HRP980462A2 - Small molecules useful in the treatment of inflammatory disease - Google Patents
Small molecules useful in the treatment of inflammatory disease Download PDFInfo
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- HRP980462A2 HRP980462A2 HRP980462A HRP980462A2 HR P980462 A2 HRP980462 A2 HR P980462A2 HR P980462 A HRP980462 A HR P980462A HR P980462 A2 HRP980462 A2 HR P980462A2
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- carbon atoms
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- formula
- alkyl
- hydrogen atom
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- 208000027866 inflammatory disease Diseases 0.000 title description 6
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- 125000002252 acyl group Chemical group 0.000 claims description 136
- 229910052757 nitrogen Inorganic materials 0.000 claims description 124
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 111
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 102
- BUYUFJZVMVFQLQ-UHFFFAOYSA-N 4-[2-(5,5,8,8-tetramethyl-6,7-dihydroquinoxalin-2-yl)ethynyl]benzoic acid Chemical group CC1(C=2N=CC(=NC=2C(CC1)(C)C)C#CC1=CC=C(C(=O)O)C=C1)C BUYUFJZVMVFQLQ-UHFFFAOYSA-N 0.000 claims description 91
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- SYUVAXDZVWPKSI-UHFFFAOYSA-N tributyl(phenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=C1 SYUVAXDZVWPKSI-UHFFFAOYSA-N 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
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- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Područje izuma Field of invention
Predloženi izum odnosi se općenito na nove male molekule, njihovu sintezu i njihovu upotrebu u liječenju upalnih bolesti. Izum se nadalje odnosi na upotrebu sličnih, ali poznatih, spojeva u liječenju upalnih bolesti. The proposed invention generally relates to new small molecules, their synthesis and their use in the treatment of inflammatory diseases. The invention further relates to the use of similar, but known, compounds in the treatment of inflammatory diseases.
Stanje tehnike State of the art
Opseg istraživanja u posljednjoj dekadi pomogao je da se objasne molekularni slučajevi čiji cilj su interakcije stanica-stanica u tijelu, posebno oni slučajevi koji su uključeni u premještanje i aktivaciju stanica u imunosnom sistemu. Vidi općenito, Sringer, T. Nature, 1990, 346, 425-434. Proteini na površini stanice, posebno stanične adhezijske molekule (e. Cellular Adhesion Molecules, CAMs) i “leukointegrini”, uključiv LFA-1, MAC-1, i gp150.95 (u WHO nomenklaturi se navode kao CD18/CD11a, CD18/CD11b, i CD18/CD11c) bili su odgovarajuće podvrgnuti farmaceutskim istraživanjaima kao i njihova ciljna intervencija u procesima ekstravazacije leukocita na strani povrede i premještanja leukocita prema određenim ciljevima. Na primjer, sada se vjeruje, da prije ekstravazacije leukocita, što je mandatna komponenta upalnog odgovora, dolazi do aktivacije integrina konstitutivno umnoženih na laukocitima i zatim slijedi tijesna interakcija liganda i receptora između integrina (npr. LFA-1) i jedne ili nekoliko određenih intracelularnih adhezijskih molekula (ICAMs) označenih nazvanih ICAM-1, ICAM-2, ICAM-3 ili ICAM-4 koje se umnažaju na površinama endotelnih stanica krvnih žila i na drugim leukocitima. Interakcija CAM molekula s leukointegrinima je vitalni stupanj u normalnom funkcioniranju imuno sistema. Svi imunosni procesi, kao što je prezentacija antigena, T-stanicama posredovana citotoksičnost i ekstravazacija leukocita, zahtjevaju staničnu adheziju posredovanu s ICAM molekulama koje ulaze u interakciju s leukointegrinima. Vidi općenito Kishimoto, T.K.; Rothlein, R. R. Adv. Pharmacol. 1994, 25: 117-138 i Diamond, M.; Springer, T. Current Biology, 1994, 4, 506-532. A body of research in the last decade has helped to elucidate the molecular events that target cell-cell interactions in the body, particularly those events involved in the movement and activation of cells in the immune system. See generally, Sringer, T. Nature, 1990, 346, 425-434. Proteins on the cell surface, especially cellular adhesion molecules (e. Cellular Adhesion Molecules, CAMs) and "leukointegrins", including LFA-1, MAC-1, and gp150.95 (in the WHO nomenclature, they are referred to as CD18/CD11a, CD18/CD11b , and CD18/CD11c) were appropriately subjected to pharmaceutical research as well as their targeted intervention in the processes of leukocyte extravasation on the side of the injury and leukocyte migration towards certain targets. For example, it is now believed that prior to leukocyte extravasation, which is a mandatory component of the inflammatory response, there is an activation of integrins constitutively multiplied on leukocytes, followed by a close ligand-receptor interaction between integrins (eg LFA-1) and one or several specific intracellular adhesion molecules (ICAMs) labeled as ICAM-1, ICAM-2, ICAM-3 or ICAM-4 that multiply on the surfaces of endothelial cells of blood vessels and on other leukocytes. The interaction of CAM molecules with leukointegrins is a vital step in the normal functioning of the immune system. All immune processes, such as antigen presentation, T-cell-mediated cytotoxicity and leukocyte extravasation, require cell adhesion mediated by ICAM molecules that interact with leukointegrins. See generally Kishimoto, T.K.; Rothlein, R.R. Adv. Pharmacol. 1994, 25: 117-138 and Diamond, M.; Springer, T. Current Biology, 1994, 4, 506-532.
Identificirana je skupina pojedinaca kojima nedostaje adogovarajuća ekspresija lukointegrina, stanje koje je nazvano “nedostatak adhezije leukocita” (E. Leukocyte Adhesion Deficiency) (Anderson, D. C., et al., Fed. Proc. 1985, 44, 2671-2677 i Anderson, D. C., et al., J. Infect. Dis. 1985, 152, 668-689). Ti pojedinci nisu sposobni dati normalne upalne i/ili imunosne odgovore zbog nesposobnosti njihovih stanica da se zaljepe na stanične supstrate. Ti podaci pokazuju da su imunosne reakcije ublažene kad se limfociti ne mogu zaljepiti na normalan način zbog nedostatka funkcionalnih adhezijskih molekula iz porodice CD18. Na temelju činjenice da LAD pacijenti, koji nemaju CD18, ne mogu dati upalne odgovore, vjeruje se da će antagonizam CD18, CD11/ICAM-1 interakcije također inhibirati upalni odgovor. A group of individuals has been identified who lack adequate leukointegrin expression, a condition termed “E. Leukocyte Adhesion Deficiency” (Anderson, D. C., et al., Fed. Proc. 1985, 44, 2671-2677 and Anderson, D. C. , et al., J. Infect. Dis. 1985, 152, 668-689). These individuals are unable to mount normal inflammatory and/or immune responses due to the inability of their cells to adhere to cellular substrates. These data show that immune reactions are attenuated when lymphocytes cannot stick together in a normal way due to the lack of functional adhesion molecules from the CD18 family. Based on the fact that LAD patients, who lack CD18, cannot mount inflammatory responses, it is believed that antagonism of the CD18, CD11/ICAM-1 interaction will also inhibit the inflammatory response.
Pokazano je da se antagonizam interakcije između CAM molekula i leukointegrina može ostvariti pomoću sredstava usmjerenih prema bilo kojoj komponenti. Posebno, blokiranje CAM molekula, kao što su na primjer ICAM-1, ili leukointegrinia, kao što su na primjer LFA-1, pomoću antitijela usmjerenih prema jednoj ili objema od tih molekula djelotvorno inhibira upalne odgovore. In vitro modeli upale i imunosni odgovori inhibirani s antitijelima prema CAM ili leukointegrinima uključuju antigenom ili mitogenom induciranu proliferaciju limfocita, homotipičnu agregaciju limfocita, citolizu posredovanu T stanicama i antigen-specifičnu induciranu toleranciju. Dotične in vitro studije su poduprte proučavanjima in vivo s antitijelima usmjerenim prema ICAM-1 ili LFA-1. Na primjer, antitijela usmjerena prema LFA-1 mogu spriječiti odbacijvanje tiroidnog grafta i produljiti preživljavanje miševa sa srčanim alograftom (Gorski, A., Immunology Today, 1994, 15, 251-255). Značajnije je da su antitijela usmjerena prema ICAM-1 pokazala učinkovitost u in vivo kao anti-upalna sredstva kod ljudskih bolesti kao što je odbacivanje renalnog alografta i reumatoidni artritis (Rothlein, R.R.; Scharschmidt, L., u Adhesion Molecules; Wegner, C.D. Ed., 1994, 1-38, Cosimi, C.B., et al., J. Immunol. 1990, 144, 4604-4612 i Kavanaugh, A., et al., Arthritis Rheum. 1994, 37, 992-1004), a antitijela usmjerena prema LFA-1 pokazala su imunosupresivne učinke kod tranplantacije koštane moždine i u prevencji ranog odbacivanja renalnih alografta (Fischer, A., et al., Lancet, 1989, 2, 1058-1060 i Le Mauff, B., et al., Transplantation, 1991, 52, 291-295). It has been shown that the antagonism of the interaction between CAM molecules and leukointegrin can be achieved by means directed towards any component. In particular, blocking CAM molecules, such as for example ICAM-1, or leukointegrins, such as for example LFA-1, by antibodies directed against one or both of these molecules effectively inhibits inflammatory responses. In vitro models of inflammation and immune responses inhibited with antibodies to CAM or leukointegrins include antigen- or mitogen-induced lymphocyte proliferation, homotypic lymphocyte aggregation, T cell-mediated cytolysis, and antigen-specific induced tolerance. The respective in vitro studies were supported by in vivo studies with antibodies directed against ICAM-1 or LFA-1. For example, antibodies directed against LFA-1 can prevent thyroid graft rejection and prolong the survival of heart allograft mice (Gorski, A., Immunology Today, 1994, 15, 251-255). More significantly, antibodies directed against ICAM-1 have shown efficacy in vivo as anti-inflammatory agents in human diseases such as renal allograft rejection and rheumatoid arthritis (Rothlein, R.R.; Scharschmidt, L., in Adhesion Molecules; Wegner, C.D. Ed ., 1994, 1-38, Cosimi, C.B., et al., J. Immunol. 1990, 144, 4604-4612 and Kavanaugh, A., et al., Arthritis Rheum. 1994, 37, 992-1004), and antibodies directed against LFA-1 have shown immunosuppressive effects in bone marrow transplantation and in the prevention of early rejection of renal allografts (Fischer, A., et al., Lancet, 1989, 2, 1058-1060 and Le Mauff, B., et al., Transplantation, 1991, 52, 291-295).
Također je pokazano, da rekombinantan topivi oblik ICAM-1 može djelovati kao inhibitor interakcije ICAM-1 s LFA-1. Topivi ICAM-1 djeluje kao izravni antagonist interakcija molekula CD18, CD11/ICAM-1 na stanicama i pokazuje inhibicijsko djelovanje u in vitro modelima imunosnog odgovora kao što je humani miješani limfocitni odgovor, citotoksičan odgovor T stanica i proliferacija T stanica u pacijenata s dijabetesom kao odgovor na stanice otočića (Becker, J. C., et al., J. Immunol. 1993, 151, 7224 i Roep, B. O., et al., Lancet, 1994, 343, 1590). It was also shown that the recombinant soluble form of ICAM-1 can act as an inhibitor of the interaction of ICAM-1 with LFA-1. Soluble ICAM-1 acts as a direct antagonist of CD18, CD11/ICAM-1 molecules interactions on cells and shows inhibitory activity in in vitro models of immune response such as human mixed lymphocyte response, cytotoxic T cell response and T cell proliferation in diabetic patients as islet cell response (Becker, J. C., et al., J. Immunol. 1993, 151, 7224 and Roep, B. O., et al., Lancet, 1994, 343, 1590).
Tako je prema stanju tehnike pokazano da brojne proteinske molekule koje antagoniziraju vezanje CAM molekula na leukointegrine imaju terapeutske mogućnosti u ublažavanju upalnih i imunoloških odgovora koji su često povezani s patogenezom mnogih autoimunosnih i upalnih bolesti. Međutim proteini imaju značajne nedostatke kao terapeutska sredstva, uključiv nemućnost njihovog oralnog davanja i moguću imunosnu reaktivnost koja ograničava upotrebljivost tih molekula za kronično davanje. Nadalje, proizvodnja terapeutskih sredstava na osnovi proteina je općenito skupa. Thus, according to the state of the art, it has been shown that numerous protein molecules that antagonize the binding of CAM molecules to leukointegrins have therapeutic possibilities in mitigating inflammatory and immune responses that are often associated with the pathogenesis of many autoimmune and inflammatory diseases. However, proteins have significant drawbacks as therapeutic agents, including the inability to administer them orally and possible immune reactivity that limits the utility of these molecules for chronic administration. Furthermore, the production of protein-based therapeutics is generally expensive.
Slijedi da bi male molekule, koje imaju sličnu sposobnost antagoniziranja vezanja CAM molekula na leukointegrine kao i velike proteinske molekule, dale prednosna teraputska sredstva. Do danas, međutim, nije obznanjeno nikakvo djelovanje malih molekula kao izravnih antagonista. It follows that small molecules, which have a similar ability to antagonize the binding of CAM molecules to leukointegrins as large protein molecules, would provide advantageous therapeutic agents. To date, however, no activity of small molecules as direct antagonists has been reported.
U literaturi je opisano nekoliko malih molekula koje ometaju interakciju CAM molekula i leukointegrina. Nađeno je da je prirodni proizvod, izoliran iz korijena Trichilia rubra, inhibitor u pokusu vezanje stanica in vitro (Musza, L.L., et al., Tetrahedron, 1994, 50, 11369-11378). Nađen je i niz molekula (Boschelli, D. H., et al., J. Med. Chem. 1994, 37, 717 i Boschelli, D. H., et al., J. Med. Chem. 1995, 38, 4597-4614) koji je oralno aktivan u reverzno pasivnoj Arthusovoj reakciji, modelu inducirane upale kojeg karakterizira akumulacija neutrofila (Chang, Y. H., et al., Eur. J. Pharmacol. 1992, 69, 155-164). Također je nađen i drugi niz molekula koji je oralno aktivan u tipu odgođene hipersenzitivne reakcije u štakora (Sanfilippo, P. J., et al., J. Med. Chem. 1995, 38, 1057-1059). Čini da sve te molekule djeluju nespecifično, bilo inhibirajući transkripciju ICAM-1 samo s drugim proteinima ili djeluju intracelularno tako da inhibiraju aktivaciju leukointegrina nepoznatim mehanizmom. Nijedna od tih molekula ne antagonizira izravno interakciju CAM molekula s leukointegrinima. Zbog nedostatka jačine, neostatka selektivnosti i nedostatka specifičnog mehanizma djelovanja, opisane male molekule se čine nezadovoljavajućima za terapeutsku upotrebu. Several small molecules that interfere with the interaction of CAM molecules and leukointegrins have been described in the literature. A natural product isolated from the roots of Trichilia rubra was found to be an inhibitor in an in vitro cell attachment assay (Musza, L.L., et al., Tetrahedron, 1994, 50, 11369-11378). A number of molecules were also found (Boschelli, D. H., et al., J. Med. Chem. 1994, 37, 717 and Boschelli, D. H., et al., J. Med. Chem. 1995, 38, 4597-4614) which orally active in the reverse passive Arthus reaction, a model of induced inflammation characterized by neutrophil accumulation (Chang, Y. H., et al., Eur. J. Pharmacol. 1992, 69, 155-164). Another set of molecules has also been found to be orally active in a type of delayed hypersensitivity reaction in rats (Sanfilippo, P. J., et al., J. Med. Chem. 1995, 38, 1057-1059). All these molecules appear to act nonspecifically, either by inhibiting ICAM-1 transcription only with other proteins or by acting intracellularly to inhibit leukointegrin activation by an unknown mechanism. None of these molecules directly antagonize the interaction of CAM molecules with leukointegrins. Due to lack of potency, lack of selectivity and lack of a specific mechanism of action, the described small molecules seem unsatisfactory for therapeutic use.
Na osnovi stanja tehnike, preostaje jasna potreba za terapeutski upotrebljivim malim molekulama koje imaju sposobnost antagoniziranja interakcije CAM molekula i leukointegrina. Based on the state of the art, there remains a clear need for therapeutically usable small molecules that have the ability to antagonize the interaction of CAM molecules and leukointegrins.
Kratki opis izuma Brief description of the invention
U prvom aspektu izum uključuje metodu za liječenje ili prevenciju upalnih i imunosnih bolesti, posredovanih stanicama, davanjem određenih novih i poznatih malih molekula. Ti spojevi djeluju tako da inhibiraju interakciju molekula celularne adhezije, posebno antagonizirajući vezanje humanih intercelularnih adhezijskih molekula (uključiv, na primjer, ICAM-1, ICAM-2 i ICAM-3) na leukointegrine (uključiv, na primjer, CD18/CD11a i CD18/CD11b). Drugi aspekt izuma uključuje nove male molekule koje imaju gore spomenuta terapeutska djelovanja. Treći aspekt izuma uključuje metode za proizvodnju tih novih spojeva. Posljednji aspekt izuma uključuje farmaceutske sastave koji sadrže gore spomenute spojeve prikladne za prevenciju ili liječenje upalnih i imunosnih stanja posredovanih stanicama. In a first aspect, the invention includes a method for treating or preventing cell-mediated inflammatory and immune diseases by administering certain novel and known small molecules. These compounds act by inhibiting the interaction of cellular adhesion molecules, specifically by antagonizing the binding of human intercellular adhesion molecules (including, for example, ICAM-1, ICAM-2, and ICAM-3) to leukointegrins (including, for example, CD18/CD11a and CD18/ CD11b). Another aspect of the invention involves novel small molecules having the above-mentioned therapeutic activities. A third aspect of the invention involves methods for producing these novel compounds. A final aspect of the invention includes pharmaceutical compositions containing the aforementioned compounds suitable for the prevention or treatment of cell-mediated inflammatory and immune conditions.
Opis izuma u pojedinostima Description of the invention in detail
U prvom aspektu izum uključuje metodu za liječenje ili prevenciju upalnih i imunosnih bolesti, posredovanih stanicama, davanjem određenih novih i poznatih malih molekula formule I In a first aspect, the invention includes a method for treating or preventing cell-mediated inflammatory and immune diseases by administering certain novel and known small molecules of formula I
[image] [image]
u kojoj where
Y je atom kisika ili sumpora; Y is an oxygen or sulfur atom;
Z je atom kisika ili sumpora; Z is an oxygen or sulfur atom;
X je dvovalentna skupina formule >CHR1, >NR1, >CHSO2R1, ili >NSO2R1, ili atom kisika ili sumpora, gdje X is a divalent group of the formula >CHR1, >NR1, >CHSO2R1, or >NSO2R1, or an oxygen or sulfur atom, where
R1 je: R1 is:
(A) atom vodika, (A) hydrogen atom,
(B) razgranata ili nerazgranata alkilna skupina koja ima od 1 do 6 ugljikovih atoma ili cikloalkilna skupina koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s: (B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with:
(i) halogenim, (i) halogen,
(ii) okso, (ii) oxo,
(iii) arilom, koji je odabran iz razreda kojeg čine fenil, naftil, indolil, tiofenil, piridil, pirimidinil, furil, pirolil, oksazolil, tiazolil, pirazolil, izoksazolil, imidazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, piridazinil, pirazinil, triazinil, indolizinil, izoindolil, benzo[b]furanil, benzo[b]tiofenil, indazolil, benztiazolil, benzimidazolil, kinolinil, izokinolinil, purinil, kinolizinil, kinolinil, ftalaninil, kinoksalinil, naftiridinil, pteridinil i kinazolinil, pri čemu jedan ili više vodikovih atoma spomenutog arilnog ostatka može biti po potrebi i neovisno nadomješteno s: (iii) aryl, which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, quinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogens atom of the mentioned aryl residue can be, if necessary, independently replaced with:
(a) alkilom koji ima 1 do 3 ugljikova atoma, (a) alkyl having 1 to 3 carbon atoms,
(b) -COOH, (b) -COOH,
(c) -SO2OH, (c) -SO2OH,
(d) -PO(OH)2, (d) -PO(OH)2,
(e) skupinom formule -COOR7, gdje R7 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (e) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(f) skupinom formule -NR8R9, gdje svaki od R8 i R9 neovisno predstavlja vodikov atom, alkil koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma ili acil koji ima od 1 do 7 ugljikovih atoma, ili u kojoj R8 i R9 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (f) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,
(g) skupinom formule -CONR10R11, gdje svaki od R10 i R11 neovisno predstavlja vodikov atom, alkil koji ima od 1 do 6 ugljikovih atoma ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R10 i R11 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (g) a group of the formula -CONR10R11, where each of R10 and R11 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R10 and R11 form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,
(h) skupinom formule -OR12a, gdje R12a predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (h) a group of the formula -OR12a, where R12a represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,
(i) skupinom formule -SR12b, gdje R12b predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (i) a group of the formula -SR12b, where R12b represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,
(j) cijano, ili (j) cyano, or
(k) amidino skupinom formule (k) amidino group of the formula
[image] [image]
u kojoj svaki od R13, R14 i R15 neovisno predstavlja vodikov atom ili alkil koji ima od 1 do 3 ugljikova atoma i u kojoj dva od R13, R14 i R15 mogu dodatno oblikovati zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom (atomima) između njih tvore heterociklički prsten, in which each of R13, R14 and R15 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them to form a heterocyclic ring,
(iv) skupinom formule -COOR16, gdje R16 predstavlja ravan ili razgranati alkil koji ima od 1 do 7 ugljikovih atoma ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, (iv) a group of the formula -COOR16, where R16 represents straight or branched alkyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms,
(v) cijano, (v) cyano,
(vi) skupinom formule -CONR17R18, gdje svaki od R17 i R18 neovisno predstavlja vodikov atom, alkil koji ima od 1 do 6 ugljikovih atoma ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R17 i R18 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (vi) a group of the formula -CONR17R18, where each of R17 and R18 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R17 and R18 form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,
(vii) skupinom formule -OR19, gdje R19 predstavlja vodikov atom ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (vii) a group of the formula -OR19, where R19 represents a hydrogen atom or an alkyl or acyl group having from 1 to 7 carbon atoms,
(viii) skupinom formule -SR20, gdje R20 predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (viii) a group of the formula -SR20, where R20 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,
(ix) skupinom formule -NR21R22, gdje svaki od R21 i R22 neovisno predstavlja (ix) a group of the formula -NR21R22, where each of R21 and R22 independently represents
(a) vodikov atom, (a) hydrogen atom,
(b) alkil ili acil koji ima od 1 do 7 ugljikovih atoma ili cikloalkil koji ima od 3 do 7 ugljikovih atoma, (b) alkyl or acyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 7 carbon atoms,
(c) skupinu formule -(CH2)mCOOH, gdje m je 0, 1 ili 2, ili (c) a group of the formula -(CH2)mCOOH, where m is 0, 1 or 2, or
(d) skupinu formule -(CH2)nCOOR23, gdje n je 0, 1 ili 2, a R23 je ravan ili razgranati alkil koji ima od 1 do 6 ugljikovih atoma, (d) a group of the formula -(CH2)nCOOR23, where n is 0, 1 or 2, and R23 is straight or branched alkyl having from 1 to 6 carbon atoms,
ili gdje R21 i R22 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, ili or where R21 and R22 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(x) kvaternom skupinom formule (x) by the quaternary group of the formula
[image] [image]
u kojoj svaki od R24, R25 i R26 neovisno predstavlja razgranatu ili nerazgranatu alkilnu skupinu koja ima od 1 do 7 ugljikovih atoma i Q- je ion klora, broma ili joda suprotnog naboja, in which each of R24, R25 and R26 independently represents a branched or unbranched alkyl group having from 1 to 7 carbon atoms and Q- is a chlorine, bromine or iodine ion of the opposite charge,
(C) razgranata ili nerazgranata skupina karboksilne kiseline koja ima od 3 do 6 ugljikovih atoma, (C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms,
(D) razgranata ili nerazgranata skupina fosfonske kiseline koja ima od 2 do 6 ugljikovih atoma, (D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms,
(E) razgranata ili nerazgranata skupina sulfonske kiseline koja ima od 2 do 6 ugljikovih atoma, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms,
(F) amidino skupina formule (F) amidino group of the formula
[image] [image]
u kojoj r je 2, 3, 4, 5 ili 6, i in which r is 2, 3, 4, 5 or 6, and
svaki od R27, R28 i R29 neovisno predstavlja vodikov atom ili alkil koji ima od 1 do 3 ugljikova atoma, i u kojoj dva od R27, R28 i R29 mogu dodatno oblikovati zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom (atomima) između njih tvore heterociklički prsten, each of R27, R28 and R29 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R27, R28 and R29 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with a nitrogen atom (atoms) between them form a heterocyclic ring,
(G) gvanidino skupina formule (G) guanidino group of the formula
[image] [image]
u kojoj s je 2, 3, 4, 5 ili 6, i in which s is 2, 3, 4, 5 or 6, i
svaki od R30, R31, R32 i R33 neovisno predstavlja vodikov atom ili alkil koji ima od 1 do 3 ugljikova atoma, i u kojoj dva od R30, R31, R32 i R33 mogu dodatno oblikovati zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom (atomima) između njih tvore heterociklički prsten, each of R30, R31, R32 and R33 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R30, R31, R32 and R33 may additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms that together with the nitrogen atom(s) between them form a heterocyclic ring,
(H) piperidil, u kojem je dušikov atom spomenute skupine po potrebi supstituiran s: (H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with:
(i) alkilom koji ima 1 do 3 ugljikova atoma, (i) alkyl having 1 to 3 carbon atoms,
(ii) skupinom karboksilnog estera koja ima 2 do 7 ugljikovih atoma, (ii) a carboxyl ester group having 2 to 7 carbon atoms,
(iii) skupinom karboksilne kiseline koja ima od 2 do 5 ugljikovih atoma, (iii) a carboxylic acid group that has from 2 to 5 carbon atoms,
(iv) skupinom fosfonske kiseline koja ima od 1 do 6 ugljikovih atoma, ili (iv) a phosphonic acid group having from 1 to 6 carbon atoms, or
(v) skupinom sulfonske kiseline koja ima od 1 do 6 ugljikovih atoma, ili (v) a sulfonic acid group having from 1 to 6 carbon atoms, or
(I) aril koji je odabran iz razreda kojeg čine fenil, naftil, indolil, tiofenil, piridil, pirimidinil, furil, pirolil, oksazolil, tiazolil, pirazolil, izoksazolil, imidazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, piridazinil, pirazinil, triazinil, indolizinil, izoindolil, benzo[b]furanil, benzo[b]tiofenil, indazolil, benztiazolil, benzimidazolil, kinolinil, izokinolinil, purinil, kinolizinil, kinolinil, ftalaninil, kinoksalinil, naftiridinil, pteridinil i kinazolinil, pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: (I) aryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl , indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, quinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms the mentioned aryl groups can be independently replaced with:
(i) alkilom koji ima 1 do 3 ugljikova atoma, (i) alkyl having 1 to 3 carbon atoms,
(ii) -COOH, (ii) -COOH,
(iii) -SO2OH, (iii) -SO2OH,
(iv) -PO(OH)2, (iv) -PO(OH)2,
(v) skupinom formule -COOR7, gdje R7 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (v) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(vi) skupinom formule -NR8R9, gdje svaki od R8 i R9 neovisno predstavlja vodikov atom, alkil koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma ili acil koji ima od 1 do 7 ugljikovih atoma, ili u kojoj R8 i R9 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (vi) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms or an acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,
(vii) skupinom formule -CONR10R11, gdje svaki od R10 i R11 neovisno predstavlja vodikov atom, alkil koji ima od 1 do 6 ugljikovih atoma ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R10 i R11 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (vii) a group of the formula -CONR10R11, where each of R10 and R11 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R10 and R11 form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,
(viii) skupinom formule -OR12a, gdje R12a predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (viii) a group of the formula -OR12a, where R12a represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,
(ix) skupinom formule -SR12b, gdje R12b predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (ix) a group of the formula -SR12b, where R12b represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,
(x) cijano, ili (x) cyano, or
(xi) amidino skupinom formule (xi) amidino group of the formula
[image] [image]
u kojoj svaki od R13, R14 i R15 neovisno predstavlja vodikov atom ili alkil koji ima od 1 do 3 ugljikova atoma, i u kojoj dva od R13, R14 i R15 mogu dodatno oblikovati zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom (atomima) između njih tvore heterociklički prsten; in which each of R13, R14 and R15 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with with nitrogen atom(s) between them they form a heterocyclic ring;
R2 je: R2 is:
(A) vodikov atom, ili (A) hydrogen atom, or
(B) razgranata ili nerazgranata alkilna skupina koja ima od 1 do 3 ugljikova atoma ili cikloalkilna skupina koja ima od 3 do 5 ugljikovih atoma pri čemu spomenuta alkilna ili cikloalkilna skupina može biti po potrebi supstituirana s: (B) a branched or unbranched alkyl group having from 1 to 3 carbon atoms or a cycloalkyl group having from 3 to 5 carbon atoms, wherein said alkyl or cycloalkyl group can be optionally substituted with:
(i) skupinom formule -OR34, gdje R34 predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma ili (i) a group of the formula -OR34, where R34 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms or
(ii) skupinom formule -NR35R36, gdje svaki od R35 i R36 neovisno predstavlja vodikov atom, alkil koji ima od 1 do 2 ugljikova atoma, ili acil koji ima od 1 do 2 ugljikova atoma; (ii) a group of the formula -NR35R36, where each of R35 and R36 independently represents a hydrogen atom, an alkyl having from 1 to 2 carbon atoms, or an acyl having from 1 to 2 carbon atoms;
R3 je skupina formule -(CR37R38)x(CR39R40)yR41, u kojoj R3 is a group of the formula -(CR37R38)x(CR39R40)yR41, in which
svaki od x i y neovisno predstavlja 0 ili 1, each of x and y independently represents 0 or 1,
svaki od R37, R38 i R39 neovisno predstavlja: each of R37, R38 and R39 independently represents:
(A) vodikov atom, (A) hydrogen atom,
(B) skupinu formule -OR42, gdje R42 predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (B) a group of the formula -OR42, where R42 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,
(C) razgranati ili nerazgranati alkil koji ima od 1 do 3 ugljikova atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (C) branched or unbranched alkyl having from 1 to 3 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
R40 je: R40 is:
(A) vodikov atom, (A) hydrogen atom,
(B) skupinu formule -OR42, gdje R42 predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (B) a group of the formula -OR42, where R42 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,
(C) razgranati ili nerazgranati alkil koji ima od 1 do 3 ugljikova atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, ili (C) branched or unbranched alkyl having from 1 to 3 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms, or
(D) aril koji je odabran iz razreda kojeg čine fenil, 2-naftil, 2-, 3-, 5- ili 6-indolil, 2- ili 3-tiofenil, 2-, 3- ili 4-piridil, 2-, 4- ili 5-pirimidinil, 2- ili 3-furil, 1-, 2- ili 3-pirolil, 2-, 4- ili 5-oksazolil, 2-, 4- ili 5-tiazolil, 1-, 3-, 4- ili 5-pirazolil, 3-, 4- ili 5-izoksazolil, 1-, 2-, 4- ili 5-imidazolil, 3-, 4- ili 5-izotiazolil, 4- ili 5-oksadiazolil, 1-, 4- ili 5-triazolil, 2-tiadiazolil, 3- ili 4-piridazinil, 2-pirazinil, 2-triazinil, 2-, 3-, 6- ili 7-indolizinil, 2-, 3-, 5- ili 6-izoindolil, 2-, 3-, 5- ili 6-benzo[b]furanil, 2-, 3-, 5- ili 6-benzo[b]tiofenil, 3-, 5- ili 6-indazolil, 2-, 5- ili 6-benztiazolil, 2-, 5- ili 6-benzimidazolil, 2-, 3-, 6- ili 7-kinolinil, 3-, 6- ili 7-izokinolinil, 2- ili 8-purinil, 2-, 3-, 7- ili 8-kinolizinil, 3-, 6- ili 7-kinolinil, 6- ili 7-ftalaninil, 2-, 3-, 6- ili 7-kinoksalinil, 2-, 3-, 6- ili 7-naftiridinil, 2-, 6- ili 7-pteridinil i 2-, 6- ili 7-kinazolinil, pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: (D) aryl which is selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6- isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5 - or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3 -, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7- naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can to be independently replaced with:
(i) R43, koji je odabran iz razreda kojeg čine fenil, 2-naftil, 2-, 3-, 5- ili 6-indolil, 2- ili 3-tiofenil, 2-, 3- ili 4-piridil, 2-, 4- ili 5-pirimidinil, 2- ili 3-furil, 1-, 2- ili 3-pirolil, 2-, 4- ili 5-oksazolil, 2-, 4- ili 5-tiazolil, 1-, 3-, 4- ili 5-pirazolil, 3-, 4- ili 5-izoksazolil, 1-, 2-, 4- ili 5-imidazolil, 3-, 4- ili 5-izotiazolil, 4- ili 5-oksadiazolil, 1-, 4- ili 5-triazolil, 2-tiadiazolil, 3- ili 4-piridazinil, 2-pirazinil, 2-triazinil, 2-, 3-, 6- ili 7-indolizinil, 2-, 3-, 5- ili 6-izoindolil, 2-, 3-, 5- ili 6-benzo[b]furanil, 2-, 3-, 5- ili 6-benzo[b]tiofenil, 3-, 5- ili 6-indazolil, 2-, 5- ili 6-benztiazolil, 2-, 5- ili 6-benzimidazolil, 2-, 3-, 6- ili 7-kinolinil, 3-, 6- ili 7-izokinolinil, 2- ili 8-purinil, 2-, 3-, 7- ili 8-kinolizinil, 3-, 6- ili 7-kinolinil, 6- ili 7-ftalaninil, 2-, 3-, 6- ili 7-kinoksalinil, 2-, 3-, 6- ili 7-naftiridinil, 2-, 6- ili 7-pteridinil i 2-, 6- ili 7-kinazolinil, pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: (i) R43, which is selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2- , 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3- , 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1- , 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6 -isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7 -naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can to be independently replaced with:
(a) razgranatom ili nerazgranatom alkilnom skupinom koja ima od 1 do 6 ugljikovih atoma ili cikloalkilnom skupinom koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s halogenim ili okso, (a) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,
(b) -COOH, (b) -COOH,
(c) -SO2OH, (c) -SO2OH,
(d) -PO(OH)2, (d) -PO(OH)2,
(e) skupinom formule -COOR44, gdje R44 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (e) a group of the formula -COOR44, where R44 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(f) skupinom formule -NR45R46, gdje svaki od R45 i R46 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma ili acil koji ima od 1 do 7 ugljikovih atoma, ili u kojoj R45 i R46 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (f) a group of the formula -NR45R46, where each of R45 and R46 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R45 and R46 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) skupinom formule -CONR47R48, gdje svaki od R47 i R48 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R47 i R48 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (g) a group of the formula -CONR47R48, where each of R47 and R48 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or in which R47 and R48 form a saturated hydrocarbon a bridge that has from 3 to 5 carbon atoms that, together with the nitrogen atom between them, form a heterocyclic ring,
(h) skupinom formule -OR49, gdje R49 predstavlja vodikov atom, ili alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (h) a group of the formula -OR49, where R49 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,
(i) skupinom formule -SR50, gdje R50 predstavlja vodikov atom, ili alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (i) a group of the formula -SR50, where R50 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,
(j) cijano, (j) cyano,
(k) nitro, (k) nitro,
(l) amidino skupinom formule (l) amidino group of the formula
[image] [image]
u kojoj svaki od R51, R52 i R53 neovisno predstavlja vodikov atom ili alkil koji ima od 1 do 3 ugljikova atoma, i u kojoj dva od R51, R52 i R53 mogu dodatno oblikovati zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom (atomima) između njih tvore heterociklički prsten, ili in which each of R51, R52 and R53 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R51, R52 and R53 may additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them to form a heterocyclic ring, or
(m) halogenim, (m) halogen,
(ii) metilom, koji može biti mono- ili polisupstituiran s atomima fluora i dodatno može biti monosupstituiran s R43, (ii) methyl, which can be mono- or polysubstituted with fluorine atoms and can additionally be monosubstituted with R43,
(iii) razgranatom ili nerazgranatom alkilnom skupinom koji ima od 2 do 6 ugljikovih atoma ili cikloalkilom skupinom koji ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s okso, (iii) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with oxo,
(iv) skupinom formule -COOR54, gdje R54 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (iv) a group of the formula -COOR54, where R54 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(v) skupinom formule -NR55R56, gdje svaki od R55 i R56 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma ili acil koji ima od 1 do 7 ugljikovih atoma, ili u kojoj R55 i R56 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, i gdje jedan od R55 i R56 može dodatno biti skupina R43, (v) a group of the formula -NR55R56, where each of R55 and R56 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R55 and R56 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R55 and R56 may additionally be the group R43,
(vi) skupinom formule -CONR57R56, gdje svaki od R57 i R58 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma, ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R57 i R58 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, i gdje jedan od R57 i R58 može dodatno biti skupina R43, (vi) a group of the formula -CONR57R56, where each of R57 and R58 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R57 and R58 form saturated a hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R57 and R58 can additionally be the group R43,
(vii) skupinom formule -COR59, gdje R59 predstavlja vodikov atom, ravan ili razgranati ili alkil koji ima od 1 do 5 ugljikovih atoma, cikloalkil koji ima od 3 do 5 ugljikovih atoma, ili R43, (vii) a group of the formula -COR59, where R59 represents a hydrogen atom, straight or branched or alkyl having from 1 to 5 carbon atoms, cycloalkyl having from 3 to 5 carbon atoms, or R43,
(viii) skupinom formule -OR60, gdje R60 predstavlja vodikov atom, alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, ili R43, (viii) a group of the formula -OR60, where R60 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R43,
(ix) skupinom formule -SR61, gdje R61 predstavlja vodikov atom, alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, ili R43, (ix) a group of the formula -SR61, where R61 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R43,
(x) cijano, (x) cyano,
(xi) nitro, ili (xi) nitro, or
(xii) halogenim, (xii) halogen,
R41 je: R41 is:
aril odabran iz razreda kojeg čine fenil, 2-naftil, 2-, 3-, 5- ili 6-indolil, 2- ili 3-tiofenil, 2-, 3- ili 4-piridil, 2-, 4- ili 5-pirimidinil, 2- ili 3-furil, 1-, 2- ili 3-pirolil, 2-, 4- ili 5-oksazolil, 2-, 4- ili 5-tiazolil, 1-, 3-, 4- ili 5-pirazolil, 3-, 4- ili 5-izoksazolil, 1-, 2-, 4- ili 5-imidazolil, 3-, 4- ili 5-izotiazolil, 4- ili 5-oksadiazolil, 1-, 4- ili 5-triazolil, 2-tiadiazolil, 3- ili 4-piridazinil, 2-pirazinil, 2-triazinil, 2-, 3-, 6- ili 7-indolizinil, 2-, 3-, 5- ili 6-izoindolil, 2-, 3-, 5- ili 6-benzo[b]furanil, 2-, 3-, 5- ili 6-benzo[b]tiofenil, 3-, 5- ili 6-indazolil, 2-, 5- ili 6-benztiazolil, 2-, 5- ili 6-benzimidazolil, 2-, 3-, 6- ili 7-kinolinil, 3-, 6- ili 7-izokinolinil, 2- ili 8-purinil, 2-, 3-, 7- ili 8-kinolizinil, 3-, 6- ili 7-kinolinil, 6- ili 7-ftalaninil, 2-, 3-, 6- ili 7-kinoksalinil, 2-, 3-, 6- ili 7-naftiridinil, 2-, 6- ili 7-pteridinil i 2-, 6- ili 7-kinazolinil, pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5- pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5- triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl , 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolisinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, whereby one or more hydrogen atoms of the mentioned aryl group can be rebi and independently substituted with:
(A) R62, koji je aril odabran iz razreda kojeg čine fenil, 2-naftil, 2-, 3-, 5- ili 6-indolil, 2- ili 3-tiofenil, 2-, 3- ili 4-piridil, 2-, 4- ili 5-pirimidinil, 2- ili 3-furil, 1-, 2- ili 3-pirolil, 2-, 4- ili 5-oksazolil, 2-, 4- ili 5-tiazolil, 1-, 3-, 4- ili 5-pirazolil, 3-, 4- ili 5-izoksazolil, 1-, 2-, 4- ili 5-imidazolil, 3-, 4- ili 5-izotiazolil, 4- ili 5-oksadiazolil, 1-, 4- ili 5-triazolil, 2-tiadiazolil, 3- ili 4-piridazinil, 2-pirazinil, 2-triazinil, 2-, 3-, 6- ili 7-indolizinil, 2-, 3-, 5- ili 6-izoindolil, 2-, 3-, 5- ili 6-benzo[b]furanil, 2-, 3-, 5- ili 6-benzo[b]tiofenil, 3-, 5- ili 6-indazolil, 2-, 5- ili 6-benztiazolil, 2-, 5- ili 6-benzimidazolil, 2-, 3-, 6- ili 7-kinolinil, 3-, 6- ili 7-izokinolinil, 2- ili 8-purinil, 2-, 3-, 7- ili 8-kinolizinil, 3-, 6- ili 7-kinolinil, 6- ili 7-ftalaninil, 2-, 3-, 6- ili 7-kinoksalinil, 2-, 3-, 6- ili 7-naftiridinil, 2-, 6- ili 7-pteridinil i 2-, 6- ili 7-kinazolinil, (A) R 62 , which is aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2 -, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3 -, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1 -, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2- , 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2- , 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:
(i) razgranatom ili nerazgranatom alkilnom skupinom koja ima od 1 do 6 ugljikovih atoma ili cikloalkilnom skupinom koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s halogenim ili okso, (i) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,
(ii) -COOH, (ii) -COOH,
(iii) -SO2OH, (iii) -SO2OH,
(iv) -PO(OH)2, (iv) -PO(OH)2,
(v) skupinom formule -COOR63, gdje R63 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (v) a group of the formula -COOR63, where R63 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(vi) skupinom formule -NR64R65, gdje svaki od R64 i R65 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma ili acil koji ima od 1 do 7 ugljikovih atoma, ili u kojoj R64 i R65 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (vi) a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R64 and R65 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) skupinom formule -CONR66R67, gdje svaki od R66 i R67 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R66 i R67 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or in which R66 and R67 form a saturated hydrocarbon a bridge that has from 3 to 5 carbon atoms that, together with the nitrogen atom between them, form a heterocyclic ring,
(viii) skupinom formule -OR68, gdje R68 predstavlja vodikov atom, ili alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (viii) a group of the formula -OR68, where R68 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,
(ix) skupinom formule -SR69, gdje R69 predstavlja vodikov atom, ili alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (ix) a group of the formula -SR69, where R69 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,
(x) cijano, (x) cyano,
(xi) nitro, ili (xi) nitro, or
(xii) amidino skupinom formule (xii) amidino group of the formula
[image] [image]
u kojoj svaki od R70, R71 i R72 neovisno predstavlja vodikov atom ili alkil koji ima od 1 do 3 ugljikova atoma, i u kojoj dva od R70, R71 i R72 mogu dodatno oblikovati zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom (atomima) između njih tvore heterociklički prsten, ili in which each of R70, R71 and R72 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R70, R71 and R72 may additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them to form a heterocyclic ring, or
(xiii) halogenim, (xiii) halogen,
(B) metilom, koji može biti mono- ili polisupstituiran s atomima fluora i dodatno može biti monosupstituiran s R62, (B) methyl, which can be mono- or polysubstituted with fluorine atoms and can additionally be monosubstituted with R62,
(C) razgranatom ili nerazgranatom alkilnom skupinom koja ima od 2 do 6 ugljikovih atoma ili cikloalkilnom skupinom koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s halogenim ili okso, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,
(D) skupinom formule -COOR73, gdje R73 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (D) a group of the formula -COOR73, where R73 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(E) skupinom formule -NR74R75, gdje svaki od R74 i R75 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma ili acil koji ima od 1 do 7 ugljikovih atoma, ili u kojoj R74 i R75 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, i gdje jedan od R74 i R75 može dodatno biti skupina R62, (E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R74 and R75 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R74 and R75 may additionally be the group R62,
(F) skupinom formule -CONR76R77, gdje svaki od R76 i R77 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma, ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R76 i R77 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, i gdje jedan od R76 i R77 može dodatno biti skupina R62, (F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R76 and R77 form saturated a hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R76 and R77 may additionally be the group R62,
(G) skupinom formule -COR78, gdje R78 predstavlja vodikov atom, ravan ili razgranati ili alkil koji ima od 1 do 5 ugljikovih atoma, cikloalkil koji ima od 3 do 5 ugljikovih atoma, ili R62, (G) a group of the formula -COR78, where R78 represents a hydrogen atom, straight or branched or alkyl having from 1 to 5 carbon atoms, cycloalkyl having from 3 to 5 carbon atoms, or R62,
(H) skupinom formule -OR79, gdje R79 predstavlja vodikov atom, alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, ili R62, (H) a group of the formula -OR79, where R79 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62,
(I) skupinom formule -SR80, gdje R80 predstavlja vodikov atom, alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, ili R62, (I) a group of the formula -SR80, where R80 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62,
(J) cijano, (J) cyano,
(K) nitro, ili (K) nitro, or
(L) halogenim, (L) halogen,
R4 je Cl ili trifluormetil; i R 4 is Cl or trifluoromethyl; and
svaki od R5 i R6 neovisno predstavlja vodik, atom fluora, klora, broma ili joda, metil ili trifluormetil; each of R5 and R6 independently represents hydrogen, a fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl;
ili njegove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.
Kako je gore spomenuto, neki od spojeva obuhvaćenih s gore opisanom vrstom spojeva su poznati i opisani su u U.S. patentu 3,668,217; U.S. patentu 4,944,791; U.S. patentnu 3,741,981; Li, W.-Y., et al., J. Pharm. Sci. 1984, 73, 553-558 i Abd El Halim, M. S., et al., Monatshefte für Chemie, 1994, 125, 1437-1442. As mentioned above, some of the compounds included in the class of compounds described above are known and described in U.S. Pat. patent 3,668,217; LOUSE. patent 4,944,791; LOUSE. patent number 3,741,981; Li, W.-Y., et al., J. Pharm. Sci. 1984, 73, 553-558 and Abd El Halim, M.S., et al., Monatshefte für Chemie, 1994, 125, 1437-1442.
U drugom aspektu izum uključuje nove spojeve formule I In another aspect, the invention includes novel compounds of formula I
[image] [image]
u kojoj su X, Y, Z, R2, R3, R4, R5 i R6 definirani kao gore osim što je u skupini R3 barem jedan od vodikovih atoma u arilnoj skupini R41 nužno, prije nego po potrebi, nadomješten s: wherein X, Y, Z, R 2 , R 3 , R 4 , R 5 and R 6 are as defined above except that in the group R 3 at least one of the hydrogen atoms in the aryl group R 41 is necessarily, rather than necessarily, replaced by:
(A) R62, koji je aril odabran iz razreda kojeg čine fenil, 2-naftil, 2-, 3-, 5- ili 6-indolil, 2- ili 3-tiofenil, 2-, 3- ili 4-piridil, 2-, 4- ili 5-pirimidinil, 2- ili 3-furil, 1-, 2- ili 3-pirolil, 2-, 4- ili 5-oksazolil, 2-, 4- ili 5-tiazolil, 1-, 3-, 4- ili 5-pirazolil, 3-, 4- ili 5-izoksazolil, 1-, 2-, 4- ili 5-imidazolil, 3-, 4- ili 5-izotiazolil, 4- ili 5-oksadiazolil, 1-, 4- ili 5-triazolil, 2-tiadiazolil, 3- ili 4-piridazinil, 2-pirazinil, 2-triazinil, 2-, 3-, 6- ili 7-indolizinil, 2-, 3-, 5- ili 6-izoindolil, 2-, 3-, 5- ili 6-benzo[b]furanil, 2-, 3-, 5- ili 6-benzo[b]tiofenil, 3-, 5- ili 6-indazolil, 2-, 5- ili 6-benztiazolil, 2-, 5- ili 6-benzimidazolil, 2-, 3-, 6- ili 7-kinolinil, 3-, 6- ili 7-izokinolinil, 2- ili 8-purinil, 2-, 3-, 7- ili 8-kinolizinil, 3-, 6- ili 7-kinolinil, 6- ili 7-ftalaninil, 2-, 3-, 6- ili 7-kinoksalinil, 2-, 3-, 6- ili 7-naftiridinil, 2-, 6- ili 7-pteridinil i 2-, 6- ili 7-kinazolinil, (A) R 62 , which is aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2 -, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3 -, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1 -, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2- , 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2- , 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s wherein one or more hydrogen atoms of the mentioned aryl group can be independently substituted with
(i) razgranatom ili nerazgranatom alkilnom skupinom koji ima od 1 do 6 ugljikovih atoma ili cikloalkilnom skupinom koji ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s halogenim ili okso, (i) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,
(ii) -COOH, (ii) -COOH,
(iii) -SO2OH, (iii) -SO2OH,
(iv) -PO(OH)2, (iv) -PO(OH)2,
(v) skupinom formule -COOR63, gdje R63 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (v) a group of the formula -COOR63, where R63 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(vi) skupinom formule -NR64R65, gdje svaki od R64 i R65 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma ili acil koji ima od 1 do 7 ugljikovih atoma, ili u kojoj R64 i R65 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (vi) a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R64 and R65 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) skupinom formule -CONR66R67, gdje svaki od R66 i R67 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R66 i R67 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, or in which R66 and R67 form a saturated hydrocarbon a bridge that has from 3 to 5 carbon atoms that, together with the nitrogen atom between them, form a heterocyclic ring,
(viii) skupinom formule -OR68, gdje R68 predstavlja vodikov atom, ili alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (viii) a group of the formula -OR68, where R68 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,
(ix) skupinom formule -SR69, gdje R69 predstavlja vodikov atom, ili alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (ix) a group of the formula -SR69, where R69 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,
(x) cijano, (x) cyano,
(xi) nitro, (xi) nitro,
(xii) amidino skupinom formule (xii) amidino group of the formula
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u kojoj svaki od R70, R71 i R72 neovisno predstavlja vodikov atom ili alkil koji ima od 1 do 3 ugljikova atoma, i u kojoj dva od R70, R71 i R72 mogu dodatno oblikovati zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom (atomima) između njih tvore heterociklički prsten, ili in which each of R70, R71 and R72 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms, and in which two of R70, R71 and R72 may additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them to form a heterocyclic ring, or
(xiii) halogenim, (xiii) halogen,
(B) metilom, koji može biti mono- ili polisupstituiran s atomima fluora i dodatno može biti monosupstituiran s R62, (B) methyl, which can be mono- or polysubstituted with fluorine atoms and can additionally be monosubstituted with R62,
(C) razgranatom ili nerazgranatom alkilnom skupinom koja ima od 2 do 6 ugljikovih atoma ili cikloalkilnom skupinom koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s halogenim ili okso, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,
(D) skupinom formule -COOR73, gdje R73 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (D) a group of the formula -COOR73, where R73 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(E) skupinom formule -NR74R75, gdje svaki od R74 i R75 neovisno predstavlja vodikov atom, alkil ili fluoralkl koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma ili acil koji ima od 1 do 7 ugljikovih atoma, ili u kojoj R74 i R75 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, i gdje jedan od R74 i R75 može dodatno biti skupina R62, (E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R74 and R75 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R74 and R75 may additionally be the group R62,
(F) skupinom formule -CONR76R77, gdje svaki od R76 i R77 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R76 i R77 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, i gdje jedan od R76 i R77 može dodatno biti skupina R62, (F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, or in which R76 and R77 form a saturated hydrocarbon a bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R76 and R77 can additionally be the group R62,
(G) skupinom formule -COR78, gdje R78 predstavlja vodikov atom, ravan ili razgranati ili alkil koji ima od 1 do 5 ugljikovih atoma, cikloalkil koji ima od 3 do 5 ugljikovih atoma, ili R62, (G) a group of the formula -COR78, where R78 represents a hydrogen atom, straight or branched or alkyl having from 1 to 5 carbon atoms, cycloalkyl having from 3 to 5 carbon atoms, or R62,
(H) skupinom formule -OR79, gdje R79 predstavlja vodikov atom, alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, ili R62, (H) a group of the formula -OR79, where R79 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62,
(I) skupinom formule -SR80, gdje R80 predstavlja vodikov atom, alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, ili R62, (I) a group of the formula -SR80, where R80 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62,
(J) cijano, (J) cyano,
(K) nitro, ili (K) nitro, or
(L) halogenim; (L) halogenim;
ili njihove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.
Prednosni spojevi formule I su oni u kojima: Preferred compounds of formula I are those in which:
Y je atom kisika ili sumpora; Y is an oxygen or sulfur atom;
Z je atom kisika ili sumpora; Z is an oxygen or sulfur atom;
X je dvovalentna skupina formule >CHR1, >NR1, >CHSO2R1, ili >NSO2R1, ili atom kisika ili sumpora, gdje X is a divalent group of the formula >CHR1, >NR1, >CHSO2R1, or >NSO2R1, or an oxygen or sulfur atom, where
R1 je: R1 is:
(A) atom vodika, (A) hydrogen atom,
(B) razgranata ili nerazgranata alkilna skupina koja ima od 1 do 6 ugljikovih atoma ili cikloalkilna skupina koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s: (B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with:
(i) halogenim, (i) halogen,
(ii) okso, (ii) oxo,
(iii) arilom odabranim iz razreda kojeg čine fenil, naftil, indolil, tiofenil, piridil, pirimidinil, furil, pirolil, oksazolil, tiazolil, pirazolil, izoksazolil, imidazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, piridazinil, pirazinil, triazinil, indolizinil, izoindolil, benzo[b]furanil, benzo[b]tiofenil, indazolil, benztiazolil, benzimidazolil, kinolinil, izokinolinil, purinil, kinolizinil, kinolinil, ftalaninil, kinoksalinil, naftiridinil, pteridinil i kinazolinil, (iii) aryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolizinyl , isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, quinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pteridinyl and quinazolinyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine mogu biti po potrebi i neovisno nadomješteno s: whereby one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:
(a) alkilom koji ima 1 do 3 ugljikova atoma, (a) alkyl having 1 to 3 carbon atoms,
(b) -COOH, (b) -COOH,
(c) -SO2OH, (c) -SO2OH,
(d) -PO(OH)2, (d) -PO(OH)2,
(e) skupinom formule -COOR7, gdje R7 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (e) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(f) skupinom formule -NR8R9, gdje svaki od R8 i R9 neovisno predstavlja vodikov atom, alkil koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma ili acil koji ima od 1 do 7 ugljikovih atoma, ili u kojoj R8 i R9 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (f) a group of the formula -NR8R9, where each of R8 and R9 independently represents a hydrogen atom, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms, or in which R8 and R9 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,
(g) skupinom formule -CONR10R11, gdje svaki od R10 i R11 neovisno predstavlja vodikov atom, alkil koji ima od 1 do 6 ugljikovih atoma ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R10 i R11 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (g) a group of the formula -CONR10R11, where each of R10 and R11 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R10 and R11 form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,
(h) skupinom formule -OR12a, gdje R12a predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 uljikovih atoma, (h) a group of the formula -OR12a, where R12a represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,
(i) skupinom formule -SR12b, gdje R12b predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (i) a group of the formula -SR12b, where R12b represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,
(j) cijano, ili (j) cyano, or
(k) amidino skupinom formule (k) amidino group of the formula
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u kojoj svaki od R13, R14 i R15 neovisno predstavlja vodikov atom ili alkil koji ima od 1 do 3 ugljikova atoma i u kojoj dva od R13, R14 i R15 mogu dodatno oblikovati zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom (atomima) između njih tvore heterociklički prsten, in which each of R13, R14 and R15 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R13, R14 and R15 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them to form a heterocyclic ring,
(iv) skupinom formule -COOR16, gdje R16 predstavlja ravan ili razgranati alkil koji ima od 1 do 7 ugljikovih atoma ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, (iv) a group of the formula -COOR16, where R16 represents straight or branched alkyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms,
(v) cijano, (v) cyano,
(vi) skupinom formule -CONR17R18, gdje svaki od R17 i R18 neovisno predstavlja vodikov atom, alkil koji ima od 1 do 6 ugljikovih atoma ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R17 i R18 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (vi) a group of the formula -CONR17R18, where each of R17 and R18 independently represents a hydrogen atom, an alkyl having from 1 to 6 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms, or in which R17 and R18 form a saturated hydrocarbon bridge that has from 3 to 5 carbon atoms which, together with the nitrogen atom between them, form a heterocyclic ring,
(vii) skupinom formule -OR19, gdje R19 predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (vii) a group of the formula -OR19, where R19 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,
(viii) skupinom formule -SR20, gdje R20 predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (viii) a group of the formula -SR20, where R20 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms,
(ix) skupinom formule -NR21R22, gdje svaki od R21 i R22 neovisno predstavlja: (ix) a group of the formula -NR21R22, where each of R21 and R22 independently represents:
(a) vodikov atom, (a) hydrogen atom,
(b) alkil ili acil koji ima od 1 do 7 ugljikovih atoma ili cikloalkil koji ima od 3 do 7 ugljikovih atoma, (b) alkyl or acyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 7 carbon atoms,
(c) skupinu formule -(CH2)mCOOH, gdje m je 0, 1 ili 2, ili (c) a group of the formula -(CH2)mCOOH, where m is 0, 1 or 2, or
(d) skupinu formule -(CH2)nCOOR23, gdje n je 0, 1 ili 2, a R23 je ravan ili razgranati alkil koji ima od 1 do 6 ugljikovih atoma, (d) a group of the formula -(CH2)nCOOR23, where n is 0, 1 or 2, and R23 is straight or branched alkyl having from 1 to 6 carbon atoms,
ili gdje R21 i R22 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, ili or where R21 and R22 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(x) kvaternom skupinom formule (x) by the quaternary group of the formula
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u kojoj svaki od R24, R25 i R26 neovisno predstavlja razgranatu ili nerazgranatu alkilnu skupinu koja ima od 1 do 7 ugljikovih atoma i Q- je ion klora, broma ili joda suprotnog naboja, in which each of R24, R25 and R26 independently represents a branched or unbranched alkyl group having from 1 to 7 carbon atoms and Q- is a chlorine, bromine or iodine ion of the opposite charge,
(C) razgranata ili nerazgranata skupina karboksilne kiseline koja ima od 3 do 6 ugljikovih atoma, (C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms,
(D) razgranata ili nerazgranata skupina fosfonske kiseline koja ima od 2 do 6 ugljikovih atoma, (D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms,
(E) razgranata ili nerazgranata skupina sulfonske kiseline koja ima od 2 do 6 ugljikovih atoma, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms,
(F) amidino skupina formule (F) amidino group of the formula
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u kojoj r je 2, 3, 4, 5 ili 6, i in which r is 2, 3, 4, 5 or 6, and
svaki od R27, R28 i R29 neovisno predstavlja vodikov atom ili alkil koji ima od 1 do 3 ugljikova atoma i u kojoj dva od R27, R28 i R29 mogu dodatno oblikovati zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom (atomima) između njih tvore heterociklički prsten, each of R27, R28 and R29 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R27, R28 and R29 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with a nitrogen atom ( atoms) between them form a heterocyclic ring,
(G) gvanidino skupina formule (G) guanidino group of the formula
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u kojoj s je 2, 3, 4, 5 ili 6, i in which s is 2, 3, 4, 5 or 6, i
svaki od R30, R31, R32 i R33 neovisno predstavlja vodikov atom ili alkil koji ima od 1 do 3 ugljikova atoma i u kojoj dva od R30, R31, R32 i R33 mogu dodatno oblikovati zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom (atomima) između njih tvore heterociklički prsten, ili each of R30, R31, R32 and R33 independently represents a hydrogen atom or alkyl having from 1 to 3 carbon atoms and in which two of R30, R31, R32 and R33 can additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with nitrogen atom(s) between them form a heterocyclic ring, or
(H) piperidil, u kojem je dušikov atom spomenute skupine po potrebi supstituiran s: (H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with:
(i) alkilom koji ima 1 do 3 ugljikova atoma, (i) alkyl having 1 to 3 carbon atoms,
(ii) skupinom karboksilnog estera koja ima 2 do 7 ugljikovih atoma, (ii) a carboxyl ester group having 2 to 7 carbon atoms,
(iii) skupinom karboksilne kiseline koja ima od 2 do 5 ugljikovih atoma, (iii) a carboxylic acid group that has from 2 to 5 carbon atoms,
(iv) skupinom fosfonske kiseline koja ima od 1 do 6 ugljikovih atoma, ili (iv) a phosphonic acid group having from 1 to 6 carbon atoms, or
(v) skupinom sulfonske kiseline koja ima od 1 do 6 ugljikovih atoma; (v) a sulfonic acid group having from 1 to 6 carbon atoms;
R2 je: R2 is:
(A) vodikov atom, ili (A) hydrogen atom, or
(B) metil; (B) methyl;
R3 je skupina formule -CH2R41, u kojoj: R3 is a group of the formula -CH2R41, in which:
R41 je: R41 is:
aril odabran iz razreda kojeg čine fenil, 2-naftil, 2-, 3-, 5- ili 6-indolil, 2- ili 3-tiofenil, 2-, 3- ili 4-piridil, 2-, 4- ili 5-pirimidinil, 2- ili 3-furil, 1-, 2- ili 3-pirolil, 2-, 4- ili 5-oksazolil, 2-, 4- ili 5-tiazolil, 1-, 3-, 4- ili 5-pirazolil, 3-, 4- ili 5-izoksazolil, 1-, 2-, 4- ili 5-imidazolil, 3-, 4- ili 5-izotiazolil, 4- ili 5-oksadiazolil, 1-, 4- ili 5-triazolil, 2-tiadiazolil, 3- ili 4-piridazinil, 2-pirazinil, 2-triazinil, 2-, 3-, 6- ili 7-indolizinil, 2-, 3-, 5- ili 6-izoindolil, 2-, 3-, 5- ili 6-benzo[b]furanil, 2-, 3-, 5- ili 6-benzo[b]tiofenil, 3-, 5- ili 6-indazolil, 2-, 5- ili 6-benztiazolil, 2-, 5- ili 6-benzimidazolil, 2-, 3-, 6- ili 7-kinolinil, 3-, 6- ili 7-izokinolinil, 2- ili 8-purinil, 2-, 3-, 7- ili 8-kinolizinil, 3-, 6- ili 7-kinolinil, 6- ili 7-ftalaninil, 2-, 3-, 6- ili 7-kinoksalinil, 2-, 3-, 6- ili 7-naftiridinil, 2-, 6- ili 7-pteridinil i 2-, 6- ili 7-kinazolinil, aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5- pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5- triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl , 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolisinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
pri čemu je jedan ili više vodikovih atoma spomenute arilne skupine nužno i neovisno nadomješteno s: whereby one or more hydrogen atoms of the mentioned aryl group are necessarily and independently substituted with:
(A) R62, koji je aril odabran iz razreda kojeg čine fenil, 2-naftil, 2-, 3-, 5- ili 6-indolil, 2- ili 3-tiofenil, 2-, 3- ili 4-piridil, 2-, 4- ili 5-pirimidinil, 2- ili 3-furil, 1-, 2- ili 3-pirolil, 2-, 4- ili 5-oksazolil, 2-, 4- ili 5-tiazolil, 1-, 3-, 4- ili 5-pirazolil, 3-, 4- ili 5-izoksazolil, 1-, 2-, 4- ili 5-imidazolil, 3-, 4- ili 5-izotiazolil, 4- ili 5-oksadiazolil, 1-, 4- ili 5-triazolil, 2-tiadiazolil, 3- ili 4-piridazinil, 2-pirazinil, 2-triazinil, 2-, 3-, 6- ili 7-indolizinil, 2-, 3-, 5- ili 6-izoindolil, 2-, 3-, 5- ili 6-benzo[b]furanil, 2-, 3-, 5- ili 6-benzo[b]tiofenil, 3-, 5- ili 6-indazolil, 3-, 5- ili 6-benztiazolil, 2-, 5- ili 6-benzimidazolil, 2-, 3-, 6- ili 7-kinolinil, 3-, 6- ili 7-izokinolinil, 2- ili 8-purinil, 2-, 3-, 7- ili 8-kinolizinil, 3-, 6- ili 7-kinolinil, 6- ili 7-ftalaninil, 2-, 3-, 6- ili 7-kinoksalinil, 2-, 3-, 6- ili 7-naftiridinil, 2-, 6- ili 7-pteridinil i 2-, 6- ili 7-kinazolinil, (A) R 62 , which is aryl selected from the group consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2 -, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3 -, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1 -, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolizinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 3- , 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2- , 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-quinolinyl, 6- or 7-phthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-naphthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:
(i) razgranatom ili nerazgranatom alkilnom skupinom koja ima od 1 do 6 ugljikovih atoma ili cikloalkilnom skupinom koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s halogenim ili s okso, (i) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or with oxo,
(ii) -COOH, (ii) -COOH,
(iii) -SO2OH, (iii) -SO2OH,
(iv) -PO(OH)2, (iv) -PO(OH)2,
(v) skupinom formule -COOR63, gdje R63 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (v) a group of the formula -COOR63, where R63 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(vi) skupinom formule -NR64R65, gdje svaki od R64 i R65 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma ili acil koji ima od 1 do 7 ugljikovih atoma, ili u kojoj R64 i R65 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (vi) a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R64 and R65 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) skupinom formule -CONR66R67, gdje svaki od R66 i R67 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R66 i R67 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, (vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms, or in which R66 and R67 form a saturated hydrocarbon a bridge that has from 3 to 5 carbon atoms that, together with the nitrogen atom between them, form a heterocyclic ring,
(viii) skupinom formule -OR68, gdje R68 predstavlja vodikov atom, ili alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (viii) a group of the formula -OR68, where R68 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,
(ix) skupinom formule -SR69, gdje R69 predstavlja vodikov atom, ili alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, (ix) a group of the formula -SR69, where R69 represents a hydrogen atom, or an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms,
(x) cijano, (x) cyano,
(xi) nitro, (xi) nitro,
(xii) amidino skupinom formule (xii) amidino group of the formula
[image] [image]
u kojoj svaki od R70, R71 i R72 neovisno predstavlja vodikov atom ili alkil ili fluoralkil koji ima od 1 do 3 ugljikova atoma, i u kojoj dva od R70, R71 i R72 mogu dodatno oblikovati zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom (atomima) između njih tvore heterociklički prsten, in which each of R70, R71 and R72 independently represents a hydrogen atom or alkyl or fluoroalkyl having from 1 to 3 carbon atoms, and in which two of R70, R71 and R72 may additionally form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(xiii) halogenim, (xiii) halogen,
(B) metilom, koji može biti mono- ili polisupstituiran s atomima fluora i dodatno može biti monosupstituiran s R62, (B) methyl, which can be mono- or polysubstituted with fluorine atoms and can additionally be monosubstituted with R62,
(C) razgranatom ili nerazgranatom alkilnom skupinom koja ima od 2 do 6 ugljikovih atoma ili cikloalkilnom skupinom koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s halogenim ili s okso, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or with oxo,
(D) skupinom formule -COOR73, gdje R73 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (D) a group of the formula -COOR73, where R73 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(E) skupinom formule -NR74R75, gdje svaki od R74 i R75 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma, cikloalkil koji ima od 3 do 6 ugljikovih atoma ili acil koji ima od 1 do 7 ugljikovih atoma, ili u kojoj R74 i R75 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, i gdje jedan od R74 i R75 može dodatno biti skupina R62, (E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms or acyl having from 1 to 7 carbon atoms , or in which R74 and R75 form a saturated hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R74 and R75 may additionally be the group R62,
(F) skupinom formule -CONR76R77, gdje svaki od R76 i R77 neovisno predstavlja vodikov atom, alkil ili fluoralkil koji ima od 1 do 6 ugljikovih atoma, ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, ili u kojoj R76 i R77 tvore zasićeni ugljikovodični most koji ima od 3 do 5 ugljikovih atoma koji zajedno s dušikovim atomom između njih tvore heterociklički prsten, i gdje jedan od R76 i R77 može dodatno biti skupina R62, (F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents a hydrogen atom, alkyl or fluoroalkyl having from 1 to 6 carbon atoms, or cycloalkyl having from 3 to 6 carbon atoms, or in which R76 and R77 form saturated a hydrocarbon bridge having from 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and where one of R76 and R77 may additionally be the group R62,
G) skupinom formule -COR78, gdje R78 predstavlja vodikov atom, ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma, cikloalkil koji ima od 3 do 5 ugljikovih atoma, ili R62, G) the group of the formula -COR78, where R78 represents a hydrogen atom, straight or branched alkyl having from 1 to 5 carbon atoms, cycloalkyl having from 3 to 5 carbon atoms, or R62,
(H) skupinom formule -OR79, gdje R79 predstavlja vodikov atom, alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, ili R62, (H) a group of the formula -OR79, where R79 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62,
(I) skupinom formule -SR80, gdje R80 predstavlja vodikov atom, alkilnu, fluoralkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, ili R62, (I) a group of the formula -SR80, where R80 represents a hydrogen atom, an alkyl, fluoroalkyl or acyl group having from 1 to 7 carbon atoms, or R62,
(J) cijano, (J) cyano,
(K) nitro, ili (K) nitro, or
(L) halogenim, (L) halogen,
R4 je Cl ili trifluormetil; i R 4 is Cl or trifluoromethyl; and
svaki od R5 i R6 neovisno predstavlja vodik, atom fluora, klora, broma ili joda, metil ili trifluormetil; each of R5 and R6 independently represents hydrogen, a fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl;
ili njihove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.
Još prednosiji su oni novi spojevi formule I u kojoj: Even more advantageous are those new compounds of formula I in which:
Y je atom kisika; Y is an oxygen atom;
Z je atom kisika; Z is an oxygen atom;
X je dvovalentna skupina formule >CHR1 ili >NR1, gdje X is a divalent group of the formula >CHR1 or >NR1, where
R1 je: R1 is:
(A) atom vodika, (A) hydrogen atom,
(B) razgranata ili nerazgranata alkilna skupina koja ima od 1 do 6 ugljikovih atoma ili cikloalkilna skupina koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s: (B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with:
(i) okso, (i) oxo,
(ii) arilom odabranim iz razreda kojeg čine fenil, tiofenil, piridil, pirimidinil, furil, pirolil, oksazolil, tiazolil, pirazolil, izoksazolil, imidazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, piridazinil, pirazinil i triazinil, (ii) aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:
(a) alkilom koji ima 1 do 3 ugljikova atoma, (a) alkyl having 1 to 3 carbon atoms,
(b) -COOH, (b) -COOH,
(c) -SO2OH, (c) -SO2OH,
(d) -PO(OH)2, (d) -PO(OH)2,
(e) skupinom formule -COOR7, gdje R7 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (e) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(f) skupinom formule -NH2, (f) group of the formula -NH2,
(g) skupinom formule -CONH2, (g) group of the formula -CONH2,
(h) skupinom formule -OR12a, gdje R12a predstavlja vodikov atom ili metil, (h) a group of the formula -OR12a, where R12a represents a hydrogen atom or methyl,
(i) amidino skupinom formule (i) amidino group of the formula
[image] [image]
u kojoj svaki od R13, R14 i R15 neovisno predstavlja vodikove atome, in which each of R13, R14 and R15 independently represents hydrogen atoms,
(iii) skupinom formule -COOR16, gdje R16 predstavlja ravan ili razgranati alkil koji ima od 1 do 7 ugljikovih atoma ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, (iii) a group of the formula -COOR16, where R16 represents straight or branched alkyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms,
(iv) skupinom formule -OR19, gdje R19 predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koja ima od 1 do 7 ugljikovih atoma, ili (iv) a group of the formula -OR19, where R19 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, or
(v) kvaternom skupinom formule (v) quaternary group of the formula
[image] [image]
u kojoj svaki od R24, R25 i R26 neovisno predstavlja metil i Q- je ion klora, broma ili joda suprotnog naboja, in which each of R24, R25 and R26 independently represents methyl and Q- is an oppositely charged chlorine, bromine or iodine ion,
(C) razgranata ili nerazgranata skupina karboksilne kiseline koja ima od 3 do 6 ugljikovih atoma, (C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms,
(D) razgranata ili nerazgranata skupina fosfonske kiseline koja ima od 2 do 6 ugljikovih atoma, (D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms,
(E) razgranata ili nerazgranata skupina sulfonske kiseline koja ima od 2 do 6 ugljikovih atoma, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms,
(F) amidino skupina formule (F) amidino group of the formula
[image] [image]
u kojoj r je 2, 3, 4, 5 ili 6, i in which r is 2, 3, 4, 5 or 6, and
svaki od R27, R28 i R29 neovisno predstavlja vodikove atome, each of R27, R28 and R29 independently represents hydrogen atoms,
(G) gvanidino skupina formule (G) guanidino group of the formula
[image] [image]
u kojoj s je 2, 3, 4, 5 ili 6, where s is 2, 3, 4, 5 or 6,
svaki od R30, R31, R32 i R33 neovisno predstavlja vodikove atome, ili each of R30, R31, R32 and R33 independently represents hydrogen atoms, or
(H) piperidil, u kojem je dušikov atom spomenute skupine po potrebi supstituiran s: (H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with:
(i) alkilom koji ima 1 do 3 ugljikova atoma, (i) alkyl having 1 to 3 carbon atoms,
(ii) skupinom karboksilnog estera koja ima 2 do 7 ugljikovih atoma, (ii) a carboxyl ester group having 2 to 7 carbon atoms,
(iii) skupinom karboksilne kiseline koja ima od 2 do 5 ugljikovih atoma, (iii) a carboxylic acid group that has from 2 to 5 carbon atoms,
(iv) skupinom fosfonske kiseline koja ima od 1 do 6 ugljikovih atoma, ili (iv) a phosphonic acid group having from 1 to 6 carbon atoms, or
(v) skupinom sulfonske kiseline koja ima od 1 do 6 ugljikovih atoma; (v) a sulfonic acid group having from 1 to 6 carbon atoms;
R2 je: R2 is:
(A) vodikov atom, ili (A) hydrogen atom, or
(B) metil; (B) methyl;
R3 je skupina formule -CH2R41, u kojoj R3 is a group of the formula -CH2R41, in which
R41 je aril odabran iz razreda kojeg čine fenil, tiofenil, piridil, pirimidinil, furil, pirolil, oksazolil, tiazolil, pirazolil, izoksazolil, imidazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, piridazinil, pirazinil i triazinil, R41 is aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,
pri čemu je jedan ili više vodikovih atoma spomenute arilne skupine nužno i neovisno nadomješteno s: whereby one or more hydrogen atoms of the mentioned aryl group are necessarily and independently substituted with:
(A) R62, koji je aril odabran iz razreda kojeg čine fenil, tiofenil, piridil, pirimidinil, furil, pirolil, oksazolil, tiazolil, pirazolil, izoksazolil, imidazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, piridazinil, pirazinil i triazinil, (A) R 62 , which is aryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:
(i) metilom, (i) methyl,
(ii) -COOH, (ii) -COOH,
(iii) -SO2OH, (iii) -SO2OH,
(iv) -PO(OH)2, (iv) -PO(OH)2,
(v) skupinom formule -COOR63, gdje R63 predstavlja metil, (v) a group of the formula -COOR63, where R63 represents methyl,
(vi) skupinom formule -NR64R65, gdje svaki od R64 i R65 neovisno predstavlja vodikov atom ili metil, (vi) a group of the formula -NR64R65, where each of R64 and R65 independently represents a hydrogen atom or methyl,
(vii) skupinom formule -CONR66R67, gdje svaki od R66 i R67 neovisno predstavlja vodikov atom ili metil, (vii) a group of the formula -CONR66R67, where each of R66 and R67 independently represents a hydrogen atom or methyl,
(viii) skupinom formule -OR68, gdje R68 predstavlja vodikov atom ili metil, (viii) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl,
(ix) skupinom formule -SR69, gdje R69 predstavlja vodikov atom ili metil, (ix) a group of the formula -SR69, where R69 represents a hydrogen atom or methyl,
(x) cijano, (x) cyano,
(xi) nitro, ili (xi) nitro, or
(xii) halogenim, (xii) halogen,
(B) metilom, koji može biti mono- ili polisupstituiran s atomima fluora i koji dodatno može biti monosupstituiran s R62, (B) methyl, which can be mono- or polysubstituted with fluorine atoms and which can additionally be monosubstituted with R62,
(C) razgranatom ili nerazgranatom alkilnom skupinom koja ima od 2 do 6 ugljikovih atoma ili cikloalkilnom skupinom koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s halogenim ili okso, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,
(D) skupinom formule -COOR73, gdje R73 predstavlja metil, (D) a group of the formula -COOR73, where R73 represents methyl,
(E) skupinom formule -NR74R75, gdje svaki od R74 i R75 neovisno predstavlja vodikov atom ili metil, i u kojoj jedan od R74 i R75 može dodatno biti skupina R62, (E) a group of the formula -NR74R75, where each of R74 and R75 independently represents a hydrogen atom or methyl, and in which one of R74 and R75 can additionally be the group R62,
(F) skupinom formule -CONR76R77, gdje svaki od R76 i R77 neovisno predstavlja vodikov atom ili metil, i u kojoj jedan od R76 i R77 može dodatno biti skupina R62, (F) a group of the formula -CONR76R77, where each of R76 and R77 independently represents a hydrogen atom or methyl, and in which one of R76 and R77 can additionally be a group R62,
(G) skupinom formule -COR78, gdje R78 predstavlja vodikov atom ili metil, ili R62, (G) a group of the formula -COR78, where R78 represents a hydrogen atom or methyl, or R62,
(H) skupinom formule -OR79, gdje R79 predstavlja vodikov atom, metil, ili R62, (H) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl, or R62,
(I) skupinom formule -SR80, gdje R80 predstavlja vodikov atom, metil, ili R62, (I) a group of the formula -SR80, where R80 represents a hydrogen atom, methyl, or R62,
(J) cijano, (J) cyano,
(K) nitro, ili (K) nitro, or
(L) halogenim; (L) halogenim;
R4 je Cl ili trifluormetil; R 4 is Cl or trifluoromethyl;
R5 je vodikov atom; i R5 is a hydrogen atom; and
R6 je Cl, ili trifluormetil; R 6 is Cl, or trifluoromethyl;
ili njihove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.
Čak još prednosnji su oni novi spojevi formule I u kojoj: Even more preferable are those new compounds of formula I in which:
Y je atom kisika; Y is an oxygen atom;
Z je atom kisika; Z is an oxygen atom;
X je dvovalentna skupina formule >CHR1 ili >NR1, gdje X is a divalent group of the formula >CHR1 or >NR1, where
R1 je: R1 is:
(A) atom vodika, (A) hydrogen atom,
(B) razgranata ili nerazgranata alkilna skupina koja ima od 1 do 6 ugljikovih atoma ili cikloalkilna skupina koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s: (B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with:
(i) okso, (i) oxo,
(ii) arilom odabran iz razreda kojeg čine fenil, tiofenil, piridil, pirimidinil, furil, pirolil, oksazolil, tiazolil, pirazolil, izoksazolil, imidazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, piridazinil, pirazinil i triazinil, (ii) aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:
(a) alkilom koji ima 1 do 3 ugljikova atoma, (a) alkyl having 1 to 3 carbon atoms,
(b) -COOH, (b) -COOH,
(c) -SO2OH, (c) -SO2OH,
(d) -PO(OH)2, (d) -PO(OH)2,
(e) skupinom formule -COOR7, gdje R7 predstavlja ravan ili razgranati alkil koji ima od 1 do 5 ugljikovih atoma ili cikloalkil koji ima od 3 do 5 ugljikovih atoma, (e) a group of the formula -COOR7, where R7 represents straight or branched alkyl having from 1 to 5 carbon atoms or cycloalkyl having from 3 to 5 carbon atoms,
(f) skupinom formule -NH2, (f) group of the formula -NH2,
(g) skupinom formule -CONH2, (g) group of the formula -CONH2,
(h) skupinom formule -OR12a, gdje R12a predstavlja vodikov atom ili metil, (h) a group of the formula -OR12a, where R12a represents a hydrogen atom or methyl,
(i) amidino skupinom formule (i) amidino group of the formula
[image] [image]
u kojoj svaki od R13, R14 i R15 neovisno predstavlja vodikove atome, in which each of R13, R14 and R15 independently represents hydrogen atoms,
(iii) skupinom formule -COOR16, gdje R16 predstavlja ravan ili razgranati alkil koji ima od 1 do 7 ugljikovih atoma ili cikloalkil koji ima od 3 do 6 ugljikovih atoma, (iii) a group of the formula -COOR16, where R16 represents straight or branched alkyl having from 1 to 7 carbon atoms or cycloalkyl having from 3 to 6 carbon atoms,
(iv) skupinom formule -OR19, gdje R19 predstavlja vodikov atom, ili alkilnu ili acilnu skupinu koji ima od 1 do 7 ugljikovih atoma, ili (iv) a group of the formula -OR19, where R19 represents a hydrogen atom, or an alkyl or acyl group having from 1 to 7 carbon atoms, or
(v) kvaternom skupinom formule (v) quaternary group of the formula
[image] [image]
u kojoj svaki od R24, R25 i R26 neovisno predstavlja metil i Q- je ion klora, broma ili joda suprotnog naboja, in which each of R24, R25 and R26 independently represents methyl and Q- is an oppositely charged chlorine, bromine or iodine ion,
(C) razgranata ili nerazgranata skupina karboksilne kiseline koja ima od 3 do 6 ugljikovih atoma, (C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms,
(D) razgranata ili nerazgranata skupina fosfonske kiseline koja ima od 2 do 6 ugljikovih atoma, (D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms,
(E) razgranata ili nerazgranata skupina sulfonske kiseline koja ima od 2 do 6 ugljikovih atoma, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms,
(F) amidino skupina formule (F) amidino group of the formula
[image] [image]
u kojoj r je 2, 3, 4, 5 ili 6, i in which r is 2, 3, 4, 5 or 6, and
svaki od R27, R28 i R29 neovisno predstavlja vodikove atome, each of R27, R28 and R29 independently represents hydrogen atoms,
(G) gvanidino skupina formule (G) guanidino group of the formula
[image] [image]
u kojoj s je 2, 3, 4, 5 ili 6, i in which s is 2, 3, 4, 5 or 6, i
svaki od R30, R31, R32 i R33 neovisno predstavlja vodikove atome, ili each of R30, R31, R32 and R33 independently represents hydrogen atoms, or
(H) piperidil, u kojem je dušikov atom spomenute skupine po potrebi supstituiran s: (H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with:
(i) alkilom koji ima 1 do 3 ugljikova atoma, (i) alkyl having 1 to 3 carbon atoms,
(ii) skupinom karboksilnog estera koja ima 2 do 7 ugljikovih atoma, (ii) a carboxyl ester group having 2 to 7 carbon atoms,
(iii) skupinom karboksilne kiseline koja ima od 2 do 5 ugljikovih atoma, (iii) a carboxylic acid group that has from 2 to 5 carbon atoms,
(iv) skupinom fosfonske kiseline koja ima od 1 do 6 ugljikovih atoma, (iv) a phosphonic acid group having from 1 to 6 carbon atoms,
(v) skupinom sulfonske kiseline koja ima od 1 do 6 ugljikovih atoma; (v) a sulfonic acid group having from 1 to 6 carbon atoms;
R2 je: R2 is:
(A) vodikov atom, ili (A) hydrogen atom, or
(B) metil; (B) methyl;
R3 je skupina formule -CH2R41, u kojoj R3 is a group of the formula -CH2R41, in which
R41 je aril odabran iz razreda kojeg čine fenil, tiofenil, piridil, pirimidinil, furil, oksazolil, tiazolil, izoksazolil, izotiazolil, oksadiazolil, tiadiazolil, piridazinil i pirazinil, R41 is aryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl and pyrazinyl,
pri čemu je jedan ili više vodikovih atoma spomenute arilne skupine nužno i neovisno nadomješteno s: whereby one or more hydrogen atoms of the mentioned aryl group are necessarily and independently substituted with:
(A) R62, koji je aril odabran iz razreda kojeg čine fenil, tiofenil, piridil, pirimidinil, furil, oksazolil, tiazolil, izoksazolil, izotiazolil, oksadiazolil, tiadiazolil, piridazinil i pirazinil, (A) R 62 , which is aryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl and pyrazinyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:
(i) metilom, (i) methyl,
(ii) -COOH, (ii) -COOH,
(iii) skupinom formule -COOR63, gdje R63 predstavlja metil, (iii) the group of the formula -COOR63, where R63 represents methyl,
(iv) skupinom formule -OR68, gdje R68 predstavlja vodikov atom ili metil, ili (iv) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, or
(v) halogenim, (v) halogen,
(B) metilom, koji može biti mono- ili polisupstituiran s atomima fluora ili koji može biti monosupstituiran s R62, (B) methyl, which can be mono- or polysubstituted with fluorine atoms or which can be monosubstituted with R62,
(C) razgranatom ili nerazgranatom alkilnom skupinom koja ima od 2 do 6 ugljikovih atoma ili cikloalkilnom skupinom koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s halogenim ili okso, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with halogen or oxo,
(D) skupinom formule -COOR73, gdje R73 predstavlja metil, (D) a group of the formula -COOR73, where R73 represents methyl,
(E) skupinom formule -CONR76R77, gdje svaki od R76 i R77 predstavlja metil, i u kojoj jedan od R76 i R77 može dodatno biti skupina R62, (E) a group of the formula -CONR76R77, where each of R76 and R77 represents methyl, and in which one of R76 and R77 can additionally be a group R62,
(F) skupinom formule -COR78, gdje R78 predstavlja vodikov atom, metil ili R62, (F) a group of the formula -COR78, where R78 represents a hydrogen atom, methyl or R62,
(G) skupinom formule -OR79, gdje R79 predstavlja vodikov atom, metil ili R62, (G) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl or R62,
(H) cijano, (H) cyano,
(I) nitro, ili (I) nitro, or
(J) halogenim, (J) halogen,
R4 je Cl ili trifluormetil; R 4 is Cl or trifluoromethyl;
R5 je vodikov atom; i R5 is a hydrogen atom; and
R6 je Cl ili trifluormetil; R 6 is Cl or trifluoromethyl;
ili njihove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.
Također, još prednosniji su novi spojevi formule I u kojoj: Also, new compounds of formula I in which:
Y je atom kisika; Y is an oxygen atom;
Z je atom kisika; Z is an oxygen atom;
X je dvovalentna skupina formule >CHR1 ili >NR1, gdje X is a divalent group of the formula >CHR1 or >NR1, where
R1 je: R1 is:
(A) atom vodika, (A) hydrogen atom,
(B) razgranata ili nerazgranata alkilna skupina koja ima od 1 do 6 ugljikovih atoma ili cikloalkilna skupina koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s: (B) a branched or unbranched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group may be mono- or polysubstituted with:
(i) okso, (i) oxo,
(ii) arilom odabranim iz razreda kojeg čine fenil ili piridil, (ii) aryl selected from the class consisting of phenyl or pyridyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:
(a) alkilom koji ima 1 do 3 ugljikova atoma, (a) alkyl having 1 to 3 carbon atoms,
(b) -COOH, (b) -COOH,
(c) -SO2OH, (c) -SO2OH,
(d) -PO(OH)2, (d) -PO(OH)2,
(e) skupinom formule -OR12a, gdje R12a predstavlja vodikov atom ili metil, (e) a group of the formula -OR12a, where R12a represents a hydrogen atom or methyl,
(f) amidino skupinom formule (f) amidino group of the formula
[image] [image]
u kojoj svaki od R13, R14 i R15 neovisno predstavlja vodikove atome, in which each of R13, R14 and R15 independently represents hydrogen atoms,
(iii) skupinom formule -OR19, gdje R19 predstavlja vodikov atom,ili (iii) a group of the formula -OR19, where R19 represents a hydrogen atom, or
(iv) alkilnu ili acilnu skupinu koji ima od 1 do 7 ugljikovih atoma, ili (iv) an alkyl or acyl group having from 1 to 7 carbon atoms, or
(v) kvaternom skupinom formule (v) quaternary group of the formula
[image] [image]
u kojoj svaki od R24, R25 i R26 neovisno predstavlja metil i Q- je ion klora, broma ili joda suprotnog naboja, in which each of R24, R25 and R26 independently represents methyl and Q- is an oppositely charged chlorine, bromine or iodine ion,
(C) razgranata ili nerazgranata skupina karboksilne kiseline koja ima od 3 do 6 ugljikovih atoma, (C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms,
(D) razgranatu ili nerazgranatu skupinu fosfonske kiseline koja ima od 2 do 6 ugljikovih atoma, (D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms,
(E) razgranata ili nerazgranata skupina sulfonske kiseline koja ima od 2 do 6 ugljikovih atoma, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms,
(F) amidino skupina formule (F) amidino group of the formula
[image] [image]
u kojoj r je 2, 3, 4, 5 ili 6, i in which r is 2, 3, 4, 5 or 6, and
svaki od R27, R28 i R29 neovisno predstavlja vodikove atome, each of R27, R28 and R29 independently represents hydrogen atoms,
(G) gvanidino skupina formule (G) guanidino group of the formula
[image] [image]
u kojoj s je 2, 3, 4, 5 ili 6, where s is 2, 3, 4, 5 or 6,
svaki od R30, R31, R32 i R33 neovisno predstavlja vodikove atome, ili each of R30, R31, R32 and R33 independently represents hydrogen atoms, or
(H) piperidil, u kojem je dušikov atom spomenute skupine po potrebi supstituiran s: (H) piperidyl, in which the nitrogen atom of the mentioned group is optionally substituted with:
(i) alkilom koji ima 1 do 3 ugljikova atoma, (i) alkyl having 1 to 3 carbon atoms,
(ii) skupinom karboksilnog estera koja ima 2 do 7 ugljikovih atoma, (ii) a carboxyl ester group having 2 to 7 carbon atoms,
(iii) skupinom karboksilne kiseline koja ima od 2 do 5 ugljikovih atoma, (iii) a carboxylic acid group that has from 2 to 5 carbon atoms,
(iv) skupinom fosfonske kiseline koja ima od 1 do 6 ugljikovih atoma, ili (iv) a phosphonic acid group having from 1 to 6 carbon atoms, or
(v) skupinom sulfonske kiseline koja ima od 1 do 6 ugljikovih atoma; (v) a sulfonic acid group having from 1 to 6 carbon atoms;
R2 je: R2 is:
(A) vodikov atom, ili (A) hydrogen atom, or
(B) metil; (B) methyl;
R3 je skupina formule -CH2R41, u kojoj R3 is a group of the formula -CH2R41, in which
R41 je aril odabran iz razreda kojeg čine fenil ili piridil, R41 is aryl selected from the class consisting of phenyl or pyridyl,
pri čemu je jedan ili više vodikovih atoma spomenute arilne skupine nužno i neovisno nadomješteno s: whereby one or more hydrogen atoms of the mentioned aryl group are necessarily and independently substituted with:
(A) R62, koji je aril odabran iz razreda kojeg čine fenil, ili piridil, (A) R62, which is aryl selected from the group consisting of phenyl, or pyridyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:
(i) metilom, (i) methyl,
(ii) -COOH, (ii) -COOH,
(iii) skupinom formule -COOR63, gdje R63 predstavlja metil, (iii) the group of the formula -COOR63, where R63 represents methyl,
(iv) skupinom formule -OR68, gdje R68 predstavlja vodikov atom ili metil, ili (iv) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, or
(vi) halogenim, (vi) halogen,
(B) metilom, koji može biti mono- ili polisupstituiran s atomima fluora ili koji dodatno može biti monosupstituiran s R62, (B) methyl, which can be mono- or polysubstituted with fluorine atoms or which can additionally be monosubstituted with R62,
(C) razgranatom ili nerazgranatom alkilnom skupinom koja ima od 2 do 6 ugljikovih atoma ili cikloalkilnom skupinom koja ima od 3 do 6 ugljikovih atoma, koja alkilna ili cikloalkilna skupina može biti mono- ili polisupstituirana s fluorom ili s okso, (C) a branched or unbranched alkyl group having from 2 to 6 carbon atoms or a cycloalkyl group having from 3 to 6 carbon atoms, which alkyl or cycloalkyl group can be mono- or polysubstituted with fluorine or with oxo,
(D) skupinom formule -COOR73, gdje R73 predstavlja metil, (D) a group of the formula -COOR73, where R73 represents methyl,
(E) skupinom formule -CONR76R77, gdje svaki od R76 i R77 predstavlja metil, u kojoj jedan od R76 i R77 je metil, a drugi je skupina R62, (E) a group of the formula -CONR76R77, where each of R76 and R77 represents methyl, in which one of R76 and R77 is methyl and the other is the group R62,
(F) skupinom formule -COR78, gdje R78 predstavlja vodikov atom, metil ili R62, (F) a group of the formula -COR78, where R78 represents a hydrogen atom, methyl or R62,
(G) skupinom formule -OR79, gdje R79 predstavlja vodikov atom, metil ili R62, (G) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl or R62,
(K) cijano, (K) cyano,
(L) nitro, ili (L) nitro, or
(M) halogen; (M) halogen;
R4 je atom klora ili trifluormetil; R4 is a chlorine atom or trifluoromethyl;
R5 je vodikov atom; i R5 is a hydrogen atom; and
R6 je atom klora ili trifluormetil; R 6 is a chlorine atom or trifluoromethyl;
ili njihove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.
Posebno prednosni novi spojevi formule I su oni u kojima: Especially preferred new compounds of formula I are those in which:
Y je atom kisika; Y is an oxygen atom;
Z je atom kisika; Z is an oxygen atom;
X je dvovalentna skupina formule >CHR1 ili >NR1, gdje X is a divalent group of the formula >CHR1 or >NR1, where
R1 je: R1 is:
(A) atom vodika, (A) hydrogen atom,
(B) alkil koji ima od 1 do 2 ugljikova atoma koji može biti monosupstituiran s: (B) alkyl having from 1 to 2 carbon atoms which may be monosubstituted with:
(i) okso, (i) oxo,
(ii) arilom odabranim iz razreda kojeg čine fenil ili piridil, (ii) aryl selected from the class consisting of phenyl or pyridyl,
pri čemu jedan vodikov atom spomenute arilne skupine može biti po potrebi nadomješten s: where one hydrogen atom of the mentioned aryl group can be replaced by:
(a) alkilom koji ima 1 do 3 ugljikova atoma, (a) alkyl having 1 to 3 carbon atoms,
(b) -COOH, (b) -COOH,
(c) -SO2OH, (c) -SO2OH,
(d) -PO(OH)2, (d) -PO(OH)2,
(e) skupinom formule -OR12a, gdje R12a predstavlja vodikov atom ili metil, ili (e) a group of the formula -OR12a, where R12a represents a hydrogen atom or methyl, or
(f) amidino skupinom formule (f) amidino group of the formula
[image] [image]
u kojoj svaki od R13, R14 i R15 predstavlja vodikove atome, ili wherein each of R13, R14 and R15 represents hydrogen atoms, or
(iii) skupinom formule -OR19, gdje R19 predstavlja vodikov atom ili metil, (iii) a group of the formula -OR19, where R19 represents a hydrogen atom or methyl,
(C) razgranata ili nerazgranata skupina karboksilne kiseline koja ima od 3 do 6 ugljikovih atoma, (C) branched or unbranched carboxylic acid group having from 3 to 6 carbon atoms,
(D) razgranata ili nerazgranata skupina fosfonske kiseline koja ima od 2 do 6 ugljikovih atoma, (D) branched or unbranched phosphonic acid group having from 2 to 6 carbon atoms,
(E) razgranata ili nerazgranata skupina sulfonske kiseline koja ima od 2 do 6 ugljikovih atoma, (E) a branched or unbranched sulfonic acid group having from 2 to 6 carbon atoms,
(F) amidino skupina formule (F) amidino group of the formula
[image] [image]
u kojoj r je 2, 3, 4, 5 ili 6, i in which r is 2, 3, 4, 5 or 6, and
svaki od R27, R28 i R29 predstavlja vodikove atome, ili each of R27, R28 and R29 represents hydrogen atoms, or
(G) gvanidino skupina formule (G) guanidino group of the formula
[image] [image]
u kojoj s je 2, 3, 4, 5 ili 6, where s is 2, 3, 4, 5 or 6,
svaki od R30, R31, R32 i R33 neovisno predstavlja vodikove atome, each of R30, R31, R32 and R33 independently represents hydrogen atoms,
R2 je: R2 is:
(A) vodikov atom, ili (A) hydrogen atom, or
(B) metil; (B) methyl;
R3 je skupina formule -CH2R41, u kojoj R3 is a group of the formula -CH2R41, in which
R41 je fenil, R41 is phenyl,
pri čemu je jedan ili više vodikovih atoma spomenute fenilne skupine nužno i neovisno nadomješteno s: whereby one or more hydrogen atoms of the mentioned phenyl group are necessarily and independently replaced by:
(A) R62, koji je aril odabran iz razreda kojeg čine fenil ili, piridil, (A) R 62 , which is aryl selected from the group consisting of phenyl or, pyridyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:
(i) metilom, (i) methyl,
(ii) skupinom formule -COOR63, gdje R63 predstavlja metil, (ii) a group of the formula -COOR63, where R63 represents methyl,
(iii) skupinom formule -OR68, gdje R68 predstavlja vodikov atom ili metil, ili (iii) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, or
(iv) halogenim, (iv) halogen,
(B) metilom, koji može biti mono- ili polisupstituiran s atomima fluora ili koji može biti monosupstituiran s R62, (B) methyl, which can be mono- or polysubstituted with fluorine atoms or which can be monosubstituted with R62,
(C) skupinom formule -COOR73, gdje R73 predstavlja metil, (C) a group of the formula -COOR73, where R73 represents methyl,
(D) skupinom formule -COR78, gdje R78 predstavlja metil ili R62, (D) a group of the formula -COR78, where R78 represents methyl or R62,
(E) skupinom formule -OR79, gdje R79 predstavlja vodikov atom, metil, ili R62, (E) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl, or R62,
(F) cijano, (F) cyano,
(G) nitro, ili (G) nitro, or
(H) halogenim, (H) halogen,
R4 je atom klora ili trifluormetil; R4 is a chlorine atom or trifluoromethyl;
R5 je vodikov atom; i R5 is a hydrogen atom; and
R6 je atom klora ili trifluormetil; R 6 is a chlorine atom or trifluoromethyl;
ili njihove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.
Ipak još posebniji prednosni novi spojevi formule I su oni u kojima: However, even more special preferred novel compounds of formula I are those in which:
Y je atom kisika; Y is an oxygen atom;
Z je atom kisika; Z is an oxygen atom;
X je dvovalentna skupina formule >NR1, gdje X is a divalent group of the formula >NR1, where
R1 je: R1 is:
(A) atom vodika, (A) hydrogen atom,
(B) metil ili etil, ili (B) methyl or ethyl, or
(C) -COCH3; (C) -COCH3;
R2 je: R2 is:
(A) vodikov atom, ili (A) hydrogen atom, or
(B) metil; (B) methyl;
R3 je skupina formule -CH2R41, u kojoj R3 is a group of the formula -CH2R41, in which
R41 je fenil, R41 is phenyl,
pri čemu je jedan ili više vodikovih atoma spomenute fenilne skupine nužno i neovisno nadomješteno s: whereby one or more hydrogen atoms of the mentioned phenyl group are necessarily and independently replaced by:
(A) R62, koji je aril odabran iz razreda kojeg čine fenil, ili piridil, (A) R62, which is aryl selected from the group consisting of phenyl, or pyridyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:
(i) metilom, (i) methyl,
(ii) skupinom formule -COOR63, gdje R63 predstavlja metil, (ii) a group of the formula -COOR63, where R63 represents methyl,
(iii) skupinom formule -OR68, gdje R68 predstavlja vodikov atom ili metil, ili (iii) a group of the formula -OR68, where R68 represents a hydrogen atom or methyl, or
(vi) halogenim, (vi) halogen,
(B) metilom, koji može biti mono- ili polisupstituiran s atomima fluora ili koji može biti monosupstituiran s R62, (B) methyl, which can be mono- or polysubstituted with fluorine atoms or which can be monosubstituted with R62,
(C) skupinom formule -COOR73, gdje R73 predstavlja metil, (C) a group of the formula -COOR73, where R73 represents methyl,
(D) skupinom formule -COR78, gdje R78 predstavlja metil ili R62, (D) a group of the formula -COR78, where R78 represents methyl or R62,
(E) skupinom formule -OR79, gdje R79 predstavlja vodikov atom, metil, ili R62, (E) a group of the formula -OR79, where R79 represents a hydrogen atom, methyl, or R62,
(F) cijano, (F) cyano,
(G) nitro, ili (G) nitro, or
(H) halogenim, (H) halogen,
R4 je atom klora ili trifluormetil; R4 is a chlorine atom or trifluoromethyl;
R5 je vodikov atom; i R5 is a hydrogen atom; and
R6 je atom klora ili trifluormetil; R 6 is a chlorine atom or trifluoromethyl;
ili njihove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.
Preposljednji prednosni novi spojevi fomule I su oni u kojima: The penultimate preferred novel compounds of formula I are those in which:
Y je atom kisika; Y is an oxygen atom;
Z je atom kisika; Z is an oxygen atom;
X je dvovalentna skupina formule >NR1, gdje X is a divalent group of the formula >NR1, where
R1 je: R1 is:
(A) atom vodika, (A) hydrogen atom,
(B) metil ili etil, ili (B) methyl or ethyl, or
(C) -COCH3; (C) -COCH3;
R2 je: R2 is:
(A) vodikov atom, ili (A) hydrogen atom, or
(B) metil; (B) methyl;
R3 je skupina formule -CH2R41, u kojoj R3 is a group of the formula -CH2R41, in which
R41 je fenil, R41 is phenyl,
pri čemu je jedan ili više vodikovih atoma spomenute fenilne skupine nužno i neovisno nadomješteno s: whereby one or more hydrogen atoms of the mentioned phenyl group are necessarily and independently replaced by:
(A) R62, koji je aril odabran iz razreda kojeg čine fenil, ili piridil, (A) R62, which is aryl selected from the group consisting of phenyl, or pyridyl,
pri čemu jedan ili više vodikovih atoma spomenute arilne skupine može biti po potrebi i neovisno nadomješteno s: where one or more hydrogen atoms of the mentioned aryl group can be independently replaced with:
(i) metilom, (i) methyl,
(ii) halogenim, (ii) halogen,
(B) metilom, koji može biti mono- ili polisupstituiran s atomima fluora, (B) methyl, which can be mono- or polysubstituted with fluorine atoms,
(C) skupinom formule -COR78, gdje R78 predstavlja metil, ili R62, (C) a group of the formula -COR78, where R78 represents methyl, or R62,
(D) halogenim, (D) halogen,
R4 je atom klora; R4 is a chlorine atom;
R5 je vodikov atom; i R5 is a hydrogen atom; and
R6 je atom klora; R 6 is a chlorine atom;
ili njihove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.
Konačno, prednosni novi spojevi formule I su posebno spojevi koji imaju slijedeće strukture: Finally, preferred new compounds of formula I are especially compounds having the following structures:
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ili njihove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.
Sinteza spojeva izuma Synthesis of the compounds of the invention
Sinteza spojeva koji su slični spojevima izuma je dobro poznata prema stanju tehnike. Ovisno o svrsi, neki putevi mogu biti bolji za dobivanje malih količina različitih spojeva, dok drugi putevi mogu biti mnogo prikladniji za sintezu velike količine određenog spoja. U nastavku je prikazano nekoliko puteva do tih spojeva i primjeri spojeva koji su bili sintetizirani dotičnim putevima. The synthesis of compounds similar to the compounds of the invention is well known in the art. Depending on the purpose, some routes may be better for obtaining small amounts of different compounds, while other routes may be much more suitable for synthesizing a large amount of a particular compound. Several routes to these compounds and examples of compounds that were synthesized by the respective routes are presented below.
Polazne amino kiseline i njihovi derivati potrebni za sintezu hidantiona i struktura tio-hidantoina komercijalno su dostupne ili se mogu proizvesti očiglednim modifikacijama postupaka poznatih iz literature (vidi npr. Williams, R.W. Synthesis of Optically Active α-Amino Acids; Pergamon: Oxford, 1989, α-Amino Acid Synthesis; O’Donnell, M.J., Ed.; Tetrahedron Symposium, u tisku; Pergamon: London, 1988: Vol. 44, 17. izdanje, Jung, M.J. Chemistry and Biochemistry od Amio Acids; Barrett, G. C., Ed.; Chapman i Hall: New York, 1985; str. 227 i Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61: 7398-7401). Kao primjer data je sinteza i rastavljanje etil 2-amino-2-(4-brombenzil)-propanoata (polazni materijal za primjer 39). The starting amino acids and their derivatives required for the synthesis of hydanthion and thio-hydantoin structures are commercially available or can be produced by obvious modifications of procedures known from the literature (see, for example, Williams, R.W. Synthesis of Optically Active α-Amino Acids; Pergamon: Oxford, 1989, α-Amino Acid Synthesis; O'Donnell, M.J., Ed.; Tetrahedron Symposium, in press; Pergamon: London, 1988: Vol. 44, 17th ed., Jung, M.J. Chemistry and Biochemistry of Amio Acids; Barrett, G. C., Ed. .; Chapman and Hall: New York, 1985; p. 227 and Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61: 7398-7401). As an example, the synthesis and decomposition of ethyl 2-amino-2-(4-bromobenzyl)-propanoate (starting material for example 39) is given.
Otopinu alanin etil ester hidroklorida (15,3 g, 99,3 mmola) u 60 ml vode miješa se 30 minuta pri sobnoj temperaturi s trietilaminom (14,6 ml, 104,8 mmola). Zatim se smjesu ekstrahira dva puta sa 100 ml metilen klorida. Organski slojevi se sjedine, osuše preko natrijevog sulfata i zgusnu u vakuumu, čime se dobije 10,0 slobodne baze amino estera (iskorištenje 86%). Ostatak se ponovno otopi u metilen kloridu i ohladi u ledenoj kupelji. Doda se magnezijev sulfat (11,3 g, 93,9 mmola) i zatim se doda trimetil acetaldehid (9,3 ml, 85,6 mmolova). Ledenu kupelj se odstrani i smjesu se miješa preko noći. Magnezijev sulfat se odstrani filtracijom i filtrat se zgusne u vakuumu, čime se dobije 11,8 g iminskog intermedijata (iskorištenje 74,6%). A solution of alanine ethyl ester hydrochloride (15.3 g, 99.3 mmol) in 60 ml of water was stirred for 30 minutes at room temperature with triethylamine (14.6 ml, 104.8 mmol). The mixture is then extracted twice with 100 ml of methylene chloride. The organic layers are combined, dried over sodium sulfate and concentrated in vacuo to give 10.0% free amino ester base (86% yield). The residue is redissolved in methylene chloride and cooled in an ice bath. Magnesium sulfate (11.3 g, 93.9 mmol) was added followed by trimethyl acetaldehyde (9.3 mL, 85.6 mmol). The ice bath was removed and the mixture was stirred overnight. The magnesium sulfate is removed by filtration and the filtrate is concentrated in vacuo to give 11.8 g of the imine intermediate (74.6% yield).
Gornji imin (11,8 g, 63,7 mmola) otopi se u toluenu (90 ml), doda se 4-brombenzil bromid (17,5 g, 70,1 mmolova) i reakcijsku smjesu se ohladi na pribl. -10oC. Doda se kalijev terc.butoksid (8,6 g, 76,5 mmolova) takovom brzinom da temperatura ne prijeđe 0oC. Reakcijsku smjesu se miješa u hladnoj kupelji dva sata, zatim se razrijedi s eterom i ispere s vodom (150 ml). Organski sloj se osuši (natrijev sulfat), profiltrira i zgusne u vakuumu čime se dobije bistro žuto ulje. To se pomiješa s 1N HCl (100 ml, 100 mmolova) i miješa se preko noći. Reakcijsku smjesu se ekstrahira s etil acetatom (100 ml) i iz vodenog sloja dobije se 14,1 g racemičnog amino ester hidroklorida (iskorištenje 68,7%). The above imine (11.8 g, 63.7 mmol) was dissolved in toluene (90 mL), 4-bromobenzyl bromide (17.5 g, 70.1 mmol) was added and the reaction mixture was cooled to approx. -10oC. Potassium tert.butoxide (8.6 g, 76.5 mmol) is added at such a rate that the temperature does not exceed 0°C. The reaction mixture was stirred in a cold bath for two hours, then diluted with ether and washed with water (150 ml). The organic layer is dried (sodium sulfate), filtered and concentrated in vacuo to give a clear yellow oil. This was mixed with 1N HCl (100 mL, 100 mmol) and stirred overnight. The reaction mixture was extracted with ethyl acetate (100 ml) and 14.1 g of racemic amino ester hydrochloride was obtained from the aqueous layer (yield 68.7%).
Racemični spojevi se mogu rastaviti na njihove sastavne enantiomere brojnim poznatim postupcima. Etil 2-(R)-amino-2-(4-brombenzil)-propanoat (polazni materijal za primjer 29) proizveden je iz racemičnog etil 2-amino-2-(4-brombenzil)-propanoata slijedećim postupkom. K 1,3 l pufera pripravljenog od 13,69 g KH2PO4 i 2 l vode doda se 20 g komercijalno dostupnog enzima lipaze L10 (Amano Enzyme USA Co., Ltd, Lombardi, IL) i zatim 12 g HCl soli racemičnog amino estera. pH se promatra i dodaje se 1N KOH koliko je potrebno da se pH smjese održi pri 6,4. Tijek reakcije promatra se pomoću HPLC reverznih faza i nakon 2 dana HPLC analiza pokazuje da je 50,4% polaznog materijala hidroliziralo. U tom trenutku doda se dovoljno krutog NaHCO3 i pH se nasmjesti na 8,1 i smjesu se ekstrahira dva puta s toluenom, eterom i EtOAc. Sjedinjeni organski slojevi se osuše i zgusnu i sirov proizvod se očisti kromatografijom na silika gelu (EtOAc:heksan) čime se dobije 5,21 g (87%) etil 2-(R)-amino-2-(4-brombenzil)-propanoata. Racemic compounds can be separated into their component enantiomers by a number of known methods. Ethyl 2-(R)-amino-2-(4-bromobenzyl)-propanoate (starting material for Example 29) was prepared from racemic ethyl 2-amino-2-(4-bromobenzyl)-propanoate by the following procedure. To 1.3 L of buffer prepared from 13.69 g of KH 2 PO 4 and 2 L of water was added 20 g of commercially available enzyme lipase L10 (Amano Enzyme USA Co., Ltd, Lombardi, IL) followed by 12 g of the HCl salt of the racemic amino ester. The pH is observed and 1N KOH is added as needed to maintain the pH of the mixture at 6.4. The course of the reaction is monitored using reverse phase HPLC and after 2 days HPLC analysis shows that 50.4% of the starting material has hydrolyzed. At this point, sufficient solid NaHCO 3 is added and the pH is adjusted to 8.1 and the mixture is extracted twice with toluene, ether and EtOAc. The combined organic layers were dried and concentrated and the crude product was purified by chromatography on silica gel (EtOAc:hexane) to give 5.21 g (87%) of ethyl 2-(R)-amino-2-(4-bromobenzyl)-propanoate .
Metoda A. Method A.
Polazni materijal amino kiselina i fenilizocijanat. Starting material amino acid and phenylisocyanate.
Ciklizacija s kiselinom. Cyclization with acid.
Odovarajuću amino kiselinu se otopi u vodenoj bazi (kao što je, na primjer, NaOH, KOH, Na2CO3, NaHCO3, K2CO3 ili KHCO3) i zagrije se na temperaturu između 20 i 90oC. U smjesu se doda odgovarajući izocijanat i dobivenu otopinu se miješa uglavnom do završetka reakcije. Kad se ohladi, smjesu se zakiseli i dobivenu ureido-octenu kiselinnu se izolira filtracijom ili ekstrakcijom u organsko otapalo. Odstranjivanjem otapala dobije se intermedijat ureido-octena kiselina. Na način koji je opisao Sauli (US patent 4,099,008) intermedijarnu ureido-octenu kiselinu se ciklizira grijanjem u prisutnosti katalitičke količine kiseline (kao što je, na primjer, sumporna kiselina, metan-sulfonska kiselina, benzensulfonska kiselina ili solna kiselina) u organskom ili vodenom otapalu, čime se dobije željeni hidantoin. Obrada se sastoji u skupljanju hidantoina filtracijom i čišćenja, na primjer, kromatografijom na silika gelu ili prekristalizacijom. The releasing amino acid is dissolved in an aqueous base (such as, for example, NaOH, KOH, Na2CO3, NaHCO3, K2CO3 or KHCO3) and heated to a temperature between 20 and 90oC. The appropriate isocyanate is added to the mixture and the resulting solution is stirred mostly until the reaction is complete. When cooled, the mixture is acidified and the resulting ureido-acetic acid is isolated by filtration or extraction into an organic solvent. By removing the solvent, the ureido-acetic acid intermediate is obtained. In the manner described by Sauli (US Patent 4,099,008) the ureido-acetic acid intermediate is cyclized by heating in the presence of a catalytic amount of acid (such as, for example, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, or hydrochloric acid) in organic or aqueous solvent, which gives the desired hydantoin. The processing consists in the collection of hydantoin by filtration and purification, for example, by silica gel chromatography or recrystallization.
Spojevi navedeni u tablici 1 proizvedeni su ovom općom metodom. The compounds listed in Table 1 were produced by this general method.
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Metoda A ilustrirana je sintezom spoja iz primjera 12 (vidi tablicu 1), koja je bila provedena kako slijedi. Homofenilalanin (1,00 g, 5,58 mmolova) otopi se u otopini NaOH (0,28 g, 6,69 mmolova) u vodi (10,0 ml) i grije se pri 45oC. Kad otopina postane homogena doda se 3,5-diklorfenil izocijanat (1,05 g, 5,58 mmolova) i smjesu se grije još 2 sata pri 45oC. Reakcijsku smjesu se ohladi i zatim se zakiseli s koncentriranom HCl na pH 2-3. Talog se skupi filtracijom, ispere s vodom i osuši u vakuumu pri 50oC, čime se dobije 0,85 g intermedijarne ureido-octene kiseline (sirovo iskorištenje 42%). Zatim se intermedijat preuzme u otopinu koncentrirane HCl (5,0 ml) i vode (5,0 ml) i grije se 5 sati pod refluksom. Reakcijsku smjesu se ohladi na sobnu temperaturu i bijelu krutu tvar se skupi filtracijom s odsisavanjem, ispere s vodom i osuši u vakuumu pri 50oC, čime se dobije 0,52 g sirovog hidantoina. Taj se materijal očisti prekristalizacijom iz EtOH čime se dobije 0,37 g (45%) spoja iz primjera 12. Method A is illustrated by the synthesis of the compound of Example 12 (see Table 1), which was carried out as follows. Homophenylalanine (1.00 g, 5.58 mmol) was dissolved in a solution of NaOH (0.28 g, 6.69 mmol) in water (10.0 ml) and heated at 45°C. When the solution becomes homogeneous, 3,5-dichlorophenyl isocyanate (1.05 g, 5.58 mmol) is added and the mixture is heated for another 2 hours at 45oC. The reaction mixture was cooled and then acidified with concentrated HCl to pH 2-3. The precipitate is collected by filtration, washed with water and dried in a vacuum at 50oC, which gives 0.85 g of intermediate ureido-acetic acid (crude yield 42%). The intermediate is then taken up in a solution of concentrated HCl (5.0 ml) and water (5.0 ml) and heated under reflux for 5 hours. The reaction mixture was cooled to room temperature and the white solid was collected by suction filtration, washed with water and dried in vacuo at 50°C, yielding 0.52 g of crude hydantoin. This material was purified by recrystallization from EtOH to give 0.37 g (45%) of the compound from Example 12.
Metoda B. Method B.
Polazni materijali amino kiselina i fenilizocijanat. Starting materials amino acid and phenylisocyanate.
Ciklizacija s EDC. Cyclization with EDC.
Odovarajuću amino kiselinu otopi se u vodenoj bazi (kao što je na primjer NaOH, KOH, Na2CO3, NaHCO3, K2CO3 ili KHCO3) i zagrije se na temperaturu između 20 i 90oC. U tu smjesu se doda odgovarajući izocijanat i dobivenu otopinu se miješa uglavnom do završetka reakcije. Kad se ohladi smjesu se zakiseli i dobivenu ureido-octenu kiselinnu se izolira filtracijom ili ekstrakcijom u organsko otapalo. Odstranjivanjem otapala dobije se intermedijat ureido-octena kiselina. Zatim se intermedijarnu ureido-octenu kiselinu se ciklizira u željeni hidantoin u organskom otapalu (kao što je na primjer DMF, NMP ili THF) upotrebom bilo kojeg od brojnih sredstava za dehidrataciju (kao što je, na primjer, dicikloheksilkarbodiimid (DCC) ili 1-(3-dimetilaminopropil)-3-etilkarbodiimid HCl (EDC) u prisutnosti sredstva za aktivaciju estera (kao što je 1-hidroksibenzotriazol hidrat (HOBT) i ne-nukleofilne baze (kao što je, na primjer, trietilamin ili N,N-diizopropil-etilamin). Obrada se sastoji u ekstrakciji u organsko otapalo i zatim čišćenja, na primjer, kromatografijom na silika gelu ili prekristalizacijom. The releasing amino acid is dissolved in an aqueous base (such as NaOH, KOH, Na2CO3, NaHCO3, K2CO3 or KHCO3) and heated to a temperature between 20 and 90oC. The appropriate isocyanate is added to this mixture and the resulting solution is stirred mostly until the reaction is complete. When it cools, the mixture is acidified and the resulting ureido-acetic acid is isolated by filtration or extraction into an organic solvent. By removing the solvent, the ureido-acetic acid intermediate is obtained. The ureido-acetic acid intermediate is then cyclized to the desired hydantoin in an organic solvent (such as, for example, DMF, NMP, or THF) using any of a number of dehydrating agents (such as, for example, dicyclohexylcarbodiimide (DCC) or 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDC) in the presence of an ester activating agent (such as 1-hydroxybenzotriazole hydrate (HOBT)) and a non-nucleophilic base (such as, for example, triethylamine or N,N-diisopropyl -ethylamine).The treatment consists in extraction into an organic solvent and then purification, for example, by silica gel chromatography or recrystallization.
Spojevi navedeni u tablici 2 proizvedeni su ovom općom metodom. The compounds listed in Table 2 were produced by this general method.
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Metoda B ilustrirana je sintezom spoja iz primjera 15 (vidi tablicu 2), koja je bila provedena kako slijedi. K otopini (R)-fenilalanina (0,33 g, 2 mmola) u 1 l 2N otopine NaOH i 10 ml vode pri 50oC doda se 3,5-diklorfenil izocijanat (0,38 g, 2 mmola). Dobivenu smjesu se zatim miješa još 1 sat. Otopinu se ohladi i pomiješa s koncentriranom HCl dok se dobije talog i otopina ostane kisela. Talog se skupi filtracijom i osuši u vakuumu čime se dobije željenu ureidooctenu kiselinu (0,60 g, 85%). Ureidooctenu kiselinu (0,35 g, 1 mmol) se otopi u 20 ml DMF-a i miješa se 1 sat pri sobnoj temperaturi s EDC (0,19 g, 1 mmol) i HOBT (0,14 g, 1 mmol). Po isteku tog perioda doda se N,N-diizopropiletilamin (0,35 ml, 2 mmola) i smjesu se miješa preko noći. Obrada se sastoji od trituriranja s vodom, skupljanja hidantoina filtracijom i čišćenja kromatografijom na sillika gelu. Iskorištenje u ovom primjeru bilo je 0,20 g (60%). Method B is illustrated by the synthesis of the compound of Example 15 (see Table 2), which was carried out as follows. 3,5-dichlorophenyl isocyanate (0.38 g, 2 mmol) is added to a solution of (R)-phenylalanine (0.33 g, 2 mmol) in 1 l of 2N NaOH solution and 10 ml of water at 50°C. The resulting mixture is then stirred for another 1 hour. The solution is cooled and mixed with concentrated HCl until a precipitate is obtained and the solution remains acidic. The precipitate was collected by filtration and dried in vacuo to give the desired ureidoacetic acid (0.60 g, 85%). Ureidoacetic acid (0.35 g, 1 mmol) was dissolved in 20 ml of DMF and stirred for 1 hour at room temperature with EDC (0.19 g, 1 mmol) and HOBT (0.14 g, 1 mmol). After this period, N,N-diisopropylethylamine (0.35 ml, 2 mmol) was added and the mixture was stirred overnight. Processing consists of trituration with water, collection of hydantoins by filtration and purification by silica gel chromatography. The yield in this example was 0.20 g (60%).
Metoda C. Method C.
Polazni materijali amino ester ili hidroksi ester i fenilizocijanat. Ciklizacija s bazom ili kiselinom. Starting materials amino ester or hydroxy ester and phenylisocyanate. Cyclization with base or acid.
Odovarajući amino ester i odgovarajući izocijanat se otope u organskom otapalu (kao što je, na primjer, DMF, THF ili DMSO) u prisutnosti baze (kao što je, na primjer, NaOH, KOH, Na2CO3, NaHCO3, K2CO3 ili KHCO3) i grije se pri temperaturi između sobne temperature i 60oC. Nakon 1 sata temperaturu reakcijske smjese se povisi na između 50 i 100oC dok se vidi da je reakcije gotova. Otopinu se zatim ohladi i razrijedi s organskim otapalom (kao što je, na primjer, EtOAc ili CH2Cl2). Organsku fazu se zatim ispere uzastopce s razrijeđenom vodenom kiselinom (npr. 1N HCl) i vodom, osuši (npr. preko MgSO4) i zgusne. Željeni hidantoin se očisti, na primjer, kromatografijom na silika gelu ili prekristalizacijom. (Alternativno, ureido-octeni ester se može ciklizirati u hidantoin grijanjem pri temperaturi između pribl. 50 i 100oC u prisutnosti kiseline kao što je, na primjer, vodena HCl dok se vidi da je reakcija gotova). The releasing amino ester and the corresponding isocyanate are dissolved in an organic solvent (such as, for example, DMF, THF, or DMSO) in the presence of a base (such as, for example, NaOH, KOH, Na2CO3, NaHCO3, K2CO3, or KHCO3) and heated at a temperature between room temperature and 60oC. After 1 hour, the temperature of the reaction mixture is raised to between 50 and 100oC until it is seen that the reaction is complete. The solution is then cooled and diluted with an organic solvent (such as, for example, EtOAc or CH 2 Cl 2 ). The organic phase is then washed successively with dilute aqueous acid (eg 1N HCl) and water, dried (eg over MgSO4) and concentrated. The desired hydantoin is purified, for example, by silica gel chromatography or recrystallization. (Alternatively, the ureido-acetic ester can be cyclized to hydantoin by heating at a temperature between about 50 and 100oC in the presence of an acid such as, for example, aqueous HCl while observing that the reaction is complete).
Spojevi navedeni u tablici 3 proizvedeni su ovom općom metodom. The compounds listed in Table 3 were produced by this general method.
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Metoda C ilustrirana je sintezom spoja iz primjera 30 u tablici 3, koja je bila provedena kako slijedi. Metil 2-amino-2-benzilmaslačna kiselina (0,21 g, 1 mmol) i 3,5-diklorfenil izocijanat (0,19 g, 1 mmol) otope se u DMSO (5 ml) u prisutnosti približno 0,2 g Na2CO3 i puste se miješati 1 sat pri 50oC. Po isteku tog perioda otopinu se grije 2 sata pri 90oC. Zatim se otopinu ohladi, razrijedi se s EtOAc i ispere s 0,1 N HCl i vodom. Organski sloj se osuši preko MgSO4 i zgusne, čime se dobije sirov proizvod koji se dalje čisti kromatografijom na silika gelu, čime se dobije 0,12 g (33%) spoja iz primjera 30. Method C is illustrated by the synthesis of the compound of Example 30 in Table 3, which was carried out as follows. Methyl 2-amino-2-benzylbutyric acid (0.21 g, 1 mmol) and 3,5-dichlorophenyl isocyanate (0.19 g, 1 mmol) were dissolved in DMSO (5 mL) in the presence of approximately 0.2 g Na2CO3 and let them mix for 1 hour at 50oC. At the end of that period, the solution is heated for 2 hours at 90oC. The solution was then cooled, diluted with EtOAc and washed with 0.1 N HCl and water. The organic layer was dried over MgSO4 and concentrated to give the crude product which was further purified by silica gel chromatography to give 0.12 g (33%) of the compound from Example 30.
Metoda D. Method D.
Sinteza na krutoj fazi. Solid phase synthesis.
Postoji nekoliko primjera u literaturi koji pokazuju da se sinteza hidantoina i njihovih prekurzorskih amino kiselinskih derivata može provesti na krutoj fazi, kojom se može proizvesti veliko mnoštvo tih spojeva prikladnih za automatizirani pristup. Primjari za sintezu prekurzorskih derivata amino kiselina prikazani su u slijedećim časopisima: J. American Chemical Society, 1996, 118, 6070-1, Tetrahedron Letters, 1997, 38, 7163-7166, Tetrahedron Letters, 1997, 38, 8821. Članak u kojem je prikazana pretvorba derivata amino kiseline u hidantoin objavljen je u J. Organic Chemistry 1997, 62, 6060-2. There are several examples in the literature showing that the synthesis of hydantoins and their precursor amino acid derivatives can be carried out on a solid phase, which can produce a large number of these compounds suitable for an automated approach. Primers for the synthesis of precursor derivatives of amino acids are presented in the following journals: J. American Chemical Society, 1996, 118, 6070-1, Tetrahedron Letters, 1997, 38, 7163-7166, Tetrahedron Letters, 1997, 38, 8821. Article in which conversion of an amino acid derivative to hydantoin was reported in J. Organic Chemistry 1997, 62, 6060-2.
Amino kiselina koja se drži za smolu krute faze pomoću svoje skupine karboksilne kiseline, preko adgovarajućeg linkera (na primjer Wangove smole: 4-benziloksi-benzil polistiren) zaštiti se na svom dušiku s reagentom koji će omogućiti alkiliranje alfa-ugljika (na primjer, derivata benzaldehida koji oblikuje imin s dušikom amino kiseline). Zaštićen spoj se dalje obradi s bazom i sa sredstvom za alkiliranje, čime se dobije derivat amino kiseline s novom zaštitnom skupinom. Zaštitna skupina se odstranjuje primjenom standardnih uvjeta (u slučaju imina to se provodi, na primjer, s vodenom HCl) i slobodna amino skupina reagira s izocijanatom, čime se dobije intermedijarna urea. Taj se intermedijat pomiješa s reagentom koji katalizira ciklizaciju dijela uree na karboksilatnom kraju molekule koja oblikuje željeni hidantoin i proizvod se odcijepi od smole. Čišćenje se vrši kromatografijom na silika gelu, HLPC reverznih faza ili prekristalizacijom. An amino acid attached to the solid-phase resin by its carboxylic acid group, through a suitable linker (for example Wang's resin: 4-benzyloxy-benzyl polystyrene) is protected on its nitrogen with a reagent that will allow alkylation of the alpha-carbon (for example, derivatives of benzaldehyde that forms an imine with an amino acid nitrogen). The protected compound is further treated with a base and an alkylating agent, resulting in an amino acid derivative with a new protective group. The protecting group is removed using standard conditions (in the case of imines, for example, with aqueous HCl) and the free amino group reacts with the isocyanate, yielding the urea intermediate. This intermediate is mixed with a reagent that catalyzes the cyclization of the urea moiety at the carboxylate end of the molecule forming the desired hydantoin and the product is cleaved from the resin. Purification is done by chromatography on silica gel, reverse-phase HLPC or recrystallization.
Spojevi navedeni u tablici 4 proizvedeni su ovom općom metodom. The compounds listed in Table 4 were produced by this general method.
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Metoda D ilustrirana je sintezom spoja iz primjera 67, koja je bila provedena kako slijedi. Reakcijsku posudu se napuni s komercijalno dostupnom Fmoc-Ala-Wang (300 mg, 0,150 mmola) i 3 ml 20%-tne otopine piperidina u N-metil pirolidinonu (NMP). Reakcijsku posudu se mućka 45 minuta pri sobnoj temperaturi na orbitnoj mućkalici. Smolu se odfltrira i ispere s NMP (3x1 ml). Reakcijsku posudu sa smolom se začepi s gumenim čepom, stavi u argon i doda se 3,4-diklorbenzaldehid (394 mg, 2,25 mmola) i trimetil ortoformat (3,5 ml) i NMP (1,5 ml). Dobivenu smjesu se mućka 15 sati pri sobnoj temperaturi. Krutu smolu se izolira filtracijom i ispere uzastopce s NMP (3x3 ml), tetrahidrofuranom (3x3 ml) i CH2Cl2 (3x3 ml). Zatim se smolu suši pod vakuumom, otprilike jedan sat, da se dobije smolu s iminskim intermedijatom. Method D is illustrated by the synthesis of the compound of Example 67, which was carried out as follows. The reaction vessel was charged with commercially available Fmoc-Ala-Wang (300 mg, 0.150 mmol) and 3 ml of a 20% solution of piperidine in N-methyl pyrrolidinone (NMP). The reaction vessel is shaken for 45 minutes at room temperature on an orbital shaker. The resin is filtered off and washed with NMP (3x1 ml). The resin reaction vessel was sealed with a rubber stopper, placed under argon, and 3,4-dichlorobenzaldehyde (394 mg, 2.25 mmol) and trimethyl orthoformate (3.5 mL) and NMP (1.5 mL) were added. The resulting mixture is shaken for 15 hours at room temperature. The solid resin was isolated by filtration and washed successively with NMP (3x3 ml), tetrahydrofuran (3x3 ml) and CH2Cl2 (3x3 ml). The resin is then dried under vacuum for approximately one hour to obtain a resin with an imine intermediate.
Smola s iminskim intermedijatom se alkilira s 2,3-difluor-4-trifluormetilbenzil bromidom (123,8 mg, 0,45 mmola) miješanjem tih dvaju reagenata, 2-terc.butilimino-2-dietilamino-1,3-dimetilperhidro-1,3,2-diazafosforina (BEMP, 0,217 ml, 0,75 mmola) i NMP (3,5 ml) i smjesu se mućka 15 sati pri sobnoj temperaturi na orbitalnoj mućkalici. Krutu tvar se izolira filtracijom i ispere uzastopce s NMP (3x3 ml), THF-om (3x3 ml) i CH2Cl2 (3x3 ml), čime se nakon sušenja dobije alkilirani iminski intermedijat na smoli. The resin with the imine intermediate is alkylated with 2,3-difluoro-4-trifluoromethylbenzyl bromide (123.8 mg, 0.45 mmol) by mixing the two reagents, 2-tert.butylimino-2-diethylamino-1,3-dimethylperhydro-1 ,3,2-diazaphosphorine (BEMP, 0.217 ml, 0.75 mmol) and NMP (3.5 ml) and the mixture was shaken for 15 hours at room temperature on an orbital shaker. The solid substance is isolated by filtration and washed successively with NMP (3x3 ml), THF (3x3 ml) and CH2Cl2 (3x3 ml), which after drying gives the alkylated imine intermediate on the resin.
Imin se odcijepi od prethodnog intermedijata obradom s vodenom 1N HCl (1,8 ml) i THF-om (3,6 ml) i mućkanjem pribl. 15 sati pri sobnoj temperaturi. Amino ester vezan na smoli se izolira filtracijom i ispere uzastopce s NMP (3x3 ml), THF-om (3x3 ml) i i CH2Cl2 (3x3 ml) i osuši u vakuumu. The imine was cleaved from the previous intermediate by treatment with aqueous 1N HCl (1.8 ml) and THF (3.6 ml) and shaking approx. 15 hours at room temperature. The amino ester bound to the resin was isolated by filtration and washed successively with NMP (3x3 ml), THF (3x3 ml) and CH2Cl2 (3x3 ml) and dried in vacuo.
Amino ester vezan na smoli se pretvori u hidantoin primjenom postupka kojim se krajnji proizvod odcjepljuje od smole. Intermedijarni amino-ester se stavi u reakcijsku posudu i pomiješa s 3 ml 20%-tne otopine N,N-diizopropil-etilamina u NMP. Nakon mućkanja pri sobnoj temperaturi ispere se s NMP (3x3 ml) i s metanolom (3x3 ml) i stavi se pod vakuum. Zatim se posudu otvori u argonu i napuni s 2,5 ml 1,75 M otopine 3,5-diklorfenilizocijanata u dimetilform-amidu (DMF, 0,45 mmola). Smjesu se mućka preko noći u argonu i pri sobnoj temperaturi i proizvod se odvoji filtracijom. Nakon ispiranja smole s etil acetatom (6x2 ml), sjedinjeni organski slojevi se razrijede s vodom i zatim se isperu s vodom (3x3 ml) i sa zasićenom vodenom otopinom NaCl (2x3 ml), osuše preko natrijevog sulfata, profiltriraju i zgusnu pod strujom dušika. Čišćenje završava primjenom HPLC reverznih faza (gradijent acetonitrila i vode). The resin-bound amino ester is converted to hydantoin using a process that cleaves the final product from the resin. The intermediate amino ester was placed in a reaction vessel and mixed with 3 ml of a 20% solution of N,N-diisopropylethylamine in NMP. After shaking at room temperature, it is washed with NMP (3x3 ml) and with methanol (3x3 ml) and placed under vacuum. The vessel was then opened under argon and filled with 2.5 ml of a 1.75 M solution of 3,5-dichlorophenylisocyanate in dimethylformamide (DMF, 0.45 mmol). The mixture is shaken overnight under argon at room temperature and the product is separated by filtration. After washing the resin with ethyl acetate (6x2 ml), the combined organic layers are diluted with water and then washed with water (3x3 ml) and with saturated aqueous NaCl solution (2x3 ml), dried over sodium sulfate, filtered and concentrated under a stream of nitrogen . The purification ends with the application of HPLC reverse phases (gradient of acetonitrile and water).
Metoda E. Method E.
Polazni materijali izocijanat-ester i anilin. Starting materials isocyanate-ester and aniline.
Ciklizacija s bazom ili kiselinom. Cyclization with base or acid.
K odgovarajućem izocijanatnom esteru otopljenom u organskom otapalu (kao što je, na primjer, metilen klorid) doda se odgovarajući anilin i smjesu se miješa između 1 i 24 sata pri sobnoj temperaturi u inertnoj atmosferi kao što je argon. Zatim se organsko otapalo odstrani u vakuumu. Suvišak anilina se odstrani (kuhanjem sirove krute tvari u heksanu i dekantiranjem tekućine, ili vakuumskom kromatografijom preko silika gela), nakon čega ostaje kruti ureido-octeni ester. Ureido-octeni ester se ciklizira u željeni hidantoin obradom s bazom (kao što je, na primjer, NaH, NaHMDS, Na2CO3, NaHCO3, K2CO3 ili KHCO3) u organskom otapalu (kao što je npr. THF ili DMF) i zatim grijanjem pri pribl. 60-90oC. Otopinu se najprije ohladi i razrijedi s organskim otapalom (kao što je na primjer EtOAc). Organsku otopinu se ispere uzastopce s razrijeđenom vodenom kiselinom (kao što je 1N HCl) i zatim s vodom, osuši (s MgSO4) i zgusne. Željeni hidantion se očisti kromatografijom na silika gelu ili prekristalizacijom. (Alternativno, intermedijarni ureido-octeni ester se može ciklizirati u hidantoin grijanjem pri pribl. 90oC u prisutnosti kiseline kao što je vodena HCl, kako je spomenuto u metodi C). To the appropriate isocyanate ester dissolved in an organic solvent (such as, for example, methylene chloride) is added the appropriate aniline and the mixture is stirred for between 1 and 24 hours at room temperature under an inert atmosphere such as argon. Then the organic solvent was removed in vacuo. Excess aniline is removed (by boiling the crude solid in hexane and decanting the liquid, or by vacuum chromatography over silica gel), leaving a solid ureido-acetic ester. The ureido-acetic ester is cyclized to the desired hydantoin by treatment with a base (such as, for example, NaH, NaHMDS, Na2CO3, NaHCO3, K2CO3 or KHCO3) in an organic solvent (such as THF or DMF) and then heating at approx. . 60-90oC. The solution is first cooled and diluted with an organic solvent (such as EtOAc). The organic solution is washed successively with dilute aqueous acid (such as 1N HCl) and then with water, dried (with MgSO4) and concentrated. The desired hydanthion is purified by silica gel chromatography or recrystallization. (Alternatively, the ureido-acetic ester intermediate can be cyclized to hydantoin by heating at approx. 90°C in the presence of an acid such as aqueous HCl, as mentioned in Method C).
Spojevi navedeni u tablici 5 proizvedeni su ovom metodom. The compounds listed in Table 5 were produced by this method.
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Metoda E ilustrirana je sintezom spoja iz primjera 70 prikazanog u tablici 5, koja je provedena kako slijedi. K otopini etil 2-izocijanato-3-fenilpropionata (99,0 ml, 0,110 g, 0,501 mmola) u suhom CH2Cl2 (5,0 ml) doda se 3,4,5-trikloranilin (0,1952 g, 0,994 mmola) kao kruta tvar. Smjesu se miješa 20 sati pri sobnoj temperaturi u atmosferi argona. Zatim se otopinu zgusne u vakuumu i ostatak se prekristalizira dva puta iz etil acetat/heksana, čime se dobije 0,14 g (65%) čiste intermedijarne uree kao bijele krute tvari. Suspenziju natrijevog hidrida (0,06 g 60%-tne disperzije u mineralnom ulju, 1,52 mmola) u suhom THF-u (4,0 ml) pomiješa se s otopinom gornje uree (0,108 g, 0,260 mmola) u suhom THF-u (4,0 ml). Smjesu se miješa 1 sat pri sobnoj temperaturi u atmosferi argona. Zatim se smjesu prelije u 100 ml 1N vodene HCl. THF se odstrani pod smanjenim tlakom i smjesu se profiltrira. Krutu tvar se očisti preparativnom tankoslojnom kromatografijom (SiO2, 1:1 heksan/etil acetat), čime se dobije krutu tvar koju se dalje čisti prekristalizacijom iz apsolutnog EtOH, čime se dobije 0,027 g čistog spoja (28%). Method E is illustrated by the synthesis of the compound of Example 70 shown in Table 5, which was carried out as follows. To a solution of ethyl 2-isocyanato-3-phenylpropionate (99.0 mL, 0.110 g, 0.501 mmol) in dry CH2Cl2 (5.0 mL) was added 3,4,5-trichloroaniline (0.1952 g, 0.994 mmol) as solid substance. The mixture is stirred for 20 hours at room temperature in an argon atmosphere. The solution was then concentrated in vacuo and the residue was recrystallized twice from ethyl acetate/hexane to give 0.14 g (65%) of pure intermediate urea as a white solid. A suspension of sodium hydride (0.06 g of a 60% dispersion in mineral oil, 1.52 mmol) in dry THF (4.0 mL) was mixed with a solution of the above urea (0.108 g, 0.260 mmol) in dry THF- in (4.0 ml). The mixture is stirred for 1 hour at room temperature in an argon atmosphere. The mixture is then poured into 100 ml of 1N aqueous HCl. The THF was removed under reduced pressure and the mixture was filtered. The solid was purified by preparative thin layer chromatography (SiO2, 1:1 hexane/ethyl acetate) to give a solid which was further purified by recrystallization from absolute EtOH to give 0.027 g of the pure compound (28%).
Metoda F. Sinteza sukcinimida. Method F. Synthesis of succinimide.
Ekvimolarne količine odgovarajućih polaznih diacida ili anhidrida i odgovarajućeg polaznog anilina refluktiraju se u otapalu (kao što je ksilen) u prisutnosti katalitičke količine baze (kao što je trietilamin) između pribl. 2 i 24 sata. Otapalo se odstrani u vakuumu i ostatak se otopi u organskom otapalu (kao što je EtOAc), ispere se uzastopce s vodenom razrijeđenom bazom (kao što je NaHCO3) i vodenom razrijeđenom kiselinom (kao što je HCl), osuši (na primjer preko MgSO4) i zgusne. Čišćenje se vrši, na primjer, prekristalizacijom ili kromatografijom preko silika gela. Equimolar amounts of the appropriate starting diacids or anhydrides and the appropriate starting aniline are refluxed in a solvent (such as xylene) in the presence of a catalytic amount of base (such as triethylamine) between approx. 2 and 24 hours. The solvent is removed in vacuo and the residue is dissolved in an organic solvent (such as EtOAc), washed successively with aqueous dilute base (such as NaHCO3) and aqueous dilute acid (such as HCl), dried (eg over MgSO4) and thickens. Purification is done, for example, by recrystallization or chromatography over silica gel.
Polazne dikiseline i anhidridi su komercijalno dostupni ili se mogu proizvesti metodama poznatim iz literature. Kao primjer dat je postupak za sintezu 2-benzil-3-karboksi-2-metilbutanske kiseline (polazni materijal za primjer 74). Starting diacids and anhydrides are commercially available or can be produced by methods known from the literature. As an example, the procedure for the synthesis of 2-benzyl-3-carboxy-2-methylbutanoic acid (starting material for example 74) is given.
Otopinu od 2,0 g 2-metil-3-fenilpropionske kiseline (12,2 mmolova), 2,2 g karbonil-diimidazola (CDI, 13,56 mmolova) u 20 ml THF-a refluktira se 1 sat u dušiku. Temperaturu se spusti na 50oC i doda se 1,2 ml krotil alkohola (14,1 mmolova) i zatim 20 mg 4-(N,N-dimetilamino)-piridina (DMAP). Smjesu se grije 3 sata pri 50oC, zgusne se i očisti kromatografjom na silika gelu, čime se dobije 1,7 g intermedijarnog estera: trans-2-butenil-2-benzil-3-karboksi-2-metilbutanoata (64%). A solution of 2.0 g of 2-methyl-3-phenylpropionic acid (12.2 mmol), 2.2 g of carbonyldiimidazole (CDI, 13.56 mmol) in 20 ml of THF was refluxed for 1 hour under nitrogen. The temperature was lowered to 50°C and 1.2 ml of crotyl alcohol (14.1 mmol) and then 20 mg of 4-(N,N-dimethylamino)-pyridine (DMAP) were added. The mixture is heated for 3 hours at 50oC, concentrated and purified by chromatography on silica gel, which gives 1.7 g of the intermediate ester: trans-2-butenyl-2-benzyl-3-carboxy-2-methylbutanoate (64%).
Ester se podvrgne [3,3] sigmatropskom premještanju da se dobije slijedeći intermedijat. U argonu pri -78oC k otopini litij-di-izopropilamida (LDA, 3,25 mmola, dobivena iz 1,3 ml 2,5 M n-BuLi i 0,54 ml Pr2NH u 3 ml THF-a, -10oC, 15 min), koja sadrži 500 mikrolitara DMPU, doda se otopinu od 560 mg intermedijarnog estera (2,57 mmola) u THF-u (1 ml). Smjesu se miješa 30 minuta i zatim se doda otopinu od 480 mg TBSCl (3,1 mmola) u 1 ml THF-a. Smjesu se miješa 30 minuta pri -78oC, 20 minuta pri sobnoj temperaturi i zatim se grije 10 sati pri 60oC. Smjesu se ohladi na 0oC, pogasi se s 2N HCl (5 ml) i miješa se 10 sati pri sobnoj temperaturi. Smjesu se zaluži na pH 10 s 2N NaOH, i ekstrahira s eterom (5 ml). Vodeni sloj se odvoji, zakiseli na pH 1 s koncentriranom HCl, ekstrahira s EtOAc i zgusne, čime se dobije 500 mg (89%) intermedijata: 2-benzil-2,3-dimetil-4-pentenska kiselina. The ester undergoes a [3,3] sigmatropic rearrangement to give the following intermediate. In argon at -78oC to a solution of lithium diisopropylamide (LDA, 3.25 mmol, obtained from 1.3 ml of 2.5 M n-BuLi and 0.54 ml of Pr2NH in 3 ml of THF, -10oC, 15 min), containing 500 microliters of DMPU, was added to a solution of 560 mg of the intermediate ester (2.57 mmol) in THF (1 ml). The mixture was stirred for 30 minutes and then a solution of 480 mg of TBSCl (3.1 mmol) in 1 ml of THF was added. The mixture is stirred for 30 minutes at -78oC, 20 minutes at room temperature and then heated for 10 hours at 60oC. The mixture is cooled to 0°C, quenched with 2N HCl (5 ml) and stirred for 10 hours at room temperature. The mixture was basified to pH 10 with 2N NaOH, and extracted with ether (5 ml). The aqueous layer was separated, acidified to pH 1 with concentrated HCl, extracted with EtOAc and concentrated to give 500 mg (89%) of the intermediate: 2-benzyl-2,3-dimethyl-4-pentenoic acid.
Mono-kiselinu se pretvori u željeni diacid oksidacijom terminalnog alkena s ozonom i dobiveni intermedijat se dalje oksidira s kromnim reagentom. Kroz otopinu od 500 mg 2-benzil-2,3-dimetil-4-pentenske kiseline (2,29 mmola) u MeOH (20 ml) i metilen kloridu (10 ml) koja sadrži 120 mikrolitara piridina pušta se brzo dovoljnu struju O3 pri -78oC, tako da se otopina vrati na lagano plavu boju. Smjesu se pomiješa s 1 ml metil sulfida i miješa se 5 minuta pri -78oC. Zatim se smjesu zagrije na sobnu temperauru, zgusne i pusti kroz kolonu silika gela (s 10% MeOH u CH2Cl2 kao sredstvom za ispiranje) i zgusne. Sirov materijal se otopi u 5 ml acetona i pomiješa s Jonesovim reagentom (16 g CrO3, 16 g konc. H2SO4 u 100 ml vode) pri sobnoj temperaturi dok narančasta boja postane trajna. Nakon dodatka vode (10 ml) smjesu se miješa 1 sat, ispere s EtOAc i zgusne. Smjesu se očisti na silika gelu kromatografijom s 3% AcOH-EtOAc, čime se dobije 300 mg željene di-kiseline (55%). The mono-acid is converted into the desired diacid by oxidation of the terminal alkene with ozone and the resulting intermediate is further oxidized with a chromium reagent. Through a solution of 500 mg of 2-benzyl-2,3-dimethyl-4-pentenoic acid (2.29 mmol) in MeOH (20 ml) and methylene chloride (10 ml) containing 120 microliters of pyridine, a sufficient stream of O3 is passed rapidly at -78oC, so that the solution returns to a slightly blue color. The mixture was mixed with 1 ml of methyl sulfide and stirred for 5 minutes at -78oC. The mixture is then warmed to room temperature, concentrated and passed through a silica gel column (with 10% MeOH in CH2Cl2 as eluent) and concentrated. The crude material is dissolved in 5 ml of acetone and mixed with Jones reagent (16 g CrO3, 16 g conc. H2SO4 in 100 ml water) at room temperature until the orange color becomes permanent. After the addition of water (10 ml), the mixture was stirred for 1 hour, washed with EtOAc and concentrated. The mixture was purified on silica gel by chromatography with 3% AcOH-EtOAc to give 300 mg of the desired di-acid (55%).
Spojevi navedeni u tablici 6 proizvedeni su ovom metodom. The compounds listed in Table 6 were produced by this method.
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Metoda F ilustrirana je sintezom spojeva iz primjera 92 i 93 (vidi tablicu 6) koja je provedena kako slijedi. Smjesu izomera polazne di-kiseline iz primjera 92 (0,58 g, 1,8 mmola, 3:1 smjesa izomera), 3,5-dikloranilina (0,35 g, 2,2 mmola), Et3N (10 ml, 0,07 mmola) u ksilenu (5 ml) refluktira se 24 sata u argonu u boci začepljenoj s Deark-Starkovim čepom. Smjesu se ohladi, zgusne i očisti kromatografijom na silika gelu (ispirući s 10% zatim s 15% etil acetata u heksanu), čime se dobije 0,45 g (52%) trans-metil izomera (primjer 73, talište 139-140oC) i 15 mg (2%) cis-metil izomera (primjer 72, talište : ulje). Method F is illustrated by the synthesis of compounds from Examples 92 and 93 (see Table 6) which was carried out as follows. A mixture of isomers of the starting di-acid from Example 92 (0.58 g, 1.8 mmol, 3:1 mixture of isomers), 3,5-dichloroaniline (0.35 g, 2.2 mmol), Et3N (10 ml, 0 .07 mmol) in xylene (5 mL) was refluxed for 24 h under argon in a Deark-Stark stoppered flask. The mixture is cooled, concentrated and purified by chromatography on silica gel (eluting with 10% then 15% ethyl acetate in hexane), which gives 0.45 g (52%) of the trans-methyl isomer (example 73, melting point 139-140oC) and 15 mg (2%) of the cis-methyl isomer (Example 72, melting point: oil).
Metoda G. Method G.
Pretvorba karbonila u tio-karbonile Conversion of carbonyls to thio-carbonyls
Nekoliko reagenata poznatih iz literature pretvaraju karbonile u tiokarbonile. Tipićna sekvenca uključuje grijanje supstrata s reagentom kao što je P2S3 u otapalu visokog vrelišta kao što je tetralin tijekom 1 do 48 sati. Izolacija proizvoda vrši se pod relativno standardnim uvjetima, kao što je razređivanje smjese u organskom otapalu, kao što je EtOAc, i ispiranje te smjese s vodom i sa zasićenom vodenom NaCl i zatim sušenjem i zgušnjavnajem. Čišćenje, kojim se dobiva željeni proizvod, vrši se kromatografijom na silika gelu ili prekristalizacijom. Several reagents known from the literature convert carbonyls into thiocarbonyls. A typical sequence involves heating the substrate with a reagent such as P2S3 in a high-boiling solvent such as tetralin for 1 to 48 hours. Isolation of the product is done under relatively standard conditions, such as diluting the mixture in an organic solvent, such as EtOAc, and washing the mixture with water and saturated aqueous NaCl, followed by drying and concentration. Purification, by which the desired product is obtained, is performed by chromatography on silica gel or by recrystallization.
Spojevi navedeni u tablici 7 proizvedeni su ovom metodom. The compounds listed in Table 7 were produced by this method.
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Metoda G ilustrirana je sintezom spoja iz primjera 78, koja je provedena kako slijedi. Polazni supstrat (1,5 g, 3,5 mmola) otopi se u 5 ml tetralina, pomiješa se s P2S3 (0,9 g, 5,7 mmolova) i grije se 2 sata pri 225oC. Kad se ohladi, smjesu se razrijedi s vodom i proizvod se ekstrahira u EtOAc. Organski sloj se ispere sa zasićenom vodenom otopinom NaCl, osuši i zgusne. Dobiveno ulje se triturira s heksanom čime se dobije žutu krutu tvar koju se izolira filtracijom. Taj se materijal očisti vakuumskom kromatografijom (1:4 EtOAc:heksan), čime se dobije 1,13 g (70%) željenog spoja. Method G is illustrated by the synthesis of the compound of Example 78, which was carried out as follows. The starting substrate (1.5 g, 3.5 mmol) was dissolved in 5 ml of tetralin, mixed with P2S3 (0.9 g, 5.7 mmol) and heated for 2 hours at 225°C. When cooled, the mixture was diluted with water and the product was extracted into EtOAc. The organic layer is washed with saturated aqueous NaCl solution, dried and concentrated. The resulting oil is triturated with hexane to give a yellow solid which is isolated by filtration. This material was purified by vacuum chromatography (1:4 EtOAc:hexane) to give 1.13 g (70%) of the desired compound.
Metoda H. Method H.
Selektivna hidroliza tio-karbonila u karbonile Selective hydrolysis of thio-carbonyl to carbonyls
Spojevi koji sadrže ditio-karbonil, proizvedeni metodom G, mogu se, ovisno o izboru uvjeta, selektivno hidrolizirati u svaki od dva monotio-karbonilna spoja. Općenito tio-karbonil u položaju 4 prstena je mnogo osjetljiviji prema nukleofilnim uvjetima. Kako se vidi u primjeru 81, on se može pretvoriti u 4-okso spoj obradom s vodenim etanolaminom i zatim kiselom hidrolizom. Tio-karbonil u položaju 2 prstena je nukleofilniji na sumporu i može se alkilirati s metil sulfatom. Taj se intermedijat može zatim hidrolizirati s blagom kiselinom. Time se dobije spoj iz primjera 80. Čišćenje spojeva bilo kojeg razreda se lako provodi kromatografijom na silika gelu ili prekristalizacijom. Compounds containing dithio-carbonyl, produced by method G, can, depending on the choice of conditions, be selectively hydrolyzed into each of the two monothio-carbonyl compounds. In general, the thio-carbonyl in the 4-position of the ring is much more sensitive to nucleophilic conditions. As seen in Example 81, it can be converted to the 4-oxo compound by treatment with aqueous ethanolamine followed by acid hydrolysis. The thio-carbonyl in the 2-position of the ring is more nucleophilic on sulfur and can be alkylated with methyl sulfate. This intermediate can then be hydrolyzed with a mild acid. This gives the compound from example 80. Purification of compounds of any class is easily carried out by silica gel chromatography or recrystallization.
Spojevi navedeni u tablici 8 proizvedeni su tom metodom. The compounds listed in Table 8 were produced by this method.
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Primjer 80 proizveden je tako da se otopinu polaznog materijala (0,23 g, 0,49 mmola) u 3 ml THF-a pomiješa s 10 ml 50%-tnog vodenog etanolamina i grije 2 sata pod refluksom. Kad se ohladi, smjesu se ekstrahira s EtOAc i organski sloj se ispere s vodom i sa zasićenom vodenom otopinom NaCl, osuši i zgusne, čime se dobije smeđu krutu tvar. Tu krutu tvar se zatim pomiješa s 20 ml 6N HCl i grije se 72 sata pod refluksom. Kad se ohladi, smjesu se ekstrahira s EtOAc i organski sloj se ispere sa zasićenom vodenom otopinom NaCl, osuši i zgusne. Proizvod se očisti preparativnom TLC preko silika gela upotrebom 1:1 EtOAc:heksana kao otapala, čime se dobije proizvod s iskorištenjem od 34%. Example 80 was prepared by mixing a solution of the starting material (0.23 g, 0.49 mmol) in 3 ml of THF with 10 ml of 50% aqueous ethanolamine and heating under reflux for 2 hours. After cooling, the mixture was extracted with EtOAc and the organic layer was washed with water and saturated aqueous NaCl, dried and concentrated to give a brown solid. This solid is then mixed with 20 ml of 6N HCl and heated under reflux for 72 hours. When cooled, the mixture was extracted with EtOAc and the organic layer was washed with saturated aqueous NaCl, dried and concentrated. The product was purified by preparative TLC over silica gel using 1:1 EtOAc:hexanes as solvent to give the product in 34% yield.
Primjer 81 proizvede se tako, da se pripravi otopinu polaznog materijala (0,5 g, 1,09 mmola) u 1,6 ml 2N NaOH. Kako se spoj odmah ne otopi, doda se 1 ml vode i 1 ml THF-a da se pomogne otapanje. Zatim se smjesu ohladi na ledenoj kupelji i kap po kap tijekom 5 minuta doda se Me2SO4 (0,12 ml, 1,3 mmola). Smjesu se miješa još 3 sata pri 0oC i zatim 45 minuta pri sobnoj temperaturi. Reakciju se pogasi dodatkom količine 1N HCl dovoljne da se dobije pH otopine niži od 2. Smjesu se ekstrahira s EtOAc i organski sloj se ispere sa zasićenom vodenom otopinom NaCl, osuši i zgusne, čime se dobije žuto ulje. To se ulje zatim pomiješa s 10 ml 6N HCl i grije se 3 sata pod refluksom. Kad se ohladi, smjesu se ekstrahira s EtOAc i organski sloj se ispere sa zasićenom vodenom otopinom NaCl, osuši i zgusne. Proizvod se očisti kromatografijom na stupcu silika gela upotrebom 1:1 EtOAc:heksana kao otapala, čime se dobije proizvod s iskorištenjem od 5%. Example 81 was prepared by preparing a solution of the starting material (0.5 g, 1.09 mmol) in 1.6 ml of 2N NaOH. As the compound does not immediately dissolve, 1 ml of water and 1 ml of THF are added to aid dissolution. The mixture was then cooled in an ice bath and Me2SO4 (0.12 ml, 1.3 mmol) was added dropwise over 5 minutes. The mixture is stirred for another 3 hours at 0oC and then 45 minutes at room temperature. The reaction was quenched by the addition of 1N HCl sufficient to obtain a pH of the solution below 2. The mixture was extracted with EtOAc and the organic layer was washed with saturated aqueous NaCl, dried and concentrated to give a yellow oil. This oil is then mixed with 10 ml of 6N HCl and heated under reflux for 3 hours. When cooled, the mixture was extracted with EtOAc and the organic layer was washed with saturated aqueous NaCl, dried and concentrated. The product was purified by silica gel column chromatography using 1:1 EtOAc:hexanes as the solvent to give the product in 5% yield.
Metoda I. Method I.
N-alkiliranje hidantoina N-alkylation of hydantoin
Odgovarajući hidantion se otopi u odgovarajućem otapalu (kao što je, na primjer, DMF, THF ili DMSO) i pomiješa se s jednim ekvivalentom baze (kao što je, na primjer, NaH, LDA, LiHMDS, KHMDS, KH ili NaHMDS). Nakon otprilike 10 minuta do 1 sata doda se odgovarajuće sredstvo za alkiliranje i smjesu se miješa pribl. 24 sata pri temperaturi između sobne temperature i 90oC. (Napredovanje reakcije može se promatrati primjenom TLC). Zatim se otopinu ohladi i razrijedi s organskim otapalom (kao što je, na primjer, EtOAc ili CH2Cl2). Organsku fazu se ispere uzastopce s razrijeđenom kiselinom (kao što je 1N HCl) i s vodom, osuši (na primjer preko MgSO4) i zgusne. Željeni hidantoin se očisti kromatografijom na silika gelu ili prekristalizacijom. The appropriate hydantion is dissolved in a suitable solvent (such as, for example, DMF, THF, or DMSO) and mixed with one equivalent of a base (such as, for example, NaH, LDA, LiHMDS, KHMDS, KH, or NaHMDS). After approximately 10 minutes to 1 hour, the appropriate alkylating agent is added and the mixture is stirred for approx. 24 hours at a temperature between room temperature and 90oC. (The progress of the reaction can be observed using TLC). The solution is then cooled and diluted with an organic solvent (such as, for example, EtOAc or CH 2 Cl 2 ). The organic phase is washed successively with dilute acid (such as 1N HCl) and water, dried (eg over MgSO4) and concentrated. The desired hydantoin is purified by silica gel chromatography or recrystallization.
Spojevi navedeni u tablici 9 proizvedeni su ovom općom metodom. The compounds listed in Table 9 were produced by this general method.
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Metoda I ilustrirana je sintezom spoja iz primjera 97 (vidi tablicu 9) koja se provedi tako da se polazni materijal (0,21 g, 0,5 mmola) otopi u DMF-u (5 ml) i pomiješa uzastopce s otopinom 1M NaHMDS (0,5 ml, 0,5 mmola) i EtJ (0,04 ml, 0,5 mmola). Nakon 1 sata reakcijsku smjesu se podijeli između EtOAc i vode i organsku fazu se ispere s vodom i osuši preko MgSO4. Kromatografijom preko stupca silika gela proizvedeno je 0,17 g (72%) željenog proizvoda. Method I is illustrated by the synthesis of the compound of Example 97 (see Table 9) which is carried out by dissolving the starting material (0.21 g, 0.5 mmol) in DMF (5 ml) and mixing successively with a solution of 1 M NaHMDS ( 0.5 ml, 0.5 mmol) and EtJ (0.04 ml, 0.5 mmol). After 1 hour, the reaction mixture was partitioned between EtOAc and water and the organic phase was washed with water and dried over MgSO4. Chromatography over a silica gel column produced 0.17 g (72%) of the desired product.
Metoda J. Method J.
C-alkiliranje heterocikla C-alkylation of heterocycles
Odgovarajući heterocikl otopi se u aprotonskom otapalu (kao što je DMF, THF ili DMSO) i pomiješa s jednim ekvivalentom baze (kao što je Et3N, LDA, KHMDS, LiMDS ili NaHMDS) pri temperaturi između pribl. -78oC do sobne temperature. Nakon otprilike 10 minuta do 2 sata doda se odgovarajuće sredstvo za akiliranje i smjesu se miješa 24 sata pri temperaturi između pribl. 0 i 90oC. (Napredovanje reakcije može se pratiti pomoću TLC). Otopinu se zatim ohladi i razrijedi s organskim otapalom (kao što je, na primjer, EtOAc). Organsku fazu se ispere uzastopce s razrijeđenom vodenom kiselinom (kao što je 1N HCl) i s vodom, osuši (na primjer, preko MgSO4) i zgusne. Željeni hidantoin se očisti, na primjer, kromatografijom na silika gelu ili prekristalizacijom. The appropriate heterocycle is dissolved in an aprotic solvent (such as DMF, THF or DMSO) and mixed with one equivalent of a base (such as Et3N, LDA, KHMDS, LiMDS or NaHMDS) at a temperature between approx. -78oC to room temperature. After approximately 10 minutes to 2 hours, a suitable acylating agent is added and the mixture is stirred for 24 hours at a temperature between approx. 0 and 90oC. (Reaction progress can be monitored by TLC). The solution is then cooled and diluted with an organic solvent (such as, for example, EtOAc). The organic phase is washed successively with dilute aqueous acid (such as 1N HCl) and water, dried (for example, over MgSO 4 ) and concentrated. The desired hydantoin is purified, for example, by silica gel chromatography or recrystallization.
Spojevi navedeni u tablici 10 proizvedeni su ovom općom metodom. The compounds listed in Table 10 were produced by this general method.
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Metoda J ilustrirana je sintezom spoja iz primjera 148 (vidi tablicu 10) koja je provedena kako slijedi. Polazni materijal (0,11 g, 040 mmola) otopi se u THF-u (5,0 ml) i ohladi se u kupelji suhi led/aceton (približno -78oC). Kap po kap doda se litijev bis(trimetilsilil)amid (LiHMDS, 405,0 μl, 0,40 mmola). Dobivenu žutu otopinu se miješa 15 minuta u hladnoj kupelji, nakon čega se k tome doda 2-fluorbenzil bromid. Smjesu se miješa još 30 minuta pri toj temperaturi i zatim još 30 minuta pri 0oC. Reakcijsku smjesu se zatim prelije u 1N HCl (40 ml) i ekstrahira u EtOAc (50 ml). Organski sloj se ispere sa zasićenom vodenom otopinom NaCl (35 ml), osuši (Na2SO4), profiltrira i zgusne u vakuumu, čime se dobije 0,16 g sirovog proizvoda. Taj se materijal očisti vakuumskom kromatografijom preko silika gela (1:3 EtOAc/heksan) čime se dobije 0,87 g (57,0%) spoja iz primjera 148. Method J is illustrated by the synthesis of Example 148 (see Table 10) which was carried out as follows. The starting material (0.11 g, 040 mmol) was dissolved in THF (5.0 mL) and cooled in a dry ice/acetone bath (approximately -78°C). Lithium bis(trimethylsilyl)amide (LiHMDS, 405.0 μl, 0.40 mmol) was added dropwise. The resulting yellow solution was stirred for 15 minutes in a cold bath, after which 2-fluorobenzyl bromide was added to it. The mixture is stirred for another 30 minutes at that temperature and then another 30 minutes at 0oC. The reaction mixture was then poured into 1N HCl (40 mL) and extracted into EtOAc (50 mL). The organic layer was washed with saturated aqueous NaCl solution (35 ml), dried (Na2SO4), filtered and concentrated in vacuo to give 0.16 g of crude product. This material was purified by vacuum chromatography over silica gel (1:3 EtOAc/hexane) to give 0.87 g (57.0%) of the compound from Example 148.
Metoda K. C-alkiliranje hidantoina upotrebom metil magnezijevog karbonata Method K. C-alkylation of hydantoin using methyl magnesium carbonate
Kako je opisao Finkbeiner (J. Org. Chem. 1965, 30, 3414), hidantoini se mogu alkilirati s alkilnim halidom upotrebom magnezijevog metil karbonata (MMC). Otopinu MMC-a u organskom otapalu (kao što je DMF) zasiti se pri pribl. 80oC sa CO2 tijekom perioda od pribl. 1 sata. Zatim se doda odgovarajući hidantion i grije se s MMC pribl. 1 do 2 sata, nakon čega se doda odgovarajući alkilni halid. Reakcijsku smjesu se zatim grije pribl. 2 do 3 sata pri pribl. 100oC, zatim se ohladi na pribl. sobnu temperaturu. Zatim se smjesu prelije u koncentriranu vodenu kiselinu (kao što je HCl) preko leda i ohladi se. Nastalu krutu tvar se skupi filtracijom i očisti kromatografijom na silika gelu i/ili prekristalizacijom željenog proizvoda. As described by Finkbeiner (J. Org. Chem. 1965, 30, 3414), hydantoins can be alkylated with an alkyl halide using magnesium methyl carbonate (MMC). A solution of MMC in an organic solvent (such as DMF) is saturated at approx. 80oC with CO2 during a period of approx. 1 hour. The appropriate hydantion is then added and heated with MMC approx. 1 to 2 hours, after which the appropriate alkyl halide is added. The reaction mixture is then heated for approx. 2 to 3 hours at approx. 100oC, then cool down to approx. room temperature. The mixture is then poured into a concentrated aqueous acid (such as HCl) over ice and cooled. The resulting solid is collected by filtration and purified by silica gel chromatography and/or recrystallization of the desired product.
Spojevi navedeni u tablici 11 proizvedeni su ovom metodom. The compounds listed in Table 11 were produced by this method.
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Metoda K ilustrirana je sintezom spoja iz primjera 181 (vidi tablicu 11) koja je provedena kako slijedi. Suhu dvogrlu tikvicu okruglog dna se evakuira i napuni s atmosferom CO2. U tikvicu se stavi magnezijev metil karbonat u DMF-u (860 μl, 2,0 M) i otopinu se zagrije na 80oC. Iz posude sa suhim ledom kroz kanulu povezanu s reakcijskom posudom uvodi se CO2 i provodi se kroz otopinu 1 sat, nakon čega se priključi cijev s argonom, a kanula se odstrani. Doda se polazni materijal (0,21 g, 0,86 mmola) u DMF-u (4,0 ml) i reakcijsku smjesu se grije 1,5 sata pri 80oC. Zatim se kap po kap doda otopinu 3-pikolil klorida (0,12 g, 0,94 mmola - HCl sol je najprije bila slobodna baza pripravljena s NaOH) u DMF-u (1,0 ml). Temperaturu uljne kupelji povisi se na 110oC i smjesu se grije 4 sata pri toj temperaturi. Kad se ohladi na sobnu temperaturu smjesu se prelije u mješavinu od 5 ml koncentrirane HCl i 10 g leda i odloži se preko noći u frižideru. Zatim se otopinu neutralizira na pH 7-8 sa 6N NaOH i dobivenu krutu tvar se skupi filtracijom uz odsisavanje i ispere s ledenom vodom. Sušenjem spoja pri 50oC u vakuumu dobije se 0,20 g sirovog proizvoda. On se očisti vakuumskom kromatografijom (5% MeOH/CH2Cl2), čime se dobije 0,06 g materijala koji se dalje čisti prekristalizacijom s ETOH, čime se dobije 0,04 g (14,9%) spoja iz primjera 181. Method K is illustrated by the synthesis of Example 181 (see Table 11) which was carried out as follows. A dry double-necked round bottom flask is evacuated and filled with a CO2 atmosphere. Magnesium methyl carbonate in DMF (860 μl, 2.0 M) was placed in the flask and the solution was heated to 80oC. CO2 is introduced from the vessel with dry ice through the cannula connected to the reaction vessel and is passed through the solution for 1 hour, after which the argon tube is connected and the cannula is removed. The starting material (0.21 g, 0.86 mmol) in DMF (4.0 ml) was added and the reaction mixture was heated for 1.5 hours at 80°C. A solution of 3-picolyl chloride (0.12 g, 0.94 mmol - the HCl salt was first the free base prepared with NaOH) in DMF (1.0 ml) was then added dropwise. The temperature of the oil bath is raised to 110oC and the mixture is heated for 4 hours at that temperature. When it has cooled to room temperature, the mixture is poured into a mixture of 5 ml of concentrated HCl and 10 g of ice and stored overnight in the refrigerator. Then the solution is neutralized to pH 7-8 with 6N NaOH and the resulting solid is collected by filtration with suction and washed with ice water. By drying the compound at 50oC in a vacuum, 0.20 g of crude product is obtained. It was purified by vacuum chromatography (5% MeOH/CH2Cl2) to give 0.06 g of material which was further purified by recrystallization from ETOH to give 0.04 g (14.9%) of the compound of Example 181.
Metoda L. Method L.
Sinteza spojeva primjenom poprečnog povezivanja s Pd kao katalizatorom Synthesis of compounds using cross-linking with Pd as a catalyst
Odgovarajuće supstituirana arilborna kiselina, ili arilstanat, pomiješa se s aril halidom ili aril triflatom i katalitičkom količinom tetrakis(trifenilfosfin) paladija u odgovarajućem sistemu otapala (kao što je benzen koji sadrži etanol i vodeni Na2CO3, DMF, NMP ili THF) u inertnoj atmosferi. Ako je potrebno mogu se dodati i druge komponente kao na primjer LiCl i trietilamin. Smjesu se grije između pribl. 2 i 48 sati pri temperaturi između pribl. 50 i 150oC. Smjesu se zatim ohladi i razrijedi s organskim otapalom (kao što je EtOAC). Organsku fazu se ispere uzastopce s vodom i zasićenom vodenom otopinom NaCl. Osuši (na primjer s Na2SO4) i zgusne, čime se dobije nečistu smjesu, iz koje se željeni materijal izolira kromatografijom na silika gelu. An appropriately substituted arylboronic acid, or arylstannate, is mixed with an aryl halide or aryl triflate and a catalytic amount of tetrakis(triphenylphosphine)palladium in an appropriate solvent system (such as benzene containing ethanol and aqueous Na2CO3, DMF, NMP, or THF) under an inert atmosphere. If necessary, other components such as LiCl and triethylamine can be added. The mixture is heated between approx. 2 and 48 hours at a temperature between approx. 50 and 150oC. The mixture is then cooled and diluted with an organic solvent (such as EtOAC). The organic phase is washed successively with water and saturated aqueous NaCl solution. It is dried (for example with Na2SO4) and concentrated, which gives an impure mixture, from which the desired material is isolated by chromatography on silica gel.
Spojevi navedeni u tablici 12 proizvedeni su ovom metodom. The compounds listed in Table 12 were produced by this method.
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Metoda L ilustrirana je sintezom spoja iz primjera 182 (vidi tablicu 12) koja je provedena kako slijedi. Na način koji su opisali Miyaura, M., Yanagy, T., Suzuki, A. Sinth. Commun. 1981, 11, 513, polazni materijal (0,24 g, 0,54 mmola) pomiješa se s fenilbornom kiselinom (0,73 g, 0,60 mmola), tetrakis(trifenilfosfin)paladijem(0) (0,31 g, 0,03 mmola), natrijevim karbonatom (0,19 g, 1,79 mmola), benzenom (3,0 ml), vodom (1,0 ml) i etanolom (1,0 ml) i miješa se 12 sati pod refluksom. Reakcijsku smjesu se zatim prelije u EtOAc (70 ml) i ispere uzastopce s vodom i sa zasićenom vodenom otopinom NaCl. Organski sloj se osuši (Na2SO4), profiltrira i zgusne u vakuumu, čime se dobije 0,25 g sirovog proizvoda. Taj se materijal očisti s dvije uzastopne kromatografije na stupcu silika gela (1:3 zatim 1:1 EtOAc/heksan), čime se dobije 0,11 g (48%) spoja iz primjera 183. Method L is illustrated by the synthesis of Example 182 (see Table 12) which was carried out as follows. In the manner described by Miyaura, M., Yanagy, T., Suzuki, A. Synth. Commun. 1981, 11, 513, starting material (0.24 g, 0.54 mmol) was mixed with phenylboronic acid (0.73 g, 0.60 mmol), tetrakis(triphenylphosphine)palladium(0) (0.31 g, 0.03 mmol), sodium carbonate (0.19 g, 1.79 mmol), benzene (3.0 ml), water (1.0 ml) and ethanol (1.0 ml) and stirred for 12 hours under reflux . The reaction mixture was then poured into EtOAc (70 ml) and washed successively with water and saturated aqueous NaCl. The organic layer is dried (Na2SO4), filtered and concentrated in vacuo to give 0.25 g of crude product. This material was purified by two successive silica gel column chromatographies (1:3 then 1:1 EtOAc/hexane) to give 0.11 g (48%) of the compound of Example 183.
Metoda M. Method M.
Sinteza spojeva primjenom poprečnog povezivanja s karbonilacijskim Pd kao katalizatorom Synthesis of compounds using cross-linking with carbonylation Pd as a catalyst
Odgovarajuće supstituirana arilborna kiselina ili arilstanat pomiješa se s aril halidom ili aril triflatom i katalitičkom količinom tetrakis(trifenilfosfin) paladija u odgovarajućem sistemu otapala (kao što je benzen koji sadrži etanol i vodeni Na2CO3, DMF, NMP ili THF) u inertnoj atmosferi ugljičnog monoksida. Ako je potrebno, mogu se dodati i druge komponente, kao na primjer LiCl i trietil-amin. Smjesu se grije između pribl. 2 i 48 sati pri temperaturi između pribl. 50 i 150oC. Smjesu se zatim ohladi i razrijedi s organskim otapalom (kao što je EtOAC). Organsku fazu se ispere uzastopce s vodom i zasićenom vodenom NaCl, Osuši (na primjer s Na2SO4) i zgusne, čime se dobije nečistu smjesu iz koje se željeni materijal izolira kromatografijom na silika gelu. An appropriately substituted arylboronic acid or arylstannate is mixed with an aryl halide or aryl triflate and a catalytic amount of tetrakis(triphenylphosphine)palladium in an appropriate solvent system (such as benzene containing ethanol and aqueous Na2CO3, DMF, NMP, or THF) under an inert atmosphere of carbon monoxide. If necessary, other components can be added, such as LiCl and triethylamine. The mixture is heated between approx. 2 and 48 hours at a temperature between approx. 50 and 150oC. The mixture is then cooled and diluted with an organic solvent (such as EtOAC). The organic phase is washed successively with water and saturated aqueous NaCl, dried (for example with Na2SO4) and concentrated, thereby obtaining an impure mixture from which the desired material is isolated by chromatography on silica gel.
Spojevi navedeni u tablici 13 proizvedeni su ovom metodom. The compounds listed in Table 13 were produced by this method.
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Metoda M ilustrirana je sintezom spoja iz primjera 215 (vidi tablicu 13) koja je provedena kako slijedi. Polazni materijal (0,23 g, 0,53 mmola) pomiješa se s feniltributil-stananom (0,86 ml, 2,64 mmola), bis(trifenilfosfin)-paladijevim(II) kloridom (0,037 g, 0,05 mmola), DMF-om (10,0 ml) i LiCl (5,1 mg, 1,6 mmola), reakcijsku smjesu se zatim prelije pročisti s argonom, zasiti s CO i miješa se 12 sati pri 115oC. Zatim se reakcijsku smjesu prelije u 1M tetrabutilamonijev fluorid (10 ml), zatim se razrijedi s 95 ml EtOAc i ispere uzastopce s vodom i sa zasićenom vodenom otopinom NaCl. Organski sloj se osuši (Na2SO4), profiltrira i zgusne u vakuumu, čime se dobije 1,2 g sirovog proizvoda. Taj se materijal očisti kromatografijom na silika gelu (1:3 EtOAc/heksan), čime se dobije 0,14 g (48%) spoja iz primjera 215. Method M is illustrated by the synthesis of Example 215 (see Table 13) which was carried out as follows. The starting material (0.23 g, 0.53 mmol) was mixed with phenyltributylstannane (0.86 ml, 2.64 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.037 g, 0.05 mmol) , DMF (10.0 ml) and LiCl (5.1 mg, 1.6 mmol), the reaction mixture was then purged with argon, saturated with CO and stirred for 12 hours at 115oC. The reaction mixture is then poured into 1M tetrabutylammonium fluoride (10 ml), then diluted with 95 ml of EtOAc and washed successively with water and saturated aqueous NaCl solution. The organic layer is dried (Na2SO4), filtered and concentrated in vacuo to give 1.2 g of crude product. This material was purified by silica gel chromatography (1:3 EtOAc/hexane) to give 0.14 g (48%) of the compound from Example 215.
Metoda N. Method N.
Elektrofilna aromatska supstitucija Electrophilic aromatic substitution
Spojevi koji sadrže aromatske prstenove mogu se modificirati s brojnim reagentima pomoću elektrofilne aromatske supstitucije. Ona uključuje postupke aciliranja, nitriranja, sulfoniranja i halogeniranja tih prstenova. Compounds containing aromatic rings can be modified with a number of reagents using electrophilic aromatic substitution. It includes the processes of acylation, nitration, sulfonation and halogenation of these rings.
Spojevi navedeni u tablici 14 proizvedeni su ovom metodom. The compounds listed in Table 14 were produced by this method.
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Takav slučaj predstavlja spoj iz primjera koji je proizveden kako slijedi. Otopinu polaznog materijala (0,4 g, 1,1 mmola) u 1 ml HOAc i 0,1 ml H2SO4 pomiješa se s NaJO3 (0,05 g, 0,2 mmola) i J2 (0,06 g, 0,5 mmola). Smjesu se zatim grije 19 sati pri 70oC i tada se ohladi na sobnu temperaturu, ekstrahira nekoliko puta u EtOAc. EtOAc se zgusne i proizvod se izolira nakon čišćenja kromatografijom na silika gelu. Iskorištenje: 33 mg (30%). Such a case is represented by the compound of the example which was produced as follows. A solution of the starting material (0.4 g, 1.1 mmol) in 1 mL of HOAc and 0.1 mL of H2SO4 was mixed with NaJO3 (0.05 g, 0.2 mmol) and J2 (0.06 g, 0.5 mmol). The mixture is then heated for 19 hours at 70oC and then cooled to room temperature, extracted several times in EtOAc. The EtOAc was concentrated and the product was isolated after purification by silica gel chromatography. Yield: 33 mg (30%).
Metoda Q. Method Q.
Deprotekcija spojeva zaštićenih s kiselo-nestabilnim skupinama Deprotection of compounds protected with acid-labile groups
Spojevi koji imaju kiselo nestabilne zaštitne skupine mogu se deprotektirati na poznat način obradom pod kiselim uvjetima. To općenito uključuje obradu supstrata s TFA, kationsku izmjenu smole (H+), HCl ili HCr u AcOH sa ili bez grijanja. Tako dobiven spoj skupi se filtracijom ili ekstrakcijom i očisti kromatografijom na silika gelu ili prekristalizacijom. Compounds that have acid-labile protecting groups can be deprotected in a known manner by treatment under acidic conditions. This generally involves treatment of the substrate with TFA, resin cation exchange (H+), HCl or HCr in AcOH with or without heating. The thus obtained compound is collected by filtration or extraction and purified by silica gel chromatography or recrystallization.
Spojevi navedeni u tablici 15 proizvedeni su ovom općom metodom. The compounds listed in Table 15 were produced by this general method.
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Metoda Q ilustrirana je sintezom spoja iz primjera 219 koja je provedena kako slijedi. Miješanu otopinu polaznog materijala (0,10 g, 0,19 mmola) u 10 ml metilen klorida ohladi se najprije na 0oC i zatim se doda 2,0 ml trifluor-octene kiseline. Miješanje se nastavi još 20 minuta i zatim se otopinu pusti polako zagrijati na sobnu temperaturu. Otopinu se miješa još 6 sati i zatim se zgusne, čime se dobije bijelu krutu tvar koju se dalje suši još 16 sati u vakuumu. Sirovu krutu tvar se zatim triturira s 10 ml kipućeg heksana i smjesu se pusti ohladiti na sobnu temperaturu. Dobiveni bijeli talog se skupi filtracijom, ispere s 5 ml heksana i suši 4 sata pod visokim vakuumom, čime se dobije 0,06 g (iskorištenje 68%) spoja iz primjera 219. Method Q is illustrated by the synthesis of the compound of Example 219 which was carried out as follows. A mixed solution of the starting material (0.10 g, 0.19 mmol) in 10 ml of methylene chloride was first cooled to 0°C and then 2.0 ml of trifluoroacetic acid was added. Stirring is continued for another 20 minutes and then the solution is allowed to slowly warm to room temperature. The solution is stirred for another 6 hours and then thickened to give a white solid which is further dried for another 16 hours under vacuum. The crude solid is then triturated with 10 ml of boiling hexane and the mixture is allowed to cool to room temperature. The resulting white precipitate was collected by filtration, washed with 5 ml of hexane and dried for 4 hours under high vacuum to give 0.06 g (68% yield) of the compound from Example 219.
Metoda P. Method P.
Saponifikacija estera u kiselinu s hidroksidom Acid saponification of esters with hydroxide
Određeni spojevi koji sadrže skupinu karboksilnog estera mogu se na poznat način pretvoriti u karboksilne kiseline obradom sa sredstvima za saponifikaciju. To općenito uključuje obradu supstrata s NaOH, KOH ili LiOH u otapalu kao što je voda koja ponekad sadrži sredstvo za solubilizaciju kao što je THF. Čišćenje općenito uključuje ekstrakciju neizreagiranog polaznog materijala s organskim otapalom, kao što je EtOAc ili CH2Cl2, zakiseljavanje vodenog sloja i čišćenje kiseline filtracijom ili ekstrakcijom u organsko otapalo, kao što je EtOAc ili CH2Cl2. Daljnje čišćenje može se provesti prekristalizacijom, kromatografijom na silika gelu ili pomoću HPLC reverznih faza, čime se dobije željeni spoj. Certain compounds containing a carboxylic ester group can be converted into carboxylic acids in a known manner by treatment with saponification agents. This generally involves treating the substrate with NaOH, KOH or LiOH in a solvent such as water which sometimes contains a solubilizing agent such as THF. Purification generally involves extracting the unreacted starting material with an organic solvent, such as EtOAc or CH2Cl2, acidifying the aqueous layer, and purifying the acid by filtration or extraction into an organic solvent, such as EtOAc or CH2Cl2. Further purification can be carried out by recrystallization, chromatography on silica gel or reverse phase HPLC to obtain the desired compound.
Spojevi navedeni u tablici 16 proizvedeni su ovom općom metodom. The compounds listed in Table 16 were produced by this general method.
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Primjer 239 (tablica 16) proizveden je tako da se polazni materijal (0,38 gm 0,65 mmola) otopi u 4 ml vode i 8 ml MeOH koji sadrži LiOH (0,08 g, 1,95 mmola) i smjesu se grije 2,5 sata pri 60oC. MeOH se odstrani zgušnjavanjem i vodeni ostatak se pomiješa s 1N HCl. Proizvod se ekstrahira u EtOAc iz kojeg kristalizira nakon hlađenja. Iskorištenje: 262 mg (72%). Example 239 (Table 16) was prepared by dissolving the starting material (0.38 gm, 0.65 mmol) in 4 ml of water and 8 ml of MeOH containing LiOH (0.08 g, 1.95 mmol) and heating the mixture 2.5 hours at 60oC. The MeOH was removed by concentration and the aqueous residue was mixed with 1N HCl. The product is extracted into EtOAc from which it crystallizes after cooling. Yield: 262 mg (72%).
Metoda Q. Method Q.
Odcjepljenje ftalimidne zaštine skupine Cleavage of the phthalimide protecting group
Primarni amini mogu se zaštititi kao njihovi derivati ftalimida. Ti derivati se brzo sintetiziraju metodom U upotrebom kalijeve soli ftalimida kao nukleofila. Amin se može osloboditi od ftalimidne zaštitne skupine upotrebom nukeofilnih reagenata, kao što je hidrazin ili metil amin, u otapalu kao što je EtOH. Čišćenje općenito uključuje zakiseljavanje vodenog sloja i ekstrakciju neizreagiranog polaznog materijala s organskim otapalom kao što je EtOAc ili CH2Cl2. Zaluživanjem vodenog sloja dobije se slobodnu bazu amina koju se očisti filtracijom ili ekstrakcijom u organsko otapalo kao što je EtOAc ili CH2Cl2. Daljnje čišćenje može se provesti prekristalizacijom, kromatografijom na silika gelu ili pomoću HPLC na reverznih faza, čime se dobije željeni spoj. Primary amines can be protected as their phthalimide derivatives. These derivatives are rapidly synthesized by method U using the potassium salt of phthalimide as a nucleophile. The amine can be liberated from the phthalimide protecting group using nucleophilic reagents, such as hydrazine or methyl amine, in a solvent such as EtOH. Purification generally involves acidifying the aqueous layer and extracting the unreacted starting material with an organic solvent such as EtOAc or CH2Cl2. Basifying the aqueous layer gives the free amine base, which is purified by filtration or extraction into an organic solvent such as EtOAc or CH2Cl2. Further purification can be carried out by recrystallization, chromatography on silica gel or reverse-phase HPLC to obtain the desired compound.
Spojevi navedeni u tablici 17 proizvedeni su ovom općom metodom. The compounds listed in Table 17 were produced by this general method.
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Spoj iz primjera 240 proizveden je tako da se polazni materijal (proizveden metodom U, 0,72 g, 1,2 mmola) otopi u 73 ml EtOH i pomiješa s 19,5 ml 33%-tne otopine MeNH2 u EtOH. Smjesu se grije 2,5 sata pod refluksom i zatim se ohladi na sobnu temperaturu. Reakcijsku smjesu se zgusne i ostatak se otopi u CH2Cl2 koju se dalje ispere s vodom i sa zasićenom vodenom otopinom NaCl. Organski sloj se osuši (Na2SO4) i zgusne. Žuto ulje se otopi u EtOH i obradi s plinovitim HCl. Amin hidroklorid spoja iz primjera 240 dobiven je s iskorištenjem od 69% (0,49 g). The compound of Example 240 was prepared by dissolving the starting material (prepared by method U, 0.72 g, 1.2 mmol) in 73 ml of EtOH and mixing with 19.5 ml of a 33% solution of MeNH 2 in EtOH. The mixture is heated for 2.5 hours under reflux and then cooled to room temperature. The reaction mixture is concentrated and the residue is dissolved in CH2Cl2, which is further washed with water and saturated aqueous NaCl solution. The organic layer is dried (Na2SO4) and concentrated. The yellow oil was dissolved in EtOH and treated with HCl gas. The amine hydrochloride of the compound from Example 240 was obtained with a yield of 69% (0.49 g).
Metoda R. Method R.
Pretvorba nitrila u amidine Conversion of nitriles to amidines
Aromatski nitrili mogu se pretvoriti u amidinske skupine na nekoliko načina. Općenito za tu pretvorbu su potrebna dva stupnja, pri čemu prvi stupanj uključuje obradu s kiselinom (kao što je na primjer HCl) i s alkoholom (kao što je na primjer MeOH ili EtOH) da se dobije intermedijarni imino eter. Zatim se taj derivat pretvori u amidin obradom s aminom. Čišćenje se obično vrši prekristalizacijom soli derivata amidina. Daljnje čišćenje se može provesti prekrisalizacijom, kromatografijom na silika gelu ili HPLC reverznih faza, čime se dobije željeni proizvod. Aromatic nitriles can be converted to amidine groups in several ways. Generally two steps are required for this conversion, with the first step involving treatment with an acid (such as, for example, HCl) and with an alcohol (such as, for example, MeOH or EtOH) to give the intermediate imino ether. This derivative is then converted into an amidine by treatment with an amine. Purification is usually done by recrystallization of amidine derivative salts. Further purification can be carried out by recrystallization, chromatography on silica gel or reverse-phase HPLC, which gives the desired product.
Spojevi navedeni u tablici 18 proizvedeni su ovom općom metodom. The compounds listed in Table 18 were produced by this general method.
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Spoj iz primjera 243 proizveden je tako da se polazni materijal (0,2 g, 0,4 mmola) otopi u 7 ml EtOH, smjesu se ohladi na ledenoj kupelji i smjesu se obrađuje 15 minuta sa suhim plinovitim HCl. Zatim se smjesu miješa 1 sat pri sobnoj temperaturi i zgusne, čime se dobije sirovi imino eter hidroklorid. Intermedijat se otopi u EtOH (10 ml), ohladi na ledenoj kupelji i obrađuje 20 minuta s bezvodnim plinovitim NH3. Nakon 5 sati reakcijsku smjesu se zgusne, čime se dobije sirovi amidin hidroklorid. Taj se materijal očisti kromatografijom na silika gelu (1:9 MeOH:CH2Cl2), čime se dobije 0,08 g (38%) proizvoda. The compound from example 243 was prepared by dissolving the starting material (0.2 g, 0.4 mmol) in 7 ml of EtOH, cooling the mixture in an ice bath and treating the mixture with dry gaseous HCl for 15 minutes. The mixture is then stirred for 1 hour at room temperature and thickened, thereby obtaining the crude imino ether hydrochloride. The intermediate was dissolved in EtOH (10 mL), cooled in an ice bath, and treated with anhydrous NH 3 gas for 20 min. After 5 hours, the reaction mixture is concentrated, thus obtaining crude amidine hydrochloride. This material was purified by chromatography on silica gel (1:9 MeOH:CH2Cl2), yielding 0.08 g (38%) of the product.
Metoda S. Method S.
Redukcija karboksilnih kiselina u alkohole Reduction of carboxylic acids into alcohols
Određeni spojevi koji imaju skupinu karboksilne kiseline mogu se na poznat način pretvoriti u alkohole obradom s redukcijskim reagentima. To općenito uključuje obradu supstrata s LiAlH4 ili reagentom na osnovi BH3 u otapalu kao što je THF ili eter. Nakon opreznog gašenja s vodenim sistemom, čišćenje obično uključuje ekstrakciju proizvoda u organsko otapalo kao što je EtOAC ili CH2Cl2 i čišćenje primjenom prekristalizacije, kromatografije na silika gelu ili HPLC reverznih faza, čime se dobije željeni proizvod. Certain compounds having a carboxylic acid group can be converted into alcohols in a known manner by treatment with reducing reagents. This generally involves treating the substrate with LiAlH4 or a BH3-based reagent in a solvent such as THF or ether. After careful quenching with an aqueous system, purification typically involves extraction of the product into an organic solvent such as EtOAC or CH2Cl2 and purification using recrystallization, silica gel chromatography, or reverse phase HPLC to yield the desired product.
Spojevi navedeni u tablici 19 proizvedeni su ovom općom metodom. The compounds listed in Table 19 were produced by this general method.
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Spoj iz primjera 244 proizveden je tako da se polazni materijal (proizveden metodama J i O, 0,16 g, 0,32 mmola) otopi u 1 ml THF, smjesu se ohladi na ledenoj kupelji i smjesu se pomiješa s 0,65 ml 1M otopine BH3-THF (0,65 mmola). Smjesu se pusti zagrijati na sobnu temperaturu i miješa se 15 sati. Reakcijsku smjesu sse pogasi tako da se polako i oprezno doda vodu i organsku komponentu se ekstrahira u EtOAc. Sloj u EtOAc se ispere s vodom, sa zasićenom vodenom otopinom NaCl i osuši preko Na2SO4. Zgušnjavanjem i kromatografijom na silika gelu (1:1 EtOAc:heksan) dobije se željeni spoj (0,06 g, 42%). The compound of Example 244 was prepared by dissolving the starting material (prepared by methods J and O, 0.16 g, 0.32 mmol) in 1 ml of THF, cooling the mixture in an ice bath and mixing the mixture with 0.65 ml of 1M of BH3-THF solution (0.65 mmol). Let the mixture warm to room temperature and stir for 15 hours. The reaction mixture was quenched by slowly and cautiously adding water and the organic component was extracted into EtOAc. The EtOAc layer was washed with water, saturated aqueous NaCl and dried over Na2SO4. Concentration and chromatography on silica gel (1:1 EtOAc:hexane) gave the desired compound (0.06 g, 42%).
Metoda T. Method T.
Deprotekcija spojeva s nukleofilnim reagentima Deprotection of compounds with nucleophilic reagents
Određeni spojevi koji imaju metoksi zaštitne skupine mogu se na poznat način deprotektirati u hidroksi derivate obradom s određenim nukleofilnim reagentima. To općenito uključuje obradu supstrata s BBr3 ili TMSI u otapalu kao što je CH2Cl2, općenito hlađenjem na ledenoj kupelji i zatim sa ili bez grijanja. Nakon između 10 minuta i 8 sati reakciju se pogasi sa slabom bazom kao što je vodena NaHCO3 i organsku komponentu se ekstrahira u otapalo kao što je EtOAc i nakon zgušnjavanja se očisti kromatografije na silika gelu ili prekristalizacijom, čime se dobije željeni proizvod. Certain compounds having methoxy protecting groups can be deprotected in a known manner into hydroxy derivatives by treatment with certain nucleophilic reagents. This generally involves treating the substrate with BBr3 or TMSI in a solvent such as CH2Cl2, generally by cooling in an ice bath and then with or without heating. After between 10 minutes and 8 hours, the reaction is quenched with a weak base such as aqueous NaHCO3 and the organic component is extracted into a solvent such as EtOAc and after concentration is purified by silica gel chromatography or recrystallization to give the desired product.
Spojevi navedeni u tablici 20 proizvedeni su ovom općom metodom. The compounds listed in Table 20 were produced by this general method.
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Metoda T ilustrirana je sintezom spoja iz primjera 246 koja je provedena kako slijedi. Miješanu otopinu polaznog materijala (0,35 g, 0,64 mmola) u 9 ml CH2Cl2 ohladi se na 0oC prije dodatka 1,0 ml BBr3 (1,07 mmola, 1M CH2Cl2). Miješanje se nastavi i zatim se otopinu pusti polako zagrijati na sobnu temperaturu. Otopinu se miješa još 4 sata i zatim se doda zasićenu vodenu otopinu NaHCO3, organski sloj se odstrani i zgusne čime se dobije sirov proizvod. Čišćenje se provodi kromatografijom na silika gelu (1:4 EtOAc/heksan), čime se dobije 0,16 g (iskorištenje 48%) željenog spoja. Method T is illustrated by the synthesis of the compound of Example 246 which was carried out as follows. A stirred solution of the starting material (0.35 g, 0.64 mmol) in 9 mL of CH2Cl2 was cooled to 0°C before the addition of 1.0 mL of BBr3 (1.07 mmol, 1M CH2Cl2). Stirring is continued and then the solution is allowed to slowly warm to room temperature. The solution is stirred for another 4 hours and then a saturated aqueous solution of NaHCO3 is added, the organic layer is removed and concentrated to obtain the crude product. Purification is carried out by chromatography on silica gel (1:4 EtOAc/hexane), which gives 0.16 g (48% yield) of the desired compound.
Metoda U. Method U.
Nukleofilno premještanje Nucleophilic displacement
Odgovarajuće nukleofilno sredstvo se otopi u aprotonskom otapalu (kao što je DMF, THF ili DMSO) i pomiješa se s jednim do tri ekvivalenta nukleofila (kao što je Me3N, Na sol imidazola, Na2SO3, NaCN, P(OEt)3, ili K sol ftalimida pri temperauri između pribl. sobne temperature i 100oC. Smjesu se miješa pribl. 24 sata pri temperaturi između pribl. 0 i 100oC. (Napredovanje reakcije može se pratiti primjenom TLC). Otopinu se zatim ohladi i razrijedi s organskim otapalom (kao što je na primjer EtOAc). Organsku fazu se ispere uzastopce s razrijeđenom vodenom kiselinom (kao što je 1N HCl) i s vodom, osuši (na primjer preko MgSO4) i zgusne. Željeni spoj se očisti kromatografijom na silika gelu, pomoću HPLC reverznih faza ili prekristalizacijom. The appropriate nucleophilic agent is dissolved in an aprotic solvent (such as DMF, THF, or DMSO) and mixed with one to three equivalents of nucleophile (such as Me3N, Na imidazole salt, Na2SO3, NaCN, P(OEt)3, or K salt phthalimide at a temperature between about room temperature and 100°C. The mixture is stirred for about 24 hours at a temperature between about 0 and 100°C. (Progress of the reaction can be monitored using TLC.) The solution is then cooled and diluted with an organic solvent (such as eg EtOAc).The organic phase is washed successively with dilute aqueous acid (such as 1N HCl) and water, dried (eg over MgSO4) and concentrated.The desired compound is purified by silica gel chromatography, reverse phase HPLC or recrystallization.
Spojevi navedeni u tablici 21 proizvedeni su ovom općom metodom. The compounds listed in Table 21 were produced by this general method.
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Metoda U ilustrirana je sintezom spoja iz primjera 262 koja je provedena kako slijedi. K polaznom materijalu (0,28 g, 0,54 mmola) doda se 1-H-pirazolkarboksamid (0,08 g, 0,54 mmola) i zatim 7 ml DMF-a i 0,2 ml N,N-diizopropil-etilamina. Dobivenu smjesu se zatim miješa 15 sati pri sobnoj temperaturi. Zatim se doda eter koji uzrokuje da smjesa postane mutna. Ako ne nastaju kristali, doda se MeOH da se ponovno otope rekacijske komponente i proizvod se istaloži kao njegova HCl sol dodatkom 1N HCl. Krutu tvar se skupi i ispere s eterom, čime se dobije 0,11 g (20%) gvanidin hidroklorida. Method U is illustrated by the synthesis of the compound of Example 262 which was carried out as follows. 1-H-pyrazolecarboxamide (0.08 g, 0.54 mmol) was added to the starting material (0.28 g, 0.54 mmol) followed by 7 ml of DMF and 0.2 ml of N,N-diisopropyl- ethylamine. The resulting mixture is then stirred for 15 hours at room temperature. Ether is then added causing the mixture to become cloudy. If no crystals form, MeOH is added to redissolve the reaction components and the product is precipitated as its HCl salt by addition of 1N HCl. The solid was collected and washed with ether to give 0.11 g (20%) of guanidine hydrochloride.
Metoda V. Method V.
Rastavljanje smjese enantiomera. Separation of a mixture of enantiomers.
Postoji nekoliko načina za rastavljanje spojeva prema izumu na njihove enantiomerno čiste oblike. Jedna takova metoda je kiralna HPLC. Jedan primjer pakovanja kolone je Chiracel-OD (Diacel Chemistry Industries). Primjer sistema otapala je 9:1 heksan:izopropil alkohol. Općenito, R-enantiomer se ispere prvi, ali to ne treba uzimati kao jedini kriterij za određivanje stereokemije. There are several ways to resolve the compounds of the invention into their enantiomerically pure forms. One such method is chiral HPLC. One example of a column packing is Chiracel-OD (Diacel Chemistry Industries). An example of a solvent system is 9:1 hexane:isopropyl alcohol. In general, the R-enantiomer is washed out first, but this should not be taken as the sole criterion for determining stereochemistry.
Spojevi navedeni u tablici 22 rastavljeni su ovom metodom. The compounds listed in Table 22 were resolved by this method.
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Opis bioloških svojstava Description of biological properties
Biološka svojstva tipičnih spojeva formule I istražena su pomoću dolje opisanih protokola pokusa. Rezultati takovih ispitivanja prikazani su u dolnjoj tablici 23. The biological properties of typical compounds of formula I were investigated using the experimental protocols described below. The results of such tests are shown in table 23 below.
Pokus određivanja inhibicije vezanja LFA-1 na ICAM-1 An attempt to determine the inhibition of LFA-1 binding to ICAM-1
Svrha ispitivanja: Purpose of the test:
Ovaj protokol ispitivanja određen je za proučavanje izravnog antagonizma, pomoću ispitnog spoja, interakcije CAM, ICAM-1 s leukointegrinom CD18/CD11a (LFA-1). This test protocol was designed to study the direct antagonism, by the test compound, of the interaction of CAM, ICAM-1 with leukointegrin CD18/CD11a (LFA-1).
Opis protokola ispitivanja: Description of the test protocol:
LFA-1 je imunosno očišćen pomoću TS2/4 antitijela iz 20 g taloga humanih JY ili SKW3 stanica, primjenom ranije opisnaog protokola (Dustin, M.J., et al., J. Immunol. 1992, 148, 2654-2660). LFA-1 je očišćen iz SKW3 lizata imunoafinitetnom kromatografijom na TS2/4 LFA-1 mAb Sepharosi i ispran pri pH 11,5 u prisutnosti 2 mM MgCl2 i 1% oktilglukozida. Nakon skupljanja i neutralizacije frakcija iz kolone TS2/4, uzorci su skupljeni i prethodno izbistreni s protein G agarozom. LFA-1 was immunopurified with TS2/4 antibody from 20 g pellet of human JY or SKW3 cells, using a previously described protocol (Dustin, M.J., et al., J. Immunol. 1992, 148, 2654-2660). LFA-1 was purified from SKW3 lysates by immunoaffinity chromatography on TS2/4 LFA-1 mAb Sepharose and washed at pH 11.5 in the presence of 2 mM MgCl2 and 1% octylglucoside. After collection and neutralization of the fractions from the TS2/4 column, the samples were collected and pre-cleared with protein G agarose.
Topivi oblik ICAM-1 je konstruiran, ekspresioniran, očišćen i karakteriziran kako je ranije opisano (Marlin, S., et al., Nature, 1990, 344, 70-72 i vidi Arruda, A. et al., Antimicrob. Agents Chemother. 1992, 36, 1186-1192). Ukratko, izoleucin 454, koji je lokaliziran na takozvanoj granici između domene 5 ektodomene i domene transmembrane, promijenjen je prema stop kodonu primjenom standardne oligonukleotidno usmjerene mutageneze. Ta konstrukcija daje molekulu identičnu s prvih 453 amino kiselina membranske granice ICAM-1. Vektor ekspresije je stvoren s genom dihidrofolat reduktaze hrčka, neomicin-rezistentnim markerom, i kodnom regijom sICAM-1 gore opisanog konstrukta, samo s promotorom, spojnim signalima, i poliadenilacijskim signalom rane regije SV40. Rekombinantni plazmid je tranfektiran u stanice HCO DUX primjenom standardnih metoda kalcijevog fosfata. Stanice su propuštene u selektivni medij (G418) i kolonije koje izlučuju sICAM-1 su uvećane upotrebom metotreksata. sICAM-1 su očišćene iz medija bez seruma primjenom konvencionalnog postupka ne-afinitetne kromatografije, uključiv ionsku izmjenu i kromatografiju isključenja po veličini. A soluble form of ICAM-1 was constructed, expressed, purified and characterized as previously described (Marlin, S., et al., Nature, 1990, 344, 70-72 and see Arruda, A. et al., Antimicrob. Agents Chemother 1992, 36, 1186-1192). Briefly, isoleucine 454, which is localized at the so-called boundary between domain 5 of the ectodomain and the transmembrane domain, was changed toward a stop codon using standard oligonucleotide-directed mutagenesis. This construction yields a molecule identical to the first 453 amino acids of the membrane boundary of ICAM-1. An expression vector was created with the hamster dihydrofolate reductase gene, the neomycin-resistant marker, and the sICAM-1 coding region of the construct described above, with only the promoter, splice signals, and SV40 early region polyadenylation signal. The recombinant plasmid was transfected into HCO DUX cells using standard calcium phosphate methods. Cells were passaged in selective medium (G418) and colonies secreting sICAM-1 were expanded using methotrexate. sICAM-1 were purified from serum-free media using conventional non-affinity chromatography procedures, including ion exchange and size exclusion chromatography.
Vezanje LFA-1 na ICAM-1 promatrano je najprije inkubacijom sICAM-1 pri 40 μg/ml u Dulbecco fosfatno puferiranoj otopini soli s kalcijem i magnezijem, s dodatnih 2 mM MgCl2 i 0,1 mM PMSF (pufer za razređivanje) u ploči s 96 jamica 30 minuta pri sobnoj temperaturi. Ploče su zatim blokirane dodatkom 2% (masa/vol.) goveđeg seruma albumina u puferu za razređivanje 1 sat pri 37oC. Otopina za blokiranje je odstranjena iz jamica i ispitni spojevi su razrijeđeni i dodani nakon čega je slijedio dodatak od približno 25 ng imunoafinitetno očišćenog LFA-1. LFA-1 je inkubiran u prisutnosti ispitnog spoja i ICAM-1 1 sat pri 37oC. Jamice su isprane s puferom za razređivanje. Vezanje LFA-1 je detektirano dodatkom poliklonskog antitijela usmjerenog prema peptidu koji odgovara citoplazmičnom kraju CD18 u 1:100 razređenju s puferom za razređivnje i 1% BSA i inkubacijom 45 minuta pri 37oC. Jamice su isprane 3 puta s puferom za ispiranje i vezanje poliklonskog antitijela detektirano je dodatkom 1:4000 razređene peroksidaze konjske rotkve konjugirane na kozji imunoglobulin usmjeren protiv zečjeg imunoglobulina. Taj reagent je inkubiran 20 minuta pri 37oC, zdjelice su isprane kao gore i supstrat za peroksidazu konjske rotkve dodat je u svaku jamicu da se razvije kvantitativni kolorimetrijski signal proporcionalan količini LFA-1 vezanoj na sICAM-1. Topive ICAM-1 (60 μg/ml) upotrijebljene su kao pozitivna kontrola za inhibiciju interakcije LFA-1/ICAM-1. Izostanak dodatka LFA-1 u pokusu vezanja primijenjen je kao osnovna kontrola za sve uzorke. Krivulje doze odgovora dobivene su za sve ispitane spojeve. Binding of LFA-1 to ICAM-1 was observed first by incubating sICAM-1 at 40 μg/ml in Dulbecco's phosphate-buffered saline with calcium and magnesium, supplemented with 2 mM MgCl2 and 0.1 mM PMSF (dilution buffer) in a plate with 96 wells for 30 minutes at room temperature. Plates were then blocked by the addition of 2% (w/v) bovine serum albumin in dilution buffer for 1 hour at 37oC. The blocking solution was removed from the wells and test compounds were diluted and added followed by the addition of approximately 25 ng of immunoaffinity purified LFA-1. LFA-1 was incubated in the presence of the test compound and ICAM-1 for 1 hour at 37°C. Wells were washed with dilution buffer. LFA-1 binding was detected by addition of a polyclonal antibody directed against a peptide corresponding to the cytoplasmic end of CD18 at a 1:100 dilution with dilution buffer and 1% BSA and incubation for 45 minutes at 37oC. Wells were washed 3 times with wash buffer and polyclonal antibody binding was detected by addition of 1:4000 diluted horseradish peroxidase conjugated to goat immunoglobulin directed against rabbit immunoglobulin. This reagent was incubated for 20 minutes at 37oC, the dishes were washed as above and horseradish peroxidase substrate was added to each well to develop a quantitative colorimetric signal proportional to the amount of LFA-1 bound to sICAM-1. Soluble ICAM-1 (60 μg/ml) was used as a positive control to inhibit the LFA-1/ICAM-1 interaction. The absence of LFA-1 addition in the binding experiment was used as a basic control for all samples. Dose-response curves were obtained for all tested compounds.
Rezultati ovih ispitivanja navedeni su kao Kd’s u μM. The results of these tests are reported as Kd's in μM.
MMT pokus za određivanje citotoksičnosti MMT test to determine cytotoxicity
Svrha ispitivanja The purpose of the examination
Da se dobije smisleni podatak iz staničnih pokusa, spojevi se moraju najprije ispitati pokusOM mjerenja stanične toksičnosti. U tu svrhu može se primijeniti pokus MTT. In order to obtain meaningful data from cellular experiments, the compounds must first be tested in an experiment measuring cellular toxicity. For this purpose, the MTT test can be applied.
Opis protokola ispitivanja: Description of the test protocol:
MTT, (3-(4,5-dimetiltiazol-2-il)-2,5-difenil-2H-tetra-zolijev bromid), je žuti supstrat koji se cijepi pomoću stanica s aktivnim mitohondrijem, čime se dobije tamno plavo/purpuran formazanski proizvod. Taj se talog može solubilizirati i količnu materijala se može brojčano odrediti spektrofotometrijskim postupcima (Gerlier, D., Thomaset, N., J. Immunol. Methods, 1986, 94, 57-63). Količina boje je proporcionalna broju stanica sposobnih za život. Ovaj sistem pokusa primijenjen je za procjenu učinka ispitnih spojeva na sposobnost stanica za život in vitro. MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide), is a yellow substrate that is cleaved by cells with active mitochondria, yielding a deep blue/purple formazan product. This precipitate can be solubilized and the amount of material can be quantified by spectrophotometric procedures (Gerlier, D., Thomaset, N., J. Immunol. Methods, 1986, 94, 57-63). The amount of dye is proportional to the number of viable cells. This test system was applied to evaluate the effect of test compounds on the ability of cells to live in vitro.
Upotrijebljene su stanice SKW3, koje ekspresioniraju LFA-1. Stanice upotrijebljene u svakom pokusu bile su namještene na 1,25x106 stanica/ml i 100 μl iz te zalihe je dispergirano u svaku jamicu mikrotitarske ploče sa 96 jamica ravnog dna. Za svaki uvjet u pojedinačnom pokusu određene su po tri jamice. Nizovi razrijeđenih otopina svakog ispitnog spoja ili samog vehikla dodani su u svaku jamicu. Prije procjenjivanja sposobnosti stanica za život, stanice su inkubirane sa spojem 4-24 sata pri 37oC. Zatim je u svaku jamicu dodano po 10 μl MMT-a steriliziranog pomoću filtera. Zaliha MTT-a je učinjena u fosfatno puferiranoj otopini soli pri koncentraciji od 5 mg/ml. Zatim su ploče inkubirane 1 sat pri 37oC u atmosferi s 5% CO2. Ploče su periodički ispitane s obzirom na razvoj kristala formazona. SKW3 cells, which express LFA-1, were used. Cells used in each experiment were seeded at 1.25x10 6 cells/ml and 100 μl of this stock was dispersed into each well of a 96-well flat bottom microtiter plate. Three wells were determined for each condition in an individual experiment. Serial dilutions of each test compound or vehicle alone were added to each well. Before assessing cell viability, cells were incubated with the compound for 4-24 hours at 37oC. Then, 10 μl of filter-sterilized MMT was added to each well. The stock of MTT was made in phosphate-buffered saline at a concentration of 5 mg/ml. Then the plates were incubated for 1 hour at 37oC in an atmosphere with 5% CO2. The plates were periodically examined for the development of formazon crystals.
Po isteku perioda inkubacije kristali formazona su otopljeni dodatkom 100 μl 0,04 N HCl u izo-propil alkoholu u svaku jamicu. Svaka jamica je temeljito promiješana ponovnim pipetiranjem s višekanalnim pipeterom. Ploče su ostavljene tako da za 15-20 minuta poprime sobnu temperaturu i zatim su očitane sa spektrofotometrom. Apsorbancija je izmjerena pri ispitnoj valnoj duljini od 570 nm. Podaci su prikazani kao područje koncentracije (u μM) u kojem 50% stanica više nije sposobno za život. At the end of the incubation period, formazon crystals were dissolved by adding 100 μl of 0.04 N HCl in iso-propyl alcohol to each well. Each well was thoroughly mixed by repeated pipetting with a multichannel pipettor. The plates were left to reach room temperature for 15-20 minutes and then read with a spectrophotometer. Absorbance was measured at a test wavelength of 570 nm. Data are presented as the concentration range (in μM) in which 50% of cells are no longer viable.
Pokus određivanja inhibicije vezanja SKW3 stanica na ICAM-1 vs. vezanju na fibronektin An attempt to determine the inhibition of binding of SKW3 cells to ICAM-1 vs. binding to fibronectin
Svrha pokusa: Purpose of the experiment:
Ovaj pokus primijenjen je za ispitivanje selektivne sposobnosti ispitnog spoja da antagonizira interakciju oblika granice stanice LFA-1 sa ICAM-1. Za pokus se koristi humana T stanična linija, stanice SKW3 koje ekspresioniraju CD18, CD11a i druge integrine koji nisu srodni s CD18, CD11a i koji se ne mogu “aktivirati” s forbol esterima. Forbol esteri pojačavaju afinitet CD18, CD11a za ICAM-1. This experiment was applied to examine the selective ability of a test compound to antagonize the interaction of the cell border form LFA-1 with ICAM-1. The experiment uses the human T cell line, SKW3 cells that express CD18, CD11a and other integrins that are not related to CD18, CD11a and that cannot be "activated" with phorbol esters. Phorbol esters enhance the affinity of CD18, CD11a for ICAM-1.
Ista limfocitna linija, SKW3, također se ljepi na fibronektin u prisutnosti forbol estera. Tu adheziju posreduju membranski proteini neovisno o interakciji LFA-1/ICAM-1. Stanice SKW3 ekpresioniraju drugi integrin, VLA4, koji je receptor za fibronektin. Zbog toga, kao preliminarna indikacija selektivnosti ispitnih spojeva da interferiraju inteakcije leukointegrin/CAM, ali ne i druge slučajeve vezanja integrin-ligand, spoj se može ispitati s obzirom na svoju sposobnost antagoniziranja staničnog vezanja fibronektin receptora u njegovoj interakciji s pročišćenim fibronektinom. Spojevi koji inhibiraju tu adheziju fibronektina nisu specifični antagonisti vezanja CD18, CD11a/ICAM-1. The same lymphocyte line, SKW3, also adheres to fibronectin in the presence of phorbol ester. This adhesion is mediated by membrane proteins independently of the LFA-1/ICAM-1 interaction. SKW3 cells express another integrin, VLA4, which is a receptor for fibronectin. Therefore, as a preliminary indication of the selectivity of the test compounds to interfere with leukointegrin/CAM interactions, but not other cases of integrin-ligand binding, the compound can be tested for its ability to antagonize cellular binding of the fibronectin receptor in its interaction with purified fibronectin. Compounds that inhibit this fibronectin adhesion are not specific antagonists of CD18, CD11a/ICAM-1 binding.
Opis protokola ispitivanja: Description of the test protocol:
Ploče s 96 jamica premazane su sa sICAM-1 (40 μg/ml) ili fibronektinom (100 μg/ml) u puferu za razređivanje 1 sat pri sobnoj temperaturi. Jamicama je dodano 100 μl odgovarajuće razrijeđenog ispitnog spoja ili 100 μl RPMI s 15% fetalnog goveđeg seruma kao kontrole. Stanice SKW3, koje ekspresioniraju CD18, CD11a i VLA-4 (Dustin, M. et al., J. Exp. Med. 1987, 165, 672-692) su isprane i suspendirane na koncentraciju od 106 stanica/ml u RPMI s 15% fetalnog goveđeg seruma. Neposredno prije dodavanja stanica u jamice, stanice su stimulirane s forbol ester 12-miristat 13-acetatom (PMA) na krajnju koncentraciju od 100 μg/ml. 100 μl stanica je zatim dodano u jamice, čime je dobivena krajnja koncentracija od 50 μg/ml PMA i 2 stanice/jamici. Ploče su inkubirane 2 sata pri 37oC. Nevezane i slabo vezane stanice su lagano isprane s RPMI. Stanice koje su se zadržale i stoga su vezane na ICAM-1 ili na fibronektin kvantificirane su pomoću istog reagenta koji je upotrijebljen u gornjem pokusu s MTT-om. 96-well plates were coated with sICAM-1 (40 μg/ml) or fibronectin (100 μg/ml) in dilution buffer for 1 hour at room temperature. 100 μl of appropriately diluted test compound or 100 μl of RPMI with 15% fetal bovine serum as a control was added to the wells. SKW3 cells, which express CD18, CD11a and VLA-4 (Dustin, M. et al., J. Exp. Med. 1987, 165, 672-692) were washed and suspended at a concentration of 10 6 cells/ml in RPMI with 15 % fetal bovine serum. Immediately before adding cells to the wells, cells were stimulated with phorbol ester 12-myristate 13-acetate (PMA) to a final concentration of 100 μg/ml. 100 μl cells were then added to the wells, giving a final concentration of 50 μg/ml PMA and 2 cells/well. The plates were incubated for 2 hours at 37oC. Unbound and weakly bound cells were gently washed with RPMI. Cells retained and therefore bound to ICAM-1 or to fibronectin were quantified using the same reagent used in the MTT experiment above.
Podaci su prikazani kao koncentracija ili područje koncentracije (u μM) pri kojoj je inhibirano 50% vezanja. Data are presented as the concentration or concentration range (in μM) at which 50% binding was inhibited.
Spojevi koji inhibiraju agregaciju JY stanica Compounds that inhibit JY cell aggregation
Svrha ispitivanja The purpose of the examination
Ovo je in vitro pokus adhezije stanice na stanicu koji se može primijeniti za ispitivanje sposobnosti ispitnog spoja da izravno inhibira agregaciju ovisnu o LFA-1 na celularnoj razini. This is an in vitro cell-to-cell adhesion assay that can be applied to test the ability of a test compound to directly inhibit LFA-1-dependent aggregation at the cellular level.
Mnoge stanice tranformirane s virusom Epstein Barr pokazuju agregaciju. Ta agregacija se može pojačati dodatkom forbol estera. Nađeno je da se takova homotipična agregacija (tj. agregacija koja uključuje samo jedan tip stanica) može blokirati s anti-LFA-1 antitijelima (Rothlein, R.R. et al., J. Exp. Med. 1986, 163, 1132-1149). Stoga se obim vezanja ovisnog o LFA-1 može odrediti procjenom obima spontane ili agregacije nastale ovisno o forbol esteru. Many cells transformed with Epstein Barr virus show aggregation. This aggregation can be enhanced by the addition of phorbol ester. It has been found that such homotypic aggregation (ie, aggregation involving only one cell type) can be blocked with anti-LFA-1 antibodies (Rothlein, R.R. et al., J. Exp. Med. 1986, 163, 1132-1149). Therefore, the extent of LFA-1-dependent binding can be determined by assessing the extent of spontaneous or phorbol ester-dependent aggregation.
Sredstvo koje interferira s LFA-1-ovisnom agegacijom može se identificirati primjenom pokusa kojim se može odrediti da li sredstvo interferira sa spontanom ili sa o forbol esteru ovisnom agregacijom stanica transformiranih s Epstein-Barr virusom. Upotrebljavaju se ponajprije stanice stanične linije JY (Terhost, L. et al., Proc. Natl. Acad. Sci. USA, 1976, 73, 910) za pokus homotipične agregacije. Taj pokus, s kojim se može mjeriti agregaciju ovisnu o LFA-1, može se primijeniti za identifikaciju sredstava koja djeluju kao antagonisti agregacije ovisne o LFA-1. Takova sredstva mogu djelovati tako da slabe sposobnost LFA-1 ili ICAM-1 za posredovanu agregaciju. Stoga se ta sredstva mogu ispitati tako da se izravno odredi jesu li su ona antagonisti LFA-1 agregacije. An agent that interferes with LFA-1-dependent aggregation can be identified by using an experiment to determine whether the agent interferes with spontaneous or phorbol ester-dependent aggregation of Epstein-Barr virus-transformed cells. Cells of the JY cell line (Terhost, L. et al., Proc. Natl. Acad. Sci. USA, 1976, 73, 910) are used primarily for the homotypic aggregation experiment. This assay, which can measure LFA-1-dependent aggregation, can be used to identify agents that act as antagonists of LFA-1-dependent aggregation. Such agents may act to attenuate the ability of LFA-1 or ICAM-1 to mediate aggregation. Therefore, these agents can be tested to directly determine whether they are antagonists of LFA-1 aggregation.
Opis protokola ispitivanja: Description of the test protocol:
Stanice JY uzgajane su u mediju za kulture RPMI 1640 nadopunjenim s 10% fetalnog telećeg seruma i 50 μg/ml gentamicina. Stanice su uzgajane pri 37oC u atmosferi s 5% CO2 pri relativnoj vlazi od 95%. JY stanice upotrijebljene u ovom ispitivanju isprane su dva puta s medijem RPMI 1640 koji je sadržavao 5 mM pufera HEPES i ponovno su suspendirane do koncentracije od 2x106 stanica/ml. U 96 jamica ravnog dna mikrotitarske ploče dodano je po 50 μl ispitnog spoja razrijeđenog u kompletnom mediju, 50 μl kompletnog medija sa ili bez pročišćenih monoklonskih antitijela (negativna i pozitivna kontrola inhibicije), 50 μl kompletnog medija koji je sadržavao 200 ng/ml forbol ester miristat acetata (PMA) i 100 μl stanica koncentracije 2x106 stanica/ml u kompletnom mediju. Time je dobivena krajnja koncentracija od 50 ng/ml PMA i 2x105 stanica/jamici. Stanice su puštene da se spontano slegnu i stupanj agregacije je zbrojen u raznim vremenskim trenucima. Rezultati su ocijenjeni od 0 do 4, gdje 0 znači da stanice uglavnom nisu u grozdovima; 1 znači da je <25% stanica u grozdovima; 2 znači da je <50% stanica u grozdovima; 3 znači da je <75% stanica u grozdovima i 4 znači da je 100% stanica agregirano. Taj postupak su opisali Rothlein, R. R., et al., J. Exp. Med. 1986, 163, 1132-1149. U tom članku također stoji da su antitijela prema LFA-1 kadra inhibirati stvaranje agragata. Dok 100% stanica oblikuje agregate u odsutnosti LFS-1 antitijela, u istom članku stoji, da je nađeno, da je manje od 20% stanica u agregatima ako se doda anti-LFA-1 antitijelo. JY cells were grown in RPMI 1640 culture medium supplemented with 10% fetal calf serum and 50 μg/ml gentamicin. Cells were grown at 37oC in an atmosphere with 5% CO2 at a relative humidity of 95%. The JY cells used in this study were washed twice with RPMI 1640 medium containing 5 mM HEPES buffer and resuspended to a concentration of 2x10 6 cells/ml. 50 μl of the test compound diluted in complete medium, 50 μl of complete medium with or without purified monoclonal antibodies (negative and positive inhibition control), 50 μl of complete medium containing 200 ng/ml phorbol ester were added to 96 flat-bottom wells of the microtiter plate. myristate acetate (PMA) and 100 μl of cells with a concentration of 2x106 cells/ml in the complete medium. This resulted in a final concentration of 50 ng/ml PMA and 2x105 cells/well. Cells were allowed to settle spontaneously and the degree of aggregation was counted at various time points. The results are graded from 0 to 4, where 0 means that the cells are mostly not in clusters; 1 means <25% of cells are in clusters; 2 means that <50% of cells are in clusters; 3 means that <75% of cells are in clusters and 4 means that 100% of cells are aggregated. This procedure is described by Rothlein, R.R., et al., J. Exp. Honey. 1986, 163, 1132-1149. The article also states that antibodies to LFA-1 are able to inhibit the formation of aggregates. While 100% of cells form aggregates in the absence of LFS-1 antibody, the same article states that less than 20% of cells are found in aggregates when anti-LFA-1 antibody is added.
Podaci su prikazani kao koncentracija ili područje koncentracije (u μM) pri kojoj je inhibirano 50% vezanja. Data are presented as the concentration or concentration range (in μM) at which 50% binding was inhibited.
Pokus za određivanje inhibicije reakcije miješanih limfocita An experiment to determine the inhibition of the reaction of mixed lymphocytes
Svrha ispitivanja The purpose of the examination
Kako je ranije rečeno, ICAM-1 je nužan za učinkovite stanične interakcije tijekom imunosnog odgovora posredovanog staničnom adhezijom ovisnom o LFA-1. Kad se zajedno uzgajaju limfociti iz dva nesrodna pojedinca, opaža se pogubna transformacija i stanična proliferacija limfocita. Taj odgovor je poznat kao reakcija miješanih limfocita (MLR) i analogan je odgovoru limfocita na dodatak antigena ili mitogena (Immunology: The Science of Self-Nonself Discrimination; Klein, J., Ed. John Wiley & Sons, NY, 1982, str. 453-458). Monoklonska antitijela usmjerena protiv ICAM-1 i LFA-1 bila su upotrijebljena kao kontrole za određivanje inhibicije stimulacije i proliferacije limfocita ovisne o staničnoj adheziji. As discussed earlier, ICAM-1 is necessary for effective cell-cell interactions during the immune response mediated by LFA-1-dependent cell adhesion. When lymphocytes from two unrelated individuals are cultured together, lethal transformation and cellular proliferation of the lymphocytes is observed. This response is known as the mixed lymphocyte response (MLR) and is analogous to the response of lymphocytes to the addition of antigen or mitogen (Immunology: The Science of Self-Nonself Discrimination; Klein, J., Ed. John Wiley & Sons, NY, 1982, p. 453-458). Monoclonal antibodies directed against ICAM-1 and LFA-1 were used as controls to determine inhibition of cell adhesion-dependent stimulation and proliferation of lymphocytes.
Ovaj protokol pokusa primijenjen je za određivanje učinka ispitnog spoja na humane MLR. Sposobnost ispitnog spoja da inhibira MLR i antigen-specifične mononuklearne stanične odgovore pokazuje da to ima terapeutsku upotrebljivost u akutnom odbacivanju grafta, kao i u srodnim imunosno posredovanim poremećajima ovisnim o interakcijama CD18, CD11a/ICAM. This experimental protocol was applied to determine the effect of the test compound on human MLRs. The ability of the test compound to inhibit MLR and antigen-specific mononuclear cell responses indicates that it has therapeutic utility in acute graft rejection as well as in related immune-mediated disorders dependent on CD18, CD11a/ICAM interactions.
Opis protokola ispitivanja Description of the test protocol
Periferna krv dobivena je od normalnih, zdravih davaoca venskom punkcijom. Krv je skupljena u heparinizirane cjevčice i razrijeđena 1:1 pri sobnoj temperaturi s Puckovom (GIBCO) izbalaciranom otopinom soli (BSS). Mješavina krvi (20 ml) je stavljna na 15 ml Ficoll/Hypaque gradijenta gustoće (Pharmacia, gustoća = 1,078, sobna temperatura) i centrifugirana 20 minuta pri 1000 x g. Zatim je skupljena dodirna površina i isprana 3 puta u Puckov G. Stanice su zbrojene na hemocitometru i ponovno suspendirane u medij za kulture RPMI 1640 (GIBCO) koji je sadržavao 0,5% gentamicina, 1 mM L-glutamina (GIBCO) i 5% toplinski inaktiviranog (56oC, 30 minuta) humanog AB sera (Flow Laboratories) (koji se u nastavku navodi kao RPMI medij za kulture). Peripheral blood was obtained from normal, healthy donors by venipuncture. Blood was collected in heparinized tubes and diluted 1:1 at room temperature with Puck's (GIBCO) balanced salt solution (BSS). The blood mixture (20 ml) was placed on a 15 ml Ficoll/Hypaque density gradient (Pharmacia, density = 1.078, room temperature) and centrifuged for 20 minutes at 1000 x g. Then the contact area was collected and washed 3 times in Puck's G. The cells were pooled on a hemocytometer and resuspended in RPMI 1640 culture medium (GIBCO) containing 0.5% gentamicin, 1 mM L-glutamine (GIBCO) and 5% heat-inactivated (56oC, 30 minutes) human AB sera (Flow Laboratories) (referred to below as RPMI culture medium).
Periferne krvne mononuklearne stanice (PBMC) su uzgajane u mediju pri 6,25x105 stanica/ml u mikrotitarskoj ploči Linbro s okruglim dnom jamica. Stimulatorske stanice (stanice koje su bile obrađene zračenjem tako da su nesposobne za proliferaciju) od posebnih davatelja uzgajane su sa stanicama od kojih se očekuje odgovar pri istoj koncentraciji. Ispitni spoj dodan je u jamice u raznim koncentracijama. Ukupni volumen po kulturi bio je 0,2 ml. Kontrole su uključile spoj samo u vehiklu (DMSO), samo stanice koje odgovaraju i samo stimulatorske stanice. Ploče s kulturama inkubirane su 5 dana pri 37oC u atmosferi vlažnog zraka s 5% CO2. Jamice su pulzirane s 0,5 μCi triciranog timidina (3HT) (New England Nuclear) tijekom posljednjih 18 sati. U nekim slučajevima može se provesti dvosmjerna MLR. Protokol je isti osim da druge donorske stanice nisu inaktivirane ozračivanjem. Peripheral blood mononuclear cells (PBMC) were cultured in medium at 6.25x10 5 cells/ml in a Linbro round-bottom microtiter plate. Stimulator cells (cells that have been irradiated so that they are unable to proliferate) from specific donors were cultured with cells expected to respond at the same concentration. The test compound was added to the wells in various concentrations. The total volume per culture was 0.2 ml. Controls included compound only in vehicle (DMSO), only responsive cells, and only stimulatory cells. Plates with cultures were incubated for 5 days at 37oC in an atmosphere of humid air with 5% CO2. Wells were pulsed with 0.5 μCi tritiated thymidine (3HT) (New England Nuclear) for the last 18 hours. In some cases, two-way MLR can be performed. The protocol is the same except that the other donor cells are not inactivated by irradiation.
Stanice su skupljene na filtere od staklenih vlakana pomoću višestrukog skupljača uzoraka (Skatron, Norveška) i isprane s vodom i metanolom. Filteri su osušeni u sušioniku u zbrojeni u Aquasolu u Beckmanovom (LS-3801) tekućinskom scintilacijskom brojaču. Cells were collected on glass fiber filters using a multiple sample collector (Skatron, Norway) and washed with water and methanol. Filters were dried in a desiccator and counted in Aquasol in a Beckman (LS-3801) liquid scintillation counter.
Podaci su navedeni kao “+” ili “-” pri datoj koncentraciji (u μM). Data are reported as “+” or “-” at the given concentration (in μM).
In vivo: model alogenskog staničnog transplantata In vivo: an allogeneic cell transplant model
Svrha pokusa The purpose of the experiment
Sposobnost stanica da prepoznaju druge svoje stanice ili stanice od drugog genetski različitog pojedinca (ne-svoje) je važno svojstvo za održavanje cjelovitosti tkiva i strukture organa. Odgovor alogenskog staničnog transplantata je važan model za proučavanje odbacivanja transplantata i imunokompetencije. Taj T-stanicama posredovani imunosni odgovor može se inducirati u odraslih miševa injekcijom limfocita iz histološki inkompatibilne vrste miševa u jastučić šape. Taj odgovor karakterizira proliferacija T- stanica koja je ograničena na poplitealni limfni čvor koji prima drenažu iz ubrizganog područja jastučića šape. Nijedan sistem in vitro ne može potpuno duplicirati taj odgovor in vivo. Stoga se taj model može upotrijebiti za ispitivanje sposobnosti ispitnog spoja da potisne odbacivanje transplantata. The ability of cells to recognize other cells of their own or cells from another genetically different individual (non-self) is an important property for maintaining the integrity of tissue and organ structure. Allogeneic cell transplant response is an important model for studying graft rejection and immunocompetence. This T-cell-mediated immune response can be induced in adult mice by injection of lymphocytes from a histologically incompatible mouse strain into the paw pad. This response is characterized by T-cell proliferation that is restricted to the popliteal lymph node that receives drainage from the injected area of the paw pad. No in vitro system can completely duplicate that in vivo response. Therefore, this model can be used to test the ability of a test compound to suppress graft rejection.
Opis protokola ispitivanja Description of the test protocol
Pokusi su provedeni na mužjacima ili ženkama miševa (20 - 26 grama). Kao populacija davaoca i primaoca može se upotrijebiti bilo koja histološki inkompatibina mišja vrsta. Kao davaoci su upotrijebljeni tipični DBA miševi, a kao primaoci su upotrijebljeni miševi C57b1/6. Prije pokusa potreban je najmanje 1 tjedan stabilizacije i perioda kondicioniranja tijekom kojeg vremena se životinje drže u skladu s uputama Animal Resource Center S.O.P. Za svako proučavanje korišteno je 36 miševa primaoca podijeljenih u skupine po 6. Ispitivanja su trajala približno 4 dana. Miševi davaoci su žrtvovani asfiksacijom CO2 i izvađene su im slezene i prerađene u staničnu suspenziju. Stanice (1,0x107/metatarsalu u 0,05 ml) su ubrizgane intra dermalno (u skladu sa standardnim protokolom) u dorsalnu metatasalnu kožu miša primaoca. Četiri dana kasnije životinje su žrtvovane udisanjem CO2 i izvađeni su i izvagani poplitealni čvorovi. Skupine miševa koji su primili tobožnja imunosupresivna sredstva su dozirani subkutano, intraperitonealno ili oralno jedan sat prije ubrizgavanja stanica i dnevno nakon toga u skladu sa standarnim protokolom. Za određivanje signifikantnih razlika između poplitealnih limfnih čvorova skupine neobrađenih miševa i onih miševa obrađenih s tobožnjim imunosupresivnim sredstvima primijenjen je Studentov T test (vidi: Kroczek, R.A., Black, C. D., Barbet. J., Shevach, E. M., Immunology, 1987, 139, 3597). Experiments were conducted on male or female mice (20 - 26 grams). Any histologically incompatible mouse species can be used as donor and recipient populations. Typical DBA mice were used as donors, and C57b1/6 mice were used as recipients. A minimum of 1 week of stabilization and conditioning period is required prior to experiments, during which time animals are maintained in accordance with Animal Resource Center S.O.P. For each study, 36 recipient mice were used, divided into groups of 6. The studies lasted approximately 4 days. Donor mice were sacrificed by CO2 asphyxiation and their spleens were removed and processed into a cell suspension. Cells (1.0x107/metatarsal in 0.05 ml) were injected intradermally (according to standard protocol) into the dorsal metatarsal skin of recipient mice. Four days later the animals were sacrificed by CO2 inhalation and the popliteal nodes were removed and weighed. Groups of mice receiving sham immunosuppressive agents were dosed subcutaneously, intraperitoneally, or orally one hour before cell injection and daily thereafter according to a standard protocol. To determine significant differences between the popliteal lymph nodes of the group of untreated mice and those of mice treated with sham immunosuppressive agents, the Student's T test was applied (see: Kroczek, R.A., Black, C.D., Barbet. J., Shevach, E.M., Immunology, 1987, 139, 3597).
Podaci su prikazani kao doza pri kojoj je opaženo 50% inhibicije i način na koji je dat spoj. Data are presented as the dose at which 50% inhibition was observed and the route in which the compound was administered.
U tablici 23 primjenjuju se slijedeće oznake: In table 23, the following symbols apply:
and = nije određeno, bpostotak inhibicije pri 160 μg/ml, cinhibicije nije opažena sve do najviše doze. Točna kvantifikacija nije uvijek moguća zbog intrinsičke toksičnosti spoja (vidi MTT rezultate). dpostotak inhibicije (koncentracija u μM). eaproksimirano iz nepotpune krivulje odgovora na dozu. Fnije određeno; spoj je intermedijat sinteze. and = not determined, bpercent inhibition at 160 μg/ml, no inhibition observed up to the highest dose. Accurate quantification is not always possible due to the intrinsic toxicity of the compound (see MTT results). dinhibition percentage (concentration in μM). approximated from an incomplete dose response curve. More specific; the compound is an intermediate of synthesis.
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Opis terapeutske upotrebe Description of therapeutic use
Nove i poznate male molekule upotrijebljene su ovom metodom u skladu s izumom za inhibiciju ICAM-1/LFA-1 ovisne homotipične agregacije humanih limfocita, prijanjanja humanih limfocita na ICAM-1 i odgovor humanih limfocita na antigen. Ovi spojevi imaju terapeutsku upotrebljivost u modulaciji imunosne stanične aktivacije/proliferacije, npr. kao kompentitivni inhibitori intracelularnih reakcija vezanja ligand/receptor koje uključuju CAMs i leukointegrine. Upalna stanja koja se mogu liječiti sa spojevima koji su obuhvaći izumom uključuju stanja koja su posljedica odgovora ne-specifičnih imunosnih sistema u sisavaca (npr. sindrom respiratornog distresa u odraslih, šok, toksičnost kisika, sekundarni sindrom multiple ozljede organa kod septicemije, sekundarni sindrom multiple ozljede organa kod traume, reperfuzijska ozljeda tkiva zbog kardiopulmonalnog bypass-a, miokardojalna infarktacija ili upotreba sa sredstvima za trombolizu, akutni glomerulonefritis, vaskulitis, reaktivni artritis, dermatoza s akutnim upalnim komponenama, udar, toplinska ozljeda, hemodijaliza, leukofereza, ulcerativni kolitis, nekrotizirajući enterokolitis i sindrom pridružene tranfuzije granulocita) i stanja koja su posljedica odgovora specifičnog imunosnog sistema u sisavaca (npr. psorijaza, odbacivanje transplantata organa/tkiva, grafta vs. reakcije domaćina i autoimunosne bolesti uključiv Raynaudov sindrom, autoimunosni tiroiditis, dermatitis, multiplu sklerozu, reumatoridni artritis, dijabetes melitus ovisan o inzulinu, uveitis, upalne trbušne bolesti uključiv Crohnovu bolest i ulcerativni kolitis, i sistemski lupus erithematosus). U skladu s izumom, novi i poznati spojevi mogu se također upotrijebiti za liječenje astme ili kao dodatak za minimalizaciju toksičnosi terapije s citokinima kod liječenja raka. Općenito, ovi spojevi se mogu upotrijebiti za liječenje onih bolesti koje se sada liječe sa steroidima. New and known small molecules are used in this method according to the invention to inhibit ICAM-1/LFA-1 dependent homotypic aggregation of human lymphocytes, adhesion of human lymphocytes to ICAM-1 and response of human lymphocytes to antigen. These compounds have therapeutic utility in modulating immune cell activation/proliferation, eg as competitive inhibitors of intracellular ligand/receptor binding reactions involving CAMs and leukointegrins. Inflammatory conditions treatable with the compounds of the invention include conditions resulting from non-specific immune system responses in mammals (eg, adult respiratory distress syndrome, shock, oxygen toxicity, secondary multiple organ injury syndrome in septicemia, secondary multiple organ injuries in trauma, tissue reperfusion injury due to cardiopulmonary bypass, myocardial infarction or use with thrombolytic agents, acute glomerulonephritis, vasculitis, reactive arthritis, dermatosis with acute inflammatory components, stroke, thermal injury, hemodialysis, leukopheresis, ulcerative colitis, necrotizing enterocolitis and associated granulocyte transfusion syndrome) and conditions resulting from a specific immune system response in mammals (eg psoriasis, organ/tissue transplant rejection, graft vs. host reactions and autoimmune diseases including Raynaud's syndrome, autoimmune thyroiditis, dermatitis, multiple sclerosis, re rheumatoid arthritis, insulin-dependent diabetes mellitus, uveitis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, and systemic lupus erythematosus). In accordance with the invention, the new and known compounds can also be used to treat asthma or as an adjunct to minimize the toxicity of cytokine therapy in the treatment of cancer. In general, these compounds can be used to treat those diseases that are now treated with steroids.
U skladu s metodom datom ovim izumom, ovi novi i poznati spojevi mogu se dati za profilaktičku ili teraputsku svrhu sami ili zajedno s drugim imunosupresivnim ili antiupalnim sredstvima. Ako se daju profilaktički, imunosupresivni spoj (spojevi) daje se prije bilo kakovog upalnog odgovora ili simptoma (na primjer prije transplantacije ili kratko nakon transplantacije organa ili tkiva, ali prije bilo kakovog simptoma odbacivanja organa). Profilaktičko davanje spoja formule I služi za sprečavanje ili ublažavanje bilo kakovog kasnijeg upalnog odgovora (kao što je na primjer odbacivanje transplantiranog organa ili tkiva, itd.). Terapeutsko davanje spoja formule I služi za ublažavanje bilo kakove akutne upale (kao na primjer odbacivanje transplatiranog organa ili tkiva). Stoga se u skladu s izumom spoj formule I može dati prije pojave upale (tako da se potisne očekivanu upalu) ili nakon početka upale. In accordance with the method provided by the present invention, these new and known compounds can be administered for prophylactic or therapeutic purposes alone or together with other immunosuppressive or anti-inflammatory agents. If administered prophylactically, the immunosuppressive compound(s) is administered prior to any inflammatory response or symptoms (for example prior to transplantation or shortly after organ or tissue transplantation but prior to any symptoms of organ rejection). Prophylactic administration of a compound of formula I serves to prevent or alleviate any subsequent inflammatory response (such as, for example, rejection of a transplanted organ or tissue, etc.). Therapeutic administration of a compound of formula I serves to alleviate any acute inflammation (such as rejection of a transplanted organ or tissue). Therefore, in accordance with the invention, the compound of formula I can be given before the onset of inflammation (so as to suppress the expected inflammation) or after the onset of inflammation.
Novi i poznati spojevi formule I u skladu s izumom daju se u jednostrukim ili podijeljenim dozama oralno, parenteralno ili površinskim putem. Prikladno oralno doziranje za spoj formule I kreće se u rasponu od pribl. 0,5 mg do 1 g dnevno. U parenteralnim formulacijama prikladna jedinica doziranja može sadržavati od 0,1 do 250 mg spomenutog spoja, pri čemu su za površinsko davanje prednosne formulacije koje sadrže 0,01 do 1% aktivnog spoja. Podrazumijeva se, međutim, da propisano doziranja može varirati od pacijenta do pacijenta i doziranje za svakog pojedinačnog pacijenta ovisit će o kliničkoj procjeni onoga tko veličinu i stanje pacijenta primjenjuje kao kriterij za utvrđivanje pravilnog doziranja, kao i o reakciji pacijenta na lijek. New and known compounds of formula I according to the invention are given in single or divided doses orally, parenterally or topically. A suitable oral dosage for a compound of formula I ranges from approx. 0.5 mg to 1 g per day. In parenteral formulations, a suitable dosage unit may contain from 0.1 to 250 mg of the mentioned compound, whereby formulations containing 0.01 to 1% of the active compound are preferred for topical administration. It is understood, however, that the prescribed dosage may vary from patient to patient and the dosage for each individual patient will depend on the clinical judgment of one who applies the size and condition of the patient as a criterion for determining the proper dosage, as well as on the patient's response to the drug.
Kad se spojevi predloženog izuma daju oralnim putem, oni se mogu dati kao lijekovi u obliku farmaceutskih pripravaka koji ih sadrže zajedno s kompetibilnim farmaceutskim nosećim materijalom. Takav noseći materijal može biti inertan organski ili anorganski noseći materijal prikladan za oralno davanje. Primjeri takovih materijala jesu voda, želatina, talk, škrob, magnezijev stearat, guma arabika, biljna ulja, polialkilen glikoli, petrolej gel i slično. When the compounds of the present invention are administered orally, they may be administered as medicaments in the form of pharmaceutical compositions containing them together with a compatible pharmaceutical carrier. Such carrier material may be an inert organic or inorganic carrier material suitable for oral administration. Examples of such materials are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene glycols, petroleum gel and the like.
Farmaceutski pripravci se mogu proizvesti na uobičajen način, a gotovi oblici doziranja mogu biti kruti oblici doziranja, na primjer tablete, dražeje, kapsule i slično, ili tekući oblici doziranja, na primjer otopine, suspenzije, emulzije i slično. Farmaceutski pripravci se mogu podvrgnuti uobičajenim farmacutskim postupcima kao što je sterilizacija. Nadalje, farmaceutski pripravci mogu sadržavati uobičajena farmaceutska pomoćna sredstva kao što su konzervansi, stabilizatori, emulgatori, sredstva za poboljšanje okusa, sredstva za kvašenje, pufere, soli za podešavanje osmotskog tlaka i slično. Kruti noseći materijal koji se može upotrijebiti uključuje, na primjer, škrob, laktozu, manitol, metil celulozu, mikrokristaliničnu celulozu, talk, silicijev oksid, dvobazičan kalcijev fosfat i polimere visoke molekulske mase (kao što je polietilen glikol). Pharmaceutical preparations can be produced in a conventional manner, and the finished dosage forms can be solid dosage forms, for example tablets, dragees, capsules and the like, or liquid dosage forms, for example solutions, suspensions, emulsions and the like. Pharmaceutical preparations may be subjected to conventional pharmaceutical procedures such as sterilization. Furthermore, pharmaceutical preparations may contain conventional pharmaceutical auxiliaries such as preservatives, stabilizers, emulsifiers, flavor enhancers, wetting agents, buffers, salts for adjusting osmotic pressure, and the like. Solid carrier material that can be used includes, for example, starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silicon oxide, dibasic calcium phosphate, and high molecular weight polymers (such as polyethylene glycol).
Za parenteralnu upotrebu spoj formule I može se dati u vodenoj ili ne-vodenoj otopini, suspenziji ili emulziji u farmaceutski prihvatljivom ulju ili mješavini tekućina, koje mogu sadržavati bakteriostatska sredstva, antioksidante, konzervanse, pufere ili druge otopine, tako da se dobije otopinu koja je izotonična s krvi, sredstva za zgušnjavanje, sredstva za suspendiranje ili druge farmaceutski prihvaljtive dodatke. Dodaci tog tipa uključuju na primjer tartaratne, citratne i acetatne pufere, etanol, propilen glikol, polietilen glikol, sredstva koja grade komplekse (kao što je EDTA), antioksidante (kao što je natrijev bisulfit, natrijev metabisulfit, i askorbinska kiselina), polimere visoke molekulske mase (kao što su tekući polietilen oksidi) za regulaciju viskoznosti i polietilenski derivati sorbitol anhidrida. Ako je potrebno također se mogu dodati konzervansi kao što je benzojeva kiselina, metil ili propil paraben, benzalkonijev klorid i drugi kvaterni amonijevi spojevi. For parenteral use, the compound of formula I may be administered in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable oil or mixture of liquids, which may contain bacteriostatic agents, antioxidants, preservatives, buffers or other solutions, so as to obtain a solution which is isotonic with blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Additives of this type include, for example, tartrate, citrate, and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complexing agents (such as EDTA), antioxidants (such as sodium bisulfite, sodium metabisulfite, and ascorbic acid), polymers of high molecular weight (such as liquid polyethylene oxides) for viscosity regulation and polyethylene derivatives of sorbitol anhydride. If necessary, preservatives such as benzoic acid, methyl or propyl paraben, benzalkonium chloride and other quaternary ammonium compounds can also be added.
Spojevi ovog izuma mogu se dati kao otopine za nazalnu aplikaciju koje osim spojeva ovog izuma dodatno mogu sadržavati prikladne pufere, sredstva za podešavanje toničnosti, mikrobiološke konzervanse, antioksidante i sredstva za povišenje viskoznosti u vodenom vehiklu. Primjeri sredstava koja se upotrebljavaju za povišenje viskoznosti jesu polivinil alkohol, derivati celuloze, polivinilpirolidinon, polisorbati ili glicerin. Dodani mikrobiološki konzervansi mogu uključiti benzalkonijev klorid, timerosal, klor-butanol ili feniletil alkohol. The compounds of this invention can be given as solutions for nasal application which, in addition to the compounds of this invention, can additionally contain suitable buffers, agents for tonicity adjustment, microbiological preservatives, antioxidants and agents for increasing viscosity in the aqueous vehicle. Examples of agents used to increase viscosity are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidinone, polysorbates or glycerin. Added microbiological preservatives may include benzalkonium chloride, thimerosal, chlorobutanol or phenylethyl alcohol.
K tome, spojevi dati ovim izumom mogu se dati kao čepići. In addition, the compounds of this invention may be administered as suppositories.
Formulacije Formulations
Spojevi formule I mogu se formulirati za terapeutsko davanje na brojne načine. Dolje su dati opisi nekoliko primjera formulacija. Compounds of formula I can be formulated for therapeutic administration in a number of ways. Below are descriptions of several example formulations.
Primjer A Example A
Kapsule ili tablete Capsules or tablets
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Spoj formule I pomiješa se u praškastu smjesu s prethodno pomiješanim pomoćnim materijalima, kako je gore navedeno s izuzetkom lubrikanta. Zatim se umiješa lubrikant i dobivenu smjesu se preša u tablete ili se puni u kapsule od tvrde želatine. The compound of formula I is mixed into a powder mixture with premixed auxiliary materials, as indicated above with the exception of the lubricant. Then the lubricant is mixed in and the resulting mixture is pressed into tablets or filled into hard gelatin capsules.
Primjer B Example B
Parenteralne otopine: Parenteral solutions:
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Pomoćni materijali se pomiješaju i zatim se dodaju k jednom od spojeva formule I u volumenu koji je potreban za otapanje. Miješanje se nastavi dok se dobije bistru otopinu. Otopinu se filtrira u odgovarajuće vijale ili ampule i sterilizira u autoklavu. The auxiliary materials are mixed and then added to one of the compounds of formula I in the volume required for dissolution. Stirring is continued until a clear solution is obtained. The solution is filtered into appropriate vials or ampoules and sterilized in an autoclave.
Primjer C Example C
Suspenzija: Suspension:
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Pomoćni materijali se pomiješaju s vodom i nakon toga se doda jedan od spojeva formule I i miješanje se nastavi dok se dobije homogenu suspenziju. Zatim se suspenziju prenese u odgovarajuće vijale ili ampule. The auxiliary materials are mixed with water and then one of the compounds of formula I is added and mixing is continued until a homogeneous suspension is obtained. Then the suspension is transferred into appropriate vials or ampoules.
Claims (17)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HRP980462 HRP980462A2 (en) | 1998-08-24 | 1998-08-24 | Small molecules useful in the treatment of inflammatory disease |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HRP980462 HRP980462A2 (en) | 1998-08-24 | 1998-08-24 | Small molecules useful in the treatment of inflammatory disease |
Publications (1)
Publication Number | Publication Date |
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HRP980462A2 true HRP980462A2 (en) | 2000-04-30 |
Family
ID=10946792
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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HRP980462 HRP980462A2 (en) | 1998-08-24 | 1998-08-24 | Small molecules useful in the treatment of inflammatory disease |
Country Status (1)
Country | Link |
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HR (1) | HRP980462A2 (en) |
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1998
- 1998-08-24 HR HRP980462 patent/HRP980462A2/en not_active Application Discontinuation
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