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US 5,684,034 AGranted
1H-indole-3-acetamide sPLA.sub.2 inhibitors
AssigneeEli Lilly and Company
InventorsNicholas J. Bach, Robert D. Dillard, Susan E. Draheim, Robert B. Hermann, Richard W. Schevitz
Life of this patent
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Abstract
A class of novel 1-indole-3-acetamides represented by the formula; ##STR1## is disclosed together with the use of such indole compounds for inhibiting sPLA.sub.2 mediated release of fatty acids.
Claims18
A 1H-indole-3-acetamide compound represented by the formula (III), or a pharmaceutically acceptable salt or prodrug derivative thereof;
- ##STR71## wherein;
- X is oxygen;
- R.sub.21 is --(CH.sub.2).sub.n --(R.sub.80), or --(NH)--(R.sub.80), where n is 1 to 8, and R.sub.80 is aryl or aryl substituted by 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 haloalkyl, C.sub.4 -C.sub.12 cycloalkyl, C.sub.1 -C.sub.10 hydroxyalkyl, carboxyl, halo, --CN, --CHO, --OH, --SH, C.sub.1 -C.sub.10 alkylthio, C.sub.1 -C.sub.10 alkoxyl, carboxyl, amino, or hydroxyamino, or a substituted or unsubstituted 5 to 8 membered heterocyclic ring;
- R.sub.22 is hydrogen, halo, C.sub.1 -C.sub.3 alkyl, ethenyl, cyclopropyl, C.sub.1 -C.sub.2 alkylthio, C.sub.1 -C.sub.2 alkoxy, --CHO, --CN;
- each R.sub.23 is independently hydrogen, halo, or methyl;
- R.sub.24 and R.sub.25 are each independently selected from (a) and (b) where;
- (a) is hydrogen, halo, alkyl, or alkoxy, and;
- (b) is a group having the formula;
- ##STR72## with the proviso that at least one of R.sub.24 and R.sub.25 must be selected from (b), and where;
- R.sub.84 and R.sub.85 are each independently selected from hydrogen, C.sub.1 -C.sub.10 alkyl, hydroxy, or R.sub.84 and R.sub.85 taken together are .dbd.O;
- p is 1 to 5,
- Z is a bond, --O--, --N(C.sub.1 -C.sub.10 alkyl)--, --NH--, or --S--;
- and
- Q is --CON(R.sub.82 R.sub.83), -5-tetrazolyl, --SO.sub.3 H, ##STR73## where n is 1 to 8, R.sub.86 is independently selected from hydrogen, a metal, or C.sub.1 -C.sub.10 alkyl, and R.sub.99 is selected from hydrogen or C.sub.1 -C.sub.10 alkyl;
- R.sub.26, and R.sub.27 are each independently hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkenyl, C.sub.1 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, aryl, aralkyl, or the adjacent hydrocarbyl groups in the groups R.sub.26 and R.sub.27 combine with the ring carbon atoms to which they are attached to form a 5 or 6 membered substituted or unsubstituted carbocyclic ring;
- or C.sub.1 -C.sub.10 haloalkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.1 -C.sub.10 haloalkoxy, C.sub.4 -C.sub.8 cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, --SH, --CN, C.sub.1 -C.sub.10 alkylthio, arylthio, thioacetal, --C(O)O(C.sub.1 -C.sub.10 alkyl), hydrazide, hydrazino, hydrazido, --NH.sub.2, --NO.sub.2, --NR.sub.82 R.sub.83, and --C(O)NR.sub.82 R.sub.83, where, R.sub.82 and R.sub.83 are independently hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 hydroxyalkyl, or taken together with N, R.sub.82 and R.sub.83 form a 5 to 8 membered heterocyclic ring;
- or a group having the formula;
- ##STR74## where, R.sub.84 and R.sub.85 are each independently selected from hydrogen, C.sub.1 -C.sub.10 alkyl, hydroxy, or R.sub.84 and R.sub.85 taken together are .dbd.O;
- p is 1 to 5,
- Z is a bond, --O--, --N(C.sub.1 -C.sub.10 alkyl)--, --NH--, or --S--;
- and
- Q is --CON(R.sub.82 R.sub.83), -5-tetrazolyl, --SO.sub.3 H, ##STR75## where n is 1 to 8, R.sub.86 is independently selected from hydrogen, a metal, or C.sub.1 -C.sub.10 alkyl, and R.sub.99 is selected from hydrogen or C.sub.1 -C.sub.10 alkyl.
19 more elements
A 1H-indole-3-acetamide compound represented by the formula (IV), or a pharmaceutically acceptable salt or prodrug derivative thereof;
- ##STR76## wherein;
- X is oxygen;
- R.sub.31 is selected from groups (i), (ii) and (iii) where;
- (i) is C.sub.6 -C.sub.20 alkyl, C.sub.6 -C.sub.20 alkenyl, C.sub.6 -C.sub.20 alkynyl, C.sub.6 -C.sub.20 haloalkyl, C.sub.4 -C.sub.12 cycloalkyl, or
- (ii) is aryl or aryl substituted by halo, --CN, --CHO, --OH, --SH, C.sub.1 -C.sub.10 alkylthio, C.sub.1 -C.sub.10 alkoxyl, carboxyl, amino, or hydroxyamino;
- (iii) is ##STR77## where R.sub.84 is hydrogen or C.sub.1 -C.sub.10 alkyl, and R.sub.87 is selected from the group;
- phenyl, naphthyl, indenyl, and biphenyl, unsubstituted or substituted by halo, --CN, --CHO, --OH, --SH, C.sub.1 -C.sub.10 alkylthio, C.sub.1 -C.sub.10 alkoxy, carboxyl, amino, hydroxyamino;
- or a substituted or unsubstituted 5 to 8 membered heterocyclic ring;
- R.sub.32 is halo, C.sub.1 -C.sub.2 alkylthio, C.sub.1 -C.sub.2 alkoxy;
- each R.sub.33 is independently hydrogen, halo, or methyl;
- R.sub.34 and R.sub.35 are each independently selected from (a) and (b) where;
- (a) is hydrogen, halo, alkyl, or alkoxy, and
- (b) is a group having the formula;
- ##STR78## with the proviso that at least one of R.sub.34 and R.sub.35 must be selected from (b), and where;
- R.sub.84 and R.sub.85 are each independently selected from hydrogen, C.sub.1 -C.sub.10 alkyl, hydroxy, or R.sub.84 and R.sub.85 taken together are .dbd.O;
- p is 1 to 5,
- Z is a bond, --O--, --N(C.sub.1 -C.sub.10 alkyl)--, --NH--, or --S--;
- and
- Q is --CON(R.sub.82 R.sub.83), -5-tetrazolyl, --SO.sub.3 H, ##STR79## where n is 1 to 8, R.sub.86 is independently selected from hydrogen, a metal, or C.sub.1 -C.sub.10 alkyl, and R.sub.99 is selected from hydrogen or C.sub.1 -C.sub.10 alkyl,
- R.sub.36 and R.sub.37 are each independently hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, aryl, aralkyl, or the adjacent hydrocarbyl groups in the groups R.sub.36 and R.sub.37 combine with the ring carbon atoms to which they are attached to form a 5 or 6 membered substituted or unsubstituted carbocyclic ring;
- or C.sub.1 -C.sub.10 haloalkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.1 -C.sub.10 haloalkoxy, C.sub.4 -C.sub.8 cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, --SH, --CN, C.sub.1 -C.sub.10 alkylthio, arylthio, thioacetal, --C(O)O(C.sub.1 -C.sub.10 alkyl), hydrazide, hydrazino, hydrazido, --NH.sub.2, --NO.sub.2, --NR.sub.82 R.sub.83, and --C(O)NR.sub.82 R.sub.83, where, R.sub.82 and R.sub.83 are independently hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 hydroxyalkyl, or taken together with N, R.sub.82 and R.sub.83 form a 5 to 8 membered heterocyclic ring;
- or a group having the formula;
- ##STR80## where, R.sub.84 and R.sub.85 are each independently selected from hydrogen, C.sub.1 -C.sub.10 alkyl, hydroxy, or R.sub.84 and R.sub.85 taken together are .dbd.O;
- p is 1 to 5,
- Z is a bond, --O--, --N(C.sub.1 -C.sub.10 alkyl)--, --NH--, or --S--;
- and
- Q is --CON(R.sub.82 R.sub.83), -5-tetrazolyl, --SO.sub.3 H, ##STR81## where n is 1 to 8, R.sub.86 is independently selected from hydrogen, a metal, or C.sub.1 -C.sub.10 alkyl, and R.sub.99 is selected from hydrogen or C.sub.1 -C.sub.10 alkyl.
24 more elements
A 1H-indole-3-acetamide compound represented by the formula (V), or a pharmaceutically acceptable salt or prodrug derivative thereof;
- ##STR82## wherein;
- X is oxygen;
- R.sub.51 is ##STR83## where, R.sub.84 is hydrogen or C.sub.1 -C.sub.10 alkyl, and R.sub.87 is --(CH.sub.2).sub.m -(phenyl) or --(CH.sub.2).sub.m -(biphenyl), wherein m is 0 to 2 and the phenyl or biphenyl radicals are unsubstituted or substituted by halo, --CN, --CHO, --OH, nitro, phenyl, --SH, C.sub.1 -C.sub.10 alkylthio, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxyl, carboxyl, amino, hydroxyamino or a substituted or unsubstituted 5 to 8 membered heterocyclic ring;
- R.sub.52 is halo, methylthio, cyclopropyl, or C.sub.1 -C.sub.3 alkyl;
- each R.sub.53 is hydrogen or halo;
- R.sub.54 and R.sub.55 are each independently selected from (a) and (b) where;
- (a) is hydrogen, and;
- (b) is a group having the formula;
- ##STR84## with the proviso that at least one of R.sub.54 and R.sub.55 must be selected from (b), and where;
- R.sub.84 and R.sub.85 are each independently selected from hydrogen, C.sub.1 -C.sub.10 alkyl, hydroxy, or R.sub.84 and R.sub.85 taken together are .dbd.O;
- p is 1 to 5,
- Z is a bond, --O--, --N(C.sub.1 -C.sub.10 alkyl)--, --NH-- or --S--;
- and
- Q is -5-tetrazolyl, --SO.sub.3 H, ##STR85## where n is 1 to 8, R.sub.86 is independently selected from hydrogen, a metal, or C.sub.1 -C.sub.10 alkyl, and R.sub.99 is selected from hydrogen or C.sub.1 -C.sub.10 alkyl;
- R.sub.56, and R.sub.57 are each independently hydrogen, C.sub.1 -C.sub.10 alkyl, aryl, aralkyl, C.sub.1 -C.sub.10 haloalkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.1 -C.sub.10 haloalkoxy, phenoxy, halo, hydroxy, carboxyl, or a group having the formula;
- ##STR86## where, R.sub.84 and R.sub.85 are each independently selected from hydrogen, C.sub.1 -C.sub.10 alkyl, hydroxy, or R.sub.84 and R.sub.85 taken together are .dbd.O;
- p is 1 to 5,
- Z is a bond, --O--, --N(C.sub.1 -C.sub.10 alkyl)--, --NH--, or --S--;
- and
- Q is -5-tetrazolyl, --SO.sub.3 H, ##STR87## where n is 1 to 8, R.sub.86 is hydrogen a metal, or C.sub.1 -C.sub.10 alkyl, and R.sub.99 is selected from hydrogen or C.sub.1 -C.sub.10 alkyl.
17 more elements
A compound selected from the following group and pharmaceutically acceptable salts and prodrug derivatives thereof:
- (A) 4-((3-(2-Amino-2-oxoethyl)-2-chloro-1-(phenylmethyl)-1H-indole-5-yl)oxy)bu tanoic acid,
- (B) 2-((3-(2-Amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)ace tic acid,
- (C) (3-((3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl)oxy)pr opyl)phosphonic acid,
- (D) 4-((3-(2-Amino-2-oxoethyl)-2-bromo-1-(phenylmethyl)-1H-indol-5-yl)oxy)buta noic acid,
- (E) 4-((3-(2-Amino-2-oxoethyl)-2-(methylthio)-1-(phenylmethyl)-1H-indol-5-yl)o xy)butanoic acid,
- (G) 4-((3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1-H-indol-5-yl)oxy)but anoic acid,
- (I) (3-((3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl)oxy)pro pyl)phosphonic acid,
- (J) (3-((3-(2-Amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl)oxy)pro pyl)phosphonic acid monomethyl ester,
- (K) (3-((3-(2-Amino-2-oxoethyl)-1-((3-chlorophenyl)methyl)-2-ethyl-1H-indol-5- yl)oxy)propyl)phosphonic acid,
- (L) ((3-(2-Amino-2-oxoethyl)-1-((3-chlorophenyl)methyl)-2-(methyl-1H-indol-4-y l)oxy)methyl)acetic acid sodium salt,
- (M) ((3-(2-Amino -2-oxoethyl)-1-((1,1'-biphenyl)-2-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)ace tic acid sodium salt,
- (N) ((3-(2-Amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid,
- (O) 2-((3-(2-Amino-2-oxoethyl)-1-((3-chlorophenyl)methyl)-2-ethyl-1H-indol-4-y l)oxy)acetic acid,
- (Q) (3-((3-(2-Amino-2-oxoethyl)-2-cyclopropyl-1-(phenylmethyl)-1H-indol-5-yl)o xy)propyl)phosphonic acid,
- (R) (3-((3-(2-Amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl)oxy)propyl)phos phonic acid,
- (S) 4-((3-(2-Amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl)oxy)butanoic acid,
- (T) 3-(4-((3-(2-Amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl)oxy)p ropane)sulfonic acid,
- (U) 3-((3-(2-Amino-2-oxoethyl)-2-bromo-1-(phenylmethyl)-(1H-indol-5-yl)oxy)pro pyl)phosphonic acid monomethyl ester,
- (X) 4-((3-(2-Amino-2-oxoethyl)-2-bromo-6-chloro-1-(phenylmethyl)-1H-indol-5-yl )oxy)butanoic acid, and
- (Y) 3-(4-((3-(2-Amino-2-oxoethyl)-6-chloro-1-(phenylmethyl)-1H-indol-5-yl)oxy) propyl)phosphonic acid.
17 more elements
A method of inhibiting sPLA.sub.2 mediated release of fatty acid which comprises contacting sPLA.sub.2 with an therapeutically effective amount of a 1H-indole-3-acetamide wherein said acetamide is substituted at the 4 and/or 5 position with an acidic group, and is substituted at the 1 position with a benzyl or substituted benzyl group and pharmaceutically acceptable salts thereof.
A method of inhibiting sPLA.sub.2 mediated release of fatty acid which comprises contacting sPLA.sub.2 with a therapeutically effective amount of a 1H-indole-3-acetamide, and pharmaceutically acceptable salts thereof, wherein said acetamide is substituted at the 4 and/or 5 position with an acidic group, and is substituted at the 2 position with a group of up to about 3 carbon atom size or equivalent containing halogen, oxygen, nitrogen or sulfur.
A method of inhibiting sPLA.sub.2 mediated release of fatty acid which comprises contacting sPLA.sub.2 with an therapeutically effective amount of a 1H-indole-3-acetamide compound represented by the formula (VI) or a pharmaceutically acceptable salt or prodrug derivative thereof:
- ##STR89## wherein X is oxygen;
- R.sub.61 is selected from groups (i), (ii) and (iii) where;
- (i) is C.sub.6 -C.sub.20 alkyl, C.sub.6 -C.sub.20 alkenyl, C.sub.6 -C.sub.20 alkynyl, C.sub.6 -C.sub.20 haloalkyl, C.sub.4 -C.sub.12 cycloalkyl, or
- (ii) is aryl or aryl substituted by halo, --CN, --CHO, --OH, --SH, C.sub.1 -C.sub.10 alkylthio, C.sub.1 -C.sub.10 alkoxylthio, carboxyl, amino, or hydroxyamino;
- (iii) is ##STR90## where R.sub.84 is hydrogen or C.sub.1 -C.sub.10 alkyl, and R.sub.85 is selected from the group;
- phenyl, naphthyl, indenyl, and biphenyl, unsubstituted or substituted by halo, --CN, --CHO, --OH, nitro, phenyl, --SH, C.sub.1 -C.sub.10 alkylthio, C.sub.1 -C.sub.10 alkoxyl, amino, hydroxyamino;
- or a substituted or unsubstituted 5 to 8 membered heterocyclic ring, or R.sub.84 and R.sub.85 taken together are .dbd.O;
- R.sub.62 is hydrogen, halo, C.sub.1 -C.sub.3 alkyl, ethenyl, cyclopropyl, C.sub.1 -C.sub.2 alkylthio, C.sub.1 -C.sub.2 alkoxy, --CHO, --CN;
- each R.sub.63 is independently hydrogen, or halo;
- R.sub.64, R.sub.65, R.sub.66, and R.sub.67 are each independently hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl groups in the set R.sub.64, R.sub.65, R.sub.66, and R.sub.67, combine with the ring carbon atoms to which they are attached to form a 5 or 6 membered substituted or unsubstituted carbocyclic ring;
- or C.sub.1 -C.sub.10 haloalkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.1 -C.sub.10 haloalkoxy, C.sub.4 -C.sub.8 cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, --SH, --CN, --S(C.sub.1 -C.sub.10 alkyl), arylthio, thioacetal, --C(O)O(C.sub.1 -C.sub.10 alkyl), hydrazide, hydrazino, hydrazido, --NH.sub.2, --NO.sub.2, --NR.sub.82 R.sub.83, and --C(O)NR.sub.82 R.sub.83, where, R.sub.82 and R.sub.83 are independently hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 hydroxyalkyl, or taken together with N, R.sub.82 and R.sub.83 form a 5 to 8 membered heterocyclic ring;
- or a group having the formula;
- ##STR91## where, R.sub.84 and R.sub.85 are each independently selected from hydrogen, C.sub.1 -C.sub.10 alkyl, hydroxy, or R.sub.84 and R.sub.85 taken together are .dbd.O;
- p is 1 to 5,
- Z is a bond, --O--, --N(C.sub.1 -C.sub.10 alkyl)--, --NH--, or --S--;
- and
- Q is --CON(R.sub.82 R.sub.83), -5-tetrazolyl, --SO.sub.3 H, ##STR92## where n is 1 to 8, R.sub.86 is independently selected from hydrogen, a metal, or C.sub.1 -C.sub.10 alkyl, and R.sub.99 is selected from hydrogen or C.sub.1 -C.sub.10 alkyl.
14 more elements
A method of inhibiting sPLA.sub.2 mediated release of fatty acid which comprises contacting sPLA.sub.2 with a therapeutically effective amount of 1H-indole-3-acetamide compound represented by the formula (I), or a pharmaceutically acceptable salt or prodrug derivative thereof;
- ##STR93## wherein;
- X is oxygen;
- R.sub.1 is selected from groups (i), (ii) and (iii) where;
- (i) is C.sub.6 -C.sub.20 alkyl, C.sub.6 -C.sub.20 alkenyl, C.sub.6 -C.sub.20 alkynyl, C.sub.6 -C.sub.20 haloalkyl, C.sub.4 -C.sub.12 cycloalkyl, or
- (ii) is selected from the group;
- phenyl, naphthyl, indenyl, and biphenyl, unsubstituted or substituted by halo, --CN, --CHO, --OH, nitro, --SH, C.sub.1 -C.sub.10 alkylthio, C.sub.1 -C.sub.10 alkoxyl, C.sub.1 -C.sub.10 alkyl, carboxyl, amino, or hydroxyamino;
- or
- (iii) is --(CH.sub.2).sub.n --(R.sub.80), or --(NH)--(R.sub.81), where n is 1 to 8, and R.sub.80 is a group recited in (i), and R.sub.81 is selected from a group recited in (i) or (ii);
- R.sub.2 is hydrogen, halo, C.sub.1 -C.sub.3 alkyl, ethenyl, cyclopropyl, C.sub.1 -C.sub.2 alkylthio, C.sub.1 -C.sub.2 alkoxy, --CHO, or --CN;
- each R.sub.3 is independently hydrogen, halo, or methyl;
- R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are each independently hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkenyl, C.sub.1 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl groups in the set R.sub.4, R.sub.5, R.sub.6, and R.sub.7, combine with the ring carbon atoms to which they are attached to form a 5 or 6 membered substituted or unsubstituted carbocyclic ring;
- or C.sub.1 -C.sub.10 haloalkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.1 -C.sub.10 haloalkoxy, C.sub.4 -C.sub.8 cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, --SH, --CN, C.sub.1 -C.sub.10 alkyl thio, arylthio, thioacetal, --C(O)O(C.sub.1 -C.sub.10 alkyl), hydrazide, hydrazino, hydrazido, --NH.sub.2, --NO.sub.2, --NR.sub.82 R.sub.83, and --C(O)NR.sub.82 R.sub.83, where, R.sub.82 and R.sub.83 are independently hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 hydroxyalkyl, or taken together with N, R.sub.82 and R.sub.83 form a 5 to 8 membered heterocyclic ring;
- or a group having the formula;
- ##STR94## where, R.sub.84 and R.sub.85 are each independently selected from hydrogen, C.sub.1 -C.sub.10 alkyl, hydroxy, or R.sub.84 and R.sub.85 taken together are .dbd.O;
- p is 1 to 5,
- Z is a bond, --O--, --N(C.sub.1 -C.sub.10 alkyl)--, --NH--, or --S--;
- and
- Q is --CON(R.sub.82 R.sub.83), -5-tetrazolyl, --SO.sub.3 H, ##STR95## where n is 1 to 8, R.sub.86 is independently selected from hydrogen, a metal, or C.sub.1 -C.sub.10 alkyl, and R.sub.99 is selected from hydrogen or C.sub.1 -C.sub.10 alkyl.
15 more elements
A method of inhibiting sPLA.sub.2 mediated release of fatty acid which comprises contacting sPLA.sub.2 with a therapeutically effective amount of 1H-indole-3-acetamide compound represented by the formula (II), or a pharmaceutically acceptable salt or prodrug derivative thereof;
- ##STR96## wherein;
- X is oxygen;
- R.sub.11 is selected from groups (i), (ii) (iii) and (iv) where;
- (i) is C.sub.6 -C.sub.20 alkyl, C.sub.6 -C.sub.20 alkenyl, C.sub.6 -C.sub.20 alkynyl, C.sub.6 -C.sub.20 haloalkyl, C.sub.4 -C.sub.12 cycloalkyl, or
- (ii) is aryl or aryl substituted by halo, nitro, --CN, --CHO, --OH, --SH, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkylthio, C.sub.1 -C.sub.10 alkoxyl, carboxyl, amino, or hydroxyamino;
- or
- (iii) is --(CH.sub.2).sub.n --(R.sub.80), or --(NH)--(R.sub.81), where n is 1 to 8, and R.sub.80 is a group recited in (i), and R.sub.81 is selected from a group recited in (i) or (ii);
- (iv) is ##STR97## where R.sub.87 is hydrogen or C.sub.1 -C.sub.10 alkyl, and R.sub.88 is selected from the group;
- phenyl, naphthyl, indenyl, and biphenyl, unsubstituted or substituted by halo, --CN, --CHO, --OH, --SH, C.sub.1 -C.sub.10 alkylthio, C.sub.1 -C.sub.10 alkoxyl, phenyl, nitro, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 haloalkyl, carboxyl, amino, hydroxyamino;
- or a substituted or unsubstituted 5 to 8 membered heterocyclic ring;
- R.sub.12 is halo, C.sub.1 -C.sub.2 alkylthio, or C.sub.1 -C.sub.2 alkoxy;
- each R.sub.13 is independently hydrogen, halo, or methyl;
- R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are each independently hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkenyl, C.sub.1 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl groups in the set R.sub.14, R.sub.15, R.sub.16, and R.sub.17, combine with the ring carbon atoms to which they are attached to form a 5 or 6 membered substituted or unsubstituted carbocyclic ring;
- or C.sub.1 -C.sub.10 haloalkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.1 -C.sub.10 haloalkoxy, C.sub.4 -C.sub.8 cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, --SH, --CN, C.sub.1 -C.sub.10 alkylthio, arylthio, thioacetal, --C(O)O(C.sub.1 -C.sub.10 alkyl), hydrazide, hydrazino, hydrazido, --NH.sub.2, --NO.sub.2, --NR.sub.82 R.sub.83, and --C(O)NR.sub.82 R.sub.83, where, R.sub.82 and R.sub.83 are independently hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 hydroxyalkyl, or taken together with N, R.sub.82 and R.sub.83 form a 5 to 8 membered heterocyclic ring;
- or a group having the formula;
- ##STR98## where, R.sub.84 and R.sub.85 are each independently selected from hydrogen, C.sub.1 -C.sub.10 alkyl, hydroxy, or R.sub.84 and R.sub.85 taken together are .dbd.O;
- p is 1 to 5,
- Z is a bond, --O--, --N(C.sub.1 -C.sub.10 alkyl)--, --NH--, or --S--;
- and
- Q is --CON(R.sub.82 R.sub.83), -5-tetrazolyl, --SO.sub.3 H, ##STR99## where n is 1 to 8, R.sub.86 is independently selected from hydrogen, a metal, or C.sub.1 -C.sub.10 alkyl, and R.sub.99 is selected from hydrogen or C.sub.1 -C.sub.10 alkyl.
17 more elements
Dependencies are inferred from the claim text.