Patent EA-003320-B1 (EA)
Title: Cell adhesion inhibitors
Inventor: ADAMS STEVEN P
IPC: A61K31/00
Filed: 1996-01-18
Abstract: onylamino, mono- or bis-(Ar'-sulfonyl)amino, Ar'-substituted alkyl-sulfonylamino, morpholinocarbonylom a compound of the formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is -CO2H, -PO<->3H, -SO2R5, SO3H, -OPO<->3 and -CO2R4; wheyl guanidino, N-alkyl urea, N,N-dialkyl urea, N-Arlkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl ("aralkyl"), aryl-substituted alkenyl or alkynyl, Y is selected from thtituted heterocyclyl; Ar'-substituted cycloalkyl o selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl; Ar'-substituted biaryl; Ar'-substituted aminocarbonylamino; Ar'-mercapto-substituted alkyl; Ar-substituted cycloalkyl, biaryl, alkenoxy, alkynox Ar'-substituted aminocycloalkyl and cycloalkenyl;tituted alkenoxy or alkynoxy, alkylamino, alkenylatuted thiourea; N-aralkoxyurea; N-hydroxylurea; N- aryl-substituted alkenylamino or alkynylamino, aryl; thioaryloxy-substituted aryl; N,N-(aryl,alkyl)hydrazine; Ar'-substituted sulfonylheterocyclyl; aralkyl-substituted heterocyclyl; cycloalkyl and cyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl-substituted aralkyl,mino; Ar'-substituted arylaminosulfonyl; thioaryl-substituted thioxy; and Ar'-substituted alkenoyl; aliphatic or aromatic acylaminocarbonyl; aliphaticlkyl, alkenyl alkynyl, cycloalkyl, cycloalkenyl, auted aminocarbonyloxy; Ar', Ar'-disubstituted aryl; aliphatic or aromatic acyl-substituted acyl; benare attached, to form a heterocycle; R3 is selected hydrazine; Ar'-substituted aminosulfonyl; Ar'-suynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, aralkoxy-substituted alkyl, amino-substituted alkyl, (aryl-substituteylcarbonylamino; Ar'-substituted aminocarbonylheterocyclyl; Ar'-substituted aminocarbonyl; Ar'-subst, (hydroxy-substituted alkylthio)-substituted alkyl, thioalkoxy-substituted alkyl, acylamino-substituted alkyl, alkylsufonylamino-substituted alkyl, aaryloxy-substituted alkoxy;heterocyclylcarbonyl; Ar'-substituted sulfonylalkyl; Ar'-amino carbocyclyyl)-carbonyl-substituted alkyl, carboxyl-substituted alkyl, and amino acid side chains selected from arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfpto; cycloalkylcarbonylalkyl; cycloalkyl-substitutine, all-isoleucine, tert-leucine, norleucine, pheylalkyl; phosphorodiamidyl acid or ester; aryloxydimethylsiloxy; 1,3-indandionylcarbonylalkyl; 1,3-ilanine, and allo-threonine; and, R2 and R3 may be enyl; formamidinyl; benzalizinyl; benzalhydrazino; arylsulfonylurea; benzilylamino; 4-(N-2-carboxyalkyl-1-(1,3-benzodioxol-5-yl)-amino-N-leucinylalkylalkenyl, cycloalkenyl, alkynyl and aryl-substituted alkyl, hydrogen, heterocyclyl, heterocyclylcarbonyl, amido, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyl, alkylarylaminocarbonyl, dihydroxyl, amino, nitro, trifluoromethyl, trifluororomatic acyl, alkyl, optionally substituted by substitients selected from the group consisting of amy, alkylamino, alkenylamino or alkynylamino, alkylcarbonyloxy, aliphatic or aromatic acyl, alkylcarbonylamino, alkoxylcarbonylamino, alkylsulfonylaminloxy, thioalkoxy, thioalkenoxy, thioalkynoxy, thionts an alkyl ether radical, wherein alkyl has beenided that when R1 is N-alkylurea-substituted alkyl, N-arylurea-substituted alkyl, and when Y is CO, R3 is different from unsubstituted 3-indolylmethyl; and wherein: alkyl is an C1-C10 alkyl radical; axy represents an alkyl thioether radical, wherein alkyl has been defined above; alkylamino represents a mono- or di-alkyl-substituted amino radical, wcyclic carbocycle containing one or more double bonds; aryl is a carbocyclic or heterocyclic aromatic group selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, and anthracenyl, furyl, thienyl, pyridine, pyrrfined above; aryloxy represents an aryl ether radical, wherein aryl has been defined above; arylaminolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-therein aryl has been defined above; biaryl represen,3,5-triazinyl, 1,3,5-trithianyl, indolyzinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benethiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalie been defined above; aliphatic acyl represents radicals of the formula alkyl-CO-, alkenyl-CO-, or alkynyl-CO-, wherein alkyl, alkenyl, and alkynyl have been defined above; aromatic acyl or aroyl represents a radical of the formula aryl-CO-, wherein fluoromethoxy, alkyl, alkenyl, alkynyl, cyano, carboxy, carboalkoxy, Ar'-substituted alkyl, Ar'-subsing or 8-11 membered bicyclic ring containing 1-4 endocyclic N, O, or S atom; and may contain up to four substituents independently selected from the lkynoxy, alkylamino, alkenylamino or alkynylamino, Ar'-substituted alkylamino, Ar'-substituted alkenylamino or alkynylamino, Ar'-substituted carbonyloxy, alkylcarbonyloxy, aliphatic or aromatic acyl, enyl or alkynyl, 1,2-dioxymethylene, 1,2-dioxyethyloxy, Ar'-substituted carbonylamino, Ar'-substituted amino, Ar'-substituted oxy, Ar'-substituted carbonyl, alkylcarbonylamino, Ar'-substituted alkylcatuted alkylamino, Ar'-substituted alkenylamino or alkynylamino, Ar'-substituted carbonyloxy, alkylcaamino, alkylsulfonylamino, mono- or bis-(Ar'-sulfonyl)amino, Ar'-substituted alkyl-sulfonylamino, moubstituted carbonylamino, Ar'-substituted amino, Ar'-substituted oxy, Ar'-substituted carbonyl, alkyyl), N-N-(Ar',Ar')guanidino, N,N-dialkyl guanidino, alkoxy-carbonylamino, Ar'-substituted alkoxycarbonyl-amino, Ar'-oxycarbonylamino, alkylsulfonylami)2 urea; acylcarbonylamino; Ar'-substituted aryl; ted alkylsulfonylamino, morpholinocarbonylamino, thiomorpholinocarbonylamino, N-alkyl guanidino, N-Acycloalkyl or cycloalkenyl; heterocyclylalkoxy; N,, Ar')guanidino, N,N-dialkyl guanidino, N,N,N-triaand cycloalkenyl; Ar'-substituted biaryl; Ar'-subsAr' urea, N,N-(Ar',alkyl)urea, N,N-(Ar')2 urea; acted alkyl; Ar' amino-substituted aryl; Ar-oxysubstituted alkyl; Ar'-substituted aminocycloalkyl and cycloalkenyl; aralkylaminosulfonyl; aralkoxyalkyl;or cycloalkenyl; heterocyclylalkoxy; N,N-(Ar', hydroxyl)urea; Ar'-substituted cycloalkyl and cycloala; heterocyclyl; thioaryloxy-substituted aryl; N,N-(aryl, alkyl) hydrazine; Ar'-substituted sulfonylr'-amino-substituted aryl; Ar-oxysubstituted alkyl; Ar'-substituted aminocycloalky and cycloalkenyl;; cycloalkyl-fused aryl; aryloxy-substituted alkyltuted thiourea; N-aralkoxyurea; N-hydroxylurea; N-onyl; thioaryl-substituted thioxy; and Ar'-substituted alkenoyl; aliphatic or aromatic acylaminocarbonyl; aliphatic or aromatic acyl-substituted alkenenyl-substituted heterocyclyl; cycloalkyl-fused aryl; aryloxy-substituted alkyl; heterocyclylamino; Ar'-substituted arylaminosulfonyl; thioaryl-substi Ar'-substituted hydrazine; Ar'-substituted aminosulfonyl; Ar'-substituted alkylimino; Ar'-substitutomatic acyl-substituted alkenyl; Ar'-substituted aAr'-substituted cycloalkenonylamino; heterocyclylahatic or aromatic acyl-substituted acyl; benzofused-heterocyclylcarbonylamino; Ar'-substituted hydrazine; Ar'-substituted aminosulfonyl; Ar'-substituttituted aminosulfonylamino; Ar'-substituted mercapAr'-disubstituted acylamino; Ar'-substituted cyclooalkoxy; alkyl- and aryloxy-substituted alkoxy; heterocyclylcarbonyl; Ar'-substituted sulfonylalkyl;nylamino; Ar'-substituted aminocarbonylheterocyciytituted alkenyl; heterocyclylalkylamino; heterocyccarbonylamino; Ar'-substituted aminosulfonylamino;noalkyl; Ar'-substituted cycloalkyl; thioaryloxyalkyl; thioaryloxymercapto; cycloalkylcarbonylalkyl;-substituted alkoxy; heterocyclylcarbonyl; Ar'-sublamino; aryloxycarbonylalkyl; phosphorodiamidyl aclkylsulfonyl; aryl-substituted alkenyl; heterocycllcarbonylalkyl; 1,3-indandionylcarbonyl; oxamindyl; heterocyclylalkylidenyl; formamidinyl; benzalizicloalkyl; thioaryloxyalkyl; thioaryloxymercapto; cino; 4-(N-2-carboxyalkyl-1-(1,3-benzodioxsol-5-yl)no; Ar'-substituted arylamino; aryloxycarbonylalkyloxy- and alkyl- and aryloxy-substituted urea; in which each Ar', independently, is aryl containing up to three substituents selected from the group cformamidinyl; benzalizinyl; benzalhydrazino; arylsulfonylurea; benzilylamino; 4-(N-2-carboxyalkyl-1-(1,3-benzodioxol-5-yl)-amino-N-leucinylalkylamidylxy, alkenoxy, alkynoxy, alkylamino, alkenylamino or alkynylamino, alkylcarbonyloxy, aliphatic or aromatic acyl, alkylcarbonylamino, alkoxylcarbonylamino, alkylsulfonylamino, and N-alkyl or N,N-dialkylresents an N-carbonylated rniomorpholino radical; herein alkyl has been defined above; alkenoxy reprmula alkyl-CONH, wherein alkyl has been defined abas been defined above; alkynyloxy represents an alkynyl ether radical, wherein alkynyl has been defiined above; alkylsulfonylamino represents a radicaer radical, wherein alkyl has been defined above; alkylamino represents a mono- or di-alkyl-substituadical of the formula aryl-SO2NH, wherein aryl has been defined above; N-alkylurea represents a radical of the formula alkyl-NH-CO-NH-, wherein alkyl has been defined above; N-arylurea represents a radical of the formula aryl-NH-CO-NH-, wherein aryl  alkynyl has been defined above; aryloxy representorine, chlorine, bromine, or iodine. 35. The cell ined above; arylamino represents a radical of the X is -CO2H. 36. The cell adhesion inhibitory compound of claim 34, wnerein R1 is aryl. 37. The cell yl-aryl-, wherein aryl has been defined above; thiR1 is (N-Ar'-urea)-para-substituted aralkyl group.n aryl has been defined above; aryl-fused cycloalkyl represents a cycloalkyl radical which shares twphenylmethyl group. 39. The cell adhesion inhibitory compound of claim 34, wherein R2 is hydrogen, mc acyl represents radicals of the formula alkyl-CO-, alkenyl-CO-, or alkynyl-CO-, wherein alkyl, alk