Patent EA-003737-B1 (EA)
Title: Cell adhesion inhibitors
Inventor: LIN KO-CHUNG P
IPC: A61P3/10
Filed: 1996-07-11
Abstract: 1. A cell adhesion inhibitory compound of formula (I), Z-(Y<1>)-(Y<2>)-(Y<3>)n-X (I) and pharmaceutically acceptable derivatives thereof; wherein: Z is selected from the group consisting of alkylsulfonyl; aralkylsulfonyl; arylsulfonyl; cycloalkylsulfonyl optionally condensed with aryl; heterocyclylsulfonyl; heterocyclylalkylsulfonyl; alkenylsulfonyl optionally substituted with aryl; alkynylsulfonyl optionally substituted with aryl; cycloalkenylsulfonyl; cycloalkylsulfonyl; biarylsulfonyl; alkoxysulfonyl; aralkoxysulfonyl; alkylaminosulfonyl; aryloxysulfonyl; arylaminosulfonyl; alkylsulfonyl substituted with N-arylurea; cycloalkenyl-substituted sulfonyl; alkenoxysulfonyl optionally substituted with aryl; alkynoxysulfonyl optionally substituted with aryl; alkenyl or alkynyl-aminosulfonyl optionally substituted with aryl; acylamino-substituted alkylsulfonyl; carbamoyl-substituted alkylsulfonyl; heterocyclylaminosulfonyl; carboxyalkyl-substituted aralkylsulfonyl; oxocarbocyclyl, condensed with arylsulfonyl; and aryloxy-substituted heterocyclylalkylsulfonyl; Y<1> is -N(R<1>)-C(R<2>)(A<1>)-C(O)-; Y<2> is -N(R<1>)-C(R<2>)(A<2>)-C(O)-; each Y<3> is represented by the formula -N(R<1>)-C(R<2>)(A<3>)-C(O)-; each R<1> is independently selected from the group consisting of hydrogen, alkyl, and aralkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkylalkyl; aryl; aminoalkyl; mono- or di-alkyl-substituted aminoalkyl; mono- or di-aralkyl-substituted aminoalkyl; hydroxyalkyl; alkoxyalkyl; mercaptoalkyl; thioalkoxyalkyl; A<1> is selected from the group consisting of amino acid side chains and corresponding protected derivatives; cycloalkyl; and alkyl optionally substituted with amino, acylamino, amino-substituted acylamino, alkoxycarbonylamino, aryl, cycloalkyl, carboxy, alkoxy, aralkyloxy, alkoxycarbonyl, aralkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (alkyl)(aralkyl)aminocarbonyl, aralkylaminocarbonyl, diaralkylaminocarbonyl, hydroxyl, carboxyalkylaminocarbonyl, hydroxylaminocarbonyl, mercapto, thioalkoxy or heterocycle; A<2> is selected from the group consisting of acidic functional groups and alkyl optionally substituted with an acidic functional group, protected acidic functional group or aryl; each A<3> is independently selected from the group consisting of amino acids side chains and corresponding protected derivatives; aryl; cycloalkyl; and alkyl optionally substituted with amino, acylamino, amino-substituted acylamino, aryl, cycloalkyl, carboxy, alkoxy, aralkyloxy, alkoxycarbonyl, aralkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (alkyl) (aralkyl)aminocarbonyl, aralkylaminocarbonyl, diaralkylaminocarbonyl, hydroxyl, carboxyalkylaminocarbonyl, hydroxylaminocarbonyl, mercapto, thioalkoxy or heterocycle; or R<1> and any A are taken together with the atoms to which they are attached form a 3- to 6-membered ring heterocycle; each R<2> is independently selected from the group consisting of hydrogen and alkyl; n is an integer from 0 to 8; and X is selected from the group consisting of alkoxy; aryloxy; aralkyloxy; hydroxyl; amino; alkylamino optionally substituted with hydroxy, aminocarbonyl, N-alkylaminocarbonyl, carboxy or alkoxycarbonyl; dialkylamino; cycloalkylamino; dicycloalkylamino; cycloalkylalkylamino; (alkyl) (aryl)amino; aralkylamino optionally substituted with carboxy; diaralkylamino; arylamino; heterocycle; and (mono- or bis-carboxylic acid)-substituted alkylamine; heterocyclylamino; heterocyclyl-substituted alkylamino, wherein alkyl is C1-10 of alkyl radical; alkenyl is C2-10 of alkenyl radical; alkynyl is C2-10 of alkynyl radical; cycloalkyl is C3-8 of cyclic alkyl radical, which can contain right up to 3 substituents each selected from the group consisting of halogen, hydroxyl, amino-group, nitrogroup, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, cyanogroup, carboxy, carboalkoxy, Ar'-substituted alkenyl or alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy or alkynoxy, Ar'-substituted alkoxy, Ar'-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, Ar'-substituted alkylamino, Ar'-substituted alkenylamino or alkynylamino, Ar'-substituted carbonyloxy, alkylcarbonyloxy, alyphatic or aromatic acyl, Ar'-substituted acyl, Ar'-substituted alkylcarbonyloxy, Ar'-substituted carbonylamino, Ar'-substituted amino, Ar'-substituted oxy, Ar'-substituted carbonyl, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, alkoxycarbonylamino, Ar'-substituted alkoxycarbonylamino, Ar'-substituted oxycarbonylamino, alkylsulfonylamino, mono- or bis- (Ar'-sulfonyl) amino, Ar'-substituted alkylsulfonylamino, morpholincarbonylamino, tiomorpholincarbolynamino, N-alkylguanidino, N-Ar-guanidino, N-N-(Ar', alkyl), N-N-(Ar', Ar') guanidine, N,N-dialkylguanidino, N,N,N-trialkylguanidino, N-alkylurea, N,N-dialkylurea, N-Ar' urea, N,N-(Ar', alkyl) urea, N,N-(Ar')2 urea, substituted with aralkyloxycarbonyl alkyl, aralkylaminocarbonyl and tioaryloxy; each Ar independently means aryl containing right up to 3 substituents, each selected from the group consisting of halogen, hydroxyl, amino, nitro, trifluormethyl, trifluormethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino or alkynylamino, alkylcarbonyloxy, aliphatic or aromatic acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl- or N.N-dialkylurea; cycloalkenyl is C4-8 cyclic carbocycle containing one or more double bindings and can consist of up to 3 substituents, which are independently selected from the group consisting of halogen, hydroxyl, amino, nitro, trifluomethyl, trifluomethoxy, alkyl, alkenyl, alkynyl, cyano, carboxy, carboalkoxy, Ar'-substituted alkyl, Ar'-substituted alkenyl or alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy or alkynoxy, Ar'-substituted alkoxy, Ar'-substituted alkenoxy or alkynoxy, alkylaminoalkenylamino or alkynylamino, Ar'-substituted alkylamino, Ar'-substituted alkenylamino or alkynylamino, Ar'-substituted carbonyloxy, alkylcarbonyloxy, aliphatic or aromatic acyl, Ar'-substituted acyl, Ar'-substituted alkylcarbonyloxy, Ar'-substituted carbonylamino, Ar'-substituted amino, Ar'-substituted oxy, Ar'-subatituted carbonyl, alkylcarbonylamino, Ar'-subatituted alkylcarbonylamino, alkoxycarbonylamino, Ar'-substituted alkoxycarbonylamino, Ar'-substituted oxycarbonylamino, alkylsulfonylamino, mono- or bis- (Ar'-sulfonyl)amino, Ar'-substituted alkylsulfonylamino, morpholincarbonylamino, tiomorpholincarbonylamino, N-alkylguanidino, N-Ar'-guanidino, N-N-(Ar', alkyl)-, N-N-(Ar', Ar')-guanidino, N,N-dialkylguanidino, N,N,N-trialkylguanidino, N-alkylurea, N,N-dialkylurea, N-Ar'urea, N,N-(Ar', alkyl)urea, N,N-(Ar')2 urea, substituted with aralkyloxycarbonyl alkyl, aralkylaminocarbonyl, and tioaryloxy; in which Ar is defined as mentioned above; aryl is carbocyclic or heterocyclic aromatic group, selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, antracenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, tiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-tiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-tritianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-digidrobenzofuranyl, benzo[b]tiophenyl, 1H-indazolyl, benzimidazolyl, benztiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pterydinyl, carbazolyl, acridinyl, phenazinyl, phenotiazinyl, phenoxazinyl, and pyrazolo[1,5-c]triazinyl; and can contain up to three substitutes, which are independently selected from the group consisting of halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, cyano, carboxy, carboalkoxy, Ar'-substituted alkyl, Ar'-substituted alkenyl or alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy or alkynoxy, Ar'-substituted alkoxy, Ar'-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, Ar'-substituted alkenylamino or alkynylamino, Ar'-substituted carbonyloxy, alkylcarbonyloxy, aliphatic or aromatic acyl, Ar'-substituted acyl, Ar'-substituted alkylcarbonyloxy, Ar'-substituted carbonylamino, Ar'-substituted amino, Ar'-substituted oxy, Ar'-substituted carbonyl, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, alkoxycarbonylamino, Ar'-substituted oxycarbonylamino, alkylsulsulfonylamino, mono- or bis-(Ar'-sulfonyl)amino, Ar'-substituted alkylsulfonylamino, morpholincarbonylamino, thiomorpholincarbonylamino, N-alkylguanidino, N-Ar'-guanidino, N-N-(Ar', alkyl)guanidino, N-N-(Ar', Ar')diguanidino, N,N-dialkylguanidino, N,N,N-trialkylguanidino, N-alkylurea, N,N-dialkylurea, N-Ar'urea, N,N-(Ar', alkyl)urea, N,N-(Ar')2 urea, substituted with aralkyloxycarbonyl alkyl, aralkylaminocarbonyl and thioaryloxy; in which Ar is defined as mentioned above; aralkyl is an aryl-substituted alkyl radical, wherein aryl and alkyl are defined as mentioned above; alkoxy is a radical of alkyl ether, wherein alkyl is defined as mentioned above; alkenoxy is a radical of alkenyl plain ether, wherein alkenyl is defined as mentioned above; alkynyloxy is a radical of plain alkynyl ether, wherein alkynyl is defined as mentioned above; thioalkyloxy is a radical of plain alkyl thioether, wherein alkyl if defined as mentioned above; alkylamino is a mono- or di- alkyl-substituted aminoradical, wherein alkyl is defined as mentioned above; alkenylamino is a mono- or di- alkenyl-substituted aminoradical, wherein alkenyl is defined as mentioned above; alkynylamino is a mono- or di- alkynyl-substituted aminoradical, wherein alkynyl is defined as mentioned above; aryloxy is a radical of plain aryl ether, wherein aryl is defined as mentioned above; arylamino is a radical of formula aryl-NH-, wherein aryl is de