US 5,961,483 A · Iontophoretic delivery of cell adhesion inhibitors

Abstract

This invention relates to novel methods and devices for iontophoretically administering therapeutic doses of cell adhesion receptor antagonists in a controlled manner through the skin. Such antagonist compounds include but are not limited to antagonists of the IIb/IIIa and .alpha..sub.v .beta..sub.3 integrins and related cell surface adhesive protein receptors. The present invention includes iontophoretic delivery devices comprising cell adhesion receptor antagonists. Such methods and devices are useful, alone or in combination with other therapeutic agents, for the treatment of thromboembolic disorders, angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.

Claims26

Dependent claims

An iontophoresis device for non-invasively administering a therapeutic dose of an .alpha..sub.v .beta..sub.3 integrin antagonist to a mammal at a delivery rate of 0.5 .mu.g/h or greater, comprising:

(a) a current distributing member;
(b) an agent reservoir containing an ionized or ionizable substance, in electrical communication with the current distributing member and adapted to be placed in ionic communication with an epithelial surface, wherein the ionized or ionizable substance is an .alpha..sub.v .beta..sub.3 integrin antagonist;
and
(c) an electrolyte reservoir containing an electrolyte, in electrical communication with an indifferent electrode and adapted to be placed in ionic communication with an epithelial surface;
(d) an electrical power source in current delivering connection with the current distribution member and the electrolyte reservoir.

2 more elements

An iontophoretic device for non-invasively administering a therapeutic dose of a cell adhesion inhibitor compound and competing compound ion thereto to a mammal, comprising:

(a) a current distributing member;
(b) an agent reservoir containing an ionized or ionizable substance, in electrical communication with the current distributing member and adapted to be placed in ionic communication with an epithelial surface, wherein the ionized or ionizable substance is a cell adhesion inhibitor compound;
and
(c) an electrolyte reservoir containing an electrolyte, in electrical communication with an indifferent electrode and adapted to be placed in ionic communication with an epithelial surface;
(d) an electrical power source in current delivering connection with the current distribution member and the electrolyte reservoir,
wherein the cell adhesion inhibitor compound has Formula I:
##STR54## 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.2 a (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--, ##STR55## Z is selected from:
a bond, O, S, S(.dbd.O), S(.dbd.O).sub.2 ;
R.sup.2 and R.sup.3 are selected independently 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 can 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.2 -C.sub.7 alkyl)-, substituted with 0-3 groups selected independently from R.sup.6 or R.sup.7 ;
-(C.sub.2 -C.sub.7 alkenyl)-, substituted with 0-3 groups selected independently from R.sup.6 or R.sup.7 ;
-(C.sub.2 -C.sub.7 alkynyl)-, substituted with 0-3 groups selected independently from R.sup.6 or R.sup.7 ;
-(phenyl)-Q--, the phenyl substituted with 0-2 groups selected independently from R.sup.6 or R.sup.7 ;
-(pyridyl)-Q--, the pyridyl substituted with 0-2 groups selected independently from R.sup.6 or R.sup.7 ;
or -(pyridazinyl)-Q--, the pyridazinyl substituted with 0-2 groups selected independently 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 C.sup.5 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 -C.sub.10 alkyloxy, C.sub.3 -C.sub.11 cycloalkyloxy, C.sub.6 -C.sub.10 aryloxy, C.sub.7 -C.sub.11 aralkyloxy, C.sub.3 -C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 -C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 -C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 -C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 -C.sub.10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 -C.sub.10 cycloalkoxycarbonylalkyloxy, C.sub.7 -C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 -C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 -C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 -C.sub.10 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 -C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy, C.sub.10 -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 can join 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 -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.1 -C.sub.6 alkoxy, benzyloxy, C.sub.6 -C.sub.10 aryl, heteroaryl, heteroarylalkyl, C.sub.7 -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, SR.sup.5a, SOR.sup.5a, SO.sub.2 R.sup.5a, SO.sub.2 NR.sup.5 R.sup.5a, Si(CH.sub.3).sub.3, 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 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 CH.sub.3, or --N(CH.sub.3).sub.2 ;
C.sub.7 -C.sub.11 arylalkyl, the 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 CH.sub.3, or --N(CH.sub.3).sub.2 ;
methylenedioxy when R.sup.6 is a substituent on aryl;
or
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein the heterocyclic ring can be saturated, partially saturated, or fully unsaturated, the 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.)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 -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, or C.sub.7 -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 the heterocyclic ring can be saturated, partially saturated, or fully unsaturated, the heterocyclic ring being substituted with 0-2 R.sup.6 ;
R.sup.12 and R.sup.13 are selected independently from:
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 the 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.1 -C.sub.10 alkoxy, substituted with 0-3 R.sup.6 ;
aryl, substituted with 0-3 R.sup.6 ;
or 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein the heterocyclic ring can be saturated, partially saturated, or fully unsaturated, the 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 ##STR56## 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, the 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, the 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' is chosen such that the number of in-chain atoms connecting R.sup.1 and Y is in the range of 8-18.

118 more elements

Dependencies are inferred from the claim text.

Iontophoretic delivery of cell adhesion inhibitors

Life of this patent

Iontophoretic delivery of cell adhesion inhibitors

Life of this patent

Abstract

Claims26