SI20744B - Derivati karboksilne kisline, ki inhibirajo vezavo integrinov na njihove receptorje - Google Patents

Derivati karboksilne kisline, ki inhibirajo vezavo integrinov na njihove receptorje Download PDF

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SI20744B
SI20744B SI200020021A SI200020021A SI20744B SI 20744 B SI20744 B SI 20744B SI 200020021 A SI200020021 A SI 200020021A SI 200020021 A SI200020021 A SI 200020021A SI 20744 B SI20744 B SI 20744B
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amino
methyl
oxo
dihydro
carbonyl
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Ronald J Biediger
Qi Chen
George W Holland
Jamal M Kassir
Wen Li
Robert V Market
Ian L Scott
Chengde Wu
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Texas Biotechnology Corp
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Abstract

Postopek za inhibiranje vezave alfa4beta1 integrira na njegove receptorje, npr. VCAM-1 (vaskularna celična adhezijska molekula-1) in fibronektin; spojine, ki inhibirajo to vezavo; farmacevtsko aktivni sestavki, ki obsegajo take spojine, in uporaba takih spojin bodisi kot zgoraj ali v pripravkih za kontrolo ali preprečevanje bolezenskih stanj, v katera je vpleten alfa4beta1.

Claims (7)

1 SI 20744 - UO Patentni zahtevki
ali njena farmacevtsko sprejemljiva sol, kjer Y pri vsakem pojavljanju neodvisno izberemo iz skupine, ki obstoji iz naslednjih, kot so C (O), N, CR1, C (R2) (R3) in CH; in je obroč, ki vsebuje Y, lahko po izbiri bicikličen obroč; q je celo število od 2 do 5; B in R6 neodvisno izberemo iz skupine, katero sestavljata vodik in alkil, R1 pri vsakem pojavljanju neodvisno izberemo iz skupine, katero sestavljajo: vodik, halogen, hidroksilna, alkilna, alkenilna, alkinilna, alkoksi, alkenoksi, alkinoksi, tioalkoksi, hidroksialkilna, alkil-C(O)-, alkenil-C(O)-, alkinil-C(O)-, -CF3, nitro, amino, ciano, karboksi, -N(Ci-C3alkil)-C(0)(Ci-C3alkilna), -NHC(0)N(CrC3alkil)C(0)NH(Ci-C3alkilna), -NHC(0)NH(CrC6alkilna), alkilamino, alkenilamino, di(Ci-C3)amino, -C(0)0-(CrC3)alkilna, -C(0)NH-(CrC3)alkilna, -C(0)N(CrC3alkilna)2, -CH=NOH, -P03H2, -0P03H2, haloalkilna, alkoksialkoksi, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, sulfonilna, -S02(CrC3alkilna), -S03(CrC3alkilna), sulfonamido, karbamatna, ariloksialkilna, karboksilna in -C(0)NH(benzilna) skupina, kjer je vsak R1 lahko nesubstituiran ali substituiran z enim ali večimi 2 SI 20744 - UO substituenti, izbranimi iz skupine, katero sestavljajo aril, Ci-C6alkoksi, alkoksialkoksi in alkil; in kjer, kadar je vsaj en Y CR1, lahko R1 in R6 skupaj tvorita obroč; R inR sta, kadar sta prisotna, vodik; R4 izberemo iz skupine, katero sestavljata alkil in aril; R5 izberemo iz skupine, katero sestavljajo aralkil, ariloksialkil in cikloalkilalkil; R je vodik; R9 in R10 izberemo iz skupine, katero sestavljata vodik in halogen; in kjer, v kolikor ni drugače navedeno, alkil, sam ali v kombinaciji, se nanaša na CpCu ravne ali razvejene nasičene verižne radikale izvedene iz nasičenih ogljikovodikov z odstranitvijo enega vodikovega atoma; alkenil, sam ali v kombinaciji, se nanaša na raven ali razvejen alkenilni radikal, ki vsebuje od 2 do 10 ogljikovih atomov; alkinil, sam ali v kombinaciji, se nanaša na raven ali razvejen alkenilni radikal, ki vsebuje od 2 do 10 ogljikovih atomov; cikloalkil se nanaša na alifatski obročni sistem, ki ima 3 do 10 ogljikovih atomov in 1 do 3 obroče, ki so lahko po izbiri substituirani z enim, dvema ali tremi substituenti, neodvisno izbranimi izmed Ci-C6alkila, haloalkila, alkoksi, tioalkoksi, amino, alkilamino, dialkilamino, hidroksi, halo, merkapto, nitro, karboksaldehida, karboksi, alkoksikarbonila in karboksamida; cikloalkenil, sam ali v kombinaciji, se nanaša na cikličen karbocikel, ki vsebuje od 4 do 8 ogljikovih atomov in eno ali več dvojnih vezi; cikloalkilalkil se nanaša na cikloalkilno skupino, pripeto na Ci-C6alkilni radikal; haloalkil se nanaša na CrC6 alkilni radikal, na katerega je pripet vsaj en halogenski substituent; alkoksi, sam ali v kombinaciji, se nanaša na alkiletrski radikal, kjer je alkil kot je definirano zgoraj; alkenoksi se nanaša na radikal s formulo alkenil-O, pod pogojem, da radikal ni enolni eter, kjer je alkenil kot je definirano zgoraj; 3 SI 20744 UO alkinoksi se nanaša na radikal s formulo alkinil-O, pod pogojem, da radikal ni-inolni eter, tioalkoksi se nanaša na tioetrski radikal s formulo alkil-S-, kjer je alkil, kot je definirano zgoraj; alkoksialkoksi se nanaša na Rg-Rh O-, kjer je Rg Ci-C6 alkil in je Rh -(CH2)n-, kjer je n' celo število od 1 do 6; alkilamino se nanaša na RjNH-, kjer je Rj CpCgalkilna skupina, pod pogojem, da radikal ni enamin; alkenilamino se nanaša na radikal s formulo, alkenil-NH-ali (alkenil)2N-, kjer je alkenil, kot je definirano zgoraj, pod pogojem, da radikal ni enamin; dialkilamino se nanaša na RjRkN-, kjer sta R, in Rk neodvisno izbrana izmed Ci.Cealkila; aril, sam ali v kombinaciji, se nanaša na karbociklično aromatsko skupino, ki ima od 6 do 12 ogljikovih atomov ali heterociklično aromatsko skupino, ki vsebuje vsaj en endocikličen N, O ali S atom, pri čemer je naveden aril po izbiri substituiran z vsaj eno skupino, izbrano iz skupine, katero sestavljajo alkoholi, etri, estri, amidi, sulfoni, sulfidi, hidroksil, nitro, ciano, karboksi, amini, heteroatomi, Ci-C6alkil, Ci-C6alkoksi, Ci-C6-alkoksi-CO-, alkoksialkoksi, aciloksi, halogeni, trifluorometoksi, trifluorometil, alkil, aralkil, alkenil, alkinil, aril, ciano, karboksi, karboalkoksi, karboksialkil, cikloalkil, cikloalkilalkil, heterociklil, alkilheterociklil, heterociklilalkil, okso, arilsulfonil in aralkilaminokarbonil, kjer so navedeni substituenti po izbiri vezani s pomočjo linkeija, izbranega izmed verige z 1-3 atomi, ki vsebuje katero koli kombinacijo od -C-, -C(O)-, -NH-, -S-, -S(O)-, -0-, -C(0)0-; tioaril se nanaša na radikal s formulo aril-S-, kjer je aril kot je definirano zgoraj; se heterociklil, sam ali v kombinaciji, nanaša na nearomatski 3-7 členski obroč, ki vsebuje vsaj en endocikličen, N, O ali S atom, pri čemer je naveden heterociklil, po izbiri arilno-pripojen in po izbiri substituiran z vsaj enim substituentom, neodvisno izbranim iz skupine, katero sestavljajo vodik, halogen, hidroksil, amino, nitro, trifluorometil, trifluorometoksi, alkil, aralkil, alkenil, alkinil, aril, ciano, karboksi, karboalkoksi, karboksialkil, okso, arilsulfonil in aralkilaminkarbonil. 4 Sl 20744 - UO
2. Spojina po zahtevku 1, kjer 4 Sl 20744 - UO
je izbrana iz skupine, katero sestavljajo
kjer R18, R19, R20 in R21 pri vsakem pojavljanju neodvisno izberemo skupine, katero sestavljajo vodik, halogen, hidroksil, alkil, alkenil, alkinil, alkoksi, alkenoksi, alkinoksi, tioalkoksi, hidroksialkil, alifatski acil, -CF3, nitro, amino, ciano, karboksi, -N(C1-C3alkil)-C(0)(C1-C3alkil), -NHC(0)N(CrC3 alkil)C(0)NH(C,-C3alkil), -NHC(0)NH(Ci-C6alkil), alkilamino, alkenilamino, di(Ci-C3)amino, -C(0)0-(C,-C3)alkil, -C(0)NH-(CrC3)alkil, -C(0)N(C,-C3 alkil)2, -CH=NOH, -P03H2, -0P03H2, haloalkil, alkoksialkoksi, karboksaldehid, karboksamid, cikloalkil, cikloalkenil, cikloalkinil, cikloalkilalkil, aril, aroil, ariloksi, arilamino, biaril, tioaril, diarilamino, heterociklil, alkilaril, aralkenil, aralkil, alkilheterociklil, heterociklilalkil, sulfonil, -S02-(Ci-C3 alkil), -S03-(Ci-C3 alkil), sulfonamido, karbamat, ariloksialkil, karboksil in -C(0)NH(benzilne) skupine; c je celo število nič do dva; d je celo število nič do tri; e je celo število nič do štiri in f je celo število nič do ena. 5 SI 20744 - UO
3. Spojina po zahtevku 1, kjer je R5 arilalkil; je R4 aril in sta B in R6 vsak neodvisno vodik. 1 n e
4. Spojina po zahtevku 1, kjer sta dve neodvisni R , R , R ali R skupini lahko povezani skupaj, da tvorita obroč.
5. Spojina po zahtevku 1, izbrana iz skupine, katero sestavljajo: (3 S)-3-[( {[2-metil-4-(2-metilpropil)-6-okso-1 -(fenilmetil)-1,6-dihidro-5-pirimidinil]amino}karbonil)amino]-3-(4-metilfenil)propanojska kislina; (3 S)-3 -(1,3 -benzodioksol-5-il)-3 - [({[2-okso-1 -(fenilmetil)-4-propil-1,2-dihidro-3 -piridinil] amino} karbonil)amino]propanoj ska kislina; (3 S)-3 - {[({1 - [(2-klorofenil)metil]-4-etil-2-okso-1,2-dihidro-3-piridinil} aminojkarbonil] amino} -3-(4-metilfenil)propanojska kislina; (3 S)-3- {[( {1 -[(2-klorofenil)metil]-2-okso-4-propil-1,2-dihidro-3-piridinil} aminojkarbonilj amino} -3-(4-metilfenil)propanojska kislina; (3 S)-3- {[({1 -[(2-klorofenil)metil]-4-metil-2-okso-1,2-dihidro-3-piridinil}amino)karbonil]amino}-3-(4-metilfenil)propanojska kislina; (3S)-3- {[({6-metil-2-okso-1 -(fenilmetil)-4-[(fenilmetil)oksi]-1,2- dihidro-3-piridinil} amino)karbonil] amino} -3-(4-metilfenil)propanojska kislina; (3S)-3-{[({l-[(2-klorofenil)metil]-2,4-dimetil-6-okso-l,6-dihidro-5-pirimidinil} aminojkarbonil] amino} -3-(4-metilfenil)propanojska kislina; (3S)-3- {[({4-amino-1 -[(2-klorofenil)metil]-6-metil-2-okso-1,2-dihidro-3- 6 Si 20744 - UO piridinil} amino)karbonil] amino} -3 -(4-metilfenil)propanoj ska kislina; (3 S)-3- {[({1 -[(2-klorofenil)metil]-4-metil-2-okso-1,2-dihidro-3-piridinil} amino)karbonil]amino} -3-(4-metiloksi)fenil]propanojska kislina; (3S)-3-{[({l-[(2-klorofenil)metil]-4-metil-2-okso-l,2-dihidro-3-piridinil}amino)karbonil]amino}-3-(3,4-dimetilfenil)propanojska kislina; (3 S)-3-{[( {4-amino-1 - [(2-klorofenil)metil]-2-okso-1,2-dihidro-3-piridinil} amino)karbonil] amino} -3-(4-metilfenil)propanojska kislina; (3S)-3- {[({1 -[(2-klorofenil)metil]-4-hidroksi-2-okso-1,2-dihidro-3-piridinil} amino)karbonil] amino } -3 -(4-metilfenil)propanoj ska kislina; (3S)-3-[( {[1 -[(2-klorofenil)metil]-4-( 1,4-oksazinan-4-il) -2-okso-1,2-dihidro-3-piridinil]-amino}karbonil)amino]-3-(4-metilfenil)propanojska kislina; (3 S)-3- [({[ 1 -[(2-klorofenil)metil]-2-okso-4-(propilamino)-1,2-dihidro-3-piridinil]-amino}karbonil)amino]-3-(4-metilfenil)propanojska kislina; (3S)-3- {[( {1 -[(2-bromofenil)metil]-4-metil-2-okso-1,2-dihidro-3-piridinil} -amino)karbonil] amino} -3 -(4-metilfenil)propanoj ska kislina; (3S)-3- {[({1 -[(2-klorofenil)metil]-4-hidroksi-2-okso-1,2-dihidro-3-piridinil} -amino)karbonil] amino } - 3 - [ 3 -metil-4-(metiloksi)fenil]propanoj ska kislina; (3S)-3- {[({1 -[(2-klorofenil)metil]-2-okso-4-fenil-1,2-dihidro-3-piridinil} -amino)karbonil]amino} -3-[4-metilfenil)propanoj ska kislina; 7 Sl 20744 UO (3S)-3- {[({l-[(2-klorofenil)metil]-4-[(2- {[2-(metiloksi)etil]oksi} etil)oksi]-2-okso-1,2-dihidro-3-piridinil}-amino)karbonil]amino}-3-(4-metilfenil)propanojska kislina; (3 S)-3- {[({1 -[(2-klorofenil)metil]-4-hidroksi-9-metil-2-okso-1,2-dihidro-3-piridinil} -amino)karbonil]amino} -3-(4-metilfenil)propanojska kislina; (3 S)-3- {[({1 -[(2-klorofenil)metil]-4-[( 1,1 -dimetiletil)amino-2-okso-1,2-dihidro-3-piridinil} -amino)karbonil]amino} -3-(4-metilfenil)propanojska kislina; (3 S)-3 - {[({1 - [(2-klorofenil)metil] -4-hidroksi-2-okso-1,2-dihidro-3 -piridinil}-amino)karbonil]amino}-3-fenilpropanojska kislina; (3S)-3-{[({l-[(2-klorofenil)metil]-4-[4-metiltetrahidro-l(2H)-pirazinil]-2- okso-l,2-dihidro-3-piridinil}-amino)karbonil]amino}-3-(4-metilfenil)propanojska kislina; (3S)-3- {[( {1 -[(2-klorofenil)metil]-4- hidroksi-2-okso-1,2-dihidro-3-piridinil}-amino)karbonil]amino}-3-[4-metiloksi)fenilpropanojska kislina; (3 S)-3- {[({1 -[(2-klorofenil)metil]-4- hidroksi-2-okso-1,2-dihidro-3-piridinil} -amino)karbonil]amino} -3-(3,5-dimetilfenil)propanojska kislina; (3S)-3- {[({l-[(2-klorofenil)metil]-4- hidroksi-2-okso-l ,2-dihidro-3-piridinil}-amino)karbonil]amino}-3-(3-metilfenil)propanojska kislina; (3S)-3- {[( {1 -[(2-klorofenil)metil]-4- hidroksi-2-okso-1,2-dihidro-3-piridinil} -amino)karbonil]amino} -3-(3-metiloksi)fenil]propanojska kislina; (3S)-3-[3,5-bis(metiloksi)fenil]-3-{[({l-[(2-klorofenil)metil]-4-hidroksi-2-okso-1,2-dihidro-3 -piridinil} amino)karbonil] amino} propanoj ska kislina; 8 SI 20744 - UO (3S)-3- {[( {1 -[(2-klorofenil)metil]-4-hidroksi-2-okso-1,2-dihidro-3-kinolinil} -amino)karbonil]amino} -3-(4-metilfenil)propanojska kislina; (3S)-3- {[({1 -[(2-klorofenil)metil]-4-hidroksi-2-okso-1,2-dihidro-3-piridinil}-amino)karbonil]amino}-3-[3-(trifluorometil)fenil]propanojska kislina; (3 S)-3- {[({1 -[(2-klorofenil)metil]-4- [({etil[(etilamino)karbonil]amino} karbonil)amino]-2-okso-1,2-dihidro-3-piridinil} -amino)karbonil]amino} -3-[4-metilfenil)propanojska kislina; (3 S)-3- {[({4-( 1 -azetanil)-1 -[(2-klorofenil)metil]-2-okso-1,2-dihidro-3-piridinil} -amino)karbonil]amino} -3-[4-metilfenil)propanojska kislina; (3S)-3-[({[l-[(2-klorofenil)metil]-4-}2-[(2-{[2-(metiloksi)etil]oksi} etil)oksi]etil} oksi)-2-okso-1,2-dihidro-3-piridinil] -amino} karbonil)amino]-3 -(4-metilfenil)propanoj ska kislina; (3 S)-3- {[({1 [(2-fluorofenil)metil]-4-hidroksi-2-okso-1,2-dihidro-3-piridinil} -amino)karbonil] amino} -3-[4-metilfenil)propanojska kislina; (3 S)-3- {[({1 [(2-kloro-6-fluorofenil)metil]-4-hidroksi-2-okso-1,2-dihidro-3-piridinil} -amino)karbonil] amino} -3-[4-metilfenil)propanojska kislina; (3 S)-3- {[({1 [(2-klorofenil)metil]-5-metil-2-okso-1,2-dihidro-3-piridinil} -amino)karbonil] amino} -3-[4-metilfenil)propanojska kislina; (3S)-3-(l,3-benzodioksol-5-il)-3-((((2-okso-l-((4-trifluorometil)fenil)metil)-l,2-dihidro-3-piridinil)amino)karbonil)amino)propanojska kislina; (3S)-3-((((l-((2-klorofenil)metil)-2-okso-l,2-dihidro-3-piridinil)amino)karbonil)amino)-3-(4-metilfenil)propanojska kislina; 9 SI 20744 - UO (3 S)-3-((((1-((2-fluorofenil)metil)-2-okso-l,2-dihidro-3-piridinil)amino)karbonil)amino)-3 -(4-metilfenil)propanoj ska kislina; (3 S)-3-(((( 1 -((2-bromofenil)metil)-2-okso-1,2-dihidro-3-piridinil)amino)karbonil)amino)-3-(4-metilfenil)propanojska kislina; (3S)-3-((((l-((2,4-diklorofenil)metil)-2-okso-l,2-dihidro-3-piridinil)amino)karbonil)amino)-3-(4-metilfenil)propanojska kislina; (3S)-3-((((l-((2-kloro-6-fluorofenil)metil)-2-okso-l,2-dihidro-3-piridinil)amino)karbonil)amino)-3 -(4-metilfenil)propanoj ska kislina; (3 S)-3-(((( 1 -((2-klorofenil)metil)-4-hidroksi-2-okso-1,2-dihidro-3-piridinil)amino)karbonil)amino)-3-(4-trifluorometil)oksi)fenil)propanojska kislina; in njihove farmacevtsko sprejemljive soli.
6. Farmacevtski sestavek, ki obsega spojino po zahtevku 1 v farmacevtsko sprejemljivem nosilcu.
7. Uporaba spojine po zahtevku 1 za izdelavo zdravila za selektivno inhibiranje (Χ4βι integrinske vezave pri sesalcu, kjer naj se njena terapevtska količina daje navedenemu sesalcu.
SI200020021A 1999-05-07 2000-05-05 Derivati karboksilne kisline, ki inhibirajo vezavo integrinov na njihove receptorje SI20744B (sl)

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