Patent ID: 6185453
Filing Date: 2001-02-06
Classification: A61K,A61N

Abstract:
An iontophoretic device comprising an integrin inhibitor compound of Formula I: ##STR9##or a pharmaceutically acceptable salt form thereof wherein:b is a carbon-carbon single or double bond;R.sup.1 is selected from R.sup.2a (R.sup.3)N--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C--, R.sup.2a (R.sup.3)N(CH.sub.2).sub.p' Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C(CH.sub.2).sub.p' Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)CN(R.sup.2)--, R.sup.2 (R.sup.3)NC(O)--, R.sup.2 (R.sup.5 O)N(R.sup.2 N.dbd.)C--, R.sup.2 (R.sup.3)N(R.sup.5 ON.dbd.)C--; ##STR10##Z is selected from: a bond, O, S, S(.dbd.O), S(.dbd.O).sub.2 ;R.sup.2 and R.sup.3 are independently selected from: H; C.sub.1 -C.sub.10 alkyl; C.sub.3 -C.sub.6 alkenyl; C.sub.3 -C.sub.11 cycloalkyl; C.sub.4 -C.sub.11 cycloalkylalkyl; C.sub.6 -C.sub.10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.7 -C.sub.11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.2 -C.sub.7 alkylcarbonyl; C.sub.7 -C.sub.11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; (C.sub.1 -C.sub.10 alkoxy)carbonyl; C.sub.4 -C.sub.11 cycloalkoxycarbonyl; C.sub.7 -C.sub.11 bicycloalkoxycarbonyl; C.sub.7 -C.sub.11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; (C.sub.1 -C.sub.6 alkyl)carbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; (C.sub.6 -C.sub.10 aryl)carbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; (C.sub.4 -C.sub.11 cycloalkylcarbonyl)oxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C.sub.1 -C.sub.5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;provided that only one of R.sup.2 and R.sup.3 may be hydroxy;R.sup.2a is R.sup.2 or R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C--;U is selected from:a single bond,--(C.sub.1 -C.sub.7 alkyl)--,-- (C.sub.2 -C.sub.7 alkenyl)--,--(C.sub.2 -C.sub.7 alkynyl)--;V is selected from:a single bond;--(C.sub.1 -C.sub.7 alkyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;--(C.sub.2 -C.sub.7 alkenyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;--(C.sub.2 -C.sub.7 alkynyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;--(phenyl)--Q--, said phenyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ;--(pyridyl)--Q--, said pyridyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ; or--(pyridazinyl)--Q--, said pyridazinyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7,Q is selected from:a single bond,--O--, --S(O).sub.m --, --N(R.sup.12)--, --(CH.sub.2).sub.m --, --C(.dbd.O)--,--N(R.sup.5a)C(.dbd.O)--, --C(.dbd.O)N(R.sup.5a)--, --CH.sub.2 O--, --OCH.sub.2 --,--CH.sub.2 N(R.sup.12)--, --N(R.sup.12)CH.sub.2 --, --CH.sub.2 C(.dbd.O)--, --C(.dbd.O)CH.sub.2 --,--CH.sub.2 S(O).sub.m --, or --S(O).sub.m CH.sub.2 --,provided that when b is a single bond, and R.sup.1 --U--V-- is a substituent on C5 of the central 5-membered ring of Formula I, then Q is not --O--, --S(O).sub.m --, --N(R.sup.12)--, --C(.dbd.O)N(R.sup.5a)--, --CH.sub.2 O--, CH.sub.2 N(R.sup.12)-- or --CH.sub.2 S(O).sub.m --;W is selected from: --(C(R.sup.4).sub.2).sub.n' C(.dbd.O)N(R.sup.5a)-- or --C(.dbd.O)--N(R.sup.5a)--(C(R.sup.4).sub.2).sub.n' --;X is --(C(R.sup.4).sub.2).sub.n' --C(R.sup.4)(R.sup.8)--C(R.sup.4)(R.sup.4a)--;Y is selected from hydroxy, C.sub.1 to C.sub.10 alkyloxy, C.sub.3 to C.sub.11 cycloalkyloxy, C.sub.6 to C.sub.10 aryloxy, C.sub.7 to C.sub.11 aralkyloxy, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 C.sub.10 cycloalkoxycarbonylalkyloxy, C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 to C.sub.11 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R.sup.2) (R.sup.3) N-- (C.sub.1 -C.sub.10 alkoxy)--;R.sup.4 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;alternately, two R.sup.4 groups on adjacent carbon atoms may join to form a bond thereby to form a carbon-carbon double or triple bond between such adjacent carbon atoms;R.sup.4a is selected from hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, N(R.sup.5)R.sup.5a, --N(R.sup.12)R.sup.13, --N(R.sup.16)R.sup.17, aryl substituted with 0-3 R.sup.6, or (C.sub.1 -C.sub.10 alkyl)carbonyl ;R.sup.4b is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.7 -C.sub.14 bicycloalkyl, hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl, C.sub.1 -C.sub.6 alkylsulfonyl, nitro, (C.sub.1 -C.sub.6 alkyl)carbonyl , C.sub.6 -C.sub.10 aryl, --N(R.sup.12)R.sup.13, halo, CF.sub.3, CN, (C.sub.1 -C.sub.6 alkoxy)carbonyl , carboxy, piperidinyl, morpholinyl or pyridinyl;R.sup.5 is selected from H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-6 R.sup.4b ;R.sup.5a is selected from hydrogen, hydroxy, C.sub.1 to C.sub.8 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.1 -C.sub.6 alkoxy, benzyloxy, C.sub.6 to C.sub.10 aryl, heteroaryl, heteroarylalkyl, C.sub.7 to C.sub.11 arylalkyl, adamantylmethyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ;alternately, R.sup.5 and R.sup.5a when both are substituents on the same nitrogen atom (as in --NR.sup.5 R.sup.5a) can be taken together with the nitrogen atom to which they are attached to form 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.10 aryl, heteroaryl, C.sub.7 -C.sub.11 arylalkyl, (C.sub.1 -C.sub.6 alkyl)carbonyl, (C.sub.3 -C.sub.7 cycloalkyl)carbonyl, (C.sub.1 -C.sub.6 alkoxy)carbonyl, (C.sub.7 -C.sub.11 arylalkoxy)carbonyl, C.sub.1 -C.sub.6 alkylsulfonyl or C.sub.6 -C.sub.10 arylsulfonyl;R.sup.5b is selected from C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ;R.sup.6 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, (C.sub.1 -C.sub.10 alkyl)carbonyl, --N(R.sup.12)R.sup.13, cyano, halo, CF.sub.3, CHO, CO.sub.2 R.sup.5, C(.dbd.O)R.sup.5a, CONR.sup.5 R.sup.5a, OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5b, OR.sup.5a, OC(.dbd.O)NR.sup.5 R.sup.5a, OCH.sub.2 CO.sub.2 R.sup.5, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5, NO.sub.2, NR.sup.5a C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O) OR.sup.5b, NR.sup.5a C(.dbd.O)NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 R.sup.5, S(O).sub.m R.sup.5a, SO.sub.2 NR.sup.5 R.sup.5a, SiMe.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl;C.sub.6 to C.sub.10 aryl optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;C.sub.7 to C.sub.11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;methylenedioxy when R.sup.6 is a substituent on aryl; ora 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.7 ;R.sup.7 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, (C.sub.1 -C.sub.10 alkyl)carbonyl, --N(R.sup.12)R.sup.13, cyano, halo, CF.sub.3, CHO, CO.sub.2 R.sup.5, C(.dbd.O)R.sup.5a, CONR.sup.5 R.sup.5a, OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5b, OR.sup.5a, OC(.dbd.O)NR.sup.5 R.sup.5a, OCH.sub.2 CO.sub.2 R.sup.5, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5, NO.sub.2, NR.sup.5a C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5b, NR.sup.5a C(.dbd.O)NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 R.sup.5, S(O).sub.m R.sup.5a, SO.sub.2 NR.sup.5 R.sup.5a, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 arylalkyl;R.sup.8 is selected from:R.sup.6 ;C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;C.sub.2 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;C.sub.2 -C.sub.10 alkynyl, substituted with 0-3 R.sup.6 ;C.sub.3 -C.sub.8 cycloalkyl, substituted with 0-3 R.sup.6 ;C.sub.5 -C.sub.6 cycloalkenyl, substituted with 0-3 R.sup.6 ;aryl, substituted with 0-3 R.sup.6 ;5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.6 ;R.sup.12 and R.sup.13 are independently H, C.sub.1 -C.sub.10 alkyl, (C.sub.1 -C.sub.10 alkoxy)carbonyl, (C.sub.1 -C.sub.10 alkyl)carbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, aryl(C.sub.2 -C.sub.10 alkenyl)sulfonyl, heteroarylsulfonyl, aryl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.7 -C.sub.11 arylalkyl, C.sub.7 -C.sub.11 arylcarbonyl, C.sub.4 -C.sub.11 cycloalkoxycarbonyl, C.sub.7 -C.sub.11 bicycloalkoxycarbonyl, C.sub.7 -C.sub.11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylsulfonyl, heteroarylalkylcarbonyl, or aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl, wherein said aryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ;R.sup.14 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl, heteroaryl or (C.sub.1 -C.sub.10 alkoxy)carbonyl, CO.sub.2 R.sup.5 or --C(.dbd.O)N(R.sup.5)R.sup.5a ;R.sup.15 is selected from:H; R.sup.6 ; --CO.sub.2 R.sup.5 ; --C(.dbd.O)N(R.sup.5)R.sup.5a ;C.sub.1 -C.sub.10 alkoxycarbonyl substituted with 0-2 R.sup.6 ;C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;C.sub.2 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;C.sub.2 -C.sub.10 alkoxy, substituted with 0-3 R.sup.6 ;aryl, substituted with 0-3 R.sup.6 ; or5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.6 ;provided that when b is a double bond, only one of R.sup.14 or R.sup.15 is present;R.sup.16 is selected from:--C(.dbd.O)--O--R.sup.18a,--C(.dbd.O)R.sup.18b,--C(.dbd.O)N(R.sup.18b).sub.2,--C(.dbd.O)NHSO.sub.2 R.sup.18a,--C(.dbd.O)NHC(.dbd.O)R.sup.18b,--C(.dbd.O)NHC(.dbd.O)OR.sup.18a,--C(.dbd.O)NHSO.sub.2 NHR.sup.18b,--C(.dbd.S)--NH--R.sup.18b,--NH--C(.dbd.O)--O--R.sup.18a,--NH--C(.dbd.O)--R.sup.18b,--NH--C(.dbd.O)--NH--R.sup.18b,--SO.sub.2 --O--R.sup.18a,--SO.sub.2 --R.sup.18a,--SO.sub.2 --N(R.sup.18b).sub.2,--SO.sub.2 --NHC(.dbd.O) OR.sup.18b,--P(.dbd.S) (OR.sup.18a).sub.2,--P(.dbd.O) (OR.sup.18a).sub.2,--P(.dbd.S) (R.sup.18a).sub.2,--P(.dbd.O) (R.sup.18a).sub.2, or ##STR11##R.sup.17 is selected from: H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.15 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.10 alkyl)--;R.sup.18a is selected from:C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.19,C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.19,C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,aryl substituted with 0-4 R.sup.19,aryl(C.sub.1 -C.sub.6 alkyl)--substituted with 0-4 R.sup.19,a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R.sup.19,C.sub.1 -C.sub.6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R.sup.19 ;R.sup.18b is selected from R.sup.18a or H;R.sup.19 is selected from H, halogen, CF.sub.3, CN, NO.sub.2, NR.sup.12 R.sup.13, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.6 alkyl)--, C.sub.1 -C.sub.6 alkoxy, heteroaryl, (C.sub.1 -C.sub.4 alkyl)sulfonyl, aryl-sulfonyl, or C.sub.1 -C.sub.4 alkoxycarbonyl;m is 0-2;n is 0-4;n' is 0-4;p' is 1-7;p"" is 1-7;r is 0-3;provided that n' are chosen such that the number of in-chain atoms connecting R.sup.1 and Y is in the range of 8-18.