Patent ID: 6239108
Filing Date: 2001-05-29
Classification: A61K,C07K

Abstract:
A cell adhesion inhibitory compound of formula (I),Z--(Y.sup.1)--(Y.sup.2)--(Y.sup.3).sub.n --X (I)and pharmaceutically acceptable derivatives thereof; wherein:Z is selected from the group consisting of alkyl; aliphatic acyl substituted with or N-arylamido; heterocycloyl; alkyl-or arylsulfonyl; aralkylcarbonyl substituted with aryl; heterocycloalkylcarbonyl; alkoxycarbonyl; aralkyloxycarbonyl; cycloalkylcarbonyl optionally fused with aryl; heterocycloalkoxycarbonyl; alkylaminocarbonyl; arylamino carbonyl and aralkylaminocarbonyl optionally substituted with bis(alkylsulfonyl)amino, alkoxycarbonylamino or alkenyl; alkylsulfonyl; aralkylsulfonyl; arylsulfonyl; cycloalkylsulfonyl optionally fused with aryl; heterocyclylsulfonyl; heterocyclylalkylsulfonyl; aralkyloxycarbonyl; aryloxycarbonyl; cycloalkyloxycarbonyl; heterocyclyloxycarbonyl; heterocyclylalkoxycabonyl; mono-or di-alkylaminocarbonyl optionally substituted with aryl; (alkyl)(aralkyl)aminocarbonyl; mono-or diaralkylaminocarbonyl; mono-or di-arylaminocarbonyl; (aryl)(alkyljaminocarbonyl; 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; alkenylor alkynyl-aminosulfonyl optionally substituted with aryl; acylamino-substituted alkanoyl; acylaminosubstituted alkylsulfonyl; aminocarbonyl-substituted alkanoyl; carbamoyl-substituted alkanoyl; carbamoylsubstituted 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.Y.sup.1 is --N(R.sup.1)--C(R.sup.2)(A.sup.1)--C(O)--;Y.sup.2 is --N(R.sup.1)--C(R.sup.2)(A.sup.1)--C(O)--;each Y.sup.3 is represented by the formula --N(R.sup.1)--C(R.sup.2)(A.sup.3)--C(O)--;each R.sup.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; thioalkoxyalkylA.sup.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.sup.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.sup.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, aminosubstituted 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.sup.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.sup.2 is independently selected from the group consisting of hydrogen and alkyl;n is an integer from 0 to 8; andX is selected from the group consisting of alkoxy; aryloxy; aralkyloxy; hydroxyl; amino; alkylamino optionally substituted with hydroxy, aminocarbonyl, Nalkylaminocarbonyl, 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.and wherein the compound of formula I is expressly notN'-carboxymethyl-N-(phenylacetyl-L-leucyl-L-aspartyl-L phenylalanyl-L-prolyl)piperazine (i. e., when Z=phenylacetyl, Y1.dbd.L, Y2.dbd.D, Y3.dbd.F/P, n=2, and X=4-carboxymethylpiperazinyl)and expressly not phenylacetylL leucyl-L-aspartyl-L-phenylalanyl-D-proline amide (i. e., when Z=phenylacetyl, Y1.dbd.L, Y2.dbd.D, Y3.dbd.F/p, n=2, and X.dbd.NH2).