pa do oko temperature refluksa, po mogućnosti oko temperature refluksa, dajući traženi spoj formule 27.
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Poželjan postupak dobivanja spojeva formule I, u kojima R3 je OH, NHSO2R7, C(OH)R7R8 ili C(=O)NHR7, je dobivanje spojeva analognih onima u kojima R3 je O-(C1-C6)alkil, a zatim deriviranjem istih, standardnim postupcima dobro poznatim u tom području tehnike i prikazanim u prethodnim shemama.
Polazni materijali upotrijebljeni u postupcima u Shemama 1-10, su ili tržišno pristupačni, ili poznati u literaturi, ili se lako dobivaju iz tržišno pristupačnih ili poznatih spojeva, postupcima dobro poznatim u tom području tehnike, ili opisanim gore.
Ukoliko nije drugačije rečeno, tlak u svakoj od gornjih reakcija nije kritičan. Obično se reakcije vode pod tlakom od oko 1 do oko 3 bara, po mogućnosti pod tlakom okoline (oko 1 bar).
Dobivanje drugih spojeva formule 1 koji nisu specifično opisani u prethodnom eksperimentalnom odjeljku, može se obaviti kombinacijom gore opisanih reakcija, što je jasno stručnjacima u tom području tehnike.
Spojevi formule 1 alkalne prirode mogu tvoriti širok spektar različitih soli s raznim anorganskim i organskim kiselinama. Kiselina koja se može upotrijebiti u pripravljanju farmaceutski prihvatljivih kiselih adicijskih soli iz alkalnih spojeva ovog izuma, je od onih koje tvore neotrovne kisele adicijske soli, tj. soli koje sadrže farmakološki prihvatljive anione, poput hidroklorida, hidrobromida, hidrojodida, nitrata, sulfata ili bisulfata, fosfata ili kiselih fosfata, acetata, laktata, citrata ili kiselih citrata, tartarata ili bitartarata, sukcinata, maleata, fumarata, glukonata, saharata, benzoata, metansulfonata i pamoata (tj. 1,1'-metilen-bis-(2-hidroksi-3-naftoata)). Iako te soli mogu bit farmaceutski prihvatljive za davanje životinjama, često je u praksi poželjno najprije izolirati spoj formule I iz reakcijske smjese kao farmaceutski neprihvatljivu sol, a zatim istu jednostavno prevesti reakcijom s alkalnim reagensom ponovo u spoj slobodne alkalije, a slobodnu alkaliju nakon toga prevesti u farmaceutski prihvatljivu kiselu adicijsku sol. Kisele adicijske soli alkalnih spojeva ovog izuma se lako dobivaju reakcijom alkalnog spoja s, u osnovi, ekvivalentnom količinom odabrane mineralne ili organske kiseline, u mediju vodenog otapala, ili u pogodnom organskom otapalu, poput metanola i etanola. Nakon pažljivog isparavanja otapala, dobije se tražena kruta sol.
Spojevi formule kisele prirode mogu tvoriti soli s raznim farmakološki prihvatljivim kationima. Ove soli se dobivaju konvencionalnim tehnikama. Kemijske alkalije koje se upotrebljavaju kao reagensi za pripravu farmaceutski prihvatljivih alkalnih soli ovog izuma su od onih koje tvore neotrovne alkalne soli s kiselim spojevima formule 1. Te neotrovne alkalne soli uključuju one koje se deriviraju iz farmakološki prihvatljivih kationa, poput natrija kalija, kalcija i magnezija, itd. Ove soli se mogu lako pripraviti reakcijom odgovarajućih kiselih spojeva s vodenom otopinom koja sadrži tražene farmakološki prihvatljive katione, a zatim uparavanjem nastale otopine do suhog, po mogućnosti pod sniženim tlakom. Alternativno, one se mogu pripremiti također miješanjem otopina kiselih spojeva u nižim alkanolima i traženog alkoksida alkalnog metala, pa zatim uparavanjem nastale otopine do suhog, na isti način kao i ranije. U svakom slučaju, poželjno je upotrebljavati stehiometrijske količine reagensa, kako bi se omogućila potpuna reakcija i maksimalni prinosi traženog konačnog produkta.
Spojevi formule 1 i njihove farmaceutski prihvatljive soli (u nastavku, navodit će se, skupno kao "aktivni spojevi ovog izuma") su pogodni za tretiranje neurodegenerativnih, psihotropnih i lijekovima ili alkoholom izazvanih deficita, a potentni su ligandi opioidnih receptora. Stoga, aktivni spojevi ovog izuma se mogu upotrebljavati u slučaju poremetnji ili stanja, poput gore navedenih, koja se mogu tretirati moduliranjem vezanja na opioidni receptor.
Sposobnost vezanja spojeva formule I na razne opioidne receptore i njihova funkcionalna aktivnost na tim receptorima, mogu se odrediti prema opisanu u nastavku. Vezanje na δ opioidni receptor se može odrediti postupcima dobro poznatim stručnjacima u tom području tehnike, poput onih koje navode Lei Fang i drugi: "J. Pharm. Exp. Ther.", 268, 836-846, (1994.) i Contreras i drugi: "Brain Research", 604, 160-164, (1993.).
U opisu vezanja i funkcionalnih testova koji slijede, upotrebljavaju se slijedeće skraćenice i terminologija:
DAMGO je [D-Ala2,N-MePhe4,Gly5-ol]enkefalin);
U69593 je ((5a,7a,8b)-(+)-N-metil-N-(7-[1-pirolidinil]-1-oksaspiro[4,5]dec-8-il)-benzenacetamid);
SNC-80 je (+)-4-[(αR)-α((2S,5R)-4-alil-2,5-dimetil-1-piperazinil)-3-metoksibenzil]-N,N-dietilbenzamid;
norBNI je nor-binaltorfimin;
CTOP je 1,2-ditia-5,8,11,14,17-pentaazacikloikosan, derivat cikličkog peptida;
DPDPE je [D-en2,D-Pen5]enkefalin;
[3H]-DAMGO, [3H]-U69593, norBNI i CTOP su tržišno pristupačni od strane poduzeća Du Pont, Amersham International, RBI and Du Pont, Amersham International, odnosno RBI i DuPont;
[3H]-SNC80 je pripravila firma Amersham International.
Testovi vezanja na opioidne receptore (μ i κ) mogu se obaviti na preparatima moždanih membrana zamorčeta. Testovi vezanja se mogu obaviti na 25 °C, tijekom 60 minuta u 50 mM puferu Tris (pH 7,4). [3H]-DAMGO (2 nM) i [3H]-U-69,593 (2 nM) se mogu za upotrebljavati za obilježavanje veznih mjesta na μ, odnosno κ receptoru. Koncentracija proteina može biti približno 200 µg/jažici. Nespecifično vezanje se može odrediti 10 µM naloksonom.
Testovi vezanja na δ opioidni receptor mogu se vršiti na stabilnoj CHO staničnoj liniji koja eksprimira ljudski δ opioidni receptor. Test vezanja može se provesti na 25 °C tijekom 120 minuta u 50 mM Tris (pH 7,4) puferu. [3H]-SNC-80 može se upotrijebiti za obilježavanje veznih mjesta na δ opioidnim receptorima. Koncentracija proteina može biti približno 12,5 µg/jažici. Nespecifično vezanje se može odrediti 10 µM naltreksonom.
Reakcija vezanja se može zaustaviti brzim filtriranjem kroz filtre od staklenih vlakana, a uzorci se mogu isprati ledeno hladnim 50 mM Tris puferom (pH 7,4).
Aktivnost agonista na δ, μ i κ opioidnim receptorima može se odrediti prema slijedećem.
Opioidna aktivnost (δ, μ i κ) se proučava, prema daljnjem opisu, na 2 izolirana tkiva, na sjemenovodu miša (MVD)(δ) i na mienteričkom spletu zamorčeta s pridruženim uzdužnim mišićem (GPMP)(μ i κ).
MVD (soj DC1, Charles River, 25-35 g) se suspendiraju u organskim kupeljima od 15 ml, koja sadrži Krebs-ov pufer bez Mg2+, slijedećeg sastava (u mM): NaCl 119; KCl, 4,7; NaHCO3, 25; KH2PO4, 1,2; CaCl2, 2,5 i glukoza, 11. Pufer se propuše s 95 % O2 i 5 % CO2. Tkiva se pričvrste između platinskih elektroda, vezanih za izometrijski transduktor uz silu od 500 mg, pa se stimuliraju pulsevima od 0,03 Hz, uz širinu pulsa od 1 ms, uz supramaksimalni napon. Vrijednosti IC50 se određuju regresijskom analizom krivulja koncentracija-odgovor inhibicije električno induciranih kontrakcija, u prisustvu 300 nM μ-selektivnog antagonista CTOP. Ovaj test je mjera δ agonizma.
Mienterički splet s pripojenim uzdužnim mišićem zamorčeta (soj Porcellus, mužjaci, 450-500 g, Dunkin Hartley), se pričvrsti uz opterećenje od 1 g u Krebs-ov pufer, pa se stimulira pulsevima od 0,1 Hz trajanje pulsa od 1 ms, uz supramaksimalni napon. μ-funkcionalna aktivnost se određuje u prisustvu 10 nM nor-BNI, uz 1 µM μ-selektivni agonist DAMGO, koji se dodaje u kupelj na kraju eksperimenta kako bi se definirao maksimalni odgovor. Ovaj test je mjera μ agonizma.
κ-funkcionalna aktivnost se određuje u prisustvu 1 µM CTOP i 1 µM κ-selektivnog agonista U-69,593, koji se dodaje na kraju eksperimenta kako bi se definirao maksimalni odgovor. Sve inhibicije visine grčenja za test spojeva se izražavaju kao postotak inhibicije koji se dobiven uz standardni agonist, pa se određuju odgovarajuće vrijednosti IC50.
Postupak koji slijedi može se upotrebljavati za određivanje aktivnosti terapeutskih sredstava ovog izuma kao agonista i kao antagonista δ opioidnih receptora.
Kultura stanica: Stanice jajnika kineskog hrčka koje eksprimiraju ljudski δ opioidni receptor, pasažiraju se dvaput tjedno kroz medij Hamis F-12 s L-glutaminom, koji sadrži 10 % seruma goveđeg fetusa i 450 µg/ml higromicina. Stanice se pripremaju za testove 3 dana prije eksperimenta. Doda se 15 ml 0,05 % tripsin/EDTA u konfluentnu trostruku tikvicu, zavrti i dekantira radi ispiranja. Ponovo se doda 15 ml 0,05 % tripsin/EDTA, pa se tikvica stavi 2 minute u inkubator na 37 °C. Stanice se uklone iz tikvice naginjanjem, a supernatant se prebaci u epruvetu od 50 ml. Zatim se doda 30 ml medija u tikvicu da se zaustavi djelovanje tripsina, pa se dekantira u epruvetu od 50 ml. Epruveta se zatim centrifugira 5 minuta pri 1000 o/min, medij se dekantira, a talog resuspendira u 10 ml medija. Vijabilnost stanica se testira tripanskim modrilom, a stanice se broje, pa se uz gustoću od 7.500 stanica/jažici stave u svaku od 96 jažica na ploči obloženoj poli-D-lizinom.
Ploča za ispitivanje antagonista: Stanice, stavljene na ploču 3 dana prije testa se dvaput isperu s PBS. Ploče se stave u vodu kupelj na 37 °C. Zatim se doda 50 µl testnog pufera (PBS, dekstroza 1 mg/ml, 5 mM MgCL2, 30 mM HEPES, 66,7 µg/ml IBMX) u odgovarajuće jažice. Potom se u odgovarajuću jažicu doda 50 µl odgovarajućeg lijeka i drži 1 minutu. Zatim se u odgovarajuće jažice doda 50 µl 10 µM forskolina + 0,4 nM DPDPE (konačna koncentracija forskolina u testu 5 je µM, a DPDPE 0,2 nM) i drži se 15 minuta. Reakcija se zaustavlja dodavanjem 10 µl 6M perklorne kiseline u sve jažice. Za neutralizaciju se u sve jažice doda 13 µl 5M KOH, a za stabilizaciju doda se u svaku jažicu 12 µl 2M Tris, pH 7,4. Miješa se u orbitalnoj tresilici 10 minuta, pa se 10 minuta centrifugira na podjeljku 7. Alikvot se prebaci na 3H ploču.
Ploča za test agonista: Stanice, stavljene na ploču 3 dana prije testa se dvaput isperu s PBS. Ploče se stave u vodenu kupelj na 37 °C. Zatim se doda 50 µl testnog pufera (PBS, dekstroza 1 mg/ml, 5 mM MgCL2, 30 mM HEPES, 66,7 µg/ml IBMX) u odgovarajuće jažice. Zatim se u sve jažice doda 50 µl odgovarajućeg lijeka + 10 µM forskolina (konačna koncentracija forskolina u testu 5 µM) i drži se 15 min. Reakcija se zatim zaustavlja dodavanjem 10 µl 6M perklorne kiseline u sve jažice. Za neutralizaciju se u sve jažice doda 13 µl 5M KOH, a za stabilizaciju doda se u svaku jažicu 12 µl 2M Tris, pH 7,4. Miješa se u orbitalnoj tresilici 10 minuta, pa se 10 minuta centrifugira na podjeljku 7. Alikvot se prebaci na 3H ploči.
Obje ploče za testiranje se ostave preko noći u kompletu za vezanje Amersham 3H cAMP, pa se saberu pomoću Skatron-a na GF/B filtrima, prethodno natopljenim u 0,5 % PEI, uz 50 mM Tris HCl, pH 7,4 na 4 °C. Filtri s kolačem se suše na zraku preko noći, a zatim stave u vrećice s 20 ml tekućine Betaplate scintilation cocktail i broje na brojaču Betaplate, 60 s po uzorku. Podaci se analiziraju uz upotrebu Excel-a.
Pripravci ovog izuma se mogu formulirati na konvencionalan način, uz upotrebu 1 ili više farmaceutski prihvatljivih podloga. Prema tome, aktivni spojevi ovog izuma mogu se pripraviti za oralno, bukalno, transdermalno (npr. flasterima), intranazalno, parenteralno (npr. intravenozno, intramuskularno ili potkožno) ili rektalno davanje, ili u obliku pogodnom za davanje inhalacijom ili insuflacijom.
Farmaceutski pripravci za oralno davanje mogu biti u obliku, npr. tableta ili kapsula, dobivenih na konvencionalne načine s farmaceutski prihvatljivim dodacima, poput veziva (npr. preželatiniranog kukuruznog škroba, polivinilpirolidona ili hidroksipropilmetilceluloze); punila (npr. laktoze, mikrokristalne celuloze ili kalcij-fosfata); mazila (npr. magnezij-stearata, talka ili silicij-dioksida); dezintegranata (npr. škroba iz krumpira ili natrij-škrob glikolata); ili močila (npr. natrij-lauril sulfata). Tablete mogu biti obložene postupcima dobro poznatim stručnjacima u tom području tehnike. Tekući pripravci za oralno davanje mogu biti u obliku, npr. otopina, sirupa ili suspenzija, ili se mogu davati kao suh proizvod za pripravljanje s vodom ili drugom pogodnom tekućom podlogom prije upotrebe. Takvi tekući pripravci se mogu pripremiti konvencionalnim načinima, s farmaceutski prihvatljivim dodacima, poput sredstava za suspendiranje (npr. sorbitolnog sirupa, metilceluloze ili hidrogeniranih jestivih masti); emulgatora (npr. lecitina ili agacije); nevodenih tekućih podloga (npr. bademovog ulja, uljnih estera ili etil alkohola); i konzervansa (npr. metil ili propil p-hidroksibenzoata ili sorbinske kiseline).
Za bukalno davanje preparati mogu biti u obliku tableta ili pastila, pripravljeni na konvencionalni način.
Aktivni spojevi ovog izuma se mogu pripraviti u obliku otopine ili suspenzije za parenteralno davanje injekcijama, uključujući upotrebu konvencionalnih tehnika kateterizacije ili infuziju. Pripravci za injekcije se mogu dati u obliku jednokratne doze, npr. u ampulama ili u ulošcima za više doza, uz dodatak konzervansa. Preparati mogu biti u obliku suspenzija, otopina ili emulzija u uljnoj ili u vodenoj podlozi, a mogu sadržavati sredstva za formuliranje, npr. sredstva za suspendiranje, stabiliziranje i/ili dispergiranje. Alternativno, aktivni sastojak može biti u obliku praha za rekonstituiranje s pogodnom tekućom podlogom prije upotrebe, npr. sterilnom vodom bez pirogena.
Aktivni spojevi ovog izuma se mogu također pripraviti kao rektalni pripravci, npr. supozitoriji ili retencijske klizme, npr. koji sadrže konvencionalnu podlogu za supozitorije, npr. kakao-maslac ili druge gliceride.
Za intranazalno ordiniranje ili ordiniranje inhalacijom, aktivni spojevi ovog izuma se pogodno daju u obliku otopina ili suspenzije, iz boce s pumpicom za sprej, koju stiska ili pumpa pacijent, ili kao aerosolni sprej iz boce pod tlakom ili nebulizatora, uz upotrebu pogodnog propelenta, npr. diklordifluormetana, trifluorklormetana, diklortetrafluoretana, ugljičnog dioksida ili drugog pogodnog plina. U slučaju aerosola pod tlakom, jedinična doza može se odrediti ventilom za oslobađanje odmjerene količine. Boca pod tlakom ili nebulizator može sadržavati otopinu ili suspenziju aktivnog spoja. Kapsule i ulošci (napravljeni, npr. od želatine) za upotrebu u inhalatoru ili insuflatoru, mogu se pripraviti tako da sadrže mješavinu praha spoja ovog izuma i pogodne praškaste podloge, poput laktoze ili škroba.
Obično je terapeutski djelotvorna dnevna oralna ili intravenozna doza spojeva formule (I) i njihovih soli u rasponu od 0,001 do 50 mg/kg tjelesne težine subjekta kojeg treba tretirati, po mogućnosti 0,2 do 20 mg/kg. Spojevi formule 1 i njihove soli se mogu također davati intravenskom infuzijom, s dozom sličnog raspona, od 0,001 do 10 mg/kg/h.
Tablete ili kapsule ovih spojeva se mogu davati jedanput, dvaput ili više puta, prema potrebi. Moguće je također spoj davati i u formulaciji sa zadržanim oslobađanjem.
Liječnik će odrediti stvarnu dozu najpogodniju za pojedinog pacijenta, a ova će varirati prema starosti, težini i odgovoru određenog pacijenta. Gore navedene doze su primjer prosječnog slučaja. Naravno, u pojedinačnim primjerima doze mogu biti više ili niže, raspon doza se podešava na optimalnost, a to je sve unutar opsega ovog izuma.
Alternativno, spojevi formule 1 se mogu davati inhalacijom ili u obliku supozitorija ili pesarija, ili se mogu primjenjivati površinski, u obliku losiona, otopina, krema, masti ili prašaka za prašenje. Alternativni načini transdermalnog ordiniranja su flasterom za kožu. Oni se, primjerice, mogu staviti u kremu od vodene emulzije polietilenglikola ili tekućeg parafina. Oni se mogu također staviti, pri koncentracijama 1 do 10 mas. %, u masti od bijelog voska ili bijele meke parafinske baze, zajedno sa stabilizatorima i konzervansima, prema potrebi.
Primjeri koji slijede ilustriraju dobivanje spojeva ovog izuma. Koriste se komercijalni reagensi, bez daljnjeg pročišćavanja. Svi NMR podaci su registrirani pri 250, 300 ili 400 MHz, u deuterokloroformu, ukoliko nije drugačije naznačeno, i dati su u dijelovima na milijun (δ), za referentni deuerijski signal uzorka otapala. Sve nevodene reakcije se obavljaju u suhom posuđu, sa suhim otapalima, u inertnoj atmosferi pogodnosti radi, kako bi se maksimalizirali prinosi. Sve reakcijske smjese se miješaju magnetskom miješalicom, ukoliko drugačije nije naglašeno. Ukoliko se drugačije ne kaže, svi maseni spektri su dobiveni uz uvjete kemijskog sudara. Temperatura okoline ili sobna temperatura se odnosi na 20-25 °C.
Primjer 1
N,N-dietil-4-[4-(3-hidroksi-fenil)-piperidin-4-il]-benzamid
A. 1-benzil-4-(3-metoksi-fenil)piperidin-4-ol
Otopini 3-bromoanisola (20,9 ml, 0,16 mmol) u THF (150 ml), na –78 °C i u atmosferi dušika, dodaje se 10 minuta n-BuLi (66 ml, 0,16 mmol, 2,5 M u heksanima). Nastala gusta suspenzija se 1 sat miješa na –78 °C. Ovoj smjesi se doda otopina N-benzil-4-piperidinona (27,8 ml, 0,15 mmol) u THF (30 ml). Reakcijska smjesa se 2 sata miješa na –78 °C, pa 10 sati na sobnoj temperaturi. Smjesa se lagano prebaci u ledenu vodu (100 ml), a vodeni sloj se ispere s EtOAc (3 × 50 ml). Sabrani organski ekstrakti se osuše (MgSO4) i koncentriraju. Sirovi ostatak se pročisti fleš kromatografijom, smjesom heksani/EtOAc (3:1), dajući 42,2 g alkohola (prinos 95 %).
1H NMR (400 MHz, CDCl3) δ 7,35-7,22 (kompl., 6H), 7,07-7,04 (kompl., 2H), 6,80-6,77 (m, 1H), 3,80 (s, 1H), 3,58 (s, 1H), 2,79 (d, 2H), 2,48 (t, 2H), 2,19-2,13 (kompl., 2H), 1,72 (dd, 2H), 1,58 (s, 1H).
MS (M + 1) 298,3.
B. 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-fenol
U otopinu 1-benzil-4-(3-metoksi-fenil)-piperidin-4-ola (21,7 g, 73,1 mmol) u (CH2)2Cl2 (200 ml) doda se fenol (20,7 g, 220 mmol), a nakon toga u dijelovima (vrlo egzotermno) AlCl3 (29,3 g, 200 mmol). Reakcijska smjesa se 10 sati grije pod refluksom. Smjesa se ohladi do sobne temperature, pa se lagano prebaci u smjesu drobljenog leda (50 ml) i 30 % vodenog NH4OH (120 ml). Smjesa se 20 minuta snažno miješa, a zatim filtrira kroz Celite. Kolač na Celite-u se ispere s CH2Cl2 (200 ml). Odvoji se organski sloj, a vodeni sloj se ispere s CH2Cl2 (3 × 100 ml). Sabrani organski slojevi se osuše (MgSO4) i koncentriraju. Sirovi ostatak se pročisti fleš kromatografijom, s heksani/Etoac (1:1), dajući 20,1 g (prinos 73 %) 4-[benzil-4-(3-metoksi-fenil)-piperidin-4-il]-fenola.
1HNMR (400 MHz, CD3OD) δ 7,28-7,20 (kompl., 5H), 7,14 (t, 1H), 7,07 (d, 2H), 6,83 (d, 2H), 6,76 (s, 1H), 6,70-6,60 (kompl., 3H), 3,69 (s, 3H), 2,50-2,40 (kompl. 4H), 2,39-2,29 (kompl., 4H).
MS (M + 1) 374,2.
C. 4-[benzil-4-(3-metoksi-fenil)-piperidin-4-il]-fenil ester trifluor-metansulfonske kiseline
U gustu otopinu 4-[benzil-4-(3-metoksi-fenil)-piperidin-4-il]-fenola (22,3 g, 59,8 mmol) u CH2Cl2 (200 ml), na 0 °C, doda se piridin (9,26 ml, 89,7 mmol), a zatim tijekom 10 minuta u kapima se dodaje triflički anhidrid (15,1 ml, 89,7 mmol). Reakcijska smjesa se 1 sat miješa na 0 °C, pa 2 sata na sobnoj temperaturi. Otopina se zatim ohladi na 0 °C, pa se doda 40 ml hladne zasićene otopine NaHCO3. Odvoji se organski sloj, a vodeni sloj se ispere s CH2Cl2 (3 × 50 ml). Sabrani organski slojevi se osuše (MgSO4) i koncentriraju. Sirovi ostatak se pročisti fleš kromatografijom, s heksani/EtOAc (3:1), dajući 22,1 g (prinos 75 %) 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-fenil estera trifluor-metanuslfonske kiseline.
1HNMR (400 MHz, CD3OD) δ 7,32-7,20 (kompl., 8H), 7,14 (d, 2H), 6,84 (d, 1H), 6,81 (s, 1H), 6,72 (dd, 1H), 3,77 (s, 3H), 3,41 (s, 2H), 2,55-2,38 (kompl., 8H).
MS (M + 1) 505,9.
D. metil ester 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzojeve kiseline
U otopinu 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-fenil estera trifluor-metansulfonske kiseline (10,0 g, 19,8 mmol) u Parr-ovoj posudi za rad pod tlakom, u MeOH (69 ml), dodaju se DMSO (62 ml) i trietilamin (21,8 ml, 157 mmol). Ovoj reakcijskoj smjesi se dodaju paladij-acetat (2,2 g, 9,1 mmol) i 1,3-bis(difenilfosfino)propan (3,75 g, 9,1 mmol). Smjesa se trese 4 sata na 70 °C pod tlakom CO od 2,76 bar. Reakcijska smjesa se ohladi do sobne temperature i razrijedi dietil eterom (600 ml). Eterski sloj se ispere vodom (5 × 60 ml), osuši (MgSO4) i koncentrira. Sirovi ostatak se pročisti fleš kromatografijom, s heksani/Etoac (1:1), dajući 6,9 g (prinos 85 %) metil estera 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzojeve kiseline.
1H NMR (400 MHz, CDCl3) δ 7,91 (d, 2H), 7,32 (d, 2H), 7,28-7,16 (kompl., 6H), 6,82 (d, 1H), 6,79 (s, 1H), 6,68 (dd, 1H), 3,86 (s, 3H), 3,74 (s, 3H), 3,38 (s, 2H), 2,47-2,44 (kompl., 8H).
MS (M + 1) 416,2.
E. 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-N,N-dietil-benzamid
U otopinu dietilamina (1,88 ml, 18,2 mmol) u CH2ClCH2Cl (7 ml), na sobnoj temperaturi, u kapima se dodaje trimetilaluminij (9,1 ml, 18,2 mmol, 2 M u heksanima). Reakcijska smjesa se 1 sat miješa na sobnoj temperaturi. Doda se otopina metil estera 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzojeve kiseline (1,51 g, 3,64 mmol) u (CH2)2Cl2 (6 ml), pa se reakcijska smjesa 14 sati grije pod refluksom. Zatim se otopinu ohladi na 0 °C, pa se u kapima dodaje zasićeni vodeni NaHCO3 (15 ml). Smjesa se filtrira kroz Celite. Kolač na Celite-u se ispere s CH2Cl2 (40 ml). Odvoji se organski sloj, a vodeni sloj se ispere s CH2Cl2 (3 × 30 ml). Sabrani organski slojevi se osuše (MgSO4) i koncentriraju. Sirovi ostatak se pročisti fleš kromatografijom, s EtOAC, dajući 1,4 g (prinos 84 %) 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-N,N-dietil-benzamida.
1H NMR (400 MHz, CDCl3) δ 7,28-7,16 (kompl., 10H), 6,84-6,80 (kompl., 2H), 6,68 (dd, 1H), 3,74 (s, 3H), 3,52-3,48 (kompl., 2H), 3,39 (s, 2H), 3,24-3,21 (kompl., 2H), 2,47-2,42 (kompl., 8H), 1,22-1,20 (kompl., 3H), 1,19-1,16 (kompl., 3H).
MS (M + 1) 457,2.
F. N,N-dietil-4-[4-(3-hidroksi-fenil)-piperidin-4-il]-benzamid
U otopinu 4-[1-benzil-4-(3-hidroksi-fenil)-piperidin-4-il]-N,N-dietilbenzamida (1,11 g, 2,49 mmol) u octenoj kiselini (8 ml), u Parr-ovoj posudi za rad pod tlakom, doda se Pd(OH)2 (10 % na ugljiku, 0,4 g). Reakcijska smjesa se 20 sati trese pod tlakom od 3,4 bar H2. Zatim se reakcijska smjesa filtrira kroz Celite. Kolač na Celite-u se ispere s EtOAc (250 ml), a organski sloj koncentrira da se ukloni octena kiselina. Ostatak se raspodjeli između CH2Cl2 (10 ml) i 30 % vodenog NH4OH (10 ml). Odvoji se organski sloj, a vodeni sloj se ispere s CH2Cl2 (3 × 20 ml). Sabrani organski slojevi se osuše (MgSO4) i koncentriraju, dajući 0,74 g N,N-dietil-4-[4-(3-hidroksi-fenil)-piperidin-4-il]-benzamida (prinos 83 %), koji se koristi bez daljnjeg pročišćavanja.
1H NMR (400 MHz, CD3CO2D) δ 7,24-7,06 (kompl., 5H), 6,75 (s, 1H), 6,70 (d, 1H), 6,58 (d, 1H), 3,49-3,40 (kompl., 2H), 3,21-3,15 (kompl., 2H), 2,90-2,85 (kompl., 4H), 2,39-2,33 (kompl., 4H), 1,20-1,15 (kompl., 3H), 1,08-1,02 (kompl., 3H).
MS (M + 1) 353,2.
Slijedeći spojevi se načine gore opisanim postupkom u Primjeru 1, polazeći od spoja analognog naslovnom u Primjeru 1A, u kome R3 je fluor ili metoksi, i dodajući odgovarajući aminski reaktant u postupku 1E.
4-[1-benzil-4-(3-metoksi-4-metil-fenil)-piperidin-4-il]-N,N-dietilbenzamid
1H NMR (400 MHz, CDCl3) δ 7,01 (d, 1H), 6,68 (d, 1H), 6,61 (s, 1H), 3,70 (s, 3H), 3,41 (s, 2H), 2,18 (s, 3H).
MS (M + 1) 471,2.
4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-N-metil-benzamid
1H NMR (400 MHz, CDCl3) δ 7,62 (d, 2H), 6,79 (d, 1H), 6,66 (d, 1H), 6,04 (br, 1H), 3,77 (s, 3H), 2,89 (s, 3H).
MS (M + 1) 415,2.
4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-2-fluor-N,N-dimetilbenzamid
1H NMR (400 MHz, CDCl3) δ 7,09 (d, 1H), 6,95 (d, 1H), 6,71 (d, 1H), 3,79 (s, 3H), 3,09 (s, 3H), 2,89 (s, 3H).
MS (M + 1) 447,2.
4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-N-etil-N-metil-benzamid
1H NMR (400 MHz, CDCl3) δ 6,85-6,79 (kompl., 2H), 6,68 (d, 1H), 3,79 (s, 3H), 3,4 (s, 2H), 3,1-2,82 (kompl., 3H).
MS (M + 1) 443,3.
4-[1-benzil-4-(3-fluor-fenil)-piperidin-4-il]-N,N-dietil-benzamid
1H NMR (400 MHz, CDCl3) δ 7,02 (d, 1H), 6,88 (d, 1H), 6,81 (t, 1H), 2,62-2,22 (kompl., 8H).
MS (M + 1) 445,2.
Primjer 2
Opći postupak redukcijskog alkiliranja N,N-dietil-4-[4-(3-hidroksi, fluor ili metoksi-fenil)-piperidin-4-il]-benzamida
U otopinu N,N-dietil-4-[4-(3-hidroksi-fenil)-piperidin-4-il]-benzamida (1 ekvivalent) u CH2Cl2 (0,4 M) doda se aldehid (1,2 ekvivalenta), a zatim slijedi dodavanje octene kiseline (1,2 ekvivalenta) i NaBH(OAc)3 (1,5 ekvivalent). Reakcijska smjesa se 16 sati miješa na sobnoj temperaturi. Ova smjesa se raspodjeli između jednakih volumena CH2Cl2 i zasićenog vodenog NaHCO3. Odvoji se organski sloj, a vodeni sloj ispere s CH2Cl2 (× 3). Sabrani organski slojevi se osuše (MgSO4) i koncentriraju. Pročišćavanje fleš kromatografijom daje tražene tercijarne amine u prinosu koji se kreće od 60-95 %.
Slijedeći spojevi su načinjeni postupkom iz Primjera 2, počevši od diarilsupstituiranog piridina, gdje R3 je fluor ili metoksi, a R2 je odgovarajuća amidna grupa.
{4-[1-3-cikloheksil-propil)-4-(3-metoksi-fenil)-piperidin-4-il]-fenil}-morfolin-4-il-metanon
1H NMR (400 MHz, CDCl3) δ 6,82 (d, 1H), 6,79 (s, 1H), 6,71 (d, 1H), 3,75 (s, 2H), 1,79-1,61 (kompl., 8H).
MS (M + 1) 505,3.
{4-[1-heksil-4-(3-metoksi-fenil)-piperidin-4-il]-fenil}-morfolin-4-il-metanon
1H NMR (400 MHz, CDCl3) δ 6,81 (d, 1H), 6,79 (d, 1H), 6,68 (d, 1H), 3,75 (s, 3H), 1,46-1,41 (kompl., 2H), 0,84 (t, 3H).
MS (M + 1) 465,3.
N,N-dietil-4-[4-(3-metoksi-fenil)-1-(2-fenil-propil)-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 6,82-6,79 (kompl., 2H), 6,66 (d, 1H), 3,77 (s, 3H), 2,85 (m, 1H), 1,22 (d, 3H).
MS (M + 1) 485,3.
N,N-dietil-4-[1-heksil-4-(3-metoksi-fenil)-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 7,18 (t, 1H), 6,82-6,80 (kompl., 2H), 6,67 (d, 1H), 3,74 (s, 3H), 3,57-3,42 (kompl., 2H), 2,26-2,20 (kompl., 2H), 0,84 (t, 3H).
MS (M + 1) 451,3.
4-[1-(3-cikloheksil-propil)-4-(3-metoksi-fenil)-piperidin-4-il]-N,N-dietil-benzamid
1H NMR (400 MHz, CDCl3) δ 6,81 (d, 1H), 6,76 (s, 1H), 6,68 (d, 1H), 3,73 (s, 3H), 3,23-3,19 (kompl., 2H), 2,47-2,39 (kompl., 2H).
MS (M + 1) 491,3.
4-[1-(3-cikloheksil-propil)-4-(3-fluor-fenil)-piperidin-4-il]-N,N-dietil-benzamid
1H NMR (400 MHz, CDCl3) δ 7,01 (d, 1H), 6,86 (d, 1H), 6,82 (t, 1H), 3,59-3,4 (kompl., 2H), 2,26-2,20 (kompl., 2H).
MS (M + 1) 479,3.
N,N-dietil-4-[4-(3-fluor-fenil)-1-(3-fenil-propil)-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 7,02 (d, 1H), 6,69 (d, 1H), 6,81 (t, 1H), 3,33-3,19 (kompl., 2H), 2,50 (t, 2H), 1,83-1,71 (kompl., 2H).
MS (M + 1) 473,2.
N,N-dietil-4-[4-(3-fluor-fenil)-1-metil-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 7,02 (d, 1H), 6,85 (d, 1H), 2,61-2,41 (kompl., 8H), 2,26 (s, 3H).
MS (M + 1) 369,2.
N,N-dietil-4-[4-(3-fluor-fenil)-1-heksil-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 7,02 (d, 1H), 6,92-6,80 (kompl., 2H), 2,52-2,40 (kompl., 2H), 1,63-1,45 (kompl., 2H), 0,79 (t, 3H).
MS (M + 1) 439,3.
N,N-dietil-4-[4-(3-fluor-fenil)-1-(4-metil-benzil)-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 7,08 (d, 2H), 7,02 (d, 1H), 6,91 (d, 1H), 3,36 (s, 2H), 2,59-2,38 (kompl., 8H), 2,31 (s, 3H).
MS (M + 1) 459,2.
N,N-dietil-4-[4-(3-fluor-fenil)-1-(2-metil-pentil)-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 7,03 (d, 1H), 6,92 (d, 1H), 6,85 (t, 1H), 3,59-3,41 (kompl., 2H), 1,75-1,59 (kompl., 2H).
MS (M + 1) 439,3.
N,N-dietil-4-[4-(3-fluor-fenil)-1-(3-metil-butil)-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 7,02 (d, 1H), 6,93 (d, 1H), 6,83 (t, 1H), 3,31-3,19 (kompl., 2H), 1,58-1,43 (m, 1H), 1,39-1,29 (kompl., 2H), 0,86 (d, 6H).
MS (M + 1) 425,3.
Primjer 3
Alkiliranje N,N-dietil-4-[4-(3-metoksi-fenil)-piperidin-4-il]benzamida
U otopinu N,N-dietil-4-[4-(3-metoksi-fenil)-piperidin-4-il]-benzamida (1 ekvivalent) u DMF (0,5 M), doda se K2CO3 (3-10 ekvivalenata) i alkil- ili heteroaril halid (1-5 ekvivalenata). Reakcijska smjesa se 3-16 sati miješa na 60-120 °C. Smjesa se zatim ohladi do sobne temperature i filtrira. Filtrat se razrijedi dietil eterom, a eterski sloj se ispere slanom vodom. Organska faza se osuši (MgSO4) i koncentrira. Pročišćavanje fleš kromatografijom daje tražene amine u prinosu koji se kreće od 30-85 %.
Slijedeći spojevi su načinjeni postupkom analognim onom u Primjeru 3, počevši od odgovarajuće amidne grupe.
4-[1-alil-4-(3-metoksi-fenil)-piperidin-4-il]-N,N-dietilbenzamid
1H NMR (400 MHz, CDCl3) δ 7,19 (t, 1H), 6,84-6,80 (kompl., 2H), 6,69 (d, 1H), 5,88-5,79 (m, 1H), 5,15-5,10 (kompl., 2H), 3,75 (s, 3H), 2,95-2,87 (kompl., 2H).
MS (M + 1) 407,2.
4-[1-ciklopropilmetil-4-(3-metoksi-fenil)-piperidin-4-il]-N,N-dietil-benzamid
1H NMR (400 MHz, CDCl3) δ 7,18 (t, 1H), 6,75-6,79 (kompl., 2H), 6,68 (d, 1H), 3,74 (s, 3H), 2,21-2,10 (kompl., 2H), 1,88-1,78 (kompl., 1H), 1,51-1,39 (kompl., 2H).
MS (M + 1) 421,2.
N,N-dietil-4-[4-(3-metoksi-fenil)-3,4,5,6-tetrahidro-2H-[1,2']bipiridin-4-il]benzamid
1H NMR (400 MHz, CDCl3) δ 8,15 (d, 1H), 7,44 (t, 1H), 6,88-6,84 (kompl., 2H), 6,69 (d, 1H), 6,64 (d, 1H), 6,57 (t, 1H), 3,75 (s, 3H), 3,71-3,56 (kompl., 4H), 2,58-2,40 (kompl., 4H).
MS (M + 1) 444,4.
N,N-dietil-4-[4-(3-metoksi-fenil)-1-pirimidin-2-il-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 8,27 (d, 2H), 6,88-6,80 (kompl., 2H), 6,68 (d, 1H), 6,44 (t, 1H), 3,95-3,75 (kompl., 4H), 3,74 (s, 3H), 3,30-3,19 (kompl., 2H).
MS (M + 1) 445,4.
Primjer 4
Skidanje zaštite s metilaril etera
U otopinu metil etera (1 ekvivalent) u CH2Cl2 (0,4 M), na –78 °C, dodaje se u kapima otopina bor-tribromida (1-5 ekvivalenata) u CH2Cl2 (1,0 M). Reakcijska smjesa se 1 sat miješa na –78 °C, pa se zagrije do sobne temperature i miješa još 4-6 sati. Smjesa se ugasi polaganim dodavanjem vode, pa se dovede do pH 8 zasićenom otopinom NH4OH u vodi. Vodeni sloj se ispere s CH2Cl2. Organska faza se osuši (MgSO4) i koncentrira. Pročišćavanje fleš kromatografijom daje tražene fenole u prinosima koji se kreću od 60-95 %.
Alternativno, s metil etera se zaštita skida natrij-hidridom i etantiolom u DMF slijedećim postupkom:
U suspenziju NaH (10 ekvivalenata) u DMF (0,2 M), na sobnoj temperaturi, u kapima se dodaje etantiol (10 ekvivalenata). Ova smjesa se miješa 5 minuta. Reakcijskoj smjesi se doda otopina metil etera (1 ekvivalent) u DMF (0,2 M). Smjesa se grije 10-16 sati na 120 °C. Reakcijska smjesa se ohladi do sobne temperature i ugasi vodom. Smjesa se razrijedi dietil eterom, a organski sloj se ispere zasićenim otopinom soli. Organska faza se osuši (MgSO4) i koncentrira. Pročišćavanje fleš kromatografijom daje tražene fenole u prinosima koji se kreću od 60-95 %.
Slijedeći spojevi su načinjeni postupkom iz Primjera 4.
N,N-dietil-4-[4-(3-hidroksi-fenil)-1-metil-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 6,72-6,67 (kompl., 2H), 6,61 (d, 1H), 3,51-3,41 (kompl., 2H), 2,24-3,19 (kompl., 2H), 1,24 (s, 3H).
MS (M + 1) 367,1.
4-[1-alil-4-(3-hidroksi-fenil)-piperidin-4-il]-N,N-dietil-benzamid
1H NMR (400 MHz, CDCl3) δ 6,74-6,65 (kompl., 2H), 6,64 (d, 1H), 5,99-5,80 (m, 1H), 5,22-5,15 (kompl., 2H), 3,35-3,19 (kompl., 2H), 3,05-2,95 (kompl., 2H).
MS (M + 1) 393,2.
4-[1-benzil-4-(3-hidroksi-fenil)-piperidin-4-il]-N,N-dietil-benzamid
1H NMR (400 MHz, CDCl3) δ 6,78 (d, 1H), 6,63 (d, 1H), 6,61 (s, 1H), 3,50 (kompl., 2H), 3,42 (s, 2H), 1,19-1,01 (kompl., 3H).
MS (M + 1) 443,2.
4-[1-ciklopropilmetil-4-(3-hidroksi-fenil)-piperidin-4-il]-N,N-dietil-benzamid
1H NMR (400 MHz, CDCl3) δ 6,90 (s, 1H), 6,78-6,61 (kompl. 2H), 3,30-3,19 (kompl., 2H), 0,69-0,64 (kompl., 2H), 0,33-0,30 (kompl., 2H).
MS (M + 1) 407,2.
N,N-dietil-4-[4-(3-hidroksi-fenil)-1-fenetil-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 6,79 (d, 1H), 6,63 (s, 1H), 2,81-2,68 (kompl., 2H).
MS (M + 1) 457,2.
N,N-dietil-4-[4-(3-hidroksi-fenil)-1-tiazol-2-ilmetil-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 7,69 (d, 1H), 7,09 (t, 1H), 6,77 (d, 1H), 6,68 (s, 1H), 6,59 (d, 1H), 3,75 (s, 2H).
MS (M + 1) 450,1.
N,N-dietil-4-[4-(3-hidroksi-fenil)-1-tiofen-2-ilmetil-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 6,94-6,91 (kompl., 2H), 6,78 (d, 1H), 6,64-6,60 (kompl., 2H), 3,62 (s, 2H), 3,55-3,45 (kompl., 2H).
MS (M + 1) 449,1.
N,N-dietil-4-[4-(3-hidroksi-fenil)-1-(4-metil-benzil)-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 6,98 (d, 2H), 6,79 (d, 1H), 6,62 (d, 1H), 6,46 (s, 1H), 3,32 (s, 3H), 2,29 (S, 3H).
MS (M + 1) 457,2.
4-[1-butil-4-(3-hidroksi-fenil)-piperidin-4-il]-N,N-dietil-benzamid
1H NMR (400 MHz, CDCl3) δ 6,74 (d, 1H9, 6,66 (s, 1H), 6,61 (d, 1H), 1,48-1,39 (kompl., 2H), 0,85 (t, 3H).
MS (M + 1) 409,3.
4-[1-(3-cikloheksil-propil)-4-(3-hidroksi-fenil)-piperidin-4-il]-N,N-dietil-benzamid
1H NMR (400 MHz, CDCl3) δ 6,78 (s, 1H), 6,72-6,66 (kompl., 2H), 1,71-1,54 (kompl., 7H), 0,83-0,72 (kompl., 2H).
MS (M + 1) 477,3.
N,N-dietil-4-[1-heksil-4-(3-hidroksi-fenil)-1-fenetil-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 6,75 (d, 1H), 6,70 (s, 1H), 6,64 (d, 1H), 1,59-1,41 (kompl., 2H), 0,84 (t, 3H).
MS (M + 1) 437,3.
N,N-dietil-4-[4-(3-hidroksi-fenil)-1-(3-metil-butil)-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 6,76 (s, 1H), 6,71 (d, 1H), 6,67 (d, 1H), 0,87 (d, 3H).
MS (M + 1) 423,3.
N,N-dietil-4-[4-(3-hidroksi-fenil)-1-izobutil-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 6,74 (d, 1H), 6,60 (d, 1H), 2,11-2,02 (kompl., 2H), 1,80-1,73 (m, 1H), 0,86 (d, 6H).
MS (M + 1) 409,3.
N,N-dietil-4-[4-(3-hidroksi-fenil)-1-(4-izopropil-benzil)-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 7,08 (t, 1H), 7,01 (d, 1H), 6,74 (d, 1H), 6,62 (d, 1H), 6,56 (s, 1H), 3,40 (s, 2H), 2,88-2,79 (m, 1H), 1,20 (d, 6H).
MS (M + 1) 485,3.
N,N-dietil-4-[4-(3-hidroksi-fenil)-3,4,5,6-tetrahidro-2H-[1,2']bipiridinil-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 8,17-8,12 (m, 1H), 7,52-7,45 (m, 1H), 6,81-6,72 (kompl., 2H), 6,66 (d, 1H), 6,61-6,55 (kompl., 2H), 3,70-3,42 (kompl., 6H).
MS (M + 1) 430,4.
N,N-dietil-4-[4-(3-hidroksi-fenil)-1-pirimidin-2-il-piperidin-4-il]-benzamid
1H NMR (400 MHz, CDCl3) δ 8,27 (kompl., 2H), 6,57 (s, 1H), 6,44 (d, 1H), 3,91-3,85 (kompl., 2H), 3,78-3,69 (kompl., 2H), 3,52-3,47 (kompl., 2H).
MS (M + 1) 431,3.
4-[1-benzoksazol-2-il-4-(3-hidroksi-fenil)-piperidin-4-il]-N,N-dietil-benzamid
1H NMR (400 MHz, CDCl3) δ 7,34 (d, 1H), 7,02 (t, 1H), 6,81-6,74 (kompl., 2H), 6,62 (dd, 1H), 3,81-3,71 (kompl., 2H), 3,69-3,60 (kompl., 2H).
MS (M + 1) 470,3.
4-[4-(3-hidroksi-fenil)-1-(4-metil-benzil)-piperidin-4-il]-N,N-dimetil-benzamid
1H NMR (400 MHz, CDCl3) δ 7,07 (d, 2H), 6,75 (d, 1H), 6,61 (d, 1H), 6,45 (s, 1H), 3,34 (s, 2H), 3,05 (s, 3H), 2,92 (s, 3H), 2,27 (s, 3H).
MS (M + 1) 429,3.
4-[4-(3-hidroksi-fenil)-1-(2-metil-pentil)-piperidin-4-il]-N,N-dimetil-benzamid
1H NMR (400 MHz, CDCl3) δ 7,09 (t, 1H), 6,76 (d, 1H), 6,68 (s, 1H), 3,07 (s, 3H), 1,1-0,98 (m, 1H), 0,88-0,82 (kompl., 6).
MS (M + 1) 409,3.
4-[4-(3-hidroksi-fenil)-1-(3-metil-butil)-piperidin-4-il]-N,N-dimetil-benzamid
1H NMR (400 MHz, CDCl3) δ 7,20-7,05 (kompl., 3H), 6,77 (s, 1H), 3,06 (s, 3H), 2,94 (s, 3H), 9,84 (d, 6H).
MS (M + 1) 395,3.
{4-[1-(4-fluor-benzil)-4-(3-hidroksi-fenil)-piperidin-4-il]-fenil}-piperidin-1-il-metanon
1H NMR (400 MHz, CDCl3) δ 6,96 (t, 2H), 6,78 (d, 1H), 6,61 (dd, 1H), 6,51 (s, 1H), 3,72-3,59 (kompl., 2H), 3,36 (s, 2H), 3,35-3,31 (kompl., 2H).
MS (M + 1) 473,2.
{4-[1-heksil-4-(3-hidroksi-fenil)-piperidin-4-il]-fenil}-morfolin-1-il-metanon
1H NMR (400 MHz, CDCl3) δ 7,09 (t, 1H), 6,75 (d, 1H), 6,64 (s, 1H), 6,60 (d, 1H), 3,86-3,22 (kompl., 8H), 0,83 (t, 3H).
MS (M + 1) 451,3.
Primjer 5
3-[1-benzil-4-(4-dietilkarbamoil-fenil)-piperidin-4-il]-fenil ester trifluor-metansulfonske kiseline
U otopinu 4-[1-benzil-4-(3-hidroksi-fenil)-piperidin-4-il]-N,N-dietil-benzamida u CH2Cl2 (14 ml), na 0 °C, doda se piridin (0,43 ml, 5,33 mmol), a zatim tijekom 5 minuta u kapima se dodaje triflički anhidrid (0,9 ml, 5,33 mmol). Reakcijska smjesa se 1 sat miješa na 0 °C, a zatim 2 sata na sobnoj temperaturi. Otopina se zatim ohladi na 0 °C, pa se doda 15 ml hladnog, zasićenog vodenog NaHCO3. Odvoji se organski sloj, a vodeni sloj se ispere s CH2Cl2 (3 × 20 ml). Sabrani organski slojevi se osuše (MgSO4) i koncentriraju. Sirovi ostatak se pročisti fleš kromatografijom, s heksani/EtOAc (4:1), dajući 1,57 g (prinos 77 %) 3-[1-benzil-4-(4-dietilkarbamoil-fenil)-piperidin-4-il]-fenil estera trifluor-metansulfonske kiseline.
1H NMR (400 MHz, CDCl3) δ 7,42-7,20 (kompl., 11H), 7,15-7,02 (kompl., 2H), 3,63-3,43 (kompl., 2H), 3,42 (s, 2H), 3,35-3,29 (kompl., 2H), 2,8-2,39 (kompl., 8H), 1,31-1,21 (kompl., 3H), 1,21-1,08 (kompl., 3H).
MS (M + 1) 575,2.
Primjer 6
4-[1-benzil-4-(3-cijano-fenil)-piperidin-4-il]-N,N-dietil-benzamid
U otopinu 3-[1-benzil-4-(4-dietilkarbamoil-fenil)-piperidin-4-il]-fenil estera trifluor-metansulfonske kiseline (1,82 g, 3,16 mmol) u DMF (14 ml), doda se cink-cijanid (0,26 g, 2,21 mmol) i tetrakis-trifenilfosfin-paladij (0,73 g, 0,63 mmol). Reakcija se 5 sati miješa u atmosferi dušika, na 90 °C. Smjesa se ohladi do sobne temperature, pa razrijedi dietil eterom (100 ml). Organski sloj se ispere slanom vodom (5 × 10 ml), osuši (MgSO4) i koncentrira. Pročišćavanje s heksani/EtOAc (1:1) daje 1,3 g (prinos 91 %) 4-[1-benzil-4-(3-cijano-fenil)-piperidin-4-il]-N,N-dietil-benzamida.
1H NMR (400 MHz, CDCl3) δ 7,69-7,20 (kompl., 13H), 3,55-3,43 (kompl., 2H), 3,41 (s, 2H), 3,31-3,19 (kompl., 2H), 2,6-2,25 (kompl., 8H), 1,28-1,19 (kompl., 3H), 1,17-1,08 (kompl., 3H).
MS (M + 1) 452,2.
Primjer 7
4-[1-benzil-4-(3-karboksamido-fenil)-piperidin-4-il]-N,N-dietil-benzamid
[image]
U otopinu 4-[1-benzil-4-(3-cijano-fenil)-piperidin-4-il]-N,N-dietil-benzamida (0,11 g, 0,24 mmol) u etanolu (0,3 ml) doda se 1,5 M vodeni Na2CO3 (0,6 ml) i 30 % vodeni H2O2 (0,15 ml). Reakcijska smjesa se 8 sati miješa na sobnoj temperaturi. Smjesa se razrijedi vodom (2 ml), a vodeni sloj ispere s CH2Cl2 (3 × 5 ml). Organski sloj se osuši (MgSO4) i koncentrira. Ostatak se pročisti fleš kromatografijom, s CH2Cl2/MeOH (10:1), dajući 35 mg (prinos 31 %) 4-[1-benzil-4-(3-cijano-fenil)-piperidin-4-il]-N,N-dietilbenzamida.
1H NMR (400 MHz, CDCl3) δ 7,79 (s, 1H), 7,55-7,20 (kompl., 12H), 6,13 (br, 1H), 5,62 (br, 1H), 3,48-3,40 (kompl., 2H), 3,38 (s, 2H), 3,23-3,19 (kompl., 2H), 2,51-2,39 (kompl., 8H), 1,27-1,20 (kompl., 3H), 1,15-1,07 (kompl., 3H).
MS (M + 1) 470,3.
Primjer 8
1-benzil-4-(3-metoksi-fenil)-4-(4-tiofen-2-il-fenil)-piperidin
U otopinu 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-fenil estera trifluor-metansuflonske kiseline (0,1 g, 0,2 mmol) u etanolu (4,5 ml) i vodi (0,5 ml), doda se 2-tiofen-boronska kiselina (0,052 g, 0,5 mmol), natrij-karbonat (0,037 g, 0,29 mmol) i tetrakis-trifenilfosfin-paladij (0,02 g, 0,18 mmol). Reakcijska smjesa se 2 sata grije pod refluksom. Smjesa se filtrira i filtrat se koncentrira pod vakuumom. Ostatak se pročisti fleš kromatografijom, s heksani/EtOAc (3:1), dajući 0,08 g (prinos 92 %) 1-benzil-4-(3-metoksi-fenil)-4-(4-tiofen-2-il-fenil)-piperidina.
1H NMR (400 MHz, CDCl3) δ 7,50 (d, 2H), 7,33-7,18 (kompl., 10H), 7,07-7,00 (m, 1H), 6,89-6,83 (kompl., 2H), 6,69 (d, 1H), 3,76 (s, 3H), 3,42 (s, 2H), 2,51-2,39 (kompl., 8H).
MS (M + 1) 440,2.
Slijedeći spojevi su načinjeni postupkom analognim onom u Primjeru 8, počevši od odgovarajućeg estera u kome R3 je metoksi, hidroksi ili fluor.
3-[1-benzil-4-(4-tiofen-2-il-fenil)-piperidin-4-il]-fenol
1H NMR (400 MHz, CDCl3) δ 7,46 (d, 2H), 7,16 (d, 2H), 6,80 (d, 1H), 6,59 (dd, 1H), 6,54 (s, 1H), 3,40 (s, 2H).
MS (M + 1) 426,0.
3-[1-benzil-4-(4'-trifluormetil-bifenil-4-il)-piperidin-4-il]-fenol
1H NMR (400 MHz, CDCl3) δ 7,67-7,58 (kompl., 4H), 7,44 (d, 2H), 7,12 (t, 1H), 6,80 (d, 1H), 6,62-6,59 (kompl., 2H).
MS (M + 1) 488,2.
3-[1-benzil-4-(4'-metil-bifenil-4-il)-piperidin-4-il]-fenol
1H NMR (400 MHz, CDCl3) δ 7,45-7,40 (kompl., 4H), 7,11 (t, 1H), 6,77 (d, 1H), 6,56 (s, 1H), 3,44 (s, 2H).
MS (M + 1) 434,3.
3-[1-benzil-4-(3'-klor-4'-fluor-bifenil-4-il)-piperidin-4-il]-fenol
1H NMR (400 MHz, CDCl3) δ 7,54 (dd, 1H), 7,20-7,11 (kompl., 2H), 6,80 (d, 1H), 6,65 (s, 1H), 6,62 (d, 1H), 3,44 (s, 2H).
MS (M + 1) 472,1.
Primjer 9
4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzonitril
U otopinu 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-fenil estera trifluor-metansulfonske kiseline (2,2 g, 4,34 mmol) u DMF (8 ml) doda se cink-cijanid (0,61 g, 5,22 mmol) i tetrakis-trifenilfosfin-paladij (0,7 g, 0,63 mol). Reakcija se 5 sati miješa u atmosferi dušika na 90 °C. Smjesa se ohladi do sobne temperature, pa razrijedi dietil eterom (100 ml). Organski sloj se ispere slanom vodom (5 × 10 ml), osuši (MgSO4) i koncentrira. Pročišćavanje smjesom heksani/EtOAc (2:1), daje 1,52 g (prinos 92 %) 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzonitrila.
1H NMR (400 MHz, CDCl3) δ 7,51 (d, 2H), 7,34 (d, 2H), 7,28-7,18 (kompl., 6H), 6,80 (d, 1H), 6,77 (s, 1H), 6,70 (d, 1H), 3,75 (s, 3H), 3,39 (s, 2H), 2,63-2,39 (kompl., 8H).
MS (M + 1) 383,2.
Primjer 10
1-benzil-4-(3-metoksi-fenil)-4-[4-(1H-tetrazol-5-il)-fenil]-piperidin
U otopinu 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzonitrila (0,24 g, 0,63 mmol) u toluenu (5 ml) dodaju se dibutilinoksid (0,025 g, 0,1 mmol) i trimetilsilil azid (0,15 g, 1,26 mmol). Reakcijska smjesa se grije 60 sati. Smjesa se zatim ohladi do sobne temperature i koncentrira pod vakuumom. Ostatak se otopi u metanolu (5 ml), pa koncentrira. Ostatak se raspodjeli između zasićene vodene otopine natrij-bikarbonata (5 ml) i etil acetata. Vodeni sloj se ispere etil acetatom (3 × 10 ml). Sabrani organski ekstrakti se osuše (MgSO4) i koncentriraju. Pročišćavanje fleš kromatografijom, s CH2Cl2/MeOH (9:1), daje 0,19 g (prinos 71 %) 1-benzil-(3-metoksi-fenil)-4-[4-(1H-tetrazol-5-il)-fenil]-piperidina.
1H NMR (400 MHz, CD3OD) δ 7,95 (d, 2H), 7,44-7,41 (kompl., 7H), 7,23-7,18 (m, 1H), 6,90-6,77 (kompl., 2H), 6,76 (d, 1H), 6,70 (d, 1H), 4,21 (s, 2H), 3,64 (s, 3H), 3,30-2,41 (kompl., 8H).
MS (M + 1) 426,2.
Primjer 11
1-benzil-4-[4-(4,4-dimetil-4,5-dihidro-oksazol-2-il)-fenil]-4-(3-metoksi-fenil)-piperidin
U otopinu 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-N-metil-benzamida (1,01 g, 2,44 mmol) u CH2Cl2 (24 ml), doda se piridin (0,30 ml, 3,71 mmol). Reakcija se ohladi na –50 °C, pa se 1 minutu u kapima dodaje triflički anhidrid (0,45 ml, 2,67 mmol). Reakcija se 1,5 sati miješa na –50 °C, pa 0,5 sati na sobnoj temperaturi. Smjesa se ohladi na –50 °C, pa se doda 2-amino-2-metilpropanol (0,36 ml, 3,77 mmol). Reakcijsku smjesu se pusti da se zagrije do sobne temperature, pa se 16 sati miješa na sobnoj temperaturi. U ovu smjesu se doda voda (65 ml), pa se vodeni sloj ekstrahira s CH2Cl2 (3 × 15 ml). Sabrani ekstrakti se osuše (MgSO4) i koncentriraju. Pročišćavanje fleš kromatografijom, smjesom heksani/EtOAc (1:1), daje 0,75 g (prinos 68 %) 1-benzil-4-[4-(4,4-dimetil-4,5-dihidro-oksazl-2-il)-fenil]-4-(3-metoksi-fenil)-piperidina.
1H NMR (400 MHz, CDCl3) δ 7,83 (d, 2H), 7,38-7,21 (kompl., 7H), 7,18 (t, 1H), 6,81-6,75 (kompl., 2H), 6,63 (d, 1H), 4,08 (s, 2H), 3,78 (s, 3H), 3,41 (s, 2H), 2,79-2,40 (kompl., 8H), 1,38 (s, 3H).
MS (M + 1) 454,2.
Primjer 12
2-{4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-fenil}-propan-2-ol
U otopinu metil estera 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzojeve kiseline (3,3 g, 7,95 mmol) u THF (30 ml), na 0 °C se doda metilmagnezij-bromid (3M u dietil eteru, 10,6 ml, 31,8 mmol). Ukloni se ledena kupelj, a reakcija se miješa 5 sati na sobnoj temperaturi , pa još 5 sati na 50 °C. Smjesa se ohladi do sobne temperature i tretira laganim dodavanjem vode (15 ml). Vodeni sloj se ispere dietil eterom (3 × 30 ml). Sabrani ekstrakti se osuše (MgSO4) i koncentriraju. Pročišćavanje fleš kromatografijom, s heksani/EtOAc, daje 3,1 g (prinos 94 %) 2-{4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-fenil}-propan-2-ola.
1H NMR (400 MHz, CDCl3) δ 7,38-7,08 (kompl., 10H), 6,61-6,59 (kompl., 2H), 3,8 (s, 3H), 3,6 (s, 2H), 2,52-2,23 (kompl., 8H), 1,42 (s, 6H).
MS (M + 1) 415,2.
Slijedeći spoj je dobiven postupkom analogan onom u Primjeru 12.
3-{4-[1-benzil-4-(3-fluor-5-metoksi-fenil)-piperidin-4-il]-2-fluor-fenil}-pentan-3-ol
1H NMR (400 MHz, CDCl3) δ 7,36 (d, 2H), 7,18 (d, 2H), 6,61‚(s, 1H), 6,39 (d, 1H), 3,73 (s, 3H), 1,54 (s, 6H).
MS (M + 1) 434,0.
Slijedeći derivati fenola su načinjeni postupkom analognim onom u Primjeru 12, nakon čega slijedi skidanje zaštite, postupkom iz Primjera 4.
3-{1-(3-cikloheksil-propil)-4-[4-(1-hidroksi-1-metil-etil)-fenil]-piperidin-4-il}-fenol
1H NMR (400 MHz, CDCl3) δ 6,74 (d, 1H), 6,63 (s, 1H), 6,58 (d, 1H), 2,21-2,18 (kompl., 2H), 1,68-1,57 (kompl., 4H), 0,82-0,79 (kompl., 2H).
MS (M + 1) 436,3.
3-{1-benzil-4-[4-(1-hidroksi-1-metil-etil)-fenil]-piperidin-4-il}-fenol
1H NMR (400 MHz, CDCl3) δ 6,80 (d, 1H), 6,60-6,51 (kompl., 2H), 3,39 (s, 2H), 2,55-2,18 (kompl., 4H).
MS (M + 1) 402,2.
3-{1-benzil-4-[4-(1-hidroksi-1-metil-etil)-fenil]-piperidin-4-il}-5-fluor-fenol
1H NMR (400 MHz, CDCl3) δ 7,06 (d, 2H), 6,46 (s, 1H), 6,42-6,30 (kompl., 2H), 3,55 (s, 2H), 1,52 (s, 6H).
MS (M + 1) 420,1.
Primjer 13
hidrazid 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzojeve kiseline
U otopinu metil estera 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzojeve kiseline (9,5 g, 22,9 mmol) u metanolu (60 ml) doda se hidrazin hidrat (8 ml). Reakcijska smjesa se 36 sati grije pod refluksom. Smjesa se ohladi do sobne temperature i koncentrira. Ostatak se otopi u toluenu (50 ml) i koncentrira pod vakuumom, a hidrazid 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzojeve kiseline se dobije u kvantitativnom prinosu. Ostatak se koristi u narednom koraku, bez pročišćavanja.
1H NMR (400 MHz, CDCl3) δ 7,82 (d, 1H), 7,67 (d, 1H), 7,39-7,05 (kompl., 8H), 6,86 (d, 1H), 6,80 (s, 1H), 6,67 (d, 1H), 3,69 (s, 3H), 3,38 (s, 2H), 2,62-2,37 (kompl., 8H).
MS (M + 1) 416,3.
Primjer 14
N'-{4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzoil}-hidrazid ciklobutan karboksilne kiseline
U otopinu hidrazida 4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzojeve kiseline (0,7 g, 1,69 mmol) u CH2Cl2 (10 ml) na 0 °C, doda se trietilamin (0,35 ml, 2,5 mmol), katalitička količina DMAP (20 mg) i ciklobutan karbonil klorid (0,19 ml, 1,69 mmol). Smjesa se 1 sat miješa na 0 °C, pa 5 sati na sobnoj temperaturi. Rastvor se ispere zasićenim otopinom soli (5 ml), osuši (MgSO4) i koncentrira. Pročišćavanje fleš kromatografijom, smjesom heksani/EtOAc (6:4), daje 0,63 g (prinos 75 %) N'-{4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzoil}-hidrazida ciklobutan karboksilne kiseline.
1H NMR (400 MHz, CDCl3) δ 8,59 (s, 1H), 7,67 (d, 2H), 7,41-7,08 (kompl., 8H), 6,82-6,61 (kompl., 3H), 3,79 (s, 3H), 2,41 (s, 2H), 3,09-3,02 (m, 1H), 2,41-2,23 (kompl., 8H), 2,19-1,67 (kompl., 6H).
MS (M + 1) 498,2.
Primjer 15
1-benzil-4-[4-(5-ciklobutil-[1,3,4]oksadiazol-2-il)-fenil]-4-(3-metoksi-fenil)-piperidin
U otopinu N'-{4-[1-benzil-4-(3-metoksi-fenil)-piperidin-4-il]-benzoil}-hidrazida ciklobutan karboksilne kiseline (0,2 g, 0,40 mmol) u CH2Cl2 (3 ml) doda se piridin (0,08 ml, 1,0 mmol). Reakcijska smjesa se ohladi na –78 °C. U kapima se dodaje triflički anhidrid (0,14 ml, 0,84 mmol). Smjesa se 1 sat miješa na –78 °C, pa 2 sata na sobnoj temperaturi. Reakcija se tretira sa zasićenim vodenim otopinom natrij-bikarbonata (3 ml). Vodeni sloj se ispere s CH2Cl2 (3 × 5 ml), a sabrani ekstrakti se osuše (MgSO4) i koncentriraju. Pročišćavanje fleš kromatografijom, s EtOAc, daje 0,19 g (kvantitativan prinos) 1-benzil-4-[4-(5-ciklobutil-[1,3,4]oksadiazol-2-il)-fenil]-4-(3-metoksi-fenil)-piperidina.
1H NMR (400 MHz, CDCl3) δ 7,92 (d, 2H), 7,37 (d, 2H), 7,36-7,16 (kompl., 6H), 6,83 (d, 1H), 6,80 (s, 1H), 6,60 (d, 1H), 3,81-3,78 (m, 1H), 3,77 (s, 3H), 3,45 (s, 2H), 2,82-2,38 (kompl., 10H), 2,21-2,19 (kompl., 2H).
MS (M + 1) 480,2.
Slijedeći spoj je postupkom analognim onom u Primjeru 15.
1-benzil-4-[4-(5-ciklopropil-[1,3,4]oksadiazol-2-il)-fenil]-4-(3-metoksi-fenil)-piperidin
1H NMR (400 MHz, CDCl3) δ 7,92-7,81 (kompl., 2H), 6,83 (d, 1H), 6,79 (s, 1H), 6,71-6,65 (m, 1H), 3,74 (s, 3H), 2,20-2,14 (m, 1H).
MS (M + 1) 466,4.
Slijedeći derivati fenola su načinjeni postupkom iz Primjera 15, nakon čega slijedi skidanje zaštite postupkom iz Primjera 4.
3-{1-benzil-4-[4-(5-metil-[1,3,4]oksadiazol-2-il)-fenil]-piperidin-4-il}-fenol
1H NMR (400 MHz, CDCl3) δ 7,79 (d, 2H), 7,41-7,37 (kompl., 2H), 7,12 (t, 1H), 3,63 (s, 2H), 2,57 (s, 3H).
MS (M + 1) 426,3.
3-{1-benzil-4-[4-(5-ciklopropil-[1,3,4]oksadiazol-2-il)-fenil]-piperidin-4-il}-fenol
1H NMR (400 MHz, CDCl3) δ 7,88-7,72 (kompl., 2H), 7,56-7,42 (kompl., 2H), 6,91-6,84 (m, 1H), 6,69-6,63 (m, 1H), 3,86 (s, 2H), 2,21-2,16 (m, 1H).
MS (M + 1) 452,2.
3-{1-benzil-4-[4-(5-etil-[1,3,4]oksadiazol-2-il)-fenil]-piperidin-4-il}-fenol
1H NMR (400 MHz, CDCl3) δ 7,79 (d, 2H), 7,11 (t, 1H), 7,75 (d, 1H), 6,65 (d, 1H), 6,55 (s, 1H), 2,90 (q, 2H), 1,38 (t, 3H).
MS (M + 1) 440,4.
3-{1-benzil-4-[4-(5-trifluormetil-[1,3,4]oksadiazol-2-il)-fenil]-piperidin-4-il}-fenol
1H NMR (400 MHz, CDCl3) δ 7,91 (d, 2H), 7,32 (d, 2H), 7,12 (t, 1H), 6,75 (d, 1H), 6,63-6,60 (kompl., 2H), 3,42 (s, 2H).
MS (M + 1) 480,2.
Primjer 16
Dodatni putovi sinteze
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Claims (16)
1. Spoj formule
[image]
naznačen time što:
R1 je vodik, (C0-C8)alkoksi-(C0-C8)alkil-, gdje ukupni broj atoma ugljika iznosi 8 ili manje, aril, aril-(C1-C8)alkil-, heteroaril, heteroaril-(C1-C8)alkil-, heterocikl, heterocikl-(C1-C8)alkil, (C3-C7)cikloalkil ili (C3-C7)cikloalkil-(C1-C8)alkil, gdje se spomenuti arilni i arilni ostaci spomenutih aril-(C1-C8)alkil- neovisno biraju između fenila i naftila, a gdje se spomenuti heteroarilni i heteroarilni ostatak u spomenutom heteroaril-(C1-C8)alkil- neovisno biraju između pirazinila, benzofuranila, kinolila, izokinolila, benzotienila, izobenzofurila, pirazolila, indolila, izoindolila, benzimidazolila, purinila, karbazolila, 1,2,5-tiadiazolila, kinazolinila, piridazinila, pirazinila, cinolinila, ftalazinila, kinoksalinila, ksantinila, hipoksantinila, pteridinila, 5-azacitidinila, 5-azauracilila, triazolopiridinila, imidazolopiridinila, pirolopirimidinila, pirazolopirimidinila, oksazolila, oksadiazolila, izoksazolila, tiazolila, izotiazolila, furanila, pirazolila, pirolila, tetrazolila, triazolila, tienila, imidazolila, piridinila i pirimidinila; i gdje se spomenuti heterocikl ili heterociklički ostatak spomenutog heterocikl-(C1-C8)alkil- biraju između zasićenih ili nezasićenih nearomatskih monocikličkih i bicikličkih sustava prstenova, pri čemu spomenuti monociklički sustavi prstenova sadrže 4 do 7 atoma ugljika u prstenu, od kojih se 1 do 3 mogu izborno zamijeniti s O, N ili S, i gdje spomenuti biciklički sustavi prstenova sadrže od 7 do 12 atoma ugljika u prstenu, od kojih se 1 do 4 mogu izborno zamijeniti s O, N ili S; i pri čemu se bilo koji od arilnih, heteroarilnih ili heterocikličkih ostataka R1 može izborno supstituirati s 1 do 3 supstituenta, po mogućnosti s 1 ili 2 supstituenta, koji se neovisno biraju između halo (tj. klor, fluor, brom i jod), (C1-C6)alkila izborno supstituiranog s 1 do 7 (po mogućnosti s 0 do 4) atoma fluora, fenila, benzila, hidroksi, acetila, amino, cijano, nitro, (C1-C6)alkoksi, (C1-C6)alkilamino i [(C1-C6) alkil]2amino, pri čemu se bilo koji od alkilnih ostataka u R1 (npr. alkilni ostatak iz alkila, alkoksi ili alkilamino grupe) može izborno supstituirati s 1 do 7 (poželjno od 0 do 4) atoma fluora;
R2 je vodik, aril, heteroaril, heterocikl, SO2R4, COR4, CONR5R6, COOR4 ili C(OH)R5R6, gdje je svaki od R4, R5 i R6 neovisno, definiran kao R1 koji je definiran gore, ili R5 i R6 uzeti zajedno s ugljikom ili dušikom uz koji su oba spojeni, tvore 3- do 7-eročlani zasićeni prsten, koji sadrži od 0 do 3 heteroatoma, koji se biraju neovisno između O, N i S, i pri čemu su aril, heteroaril i heterocikl definirani gore u definiciji za R1, i pri čemu se bilo koji arilni, heteroarilni i heterociklički ostatak u R2 može izborno supstituirati s 1 do 3 supstituenta, po mogućnosti s 1 do 2 supstituenta, koji se neovisno biraju između halo (tj. klor, fluor, brom ili jod), (C1-C6)alkila izborno supstituiranog s 1 do 7 (po mogućnosti od 0 do 4) atoma fluora, fenila, benzila, hidroksi, acetila, amino, cijano, nitro, (C1-C6)alkoksi izborno supstituiranog s 1 do 7 (po mogućnosti 0 do 4) atoma fluora, (C1-C6)alkilamino i [(C1-C6)alkil]2amino;
R3 je hidroksi, NHSO2R7, C(OH)R7R8, fluor ili CONHR7, pri čemu su R7 i R8 isti ili različiti, a biraju se između vodika, (C1-C4)alkila, (C1-C4)alkoksi i (C1-C4)alkoksi-(C1-C4)alkila, koji imaju ukupno 4 ili manje atoma ugljika, pri čemu se bilo koji od alkilnih ostataka u R7 i R8 može izborno supstituirati s 1 do 7 (po mogućnosti 0 do 4) atoma fluora; i
Z1 i Z2 se neovisno biraju između vodika, halo i (C1-C5)alkila;
uz uvjet da u prstenu ne postoje 2 susjedna atoma kisika i da ni 1 atom kisika u prstenu nije susjed bilo kome od atoma dušika u prstenu ili atoma sumpora u prstenu, u bilo kome od heterocikličkih ili heteroarilnih ostataka u formuli 1;
ili farmaceutski prihvatljiva sol ovog spoja.
2. Spoj prema zahtjevu 1, naznačen time što se R5 i R6 neovisno biraju iz grupe navedene u definiciji za R7 i R8.
3. Spoj prema zahtjevu 1, naznačen time što R1 predstavlja ciklopropilmetil, 3-cikloheksilpropil, 2-feniletil, 2-metilfenil, p-metilbenzil, 2,2,2-trifluoretil ili 1-metilpentil.
4. Spoj prema zahtjevu 2, naznačen time što R1 predstavlja ciklopropilmetil, 3-cikloheksilpropil, 2-feniletil, 2-metilfenil, p-metilbenzil, 2,2,2-trifluoretil ili 1-metilpentil.
5. Spoj prema zahtjevu 1, naznačen time što R2 predstavlja metiletilamid, dietilamid, dietilkarbinol, tetrazol ili pirazol.
6. Spoj prema zahtjevu 2, naznačen time što R2 predstavlja metiletilamid, dietilamid, dietilkarbinol, tetrazol ili pirazol.
7. Spoj prema zahtjevu 1, naznačen time što R3 predstavlja hidroksi, fluor, CONH2, NHSO2CH3 ili metoksi.
8. Spoj prema zahtjevu 2, naznačen time što R3 predstavlja hidroksi, fluor, CONH2, NHSO2CH3 ili metoksi.
9. Farmaceutski pripravak za tretiranje poremetnje ili stanja koje se bira između upalnih bolesti poput artritisa psorijaze, astme, ili upalne bolesti utrobe, poremetnji dišne funkcije, poput astme, kašlja, apneje, alergija, gastrointestinalnih poremetnji, poput gastritisa, funkcionalne bolesti utrobe, sindroma nadražljive utrobe, funkcionalne dijareje, funkcionalne nadutosti, funkcionalne boli, neulcerogene dispepsije i drugih poremetnji motiliteta ili lučenja, i povraćanja, moždanog udara, šoka, edema mozga, povrede glave, povrede kralježnične moždine, cerebralne ishemije, cerebralne deficijencije nakon kirurgije srčane premosnice i presatka, poremetnji urogenitalnog trakta poput inkontinencije mokraće, ovisnosti i navikavanja na kemijska sredstva (poput ovisnosti ili navikavanja na alkohol, opijate, benzodiazepine, nikotin, heroin ili kokain), kronične boli, nesomatske boli, akutne boli i neurogene boli, sistemskog lupus eritematozusa, Hodgkin-ove bolesti, Sjogren-ove bolesti, epilepsije i odbacivanja organskih transplantata i presadaka kože kod sisavca, naznačen time što sadrži količinu spoja prema zahtjevu 1, djelotvornu u tretiranju takve poremetnje ili stanja, i farmaceutski prihvatljivu podlogu.
10. Farmaceutski pripravak za tretiranje poremetnje ili stanja kod kojeg se tretman ili prevencija može ostvariti ili olakšati moduliranjem vezanja za opioidne receptore kod sisavca, naznačen time što sadrži količinu spoja prema zahtjevu 1, djelotvorne u tretiranju takve poremetnje ili stanja, i farmaceutski prihvatljivu podlogu.
11. Postupak tretiranja poremetnje ili stanja koje se bira između upalnih bolesti poput artritisa psorijaze, astme, ili upalne bolesti utrobe, poremetnji dišne funkcije, poput astme, kašlja, apneje, alergija, gastrointestinalnih poremetnji, poput gastritisa, funkcionalne bolesti utrobe, sindroma nadražljive utrobe, funkcionalne dijareje, funkcionalne nadutosti, funkcionalne boli, neulcerogene dispepsije i drugih poremetnji motiliteta ili lučenja, i povraćanja, moždanog udara, šoka, edema mozga, povrede glave, povrede kralježnične moždine, cerebralne ishemije, cerebralne deficijencije nakon kirurgije srčane premosnice i presatka, poremetnji urogenitalnog trakta poput inkontinencije mokraće, ovisnosti i navikavanja na kemijska sredstva (poput ovisnosti ili navikavanja na alkohol, opijate, benzodiazepine, nikotin, heroin ili kokain), kronične boli, nesomatske boli, akutne boli i neurogene boli, sistemskog lupus eritematozusa, Hodgkin-ove bolesti, Sjogren-ove bolesti, epilepsije i odbacivanja organskih transplantata i presadaka kože kod sisavca, naznačen time što se sisavcu kome je nužan takav tretman daje količina spoja prema zahtjevu 1, djelotvorna u tretiranju takve poremetnje ili stanja.
12. Postupak tretiranja poremetnje ili stanja kod kojih se tretman može ostvariti ili olakšati moduliranjem vezanja na opioidne receptore kod sisavca, naznačen time što se sisavcu kome je nužan takav tretman daje količina spoja prema zahtjevu 1, djelotvorna u tretiranju takve poremetnje ili stanja.
13. Farmaceutski pripravak za tretiranje poremetnje ili stanja koje se bira između upalnih bolesti poput artritisa psorijaze, astme, ili upalne bolesti utrobe, poremetnji dišne funkcije, poput astme, kašlja, apneje, alergija, gastrointestinalnih poremetnji, poput gastritisa, funkcionalne bolesti utrobe, sindroma nadražljive utrobe, funkcionalne dijareje, funkcionalne nadutosti, funkcionalne boli, neulcerogene dispepsije i drugih poremetnji motiliteta ili lučenja, i povraćanja, moždanog udara, šoka, edema mozga, povrede glave, povrede kralježnične moždine, cerebralne ishemije, cerebralne deficijencije nakon kirurgije srčane premosnice i presatka, poremetnji urogenitalnog trakta poput inkontinencije mokraće, ovisnosti i navikavanja na kemijska sredstva (poput ovisnosti ili navikavanja na alkohol, opijate, benzodiazepine, nikotin, heroin ili kokain), kronične boli, nesomatske boli, akutne boli i neurogene boli, sistemskog lupus eritematozusa, Hodgkin-ove bolesti, Sjogren-ove bolesti, epilepsije i odbacivanja organskih transplantata i presadaka kože kod sisavca, naznačen time što sadrži količinu spoja prema zahtjevu 1, djelotvornu u moduliranju vezanja na opioidne receptore, i farmaceutski prihvatljivu podlogu.
14. Farmaceutski pripravak za tretiranje poremetnje ili stanja kod kojeg se tretman ili prevencija može ostvariti ili olakšati moduliranjem vezanja na opioidne receptore kod sisavca, naznačen time što sadrži količinu spoja prema zahtjevu 1, djelotvornu u moduliranju vezanja na opioidne receptore, i farmaceutski prihvatljivu podlogu.
15. Postupak tretiranja poremetnje ili stanja koje se bira između upalnih bolesti poput artritisa psorijaze, astme, ili upalne bolesti utrobe, poremetnji dišne funkcije, poput astme, kašlja, apneje, alergija, gastrointestinalnih poremetnji, poput gastritisa, funkcionalne bolesti utrobe, sindroma nadražljive utrobe, funkcionalne dijareje, funkcionalne nadutosti, funkcionalne boli, neulcerogene dispepsije i drugih poremetnji motiliteta ili lučenja, i povraćanja, moždanog udara, šoka, edema mozga, povrede glave, povrede kralježnične moždine, cerebralne ishemije, cerebralne deficijencije nakon kirurgije srčane premosnice i presatka, poremetnji urogenitalnog trakta poput inkontinencije mokraće, ovisnosti i navikavanja na kemijska sredstva (poput ovisnosti ili navikavanja na alkohol, opijate, benzodiazepine, nikotin, heroin ili kokain), kronične boli, nesomatske boli, akutne boli i neurogene boli, sistemskog lupus eritematozusa, Hodgkin-ove bolesti, Sjogren-ove bolesti, epilepsije i odbacivanja organskih transplantata i presadaka kože kod sisavca, naznačen time što se sisavcu kome je nužan takav tretman daje količina spoja prema zahtjevu 1, djelotvorna u tretiranju takve poremetnje ili stanja.
16. Farmaceutski pripravak za tretiranje poremetnje ili stanja kod kojeg se tretman ili prevencija može ostvariti ili olakšati moduliranjem vezanja na opioidne receptore kod sisavca, naznačen time što se sisavcu kome je nužan takav tretman daje količina spoja prema zahtjevu 1, djelotvorna u tretiranju takve poremetnje ili stanja.
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PCT/IB1999/001512 WO2000014066A1 (en) | 1998-09-09 | 1999-09-06 | 4,4-biarylpiperidine derivatives with opioid receptor activity |
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EE (1) | EE200100145A (hr) |
ES (1) | ES2252960T3 (hr) |
GE (1) | GEP20033025B (hr) |
GT (1) | GT199900146A (hr) |
HK (1) | HK1040396A1 (hr) |
HN (1) | HN1999000149A (hr) |
HR (1) | HRP20010167A2 (hr) |
HU (1) | HUP0103542A3 (hr) |
ID (1) | ID29129A (hr) |
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NO (1) | NO20011183L (hr) |
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PA (1) | PA8481301A1 (hr) |
PE (1) | PE20001053A1 (hr) |
PL (1) | PL346648A1 (hr) |
SK (1) | SK3032001A3 (hr) |
SV (1) | SV1999000147A (hr) |
TN (1) | TNSN99169A1 (hr) |
TR (1) | TR200100694T2 (hr) |
WO (1) | WO2000014066A1 (hr) |
YU (1) | YU11501A (hr) |
ZA (1) | ZA200101744B (hr) |
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EP1485088B1 (en) | 2002-02-07 | 2008-08-06 | The Curators Of The University Of Missouri | Opioid receptor active 4-(3-hydroxyphenyl) or 4-(3-alkoxyphenyl)-1,2,4-triazole compounds |
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US20070078120A1 (en) * | 2003-10-21 | 2007-04-05 | Hitoshi Ban | Novel piperidine derivative |
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US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
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MX2009010552A (es) | 2007-03-29 | 2009-12-14 | Progenics Pharm Inc | Antagonistas de receptor de opioide periferico y usos de los mismos. |
MX2009010515A (es) | 2007-03-29 | 2009-10-19 | Wyeth Corp | Antagonistas del receptor opioide periferico y usos de los mismos. |
KR101581480B1 (ko) * | 2008-02-06 | 2015-12-30 | 프로제닉스 파머슈티컬스, 인코포레이티드 | (r),(r)-2,2'-비스-메틸날트렉손의 제조법 및 용도 |
CA2719134C (en) | 2008-03-21 | 2015-06-30 | The University Of Chicago | Treatment with opioid antagonists and mtor inhibitors |
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EP3570838A4 (en) | 2017-01-17 | 2021-01-27 | Mebias Discovery, Inc. | SUBSTITUTED 3-DIALKYLAMINOMETHYL-PIPERIDINE-4-YL-BENZAMIDE AND METHOD FOR MANUFACTURING AND USING THEREOF |
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US11584765B2 (en) | 2017-03-12 | 2023-02-21 | Ecstasy LLC | Polycyclic amines as sigma receptor modulators |
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DE2166997C3 (de) | 1971-08-04 | 1980-03-27 | Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz | Verfahren zur Herstellung von 4,4-Diphenyl-piperidinen |
DE2139085C3 (de) * | 1971-08-04 | 1979-01-18 | Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz | Halogenierte 4,4-Diphenyl-piperidine, Verfahren zu deren Herstellung und sie enthaltende Arzneimittel |
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EP0819001A1 (de) * | 1995-04-05 | 1998-01-21 | Byk Gulden Lomberg Chemische Fabrik GmbH | Verwendung von substituierten piperidin- oder pyrrolidinverbindungen zur behandlung von sigma-rezeptor modulierten krankheiten |
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JP4403212B2 (ja) | 1996-05-31 | 2010-01-27 | エヌピーエス ファーマシューティカルズ インコーポレイテッド | 神経障害および神経心理学的障害の治療のための製剤学的薬剤 |
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