HRP20040412A2 - Anthranilic acid amides and pharmaceutical use thereof - Google Patents
Anthranilic acid amides and pharmaceutical use thereof Download PDFInfo
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- HRP20040412A2 HRP20040412A2 HR20040412A HRP20040412A HRP20040412A2 HR P20040412 A2 HRP20040412 A2 HR P20040412A2 HR 20040412 A HR20040412 A HR 20040412A HR P20040412 A HRP20040412 A HR P20040412A HR P20040412 A2 HRP20040412 A2 HR P20040412A2
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- Prior art keywords
- formula
- compound
- tautomer
- trifluoromethyl
- salt
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- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical class NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 title claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 115
- 150000003839 salts Chemical class 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 150000001204 N-oxides Chemical class 0.000 claims description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 20
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- -1 perfluoro Chemical group 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 17
- 150000001408 amides Chemical class 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
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- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
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- 206010064930 age-related macular degeneration Diseases 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- XVJOUYLQGCSLGU-UHFFFAOYSA-N n-(4-bromophenyl)-2-(pyridin-4-ylmethylamino)benzamide Chemical compound C1=CC(Br)=CC=C1NC(=O)C1=CC=CC=C1NCC1=CC=NC=C1 XVJOUYLQGCSLGU-UHFFFAOYSA-N 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 6
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
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- USVUTPQVJFNOFP-UHFFFAOYSA-N n-[4-prop-1-ynyl-3-(trifluoromethyl)phenyl]-2-(pyridin-4-ylmethylamino)benzamide Chemical compound C1=C(C(F)(F)F)C(C#CC)=CC=C1NC(=O)C1=CC=CC=C1NCC1=CC=NC=C1 USVUTPQVJFNOFP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
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- DAZIKVHZJQGBLZ-UHFFFAOYSA-N n-(4-prop-1-ynylphenyl)-2-(pyridin-4-ylmethylamino)benzamide Chemical compound C1=CC(C#CC)=CC=C1NC(=O)C1=CC=CC=C1NCC1=CC=NC=C1 DAZIKVHZJQGBLZ-UHFFFAOYSA-N 0.000 claims description 3
- UOMBFRPWZLSXSD-PVOKDAACSA-N n-[4-[(z)-prop-1-enyl]-3-(trifluoromethyl)phenyl]-2-(pyridin-4-ylmethylamino)benzamide;hydrochloride Chemical compound Cl.C1=C(C(F)(F)F)C(\C=C/C)=CC=C1NC(=O)C1=CC=CC=C1NCC1=CC=NC=C1 UOMBFRPWZLSXSD-PVOKDAACSA-N 0.000 claims description 3
- GXVUFJFHYMRVBU-UHFFFAOYSA-N 2-[[3-(methylcarbamoyl)phenyl]methylamino]-n-[3-(trifluoromethyl)phenyl]benzamide Chemical compound CNC(=O)C1=CC=CC(CNC=2C(=CC=CC=2)C(=O)NC=2C=C(C=CC=2)C(F)(F)F)=C1 GXVUFJFHYMRVBU-UHFFFAOYSA-N 0.000 claims description 2
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- ANNJRRWDKJXWBM-UHFFFAOYSA-N n-[4-propyl-3-(trifluoromethyl)phenyl]-2-(pyridin-4-ylmethylamino)benzamide Chemical compound C1=C(C(F)(F)F)C(CCC)=CC=C1NC(=O)C1=CC=CC=C1NCC1=CC=NC=C1 ANNJRRWDKJXWBM-UHFFFAOYSA-N 0.000 claims description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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Description
Izum se odnosi na nove derivate amida antranilične kiseline, postupke njihove proizvodnje, njihovu primjenu u postupku tretiranja ljudi i životinja, njihovu upotrebu- samih ili u kombinaciji s jednim ili više farmaceutski aktivnih spojeva-za tretiranje posebno neoplastičnih bolesti, kao što su tumorske bolesti, retinopatija i makularne degeneracije povezane sa starosti; postupke za tretiranje takvih bolesti životinja, osobito u ljudi, i upotreba takvog spoja - samog ili u kombinaciji s jednim ili više drugih farmaceutski aktivnih spojeva - za proizvodnju farmaceutskih preparata (lijeka) za tretiranje neoplastičnih bolesti, retinopatija ili makularne degeneracije povezane sa starošću.
Poznato je da su određene bolesti povezane s dereguliranorn angiogenezom, naprimjer bolestima uzrokovanim okularnom neoveskularizacijom, kao što su retinopatije (uključujući dijabetičku retinopatiju), makularnom degeneracijom povezanom sa starosti, psorijazom, hemangioblastomom, hemangiomom, arteriosklerozom, upalnim bolestima, kao što su reumatoidne ili reumatske upalne bolesti, posebno artritis, kao što je reumatoidni artritis, ili drugi kronični upalni poremećaji, kao što je kronična astma, arterijalna ili post-transplataci ska ateroskleroza, endometrioze, i osobito neoplastične bolesti, naprimjer takozvani čvrsti tumori i tekući tumori (kao što je leukemija).
U centru mreže regulacije rasta i diferencijacije vaskularnog sustava i njegove komponente tijekom embrionalnog razvoja, normalan rast i veliki broj patoloških anomalija i bolesti, postojanje angiogenog faktora poznatog kao «vaskularni endotelialni faktor rasta» (VGEF), dimerični, disulfid-vezani 46-kDa glikoproteina, zajedno s njegovim celularnim receptorima (vidi Breier,G., et al., Trends in Cell Biology 6, 454-6 [1996]).
VEGF receptori su transmenbranozni receptori tirozin kinaze. Poznati su različiti tipovi VEGF receptora, npr. VEGFR-1, VEGFR-2 i VEGFR-3.
Veliki broj humanih tumora, osobito glioma i karcinoma, pokazuju visoki nivoe VEGF i njihovih receptora. To dovodi do hipoteze da VEGF otpušten od tumorskih stanica može stimulirati rast kapilara i proliferavciju tumorskog endotela na parakrini način i tako, preko osiguravanja dostave krvi, ubrzavati rast. Direktno bilježenje uloge VEGF kao faktora angiogeneze tumora in vivo dobiveno je iz studija u kojima je VEGF aktivitet inhibiran protutijelima.
Angiogeneza se smatra kao apsolutno potrebna za te tumore koji rastu preko maksimalnog dijametra od oko 1-2 mm; sve do tog limita, kisik i nutrijenti mogu biti dostavljeni difuzijom tumorskih stanica.
Tri glavna mehanizma igraju značajnu ulogu u aktivnosti inhibitora angiogeneze protiv tumora: 1) inhibicija rasta krvnih žila, osobito kapilara, u vaskularizaciji preostalog tumora, s rezultatom da to nije mrežasti rast tumora zbog balansa kojim je ispunjen između apoptoze i proliferacije; 2) prevencija migracije tumorskih stanica zbog odsutnosti protoka krvi u i iz tumora; i 3) inhibicija enditelijalne proliferacije stanica, tako dovodi do parakrinog rasta stimulirajućeg učinka koji se očituje na okolnom tkivu s endotelijalnim stanicama s normalnim linijama krvnih žila.
U WO00/27820 opisani su spojevi koji pripadaju u klasu amida antranilične kiseline, spojevi koji su navedeni da inhibiraju aktivnost VEGF receptor tirozin kinaze, rast tumora i o VEGF-ovisne proliferacije stanica.
Neočekivano, utvrđeno je da derivati amida antranilične kiseline formule I, prikazane niže, imaju poželjna farmakološka svojstva i inhibiraju, naprimjer aktivnost VEGF receptor tirozin kinaze, rast tumora i VEGF-ovisne proliferacije stanice.
Derivati amida antranilične kiseline formule I su prikladni, naprimjer, za upotrebu u tretiranju bolesti, osobito bolesti u tretiranju i isto za prevenciju onih, na koje pokazuju dobar učinak na inhibiciju angiogeneze i/ili VEGF receptor tirozin kinaze.
U izum spadaju amidi antranilične kiseline formule I,
[image]
gdje Ar je predstavljen podformulom Ia
[image]
gdje
Rapredstavlja H ili niži alkil
R1predstavlja H ili perfluor niži alkil, i
R2 predstavlja H, halogen, C2-C7alkil, C2-C7alkenil; ili niži alkinil, ili
Ar je predstavljen podformulom Ib,
[image]
R1 predstavlja perfluor niži alkil, i
R2 predstavlja brom, jod, C2-C7alkil, C2-C7alkenil ili niži alkinil, ili
R1predstavlja H, i
R2 predstavlja, fluor, brom, jod, etil, C5-C7alkil, C2-C7alkenil ili niži alkinil
na njegovim N-oksidima ili tautomerima
i solima takvih amida antranilične kiseline, njegovim N-oksidima i tautomerima.
Opći pojmovi koji se koriste gore i dolje u tekstu preferirano unutar konteksta prikaza imaju sljedeće značenje, osim ako nije drugačije navedeno:
Prefiks «niži» označava da radi kal ima sve do i uključujući maksimum 7, osobito sve do i uključujući maksimum 4 atoma ugljika, radikali su u stvari i linearni ili razgranati s jednim ili više granjanja.
Kada se koristi višestruki oblik za spojeve, soli, i slično, tada je uzeto značenje i za sami spoj, sol ili slično.
Bilo koji asimetrični atom ugljika (naprimjer u spojevima formule I, gdje R9 je niži alkil) može se predstaviti (R)-, (S)- ili (R,S)-konfiguracijom, preferirano s (R)- ili (S)-konfiguracijom. Spojevi mogu tako biti prisutni kao smjesa izomera ili kao čisti izomeri, preferirano kao enantiomer-čisti diastereomeri.
Izum se odnosi i na moguće tautomere spojeva, formule I.
U preferiranom ostvarenju, alkil ima sve do maksimalno 12 atoma ugljika i osobito je niži alkil.
Niži alkil je preferirano alkil s od i uključujući 1 sve do i uključujući 7, preferirano od i uključujući 1 do i uključujući 4, i linearan ili razgranati, preferirani, niži alkil je butil, kao što je n-butil, sec-butil, izobutil, tert-butil, propil, kao što je n-propil ili izopropil, etil ili preferirano metil.
Pojam «perfluor niži alkil» koristi se ovdje u značenju nižeg alkil radikala gdje svi atomi vodika su zamijenjeni s atomima fluora.
Halogen je posebno fluor, klor, brom ili jod, osobito fluor, klor, ili brom.
Takve soli su formirane, naprimjer, kao soli dodanih kiselina, preferirano organskih ili anorganskih kiselina, od spojeva formule I s baznim atomom dušika, osobito farmaceutski prihvatljive soli. Prikladne anorganske soli su, naprimjer, halogene kiseline, kao što je klorovodična kiselina, sumporna kiselina, ili fosforna kiselina. Prikladne organske kiseline su, naprimjer, karboksilna kiselina, fosforna, sulfonska ili sulfaminska kiselina, naprimjer octena kiselina, propionska kiselina, oktanoična kiselina, dekanoična kiselina, dodekanoična kiselina, glikolna kiselina, mliječna kiselina, fumarna kiselina, sukcininska kiselina, adipična kiselina, pimelična kiselina, azelaična kiselina, jabučna kiselina, vinska kiselina, limunska kiselina, amino kiseline kao što je glutaminska kiselina ili aspartinska kiselina, maleinska kiselina, hidroksimaleinska kiselina, metilmaleinska kiselina, cikloheksankarboksilna kiselina, adamantankarboksilna kiselina, benzojeva kiselina, salicilna kiselina, 4-aminosalicilna kiselina, ftalična kiselina, feniloctena kiselina, bademova kiselina, cinamična kiselina, metan- ili etan-sulfonska kiselina, 2-hidroksietansulfonska kiselina, etan-1,2-disulfonska kiselina, 2-naftalensulfonska kiselina, 1,5-naftalen-disulfonska kiselina, 2-, 3- ili 4-metilbenzen-sulfonska kiselina, metilsumporna kiselina, etilsumporna kiselina, dodecilsumporna kiselina, N-cikloheksilsulfamična kiselina, N-metil-, N-etil- ili N-propil-sulamična kiselina, ili druge organske kiseline, kao što je askorbinska kiselina.
U svrhu izolacije ili purifikacije isto je moguće koristiti farmaceutski neprihvatljive soli, naprimjer piktrate ili perklorate. Za terapijsku upotrebu, koriste se samo farmaceutski prihvatijive soli ili slobodni spojevi (kada se primjenjuju u obliku farmaceutskih proizvoda), a oni su ovdje preferirani.
U svjetlu bliskih odnosa između novih spojeva u slobodnom obliku i onih u obliku njihovih soli, uključujući te soli koje se mogu koristiti kao intermedijeri, naprimjer u purifikaciji ili identifikaciji novih spojeva, svaka referencija za slobodne spojeve gore i dolje navedene će se razumjeti kao navodi za korespondirajuće soli, kao prikladne i korisne.
Spojevi formule I i njezini N-oksidi imaju vrijedna farmakološka svojstva kao što je opisano gore i kasnije.
Učinkovitost spojeva izuma kao inhibitora aktivnosti VEGF-receptora tirozin kinaze može se prikazati kao što slijedi:
Test aktiviteta protiv VEGP-receptora tirozin kinaze. Test se izvodi upotrebom Flt-1 VEGP-receptora tirozin kinaze. Detaljni postupak je kao što slijedi: 30 μl otopine kinaze (10 ng kinaze područja Flt-1, Shibuya et al., Oncogene 5, 519-24 [1990]) u 20 mM Tris●HCl pH 7.5, 3 mM mangan diklorida (MnCl2), 3 mM magnezij klorida (MgCl2), 10 μM natrij vanadata, 0.25 mg/ml polietilenglikola (PEG) 20000, 1 mM ditiotreitola i 3 μg/μl poli(Glu, Tyr) 4:1 (Sigma, Buchs, Switzerland), 8 μM[33P] -ATP (0.2 μCi), 1% dimetil sulfoksida, i 0 do 100 μM spoja kojeg se ispituje inkubira se zajedno kroz 10 minuta na sobnoj temperaturi. Reakcija se završi dodavanjem 10 μl 0.25 M etilendiamintetraacetata (EDTA) pH 7. Koristi se multikanalni dispenzor (LAB SYSTEMS; USA); alikvot od 20 μl se primjeni na PVDF (=polivinil difluorid) Immobilon P membrane (Millipore, USA), preko Millipore microtiter filter manifold i spoji na vakuum. Nakon kompletne eliminacije tekućine, membrana se ispere 4 puta postepeno u kupelji koja sadržava 0.5% fosforne kiseline (H3PO4) i jedanput s etanolom, inkubira se 10 minuta dok se trese, potom se prenese u Hewlett Packard TopCount Manifold i radioaktivnost izmjeri nakon dodavanja 10 μl Microscint®(β-scintilation counter liguid). IC50-vrijednost određena je analizom linearne regresije postotka inhibicije svakog spoja u tri koncentracije (kao pravilo 0.01, 0.1, i 1 μmol). IC50-vrijednost tako se može naći za spojeve formule I da su u granici 0.001 do 1 μM, preferirano u granici od 0.001 do 0.1 μM.
Antitumorska učinkovitost spojeva izuma može se prikazati in vivo kao što slijedi:
In vivo učinkovitost na modelu ksenotransplantata nudo miševa: ženke BALB/c nudo miševa (8-12 tjedana stari); Novartis Animal Farm, Sisseln, Switzerland) su držani u sterilnim uvjetima s vodom i hranom ad libitum. Tumori su inducirani subkutanom aplikacijom tumorskih stanica (naprimjer, linije Du 145 karcinom prostate (ATCC br. HTB 81; vidi Cancer Research 37, 4049-58 (1978)) ili s implantacijom tumorskih fragmenata (oko 25 mg) subkutano u lijevi bok miša koristeći 13-gauge trocar igle pod Forene®anestezijom (Abbott, Švicarska). Tretiranje s test spojem počinje odmah nakon što se postigne srednji volumen od 100 mm3. Rast tumora se mjeri dva do tri puta tjedno i 24 sata nakon posljednjeg tretmana određivanjem dužine dvije perpendikularne osi. Volumne tumora se računa u skladu s objavljenim metodama (vidi Evans at al., Brit. J. Cancer 45, 466-8 [1982]). Antitumorsko djelovanje je određeno kao srednje smanjenje volumena tumora tretiranih životinja podijeljeno sa srednjim smanjenjem volumena tumora netretiranih životinja (kontrola) i, nakon množenja sa 100, izraženo kao T/C%. Regresija tumora (dato u %) je izraženo kao najmanji srednji volumen tumora u odnosu na srednji volumen tumora na početku tretmana. Testirani spoj je apliciran dnevno kljukanjem.
Kao alternativa mogu se isto koristiti na isti način druge linije stanica, naprimjer:
- MCF-7 linijske stanice adenokarcinoma prsa (ATCC br. HTB 22 ,-vidi i J.Natl.Cancer Inst (Bethesda) 51, 1409-16 [1973]);
- MDA-MB 468 linijske stanice adenokarcinoma prsa (ATCC br. HTB 132; vidi isto In Vitro 14, 911-15 [1978]);
- MDA-MB 231 linijske stanice adenokarcinoma prsa (ATCC br. HTB 26; vidi i J.Natl.Cancer Inst (Bethesda) 53, 661-74 [1974]);
- Golo 205 linijske stanice karcinoma kolona (ATCC br. CCL 222; vidi i Cancer Res. 38, 1345-55 [1978]);
- HCT 116 linijske stanice karcinoma kolona (ATCC br. CCL 247; vidi i Cancer Res. 41, 1751-6 [1981]);
- DU 145 linijske stanice karcinoma prostate DU 145 (ATCC br., HTB 81; vidi i Cancer Res. 37, 4049-58 [1978]);
- PC-3 linijske stanice karcinoma prostate PC-3 (ATCC br. CRL 1435; vidi i Cancer Res. 40, 524-34 [1980]);
Inhibicija VEGF-induciraneg KDR-receptora autofosforilacijom može se potvrditi s daljnjim in vitro pokusima u stanicama: transfektirane CHO stanice, koje permanentno ekspresiraju humani VEGF receptor (KDR), su zasijane u medij za kultiviranje (s 10% fetalnog seruma= FCS) u ploče za stanične kulture sa 6-bunarića i inkubirane na 37°C pod 5% CO2 sve dok ne pokazuju 80% gustoću. Spojevi koji će biti testirani se razrijede u mediju za kulturu (bez FCS, s 0.1% bovinog albumina) i doda se u stanice. (Kontrola sadržava medij bez test spoja). Nakon dvosatne inkubacije na 37°C, doda se rekombinant VEGF; finalna koncentracij a VEGF je 20 ng/ml). Nakon sljedećih pet minuta inkubacije na 37°C, stanice se isperu dvaput s led-hladnim PBS (fosfat-buferirana otopina soli) i odmah lizira u 100 μl pufera za lizu po bunarčiću. Lizat se potoni centrifugira da se odstrane stanične jezgre, a koncentracija proteina supernatanta su odredi upotrebom komercijalne analize proteina (BIORAD). Lizat se može potom odmah koristiti, a ako je potrebno, čuva se na -20°C.
Sandwich ELISA izvodi se za mjerenje KDR-receptor fosforilacije : monoklonalna protutijela za KDR (naprimjer Mab 1495.12.14; proizvod H.Towbin) se imobilizira na crnim ELISA pločama (OptiPlate ™HTRF-96 od Packard-a). Ploče se potom operu a mjesta za vezanje preostalog slobodnog proteina zasite se s 1% BSA u PBS: Stanični lizat (20 μg proteina po bunariću) potom se inkubira na tim pločama preko noći na 4°C zajedno s antifosfotirozin protutijelima vezanim s alkalnom fosfatazom (PY20: AP od Transduction Laboratories). (Ploče su oprane ponovo i) vežu antifosfotirozin protutijela na uhvaćeni fosforilirani receptor što je potom prikazano upotrebom luminiscentnog AP supstrata (CDP-star, gotov za upotrebu, s Emerald II; TROPIX). Luminiscencija se mjeri s Packard Top Count Microplate Scintillation Counter (Top Count). Razlika između signala pozitivne kontrole (stimulirane s VEGF) i potom negativne kontrole (nestimulirane s VEGF) korespondira s VEGF induciranom KDR-receptor fosforilacijom (=100%). Aktivitet testiranog spoja je izračunat kao % inhibicije VEGF inducirane fosforilacije KDR receptora, gdje koncentracija spoja tako inducira polovicu maksimalne inhibicije definirane kao ED50 (efektivna doza za 50% inhibicije).
Spoj formule I ili njegov N-oksid isto inhibiraju različit stupanj druge tirozin kinaze uključene u signal transdukcije koji je posredovan trofičnim faktorima, naprimjer kinazama iz Src porodice, osobito c-Src kinaza, Lck, i Fyn; isto kinaze EGF porodice, naprimjer, c-erbB2 kinaza (HER-2), c-erbB3 kinaza, c-erbB4 kinaza; inzulinu sličan faktor receptor kinaza (IGF-1 kinaza), osobito članovi PGDF-receptor tirozin kinaza porodice, kao što je PDGF-receptor kinaze, CSF-1-receptor kinaza, Kit-receptor kinaza i VGF-receptor kinaza, i isto serin-treonin kinaze, sve koje igraju ulogu u regulaciji rasta i transformaciji stanica sisavaca, uključujući humane stanice.
Na osnovi tih studija, spoj formule I u skladu s izumom pokazuje učinkovitost osobito protiv poremećaja ovisnih o protein kinazi, osobito proliferativnih bolesti.
Upotrebljivost spoja formule I u tretiranju artritisa kao što je naprimjer inflamatorni reumatski ili reumatske bolesti može se prikazati kao što slijedi:
Koristi je dobro poznati model adjuvant artritis štakora (Pearson, Proc.Soc.Exp.Biol. 91, 95-101 (1956)) za testiranje anti-artritičnog djelovanja spojeva formule I, ili njegovih soli. Adjuvant artritis može se tretirati upotrebom dva različita rasporeda doziranja: ili (i) polazeći od vremena imunizacije s adjuvantom (profilaktično doziranje); ili od 15 dana kada je artritički odgovor potpuno uspostavljen (terapijsko doziranje). Preferirano se koristi upotreba terapijskog rasporeda. Za komparaciju, ciklooksigenaza-2 inhibitor, kao što je 5-brom-2-(4-fluorfenil)-3-[4-(metilsulfonil)fenil]tiofen ili diklofenak, aplicira se odvojenoj skupini.
Detaljno, mužjaci Wistar štakora (5 životinja po skupini, težine aproksimativno 200 g, porijeklom Iffa Gredo, Francuska) tretira se i.d. (intra-dermalno) na bazi repa s 0.1 ml mineralnog ulja koje sadržava 0.6 mg liofiliziranog temperaturom-uništenog Mycobacterium tuberculosis. Štakore se tretira s ispitivanim spojem (3, 10 ili 30 mg/kg p.o. jedanput dnevno), ili nosačem (voda) od 15 do 22 dana (terapijski raspored doziranja). Na kraju pokusa, mjeri se otok tarzalnog zgloba pomoću mico-calliper. Postotak inhibicije otoka šape kalkulira se s referentnim nosačem tretirane životinje s artritisom (0% inhibicije) i nosačem tretirane normalne životinje (100 % inhibicija).
Na osnovi tih studija, spoj formule I neočekivano je upotrebljen za tretiranje upalnih (osobito reumatskih ili reumatoidnih) bolesti.
Na osnovi njihove učinkovitosti kao inhibitora aktiviteta VEGF-receptora tirozin kinaze spoja formule I primarno inhibira rast krvnih žila i tako je, naprimjer, učinkovit protiv brojnih bolesti povezanih s dereguliranom angiogenezom, osobito bolesti uzrokovanih okularnom neovaskularizacijom, osobito retinopatije kao što su dijabetičke retinopatije ili sa starost i povezana makularna degeneracija, psorijaza, haemangioblastom, kao što je haemangiom, proliferativne poremetnje mesangialnih stanica, kao što je kronične ili akutne renalne bolesti, npr. diabetička nefropatija, maligne nefroskleroze, sindrom trombotične mikroangiopatije ili odbacivanje transplantata, ili osobito inflamatorna bolesti bubrega, kao što je glomerulonefritis, osobito mezangioproliferativni glomerulonefritis, hemolitično-uremični sindrom, diabetička nefropatija, hipertenzivna nefroskleroza, aterom, arterijska restenoza, autoimune bolesti, akutne upale, fibrotične poremetnje (npr. ciroza jetre), dijabetes, endometrioze, kronična astma, arterijska ili post-transplantacijska ateroskleroza, neurodegenerativne poremetnje i osobito neoplastične bolesti slične leukemiji, osobito akutna limfoblastična leukemija, akutna mieloidna leukemija i kronična mieloidna leukemija, i drugi «tekući tumori», osobito oni označeni s c-kit, KDR ili flt-1, i čvrsti tumori, osobito karcinom prsa, karcinom kolona, karcinom pluća (osobito karcinom malih-stanica pluća), karcinom prostate ili Kaposi-ev sarkom. Spoj formule I (ili njegov N-oksid) inhibira rast tumora i osobito je prikladan za prevenciju metastatskog širenja tumora i rasta mikrometastaza.
Spoj formule I može se aplicirati sam ili u kombinaciji s jednim ili više drugih terapijskih sredstava, moguće kombinacije terapije su u obliku fiksnih kombinacija ili aplikacija spoja izuma i jednog ili više terapijskih sredstava su nestalne ili date neovisno jedna o drugoj, ili kombinirana aplikacija fiksne kombinacije i jednog ili više terapijskih sredstava. Osini toga spoj formule I ili uz to aplicira se posebno za terapiju tumora u kombinaciji s kemoterapijom, radioterapijom, imunoterapijom, kirurškim intervencijama, ili kombinacijom istih. Dugotrajna terapija je jednako moguća s adjuvantnom terapijom u kontekstu drugih strategija tretmana, kao što je gore opisano. Drugi mogući tretmani su terapija koja podržava pacijentov status nakon regresije tumora, ili čak kemopreventivne terapije, naprimjer na rizik pacijenta.
Terapijska sredstva za moguću kombinaciju su osobito jedan ili više citostatika ili citotoksičnih spojeva, naprimjer, kemoterapijsko sredstvo ili nekoliko odabranih iz skupine koja uključuje, ali ne limitira, inhibitor biosinteze poliamina, inhibitor protein kinaze, osobito serin/treonin protein kinaze, kao što je protein kinaza C, ili EGF tirozin protein kinaza, npr. PKI, VEGF receptor kinaze, npr. PTK787, ili PDGF receptor tirozin kinaze, npr. STI571, citokin, negativni regulator rasta, kao što je TGF-β ili IFN-β, inhibitor aromatoze, npr. letrozol ili anastrozol, inhibitor interakcije SH2 domaina s fosforilatiranim proteinom, antiestriogeni, inhibitori topoizomeraze I, kao što je iriotekan, topoizomeraze II, sredstva aktivna na mikrotubule, npr. paklitaksel, diskodermolid ili epotilon, sredstva za alkilaciju, antineoplastični antimetaboliti, kao što su gemcitabin, spojevi platine, kao što je karboplatin ili cisplatin, anti-angiogeneni spojevi, agonisti gonadorelina, anti-androgeni, bifosfonati, npr. AREDIA® ili ZOMETA® i trastuzumab. Strukture aktivnih tvari su identificirane kodnim brojem, generičnim ili zaštićenim imenom mogu se uzeti iz aktualnog izdanja standardnog kompendija «The Merck Index» ili iz baze podataka, npr. Patents International (npr. IMS World Publikations). Njihov sadržaj je ovdje uključen u cjelini s referencijama.
Sa skupinom preferiranih spojeva formule I i njegovih oksida ovdje navedenih kasnije, definicije substituenata iz opće definicije navedene prije mogu se razborito koristiti, naprimjer, za zamjenu više općenitih definicija s specifičnijim definicijama ili osobito s definicijama naznačenim da se preferiraju;
Osim toga, izum se odnosi na upotrebu spoj a formule I, gdje radikali i simboli imaju značenje kao što je gore definirano, ili N-oksid ili njihova farmaceutski prihvatljiva sol za proizvodnju farmaceutskog produkta za tretiranje retinopatija ili sa starosti povezanom makularnom degeneracijom.
Osim toga, izum se odnosi na postupak tretiranja neoplastičnih bolesti koje su odgovor na inhibiciju aktiviteta VEGF-receptora tirozin kinaze, koja obuhvaća aplikaciju spoja formule I ili N-oksida ili njihove farmaceutski prihvatljive soli, gdje radikali i simboli imaju značenje kao što je definirano gore, u učinkovitoj količini protiv navedenih bolesti, toplokrvnih životinja za koje se zahtjeva tretman.
Osim toga, izum se odnosi na postupak za tretiranje retinopatija ili makularne degeneracije povezane sa starosti, koja obuhvaća aplikaciju spoja I ili N-oksida ili njihovih farmaceutski prihvatljivih soli, gdje radikali i simboli imaju značenje kao što je definirano gore, u učinkovitoj količini protiv navedenih bolesti, toplokrvnih životinja za koje se zahtjeva tretman.
Izum se posebno odnosi na spoj formule I, gdje
Ar je predstavljen podformulom Ia
gdje
Ra predstavlja H ili niži alkil, a
R1 predstavlja H ili trifluormetil,
R2 predstavlja H, halogen, C2-C7alkil, C2-C7alkenil ili niži alkil,
Ar je predstavljen podformulom Ib, a gdje
Ra predstavlja H ili niži alkil, a
R1 predstavlja trifluormetil, a
R2 predstavlja brom, jod, C2-C7alkil, C2-C7alkenil ili niži alkil,
R1predstvalja H, a
R2 predstavlja fluor, brom, jod, etil, C5-C7alkil, C5-C7alkenil ili niži alkinil,
na njegovom H-oksidu ili tautomeru, i na soli takvog spoja, njegov N-oksida ili tautomera.
Preferirani su spojevi formule I, gdje
Ar je predstavljen podformulom Ia
gdje
Ra predstavlja H ili niži alkil,
R1predstavlja H ili trifluormetil, a
R2 predstavlja H, halogen, C2-C7alkil, C2-C7alkenil ili niži alkil.
Isto su preferirani spojevi formule I, gdje
Ar je predstavljen podformulom Ib,
R1 predstavlja trifluormetil, a
R2 predstavlja brom, jod, C2-C7alkil, C2-C7alkenil ili niži alkil, ili
R1 predstavlja H, a
R2 predstavlja fluor, brom, jod, etil, C5-C7alkil, C5-C7alkenil ili niži alkini.
Više se preferira spojeve formule I, gdje
Ar je predstavljen podformulom Ib,
R1 predstavlja trifluormetil, a
R2 predstavlja brom, propil, propenil ili propinil, ili
R1 predstavlja H, a
R2 predstavlja fluor, brom, propenil ili propinil.
Jedno od ostvarenja odnosi se na amide antranilične kiseline formule I, gdje
Ar je predstavljen N-oksidom podformule Ib,
R1 predstavlja trifluormetil, a
R2 predstavlja brom, propil, propenil ili propinil.
Preciznije, prednost je data sljedećim spojevima formule I:
2-[4-piridinilmetil]amino-N-[4-brom-3-(trifluormetil)fenil]benzamid,
2-[4-piridinilmetil]amino-N-[4-bromfenil]benzamid,
2-[[3-[(metilamino)karbonil]-fenil]metil]amino-N-[3-(trifluormetil)fenil]benzamid,
2-[4-piridinilmetil]amino-N-[4-(1-propinil)-3-(trifluormetil)fenil]benzamid,
2-[4-piridinilmetil]amino-N-[4-(1-propinil)fenil]benzamid,
2-[4-piridinilmetil]amino-N-[4-[(Z)-1-propenil]-3-(trifluormetil)fenil]benzamid hidroklorid sol,
2-[4-piridinilmetil]amino-N-[4-(1-propil)-3-(trifluormetil)fenil]benzamid,
N-(4-klor-3-trifluormetil-fenil)-2-[(1-oksi-piridin-4-ilmetil)-amino]-benzamid, i
N-(4-fluor-3-trifluormetil-fenil)-2-[(1-oksi-piridin-4-ilmetil)-amino]-benzamid,
i njegove tautomere,
ili soli takvog spoja ili njegovih tautomera.
Spoj izuma može se proizvesti postupkom tako, iako nije primjenjen dosada za nove spojeve prezentiranog izuma, koji su poznati per se, osobito postupak karakteriziran time da za sintezu spoja formule I gdje R2 predstavlja vodik ili halogen a preostali simboli R1 i Ar su kao što je definirano za spoj formule I, spoj formule II
[image]
gdje R1 i R2 su definirani gore, je reagirali s karbonil spojem formule III
[image]
gdje
Ar je kao što je definirano gore za spoj formule I u prisutnosti sredstva za redukciju,
gdje polazni spojevi formule II i III mogu isto biti prisutni s funkcionalnom skupinom u zaštićenom obliku, ako je neophodno, i/ili u obliku soli, prisutna je sol-formirajuća skupina a moguća je reakcija u obliku soli;
gdje svaka zaštitna skupina koja štiti derivaciju spoja formule I je odstranjena;
i ako se zahtjeva, spoj formule I koji se može dobiti je pretvoren u drugi spoj formule I ili njegov N-oksid, slobodni spoj formule I je pretvoren u sol, sol formule I koja se može dobiti je pretvorena u slobodan spoj ili drugu sol, i/ili smjesu izomernih spojeva formule I je odvojen u pojedine izomere.
Alternativno, spoj formule II može reagirati sa spojem formule III u prisutnosti kiseline, npr. kamfor-10-sulfonska kiselina, u odgovarajućem otapalu kao što je toluen ili benzen na temperaturi refluksa između 15 minuta i 6 sati da bi se osiguralo biciklični spoj formule IV,
[image]
gdje R2 predstavlja vodik ili halogen a preostali simboli R1 i Ar su kao što je definirano gore za spoj formule I, koji biciklični spoj formule IV može dalje reagirati u odgovarajućem otapalu s trietilsilan i trifluoroctenoj kiselini na temperaturi između 60°C i 90°C kroz 4 do 12 sati da se dobije spoj formule I gdje R2 predstavlja vodik ili halogen a preodtali simboli R1 i Ar su kao sto je definirano gore za spoj formule I.
Detaljni opis reduktivne alkilacije:
Detaljniji opis dolje navedenog procesa, R1, R2 i Ar su kao što je definirano za spojeve formule I, ukoliko nije drugačije navedeno.
Karbonil spojevi formule III može isto biti prisutan u obliku reaktivnih derivata; međutim, slobodni aldehidi ili ketoni se preferiraju.
Reaktivni derivati spojevi formule III su, naprimjer, odgovarajući dovedeni sulfiti ili posebno semiacetali, acetali, semiketali ili ketali spojeva formule III s alkoholima, naprimjer niži alkanoli; ili tioacetali i tioketali spojeva formule III s merkaptanima, naprimjer niži alkansulfidi.
Reduktivna alkilacija preferirano se izvodi s hidrogenacijom u prisutnosti katalizatora, osobito katalizator plemenitog metala, kao što je platina ili osobito paladij, koji je preferirano vezan na nosač, kao što je ugljik, ili katalizator teški metal, kao što je Raney nikl, na normalnom tlaku ili na tlaku od 0.1 do 10 MegaPaskal (MPa), ili s redukcijom pomoću kompleks hidrida, kao što su borhidridi, osobito alkali metal cijanoborhidridi, naprimjer natrij cijanoborhidrid, u prisutnosti prikladne kiseline, preferirano relativno slabih kiselina, kao što je niža alkankarboksilna kiselina, osobito octena kiselina, ili sulfonska kiselina, kao što je p-toluensulfonska kiselina; u uobičajenom otapalu, naprimjer alkoholima, kao što je metanol ili etanol, ili eterima, naprimjer ciklični eterima, kao što je tetrahidrofuran, u prisutnosti ili odsutnosti vode.
Zaštićene skupine
Ako jedna ili više drugih funkcionalnih skupina, naprimjer karboksi, hidroksi, amino, ili merkapto su ili trebaju biti zaštićene u spoju formule II ili III, zbog toga što ne treba sudjelovati u reakciji, to su takve skupine koje se uobičajeno koriste u sintezi peptidnih spojeva, a isto cefalosporina i penicilina, kao što su derivati nukleinskih kiselina i šećeri.
Zaštićene skupine mogu već biti prisutne u prekursorima i trebaju zaštiti funkcionalne skupine koje se tiču neočekivanih sekundarnih reakcija, kao što su acilacije, eterifikacije, esterifikacije, oksidacije, solvolize, i slične reakcije. Karakteristično je za zaštićene skupine da one pružaju same gotove, tj. bez neželjenih sekundarnih reakcija, za odstranjivanje, uobičajene solvolize, redukcije, fotolize i isto djelovanje enzima, naprimjer pod uvjet im analognim fiziološkim uvjetima, i da oni nisu prisutni u finalnom produktu. Specijalisti znaju, ili mogu brzo utvrditi, koje su zaštićene skupine prikladne u reakcijama navedenim prije i poslije.
Zaštita takvih funkcionalnih skupina s takvim zaštićenim skupinama, zaštićene skupine one same, i njihove reakcije odstranjivanja su opisane naprimjer u standardnim referentnim poslovima, ako kod J.F.W- McOmie, «Protective Groups in Organic Chemistry», Plenum Press, London and New York 1981, Volumen 3 (izdavač: E.Gross and J.Meienhofer Acadeniic Press, London and New York 1981; u «Methoden der organischen Chemie» (Methods of organic chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-DS.Jakubke and H.Jescheit, «Aminosauren, Peptide, Proteine» (Amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Eeach, and Basel 1982, i u Jochen Lehmann, «Chemie der Kohlenhydrate: Monosaccaride und Derivate» (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.
Dodatne faze procesa
Soli spojeva formule I sa skupinom koja formira sol može se proizvesti na način per se. Soli dodanih kiselina spojeva formule I može se tako dobiti tretiranjem s kiselinom ili bez odgovarajućeg reagensa za mijenjanje aniona. Sol s dvije molekule kiseline (naprimjer dihalogenid spoja formule I) može isto biti pretvoren u sol s jednom molekulom kiseline po spoju (naprimjer monohalogenid); to se može napraviti zagrijavanjem do tališta, ili naprimjer zagrijavanjem krutine pod visokim vakuumom na povišenoj temperaturi, naprimjer od 130 do 170°C, jedna molekula kiseline će biti izbačena po molekuli spoja formule I.
Soli se mogu uobičajeno pretvoriti u slobodne spojeve, tj. tretiranjem s odgovarajućim bazičnim sredstvima, naprimjer s alkali metal karbonatima, alkali metal hidrogenkarbonate, ili alkali metal hidroksidima, obično kalij karbonat ili natrij hidroksid.
Amid antralinične kiseline formule I gdje R2 predstavlja halogen, preferirano brom, koji može dalje reagirati u skladu sa sljedećim postupkom.
Amid antralinične kiseline formule I gdje R2 predstavlja halogen je otopljen u odgovarajućem aromatskom otapalu kao što je benzen, toluen ili ksilen i reagira sa stananom formule VII,
[image]
gdje R3 je H ili niži alkil, u prisutnosti odgovarajućeg katalizatora, preferirano tetrakis(trifenilfosfin)paladija(O), na temperaturi između 90°C i 150°C, preferirano u atmosferi argona, između 12 i 36 sati u odgovarajućem aromatskom otapalu kao što je benzen, toluen ili ksilen.
Dobiveni spoj formule I gdje R2 predstavlja alkinil radikal -C≡C-R3 koji može biti transformiran u odgovarajuće alkenil ili alkil radikale poznate u struci.
Naprimjer, spoj formule I gdje R2 predstavlja alkinil radikal -C≡C-R3 može se hidrogenirati u metanolu pod atmosferskim tlakom preko Raney nikla na temperaturi između 15ºC i 30°C, da se dobije spoj formule I gdje R2 predstavlja C2-7alkenil. Tako dobivenu spoj formule I gdje R2 predstavlja C2-7alkenil može se dalje hidrogenirati u metanolu na atmosferskom tlaku preko 5% platine na ugljiku na temperaturi između 15°C i 30°C, da se dobije spoj formule I gdje R2 predstavlja C2-7alkil
Kratice:
DMF dimetilformamid
EtOAc etil acetat
MS maseni spektar
RT sobna temperatura
TLC kromatogram tankoslojne kromatografije
Sljedeći Primjeri su dati za ilustraciju izuma bez ograničavanja izuma u njegovom cilju. Temperature su mjerene stupnjevima celzijusa (°C). Ako nije drugačije navedeno reakcije se izvode na sobnoj temperaturi.
PRIMJERI
Referentni Primjer 1
2-[[6-metoksi-3-piridinil]metil]amino-N-_[4-brom-3-(trifluor-metil)fenil]benzamid (ne zahtjeva se)
Natrij cijanoborhidrid (8.80 g 95%, 133 mmol) se doda u porcijama preko 30 minuta uz miješanje smjese octene kiseline (3.8 mL), 6-metoksi-3-piridinkarboksaledehid (Fluka, Buchs, Switzerland; 7.80 g, 57 mmol) i 2-amino-N-(4-brom-3-trifluormetilfenil)-benzamid (faza 1.2, 13.65 g, 38 mmol) u metanolu (380 mL) na 25°C, Smjesa se miješa kroz 16 sati. Otapalo se evaporira pod reduciranim tlakom da se dobije ostatak koji se tretira sa zasićenom vodenom otopinom natrij hidrogen karbonata (500 mL) i ekstarhira s dikiormetanom (3×150 mL). Spojeni ekstrakti se osuše (Na2SO4), filtrira a otapalo se evaporira pod reduciranim tlakom da bi se dobio sirovi produkt tako da se purificira kolonskom kromatografijom na silika gelu, eluent 5% EtOAc u diklormetanu i rekristalizira se iz dietileter-heksan da se dobije imenovani spoj kao bež kristalna krutina, 1.1. 101-103°C.
Faza 1.1: 2-nitro-N-(4-brom-3-trifluormetilfenil)benzamid
Otopini 3-amino-6-brombenzotrifluorid (Fluka, Buchs, Switzerland; 24.0 g, 100 mmol) u EtOAc (240 mL) se doda uz miješanje vodena otopina natrij hidroksida (110 mL 1M) na sobnoj temperaturi. Tako izmješana otopina se tretira s kap po kap tijekom 30 minuta s otopinom 2-nitrobenzoil klorida (Fluka, Buchs, Switzerland; 14.5 mL, 110 mmol) u EtOAc (150 mL). Nastala smjesa se miješa kroz 30 minuta na temperaturi ambijenta. Smjesa se ekstrahira s EtOAc (3×100 mL) i spojeni ekstrakt se kasnije ispere s klorovodičnom kiselinom (2×100 mL 2M), vodom (2×100 mL), zasićenom vodenom otopinom natrij klorida (1×100 mL), osuši (MgSO4), filtrira a otapalo se evaporira pod reduciranim tlakom da se dobije sirovi produkt koji se purificira rekristalizacijom iz EtOAc-heksan da se dobije imenovani spoj kao bež čvrsti kristali, t.t. 157-158°C
Faza 1.2: 2-amino-N-(4-brom-3-trifluormetilfenil)benzamid
Otopina 2-nitro-N-(4-brom-3–trifluormetilfenil)benzamid (intermedijer 1a; 32 g, 82 mmol) u metanolu (1000 mL) se hidrogenira na atmosferskom tlaku preko Raney nikla (6 g) na 21°C. Kalkulirana količina vodika se postigne nakon 7 sati. Smjesa se filtrira a otapalo se evaporira pod reduciranim tlakom da se dobije sirovi produkt koji se purificira rekristalizacijom iz dietileter-heksan da se dobije imenovani spoj kao čvrsti bezbojni kristali, t.t. 142-144 °C.
Primjer 2
2-[4-piridinilmetil]amino-N-[4-brom-3-(trifluor-metil)fenil]benzamid
Imenovani spoj se proizvodi postupkom analognim onom opisanom u Primjeru 1 koristeći intermedijer iz faze 1.2 i 4-piridinkarboksaldehid; t.t. 123-124 °C.
Primjer 3
2-[4-piridinilmetil]amino-N-(4-bromfenil)benzamid
Imenovani spoj se proizvodi postupkom analognim onom opisanom u Primjeru l uz korištenje intermedijera iz faze 3.2 i 4-piridinkarboksaldehida; t.t. 136-137°C.
Faza 3.1: 2-nitro-N-(4-bromfenil)benzamid
Imenovani spoj se proizvodi analogno fazi 1.1 uz korištenje 4-bromanilina (Fluka, Buchs, Switzerland); t.t. 202-205°C.
Faza 3.2: 2-amino-N-(4-bromfenil)benzamid
Imenovani spoj se proizvodi analogno fazi 1.2 uz korištenje 2-nitro-N-(4-bromfenil)benzamida (faza 3.1); 1.1. 139-144°C.
Referentni Primjer 4
2-[[3-[(metilamino)karbonil]-fenil]metil]amino]-N-[3-(trifluormetil)fenil]benzamid
Imenovani spoj se proizvede postupkom analognim opisanom u Primjeru 1 uz korištenje intermedijera iz faze 4.2 i 3-formil-N-metol-benzamida (proizvedenog u skladu s postupkom opisanim u WO98/1449); 1.1. 166-167°C.
Faza 4.1: 2-nitro-N-[3-(trifluormetil)fenil]benzamid
Imenovani spoj se proizvodi analogno fazi 1.1 uz korištenje 3-(trifluormetil)-benzenamina (Aldrich, Buchs, Switzerland); t.t. 134-135°C.
Faza 4.2: 2-amino-N-[3-(trifluormetil)fenil]benzamid
Imenovani spoj se proizvodi analogno fazi 1.2 uz korištenje 2-nitro-N- [3-{trifluormetil)fenil]benzamida(faza 2.1); 1.1. 132-133 °C.
Primjer 5
2-[[(6-metoksi-3-piridinil)metil]amino]-N-[4-(1-propinil)-3-(trifluormetil)fenil]benzamid (ne zahtjeva se)
Izmješana otopina 2-[[6-metoksi-3-piridinil[metil]amino-N-[4-brom-3-(trifluormetil)fenil]benzamid (Primjer 1; 3,98 g, 8.3 mmol) u suhom toluenu (200 ml) se pročisti s argonom tijekom 20 minuta na 25°C. Tributil-1-propinilstanan (4.1 80%, 9.96 mmol) i tetrakis(trifenilfosfin)paladij (O) (260 mg) se doda a nastala smjesa se zagrije na 100°C kroz 17 sati pod atmosferom dušika. Smjesa se ohladi, tretira s vodenom otopinom natrij hidroksida (85 ml 0.1 M) i pročisti sa zrakom kroz 2 sata. Nastala smjesa se ekstrahira s EtOAc (3×100 mL). Organska faza se postepeno ispere s vodom (2×40 mL) i zasićenom vodenom otopinom natrij klorida (1×40 mL), osuši (Ka2SO4), filtrira a otapalo se evaporira pod reduciranim tlakom da se dobij e sirovi produkt koji se purificira kolonskom kromatografijom na silika gelu, eluent 33% EtOAc u heksanu i rekristalizira iz dietileter-heksan da se dobije spoj kao svijetlo-žuta krutina; t.t. 123-124°C.
Primjer 6
2-[4-piridinilmetil]amino-N-[4-(1-propinil)-3-(trifluormetil)fenil]benzamid
Imenovani spoj se proizvodi postupkom analognim onom opisanom u Primjeru 5 s time da se koristi 2-[4-piridinilmetil]amino-N-[4-brom-3-(trifluormetil)fenil]benzamid (Primjer 2); 1.1, 165-166°C.
Primjer 7
2-[4-piridinilmetil]amino-N-[4-(1-propinil)fenil]benzamid
Imenovani spoj se proizvodi postupkom analognim onom opisanom u Primjeru 5 s time da se koristi 2-[4-piridinilmetil]amino-N-[4-bromfenil]benzamid (Primjer 3); t.t. 147-155°C.
Primjer 8
2-[4-piridinilmetil]amino-N-[4-[(Z)-(1-propenil)]-3-(trifluormetil)fenil]benzamid hidroklorid sol
Otopina 2-[4-piridinilmetil]amino-N-4- (1-propinil)-3-(trifluor metil)fenil]benzamid (Primjer 6; 0.13 g, 0.32 mmol) u metanolu (6 mL) se hidrogenira na atmosferskom tlaku iznad Raney nikla (50 mg) na 22°C. Planirana količina vodika se postigne nakon 7 sati. Smjesa se filtrira a otapalo se evaporira pod reduciranim tlakom da bi se dobio sirovi produkt koji se purificira kolonskom kromatografijom na silika gelu, eluent 50 % EtOAc u diklormetanu da se dobije produkt kao ulje. Ulje se rastopi u etanolu, zakiseli s otopinom klorovodika u EtOAc (2M) i razrijedi s dietileterom. Nastali precipitat se odfiltrira, ispere s dietileterom, osuši i purificira rekristalizacijom iz dietileter-etanol da se dobije imenovana bež krutina.
Primjer 9
2-[4-piridinilmetil]amino-N-[4-(1-propinil)-3-(trifluormetil)fenil]benzamid
Otopina 2-[4-piridinilnnetil]amino-N-[4-[(Z)-(1-propenil)]-3-(trifluormetil)fenil]benzamida (Primjer 8, 0.80 g, 1.75 mmol) u metanolu se hidrogenira na atmosferskom tlaku preko 5% paladija na ugljiku (0.2 g) na 22°C. Kalkulirana količina vodika se dobije nakon 12 sati. Smjesa se filtrira a otapalo se evaporira pod reduciranim tlakom da se dobije sirovi produkt koji se purificira kolonskom krornatograf ijom na silika gelu, eluent 20% diklormetan u EtOAc i rekristalizira iz dietilete-heksan da se dobije imenovani spoj kao bezbojna kristalna krutina; t.t. 134-135°C.
Primjer 10
N-(4-klor-3-trifluormetil-fenil)-2-[(1-oksi-piridin-4-ilmetil)-amino]benzamid
Pod atmosferom N2, 0.50 g (1,2 mMol) rac. 3-(4-klor-trifluormetil-fenil)-2-(1-oksi-piridin-4-il)-2,3-dihidro-1H-kvinazolin-4-one suspendira se u 8 ml ledom oglađenog 1,2-dikloretana. Doda se 0.47 ml (3.0 mMol) trietilsilana, slijedi nakon 5 minuta 0.56 ml (7.2 mMol) trifluoroctena kiselina. Nastala otopina se miješa kroz 7 sati na 80°C, ohladi na RT i razrijedi s 100 ml EtOAc. Potom se otopina dvaput ispere sa zasićenom otopinom NaHCO3 i slanom vodom. Vodeni sloj se 2 puta ekstarhira s EtOAc, organske faze se osuše (Na2SO4) i djelomično koncentrira u vakuumu sve dok produkt ne kristalizira. Filtracija i ispiranje s ETOAc daju imenovani spoj; T.t. 213-214°C. Dodatno se može dobiti produkt iz filtrata kolonskom kromatografijom (SiO2; EtOAc/MeOH 8:2).
Faza 10.1: rac.3-(4-klor-3-trifluormetil-fenil)-2-(1-oksi-piridin-4-il)-2,3-dihidro-1H-kvinazolin-4-one
Suspenzija od 10.04 g (31.9 mMol) 2-amino-N-[4-klor-3-trifluormetil)fenil]-benzamid (proizvodnju vidi u WO00/27821; intermedijer 2f) u 80 ml toluena se proizvede u posudi s opremom za odvajanje vode. Doda se 1-oksi-piridin-4-karbalaldehida i 23 mg kamfor-10 sulfonske kiseline. Smjesa se zagrije na 120°C kroz 1 sat. Nakon hlađenja na RT, reakcijska smjesa se filtrira a dobiveni se ostatak ispere s tolueneom i dietil eterom, dobije se imenovani spoj; t.t. 261-262°C.
Primjer 11
N-(4-fluor-3-trifluormetil-fenil)-2-[(1-oksi-piridin-4-ilmetil)-amino]benzamid
Pod atmosferom N2, 1.50 g (3.7 mMol) rac. 3-(4-fluor-trifluormetil-fenil)-2-(1-oksi-piridin-4-il)-2,3-dihidro-1H-kvinazolin-4-one suspendira se u 25 ml ledom oglađenog dikloretana. Potom se doda 0.83 ml (5,2 mMol) trietilsilana, slijedi 1.79 ml (23 mMol) trifluoroctena kiselina. Nastala otopina se miješa kroz 72 sati na RT, dodatno se doda 0.42 ml trietilsilana. Nakon ukupno 138 sati na RT, otopina se razrijedi s 300 ml EtOAc i 300 ml zasićene otopine NaHCO3. Vodeni sloj se odvoji i 2 puta ekstarhira s EtOAc. Organske faze se ispere s zasićenom otopinom NaHCO3 i slanom otopinom, osuše (Na2SO4) i koncentrira. Ostatak se rastopi u metanolu, doda se SiO2 i smjesa koncentrira. Nastali prašak se stavi u kolonu za kromatografiranje (SiO2). Eluira s aceto/EtOH 3:1 da se dobije imenovani spoj; Filtracija i ispiranje s ETOAc daju imenovani spoj; t.t. 182-184°C.
Faza 11.1: rac.3-(4-fluor-3-trifluormetil-fenil)-2-(1-oksi-piridin-4-il)-2,3-dihidro-1H-kvinazolin-4-one
Kondenzira se 2.42 g (8.1 mMol) 2-amino-N-[4-fluor-3-trifluormetil)fenil]-benzamid (proizvodnju vidi u WO00/27820; intermedijer 2h) i 980 mg (7.96 mMol) 1-oksi-piridin-4-karbalaldehida i 20 mg toluena i 5 mg kamfor-10 sulfonske analogno Fazi 10.1 da se dobije imenovani spoj; 1.1. 257-258°C.
Primjer 12
mekane kapsule
5000 mekanih želetinoznih kapsula, svaka sadržava 0.05 g aktivne tvari jednog od spojeva formule I navedene u prethodnim primjerima, koje su proizvedene kao što slijedi:
Sastav
Aktivna tvar 250 g
Lauroglikol 2 litre
Postupak proizvodnje: Praškasta aktivna tvar se suspendira u Laurilglikol®-u (propilen glikol laurat, Gattefosse S.A., Saint Priest, France) i stavi se u vlažnu spravu kojom se pretvara u prašinu za proizvodnju veličine čestica od oko 1 do oko 3 μm. Potom se 0.419 g smjese uvede u mekane kapsule upotrebom stroja za punjenje kapsula.
Claims (13)
1. Amid antranilične kiseline formule I;
[image]
naznačen time, da je Ar predstavljen podformulom I;
[image]
gdje
R2 predstavlja H ili niži alkil, i
R1predstavlja H ili perfluor niži alkil,
R2 predstavlja H, halogen, C2-C7alkil, C2-C7alkenil ili niži alkinil, ili
Ar je predstavljen podformulom Ib, i
[image]
R1 predstavlja perfluor niži alkil, i
R2 predstavlja brom, jod, C2-C7alkil, C2-C7alkenil ili niži alkinil, ili
R1predstavlja H, i
R3 predstavlja fluor, brom, jod, etil, C5-C7alkil, C2-C7alkenil ili niži alkinil,
ili njezin N-oksid ili tautomer,
ili sol takvog amida antranilične kiseline, njezin H-oksid ili tautomer.
2. Amid antranilične kiseline formule I u skladu sa zahtjevom 1, naznačeni time, da
Ar je predstavljen podformulom Ia
gdje
Ra predstavlja H ili niži alkil, i
R1 predstavlja H ili trifluorrnetil, i
R2 predstavlja H, halogen, C2-C7alkil, C2-C7alkenil ili niži alkinil; ili
Ar je predstavljen podformulom Ib, i
R1 predstavlja trifluormetil, i
R2 predstavlja brom, jod, C2-C7alkinil, C2-C7alkenil ili niži alkinil, ili
R1 predstavlja H, i
R2 predstavlja fluor, brom, jod, etil, C5-C7alkinil, C2-C7alkenil ili niži alkinil, ili
ili njegov N-oksid ili tautomer,
ili sol takvog amida antranilične kiseline, njezin N-oksid ili tautomer.
3. Amid antranilične kiseline formule I u skladu sa zahtjevom 1 ili 2, naznačeni time, da
Ar je predstavljen podformulom Ia
gdje
Ra predstavlja H ili niži alkil,
R1 predstavlja H ili trifluormetil, i
R2 predstavlja halogen, C2-C7alkinil, C2-C7alkenil ili niži alkinil,
ili njegov tautomer,
ili sol takvog amida antranilične kiseline, ili njezin tautomer.
4. Amid antralinične kiseline formule I u skladu sa zahtjevom 1 ili 2, naznačen time, da
Ar je predstavljen podformulom Ib
R1 predstavlja trifluormetil, i
R2 predstavlja brom, jod, C2-C7alkinil, C2-C7alkenil ili niži alkinil, ili
R1 predstavlja H, i
R2 predstavlja fluor, brom, jod, C5-C7alkil, C2-C7alkenil ili niži alkinil, ili
ili njegov N-oksid ili tautomer,
ili sol takvog amida antranilične kiseline, ili njezin N-oksid ili tautomer.
5. Amid antralinične kiseline formule I u skladu sa zahtjevom 4, naznačen time, da
Ar je predstavljen pođformulom lb
R1 predstavlja trifluormetil, i
R2 predstavlja brom, propil, propenil ili propinil, ili
R1 predstavlja H, i
R2 predstavlja fluor, brom, propenil ili propinil,
ili njegov N-oksid ili tautomer,
ili sol takvog amida antranilične kiseline, ili njezin N-oksid ili tautomer.
6. Amid antralinične kiseline formule I u skladu sa zahtjevom 4, naznačen time, da
Ar je predstavljen podformulom Ib
R1 predstavlja trifluormetil, i
R2 predstavlja brom, propil, propenil ili propinil,
ili njegov tautomer,
ili sol takvog amida antranilične kiseline, ili njezin tautomer.
7. Amid antralinične kiseline formule I u skladu sa zahtjevom 1, naznačen time, da su odabrani od
2-[4-piridinilmetil]amino-N-[4-brom-(trifluormetil)fenil]benzamid,
2-[4-piridinilmetil]amino-N-(4-bromfenil)benzamid,
2-[[3-[(metilamino)karbonil]-fenil]metil]amino-N-[3-(trifluormetil)fenil]benzamid,
2-[4-piridinilmetil]amino-N-[4-(1-propinil)-3-(trifluormetil)fenil]benzamid,
2-[4-piridinilmetil]amino-N-[4-(1-propinil)-fenil]benzamid,
2-[4-piridinilmetil]amino-N-[4-[(Z)-1-propenil]-3-(trifluormetil)fenil]benzamid hidroklorid sol,
2-[4-piridinilmetil]amino-N-[4-(1-propil)-3-(trifluormetil)fenil]benzamid,
N-(4-klor-3-trifluormetil-fenil)-2-[(1-oksi-piridin-4-ilmetil)-amino]-benzamid, i
N-(4-fluor-3-trifluormetil-fenil)-2-[(1-oksi-piridin-4-ilmetil)-amino]-benzamid, i
ili njegov N-oksid ili tautomer,
ili sol amida antranilične kiseline, njezin N-oksid ili tautomer.
8. Amid antranilične kiseline formule I u skladu sa bilo kojim od zahtjeva 1 do 7, ili njegovim N-oksidom ili tautomerom, ili farmaceutski prihvatljivom soli takvog spoja, naznačen time, da se koristi u postupku tretiranja ljudi i životinja.
9. Upotreba amida antralinične kiseline formule 1 naznačena time, da radikali i simboli imaju značenje kao što je definirano u zahtjevima 1 do 7, ili njegovog N-oksida ili tautomera, ili farmaceutski prihvatljiva sol takvog spoja, za proizvodnju farmaceutskog produkta za tretiranje neoplastičnih bolesti.
10. Upotreba amida antralinične kiseline formule 1 naznačena time, da radikali i simboli imaju značenje kao što je definirano u zahtjevima 1 do 7, ili njegovog N-oksida ili tautomera, ili farmaceutski prihvatljiva sol takvog spoja, za proizvodnju farmaceutskog produkta za tretiranje retinopatije ili makularne degeneracije povezane sa starosti.
11. Postupak za tretiranje neoplastičnih bolesti koje odgovaraju na inhibiciju aktivnosti VEGF-receptora tirozin kinaze, obuhvaća aplikaciju amida antranilične kiseline formule I ili njezinog N-oksida ili tautomera, naznačen time, da radikali i simboli imaju značenje kao u zahtjevima 1 do 7, u učinkovitoj količini protiv navedenih bolesti, za toplokrvne životinje kod kojih se zahtjevaju takav tretman.
12. Farmaceutski proizvod, naznačen time, da sadržava atnid antranilične kiseline formule I u skladu s svakim od zahtjeva 1 do 7, ili njegovim N-oksidom ili tautomerom, ili farmaceutski prihvatljiva sol takvog spoja, ili njegovi hidrati ili solvati i najmanje jedan farmaceutski prihvatljiv nosač.
13. Postupak proizvodnje amida antranilične kiseline formule I
[image]
naznačen time, da R2 predstavlja vodik ili halogen a preostali simboli R1 i Ar su kao što je definirano u zahtjevu 1, gdje spoj formule II
[image]
gdje su R1 i R2 kao što je definirano za spoj formule I, reagira s karbonil spojem formule III
[image]
gdje Ar ja kao što je definirano za spoj formule I u prisutnosti sredstva za redukciju,
gdje polazni spojevi formule II i III mogu isto biti prisutni s funkcionalnim skupinama u zaštićenom obliku, ako je neophodno, i/ili u obliku soli, osiguranu sol-formirajućom skupinom i reakcija za formiranje soli je moguća;
gdje sve zaštićene skupine u zaštićenom derivatu spoja formule I su odstranjene;
i, ako se zahtjeva, spoj formule I koji je pretvori u drugi spoj formule I ili njegov N-oksid, slobodni spoj formule I je pretvoren u sol, sol koja se može dobiti od spoja formule I je pretvorena u slobodni spoj ili drugu sol, i/ili smjesu izomeričnih spojeva formule I je odvojen u pojedine izomere.
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UA89035C2 (ru) | 2003-12-03 | 2009-12-25 | Лео Фарма А/С | Эфиры гидроксамовых кислот и их фармацевтическое применение |
BR122015027139B1 (pt) | 2004-01-28 | 2016-05-10 | Mitsui Chemicals Inc | compostos derivados de amida, inseticida compreendendo os mesmos e método de uso dos mesmos como inseticida |
DE102004009238A1 (de) * | 2004-02-26 | 2005-09-08 | Merck Patent Gmbh | Arylamid-Derivate |
JPWO2006070878A1 (ja) * | 2004-12-28 | 2008-06-12 | アステラス製薬株式会社 | カルボン酸誘導体またはその塩 |
EP2145873A1 (fr) * | 2008-06-17 | 2010-01-20 | Commissariat A L'energie Atomique | Nouveaux composés ayant une activité protectrice vis-à-vis de l'action de toxines et de virus au mode d'action intracellulaire |
PA8840701A1 (es) | 2008-08-27 | 2010-04-21 | Leo Pharma As | NUEVO RECEPTOR VEGF-2 e INHIBIDORES DE PROTEÍNAS TIROSINA QUINASA Y SU USO FARMACÉUTICO DE LOS MISMOS |
JP2011057661A (ja) * | 2009-08-14 | 2011-03-24 | Bayer Cropscience Ag | 殺虫性カルボキサミド類 |
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US3226394A (en) * | 1964-06-16 | 1965-12-28 | Shulton Inc | Pyridylethylated anthranilamides and derivatives thereof |
WO1998014449A1 (en) | 1996-10-02 | 1998-04-09 | Novartis Ag | Fused pyrazole derivatives and processes for their preparation |
GB9824579D0 (en) * | 1998-11-10 | 1999-01-06 | Novartis Ag | Organic compounds |
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