HRP20020451A2 - 1-tia-3-aza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof - Google Patents
1-tia-3-aza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof Download PDFInfo
- Publication number
- HRP20020451A2 HRP20020451A2 HR20020451A HRP20020451A HRP20020451A2 HR P20020451 A2 HRP20020451 A2 HR P20020451A2 HR 20020451 A HR20020451 A HR 20020451A HR P20020451 A HRP20020451 A HR P20020451A HR P20020451 A2 HRP20020451 A2 HR P20020451A2
- Authority
- HR
- Croatia
- Prior art keywords
- dibenzo
- aza
- dithia
- azulene
- trifluoromethyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 21
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- 239000000543 intermediate Substances 0.000 title claims description 6
- 108060008682 Tumor Necrosis Factor Proteins 0.000 title description 38
- 239000003112 inhibitor Substances 0.000 title description 7
- 102000003390 tumor necrosis factor Human genes 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 103
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 37
- -1 C1-C4-alkoxycarbonyl Chemical group 0.000 claims description 36
- 229910052717 sulfur Inorganic materials 0.000 claims description 28
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 11
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 8
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000003435 aroyl group Chemical group 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 6
- 102000004127 Cytokines Human genes 0.000 claims description 5
- 108090000695 Cytokines Proteins 0.000 claims description 5
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 230000001575 pathological effect Effects 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 3
- PTVFNZZZZATPQA-UHFFFAOYSA-N C12=CC=CC=C2OC2=CC=C(Cl)C=C2C2=C1SC(CO)=N2 Chemical compound C12=CC=CC=C2OC2=CC=C(Cl)C=C2C2=C1SC(CO)=N2 PTVFNZZZZATPQA-UHFFFAOYSA-N 0.000 claims description 3
- WFILCHQWYZCTFT-UHFFFAOYSA-N C12=CC=CC=C2OC2=CC=C(F)C=C2C2=C1SC(CO)=N2 Chemical compound C12=CC=CC=C2OC2=CC=C(F)C=C2C2=C1SC(CO)=N2 WFILCHQWYZCTFT-UHFFFAOYSA-N 0.000 claims description 3
- GQMHIIXRIBMULE-UHFFFAOYSA-N C12=CC=CC=C2SC2=CC(Cl)=CC=C2C2=C1SC(C=C)=N2 Chemical compound C12=CC=CC=C2SC2=CC(Cl)=CC=C2C2=C1SC(C=C)=N2 GQMHIIXRIBMULE-UHFFFAOYSA-N 0.000 claims description 3
- YSWWQBXFHGXJMY-UHFFFAOYSA-N C12=CC=CC=C2SC2=CC(Cl)=CC=C2C2=C1SC(CCOCCCN(C)C)=N2 Chemical compound C12=CC=CC=C2SC2=CC(Cl)=CC=C2C2=C1SC(CCOCCCN(C)C)=N2 YSWWQBXFHGXJMY-UHFFFAOYSA-N 0.000 claims description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 3
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- MTCBIAFZEQYHCD-UHFFFAOYSA-N (5-fluoro-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-yl)-methanol Chemical compound C12=CC=CC=C2SC2=CC=C(F)C=C2C2=C1SC(CO)=N2 MTCBIAFZEQYHCD-UHFFFAOYSA-N 0.000 claims description 2
- JUZFUOIIPXZSEP-UHFFFAOYSA-N (6-chloro-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-yl)-acetonitrile Chemical compound C12=CC=CC=C2SC2=CC(Cl)=CC=C2C2=C1SC(CC#N)=N2 JUZFUOIIPXZSEP-UHFFFAOYSA-N 0.000 claims description 2
- AOWMZDRASCRFAM-UHFFFAOYSA-N 13-oxa-3-thia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7,9,11,14,16-octaen-4-ylmethanol Chemical compound C12=CC=CC=C2OC2=CC=CC=C2C2=C1SC(CO)=N2 AOWMZDRASCRFAM-UHFFFAOYSA-N 0.000 claims description 2
- PEXIGZVSSOKOKY-UHFFFAOYSA-N 13-oxa-3-thia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7,9,11,14,16-octaene-4-carbaldehyde Chemical compound C12=CC=CC=C2OC2=CC=CC=C2C2=C1SC(C=O)=N2 PEXIGZVSSOKOKY-UHFFFAOYSA-N 0.000 claims description 2
- QXVIZBQTDRQEST-UHFFFAOYSA-N 2-(10-chloro-3,13-dithia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7(12),8,10,14,16-octaen-4-yl)ethanol Chemical compound C12=CC=CC=C2SC2=CC(Cl)=CC=C2C2=C1SC(CCO)=N2 QXVIZBQTDRQEST-UHFFFAOYSA-N 0.000 claims description 2
- CNZVOASUSIRXRP-UHFFFAOYSA-N 2-(3,13-dithia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7,9,11,14,16-octaen-4-ylmethoxy)-N,N-dimethylethanamine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2C2=C1SC(COCCN(C)C)=N2 CNZVOASUSIRXRP-UHFFFAOYSA-N 0.000 claims description 2
- OAHMBFKSFPVRDM-UHFFFAOYSA-N 2-[(9-chloro-13-oxa-3-thia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7(12),8,10,14,16-octaen-4-yl)methoxy]-N,N-dimethylethanamine Chemical compound C12=CC=CC=C2OC2=CC=C(Cl)C=C2C2=C1SC(COCCN(C)C)=N2 OAHMBFKSFPVRDM-UHFFFAOYSA-N 0.000 claims description 2
- CSDNVMZGFFVXEF-UHFFFAOYSA-N 2-[(9-fluoro-13-oxa-3-thia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7(12),8,10,14,16-octaen-4-yl)methoxy]-N,N-dimethylethanamine Chemical compound C12=CC=CC=C2OC2=CC=C(F)C=C2C2=C1SC(COCCN(C)C)=N2 CSDNVMZGFFVXEF-UHFFFAOYSA-N 0.000 claims description 2
- VVIWCPJFLVYJHE-UHFFFAOYSA-N 3,13-dithia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7,9,11,14,16-octaene-4-carbaldehyde Chemical compound C12=CC=CC=C2SC2=CC=CC=C2C2=C1SC(C=O)=N2 VVIWCPJFLVYJHE-UHFFFAOYSA-N 0.000 claims description 2
- ZMKDSCQDEWVIBS-UHFFFAOYSA-N 3-[(9-chloro-13-oxa-3-thia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7(12),8,10,14,16-octaen-4-yl)methoxy]-N,N-dimethylpropan-1-amine Chemical compound C12=CC=CC=C2OC2=CC=C(Cl)C=C2C2=C1SC(COCCCN(C)C)=N2 ZMKDSCQDEWVIBS-UHFFFAOYSA-N 0.000 claims description 2
- DIGZMTZERQUQEZ-UHFFFAOYSA-N 3-[(9-fluoro-13-oxa-3-thia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7(12),8,10,14,16-octaen-4-yl)methoxy]-N,N-dimethylpropan-1-amine Chemical compound C12=CC=CC=C2OC2=CC=C(F)C=C2C2=C1SC(COCCCN(C)C)=N2 DIGZMTZERQUQEZ-UHFFFAOYSA-N 0.000 claims description 2
- MVPXMPNBDVTAOR-UHFFFAOYSA-N 4-methyl-13-oxa-3-thia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7,9,11,14,16-octaene Chemical compound C12=CC=CC=C2OC2=CC=CC=C2C2=C1SC(C)=N2 MVPXMPNBDVTAOR-UHFFFAOYSA-N 0.000 claims description 2
- DKYJVDQOJFXBLK-UHFFFAOYSA-N 4-phenyl-10-(trifluoromethyl)-3,13-dithia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7(12),8,10,14,16-octaene Chemical compound S1C=2C3=CC=CC=C3SC3=CC(C(F)(F)F)=CC=C3C=2N=C1C1=CC=CC=C1 DKYJVDQOJFXBLK-UHFFFAOYSA-N 0.000 claims description 2
- PRFOWOWBVPKKOR-UHFFFAOYSA-N 4-pyridin-4-yl-10-(trifluoromethyl)-13-oxa-3-thia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7(12),8,10,14,16-octaene Chemical compound S1C=2C3=CC=CC=C3OC3=CC(C(F)(F)F)=CC=C3C=2N=C1C1=CC=NC=C1 PRFOWOWBVPKKOR-UHFFFAOYSA-N 0.000 claims description 2
- WQTCKGFCFBQLEL-UHFFFAOYSA-N 5-fluoro-2-methyl-8-oxa-1-thia-3-aza-dibenzo[e,h]azulene Chemical compound C12=CC=CC=C2OC2=CC=C(F)C=C2C2=C1SC(C)=N2 WQTCKGFCFBQLEL-UHFFFAOYSA-N 0.000 claims description 2
- GSDSWPKSDAVWOY-UHFFFAOYSA-N 8-oxa-1-thia-3-aza-dibenzo[e,h]azulene Chemical compound C12=CC=CC=C2OC2=CC=CC=C2C2=C1SC=N2 GSDSWPKSDAVWOY-UHFFFAOYSA-N 0.000 claims description 2
- AOBRMDCJPLVRLM-UHFFFAOYSA-N 9-chloro-4-methyl-3,13-dithia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7(12),8,10,14,16-octaene Chemical compound C12=CC=CC=C2SC2=CC=C(Cl)C=C2C2=C1SC(C)=N2 AOBRMDCJPLVRLM-UHFFFAOYSA-N 0.000 claims description 2
- MBNZQQXTJWCFKY-UHFFFAOYSA-N 9-fluoro-13-oxa-3-thia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7(12),8,10,14,16-octaene Chemical compound C12=CC(F)=CC=C2OC2=CC=CC=C2C2=C1N=CS2 MBNZQQXTJWCFKY-UHFFFAOYSA-N 0.000 claims description 2
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- XOKLDXCTYVNPES-UHFFFAOYSA-N N,N-dimethyl-2-(13-oxa-3-thia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7,9,11,14,16-octaen-4-ylmethoxy)ethanamine Chemical compound C12=CC=CC=C2OC2=CC=CC=C2C2=C1SC(COCCN(C)C)=N2 XOKLDXCTYVNPES-UHFFFAOYSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
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- IKGOXVIGOYMVPQ-UHFFFAOYSA-N [3-(5-fluoro-1,8-dithia-3-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethylamine Chemical compound C12=CC=CC=C2SC2=CC=C(F)C=C2C2=C1SC(COCCCN(C)C)=N2 IKGOXVIGOYMVPQ-UHFFFAOYSA-N 0.000 claims description 2
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- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 6
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 claims 2
- GREMVYZPMVTGTO-UHFFFAOYSA-N 10-(trifluoromethyl)-4-[3-(trifluoromethyl)phenyl]-3,13-dithia-5-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7(12),8,10,14,16-octaene Chemical compound FC(F)(F)C1=CC=CC(C=2SC3=C(C4=CC=C(C=C4SC4=CC=CC=C43)C(F)(F)F)N=2)=C1 GREMVYZPMVTGTO-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines Containing Plant Substances (AREA)
Description
Ovaj se izum odnosi na derivate 1-tia-3-aza-dibenzoazulena, njihove farmakološki prihvatljive soli i solvate, postupke i međuprodukte za njihovu pripravu, kao i na njihove anti-inflamatorne učinke, a posebno na inhibiciju produkcije faktora nekroze tumora-α (TNF-α od engl. tumor necrosis factor-α) i inhibiciju produkcije interleukina-1 (IL-1), te na njihovo analgetsko djelovanje.
Stanje na području tehnike
Poznati su neki derivati 1,3 diaza-dibenzoazulena i njihove soli kao nova klasa spojeva s anti-inflamatornim učinkom (US Pat. Br. 3,711,489, US Pat. Br. 4,198,421 i CA Pat. Br. 967,573).
Iz reda 1-tia-dibenzoazulena u literaturi su opisani derivati koji su na položaju 2 supstituirani metilom, metil-ketonom, nitro skupinom ili derivatima karboksilne skupine (Cagniant PG, C. R. Hebd. Sceances Acad. Sci., 1976, 283:683-686) te derivati 1-tia-dibenzoazulena koji u položaju 2 imaju alkiloksi supstituente (WO Pat. prijava Br. 01/878990 ) koji također pokazuju anti-inflamatorni učinak.
Prema našim saznanjima i dostupnim literaturnim podacima poznati su derivati 1,8-ditia-3-aza-dibenzoazulena koji u položaju 2 imaju aminoskupinu (Kovtunenko VA at al., Ukr. Khim. Zh., 1983 43:975-978) dok drugi derivati, a posebno takvi gdje se u položaju 2 nalaze alkilne ili neke druge skupine koje su alkilni derivati i međuprodukti za njihovu pripravu, sada su po prvi put priređeni i opisani. Isto tako, do sada nije poznato da dibenzoazuleni iz reda tiazola pokazuju anti-inflamatorno (inhibitori produkcije TNF-α, inhibitori produkcije IL-1) i/ili analgetsko djelovanje.
TNF-α je definiran kao serumski faktor induciran endotoksinom koji uzrokuje nekrozu tumora in vitro i in vivo (Carswell EA et al., Proc. Natl. Acad. Sci. U.S.A., 1975, 72:3666-3670). Osim antitumorske aktivnosti TNF-α posjeduje i brojne druge biološke aktivnosti važne u homeostazi organizma te u patofiziološkim stanjima. Glavni izvori TNF-α su monociti-makrofazi, T-limfociti i mastociti.
Otkriće da anti-TNF-α protutijela (cA2) imaju učinak u tretiranju oboljelih od reumatoidnog artritisa (RA) (Elliott M et al., Lancet, 1994, 344:1105-1110) dovelo je do povećanog interesa za pronalaženje novih inhibitora produkcije TNF-α kao mogućih potentnih lijekova za RA. Reumatoidni artritis je autoimuna kronična upalna bolest karakterizirana ireverzibilnim patološkim promjenama na zglobovima. Osim u liječenju RA, TNF-α antagonisti mogu se primijeniti i kod brojnih patoloških stanja i bolesti kao što su spondilitis, osteoartritis, giht i ostala artritična stanja, sepsa, septički šok, toksični šok sindrom, atopijski dermatitis, kontaktni dermatitis, psorijaza, glomerulonefritis, lupus eritematosus, skleroderma, astma, kaheksija, kronična opstruktivna plućna bolest, kongestivni zastoj srca, rezistencija na inzulin, plućna fibroza, multipla skleroza, Chronova bolest, ulcerativni kolitis, virusne infekcije i AIDS.
Neki od dokaza koji upućuju na biološku važnost TNF-α dobiveni su in vivo eksperimentima na miševima kojima su inaktivirani geni za TNF-α ili njegov receptor. Takve su životinje rezistentne na kolagenom inducirani artritis (Mori L et al., J. Immunol., 1996, 157:3178-3182) i na endotoksinom izazvani šok (Pfeffer K et al., Cell, 1993, 73:457-467). U pokusima sa životinjama kod kojih je razina TNF-α povišena dolazi do kroničnog upalnog poliartritisa (Georgopoulos S et al., J.Inflamm., 1996, 46:86-97; Keffer J et al., EMBO J., 1991, 10:4025-4031) koji ima sličnosti sa RA i čiju kliničku sliku ublažavaju inhibitori produkcije TNF-α. Tretman ovakvih upalnih i patoloških stanja obično uključuje primjenu nesteroidnih protuupalnih lijekova, a u težim oblicima daju se soli zlata, D-penicilinamin ili metotreksat. Navedeni lijekovi djeluju simptomatski, ali ne zaustavljaju patološki proces. Novi pristupi u terapiji reumatoidnog artritisa zasnivaju se na lijekovima kao što su tenidap, leflunomide, ciklosporin, FK-506 te na biomolekulama koje neutraliziraju djelovanje TNF-α. Na tržištu se trenutno nalaze fuzijski protein solubilnog receptora za TNF-α etanercept (Enbrel, Immunex/Wyeth) te kimeričko monoklonsko protutijelo miša i čovjeka infliximab (Remicade, Centocor). Osim u terapiji RA, etanercept i infliximab su odobreni i u liječenju Chronove bolesti (Exp. Opin. Invest. Drugs, 2000, 9:103).
U optimalnoj terapiji RA uz inhibiciju produkcije TNF-α važna je i inhibicija produkcije IL-1 jer je IL-1 važan citokin u staničnoj regulaciji i imunoregulaciji te u patofiziološkim stanjima kao što je upala (Dinarello CA et al., Rev. Infect. Disease, 1984, 6:51). Poznate biološke aktivnosti IL-1 su: aktivacija T-stanica, indukcija povišene temperature, stimulacija sekrecije prostanglandina ili kolagenaze, kemotaksija neutrofila te smanjenje nivoa željeza u plazmi (Dinarello CA, J. Clinical Immunology, 1985, 5:287). Poznata su dva receptora na koji se IL-1 može vezati: IL-1RI i IL-1RII. Dok IL-1RI prenosi signal intracelularno, IL-1RII iako na površini stanice ne prenosi signal unutar stanice. Budući da IL1-RII veže IL-1 kao i IL1-RI, on može djelovati kao negativni regulator učinaka IL-1. Osim tog mehanizma regulacije prijenosa signala u stanicama prisutan je još jedan prirodni antagonist IL-1 receptora (IL-1ra). Ovaj protein veže se na IL-1RI, ali ne dovodi do njegove pobude. Potentnost IL-1ra u zaustavljanju IL-1 potaknutog prijenosa signala nije velika te je potrebna 500 puta veća koncentracija IL-1ra od koncentracije IL-1 da bi se postigao prekid u prijenosu signala. Rekombinantni humani IL-1ra (Amgen) je testiran klinički (Bresnihan B et al., Arthrit. Rheum., 1996, 39:73) i dobiveni rezultati ukazuju na poboljšanje kliničke slike kod RA pacijenata u odnosu na placebo. Ovi rezultati upućuju na važnost inhibicije djelovanja IL-1 pri tretiranju bolesti kao što je RA kod kojih je IL-1 produkcija poremećena. Budući da postoji sinergijsko djelovanje TNF-α i IL-1, dualni TNF-α i IL-1 inhibitori se mogu primjenjivati u tretiranju stanja i bolesti vezanih uz povećanu produkciju TNF-α i IL-1.
Rješenje tehničkog problema
Ovaj izum odnosi se na 1-tia-3-aza-dibenzoazulene formule I,
[image]
gdje
X može biti CH2, ili heteroatom kao O, S, S(=O), S(=O)2, ili NRa gdje je Ra vodik ili zaštitna skupina;
Y i Z neovisno jedan o drugom označavaju jedan ili više istovjetnih ili različitih supstituenata vezanih na bilo koji raspoloživi ugljikov atom, a koji mogu biti halogen, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, halo-C1-C4-alkil, hidroksi, C1-C4-alkoksi, trifluorometoksi, C1-C4-alkanoil, amino, amino-C1-C4-alkil, N-(C1-C4-alkil)amino, N,N-di(C1-C4-alkil)amino, tiol, C1-C4-alkiltio, sulfonil, C1-C4-alkilsulfonil, sulfinil, C1-C4-alkilsulfinil, karboksi, C1-C4-alkoksikarbonil, cijano, nitro;
R1 može biti biti vodik, halogen, po potrebi supstituiran C1-C7-alkil ili C2-C7-alkenil, C2-C7-alkinil, po potrebi supstituiran aril ili heteroaril te heterocikl, hidroksi, hidroksi-C2-C7-alkenil, hidroksi-C2-C7-alkinil, C1-C7-alkoksi, tiol, tio-C2-C7-alkenil, tio-C2-C7-alkinil, C1-C7-alkiltio, amino-C2-C7-alkenil, amino-C2-C7-alkinil, amino-C1-C7-alkoksi, C1-C7-alkanoil, aroil, okso-C1-C7-alkil, C1-C7-alkanoiloksi, karboksi, po potrebi supstituiran (C1-C7-alkiloksikarbonil ili ariloksikarbonil), karbamoil, N-(C1-C7-alkil)karbamoil, N,N-di(C1-C7-alkil)karbamoil, cijano, cijano-C1-C7-alkil, sulfonil, C1-C7-alkilsulfonil, sulfinil, C1-C7-alkilsulfinil, nitro,
ili supstituent prikazan formulom II:
[image]
gdje
R2 i R3 istovremeno ili neovisno jedan o drugom mogu biti vodik, C1-C4-alkil, aril ili zajedno s N imaju značenje po potrebi supstituiranog heterocikla ili heteroarila;
m ima značenje cijelog broja od 1 do 3;
n ima značenje cijelog broja od 0 do 3;
Q1 i Q2 neovisno jedan o drugom imaju značenje kisika, sumpora ili skupine:
[image]
gdje supstituenti
y1 i y2 neovisno jedan o drugom mogu biti vodik, halogen, po potrebi supstituiran C1-C4-alkil ili aril, hidroksi, C1-C4-alkoksi, C1-C4-alkanoil, tiol, C1-C4-alkiltio, sulfonil, C1-C4-alkilsulfonil, sulfinil, C1-C4-alkilsulfinil, cijano, nitro, ili zajedno čine karbonilnu ili imino skupinu;
kao i njihove farmakološki prihvatljive soli i solvate.
Izraz "halo", "hal" ili "halogen" odnosi se na atom halogena, koji može biti: fluor, klor, brom ili jod.
Izraz "alkil" odnosi se na alkilne skupine koje imaju značenje alkana iz kojih su izvedeni radikali koji mogu biti ravnolančani, razgranati ili ciklički ili pak kombinacija ravnolančanih i cikličkih te razgranatih i cikličkih. Preferirani ravnolančani ili razgranati alkili su npr. metil, etil, propil, iso-propil, butil, sec-butil i tert-butil. Preferirani ciklički alkili su npr. ciklopentil ili cikloheksil.
Izraz "haloalkil" odnosi se na alkilne skupine koje moraju biti supstituirane s najmanje jednim atomom halogena. Najčešći haloalkili su npr. klormetil, diklormetil, trifluormetil ili 1,2-diklorpropil.
Izraz "alkenil" odnosi se na alkenilne skupine koje imaju značenje ugljikovodičnih radikala koji mogu biti ravnolančani, razgranati ili ciklički ili su pak kombinacija ravnolančanih i cikličkih ili razgranatih i cikličkih, a imaju najmanje jednu ugljik-ugljik dvostruku vezu. Najčešći alkenili su etenil, propenil, butenil ili cikloheksenil.
Izraz "alkinil" odnosi se na alkinilne skupine koje imaju značenje ugljikovodičnih radikala koji su ravnolančani ili razgranati i sadrže najmanje jednu, a najviše dvije trostruke ugljik-ugljik veze. Najčešći alkinili su npr. etinil, propinil ili butinil.
Izraz "alkoksi" odnosi se na ravnolančane ili razgranate lance alkoksi skupine. Primjeri takvih skupina su metoksi, propoksi, prop-2-oksi, butoksi, but-2-oksi ili metilprop-2-oksi.
Izraz "aril" odnosi se na skupine koje imaju značenje aromatskog prstena npr. fenil, kao i na kondenzirane aromatske prstenove. Aril sadrži jedan prsten s najmanje 6 ugljikovih atoma ili dva prstena s ukupno 10 ugljikovih atoma te s naizmjeničnim dvostrukim (rezonantnim) vezama između ugljikovih atoma. Najčešće korišteni arili su npr. fenil ili naftil. Općenito, arilne skupine mogu biti vezane na ostatak molekule bilo kojim raspoloživim ugljikovim atomom direktnom vezom ili preko C1-C4-alkilenske skupine kao npr. metilen ili etilen.
Izraz "heteroaril" odnosi se na skupine koje imaju značenje aromatskih i djelomično aromatskih skupina monocikličkog ili bicikličkog prstena s 4 do 12 atoma od kojih je najmanje jedan heteroatom kao što su O, S ili N, pri čemu je raspoloživi dušikov ili ugljikov atom mjesto vezanja skupine za ostatak molekule bilo direktnom vezom ili preko ranije definirane C1-C4-alkilenske skupine. Primjeri ovog tipa su tiofenil, pirolil, imidazolil, piridinil, oksazolil, tiazolil, pirazolil, tetrazolil, pirimidinil, pirazinil, kinolinil ili triazinil.
Izraz "heterocikl" odnosi se na peteročlane ili šesteročlane potpuno zasićene ili djelomično nezasićene heterocikličke skupine koje sadrže najmanje jedan heteroatom kao što su O, S ili N pri čemu je raspoloživ dušikov ili ugljikov atom mjesto vezanja skupine za ostatak molekule bilo direktnom vezom ili preko ranije definirane C1-C4-alkilenske skupine. Najčešći primjeri su morfolinil, piperidil, piperazinil, pirolidinil, pirazinil ili imidazolil.
Izraz "alkanoil" skupina odnosi se na ravnolančane lance acil skupine kao što su npr. formil, acetil ili propanoil.
Izraz "aroil" skupina odnosi se na aromatske acil skupine kao što je npr. benzoil.
Izraz "po potrebi supstituirani" alkil odnosi se na alkilne skupine koje mogu biti po potrebi dodatno supstituirane s jednim, dva, tri ili više supstituenata. Takvi supstituenti mogu biti atom halogena (prvenstveno fluor ili klor), hidroksi, C1-C4-alkoksi (prvenstveno metoksi ili etoksi), tiol, C1-C4-alkiltio (prvenstveno metiltio ili etiltio), amino, N-(C1-C4)alkilamino (prvenstveno N-metilamino ili N-etilamino), N,N-di(C1-C4-alkil)amino (pvenstveno dimetilamino ili dietilamino), sulfonil, C1-C4-alkilsulfonil (prvenstveno metilsulfonil ili etilsulfonil), sulfinil, C1-C4-alkilsulfinil (prvenstveno metilsulfinil).
Izraz "po potrebi supstituirani" alkenil odnosi se na alkenilne skupine po potrebi dodatno supstituirane s jednim, dva ili tri atoma halogena. Takvi supstituenti mogu npr. biti 2-kloretenil, 1,2-dikloretenil ili 2-brom-propen-1-il.
Izraz "po potrebi supstituirani" aril, heteroaril ili heterocikl odnosi se na arilne, heteroarilne i heterocikličke skupine koje mogu biti po potrebi dodatno supstituirane s jednim ili dva supstituenta. Supstituenti mogu biti halogen (prvenstveno klor ili fluor), C1-C4-alkil (prvenstveno metil, etil ili izopropil), cijano, nitro, hidroksi, C1-C4-alkoksi (prvenstveno metoksi ili etoksi), tiol, C1-C4-alkiltio (prvenstveno metiltio ili etiltio), amino, N-(C1-C4)alkilamino (prvenstveno N-metilamino ili N-etilamino), N,N-di(C1-C4-alkil)amino (prvenstveno N,N-dimetilamino ili N,N-dietilamino), sulfonil, C1-C4-alkilsulfonil (prvenstveno metilsulfonil ili etilsulfonil), sulfinil, C1-C4-alkilsulfinil (prvenstveno metilsulfinil).
Kada X ima značenje NRa, a Ra značenje zaštitne skupine, onda se Ra odnosi na skupine kao što su alkil (prvenstveno metil ili etil), alkanoil (prvenstveno acetil), alkoksikarbonil (prvenstveno metoksikarbonil ili tert-butoksikarbonil), arilmetoksikarbonil (prvenstveno benziloksikarbonil), aroil (prvenstveno benzoil), arilalkil (prvenstveno benzil), alkilsilil (prvenstveno trimetilsilil) ili alkilsililalkoksialkil (prvenstveno trimetilsililetoksimetil).
Kada R2 i R3 zajedno s N imaju značenje heteroarila ili heterocikla to znači da takvi heteroarili ili heterocikli imaju barem jedan ugljikov atom zamijenjen atomom dušika preko kojeg su skupine povezane s ostatkom molekule. Primjeri takvih skupina su morfolin-4-il, piperidin-1-il, pirolidin-1-il, imidazol-1-il ili piperazin-1-il.
Izraz "farmaceutski prikladne soli" odnosi se na soli spojeva formule I, a uključuju npr. soli s C1-C4-alkilhalogenidima (prvenstveno metilbromidom, metilkloridom) (kvaterne amonijeve soli), anorganskim kiselinama (klorovodična, bromovodična, fosforna, metafosforna, dušična ili sumporna) ili organskim kiselinama (vinska, octena, limunska, maleinska, mliječna, fumaratna, benzojeva, sukcinatna, metansulfonska ili p-toluensulfonska).
Neki spojevi formule I mogu s organskim ili anorganskim kiselinama ili bazama formirati soli te su i one uključene u ovaj izum.
Solvati (najčešće hidrati) koje mogu tvoriti spojevi formule I ili njihove soli su također predmet ovog izuma.
Ovisno o prirodi pojedinih supstituenata, spojevi formule I mogu imati geometrijske izomere te jedan ili više kiralnih centara, tako da mogu postojati enantiomeri ili diastereoizomeri. Ovaj izum odnosi se i na takve izomere i njihove smjese, uključujući i racemate.
Ovaj izum odnosi se također na sve moguće tautomerne forme pojedinih spojeva formule I.
Daljnji predmet ovog izuma odnosi se na pripravu spojeva formule I prema postupcima koji uključuju:
a) ciklizaciju α-bromketona formule III:
[image]
sa spojevima formule IV:
[image]
b) za spojeve formule I, gdje Q1 ima značenje -O-
reakciju alkohola formule V:
[image]
sa spojevima formule VI:
[image]
gdje R4 ima značenje odlazeće skupine
c) za spojeve formule I, gdje Q1 ima značenje -O-, -NH-,-S- ili -C≡C-
reakciju formule Va:
[image]
gdje L ima značenje odlazeće skupine
sa spojevima formule VIa:
[image]
d) za spojeve gdje Q1 ima značenje heteroatoma -O-, -NH- ili -S-
reakciju spojeva formule Vb:
[image]
sa spojevima formule VI, gdje R4 ima značenje odlazeće skupine
e) za spojeve gdje Q1 ima značenje -C=C-
reakciju spojeva formule Va, gdje Q1 ima značenje karbonila s fosfornim ilidima.
Metode priprave:
a) Ciklizacija α-bromketona formule III i tioamida formule IV provodi se prema metodama koje su opisane za pripravu analognih spojeva (Teitei, Aust. J. Chem., 1980, 33:605-611). Reakcija se odvija u pogodnom otapalu kao što su npr. etanol, propanol, izopropanol, N,N-dimetilformamid, N,N-dimetilacetamid, toluen ili ksilen pri povišenoj temperaturi (najbolje od 50oC do 150oC). Nastali tetraciklički produkti mogu se izolirati kromatografijom na stupcu ili prekristalizacijom iz pogodnog otapala.
Polazne supstancije za tu reakciju su od ranije poznati spojevi ili spojevi koji su priređeni metodama opisanim za pripravu analognih spojeva; za α-bromketone formule III npr. u US Pat. Br. 3,711,489 ili US Pat. Br. 4,198,421 ili za tioamide formule IV npr. u Kavtunenko V.A. at al., Ukr. Khim. Zh., 1983, 49:975-978. Tako dobiveni spojevi mogu se očistiti, izolirati i karakterizirati ili bez izolacije koristiti u daljnjoj reakciji ciklizacije.
b) Spojeva formule I prema ovom postupku mogu se pripraviti reakcijom alkohola formule V i spojeva formule VI, gdje R4 ima značenje odlazeće skupine koja može biti atom halogena (najčešće brom, jod ili klor) ili sulfoniloksi skupinom (najčešće trifluorometilsulfoniloksi ili p-toluensulfoniloksi). Reakcija kondenzacije može biti provedena prema metodama koje su opisane za pripravu analognih spojeva (Menozzi G et al., J. Heterocyclic Chem., 1997, 34:963-968 ili WO Pat prijava Br. 01/87890). Reakcija se provodi pri temperaturi od 20oC do 100oC, kroz 1-24 sata, u dvofaznom sustavu (najbolje 50 %-nom NaOH/toluen) u prisutnosti phase-transfer katalizatora (najbolje benzil-trietil-amonij-klorida, benzil-trietil-amonij-bromida, cetil-trimetil-bromida). Nastali produkti su nakon obrade reakcijske smjese izolirani prekristalizacijom ili kromatografijom na stupcu silikagela.
Polazni spojevi, alkoholi formule V, mogu se prirediti iz spojeva formule I, gdje R1 ima značenje pogodne funkcionalne skupine. Tako se npr. alkoholi formule V mogu dobiti redukcijom alkanoilne skupine (npr. formil) ili alkiloksikarbonilne skupine (npr. metlioksikarbonil ili etiloksikarbonil) korištenjem metalnih hidrida kao što su litij aluminij hidrid ili natrij borhidrid. Nadalje alkoholi formule IV mogu se pripraviti hidrolizom odgovarajućih estera u baznom ili kiselim mediju.
Polazni spojevi formule VI su od ranije poznati ili su priređeni prema metodama koje su opisane za pripravu analognih spojeva.
c) Spojevi formule I prema ovom postupku mogu se pripraviti reakcijom spojeva formule Va, gdje L ima značenje odlazeće skupine ranije definirane za R4 i spojeva formule VIa, gdje Q1 ima značenje kisika, dušika, sumpora ili -C≡C-. Najpogodnije reakcije kondenzacije literaturno su opisane reakcije nukleofilne supstitucije na zasićenom ugljikovom atomu.
Polazne spojeve formule Va (najčešće halogenide) moguće je dobiti halogeniranjem (npr. bromiranje ili kloriranje) spojeva formule V uobičajenim sredstvima za halogeniranje (npr bromovodična kiselina, PBr3, SOCl2 ili PCl5) literaturno opisanim postupcima. Dobiveni spojevi mogu se izolirati ili se bez izolacije kao pogodni intermedijeri koristiti za pripravu spojeva formule I.
Polazni spojevi formule VIa su od ranije poznati ili su priređeni prema metodama koje su opisane za pripravu analognih spojeva.
d) Spojeve formule I, gdje Q1 ima značenje -O-, -NH- ili -S- moguće je pripraviti kondenzacijom spojeva formule Vb i spojeva formule VI, gdje R4 ima značenje ranije definirane odlazeće skupine. Reakciju je moguće provesti kod reakcijskih uvjeta opisanih u Metodi b ili literaturno opisanim reakcijama nukleofilne supstitucije. Polazni alkoholi, amini ili tioli mogu se dobiti reakcijom vode, amonijaka ili sumporovodika sa spojevima Va prema literaturno opisanim postupcima.
e) Alkoholi strukture V mogu se oksidirati u odgovarajuće spojeve formule Vb, gdje Q1 ima značenje karbonila, a koji dalje mogu reakcijom s odgovarajućim ilidnim reagensima rezultirati produženjem lanca i formiranjem alkenilnog supstituenta s karbonilnom ili esterskom skupinom kao što je opisano u HR Pat. prijava Br. 20000310.
Osim gore spomenutih reakcija, spojevi formule I mogu biti pripravljeni transformacijom drugih spojeva formule I te se podrazumjeva da ovaj izum obuhvaća i takve spojeve i postupke. Posebni primjer promjene funkcionalne skupine je reakcija aldehidne skupine s odabranim fosfornim ilidima, pri čemu dolazi do produženja lanca i formiranja alkenilnog supstituenta s karbonilnom ili esterskom skupinom kao što je to opisano u HR Pat. prijava Br. 20000310. Ove reakcije provode se u otapalima kao što su npr. benzen, toluen ili heksan pri povišenoj temperaturi (najčešće pri temperaturi vrenja).
Reakcijom spojeva formule Va s 1-alkinom u baznom mediju (kao što je natrij amid u amonijaku) dobivaju se spojevi formule I, gdje je Q1 -C≡C-. Reakcijski uvjeti ovog postupka literaturno su opisani. U sličnim reakcijskim uvjetima (nukleofilna supstitucija) mogu se pripraviti različiti eterski, tioeterski ili aminski derivati.
Daljnji općeniti primjer transformacije je formiliranje spojeva formule I postupcima kao npr. Vilsmeir-ovom acilacijom ili reakcijom n-BuLi i N,N-dimetilformamida. Reakcijski uvjeti ovih postupaka literaturno su poznati.
Hidrolizom spojeva formule I koji posjeduju nitrilnu, amidnu ili estersku skupinu moguće je pripraviti spojeve s karboksilnom skupinom, koji su pogodni intermedijeri za pripravu drugih spojeva s novim funkcionalnim skupinama kao što su npr. esteri, amidi, halogenidi, anhidridi, alkoholi ili amini.
Daljnja mogućnost promjene supstituenata u spojevima formule I su reakcije oksidacije ili redukcije. Najčešće korištena oksidacijska sredstava su peroksidi (vodikov peroksid, m-klorperbenzojeva kiselina ili benzoilperoksid) ili permanganatni, kromatni ili perkloratni ion. Tako npr. oksidacijom alkoholne skupine piridinil-dikromatom ili piridinil-klorkromatom nastaje aldehidna skupina, koju je daljnjom oksidacijom moguće prevesti u karboksilnu skupinu. Oksidacijom spojeva formule I, gdje R1 ima značenje alkila, s olovo tetraacetatom u octenoj kiselini ili N-bromsukcinimidom uz katalitičku količinu benzoilperoksida dobije se odgovarajući karbonilni derivat.
Selektivnom oksidacijom alkiltio skupine moguće je pripraviti alkilsulfinilne ili aklilsulfonilne skupine.
Redukcija spojeva s nitro skupinom omogućava pripravu amino spojeva. Reakcija se odvija kod uobičajenih uvjeta katalitičke hidrogenacije ili elektrokemijskim načinom. Katalitičkom hidrogenacijom uz paladij na ugljenu moguće je alkenilne supstituente prevesti u alkilne ili nitrilnu skupinu u aminoalkil.
Različiti supstituenti aromatskog sustava u spojevima formule I mogu se uvesti standardnim reakcijama supstitucije ili uobičajenim promjenama pojedinih funkcionalnih skupina. Primjeri takvih reakcija su aromatske supstitucije, alkilacije, halogeniranje, hidroksiliranje kao i oksidacija ili redukcija supstituenata. Reagensi i reakcijski uvjeti su literaturno poznati. Tako se npr. aromatskom supstitucijom uvodi nitro skupina u prisutnosti koncentrirane dušične i sumporne kiseline. Korištenjem acilhalogenida ili alkilhalogenida moguće je uvođenje acilne skupine ili alkilne skupine. Reakcija se odvija uz prisutnost Lewis-ovih kiselina kao npr. aluminij ili željezo triklorida u uvjetima Friedel-Crafts reakcije. Redukcijom nitro skupine dobiva se amino skupina koja se reakcijom diazotiranja prevodi u dobru izlaznu skupinu koja može biti zamjenjena jednom od sljedećih skupina: H, CN, OH, Hal.
Da bi se spriječilo nepoželjno sudjelovanje u kemijskim reakcijama često je potrebno zaštiti određene skupine kao što su npr. hidroksi, amino, tio ili karboksi. U tu svrhu može se koristiti velik broj zaštitnih skupina [Green TW, Wuts PGH, Protective Groups in Organic Synthesis, John Wiley and Sons, 1999], a njihov odabir, upotreba i uklanjanje uobičajene su metode u kemijskoj sintezi.
Pogodna zaštita za amino ili alkilamino grupu su skupine kao npr. alkanoilna (acetil), alkoksikarbonilna (metoksikarbonil, etoksikarbonil ili tert-butoksikarbonil); arilmetoksikarbonilna (benziloksikarbonil), aroil (benzoil) ili alkilsililna skupina (trimetilsilil ili trimetilsililetoksimetil). Uvjeti uklanjanja zaštitne skupine ovise o izboru i svojstvima te skupine. Tako se npr. acilne skupine kao što su alkanoil, alkoksikarbonil ili aroil mogu ukloniti hidrolizom u prisutnosti baze (natrijev ili kalijev hidroksid), tert-butoksikarbonil ili alkilsilil (trimetilsilil) mogu se ukloniti obradom pogodnom kiselinom (solna, sumporna, fosforna ili trifluoroctena), dok arilmetoksikarbonilna skupina (benziloksikarbonil) može biti uklonjena hidrogenacijom uz katalizator kao što je paladij na ugljenu.
Soli spojeva formule I mogu se prirediti opće poznatim postupcima kao npr. reakcijom spojeva formule I s odgovarajućom bazom ili kiselinom u pogodnom otapalu ili smjesi otapala npr. eterima (dietileter) ili alkoholima (etanol, propanol ili iso-propanol).
Daljnji predmet ovog izuma odnosi se na upotrebu predmetnih spojeva u liječenju inflamatornih bolesti i stanja, a posebno u svim bolestima i stanjima izazvanim prekomjernom produkcijom TNF-α i IL-1.
Efektivna doza inhibitora produkcije citokina ili medijatora upale koji su predmet ovog izuma ili farmakološki prihvatljive soli istih upotrebljivi su u proizvodnji lijekova za liječenje i profilaksi bilo kojeg patološkog stanja ili bolesti koji su izazvani prekomjernom nereguliranom produkcijom citokina ili medijatora upale. Ovaj izum više se specifično odnosi na efektivnu dozu inhibitora TNF-α koja se može odrediti uobičajenim metodama.
Nadalje, ovaj izum odnosi se na farmaceutski pripravak koji sadrži efektivnu netoksičnu dozu spojeva koji su predmet ovog izuma kao i farmaceutski prihvatljive nosioce ili otapala.
Priprava farmaceutskih pripravaka može uključivati miješanje, granuliranje, tabletiranje i otapanje sastojaka. Kemijski nosači mogu biti kruti ili tekući. Kruti nosači mogu biti: laktoza, sukroza, talk, želatina, agar, pektin, magnezijev stearat, masne kiseline i sl. Tekući nosači mogu biti sirupi, ulja kao što su maslinovo, suncokretovo ili sojino, voda i sl. Slično tomu, nosač može još sadržavati i komponentu za usporeno otpuštanje aktivne komponente kao npr. gliceril monostearat ili gliceril distearat. Razni oblici farmaceutskih pripravaka mogu biti primijenjeni. Tako, ako je upotrijebljen kruti nosač, to mogu biti tablete, tvrde želatinozne kapsule, prašak, ili zrnca koja se mogu davati u kapsulama per os. Količina tvrdog nosača može varirati, ali je uglavnom od 25 mg do 1 g. Ako je upotrebljen tekući nosač, preparat bi bio u formi sirupa, emulzije, mekih želatinoznih kapsula, sterilnih injektabilnih tekućina kao što su ampule ili nevodenih tekućih suspenzija.
Spojevi koji su predmet ovog izuma mogu se aplicirati per os, parenteralno, lokalno, intranazalno, intrarektalno i intravaginalno. Parenteralni način ovdje ima značenje intravenozne, intramuskularne i subkutane aplikacije. Odgovarajuće pripravke spojeva koji su predmet ovog izuma moguće je primjenjivati u profilaksi, ali i u tretmanu upalnih bolesti koje su uzrokovane prevelikom nereguliranom produkcijom citokina ili medijatora upale, u prvom redu TNF-α. Tu spadaju npr. reumatoidni artritis, reumatoidni spondilitis, osteoartritis te druga artritična patološka stanja i bolesti, ekcemi, psorijaza i druga upalna stanja kože, upalne bolesti oka, Chronova bolest, ulcerativni kolitis i astma.
Inhibitorni učinak spojeva koji su predmet ovog izuma na produkciju TNF-α i IL-1 određen je sljedećim in vitro i in vivo eksperimentima:
Određivanje lučenja TNF-α i IL-1 u monunuklearnim stanicama periferne krvi čovjeka in vitro
Mononuklearne stanice humane periferne krvi (PBMC, od engleskog peripheral blood mononuclear cells) pripravljene su iz heparinizirane pune krvi nakon odvajanja PBMC na Ficoll-PaqueTMPlus (Amersham-Pharmacia). Za određivanje razine TNF-α 3.5-5x104 stanica je kultivirano u ukupnom volumenu od 200 µL 18 do 24 sata na mikrotitarskim pločicama sa ravnim dnom (96 bunarića, Falcon) u RPMI 1640 mediju u koji je dodano 10 % FBS (Fetal Bovine Serum, Biowhittaker) prethodno inaktiviranog na 54°C / 30 min, 100 jedinica/mL penicilina, 100 mg/mL streptomicina i 20 mM HEPES (GIBCO). Stanice su inkubirane na 37°C u atmosferi s 5% CO2 i 90% vlage. U negativnoj kontroli stanice su kultivirane samo u mediju (NK), dok je lučenje TNF-α u pozitivnoj kontroli pobuđeno dodatkom 1 ng/mL lipopolisaharida (LPS, E. coli serotype 0111:B4, SIGMA) (PK). Učinak testiranih supstanci na lučenje TNF-α ispitivan je nakon njihova dodatka u kulture stanica stimuliranih s LPS-om (TS). Razina TNF-α u staničnom supernatantu je određena postupkom ELISA prema sugestijama proizvođača (R&D Systems). Osjetljivost testa bila je <3 pg/mL TNF-α. Razina IL-1 određena je u testu s istim uvjetima i jednakim brojem stanica te jednakom koncentracijom stimulusa postupkom ELISA (R&D Systems). Postotak inhibicije produkcije TNF-α ili IL-1 izračunat je formulom:
% inhibicije = [1- (TS-NK)/(PK-NK)] * 100.
IC50 vrijednost definirana je kao ona koncentracija supstance kod koje je inhibirano 50 % produkcije TNF-α.
Aktivni su spojevi koji pokazuju IC50 s 20 μM ili nižim koncentracijama.
Određivanje lučenja TNF-α i IL-1 u peritonealnim makrofazima miša in vitro
Za dobivanje peritonealnih makrofaga mužjaci Balb/C mišjeg soja stari 8 do 12 tjedana su injicirani i.p. s 300 µg zimozana (SIGMA) otopljenog u fosfatnom puferu (PBS) u ukupnom volumenu od 0,1 mL/mišu. Nakon 24 sata miševi su eutanazirani u skladu sa Zakonom o dobrobiti laboratorijskih životinja. Peritonealna šupljina je isprana s 5 mL sterilne fiziološke otopine. Dobiveni peritonealni makrofazi isprani su dva puta sterilnom fiziološkom otopinom, te nakon zadnjeg centrifugiranja (350 g / 10 min) resuspendirani u RPMI 1640 kojem je dodano 10% FBS-a. Za određivanje lučenja TNF-α 5x104 stanica/bunariću je kultivirano u ukupnom volumenu od 200 µL, 18 do 24 sata u mikrotitarskim pločicama sa ravnim dnom (96 bunarića, Falcon) u RPMI 1640 mediju u koji je dodano 10% toplinom inaktiviranog fetalnog seruma goveda (FBS, Biowhittaker), 100 jedinica/ml penicilina, 100 mg/ml streptomicina, 20 mM HEPES i 50 μM 2-merkaptoetanola (sve od GIBCO). Stanice su inkubirane na 37°C u atmosferi s 5% CO2 i 90% vlage. U negativnoj kontroli (NK) stanice su kultivirane samo u mediju dok je lučenje TNF-α u pozitivnoj kontroli (PK) pobuđeno dodatkom 10 ng/mL lipopolisaharida (LPS, E. coli serotype 0111:B4, SIGMA). Učinak supstanci na lučenje TNF-α ispitivan je nakon njihova dodatka u kulture stanica stimuliranih s LPS (TS). Razina TNF-α u staničnom supernatantu određena je postupkom ELISA specifičnom za TNF-α ili IL-1 (R&D Systems, Biosource). Postotak inhbicije produkcije TNF-α ili IL-1 izračunat je formulom:
% inhibicije = [1- (TS-NK)/(PK-NK)] * 100.
IC50 vrijednost definirana je kao ona koncentracija supstance kod koje je inhibirano 50% produkcije TNF-α. Aktivni su spojevi kojima je IC50 10 μM ili manje.
In vivo model LPS-om inducirane prekomjerne sekrecije TNF-α ili IL-1 u miševa
TNF-α ili IL-1 sekrecija u miševa bila je izazvana po prethodno opisanoj metodi (Badger AM et al., J. Pharmac. Env. Therap., 1996, 279:1453-1461). U testu su korišteni Balb/C mužjaci, 8-12 tjedana starosti, u grupama od 6-10 životinja. Životinje su tretirane p.o. bilo samo otapalom (u negativnoj i pozitivnoj kontroli), bilo otopinama supstanci 30 min prije no što su tretirane i.p. s LPS-om (E. coli serotip 0111:B4, Sigma) u dozi od 1-25 μg/životinji. Dva sata kasnije životinje su eutanizirane pomoću i.p. injekcije Roumpun-a (Bayer) i Ketanest-a (Parke-Davis). Uzorak krvi od svake životinje uziman je u “Vacutainer” tube (Becton Dickinson) te je plazma odvojena prema uputama proizvođača. Razina TNF-α u plazmi bila je određena pomoću ELISA-postupka (Biosource, R&D Systems) po postupku propisanom od proizvođača. Osjetljivost testa bila je < 3 pg/mL TNF-α. Razina IL-1 određena je ELISA-postupkom (R&D Systems). Postotak inhibicije produkcije TNF-α ili IL-1 izračunavan je formulom:
% inhibicije = [1- (TS-NK)/(PK-NK)] * 100.Aktivni su spojevi koji kod doze od 10 mg/kg pokazuju 30% inhibicije produkcije TNF-α ili više.
”Writhing” test za analgetsku aktivnost
U ovom testu bol se izaziva injekcijom iritanta, najčešće octene kiseline, u peritonealnu šupljinu miša. Životinje reagiraju karakterističnim istezanjima po kojima je test dobio ime. (Collier HOJ et al., Pharmac. Chemother., 1968, 32:295-310; Fukawa K et al., J. Pharmacol. Meth ., 1980, 4:251-259; Schweizer A et al., Agents Actions, 1988, 23:29-31). Test je pogodan za određivanje analgetske aktivnosti spojeva. Postupak: korišteni su Balb/C miševi (Charles River, Italy) starosti 8-12 tjedana, muškog spola. Kontrolna grupa dobila je p.o metil-celulozu 30 minuta prije i.p. aplikacije octene kiseline u koncentraciji od 0.6%, a test-grupe dobile su p.o. standard (acetilsalicilnu kiselinu) ili test supstance u metil-celulozi 30 minuta prije i.p. aplikacije 0.6%-tne octene kiseline (volumen 0.1 ml/10 g). Miševi su smještani pojedinačno pod staklene lijevke te se tijekom 20 minuta bilježio broj istezanja za svaku životinju. Postotak inhibicije istezanja izračunavan je prema formuli:
% inhibicije = [(srednja vrijednost broja istezanja u kontrolnoj grupi - broj istezanja u test grupi) /broj istezanja u kontrolnoj grupi ]* 100.
Aktivni su spojevi koji pokazuju analgetsku aktivnost kao i acetilsalicilna kiselina ili bolju.
In vivo model LPS izazvanog šoka u miševa
Korišteni su Balb/C miševi muškog spola stari 8-12 tjedana (Charles River, Italy). LPS izoliran iz Serratie marcessans (Sigma, L-6136) razrijeđen je u sterilnoj fiziološkoj otopini. Prva injekcija LPS dana je intradermalno u dozi od 4 µg/mišu. 18-24 sata kasnije davan je LPS i.v. u dozi od 90-200 µg/mišu. Kontrolna grupa je dobila dvije injekcije LPS-a na gore opisani način. Test grupe dobile su supstance p.o pola sata prije svake aplikacije LPS-a. Promatrano je preživljenje nakon 24 sata.
Aktivni su spojevi kod kojih je preživljavanje kod doze od 30 mg/kg 40% ili bolje.
Spojevi iz Primjera (19 i 20) pokazuju aktivnost u najmanje dva ispitivana testa iako ovi rezultati predstavljaju samo ilustraciju biološke aktivnosti spojeva, ali ni u čemu ne ograničavaju ovaj izum.
POSTUPCI PRIPRAVE S PRIMJERIMA
Ovaj izum ilustriran je sljedećim primjerima, koji ga ne limitiraju ni u kom pogledu.
Primjer 1
2-Fenil-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen (1; Tablica 1)
Otopina 11-bromo-7-trifluorometil-11H-dibenzo[b,f]tiepin-10-ona (0.3 mmol) i tiobenzamida (0.6 mmol) u N,N-dimetilformamidu (4 mL) zagrijava se 6 sati pri temperaturi 80oC. Otapalo se upari kod sniženog tlaka do suhog ostatka, a sirovi produkt pročisti se ekstrakcijom na čvrstoj fazi(reverzno-fazna kolona RP-C18).
Prema gornjem postupku reakcijom 11-bromo-7-trifluorometil-11H-dibenzo[b,f]tiepin-10-ona i odgovarajućeg tioamida dobiveni su odgovarajući azuleni (Tablica 1, spojevi 2-33)
Tablica 1
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[image] [image] [image]
Primjer 2
2-Piridin-4-il-6-trifluorometil-8-oxa-1-tia-3-aza-dibenzo[e,h]azulen (34; Tablica 2)
Otopina 11-bromo-7-trifluorometil-11H-dibenzo[b,f]oksepin-10-ona (0.4 mmol) i piridinij-bromida perbromida (0.45 mmol) u toluenu (5 mL) miješa se pri sobnoj temperaturi 4 sata. Potom se u reakcijsku smjesu doda K2CO3 (50 mg). Reakcijska smjesa miješa se još 10 minuta i profiltrira. Otapalo se upari kod sniženog tlaka do suhog ostatka. Dobivenom 11-bromo-7-trifluorometil-11H-dibenzo[b,f]oksepin-10-onu doda se tioizonikotinamid (0.5 mmol) otopljen u N,N-dimetilformamidu (4 mL). Reakcijska smjesa zagrijava se 6 sati pri 80oC. Otapalo se upari kod sniženog tlaka do suhog ostatka, a sirovi produkt pročisti se ekstrakcijom na čvrstoj fazi (reverzno-fazna kolona RP-C18).
Prema gornjem postupku reakcijom tioizonikotinamida i odgovarajućeg bromketona dobiveni su odgovarajući azuleni (Tablica 2, spojevi 35-49)
Tablica 2
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[image]
U svim primjerima navedenim u Tablici 2. Z = H.
Primjer 3
8-Oksa-1-tia-3-aza-dibenzo[e,h]azulen (50; Tablica 3)
U otopinu fosfor (V)-sulfida (6.54 mmol) u formamidu (102 mmol; 4.08 mL) doda se toluenska otopina (8.2 mL) 11-bromo-11H-dibenzo[b,f]oksepin-10-ona (4.60 mmol). Reakcijska smjesa zagrijava se uz miješanje i refluks 4 sata. Potom se reakcijska smjesa neutralizira 10 %-tnim natrij-hidroksidom i ekstrahira kloroformom. Nakon pročišćavanja kromatografijom na stupcu silikagela izoliran je kristalinični produkt.
Prema gornjem postupku polazeći od spojeva:
11-bromo-8-fluoro-11H-dibenzo[b,f]oksepin-10-ona;
11-bromo-8-kloro -11H-dibenzo[b,f]oksepin-10-ona;
11-bromo-11H-dibenzo[b,f]tiepin-10-ona
pripravljeni su:
5-fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen;
5-kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen;
1,8-ditia-3-aza-dibenzo[e,h]azulen,
(Tablica 3, spojevi 51-53).
Primjer 4
5-Fluoro-2-metil-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen (54; Tablica 3)
U otopinu 11-bromo-8-fluoro-11H-dibenzo[b,f]oksepin-10-ona (2.34 mmol) u suhom N,N-dimetilformamidu (12 mL) doda se tioacetamid (2.8 mmol). Reakcijska smjesa zagrijava se uz miješanje pri 90oC 3 sata. Potom se otapalo upari pod sniženim tlakom, a zaostali uljasti produkt otopi se u etil-acetatu i vodi. Nakon ekstrakcije organski slojevi isperu se zasićenom vodenom otopinom NaHCO3, vodom i zasićenom vodenom otopinom natrij-klorida. Nakon pročišćavanja kromatografijom na stupcu silikagela izoliran je kristalinični produkt.
Prema gornjem postupku polazeći od spojeva:
11-bromo-8-kloro-11H-dibenzo[b,f]oksepin-10-ona;
11-bromo-7-kloro-11H-dibenzo[b,f]tiepin-10-ona;
11-bromo-7-trifluorometil-11H-dibenzo[b,f]tiepin-10-ona;
7,11-dibromo-11H-dibenzo[b,f]tiepin-10-ona;
8,11-dibromo-11H-dibenzo[b,f]tiepin-10-ona;
11-bromo-8-kloro-11H-dibenzo[b,f]tiepin-10-ona;
11-bromo-11H-dibenzo[b,f]tiepin-10-ona;
11-bromo-11H-dibenzo[b,f]oksepin-10-ona
pripravljeni su:
5-kloro-2-metil-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen;
6-kloro-2-metil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-metil-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
6-bromo-2-metil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
5-bromo-2-metil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
5-kloro-2-metil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-metil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-metil-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen,
(Tablica 3, spojevi 55-62).
Primjer 5
(6-Kloro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-acetonitril (63; Tablica 3)
U otopinu 11-bromo-7-kloro-11H-dibenzo[b,f]tiepin-10-ona (3.75 mmol) u apsolutnom etanolu (19 mL) doda se 2-cijanotioacetamid (5.63 mmol). Reakcijska smjesa zagrijava se uz miješanje i refluks 8 sati. Potom se otapalo upari pod sniženim tlakom, a zaostali suhi ostatak otopi se u vodi i etil-acetatu. Nakon ekstrakcije organski slojevi isperu se zasićenom vodenom otopinom NaHCO3, vodom i zasićenom vodenom otopinom natrij-klorida. Nakon pročišćavanja kromatografijom na stupcu silikagela izoliran je kristalinični produkt.
Primjer 6
6-Trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-karboksilna kiselina etilni-ester (70; Tablica 3)
U otopinu 11-bromo-7-trifluorometil-11H-dibenzo[b,f]tiepin-10-ona (1.37 mmol) u suhom N,N-dimetilformamidu (7 mL) doda se etil-tiooksamat (1.5 mmol). Reakcijska smjesa zagrijava se uz miješanje pri 80oC 3 sata. Potom se otapalo upari pod sniženim tlakom, a zaostali uljasti produkt otopi se u etil-acetatu i vodi. Nakon ekstrakcije organski sloj ispire se zasićenom vodenom otopinom NaHCO3, vodom i zasićenom vodenom otopinom natrij-klorida. Nakon pročišćavanja kromatografijom na stupcu silikagela izoliran je kristalinični produkt.
Prema gornjem postupku polazeći od
11-bromo-8-fluoro-11H-dibenzo[b,f]tiepin-10-ona priređen je
5-fluoro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-karboksilna kiselina etilni-ester (71; Tablica 3).
Primjer 7
8-Oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-karbaldehid (64; Tablica3)
U otopinu spoja 50 (1.99 mmol) u suhom tetrahidrofuranu (5 mL) ohlađenu na -78°C doda se n-BuLi (5.77 mmol). Nakon 15 minuta u reakcijsku smjesu doda se N,N-dimetilformamid (4.98 mmol; 0.38 mL). Reakcijska smjesa miješa se pri sobnoj temperaturi 1 sat, a potom se doda voda i ekstrahira se etil-acetatom. Spojeni organski ekstrakti upareni su pod sniženim tlakom, a zaostali suhi ostatak pročišćen je kromatografijom na stupcu silikagela.
Prema gornjem postupku, a polazeći od spojeva 51-53 pripravljeni su aldehidi:
5-fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-karbaldehid;
5-kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-karbaldehid;
1,8-ditia-3-aza-dibenzo[e,h]azulen-2-karbaldehid,
(spojevi 65-67; Tablica 3).
Primjer 8
(6-Kloro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-octena kiselina etilni-ester (69; Tablica 3)
U otopinu spoja 63 (0.53 mmol) u etanolu (2 mL) uz miješanje se dokapa koncentrirana sulfatna kiselina (0.5 mL). Reakcijska smjesa zagrijava se uz refluks 4 sata, a zatim se ohladi na sobnu temperaturu i prelije u vodu (5 mL). Reakcijska smjesa ekstrahira se etil-acetatom. Spojeni organski ekstrakti upare se pod sniženim tlakom pri čemu zaostaje uljasti produkt.
Primjer 9
5-Fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-il-octena kiselina metilni-ester (72; Tablica 3)
U otopinu spoja 54 ( 0.21 mmol) u octenoj kiselini (5 mL) uz miješanje doda se olovo (IV)-acetat. Reakcijska smjesa zagrijava se uz refluks 8 sati. Zatim se octena kiselina upari pod sniženim tlakom, a preostali suhi ostatak otopi se u vodi i ekstrahira etil-acetatom. Spojeni ekstrakti isperu se vodom i zasićenom vodenom otopinom natrij-klorida te upare pod sniženim tlakom. Nakon pročišćavanja kromatografijom na stupcu silikagela izoliran je kristalinični produkt.
Prema gornjem propisu, a polazeći od spoja 55 pripravljen je 5-kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-il-octena kiselina metilni-ester (73; Tablica 3).
Tablica 3
[image]
I
[image] [image]
U svim primjerima navedenim u Tablici 3. Z = H.
Primjer 10
(8-Oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-il)-metanol (74; Tablica 4)
U otopinu spoja 64 (0.60 mmol) u metanolu (10 mL) doda se uz miješanje pri sobnoj temperaturi NaBH4 (0.90 mmol). Reakcijska smjesa miješa se 15 minuta. Nakon što je sva količina aldehida izreagirala reakcijska smjesa neutralizira se s octenom kiselinom, a otapalo se upari pod sniženim tlakom. Dobiveni suhi ostatak otopi se u zasićenoj vodenoj otopini NaHCO3 i ekstrahira etil-acetatom. Organski ekstrakt ispere se vodom i zasićenom vodenom otopinom natrij-klorida. Otapalo se upari pod sniženim tlakom, a sirovi produkt se zatim preklistalizira iz smjese etil-acetata i heksana.
Prema gornjem postupku, a polazeći od aldehida 65-67 pripravljeni su alkoholi:
(5-fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-il)-metanol;
(5-kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-il)-metanol;
(1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-metanol,
(Tablica 4, spojevi 75-77).
Primjer 11
2-(6-Kloro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-etanol (78;Tablica 4)
U suspenziju LiAlH4 u suhom eteru (2 mmol / 5 mL suhog etera) dokapa se eterska otopina estera 69 (1 mmol / 5 mL). Reakcijska smjesa miješa se pri sobnoj temperaturi 2 sata. Nakon što je sva količina estera izreagirala, suvišak LiAlH4 razori se dodatkom dietiletera i vode. Nastali bijeli talog se odfiltrira, a filtrat se nakon sušenja na bezvodnom natrij-sulfatu upari pod sniženim tlakom. Sirovi produkt pročišćen je kromatografijom na stupcu silikagela.
Primjer 12
(6-Trifluorometi-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-metanol (79; Tablica 4)
U otopinu spoja 70 (0.60 mmol) u metanolu (10 mL) doda se uz miješanje na sobnoj temperaturi NaBH4 (0.90 mmol). Reakcijska smjesa miješa se 15 minuta. Nakon što je sva količina estera izreagirala reakcijska smjesa neutralizira se octenom kiselinom, a otapalo se upari pod sniženim tlakom. U dobiveni suhi ostatak doda se zasićena vodena otopina NaHCO3 i ekstrahira etil-acetatom. Organski ekstrakt ispere se vodom i zasićenom vodenom otopinom natrij-klorida. Otapalo se upari pod sniženim tlakom, a sirovi produkt se preklistalizira iz smjese etil-acetata i heksana te se dobije čisti produkt.
Prema gornjem postupku, a polazeći od estera 71 pripravljen je (5-fluoro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-metanol (80; Tablica 4)
Primjer 13
(5-Fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-il)-metanol (75; Tablica 4)
U otopinu estera 72 (1 mmol) u etanolu (36 mL) doda se kalij-hidroksid (2.5 mmol) i voda (4 mL). Reakcijska smjesa miješa se i zagrijava uz refluks 1 sat. Nakon što je sva količina estera izreagirala, etanol se upari pod sniženim tlakom. Dobiveni suhi ostatak otopi se u vodi i ekstrahira etil-acetatom. Organski ekstrakti isperu se zasićenom vodenom otopinom NaHCO3, vodom i zasićenom vodenom otopinom natrij-klorida. Dobiveni suhi ostatak pročišćen je kromatografijom na stupcu silikagela.
Prema gornjem postupku, a polazeći od estera 73 priređen je alkohol (5-kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-il)-metanol (76; Tablici 4).
Tablica 4
[image]
V
[image]
U svim primjerima navedenim u Tablici 4. Z = H.
Primjer 14
a) Dimetil-[2-(8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-etil]-amin (I; X = O, Y = Z = H, R1 = (CH3)2N(CH2)2OCH2)
U otopinu 2-dimetilaminoetilklorid-hidroklorida (14 mmol) u 50%-tnom natrijevom hidroksidu (5 mL) doda se benziltrietilamonijev klorid (0.44 mmol) te otopina alkohola 74 (1 mmol) u toluenu (3 mL). Reakcijska smjesa zagrijava se uz refluks i snažno miješanje 4 sata. Potom se ohladi na sobnu temperaturu, razrijedi vodom te ekstrahira diklorometanom. Nakon pročišćavanja kromatografijom na stupcu silikagela izoliran je uljasti produkt;
1H NMR (ppm, CDCl3): 2.58 (s, 6H); 2.92-2.95 (t, 2H); 3.92-3.98 (t, 2H); 4.91(s, 2H); 7.15-7.90 (m, 8H);
MS(m/z): 353.3 (MH+).
b) Dimetil-[3-(8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-amin (I; X = O, Y = Z = H, R1 = (CH3)2N(CH2)3OCH2)
Reakcijom alkohola 74 (1.5 mmol) i 3-dimetilaminopropilklorid-hidroklorida (21 mmol) dobiven je uljasti produkt;
1H NMR (ppm, CDCl3): 2.23 (m, 2H); 2.83-2.85 (d, 6H); 3.15-3.25 (m, 2H); 3.72-3.84 (t, 2H); 4.90 (s, 2H): 7.18-7.91(m, 8H);
MS(m/z): 367.3 (MH+).
c) 3-(8-Oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-amin (I; X = O, Y = Z = H, R1 = H2N(CH2)3OCH2)
Reakcijom alkohola 74 (1.5 mmol) i 3-aminopropilklorid-hidroklorida (21 mmol) dobiven je uljasti produkt;
MS(m/z): 339.1 (MH+).
Primjer 15
a) [2-(5-Fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-etil]-dimetilamin (I; X = O, Y = 5-F, Z = H, R1 = (CH3)2N(CH2)2OCH2)
U otopinu 2-dimetilaminoetilklorid-hidroklorida (21 mmol) u 50 %-tnom natrijevom hidroksidu (5 mL) doda se benziltrietilamonijev klorid (0.25 g) te otopina alkohola 75 (1.5 mmol) u toluenu (5 mL). Reakcijska smjesa zagrijava se uz refluks i snažno miješanje 3 sata. Potom se ohladi na sobnu temperaturu, razrijedi vodom te ekstrahira diklorometanom. Nakon pročišćavanja kromatografijom na stupcu silikagela izoliran je uljasti produkt;
1H NMR (ppm, CDCl3): 2.67 (s, 6H); 2.92-3.03 (m, 2H); 4.02-4.10 (m, 2H); 4.91 (s, 2H); 7.02-7.59(m, 7H);
MS(m/z): 371.3 (MH+).
b) [3-(5-Fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-dimetilamin (I; X = O, Y = 5-F, Z = H, R1 = (CH3)2N(CH2)3OCH2)
Reakcijom alkohola 75 (1.5 mmol) i 3-dimetilaminopropilklorid-hidroklorida (21 mmol) dobiven je uljasti produkt;
MS(m/z): 385.0 (MH+).
Primjer 16
a) [2-(5-Kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-etil]-dimetilamin (I; X = O, Y = 5-Cl, Z = H, R1 = (CH3)2N(CH2)2OCH2)
U otopinu 2-dimetilaminoetilklorid-hidroklorida (21 mmol) u 50%-tnom natrijevom hidroksidu (5 mL) dodan je benziltrietilamonijev klorid (0.25 g) te otopina alkohola 76 (1.5 mmol) u toluenu (4 mL). Reakcijska smjesa se zagrijava uz refluks i snažno miješanje 3 sata. Potom se ohladi na sobnu temperaturu, razrijedi vodom te ekstrahira diklorometanom. Nakon pročišćavanja kromatografijom na stupcu silikagela i izoliran je uljasti produkt;
MS(m/z): 386.9 (MH+).
b) [3-(5-Kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-dimetilamin (I; X = O, Y = 5-Cl, Z = H, R1 = (CH3)2N(CH2)3OCH2)
Reakcijom alkohola 76 (1.5 mmol) i 3-dimetilaminopropilklorid-hidroklorida (21 mmol) dobiven je uljasti produkt;
1H NMR (ppm, CDCl3): 1.87-2.00 (m, 2H); 2.32 (s, 6H); 2.39-2.54 (t, 2H); 3.57-3.87 (t, 2H);4.86 ( s, 2H); 7.17-7.88 (m, 7H);
MS(m/z): 401.0 (MH+).
Primjer 17
a) [2-(1,8-Ditia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-etil]-dimetilamin (I; X = S, Y = Z = H, R1 = (CH3)2N(CH2)2OCH2)
U otopinu 2-dimetilaminoetilklorid-hidroklorida (21 mmol) u 50%-tnom natrijevom hidroksidu (5 mL) doda se benziltrietilamonijev klorid (0.25 g) te otopina alkohola 77 (1.5 mmol) u toluenu (3 mL). Reakcijska smjesa zagrijava se uz refluks i snažno miješanje 3 sata. Potom se ohladi na sobnu temperaturu, razrijedi vodom te ekstrahira diklorometanom. Nakon pročišćavanja kromatografijom na stupcu silikagela izoliran je uljasti produkt;
MS(m/z): 369.2 (MH+).
b) [3-(1,8-Ditia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-dimetilamin (I; X = S, Y = Z = H, R1 = (CH3)2N(CH2)3OCH2)
Reakcijom alkohola 77 (1.5 mmol) i 3-dimetilaminopropilklorid-hidroklorida (21 mmol) dobiven je uljasti produkt;
1H NMR (ppm, CDCl3): 2.27-2.32 (m, 2H); 2.83-2.84 (d, 6H); 3.15-3.25 (t, 2H); 3.83-3.87 (t, 2H); 4.99 (s, 2H); 7.08-7.55 (m, 8H);
MS( m/z) : 383.1 (MH+).
Primjer 18
{3-[2-(6-Kloro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-etoksi]-propil}-dimetilamin (I; X = S, Y = 6-Cl, Z = H, R1 = (CH3)2N(CH2)3O(CH2)2)
6-Kloro-2-vinil-1,8-ditia-3-aza-dibenzo[e,h]azulen (I; X = S, Y = 6-Cl, Z = H, R1 = (CH 2 = CH)
U otopinu 3-dimetilaminopropilklorid-hidroklorida (14 mmol) u 50%-tnom natrijevom hidroksidu (5 mL) doda se benziltrietilamonijev klorid (0.25 g) te otopina alkohola 78 (1 mmol) u toluenu (2 mL). Reakcijska smjesa zagrijava se uz refluks i snažno miješanje 3 sata. Potom se ohladi na sobnu temperaturu, razrijedi vodom te ekstrahira diklorometanom. Nakon pročišćavanja kromatografijom na stupcu silikagela izoliran je uljasti produkt. {3-[2-(6-kloro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-etoksi]-propil}-dimetilamin;
MS(m/z): 431.3 (MH+),
i kristalinični 6-kloro-2-vinil-1,8-ditia-3-aza-dibenzo[e,h]azulen (68; Tablica 3).
Primjer 19
a) Dimetil-[2-(6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-etil]-amin (I; X = S, Y = 6-CF3, Z = H, R1 = (CH3)2N(CH2)2OCH2)
U otopinu 2-dimetilaminoetilklorid-hidroklorida (12 mmol) u 50%-tnom natrijevom hidroksidu (5 mL) doda se benziltrietilamonijev klorid (0.044 mmol) te otopina alkohola 79 (1.1 mmol) u toluenu (4 mL). Reakcijska smjesa zagrijava se uz refluks i snažno miješanje 3 sata. Potom se ohladi na sobnu temperaturu, razrijedi vodom te ekstrahira diklorometanom. Nakon pročišćavanja kromatografijom na stupcu silikagela izoliran je uljasti produkt;
MS(m/z): 437.1 (MH+).
b) Dimetil-[3-(6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-amin (I; X = S, Y = 6-CF3, Z = H, R1 = (CH3)2N(CH2)3OCH2)
Reakcijom alkohola 79 (0.84 mmol) i 3-dimetilaminopropilklorid-hidroklorida (0.019 mol) dobiven je uljasti produkt;
MS(m/z): 451 (MH+).
Primjer 20
a) [2-(5-Fluoro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-etil]-dimetilamin (I; X = S, Y = 5-F, Z = H, R1 = (CH3)2N(CH2)2OCH2)
U otopinu 2-dimetilaminoetilklorid-hidroklorida (12 mmol) u 50%-tnom natrijevom hidroksidu (5 mL) dodan je benziltrietilamonijev klorid (0.65 mmol) te otopina alkohola 80 (1.1 mmol) u toluenu (5 mL). Reakcijska smjesa je uz snažno miješanje i refluks zagrijavana 3 sata. Potom je ohlađena na sobnu temperaturu, razrijeđena vodom te ekstrahirana s diklorometanom. Nakon pročišćavanja kromatografijom na stupcu silikagela izoliran je uljasti produkt;
MS(m/z): 387.1 (MH+).
b) [3-(5-Fluoro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-dimetilamin (I; X = S, Y = 5-F, Z = H, R1 = (CH3)2N(CH2)3OCH2)
Reakcijom alkohola 80 (0.84 mmol) i 3-dimetilaminopropilklorid-hidroklorida (19 mmol) dobiven je uljasti produkt;
MS(m/z): 401.0 (MH+).
PRIPRAVA POLAZNIH SPOJEVA
Priprava α-bromketona
11-Bromo-11H-dibenzo[b,f]oksepin-10-on (III; X = O, Y = Z = H)
U otopinu 11H-dibenzo[b,f]oksepin-10-ona (6.8 mmol) u 6 mL octene kiseline prethodno zagrijane na 55-60oC uz miješanje se dokapava otopina broma (7.5 mmol, 0.382 mL) u 3 mL octene kiseline. Reakcijska smjesa miješa se pri temperaturi od 60oC 1.5 sat, a zatim se propuše strujom argona pri čemu se oslobađa bromovodik. Nakon što je ohlađena na sobnu temperaturu reakcijska smjesa se izlije u vodu i ekstrahira diklorometanom. Dobiveni talog prekristalizira se iz etanola te se dobiveni kristali odfiltriraju.
Prema gornjem postupku polazeći od:
8-fluoro-11H-dibenzo[b,f]oksepin-10-ona;
8-kloro-11H-dibenzo[b,f]oksepin-10-ona;
11H-dibenzo[b,f]tiepin-10-ona;
7-kloro-11H-dibenzo[b,f]tiepin-10-ona;
7-trifluorometil-11H-dibenzo[b,f]tiepin-10-ona;
8-fluoro-11H-dibenzo[b,f]tiepin-10-ona;
8-kloro-11H-dibenzo[b,f]tiepin-10-ona;
7-bromo-11H-dibenzo[b,f]tiepin-10-ona;
8-bromo-11H-dibenzo[b,f]tiepin-10-ona,
7,8-dikloro-11H-dibenzo[b,f]tiepin-10-ona;
8-metoksi-11H-dibenzo[b,f]tiepin-10-ona
pripravljeni su spojevi:
11-bromo-8-fluoro-11H-dibenzo[b,f]oksepin-10-on (III; X = O, Y = 8-F, Z = H);
11-bromo-8-kloro-11H-dibenzo[b,f]oksepin-10-on (III; X = O, Y = 8-Cl, Z = H);
11-bromo-11H-dibenzo[b,f]tiepin-10-on (III; X = S, Y = Z = H);
11-bromo-7-kloro-11H-dibenzo[b,f]tiepin-10-on (III; X = S, Y = 7-Cl, Z = H);
11-bromo-7-trifluorometil-11H-dibenzo[b,f]tiepin-10-on (III; X = S, Y = 7-CF3, Z = H);
11-bromo-8-fluoro-11H-dibenzo[b,f]tiepin-10-on (III; X = S, Y = 8-F, Z = H);
11-bromo-8-kloro-11H-dibenzo[b,f]tiepin-10-on (III; X = S, Y = 8-Cl, Z = H);
7,11-dibromo-11H-dibenzo[b,f]tiepin-10-on (III; X = S, Y = 7-Br,Z = H);
8,11-dibromo-11H-dibenzo[b,f]tiepin-10-on (III; X = O, Y = 8-Br, Z = H);
11-bromo-7,8-dikloro-11H-dibenzo[b,f]tiepin-10-on (III; X = S, Y = 7-Cl i 8-Cl, Z = H);
11-bromo-8-metoksi-11H-dibenzo[b,f]tiepin-10-on (III; X = S, Y = 5-OCH3, Z = H).
Karakteristike dobivenih produkata formule III, prikazane su u Tablici 5
Tablica 5
[image]
III
[image]
U svim primjerima navedenim u Tablici 5. Z = H.
Claims (15)
1. Spoj formule I
[image]
I
naznačen time da
X može biti CH2, ili heteroatom kao O, S, S(=O), S(=O)2, ili NRa gdje je Ra vodik ili zaštitna skupina;
Y i Z neovisno jedan o drugom označavaju jedan ili više istovjetnih ili različitih supstituenata vezanih na bilo koji raspoloživi ugljikov atom, a koji mogu biti halogen, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, halo-C1-C4-alkil, hidroksi, C1-C4-alkoksi, trifluorometoksi, C1-C4-alkanoil, amino, amino-C1-C4-alkil, N-(C1-C4-alkil)amino, N,N-di(C1-C4-alkil)amino, tiol, C1-C4-alkiltio, sulfonil, C1-C4-alkilsulfonil, sulfinil, C1-C4-alkilsulfinil, karboksi, C1-C4-alkoksikarbonil, cijano, nitro;
R1 može biti biti vodik, halogen, po potrebi supstituiran C1-C7-alkil ili C2-C7-alkenil, C2-C7-alkinil, po potrebi supstituiran aril ili heteroaril te heterocikl, hidroksi, hidroksi-C2-C7-alkenil, hidroksi-C2-C7-alkinil, C1-C7-alkoksi, tiol, tio-C2-C7-alkenil, tio-C2-C7-alkinil, C1-C7-alkiltio, amino-C2-C7-alkenil, amino-C2-C7-alkinil, amino-C1-C7-alkoksi, C1-C7-alkanoil, aroil, okso-C1-C7-alkil, C1-C7-alkanoiloksi, karboksi, po potrebi supstituiran (C1-C7-alkiloksikarbonil ili ariloksikarbonil), karbamoil, N-(C1-C7-alkil)karbamoil, N,N-di(C1-C7-alkil)karbamoil, cijano, cijano-C1-C7-alkil, sulfonil, C1-C7-alkilsulfonil, sulfinil, C1-C7-alkilsulfinil, nitro,
ili supstituent prikazan formulom II:
[image]
gdje
R2 i R3 istovremeno ili neovisno jedan o drugom mogu biti vodik, C1-C4-alkil, aril ili zajedno s N imaju značenje po potrebi supstituiranog heterocikla ili heteroarila;
m ima značenje cijelog broja od 1 do 3;
n ima značenje cijelog broja od 0 do 3;
Q1 i Q2 neovisno jedan o drugom imaju značenje kisika, sumpora ili skupine:
[image]
gdje supstituenti
y1 i y2 neovisno jedan o drugom mogu biti vodik, halogen, po potrebi supstituiran C1-C4-alkil ili aril, hidroksi, C1-C4-alkoksi, C1-C4-alkanoil, tiol, C1-C4-alkiltio, sulfonil, C1-C4-alkilsulfonil, sulfinil, C1-C4-alkilsulfinil, cijano, nitro, ili zajedno čine karbonilnu ili imino skupinu;
kao i njihove farmakološki prihvatljive soli i solvate.
2. Spoj prema zahtjevu 1. naznačen time da Y i Z imaju značenje H, F, Cl, Br, CF3, OCH3.
3. Spoj prema zahtjevu 2. naznačen time da R1 ima značenje H, CH3, CH2CN, CHO, CH=CH2, CH2COOC2H5, COOC2H5, CH2OCOCH3.
4. Spoj prema zahtjevu 1. naznačen time da R1 ima značenje arila, heteroarila.
5. Spoj prema zahtjevu 2. naznačen time da R1 ima značenje (CH2)mOH.
6. Spoj prema zahtjevu 5. naznačen time da simbol m ima značenje 1 ili 2.
7. Spoj prema zahtjevu 2. naznačen time da R1 ima značenje formule II.
8. Spoj prema zahtjevu 7. naznačen time da m ima značenje 1 ili 2, n ima značenje 1 ili 2, Q1 značenje O, Q2 značenje CH2 , a R2 i R3 značenje vodika i metila.
9. Selektirani spojevi prema zahtjevu 3.:
8-Oksa-1-tia-3-aza-dibenzo[e,h]azulen;
5-Fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen;
5-Kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen;
1,8-Ditia-3-aza-dibenzo[e,h]azulen;
5-Kloro-2-metil-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen;
5-Fluoro-2-metil-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen;
6-Kloro-2-metil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-Metil-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
6-Bromo-2-metil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
5-Bromo-2-metil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
5-Kloro-2-metil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-Metil-1,8-ditia-3-aza-dibenzo[eh]azulen;
2-Metil-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen;
(6-Kloro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-acetonitril;
8-Oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-karbaldehid;
5-Fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2- karbaldehid;
5-Kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2- karbaldehid;
1,8-Ditia-3-aza-dibenzo[e,h]azulen-2- karbaldehid;
6-Kloro-2-vinil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
(6-Kloro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-octena kiselina etilni-ester;
6-Trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-karboksilna kiselina etilni-ester;
5-Fluoro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-karboksilna kiselina etilni-ester;
5-Fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-il-octena kiselina metilni-ester;
5-Kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-il-octena kiselina metilni-ester.
10. Selektirani spojevi prema zahtjevu 4.:
2-Fenil-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(4-Kloro-fenil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-Piridin-3-il-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-Piridin-4-il-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-Tiofen-3-il-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(3-Pirol-1-il-fenil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(3-Kloro-4-fluoro-fenil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(4-Tert-butil-fenil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-Pirazin-2-il-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
6-Trifluorometil-2-(4-trifluorometil-fenil)-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(4-[1,3]Dioksolan-2-il-fenil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
(6-Trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-(3,4,5-trimetoksi-fenil)amin;
(3-Metoksi-fenil)-(6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-amin;
2-(3,5-Dibromo-fenil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(3-Fluoro-4-metil-fenil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(2,3-Dihidro-benzofuran-5-il)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-p-Toluil-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(4-[1,2,3]Tiadiazol-4-il-fenil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-Isoksazol-5-il-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(2-Metil-tiazol-4-il)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(6-Metil-piridin-3-il)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(6-Metoksi-piridin-3-il)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(3-Kloro-5-trifluorometil-piridin-2-il)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(2,6-Dikloro-benzil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
6-Trifluorometil-2-(4-trifluorometil-piridin-3-il)-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(2,6-Dikloro-4-trifluorometil-fenil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(2,4-Dikloro-fenil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
6-Trifluorometil-2-(3-trifluorometil-fenil)-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(5-Metil-isoksazol-3-il)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(2-Kloro-fenil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(2,6-Dikloro-piridin-4-il)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
6-Trifluorometil-2-(6-trifluorometil-piridin-2-il)-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-(2,4-Difluoro-fenil)-6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-Piridin-4-il-6-trifluorometil-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen;
5,6-Dikloro-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
2-Piridin-4-il-8H-1-tia-3-aza-dibenzo[e,h]azulen;
5-Metoksi-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
5-Fluoro-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
7-Kloro-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
7-Bromo-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
6-Kloro-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
5-Bromo-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
7-Kloro-5-fluoro-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
5-Metil-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
7-Metil-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
5-Kloro-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
6-Metil-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
6-Kloro-5-fluoro-2-piridin-4-il-1,8-ditia-3-aza-dibenzo[e,h]azulen;
1-(2-Piridin-4-il-1-tia-3,8-diaza-dibenzo[e,h]azulen-8-il)-etanone,
11. Selektirani spojevi prema zahtjevu 6.:
(8-Oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-il)-metanol;
(5-Fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-il)-metanol;
(5-Kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-il)-metanol;
(1,8-Ditia-3-aza-dibenzo[e,h]azulen-2-il)-metanol;
2-(6-Kloro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-etanol;
(6-Trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-metanol;
(5-Fluoro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-metanol,
12. Selektirani spojevi prema zahtjevu 8.:
Dimetil-[2-(8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-etil]-amin;
Dimetil-[3-(8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-amin;
3-(8-Oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-amin;
[2-(5-Fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-etil]-dimetilamin;
[3-(5-Fluoro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-dimetilamin;
[2-(5-Kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-etil]-dimetilamin;
[3-(5-Kloro-8-oksa-1-tia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-dimetilamin;
[2-(1,8-Ditia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-etil]-dimetilamin;
[3-(1,8-Ditia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-dimetilamin;
{3-[2-(6-Kloro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-il)-etoksi]-propil}-dimetilamin;
Dimetil-[2-(6-trifluorometil-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-etil]-amin;
[2-(5-Fluoro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-dimetilamin;
Dimetil- [2-(5-fluoro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-etil]-dimetilamin;
[3-(5-Fluoro-1,8-ditia-3-aza-dibenzo[e,h]azulen-2-ilmetoksi)-propil]-dimetilamin,
13. Postupak za pripravu spojeva formule I
[image]
gdje
X može biti CH2, ili heteroatom kao O, S, S(=O), S(=O)2, ili NRa gdje je Ra vodik ili zaštitna skupina;
Y i Z neovisno jedan o drugom označavaju jedan ili više istovjetnih ili različitih supstituenata vezanih na bilo koji raspoloživi ugljikov atom, a koji mogu biti halogen, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, halo-C1-C4-alkil, hidroksi, C1-C4-alkoksi, trifluorometoksi, C1-C4-alkanoil, amino, amino-C1-C4-alkil, N-(C1-C4-alkil)amino, N,N-di(C1-C4-alkil)amino, tiol, C1-C4-alkiltio, sulfonil, C1-C4-alkilsulfonil, sulfinil, C1-C4-alkilsulfinil, karboksi, C1-C4-alkoksikarbonil, cijano, nitro;
R1 može biti biti vodik, halogen, po potrebi supstituiran C1-C7-alkil ili C2-C7-alkenil, C2-C7-alkinil, po potrebi supstituiran aril ili heteroaril te heterocikl, hidroksi, hidroksi-C2-C7-alkenil, hidroksi-C2-C7-alkinil, C1-C7-alkoksi, tiol, tio-C2-C7-alkenil, tio-C2-C7-alkinil, C1-C7-alkiltio, amino-C2-C7-alkenil, amino-C2-C7-alkinil, amino-C1-C7-alkoksi, C1-C7-alkanoil, aroil, okso-C1-C7-alkil, C1-C7-alkanoiloksi, karboksi, po potrebi supstituiran (C1-C7-alkiloksikarbonil ili ariloksikarbonil), karbamoil, N-(C1-C7-alkil)karbamoil, N,N-di(C1-C7-alkil)karbamoil, cijano, cijano-C1-C7-alkil, sulfonil, C1-C7-alkilsulfonil, sulfinil, C1-C7-alkilsulfinil, nitro, ili supstituent prikazan formulom II:
[image]
gdje
R2 i R3 istovremeno ili neovisno jedan o drugom mogu biti vodik, C1-C4-alkil, aril ili zajedno s N imaju značenje po potrebi supstituiranog heterocikla ili heteroarila;
m ima značenje cijelog broja od 1 do 3;
n ima značenje cijelog broja od 0 do 3;
Q1 i Q2 neovisno jedan o drugom imaju značenje kisika, sumpora ili skupine:
[image]
gdje supstituenti
y1 i y2 neovisno jedan o drugom mogu biti vodik, halogen, po potrebi supstituiran C1-C4-alkil ili aril, hidroksi, C1-C4-alkoksi, C1-C4-alkanoil, tiol, C1-C4-alkiltio, sulfonil, C1-C4-alkilsulfonil, sulfinil, C1-C4-alkilsulfinil, cijano, nitro, ili zajedno čine karbonilnu ili imino skupinu;
kao i njihove farmakološki prihvatljive soli i solvate
naznačen time da postupak priprave uključuje:
a) ciklizaciju α-bromketona formule III:
[image]
sa spojevima formule IV:
[image]
b) za spojeve formule I, gdje Q1 ima značenje -O-
reakciju alkohola formule V:
[image]
sa spojevima formule VI:
[image]
gdje R4 ima značenje odlazeće skupine
c) za spojeve formule I, gdje Q1 ima značenje -O-, -NH-,-S- ili -C≡C-
reakciju formule Va:
[image]
gdje L ima značenje odlazeće skupine
sa spojevima formule VIa:
[image]
d) za spojeve gdje Q1 ima značenje heteroatoma -O-, -NH- ili -S-
reakciju spojeva formule Vb:
[image]
sa spojevima formule VI, gdje R4 ima značenje odlazeće skupine
e) za spojeve gdje Q1 ima značenje -C=C-
reakciju spojeva formule Va, gdje Q1 ima značenje karbonila s fosfornim ilidima.
14. Upotreba spojeva formule I navedenih u zahtjevu 3. naznačena time da se koriste kao međuprodukti za pripravu novih spojeva dibenzoazulena tiazolskog reda s anti-inflamatornim djelovanjem.
15. Upotreba spojeva formule I navedenih u zahtjevu 7. naznačena time da se upotrebljavaju u liječenju i profilaksi bilo kojeg patološkog stanja ili bolesti izazvanoj prekomjernom nereguliranom produkcijom citokina ili medijatora upale s time da se netoksična doza pogodnih farmaceutskih pripravaka može aplicirati per os, parenteralno ili lokalno.
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HR20020451A HRP20020451A2 (en) | 2002-05-23 | 2002-05-23 | 1-tia-3-aza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof |
EP03755235A EP1509532A1 (en) | 2002-05-23 | 2003-05-20 | 1-thia-3-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |
CNB038161060A CN1315847C (zh) | 2002-05-23 | 2003-05-20 | 作为肿瘤坏死因子产生的抑制剂的1-硫杂-3-氮杂-二苯并薁类和制备该抑制剂的中间体 |
PL03374385A PL374385A1 (en) | 2002-05-23 | 2003-05-20 | 1-thia-3-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |
CA002486821A CA2486821A1 (en) | 2002-05-23 | 2003-05-20 | 1-thia-3-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |
YU100004A RS100004A (en) | 2002-05-23 | 2003-05-20 | 1-thia-3-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |
AU2003232370A AU2003232370A1 (en) | 2002-05-23 | 2003-05-20 | 1-thia-3-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |
US10/515,700 US7262302B2 (en) | 2002-05-23 | 2003-05-20 | 1-thia-3-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |
PCT/HR2003/000023 WO2003099827A1 (en) | 2002-05-23 | 2003-05-20 | 1-thia-3-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |
JP2004507484A JP2005529157A (ja) | 2002-05-23 | 2003-05-20 | 腫瘍壊死因子産生の阻害剤としての1−チア−3−アザ−ジベンゾアズレン類及びその製造用中間体 |
ARP030101802A AR039860A1 (es) | 2002-05-23 | 2003-05-23 | 1-tia-3-aza-dibenzoazulenos como inhibidores de la produccion del factor de necrosis tumoral e intermediarios para la preparacion de los mismos |
IS7566A IS7566A (is) | 2002-05-23 | 2004-11-29 | 1-þía-3-asa-díbensóasúlen sem latar æxlisdrepþáttar framleiðslu og milliefni til framleiðslu á þeim |
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HRP20030957A2 (en) * | 2003-11-21 | 2005-08-31 | Pliva-Istra�iva�ki institut d.o.o. | USE OF 1-THIA-3-AZA-DIBENZO[e,h]AZULENES FOR THE MANUFACTURE OF PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT AND PREVENTION OF CENTRAL NERVOUS SYSTEM DISEASES AND DISORDERS |
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US8779154B2 (en) | 2006-09-26 | 2014-07-15 | Qinglin Che | Fused ring compounds for inflammation and immune-related uses |
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US3711489A (en) * | 1971-03-31 | 1973-01-16 | Pfizer | Certain 8,9-dihydro(3,4,7,8)cycloocta(1,2-d)imidazoles |
CA967573A (en) | 1972-12-22 | 1975-05-13 | Joseph G. Lombardino | Tetracyclic anti-inflammatory agents |
US4198421A (en) * | 1978-11-30 | 1980-04-15 | E. I. Du Pont De Nemours And Company | Antiinflammatory 2-substituted-dibenzo[2,3:6,7]oxepino[4,5-d]imidazoles |
HRP20000310A2 (en) * | 2000-05-17 | 2002-02-28 | Pliva Farmaceutska Ind Dioniko | New dibenzoazulene compounds as tumor necrosis factor inhibitors |
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2002
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2003
- 2003-05-20 WO PCT/HR2003/000023 patent/WO2003099827A1/en active Application Filing
- 2003-05-20 US US10/515,700 patent/US7262302B2/en not_active Expired - Fee Related
- 2003-05-20 EP EP03755235A patent/EP1509532A1/en not_active Withdrawn
- 2003-05-20 PL PL03374385A patent/PL374385A1/xx not_active Application Discontinuation
- 2003-05-20 JP JP2004507484A patent/JP2005529157A/ja active Pending
- 2003-05-20 CN CNB038161060A patent/CN1315847C/zh not_active Expired - Fee Related
- 2003-05-20 CA CA002486821A patent/CA2486821A1/en not_active Abandoned
- 2003-05-20 AU AU2003232370A patent/AU2003232370A1/en not_active Abandoned
- 2003-05-20 RS YU100004A patent/RS100004A/sr unknown
- 2003-05-23 AR ARP030101802A patent/AR039860A1/es unknown
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2004
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CN1315847C (zh) | 2007-05-16 |
CN1665822A (zh) | 2005-09-07 |
RS100004A (en) | 2006-10-27 |
IS7566A (is) | 2004-11-29 |
US20060111340A1 (en) | 2006-05-25 |
WO2003099827A1 (en) | 2003-12-04 |
JP2005529157A (ja) | 2005-09-29 |
US7262302B2 (en) | 2007-08-28 |
AU2003232370A1 (en) | 2003-12-12 |
CA2486821A1 (en) | 2003-12-04 |
EP1509532A1 (en) | 2005-03-02 |
PL374385A1 (en) | 2005-10-17 |
AR039860A1 (es) | 2005-03-02 |
HK1081949A1 (en) | 2006-05-26 |
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