PHENYLALANINOL DERIVATIVES

• Main Authors: JEFFERSON WRIGHT TILLEY, ACHYTHARAO SIDDURI
• Format: Patent
• Language: English
• Published: 28.02.2006
• Subjects: ACYCLIC OR CARBOCYCLIC COMPOUNDS; APPARATUS THEREFOR; CHEMISTRY; GENERAL METHODS OF ORGANIC CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

Spoj, naznačen time, da ima formulu: u kojoj je Xskupina formule X-1pri čemu: R15 je halogen, nitro, C1-6alkil sulfonil, cijano, C1-6alkil, C1-6alkoksi, C1-6alkoksikarbonil, karboksi, C1-6alkil aminosulfonil, perfluoro C1-6alkil, C1-6alkiltio, hidroksi C1-6alkil, alkoksi C1-6alkil, alkiltio C1-6alkil, alkilsulfinil C1-6alkil, alkilsufonil C1-6alkil, C1-6alkilsulfinil, C1-6alkilkarbonil, aroil, aril, ariloksi; R16 je vodik, halogen, nitro, cijano, C1-6alkil, OH, perfluoro C1-6alkil, ili C1-6alkiltio; ili je X skupina formule X-2u kojoj je Het 5- ili 6-člani heteroaromatski prsten koji sadrži 1, 2 ili 3 heteroatoma izabranih između N,O i S, iliHet je 9- ili 10-člani biciklički heteroaromatski prsten koji sadrži 1, 2, 3 ili 4 heteroatoma izabranih između O, S i N; R15 i R16 su kao u X-1 iznad, iR30 je vodik ili C1-6alkil, p je cijeli broj od 0 do 1; ili je X skupina formule X-3u kojoj: R18 je aril, heteroaril, R19 je supstituirani ili nesupstituirani C1-6alkil, aril, heteroaril, arilalkil, heteroarilalkil, iR20 je supstituirani ili nesupstituirani C1-6alkilkarbonil ili aroil; Y je skupina formule Y-lu kojoj: R22 i R23 su nezavisno vodik, C1-6alkil, C1-6alkoksi, C 3-7 cikloalkil, aril, arilalkil, nitro, cijano, C1-6alkiltio, C1-6alkilsulfinil, C1-6alkilsulfonil, C1-6alkilkarbonil, halogen ili perfluoro C1-6alkil i barem jedan od R22 i R23 različit je od vodika iR24 je vodik, C1-6alkil, C1-6alkoksi, aril, nitro, cijano, C1-6alkilsulfonil, ili halogen; ili je Y skupina Y-2 koja je petero- ili šesteročlani heteroaromatski prsten povezan preko ugljikova atoma s amid karbonilom pri čemu spomenuti prsten sadrži jedan, dva ili tri heteroatoma izabrana iz skupine koja se sastoji odN, O i S i jedan ili dva atoma spomenutog prstenanezavisno su supstituirani C1-6alkilom, cikloalkilom, halogenom, cijano, perfluoroalkilom ili arilom i barem jedan od spomenutih supstituiranih atomaje susjedni ugljikovu atomu povezanom s amid karbonilom; ili je Y skupina Y-3 koja je tri- do sedmeročlani prsten formule: u kojoj: R25 je C1-6alkil,nesupstituirani ili fluorom supstituirani C2-6alkenil, ili skupina formule R26-(CH2)e-, R26 je aril, heteroaril, azido, cijano, hidroksi, C1-6alkoksi, C1-6alkoksikarbonil, C1-6alkilkarbonil, C1-6alkiltio, C1-6alkilsulfonil, C1-6alkil sulfinil, perfluoro C1-6alkilkarbonil, nitro, ili je R26 skupina formule -NR28R29; R28 je H ili C1-6alkil; R29 je vodik, C1-6alkil, C1-6alkoksikarbonil, C1-6alkilkarbonil, aroil, perfluoro C1-6alkilkarbonilamino, C1-6alkil sulfonil, C1-6alkilaminokarbonil, arilaminokarbonil, ili R28 i R29 uzeti zajedno oblikuju 4,5 ili 6-člani zasićeni karbociklički prsten koji može sadržavati jedan heteroatom izabran između O, S i N; pri čemu su ugljikovi atomi u prstenu nesupstituirani ili supstituirani C1-6alkilom ili halogenom; Q je -(CH2)fO-,-(CH2)fS-, - (CH2)f N (R27)-,-(CH2)f-ili veza; R27 je H, C1-6alkil, aril, C1-6alkilkarbonil, aroil ili C1-6alkoksikarbonil; e jecijeli broj od 0 do 4; f je cijeli broj od 1 do 3; i točk New Phenylalaninol derivatives (I). Phenylalaninol derivatives of formula (I) are new: [Image] X : a benzamide group of formula (i), a heterocyclyl-amide group of formula (ii) or an imidazolin-3-yl-4-one group of formula (iii): [Image] R 15halo, NO 2, CN, lower alkylsulfonyl, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkylaminosulfonyl, lower perfluoroalkyl, lower alkylthio, lower hydroxyalkyl, alkoxy-lower alkyl, alkylthio-lower alkyl, alkylsulfinyl-lower alkyl, alkylsulfonyl-lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl or aryloxy; R 16H, halo, NO 2, CN, lower alkyl, OH lower perfluoroalkyl or lower alkylthio; Het : 5-6 membered heteroaryl containing 1-2 N, O or S; or 9-10 membered bicyclic heteroaryl containing 1-4 O, S or N; R 30H or lower alkyl; p : 0-1; R 18aryl or heteroaryl; R 19optionally substituted lower alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R 20lower alkanoyl or aroyl; Y : a group of formula (iv) or (v) or a 5-6 membered heteroaryl, bonded via C and containing 1-3 O, N or S and optionally substituted by 1-2 lower alkyl, cycloalkyl, halo, CN, perfluoroalkyl or aryl, provided that at least one of the substituents is adjacent to the bonding C; [Image] a : an optional double bond; R 22, R 23H, lower alkyl, lower alkoxy, lower cycloalkyl, aryl aralkyl, NO 2, CN, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkanoyl, halo or perfluoro lower alkyl; provided that at least one is not H; R 24H, lower alkyl, lower alkoxy, aryl, NO 2, CN, lower alkylsulfony or halo; R 25lower alkyl, lower alkenyl (optionally fluorinated) or R 26(CH 2) e; R 26aryl, heteroaryl, N 3, CN, OH, lower alkoxy. lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, perfluoro-lower alkanoyl, NO 2 or NR 28R 29; R 28H or lower alkyl; R 29H, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower alkanoylamino, lower alkylsulfonyl, lower alkylaminocarbonyl or arylaminocarbonyl; or R 28 + R 294-6 membered carbocyclic ring optionally containing 1 O, N or S and optionally substituted on C by lower alkyl or halo; Q : (CH 2) fO, (CH 2) fS, (CH 2) fN(R 27), (CH 2) f or a bond; R 27H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl; e : 0-4; and f : 1-3. An independent claim is included for preparation of (I). ACTIVITY : Antirheumatic; antiarthritic; antiasthmatic; antiinflammatory; neuroprotective. MECHANISM OF ACTION : (I) inhibit the binding of vascular cell adhesion molecule-1 (VCAM1) and fibronectin to the integrin VLA-4 (not defined) on circulating lymphocytes, eosinophils, basophils and monocytes.