Patent EA-001594-B1 (EA)
Title: Cell adhesion inhibitors
Inventor: LIN KO-CHUNG
IPC: A61K31/00
Filed: 1996-07-11
Abstract: 1. A cell adhesion inhibitory compound of formula (I'), Z-N(R<1>)-C(R<2>)(A<1>)-C(O)-N(R<1>)-C(R<2>)(A<2>)-C(O)-{-N(R<1>)-C(R<2>)(A<3>)-C(O)}n-X        (I') which also can be described by formula (I) Z-(Y<1>)-(Y<2>)-(Y<3>)n-X                      (I) wherein Y<1>=-N(R<1>)-C(R<2>)(A<1>)-C(O)-, Y<2>=-N(R<1>)-C(R<2>)(A<2>)-C(O)-, and Y<3>=-N(R<1>)-C(R<2>)(A<3>)-C(O)-, and pharmaceutically acceptable derivatives thereof; wherein: Z is selected from the group consisting of alkyl; aliphatic acyl optionally substituted with N-alkyl- or N-arylamido; aroyl; heterocycloyl; alkyl- or arylsulfonyl; aralkylcarbonyl optionally substituted with aryl; heterocycloalkylcarbonyl; alkoxycarbonyl; aralkyloxycarbonyl; cycloalkylcarbonyl optionally fused with aryl; heterocycloalkoxycarbonyl; alkylaminocarbonyl; arylaminocarbonyl and aralkylaminocarbonyl optionally substituted with bis(alkylsulfonyl)amino, alkoxycarbonylamino or alkenyl; alkylsulfonyl; aralkylsulfonyl; arylsulfonyl; cycloalkylsulfonyl optionally fused with aryl; heterocyclylsulfonyl; hererocyclylalkylsulfonyl; aralkoxycarbonyl; aryloxycarbonyl; cycloalkyloxycarbonyl; heterocyclyloxycarbonyl; heterocyclylalkoxycarbonyl; mono- or dialkylaminocarbonyl optionally substituted with aryl; (alkyl)(aralkyl)aminocarbonyl; mono- or diaralkylaminocarbonyl; mono- or diarylaminocarbonyl; (aryl)(alkyl)aminocarbonyl; mono- or dicycloalkylaminocarbonyl; heterocyclylaminocarbonyl; heterocyclylalkylaminocarbonyl; (alkyl)(heterocyclyl)aminocarbonyl; (alkyl)(heterocyclylalkyl)aminocarbonyl; (aralkyl)(heterocyclyl)aminocarbonyl; (aralkyl)(heterocyclylalkyl)aminocarbonyl; alkenoyl optionally substituted with aryl; alkenylsulfonyl optionally substituted with aryl; alkynoyl optionally substituted with aryl; alkynylsulfonyl optionally substituted with aryl; cycloalkenylcarbonyl; cycloalkenylsulfonyl; cycloalkylalkanoyl; cycloalkylalkylsulfonyl; arylaroyl, biarylsulfonyl; alkoxysulfonyl; aralkoxysulfonyl; alkylaminosulfonyl; aryloxysulfonyl; arylaminosulfonyl; N-arylurea-substituted alkanoyl; N-arylurea-substituted alkylsulfonyl; cycloalkenyl-substituted carbonyl; cycloalkenyl-substituted sulfonyl; alkenoxycarbonyl optionally substituted with aryl; alkenoxysulfonyl optionally substituted with aryl; alkynoxycarbonyl optionally substituted with aryl; alkynoxysulfonyl optionally substituted with aryl; alkenyl- or alkynylaminocarbonyl optionally substituted with aryl; alkenyl-or alkynylaminosulfonyl optionally substituted with aryl; acylamino-substituted alkanoyl; acylamino-substituted alkylsulfonyl; aminocarbonyl-substituted alkanoyl; carbamoyl-substituted alkanoyl; carbamoyl-substituted alkylsulfonyl; heterocyclylalkanoyl; heterocyclylaminosulfonyl; carboxyalkyl-substituted aralkoyl; carboxyalkyl-substituted aralkylsulfonyl; oxocarbocyclyl-fused aroyl; oxocarbocyclyl-fused arylsulfonyl; heterocyclylalkanoyl; N',N'-alkyl, arylhydrazinocarbonyl; aryloxy-substituted alkanoyl and heterocyclylalkylsulfonyl, each R<1> is independently selected from the group consisting of hydrogen, alkyl and aralkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkylalkyl; aryl; aminoalkyl; mono- or dialkyl-substituted aminoalkyl; mono- or diaralkyl-substituted aminoalkyl; hydroxyalkyl; alkoxyalkyl; mercaptoalkyl; thioalkoxyalkyl; A' 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 acid 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; and dialkylamino; cycloalkylamino; dicycloalkylamino; cycloalkylalkylamino; (alkyl)(aryl) amino; aralkylamino optionally substituted with carboxy; diaralkylamino; arylamino; heterocycle; and mono- or biscarboxylic acid-substituted alkylamine; heterocyclylamino; heterocyclyl-substituted alkylamino, and wherein terms used are determined as follows: alkyl is C1-C10 alkyl radical; alkenyl is C2-C10 alkenyl radical; alkynyl is C2-C10 alkynyl radical; cycloalkyl is C3-C8 cyclyc alkyl radical; which can comprise up to three substituents independently selected from the group, consisting of halo, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, 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, alkylamino, alkenylamino 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'-substituted carbonyl, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, alkoxycarbonylamino, Ar'-substituted alkoxycarbonylamino, Ar'-substituted oxycarbonylamino, alkylsulfonylamino, mono- or bis-(Ar'-sulfonyl)amino, Ar'-substituted alkylsulfonylamino, morpholinocarbonylamino, thiomorpholinocarbonylamino, 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')2urea, aralkyloxycarbonyl-substituted alkyl, aralkylaminocarbonyl and thioaryloxy; wherein each Ar' independently represents aryl, which can comprise up to three substituents independently selected from the group, consisting of halo, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, 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-C8 cyclic carbocycle; which comprises one or more double bonds, and can comprise up to three substituents independently selected from the group, consisting of halo, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, 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, alkylamino, alkenylamino 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'-substituted carbonyl, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, alkoxycarbonylamino, Ar'-substituted alkoxycarbonylamino, Ar'-substituted oxycarbonylamino, alkylsulfonylamino, mono- or bis-(Ar'-sulfonyl)amino, Ar'-substituted alkylsulfonylamino, morpholinocarbonylamino, thiomorpholinocarbonylamino, 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')2urea, aralkyloxycarbonyl-substituted alkyl, aralkylaminocarbonyl and thioaryloxy; wherein each Ar' is determined above, aryl represents carbocyclic or heterocyclic aromatic group, selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolynyl, pyrazolidynyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolynyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthiridinyl, pterydinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and pyrazolo[1,5-c]triazinyl, and may comprise up to three substituents independently selected from the group, consisting of halo, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, 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, alkylamino, alkenylamino or alkynylam