U.S. patent application number 10/306019 was filed with the patent office on 2003-10-23 for pharmaceutical formulation comprising an immune response modifier.
This patent application is currently assigned to 3M Innovative Properties Company. Invention is credited to Busch, Terri F., Fretland, Mary, Gust-Heiting, Amy L., Scholz, Matthew T., Skwierczynski, Raymond D..
Application Number | 20030199538 10/306019 |
Document ID | / |
Family ID | 26992178 |
Filed Date | 2003-10-23 |
United States Patent
Application |
20030199538 |
Kind Code |
A1 |
Skwierczynski, Raymond D. ;
et al. |
October 23, 2003 |
Pharmaceutical formulation comprising an immune response
modifier
Abstract
Pharmaceutical formulations comprising an immune response
modifier (IRM) chosen from imidazoquinoline amines,
imidazotetrahydroquinoline amines, imidazopyridine amines,
6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged
imidazoquinoline amines, thiazolo-quinolineamines,
oxazolo-quinolinamines, thiazolo-pyridinamines,
oxazolo-pyridinamines, imidazonaphthyridine amines,
tetrahydroimidazonaphthyridine amines, and thiazolonaphthyridine
amines; a fatty acid; and a hydrophobic, aprotic component miscible
with the fatty acid are useful for the treatment of dermal
associated conditions. Novel topical formulations are provided. In
one embodiment, the topical formulations are advantageous for
treatment of actinic keratosis, postsurgical scars, basal cell
carcinoma, atopic dermatitis, and warts.
Inventors: |
Skwierczynski, Raymond D.;
(Oakdale, MN) ; Busch, Terri F.; (St. Paul,
MN) ; Gust-Heiting, Amy L.; (Hudson, WI) ;
Fretland, Mary; (Eagan, MN) ; Scholz, Matthew T.;
(Woodbury, MN) |
Correspondence
Address: |
Attention: Dean A. Ersfeld
Office of Intellectual Property Counsel
3M Innovative Properties Company
P.O. Box 33427
St. Paul
MN
55133-3427
US
|
Assignee: |
3M Innovative Properties
Company
|
Family ID: |
26992178 |
Appl. No.: |
10/306019 |
Filed: |
November 27, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60340605 |
Nov 29, 2001 |
|
|
|
60378452 |
May 6, 2002 |
|
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Current U.S.
Class: |
514/291 ;
514/292; 514/558 |
Current CPC
Class: |
A61K 31/4375 20130101;
A61P 17/00 20180101; A61K 9/0014 20130101; A61K 47/14 20130101;
A61P 17/12 20180101; A61K 47/44 20130101; A61K 31/4365 20130101;
A61K 31/4745 20130101; A61K 31/437 20130101; A61K 47/36 20130101;
A61K 31/4355 20130101; A61P 17/02 20180101; A61P 35/00 20180101;
A61K 47/10 20130101; A61P 17/16 20180101; A61K 47/32 20130101; A61P
37/02 20180101 |
Class at
Publication: |
514/291 ;
514/292; 514/558 |
International
Class: |
A61K 031/4745; A61K
031/20 |
Claims
What is claimed is:
1. A pharmaceutical formulation comprising: an immune response
modifier (IRM) compound selected from imidazoquinoline amines,
imidazotetrahydroquinoline amines, imidazopyridine amines,
6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged
imidazoquinoline amines, thiazoloquinoline amines, oxazoloquinoline
amines, thiazolopyridine amines, oxazolopyridine amines,
imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines,
and thiazolonaphthyridine amines; a fatty acid; a hydrophobic,
aprotic component miscible with the fatty acid and comprising a
hydrocarbyl group of 7 or more carbon atoms; and a hydrophilic
viscosity enhancing agent selected from cellulose ethers and
carbomers.
2. The formulation according to claim 1 wherein the formulation
further comprises a preservative system and an emulsifier.
3. The formulation according to claim 1 wherein the hydrophobic,
aprotic component has a hydrophilic lipophilic balance of less than
2.
4. The formulation according to claim 1 wherein the hydrophobic,
aprotic component has a pKa greater than 14.2.
5. The formulation according to claim 1 wherein the ratio of the
hydrophobic, aprotic component to the fatty acid is 0.025:1 to
600:1.
6. The formulation according to claim I wherein the combined weight
percent of the hydrophobic, aprotic component and the fatty acid is
2 to 50.
7. The formulation according to claim 1 wherein the fatty acid is
isostearic acid.
8. The formulation according to claim 1 wherein the hydrophobic,
aprotic component is selected from aprotic fatty acid esters,
hydrocarbons of 8 or more carbon atoms, and waxes.
9. The formulation according to claim 8 wherein the aprotic fatty
acid ester is isopropyl myristate, isopropyl palmitate, diisopropyl
dimer dilinoleate, caprylic/capric triglyceride, cetyl esters wax,
or a combination thereof.
10. The formulation according to claim 8 wherein the hydrocarbon of
8 or more carbon atoms is mineral oil or petrolatum.
11. The formulation according to claim 1 wherein the hydrophilic
viscosity enhancing agent comprises a carbomer.
12. The formulation according to claim 2 wherein the preservative
system comprises methylparaben at 0.01 to 0.5% w/w of the
formulation and propylparaben at 0.01 to 0.5% w/w of the
formulation.
13. The formulation according to claim 2 wherein the preservative
system comprises methylparaben at 0.01 to 0.5% w/w of the
formulation and ethylparaben at 0.01 to 0.5% w/w of the
formulation.
14. The formulation according to claim 2 wherein the preservative
system comprises iodopropynyl butylcarbamate.
15. The formulation according to claim 2 wherein the preservative
system comprises iodopropynyl butylcarbamate and one or more of
methylparaben, ethylparaben, propylparaben, or phenoxyethanol.
16. The formulation according to claim 2 wherein the preservative
system comprises iodopropynyl butylcarbamate, methylparaben, and
ethylparaben.
17. The formulation according to claim 2 wherein the preservative
system comprises phenoxyethanol and one or both of methylparaben
and ethylparaben.
18. The formulation according to claim 2 wherein the preservative
system comprises a preservative enhancing solubilizer.
19. The formulation according to claim 18 wherein the preservative
enhancing solubilizer comprises diethylene glycol monoethyl ether,
propylene glycol or a combination thereof.
20. The formulation of claim 2 comprising: (a) 0.001 to 5% w/w
2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N'-c-
yclohexylurea,
1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine,
2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine,
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
2-methylthiazolo[4,5-c]quinolin-4-amine,
2-ethoxymethyl-1-phenylmethyl-1H-
-imidazo[4,5-c][1,5]naphthyridin-4-amine,
2-ethylthiazolo[4,5-c]quinolin-4- -amine,
4-amino-2-butyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c][1,5]nap-
hthyridine-1-ethanol,
1-{2-[3-(3-pyridyl)propoxy]ethyl}-1H-imidazo[4,5-c]q-
uinolin-4-amine,
1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine,
1-[(R)-1-phenylethyl]-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
1-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amin-
e,
1-[2-(pyridin-4-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine,
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclohexanec-
arboxamide,
2-butyl-1-{2-[(1-methylethyl)sulfonyl]ethyl}-1H-imidazo[4,5-c]-
quinolin-4-amine,
N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-
-1-yl]ethyl}ethanesulfonamide,
N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4-
,5-c]quinolin-1-yl]ethyl}propanamide,
1-[2-(methylsulfonyl)ethyl]-2-propyl-
-1H-imidazo[4,5-c]quinolin-4-amine,
2-ethyl-1-{4-[(1-methylethyl)sulfonyl]-
butyl}-1H-imidazo[4,5-c]quinolin-4-amine,
2-ethyl-1-[4-(ethylsulfonyl)buty-
l]-1H-imidazo[4,5-c]quinolin-4-amine,
N-{3-[4-amino-2-(ethoxymethyl)-1H-im-
idazo[4,5-c]quinolin-1-yl]propyl}cyclopentanecarboxamide,
1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine,
8,9,10,11-tetrahydropyrido[1',2':1,2]imidazo[4,5-c]quinolin-6-amine,
4-amino-.alpha.,.alpha.,2-trimethyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]q-
uinoline-1-ethanol,
2-hydroxymethyl-1-(2-methylpropyl)-6,7,8,9-tetrahydro--
1H-imidazo[4,5-c]quinolin-4-amine,
2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4-
,5-c][1,5]naphthyridin-4-amine, or a combination thereof; (b) 0.05
to 40% w/w isostearic acid; (c) 1 to 30% w/w hydrophobic, aprotic
component; (d) 0.5 to 10% w/w emulsifier; (e) 0.01 to 30% w/w
preservative system; and (f) 0.1 to 10% carbomer.
21. The formulation of claim 20 comprising: (a) 0.03 to 3% w/w
2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-yl)butyl]-N'-cyc-
lohexylurea,
2-butyl-1-{2-[(1-methylethyl)sulfonyl]ethyl}-1H-imidazo[4,5-c-
]quinolin-4-amine, or a combination thereof; (b) 3 to 25% w/w
isostearic acid; (c) 3 to 15% w/w hydrophobic, aprotic component;
(d) 0.75 to 3.5% w/w emulsifier; (e) 0.1 to 25% w/w preservative
system; and (f) 0.5 to 5% w/w carbomer.
22. A method of treating a dermal associated condition, the method
comprising a step of: applying to skin a formulation comprising an
immune response modifier (IRM) selected from imidazoquinoline
amines, imidazotetrahydroquinoline amines, imidazopyridine amines,
6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged
imidazoquinoline amines, thiazoloquinoline amines, oxazoloquinoline
amines, thiazolopyridine amines, oxazolopyridine amines,
imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines,
and thiazolonaphthyridine amines; a fatty acid; a hydrophobic,
aprotic component miscible with the fatty acid and comprising a
hydrocarbyl group of 7 or more carbon atoms; and a hydrophilic
viscosity enhancing agent selected from cellulose ethers and
carbomers.
23. The method according to claim 22 wherein the ratio of the
hydrophobic, aprotic component to the fatty acid is 0.025:1 to
600:1.
24. The method according to claim 22 wherein the combined weight
percent of the hydrophobic, aprotic component and the fatty acid is
2 to 50.
25. The method according to claim 22 wherein the hydrophobic,
aprotic component is selected from the group consisting of aprotic
fatty acid esters, hydrocarbons of 8 or more carbon atoms, and
waxes.
26. The method according to claim 25 wherein the aprotic fatty acid
ester is isopropyl myristate, isopropyl palmitate, diisopropyl
dimer dilinoleate, caprylic/capric triglyceride, cetyl esters wax,
or combinations thereof.
27. The method according to claim 22 wherein the hydrophilic
viscosity enhancing agent comprises a carbomer.
28. The method according to claim 22 wherein the topical
formulation further comprises: a preservative system; and an
emulsifier.
29. The method according to claim 22 wherein the IRM is
2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N'-c-
yclohexylurea,
1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine,
2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine,
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
2-methylthiazolo[4,5-c]quinolin-4-amine,
2-ethoxymethyl-1-phenylmethyl-1H-
-imidazo[4,5-c][1,5]naphthyridin-4-amine,
2-ethylthiazolo[4,5-c]quinolin-4- -amine,
4-amino-2-butyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c][1,5]nap-
hthyridine-1-ethanol,
1-{2-[3-(3-pyridyl)propoxy]ethyl}-1H-imidazo[4,5-c]q-
uinolin-4-amine,
1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine,
1-[(R)-1-phenylethyl]-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
1-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amin-
e,
1-[2-(pyridin-4-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine,
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclohexanec-
arboxamide, 2-butyl-1-{2-[(1-methylethyl)sulfonyl]ethyl}-1
H-imidazo[4,5-c]quinolin-4-amine,
N-{2-[4-amino-2-(ethoxymethyl)-1H-imida-
zo[4,5-c]quinolin-1-yl]ethyl}ethanesulfonamide,
N-{2-[4-amino-2-(ethoxymet-
hyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}propanamide,
1-[2-(methylsulfonyl)ethyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine,
2-ethyl-1-{4-[(1-methylethyl)sulfonyl]butyl}-1H-imidazo[4,5-c]quinolin-4--
amine,
2-ethyl-1-[4-(ethylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amin-
e,
N-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cy-
clopentanecarboxamide,
1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,-
5-c]quinolin-4-amine, 8,9,10,11-tetrahydropyrido[1',2':
1,2]imidazo[4,5-c]quinolin-6-amine,
4-amino-.alpha.,.alpha.,2-trimethyl-6-
,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-ethanol,
2-hydroxymethyl-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]qu-
inolin-4-amine,
2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyri-
din-4-amine, or a combination thereof.
30. The method according to claim 22 wherein the dermal associated
condition is selected from actinic keratosis, postsurgical scars,
basal cell carcinoma, atopic dermatitis, and warts.
31. The method according to claim 30 wherein the IRM is
2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N'-c-
yclohexylurea,
1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine,
2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine,
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
2-methylthiazolo[4,5-c]quinolin-4-amine,
2-ethoxymethyl-1-phenylmethyl-1H-
-imidazo[4,5-c][1,5]naphthyridin-4-amine,
2-ethylthiazolo[4,5-c]quinolin-4- -amine,
4-amino-2-butyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c][1,5]nap-
hthyridine-1-ethanol,
1-{2-[3-(3-pyridyl)propoxy]ethyl}-1H-imidazo[4,5-c]q-
uinolin-4-amine,
1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine,
1-[(R)-1-phenylethyl]-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
1-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amin-
e,
1-[2-(pyridin-4-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine,
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclohexanec-
arboxamide, 2-butyl-1-{2-[(1-methylethyl)sulfonyl]ethyl}
-1H-imidazo[4,5-c]quinolin-4-amine,
N-{2-[4-amino-2-(ethoxymethyl)-1H-imi-
dazo[4,5-c]quinolin-1-yl]ethyl}ethanesulfonamide,
N-{2-[4-amino-2-(ethoxym-
ethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}propanamide,
1-[2-(methylsulfonyl)ethyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine,
2-ethyl-1-{4-[(1-methylethyl)sulfonyl]butyl}-1H-imidazo[4,5-c]quinolin-4--
amine,
2-ethyl-1-[4-(ethylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amin-
e,
N-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cy-
clopentanecarboxamide,
1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,-
5-c]quinolin-4-amine,
8,9,10,11-tetrahydropyrido[1',2':1,2]imidazo[4,5-c]q-
uinolin-6-amine,
4-amino-.alpha.,.alpha.,2-trimethyl-6,7,8,9-tetrahydro-1H-
-imidazo[4,5-c]quinoline-1-ethanol,
2-hydroxymethyl-1-(2-methylpropyl)-6,7-
,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine,
2-butyl-1-(2-phenoxyeth-
yl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine, or a combination
thereof.
32. The method according to claim 30 wherein the formulation
further comprises a preservative system and an emulsifier.
33. The method according to claim 32 wherein the preservative
system comprises methylparaben at 0.01 to 0.5% w/w of the
formulation and propylparaben at 0.01 to 0.5% w/w of the
formulation.
34. The method according to claim 32 wherein the preservative
system comprises methylparaben at 0.01 to 0.5% w/w of the
formulation and ethylparaben at 0.01 to 0.5% w/w of the
formulation.
35. The method according to claim 32 wherein the preservative
system comprises iodopropynyl butylcarbamate.
36. The method according to claim 32 wherein the preservative
system comprises iodopropynyl butylcarbamate and one or more of
methylparaben, ethylparaben, propylparaben, or phenoxyethanol.
37. The method according to claim 32 wherein the preservative
system comprises iodopropynyl butylcarbamate, methylparaben, and
ethylparaben.
38. The method according to claim 32 wherein the preservative
system comprises phenoxyethanol and one or both of methylparaben
and ethylparaben.
39. The method according to claim 32 wherein the preservative
system comprises a preservative enhancing solubilizer.
40. The method according to claim 39 wherein the preservative
enhancing solubilizer comprises diethylene glycol monoethyl ether,
propylene glycol or a combination thereof.
41. A method for delivering an immune response modifier (IRM) to a
dermal surface, the method comprising the steps of: selecting a
formulation comprising: (a) an immune response modifier selected
from imidazoquinoline amines, imidazotetrahydroquinoline amines,
imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines,
1,2-bridged imidazoquinoline amines, thiazoloquinoline amines,
oxazoloquinoline amines, thiazolopyridine amines, oxazolopyridine
amines, imidazonaphthyridine amines, imidazotetrahydronaphthyridine
amines, and thiazolonaphthyridine amines; (b) a fatty acid; (c) a
hydrophobic, aprotic component miscible with the fatty acid and
comprising a hydrocarbyl group of 7 or more carbon atoms; and (d) a
hydrophilic viscosity enhancing agent selected from cellulose
ethers and carbomers; and applying the selected topical formulation
to the dermal surface.
42. A pharmaceutical formulation comprising: an immune response
modifier (IRM) compound selected from the group consisting of
imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines,
and thiazolonaphthyridine amines; a fatty acid; and a hydrophobic,
aprotic component miscible with the fatty acid and comprising a
hydrocarbyl group of 7 or more carbon atoms.
43. The formulation according to claim 42 wherein the formulation
further comprises a preservative system.
44. The formulation according to claim 42 wherein the hydrophobic,
aprotic component has a hydrophilic lipophilic balance of less than
2.
45. The formulation according to claim 42 wherein the hydrophobic,
aprotic component has a pKa greater than 14.2.
46. The formulation according to claim 42 wherein the ratio of the
hydrophobic, aprotic component to the fatty acid is 0.025:1 to
600:1.
47. The formulation according to claim 42 wherein the combined
weight percent of the hydrophobic, aprotic component and the fatty
acid is 2 to 50.
48. The formulation according to claim 42 wherein the fatty acid is
isostearic acid.
49. The formulation according to claim 42 wherein the hydrophobic,
aprotic component is selected from aprotic fatty acid esters,
hydrocarbons of 8 or more carbon atoms, and waxes.
50. The formulation according to claim 49 wherein the aprotic fatty
acid ester is isopropyl myristate, isopropyl palmitate, diisopropyl
dimer dilinoleate, caprylic/capric triglyceride, cetyl esters wax,
or combinations thereof.
51. The formulation of claim 49 wherein the hydrocarbon of 8 or
more carbon atoms is mineral oil or petrolatum.
52. The formulation according to claim 43 wherein the preservative
system comprises methylparaben at 0.01 to 0.5% w/w of the
formulation and propylparaben at 0.01 to 0.5% w/w of the
formulation.
53. The formulation according to claim 43 wherein the preservative
system comprises methylparaben at 0.01 to 0.5% w/w of the
formulation and ethylparaben at 0.01 to 0.5% w/w of the
formulation.
54. The formulation according to claim 43 wherein the preservative
system comprises iodopropynyl butylcarbamate.
55. The formulation according to claim 43 wherein the preservative
system comprises iodopropynyl butylcarbamate and one or more of
methylparaben, ethylparaben, propylparaben, or phenoxyethanol.
56. The formulation according to claim 43 wherein the preservative
system comprises iodopropynyl butylcarbamate, methylparaben, and
ethylparaben.
57. The formulation according to claim 43 wherein the preservative
system comprises phenoxyethanol and one or both of methylparaben
and ethylparaben.
58. The formulation according to claim 43 wherein the preservative
system comprises a preservative enhancing solubilizer.
59. The formulation according to claim 58 wherein the preservative
enhancing solubilizer comprises diethylene glycol monoethyl ether,
propylene glycol or a combination thereof.
60. The formulation of claim 43 comprising: (a) 0.001 to 5% w/w
imidazonaphthyridine amine, imidazotetrahydronaphthyridine amine,
thiazolonaphthyridine amine, or a combination thereof; (b) 0.05 to
40% w/w isostearic acid; (c) 1 to 30% w/w hydrophobic, aprotic
component; and (d) 0.01 to 30% w/w preservative system.
61. The formulation of claim 43 further comprising an emulsifier
and a hydrophilic viscosity enhancing agent.
62. The formulation of claim 60 further comprising an emulsifier
and a hydrophilic viscosity enhancing agent.
63. The formulation of claim 62 wherein the viscosity enhancing
agent comprises a carbomer.
64. The formulation of claim 63 comprising: (a) 0.03 to 3% w/w
2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N'-c-
yclohexylurea,
2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyrid-
in-4-amine,
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
4-amino-2-butyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c][1,5]naphthyrid-
ine-1-ethanol,
1-[(R)-1-phenylethyl]-1H-imidazo[4,5-c][1,5]naphthyridin-4-- amine,
2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-ami-
ne, or a combination thereof; (b) 3 to 25% w/w isostearic acid; (c)
3 to 15% w/w hydrophobic, aprotic component; (d) 0.1 to 25% w/w
preservative system; (e) 0.75 to 3.5% w/w emulsifier; and (f) 0.5
to 5% w/w carbomer.
65. A method of treating a dermal associated condition, the method
comprising a step of: applying to skin a formulation comprising an
immune response modifier (IRM) chosen from imidazonaphthyridine
amines, imidazotetrahydronaphthyridine amines, and
thiazolonaphthyridine amines; a fatty acid; and a hydrophobic,
aprotic component miscible with the fatty acid and comprising a
hydrocarbyl group of 7 or more carbon atoms.
66. The method according to claim 65 wherein the ratio of the
hydrophobic, aprotic component to the fatty acid is 0.025:1 to
600:1.
67. The method according to claim 65 wherein the combined weight
percent of the hydrophobic, aprotic component and the fatty acid is
2 to 50.
68. The method according to claim 65 wherein the hydrophobic,
aprotic component is selected from the group consisting of aprotic
fatty acid esters, hydrocarbons of 8 or more carbon atoms, and
waxes.
69. The method according to claim 68 wherein the aprotic fatty acid
ester is isopropyl myristate, isopropyl palmitate, diisopropyl
dimer dilinoleate, caprylic/capric triglyceride, cetyl esters wax,
or combinations thereof.
70. The method according to claim 65 wherein the formulation
further comprises: a preservative system; and an emulsifier.
71. The method according to claim 65 wherein the IRM is
2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N'-c-
yclohexylurea,
2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyrid-
in-4-amine,
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
4-amino-2-butyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c][1,5]naphthyrid-
ine-1-ethanol,
1-[(R)-1-phenylethyl]-1H-imidazo[4,5-c][1,5]naphthyridin-4-- amine,
2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-ami-
ne, or a combination thereof.
72. The method according to claim 65 wherein the dermal associated
condition is actinic keratosis, postsurgical scars, basal cell
carcinoma, atopic dermatitis, and warts.
73. The method according to claim 72 wherein the IRM is
2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N'-c-
yclohexylurea,
2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyrid-
in-4-amine,
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
4-amino-2-butyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c][1,5]naphthyrid-
ine-1-ethanol,
1-[(R)-1-phenylethyl]-1H-imidazo[4,5-c][1,5]naphthyridin-4-- amine,
2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-ami-
ne, or a combination thereof.
74. The method according to claim 72 wherein the formulation
further comprises: a preservative system; and an emulsifier.
75. The method according to claim 74 wherein the preservative
system comprises methylparaben at 0.01 to 0.5% w/w of the
formulation and propylparaben at 0.01 to 0.5% w/w of the
formulation.
76. The method according to claim 74 wherein the preservative
system comprises methylparaben at 0.01 to 0.5% w/w of the
formulation and ethylparaben at 0.01 to 0.5% w/w of the
formulation.
77. The method according to claim 74 wherein the preservative
system comprises iodopropynyl butylcarbamate.
78. The method according to claim 74 wherein the preservative
system comprises iodopropynyl butylcarbamate and one or more of
methylparaben, ethylparaben, propylparaben, or phenoxyethanol.
79. The method according to claim 74 wherein the preservative
system comprises iodopropynyl butylcarbamate, methylparaben, and
ethylparaben.
80. The method according to claim 74 wherein the preservative
system comprises phenoxyethanol and one or both of methylparaben
and ethylparaben.
81. The method according to claim 74 wherein the preservative
system comprises a preservative enhancing solubilizer.
82. The method according to claim 81 wherein the preservative
enhancing solubilizer comprises diethylene glycol monoethyl ether,
propylene glycol or a combination thereof.
83. A method for delivering an immune response modifier (IRM) to a
dermal surface, the method comprising the steps of: selecting a
formulation comprising: (a) an immune response modifier selected
from imidazonaphthyridine amines, imidazotetrahydronaphthyridine
amines, and thiazolonaphthyridine amines; (b) at fatty acid; (c) a
hydrophobic, aprotic component miscible with the fatty acid and
comprising a hydrocarbyl group of 7 or more carbon atoms; and
applying the selected formulation to the dermal surface.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to Provisional Patent
Application Serial No. 60/340,605, filed Nov. 29, 2001 and
Provisional Patent Application Serial No. 60/378,452, filed May 6,
2002.
FIELD OF THE INVENTION
[0002] The present invention is directed to pharmaceutical
formulations comprising at least one immune response modifier
chosen from imidazoquinoline amines, imidazopyridine amines,
6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged
imidazoquinoline amines, thiazoloquinoline amines, oxazoloquinoline
amines, thiazolopyridine amines, oxazolopyridine amines,
imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines,
and thiazolonaphthyridine amines. Embodiments of the present
invention are directed to topical formulations for application to
the skin of a mammal. Other embodiments of the present invention
are directed to methods for treating dermal diseases.
BACKGROUND
[0003] Many imidazoquinoline amine, imidazopyridine amine,
6,7-fused cycloalkylimidazopyridine amine, 1,2-bridged
imidazoquinoline amine, thiazoloquinoline amine, oxazoloquinoline
amine, thiazolopyridine amine, oxazolopyridine amine,
imidazonaphthyridine amine, imidazotetrahydronaphthyridine amine,
and thiazolonaphthyridine amine compounds have demonstrated potent
immunostimulating, antiviral and antitumor (including anticancer)
activity, and have also been shown to be useful as vaccine
adjuvants. These compounds are hereinafter collectively referred to
as "IRM" (immune response modifier) compounds. One of these IRM
compounds, known as imiquimod, has been commercialized in a topical
formulation, Aldara.TM., for the treatment of anogenital warts
associated with human papillomavirus.
[0004] The mechanism for the antiviral and antitumor activity of
these IRM compounds is thought to be due in substantial part to
enhancement of the immune response by induction of various
important cytokines (e.g., interferons, interleukins, tumor
necrosis factor, etc.). Such compounds have been shown to stimulate
a rapid release of certain monocyte/macrophage-derived cytokines
and are also capable of stimulating B cells to secrete antibodies
which play an important role in these IRM compounds' antiviral and
antitumor activities. One of the predominant immunostimulating
responses to these compounds is the induction of interferon
(IFN)-.alpha. production, which is believed to be very important in
the acute antiviral and antitumor activities seen. Moreover, up
regulation of other cytokines such as, for example, tumor necrosis
factor (TNF), Interleukin-1 (IL-1) and IL-6 also have potentially
beneficial activities and are believed to contribute to the
antiviral and antitumor properties of these compounds.
[0005] Although some of the beneficial effects of IRMs are known,
the ability to provide therapeutic benefit via topical application
of an IRM compound for treatment of a particular condition at a
particular location may be hindered by a variety of factors. These
factors include irritation of the skin to which the formulation is
applied, formulation wash away, insolubility and/or degradation of
the IRM compound in the formulation, physical instability of the
formulation (e.g., separation of components, thickening,
precipitation/agglomerization of active ingredient, and the like),
poor permeation, and undesired systemic delivery of the topically
applied IRM compound. Accordingly, there is a continuing need for
new methods and formulations to provide the greatest therapeutic
benefit from this class of compounds.
SUMMARY OF THE INVENTION
[0006] At several locations throughout the specification, guidance
is provided through lists of examples. In each instance, the
recited list serves only as a representative group; it is not meant
that the list is exclusive.
[0007] In one aspect, the present invention is directed to a
pharmaceutical formulation comprising an immune response modifier
selected from imidazoquinoline amines, imidazotetrahydroquinoline
amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine
amines, 1,2-bridged imidazoquinoline amines, thiazoloquinoline
amines, oxazoloquinoline amines, thiazolopyridine amines,
oxazolopyridine amines, imidazonaphthyridine amines,
imidazotetrahydronaphthyridine amines, and thiazolonaphthyridine
amines; a fatty acid; a hydrophobic, aprotic component miscible
with the fatty acid and comprising a hydrocarbyl group of 7 or more
carbon atoms; and a hydrophilic viscosity enhancing agent selected
from cellulose ethers and carbomers.
[0008] In one embodiment, the pharmaceutical formulation comprises
an immune response modifier selected from imidazonaphthyridine
amines, imidazotetrahydronaphthyridine amines, and
thiazolonaphthyridine amines; a fatty acid; and a hydrophobic,
aprotic component miscible with the fatty acid and comprising a
hydrocarbyl group of 7 or more carbon atoms.
[0009] The formulation can further comprise one or more of a
preservative system, an emulsifier, and water.
[0010] In another aspect, the present invention is directed to a
method of treatment of a dermal associated condition comprising
applying to skin a topical formulation comprising an immune
response modifier selected from imidazoquinoline amines,
imidazotetrahydroquinoline amines, imidazopyridine amines,
6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged
imidazoquinoline amines, thiazoloquinoline amines, oxazoloquinoline
amines, thiazolopyridine amines, oxazolopyridine amines,
imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines,
and thiazolonaphthyridine amines; a fatty acid; a hydrophobic,
aprotic component miscible with the fatty acid and comprising a
hydrocarbyl group of 7 or more carbon atoms; and a hydrophilic
viscosity enhancing agent selected from cellulose ethers and
carbomers.
[0011] In one embodiment, the method of treatment of a dermal
associated condition comprises applying to skin a formulation
comprising an immune response modifier selected from
imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines,
and thiazolonaphthyridine amines; a fatty acid; and a hydrophobic,
aprotic component miscible with the fatty acid and comprising a
hydrocarbyl group of 7 or more carbon atoms.
[0012] In other embodiments, the method of treatment of a dermal
associated condition comprises applying to skin a formulation
comprising an immune response modifier selected from
imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines,
and thiazolonaphthyridine amines; a fatty acid; a hydrophobic,
aprotic component miscible with the fatty acid and comprising a
hydrocarbyl group of 7 or more carbon atoms; and further comprising
one or more of a preservative system, an emulsifier, and water.
[0013] In one embodiment, the dermal associated condition is
selected from actinic keratosis, postsurgical scars, basal cell
carcinoma, atopic dermatitis, and warts.
[0014] In another aspect, the present invention is directed to a
method for delivering an immune response modifier to a dermal
surface, the method comprising the steps of selecting a formulation
comprising a compound selected from imidazoquinoline amines,
imidazotetrahydroquinolin- e amines, imidazopyridine amines,
6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged
imidazoquinoline amines, thiazoloquinoline amines,
oxazolo-quinoline amines, thiazolopyridine amines, oxazolopyridine
amines, imidazonaphthyridine amines, imidazotetrahydronaphthyridine
amines, and thiazolonaphthyridine amines; a fatty acid; a
hydrophobic, aprotic component miscible with the fatty acid and
comprising a hydrocarbyl group of 7 or more carbon atoms; and a
hydrophilic viscosity enhancing agent selected from cellulose
ethers and carbomers; and applying the selected formulation to the
dermal surface for a time sufficient to allow the formulation to
deliver the IRM to the dermal surface.
[0015] In one embodiment, the selected formulation comprises an
immune response modifier selected from imidazonaphthyridine amines,
imidazotetrahydronaphthyridine amines, and thiazolonaphthyridine
amines; a fatty acid; and a hydrophobic, aprotic component miscible
with the fatty acid and comprising a hydrocarbyl group of 7 or more
carbon atoms.
[0016] Unless otherwise indicated, all numbers expressing
quantities, ratios, and numerical properties of ingredients,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about".
[0017] As used herein, "a" or "an" or "the" are used
interchangeably with "at least one", to mean "one or more" of the
element being modified.
DETAILED DESCRIPTION
[0018] In one aspect, the present invention is directed to a
formulation comprising an immune response modifier compound
selected from imidazoquinoline amines, imidazotetrahydroquinoline
amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine
amines, 1,2-bridged imidazoquinoline amines, thiazoloquinoline
amines, oxazoloquinoline amines, thiazolopyridine amines,
oxazolopyridine amines, imidazonaphthyridine amines,
imidazotetrahydronaphthyridine amines, and thiazolonaphthyridine
amines; a fatty acid; a hydrophobic, aprotic component miscible
with the fatty acid and comprising a hydrocarbyl group of 7 or more
carbon atoms, and a hydrophilic viscosity enhancing agent selected
from cellulose ethers and carbomers.
[0019] These immune response modifier compounds, methods of making
them, methods of using them and compositions containing them are
disclosed in U.S. Pat. Nos. 4,689,338; 4,929,624; 4,988,815;
5,037,986; 5,175,296; 5,238,944; 5,266,575; 5,268,376; 5,346,905;
5,352,784; 5,367,076; 5,389,640; 5,395,937; 5,446,153; 5,482,936;
5,693,811; 5,741,908; 5,756,747; 5,939,090; 6,039,969; 6,083,505;
6,110,929; 6,194,425; 6,245,776; 6,331,539; 6,376,669; and
6,451,810; European Patent 0 394 026; US Publication 2002/0055517;
and PCT Publications WO 00/47719; WO 00/76518; WO 01/74343; WO
02/46188; WO 02/46189; WO 02/46190; WO 02/46191; WO 02/46192; WO
02/46193; WO 02/46194; and WO 02/46749 the disclosures of which are
incorporated by reference herein.
[0020] As noted above, many of the IRM compounds useful in the
present invention have demonstrated significant immunomodulating
activity. In certain embodiments of the present invention, the IRM
compound can be chosen from imidazoquinoline amines, for example,
1H-imidazo[4,5-c]quinol- in-4-amines defined by one of Formulas I-V
below: 1
[0021] wherein
[0022] R.sub.11 is chosen from alkyl of one to ten carbon atoms,
hydroxyalkyl of one to six carbon atoms, acyloxyalkyl wherein the
acyloxy moiety is alkanoyloxy of two to four carbon atoms or
benzoyloxy, and the alkyl moiety contains one to six carbon atoms,
benzyl, (phenyl)ethyl and phenyl, said benzyl, (phenyl)ethyl or
phenyl substituent being optionally substituted on the benzene ring
by one or two moieties independently chosen from alkyl of one to
four carbon atoms, alkoxy of one to four carbon atoms and halogen,
with the proviso that if said benzene ring is substituted by two of
said moieties, then said moieties together contain no more than six
carbon atoms;
[0023] R.sub.21 is chosen from hydrogen, alkyl of one to eight
carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl,
(phenyl)ethyl or phenyl substituent being optionally substituted on
the benzene ring by one or two moieties independently chosen from
alkyl of one to four carbon atoms, alkoxy of one to four carbon
atoms and halogen, with the proviso that when the benzene ring is
substituted by two of said moieties, then the moieties together
contain no more than six carbon atoms; and
[0024] each R.sub.1 is independently chosen from alkoxy of one to
four carbon atoms, halogen, and alkyl of one to four carbon atoms,
and n is an integer from 0 to 2, with the proviso that if n is 2,
then said R.sub.1 groups together contain no more than six carbon
atoms; 2
[0025] wherein
[0026] R.sub.12 is chosen from straight chain or branched chain
alkenyl containing two to ten carbon atoms and substituted straight
chain or branched chain alkenyl containing two to ten carbon atoms,
wherein the substituent is chosen from straight chain or branched
chain alkyl containing one to four carbon atoms and cycloalkyl
containing three to six carbon atoms; and cycloalkyl containing
three to six carbon atoms substituted by straight chain or branched
chain alkyl containing one to four carbon atoms; and
[0027] R.sub.22 is chosen from hydrogen, straight chain or branched
chain alkyl containing one to eight carbon atoms, benzyl,
(phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl
substituent being optionally substituted on the benzene ring by one
or two moieties independently chosen from straight chain or
branched chain alkyl containing one to four carbon atoms, straight
chain or branched chain alkoxy containing one to four carbon atoms,
and halogen, with the proviso that when the benzene ring is
substituted by two such moieties, then the moieties together
contain no more than six carbon atoms; and
[0028] each R.sub.2 is independently chosen from straight chain or
branched chain alkoxy containing one to four carbon atoms, halogen,
and straight chain or branched chain alkyl containing one to four
carbon atoms, and n is an integer from zero to 2, with the proviso
that if n is 2, then said R.sub.2 groups together contain no more
than six carbon atoms; 3
[0029] wherein
[0030] R.sub.23 is chosen from hydrogen, straight chain or branched
chain alkyl of one to eight carbon atoms, benzyl, (phenyl)ethyl and
phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being
optionally substituted on the benzene ring by one or two moieties
independently chosen from straight chain or branched chain alkyl of
one to four carbon atoms, straight chain or branched chain alkoxy
of one to four carbon atoms, and halogen, with the proviso that
when the benzene ring is substituted by two such moieties, then the
moieties together contain no more than six carbon atoms; and
[0031] each R.sub.3 is independently chosen from straight chain or
branched chain alkoxy of one to four carbon atoms, halogen, and
straight chain or branched chain alkyl of one to four carbon atoms,
and n is an integer from zero to 2, with the proviso that if n is
2, then said R.sub.3 groups together contain no more than six
carbon atoms; 4
[0032] wherein
[0033] R.sub.14 is --CHR.sub.xR.sub.y wherein R.sub.y is hydrogen
or a carbon-carbon bond, with the proviso that when R.sub.y is
hydrogen R.sub.x is alkoxy of one to four carbon atoms,
hydroxyalkoxy of one to four carbon atoms, 1-alkynyl of two to ten
carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy
moiety contains one to four carbon atoms and the alkyl moiety
contains one to four carbon atoms, or 2-, 3-, or 4-pyridyl, and
with the further proviso that when R.sub.y is a carbon-carbon bond
R.sub.y and R.sub.x together form a tetrahydrofuranyl group
optionally substituted with one or more substituents independently
chosen from hydroxy and hydroxyalkyl of one to four carbon
atoms;
[0034] R.sub.24 is chosen from hydrogen, alkyl of one to four
carbon atoms, phenyl, and substituted phenyl wherein the
substituent is chosen from alkyl of one to four carbon atoms,
alkoxy of one to four carbon atoms, and halogen; and
[0035] R.sub.4 is chosen from hydrogen, straight chain or branched
chain alkoxy containing one to four carbon atoms, halogen, and
straight chain or branched chain alkyl containing one to four
carbon atoms; 5
[0036] wherein
[0037] R.sub.15 is chosen from: hydrogen; straight chain or
branched chain alkyl containing one to ten carbon atoms and
substituted straight chain or branched chain alkyl containing one
to ten carbon atoms, wherein the substituent is chosen from
cycloalkyl containing three to six carbon atoms and cycloalkyl
containing three to six carbon atoms substituted by straight chain
or branched chain alkyl containing one to four carbon atoms;
straight chain or branched chain alkenyl containing two to ten
carbon atoms and substituted straight chain or branched chain
alkenyl containing two to ten carbon atoms, wherein the substituent
is chosen from cycloalkyl containing three to six carbon atoms and
cycloalkyl containing three to six carbon atoms substituted by
straight chain or branched chain alkyl containing one to four
carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl
wherein the alkoxy moiety contains one to four carbon atoms and the
alkyl moiety contains one to six carbon atoms; acyloxyalkyl wherein
the acyloxy moiety is alkanoyloxy of two to four carbon atoms or
benzoyloxy, and the alkyl moiety contains one to six carbon atoms;
benzyl; (phenyl)ethyl; and phenyl; said benzyl, (phenyl)ethyl or
phenyl substituent being optionally substituted on the benzene ring
by one or two moieties independently chosen from alkyl of one to
four carbon atoms, alkoxy of one to four carbon atoms, and halogen,
with the proviso that when said benzene ring is substituted by two
of said moieties, then the moieties together contain no more than
six carbon atoms;
[0038] R.sub.25 is 6
[0039] wherein
[0040] R.sub.S and R.sub.T are independently chosen from hydrogen,
alkyl of one to four carbon atoms, phenyl, and substituted phenyl
wherein the substituent is chosen from alkyl of one to four carbon
atoms, alkoxy of one to four carbon atoms, and halogen;
[0041] X is chosen from alkoxy containing one to four carbon atoms,
alkoxyalkyl wherein the alkoxy moiety contains one to four carbon
atoms and the alkyl moiety contains one to four carbon atoms,
hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four
carbon atoms, alkylamido wherein the alkyl group contains one to
four carbon atoms, amino, substituted amino wherein the substituent
is alkyl or hydroxyalkyl of one to four carbon atoms, azido,
chloro, hydroxy, 1-morpholino, 1-pyrrolidino, alkylthio of one to
four carbon atoms; and
[0042] R.sub.5 is chosen from hydrogen, straight chain or branched
chain alkoxy containing one to four carbon atoms, halogen, and
straight chain or branched chain alkyl containing one to four
carbon atoms;
[0043] and a pharmaceutically acceptable salt of any of the
foregoing.
[0044] The IRM compound can also be chosen from 6,7 fused
cycloalkylimidazopyridine amines defined by Formula VI below: 7
[0045] wherein m is 1, 2, or 3;
[0046] R.sub.16 is chosen from hydrogen; cyclic alkyl of three,
four, or five carbon atoms; straight chain or branched chain alkyl
containing one to ten carbon atoms and substituted straight chain
or branched chain alkyl containing one to ten carbon atoms, wherein
the substituent is chosen from cycloalkyl containing three to six
carbon atoms and cycloalkyl containing three to six carbon atoms
substituted by straight chain or branched chain alkyl containing
one to four carbon atoms; fluoro- or chloroalkyl containing from
one to ten carbon atoms and one or more fluorine or chlorine atoms;
straight chain or branched chain alkenyl containing two to ten
carbon atoms and substituted straight chain or branched chain
alkenyl containing two to ten carbon atoms, wherein the substituent
is chosen from cycloalkyl containing three to six carbon atoms and
cycloalkyl containing three to six carbon atoms substituted by
straight chain or branched chain alkyl containing one to four
carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl
wherein the alkoxy moiety contains one to four carbon atoms and the
alkyl moiety contains one to six carbon atoms; acyloxyalkyl wherein
the acyloxy moiety is alkanoyloxy of two to four carbon atoms or
benzoyloxy, and the alkyl moiety contains one to six carbon atoms,
with the proviso that any such alkyl, substituted alkyl, alkenyl,
substituted alkenyl, hydroxyalkyl, alkoxyalkyl, or acyloxyalkyl
group does not have a fully carbon substituted carbon atom bonded
directly to the nitrogen atom; benzyl; (phenyl)ethyl; and phenyl;
said benzyl, (phenyl)ethyl or phenyl substituent being optionally
substituted on the benzene ring by one or two moieties
independently chosen from alkyl of one to four carbon atoms, alkoxy
of one to four carbon atoms, and halogen, with the proviso that
when said benzene ring is substituted by two of said moieties, then
the moieties together contain no more than six carbon atoms;
[0047] and --CHR.sub.xR.sub.y
[0048] wherein
[0049] R.sub.y is hydrogen or a carbon-carbon bond, with the
proviso that when R.sub.y is hydrogen R.sub.x is alkoxy of one to
four carbon atoms, hydroxyalkoxy of one to four carbon atoms,
1-alkynyl of two to ten carbon atoms, tetrahydropyranyl,
alkoxyalkyl wherein the alkoxy moiety contains one to four carbon
atoms and the alkyl moiety contains one to four carbon atoms, or
2-, 3-, or 4-pyridyl, and with the further proviso that when
R.sub.y is a carbon-carbon bond R.sub.y and R.sub.x together form a
tetrahydrofuranyl group optionally substituted with one or more
substituents independently chosen from hydroxy and hydroxyalkyl of
one to four carbon atoms,
[0050] R.sub.26 is chosen from hydrogen, straight chain or branched
chain alkyl containing one to eight carbon atoms, straight chain or
branched chain hydroxyalkyl containing one to six carbon atoms,
morpholinoalkyl, benzyl, (phenyl)ethyl and phenyl, the benzyl,
(phenyl)ethyl or phenyl substituent being optionally substituted on
the benzene ring by a moiety chosen from methyl, methoxy, and
halogen; and
[0051] --C(R.sub.S)(R.sub.T)(X) wherein R.sub.S and R.sub.T are
independently chosen from hydrogen, alkyl of one to four carbon
atoms, phenyl, and substituted phenyl wherein the substituent is
chosen from alkyl of one to four carbon atoms, alkoxy of one to
four carbon atoms, and halogen;
[0052] X is chosen from alkoxy containing one to four carbon atoms,
alkoxyalkyl wherein the alkoxy moiety contains one to four carbon
atoms and the alkyl moiety contains one to four carbon atoms,
haloalkyl of one to four carbon atoms, alkylamido wherein the alkyl
group contains one to four carbon atoms, amino, substituted amino
wherein the substituent is alkyl or hydroxyalkyl of one to four
carbon atoms, azido, alkylthio of one to four carbon atoms, and
morpholinoalkyl wherein the alkyl moiety contains one to four
carbon atoms, and
[0053] R.sub.6 is chosen from hydrogen, fluoro, chloro, straight
chain or branched chain alkyl containing one to four carbon atoms,
and straight chain or branched chain fluoro- or chloroalkyl
containing one to four carbon atoms and at least one fluorine or
chlorine atom; and pharmaceutically acceptable salts thereof.
[0054] In other embodiments of the present invention, the IRM
compound can be chosen from imidazopyridine amines defined by
Formula VII below: 8
[0055] wherein
[0056] R.sub.17 is chosen from hydrogen; --CH.sub.2R.sub.W wherein
R.sub.W is chosen from straight chain, branched chain, or cyclic
alkyl containing one to ten carbon atoms, straight chain or
branched chain alkenyl containing two to ten carbon atoms, straight
chain or branched chain hydroxyalkyl containing one to six carbon
atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four
carbon atoms and the alkyl moiety contains one to six carbon atoms,
and phenylethyl; and --CH.dbd.CR.sub.ZR.sub.Z wherein each R.sub.Z
is independently straight chain, branched chain, or cyclic alkyl of
one to six carbon atoms;
[0057] R.sub.27 is chosen from hydrogen; straight chain or branched
chain alkyl containing one to eight carbon atoms; straight chain or
branched chain hydroxyalkyl containing one to six carbon atoms;
alkoxyalkyl wherein the alkoxy moiety contains one to four carbon
atoms and the alkyl moiety contains one to six carbon atoms;
benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl oand
phenyl being optionally substituted on the benzene ring by a moiety
chosen from methyl, methoxy, and halogen; and morpholinoalkyl
wherein the alkyl moiety contains one to four carbon atoms;
[0058] R.sub.67 and R.sub.77 are independently chosen from hydrogen
and alkyl of one to five carbon atoms, with the proviso that
R.sub.67 and R.sub.77 taken together contain no more than six
carbon atoms, and with the further proviso that when R.sub.77 is
hydrogen then R.sub.67 is other than hydrogen and R.sub.27 is other
than hydrogen or morpholinoalkyl, and with the further proviso that
when R.sub.67 is hydrogen then R.sub.77 and R.sub.27 are other than
hydrogen;
[0059] and pharmaceutically acceptable salts thereof.
[0060] In yet another embodiment of the present invention, the IRM
compound can be chosen from 1,2-bridged imidazoquinoline amines
defined by Formula VIII below: 9
[0061] wherein
[0062] Z is chosen from:
[0063] --(CH.sub.2).sub.p-- wherein p is 1 to 4;
[0064] --(CH.sub.2).sub.a--C(R.sub.DR.sub.E)(CH.sub.2).sub.b--,
wherein a and b are integers and a+b is 0 to 3, R.sub.D is hydrogen
or alkyl of one to four carbon atoms, and R.sub.E is chosen from
alkyl of one to four carbon atoms, hydroxy, --OR.sub.F wherein
R.sub.F is alkyl of one to four carbon atoms, and
--NR.sub.GR'.sub.G wherein R.sub.G and R'.sub.G are independently
hydrogen or alkyl of one to four carbon atoms; and
[0065] --(CH.sub.2).sub.a--(Y)--(CH.sub.2).sub.b-- wherein a and b
are integers and a+b is 0 to 3, and Y is O, S, or --NR.sub.J--
wherein R.sub.J is hydrogen or alkyl of one to four carbon
atoms;
[0066] and wherein q is 0 or 1 and R.sub.8 is chosen from alkyl of
one to four carbon atoms, alkoxy of one to four carbon atoms, and
halogen,
[0067] and pharmaceutically acceptable salts thereof.
[0068] In a further embodiment, the IRM compound can be chosen from
thiazoloquinoline amines, oxazoloquinoline amines,
thiazolonaphthyridine amines, thiazolopyridine amines, and
oxazolopyridine amines of Formula IX: 10
[0069] wherein:
[0070] R.sub.19 is chosen from oxygen, sulfur and selenium;
[0071] R.sub.29 is chosen from
[0072] -hydrogen;
[0073] -alkyl;
[0074] -alkyl-OH;
[0075] -haloalkyl;
[0076] -alkenyl;
[0077] -alkyl-X-alkyl;
[0078] -alkyl-X-alkenyl;
[0079] -alkenyl-X-alkyl;
[0080] -alkenyl-X-alkenyl;
[0081] -alkyl-N(R.sub.59).sub.2;
[0082] -alkyl-N.sub.3;
[0083] -alkyl-O--C(O)--N(R.sub.59).sub.2;
[0084] -heterocyclyl;
[0085] -alkyl-X-heterocyclyl;
[0086] -alkenyl-X-heterocyclyl;
[0087] -aryl;
[0088] -alkyl-X-aryl;
[0089] -alkenyl-X-aryl;
[0090] -heteroaryl;
[0091] -alkyl-X-heteroaryl; and
[0092] -alkenyl-X-heteroaryl;
[0093] R.sub.39 and R.sub.49 are each independently:
[0094] -hydrogen;
[0095] --X-alkyl;
[0096] -halo;
[0097] -haloalkyl;
[0098] --N(R.sub.59).sub.2;
[0099] or when taken together, R.sub.39 and R.sub.49 form a fused
aromatic, heteroaromatic, cycloalkyl or heterocyclic ring;
[0100] X is chosen from --O--, --S--, --NR.sub.59--, --C(O)--,
--C(O)O--, --OC(O)--, and a bond; and
[0101] each R.sub.59 is independently H or C.sub.1-8alkyl;
[0102] and pharmaceutically acceptable salts thereof.
[0103] In another embodiment, the IRM compound can be chosen from
imidazonaphthyridine amines and imidazotetrahydronaphthyridine
amines of Formulae X and XI below: 11
[0104] wherein
[0105] A is .dbd.N--CR.dbd.CR--CR.dbd.; .dbd.CR--N.dbd.CR--CR--;
.dbd.CR--CR.dbd.N--CR.dbd.; or .dbd.CR--CR.dbd.CR--N.dbd.;
[0106] R.sub.110 is chosen from:
[0107] -hydrogen;
[0108] --C.sub.1-20alkyl or C.sub.2-20alkenyl that is unsubstituted
or substituted by one or more substituents chosen from:
[0109] -aryl;
[0110] -heteroaryl;
[0111] -heterocyclyl;
[0112] --O--C.sub.1-20alkyl,
[0113] --O--(C.sub.1-20alkyl).sub.0-1-aryl;
[0114] --O--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0115] --O--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0116] --CO--O--C.sub.1-20alkyl;
[0117] --S(O).sub.0-2--C.sub.1-20alkyl;
[0118] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-aryl;
[0119] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0120] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0121] --N(R.sub.310).sub.2;
[0122] --N.sub.3;
[0123] oxo;
[0124] -halogen;
[0125] --NO.sub.2;
[0126] --OH; and
[0127] --SH; and
[0128] --C.sub.1-20alkyl-NR.sub.310-Q-X--R.sub.410 or
--C.sub.2-20alkenyl-NR.sub.310-Q-X--R.sub.410 wherein Q is --CO--
or --SO.sub.2--; X is a bond, --O-- or --NR.sub.310-- and R.sub.410
is aryl; heteroaryl; heterocyclyl; or --C.sub.1-20 alkyl or
C.sub.2-20alkenyl that is unsubstituted or substituted by one or
more substituents chosen from:
[0129] -aryl;
[0130] -heteroaryl;
[0131] -heterocyclyl;
[0132] --O--C.sub.1-20alkyl,
[0133] --O--(C.sub.1-20alkyl).sub.0-1-aryl;
[0134] --O--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0135] --O--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0136] --CO--O--C.sub.1-20alkyl;
[0137] --S(O).sub.0-2--C.sub.1-20alkyl;
[0138] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-aryl;
[0139] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0140] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0141] --N(R.sub.310).sub.2;
[0142] --NR.sub.310--CO--O--C.sub.1-20alkyl;
[0143] --N.sub.3;
[0144] oxo;
[0145] -halogen;
[0146] --NO.sub.2;
[0147] --OH; and
[0148] --SH; or R.sub.410 is 12
[0149] wherein Y is --N-- or --CR--;
[0150] R.sub.210 is chosen from:
[0151] -hydrogen;
[0152] --C.sub.1-10alkyl;
[0153] --C.sub.2-10alkenyl;
[0154] -aryl;
[0155] --C.sub.1-10alkyl-O--C.sub.1-10alkyl;
[0156] --C.sub.1-10alkyl-O--C.sub.2-10alkenyl; and
[0157] --C.sub.1-10alkyl or C.sub.2-10alkenyl substituted by one or
more substituents chosen from:
[0158] --OH;
[0159] -halogen;
[0160] --N(R.sub.310).sub.2;
[0161] --CO--N(R.sub.310).sub.2;
[0162] --CO--C.sub.1-10alkyl;
[0163] --N.sub.3;
[0164] -aryl;
[0165] -heteroaryl;
[0166] -heterocyclyl;
[0167] --CO-aryl; and
[0168] --CO-heteroaryl;
[0169] each R.sub.310 is independently chosen from hydrogen and
C.sub.1-10alkyl; and
[0170] each R is independently chosen from hydrogen,
C.sub.1-10alkyl, C.sub.1-10alkoxy, halogen and trifluoromethyl,
[0171] and pharmaceutically acceptable salts thereof; 13
[0172] wherein
[0173] B is --NR--C(R).sub.2--C(R).sub.2--C(R).sub.2--;
--C(R).sub.2--NR--C(R).sub.2--C(R).sub.2--;
--C(R).sub.2--C(R).sub.2--NR-- -C(R).sub.2-- or
--C(R).sub.2--C(R).sub.2--C(R).sub.2--NR--;
[0174] R.sub.111 is chosen from:
[0175] -hydrogen;
[0176] --C.sub.1-20alkyl or C.sub.2-20alkenyl that is unsubstituted
or substituted by one or more substituents chosen from:
[0177] -aryl;
[0178] -heteroaryl;
[0179] -heterocyclyl;
[0180] --O--C.sub.1-20alkyl;
[0181] --O--(C.sub.1-20alkyl).sub.0-1-aryl;
[0182] --O--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0183] --O--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0184] --CO--O--C.sub.1-20alkyl;
[0185] --S(O).sub.0-2--C.sub.1-20alkyl;
[0186] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-aryl;
[0187] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0188] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0189] --N(R.sub.311).sub.2;
[0190] --N.sub.3;
[0191] oxo;
[0192] -halogen;
[0193] --NO.sub.2;
[0194] --OH; and
[0195] --SH; and
[0196] --C.sub.1-20alkyl-NR.sub.311-Q-X--R.sub.411 or
--C.sub.2-20alkenyl-NR.sub.311-Q-X--R.sub.411 wherein Q is --CO--
or --SO.sub.2--; X is a bond, --O-- or --NR.sub.311-- and R.sub.411
is aryl; heteroaryl; heterocyclyl; or --C.sub.1-20alkyl or
C.sub.2-20alkenyl that is unsubstituted or substituted by one or
more substituents chosen from:
[0197] -aryl;
[0198] -heteroaryl;
[0199] -heterocycyl;
[0200] --O--C.sub.1-20alkyl,
[0201] --O--(C.sub.1-20alkyl).sub.0-1-aryl;
[0202] --O--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0203] --O--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0204] --CO--O--C.sub.1-20alkyl;
[0205] --S(O).sub.0-2--C.sub.1-20alkyl;
[0206] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-aryl;
[0207] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0208] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0209] --N(R.sub.311).sub.2;
[0210] --NR.sub.311--CO--O--C.sub.1-20alkyl;
[0211] --N.sub.3;
[0212] oxo;
[0213] -halogen;
[0214] --NO.sub.2;
[0215] --OH; and
[0216] --SH; or R.sub.411 is 14
[0217] wherein Y is --N-- or --CR--;
[0218] R.sub.211 is chosen from:
[0219] -hydrogen;
[0220] --C.sub.1-10alkyl;
[0221] --C.sub.2-10alkenyl;
[0222] -aryl
[0223] --C.sub.1-10alkyl --O--C.sub.1-10-alkyl;
[0224] --C.sub.1-10alkyl-O--C.sub.2-10alkenyl; and
[0225] --C.sub.1-10alkyl or C.sub.2-10alkenyl substituted by one or
more substituents chosen from:
[0226] -OH;
[0227] -halogen;
[0228] --N(R.sub.311).sub.2;
[0229] --CO--N(R.sub.311).sub.2;
[0230] --CO--C.sub.1-10alkyl;
[0231] --N.sub.3;
[0232] -aryl;
[0233] -heteroaryl;
[0234] -heterocyclyl;
[0235] --CO-aryl; and
[0236] --CO-heteroaryl;
[0237] each R.sub.311 is independently chosen from hydrogen and
C.sub.1-10alkyl; and
[0238] each R is independently chosen from hydrogen,
C.sub.1-10alkyl, C.sub.1-10alkoxy, halogen and trifluoromethyl,
[0239] and pharmaceutically acceptable salts thereof.
[0240] In a further embodiment, the IRM compound can be chosen from
imidazoquinoline amines and imidazotetrahydroquinoline amines, for
example, 1H-imidazo[4,5-c]quinolin-4-amines and
tetrahydro-1H-imidazo[4,5- -c]quinolin-4-amines defined by Formulas
XII, XIII and XIV below: 15
[0241] wherein
[0242] R.sub.112 is -alkyl-NR.sub.312--CO--R.sub.412 or
-alkenyl-NR.sub.312--CO--R.sub.412 wherein R.sub.412 is aryl,
heteroaryl, alkyl or alkenyl, each of which may be unsubstituted or
substituted by one or more substituents chosen from:
[0243] -alkyl;
[0244] -alkenyl;
[0245] -alkynyl;
[0246] -(alkyl).sub.0-1-aryl;
[0247] -(alkyl).sub.0-1-(substituted aryl);
[0248] -(alkyl).sub.0-1-heteroaryl;
[0249] --(alkyl).sub.0-1-(substituted heteroaryl);
[0250] --O-alkyl;
[0251] --O-(alkyl).sub.0-1-aryl;
[0252] --O-(alkyl).sub.0-1-(substituted aryl);
[0253] --O-(alkyl).sub.0-1-heteroaryl;
[0254] --O-(alkyl).sub.0-1-(substituted heteroaryl);
[0255] --CO-aryl;
[0256] --CO-(substituted aryl);
[0257] --CO-heteroaryl;
[0258] --CO-(substituted heteroaryl);
[0259] --COOH;
[0260] --CO--O-alkyl;
[0261] --CO-alkyl;
[0262] --S(O).sub.0-2-alkyl;
[0263] --S(O).sub.0-2-(alkyl).sub.0-1-aryl;
[0264] --S(O).sub.0-2-(alkyl).sub.0-1-(substituted aryl);
[0265] --S(O).sub.0-2-(alkyl).sub.0-1-heteroaryl;
[0266] --S(O).sub.0-2-(alkyl).sub.0-1-(substituted heteroaryl);
[0267] --P(O)(OR.sub.312).sub.2;
[0268] --NR.sub.312--CO--O-alkyl;
[0269] --N.sub.3;
[0270] -halogen;
[0271] --NO.sub.2;
[0272] --CN;
[0273] -haloalkyl;
[0274] --O-haloalkyl;
[0275] --CO-haloalkyl;
[0276] --OH;
[0277] --SH; and in the case of alkyl, alkenyl, or heterocyclyl,
oxo;
[0278] or R.sub.412 is 16
[0279] wherein R.sub.512 is an aryl, (substituted aryl),
heteroaryl, (substituted heteroaryl), heterocyclyl or (substituted
heterocyclyl) group;
[0280] R.sub.212 is chosen from:
[0281] -hydrogen;
[0282] -alkyl;
[0283] -alkenyl;
[0284] -aryl;
[0285] -(substituted aryl);
[0286] -heteroaryl;
[0287] -(substituted heteroaryl);
[0288] -heterocyclyl;
[0289] -(substituted heterocyclyl);
[0290] -alkyl-O-alkyl;
[0291] -alkyl-O-alkenyl; and
[0292] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0293] --OH;
[0294] -halogen;
[0295] --N(R.sub.312).sub.2;
[0296] --CO--N(R.sub.312).sub.2;
[0297] --CO--C.sub.1-10alkyl;
[0298] --CO--O--C.sub.1-10alkyl;
[0299] --N.sub.3;
[0300] -aryl;
[0301] -(substituted aryl);
[0302] -heteroaryl;
[0303] -(substituted heteroaryl);
[0304] -heterocyclyl;
[0305] -(substituted heterocyclyl);
[0306] --CO-aryl; and
[0307] --CO-heteroaryl;
[0308] each R.sub.312 is independently chosen from hydrogen;
C.sub.1-10alkyl-heteroaryl; C.sub.1-10alkyl-(substituted
heteroaryl); C.sub.1-10alkyl-aryl; C.sub.1-10alkyl-(substituted
aryl) and C.sub.1-10alkyl;
[0309] v is 0 to 4;
[0310] and each R.sub.12 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, halogen and trifluoromethyl;
17
[0311] wherein
[0312] R.sub.113 is -alkyl-NR.sub.313--SO.sub.2--X--R.sub.413 or
-alkenyl-NR.sub.313--SO.sub.2--X--R.sub.413;
[0313] X is a bond or --NR.sub.513--;
[0314] R.sub.413 is aryl, heteroaryl, heterocyclyl, alkyl or
alkenyl, each of which may be unsubstituted or substituted by one
or more substituents chosen from:
[0315] -alkyl;
[0316] -alkenyl;
[0317] -aryl;
[0318] -heteroaryl;
[0319] -heterocyclyl;
[0320] -substituted cycloalkyl;
[0321] -substituted aryl;
[0322] -substituted heteroaryl;
[0323] -substituted heterocyclyl;
[0324] --O-alkyl;
[0325] --O-(alkyl).sub.0-1-aryl;
[0326] --O-(alkyl).sub.0-1-substituted aryl;
[0327] --O-(alkyl).sub.0-1-heteroaryl;
[0328] --O-(alkyl).sub.0-1-substituted heteroaryl;
[0329] --O-(alkyl).sub.0-1-heterocyclyl;
[0330] --O-(alkyl).sub.0-1-substituted heterocyclyl;
[0331] --COOH;
[0332] --CO--O-alkyl;
[0333] --CO-alkyl;
[0334] --S(O).sub.0-2-alkyl;
[0335] --S(O).sub.0-2-(alkyl).sub.0-1-aryl;
[0336] --S(O).sub.0-2-(alkyl).sub.0-1-substituted aryl;
[0337] --S(O).sub.0-2-(alkyl).sub.0-1-heteroaryl;
[0338] --S(O).sub.0-2-(alkyl).sub.0-1-substituted heteroaryl;
[0339] --S(O).sub.0-2-(alkyl).sub.0-1-heterocyclyl;
[0340] --S(O).sub.0-2-(alkyl).sub.0-1-substituted heterocyclyl;
[0341] -(alkyl).sub.0-1-NR.sub.313R.sub.313;
[0342] -(alkyl).sub.0-1-NR.sub.313--CO--O-alkyl;
[0343] -(alkyl).sub.0-1-NR.sub.313--CO-alkyl;
[0344] -(alkyl).sub.0-1-NR.sub.313--CO-aryl;
[0345] -(alkyl).sub.0-1-NR.sub.313--CO-substituted aryl;
[0346] -(alkyl).sub.0-1-NR.sub.313--CO-heteroaryl;
[0347] -(alkyl).sub.0-1-NR.sub.313--CO-substituted heteroaryl;
[0348] --N.sub.3;
[0349] -halogen;
[0350] -haloalkyl;
[0351] -haloalkoxy;
[0352] --CO-haloalkyl;
[0353] --CO-haloalkoxy;
[0354] --NO.sub.2;
[0355] --CN;
[0356] --OH;
[0357] --SH; and in the case that R.sub.413 is alkyl, alkenyl, or
heterocyclyl, oxo;
[0358] R.sub.213 is chosen from:
[0359] -hydrogen;
[0360] -alkyl;
[0361] -alkenyl;
[0362] -aryl;
[0363] -substituted aryl;
[0364] -heteroaryl;
[0365] -substituted heteroaryl;
[0366] -alkyl-O-alkyl;
[0367] -alkyl-O-alkenyl; and
[0368] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0369] --OH;
[0370] -halogen;
[0371] --N(R.sub.313).sub.2;
[0372] --CO--N(R.sub.313).sub.2;
[0373] --CO--C.sub.1-10alkyl;
[0374] --CO--O--C.sub.1-10alkyl;
[0375] --N.sub.3;
[0376] -aryl;
[0377] -substituted aryl;
[0378] -heteroaryl;
[0379] -substituted heteroaryl;
[0380] -heterocyclyl;
[0381] -substituted heterocyclyl;
[0382] --CO-aryl;
[0383] --CO-(substituted aryl);
[0384] -CO-heteroaryl; and
[0385] -CO-(substituted heteroaryl);
[0386] each R.sub.313 is independently chosen from hydrogen,
C.sub.1-10alkyl, and when X is a bond R.sub.313 and R.sub.413 can
combine to form a 3 to 7 membered heterocyclic or substituted
heterocyclic ring;
[0387] R.sub.513 is chosen from hydrogen, C.sub.1-10alkyl, and
R.sub.413 and R.sub.513 can combine to form a 3 to 7 membered
heterocyclic or substituted heterocyclic ring;
[0388] v is 0 to 4 and each R.sub.13 present is independently
chosen from C.sub.1-10alkyl, C.sub.1-10alkoxy, halogen and
trifluoromethyl; 18
[0389] wherein
[0390] R.sub.114 is -alkyl-NR.sub.314--CY--NR.sub.514--X--R.sub.414
or -alkenyl-NR.sub.314--CY--NR.sub.514--X--R.sub.414
[0391] wherein
[0392] Y is .dbd.O or .dbd.S;
[0393] X is a bond, --CO-- or --SO.sub.2--;
[0394] R.sub.414 is aryl, heteroaryl, heterocyclyl, alkyl or
alkenyl, each of which may be unsubstituted or substituted by one
or more substituents chosen from:
[0395] -alkyl;
[0396] -alkenyl;
[0397] -aryl;
[0398] -heteroaryl;
[0399] -heterocyclyl;
[0400] -substituted aryl;
[0401] -substituted heteroaryl;
[0402] -substituted heterocycyl;
[0403] --O-alkyl;
[0404] --O-(alkyl).sub.0-1-aryl;
[0405] --O-(alkyl).sub.0-1-substituted aryl;
[0406] --O-(alkyl).sub.0-1-heteroaryl;
[0407] --O-(alkyl).sub.0-1-substituted heteroaryl;
[0408] --O-(alkyl).sub.0-1-heterocyclyl;
[0409] --O-(alkyl).sub.0-1-substituted heterocyclyl;
[0410] --COOH;
[0411] --CO--O-alkyl;
[0412] --CO-alkyl;
[0413] --S(O).sub.0-2-alkyl;
[0414] --S(O).sub.0-2-(alkyl).sub.0-1-aryl;
[0415] --S(O).sub.0-2-(alkyl).sub.0-1-substituted aryl;
[0416] --S(O).sub.0-2-(alkyl).sub.0-1-heteroaryl;
[0417] --S(O).sub.0-2-(alkyl).sub.0-1-substituted heteroaryl;
[0418] --S(O).sub.0-2-(alkyl).sub.0-1-heterocyclyl;
[0419] --S(O).sub.0-2-(alkyl).sub.0-1-substituted heterocyclyl;
[0420] -(alkyl).sub.0-1-NR.sub.314R.sub.314;
[0421] -(alkyl).sub.0-1-NR.sub.314--CO--O-alkyl;
[0422] -(alkyl).sub.0-1-NR.sub.314--CO-alkyl;
[0423] -(alkyl).sub.0-1-NR.sub.314--CO-aryl;
[0424] -(alkyl).sub.0-1-NR.sub.314--CO-substituted aryl;
[0425] -(alkyl).sub.0-1-NR.sub.314--CO-heteroaryl;
[0426] -(alkyl).sub.0-1-NR.sub.314--CO-substituted heteroaryl;
[0427] --N.sub.3;
[0428] -halogen;
[0429] -haloalkyl;
[0430] -haloalkoxy;
[0431] --CO-haloalkoxy;
[0432] --NO.sub.2;
[0433] --CN;
[0434] --OH;
[0435] --SH; and, in the case that R.sub.414 is alkyl, alkenyl or
heterocyclyl, oxo; with the proviso that when X is a bond R.sub.414
can additionally be hydrogen;
[0436] R.sub.214 is chosen from:
[0437] -hydrogen;
[0438] -alkyl;
[0439] -alkenyl;
[0440] -aryl;
[0441] -substituted aryl;
[0442] -heteroaryl;
[0443] -substituted heteroaryl;
[0444] -alkyl-O-alkyl;
[0445] -alkyl-O-alkenyl; and
[0446] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0447] --OH;
[0448] -halogen;
[0449] --N(R.sub.314).sub.2;
[0450] --CO--N(R.sub.314).sub.2;
[0451] --CO--C.sub.1-10alkyl;
[0452] --CO--O--C.sub.1-10alkyl;
[0453] --N.sub.3;
[0454] -aryl;
[0455] -substituted aryl;
[0456] -heteroaryl;
[0457] -substituted heteroaryl;
[0458] -heterocyclyl;
[0459] -substituted heterocyclyl;
[0460] --CO-aryl;
[0461] --CO-(substituted aryl);
[0462] --CO-heteroaryl; and
[0463] --CO-(substituted heteroaryl);
[0464] each R.sub.314 is independently chosen from hydrogen and
C.sub.1-10alkyl;
[0465] R.sub.514 is chosen from hydrogen, C.sub.1-10alkyl, and
R.sub.414 and R.sub.514 can combine to form a 3 to 7 membered
heterocyclic or substituted heterocyclic ring;
[0466] v is 0 to 4 and each R.sub.14 present is independently
chosen from C.sub.1-10alkyl, C.sub.1-10alkoxy, halogen and
trifluoromethyl,
[0467] and pharmaceutically acceptable salts thereof.
[0468] In yet another embodiment, the IRM compound can be chosen
from imidazoquinoline amines and imidazotetrahydroquinoline amines,
for example, 1H-imidazo[4,5-c]quinolin-4-amines and
tetrahydro-1H-imidazo[4,5- -c]quinolin-4-amines defined by Formulas
XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, and
XXVI below 19
[0469] wherein:
[0470] X is --CHR.sub.515--, --CHR.sub.515-alkyl-, or
--CHR.sub.515-alkenyl-;
[0471] R.sub.115 is chosen from:
[0472] --R.sub.415--CR.sub.315-Z-R.sub.615-alkyl;
[0473] --R.sub.415--CR.sub.315-Z-R.sub.615-alkenyl;
[0474] --R.sub.415--CR.sub.315-Z-R.sub.615-aryl;
[0475] --R.sub.415--CR.sub.315-Z-R.sub.615-heteroaryl;
[0476] --R.sub.415--CR.sub.315-Z-R.sub.615-heterocyclyl;
[0477] --R.sub.415--CR.sub.315-Z-H;
[0478] --R.sub.415--NR.sub.715--CR.sub.315--R.sub.615-alkyl;
[0479] --R.sub.415--NR.sub.715--CR.sub.315--R.sub.615-alkenyl;
[0480] --R.sub.415--NR.sub.715--CR.sub.315--R.sub.615-aryl;
[0481]
--R.sub.415--NR.sub.715--CR.sub.315--R.sub.615-heteroaryl;
[0482] --R.sub.415--NR.sub.715--CR.sub.315--R.sub.615-heterocyclyl;
and
[0483] --R.sub.415--NR.sub.715--CR.sub.315--R.sub.815;
[0484] Z is --NR.sub.515--, --O--, or --S--;
[0485] R.sub.215 is chosen from:
[0486] -hydrogen;
[0487] -alkyl;
[0488] -alkenyl;
[0489] -aryl;
[0490] -heteroaryl;
[0491] -heterocyclyl;
[0492] -alkyl-Y-alkyl;
[0493] -alkyl-Y- alkenyl;
[0494] -alkyl-Y-aryl; and
[0495] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of:
[0496] --OH;
[0497] -halogen;
[0498] --N(R.sub.515).sub.2;
[0499] --CO--N(R.sub.515).sub.2;
[0500] --CO--C.sub.1-10alkyl;
[0501] --CO--O--C.sub.1-10alkyl;
[0502] --N.sub.3;
[0503] -aryl;
[0504] -heteroaryl;
[0505] -heterocyclyl;
[0506] --CO-aryl; and
[0507] --CO-heteroaryl;
[0508] R.sub.315 is .dbd.O or .dbd.S;
[0509] R.sub.415 is alkyl or alkenyl, which may be interrupted by
one or more --O-- groups;
[0510] each R.sub.515 is independently H or C.sub.1-10alkyl;
[0511] R.sub.615 is a bond, alkyl, or alkenyl, which may be
interrupted by one or more --O-- groups;
[0512] R.sub.715 is H, C.sub.1-10alkyl, arylalkyl, or R.sub.415 and
R.sub.715 can join together to form a 5 to 7 membered heterocylcic
ring;
[0513] R.sub.815 is H, C.sub.1-10alkyl, or R.sub.715 and R.sub.815
can join together to form a 5 to 7 membered heterocyclic ring;
[0514] Y is --O-- or --S(O).sub.0-2--;
[0515] v is 0 to 4; and
[0516] each R.sub.15 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, hydroxy, halogen and
trifluoromethyl; 20
[0517] wherein:
[0518] X is --CHR.sub.516--, --CHR.sub.516-alkyl-, or
--CHR.sub.516-alkenyl-;
[0519] R.sub.116 is chosen from:
[0520] --R.sub.416--CR.sub.316-Z-R.sub.616-alkyl;
[0521] --R.sub.416--CR.sub.316-Z-R.sub.616-alkenyl;
[0522] --R.sub.416--CR.sub.316-Z-R.sub.616-aryl;
[0523] --R.sub.416--CR.sub.316-Z-R.sub.616-heteroaryl;
[0524] --R.sub.416--CR.sub.316-Z-R.sub.616-heterocyclyl;
[0525] --R.sub.416--CR.sub.316-Z-H;
[0526] --R.sub.416--NR.sub.716--CR.sub.316--R.sub.616-alkyl;
[0527] --R.sub.416--NR.sub.716--CR.sub.316--R.sub.616-alkenyl;
[0528] --R.sub.416--NR.sub.716--CR.sub.316--R.sub.616-aryl;
[0529]
--R.sub.416--NR.sub.716--CR.sub.316--R.sub.616-heteroaryl;
[0530] --R.sub.416--NR.sub.716--CR.sub.316--R.sub.616-heterocyclyl;
and
[0531] --R.sub.416--NR.sub.716--CR.sub.316--R.sub.816;
[0532] Z is --NR.sub.516--, --O--, or --S--;
[0533] R.sub.216 is chosen from:
[0534] -hydrogen;
[0535] -alkyl;
[0536] -alkenyl;
[0537] -aryl;
[0538] -heteroaryl;
[0539] -heterocyclyl;
[0540] -alkyl-Y-alkyl;
[0541] -alkyl-Y-alkenyl;
[0542] -alkyl-Y-aryl; and
[0543] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0544] --OH;
[0545] -halogen;
[0546] --N(R.sub.516).sub.2;
[0547] --CO--N(R.sub.516).sub.2;
[0548] --CO--C.sub.1-10alkyl;
[0549] --CO--O--C.sub.1-10alkyl;
[0550] --N.sub.3;
[0551] -aryl;
[0552] -heteroaryl;
[0553] -heterocyclyl;
[0554] --CO-aryl; and
[0555] --CO-heteroaryl;
[0556] R.sub.316 is .dbd.O or .dbd.S;
[0557] R.sub.416 is alkyl or alkenyl, which may be interrupted by
one or more --O-- groups;
[0558] each R.sub.516 is independently H or C.sub.1-10alkyl;
[0559] R.sub.616 is a bond, alkyl, or alkenyl, which may be
interrupted by one or more --O-- groups;
[0560] R.sub.716 is H, C.sub.1-10alkyl, arylalkyl, or R.sub.416 and
R.sub.716 can join together to form a 5 to 7 membered hetercyclic
ring;
[0561] R.sub.816 is H or C.sub.1-10alkyl; or R.sub.716 and
R.sub.816 can join together to form a 5 to 7 membered heterocyclic
ring;
[0562] Y is --O-- or --S(O).sub.0-2--;
[0563] v is 0 to 4; and
[0564] each R.sub.16 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, hydroxy, halogen, and
trifluoromethyl; 21
[0565] wherein:
[0566] X is --CHR.sub.317--, --CHR.sub.317-alkyl-, or
--CHR.sub.317-alkenyl-;
[0567] R.sub.117 is chosen from:
[0568] -alkenyl;
[0569] -aryl; and
[0570] --R.sub.417-aryl;
[0571] R.sub.217 is chosen from:
[0572] -hydrogen;
[0573] -alkyl;
[0574] -alkenyl;
[0575] -aryl;
[0576] -heteroaryl;
[0577] -heterocyclyl;
[0578] -alkyl-Y-alkyl;
[0579] -alkyl-Y-alkenyl;
[0580] -alkyl-Y-aryl; and
[0581] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0582] --OH;
[0583] -halogen;
[0584] --N(R.sub.317).sub.2;
[0585] --CO--N(R.sub.317).sub.2;
[0586] --CO--C.sub.1-10alkyl;
[0587] --CO--O--C.sub.1-10alkyl;
[0588] --N.sub.3;
[0589] -aryl;
[0590] -heteroaryl;
[0591] -heterocyclyl;
[0592] --CO-aryl; and
[0593] --CO-heteroaryl;
[0594] R.sub.417 is alkyl or alkenyl, which may be interrupted by
one or more --O-- groups;
[0595] each R.sub.317 is independently H or C.sub.1-10alkyl;
[0596] each Y is independently --O-- or --S(O).sub.0-2--;
[0597] v is 0 to 4; and
[0598] each R.sub.17 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, hydroxy, halogen and
trifluoromethyl; 22
[0599] wherein:
[0600] X is --CHR.sub.318--, --CHR.sub.318-alkyl-, or
--CHR.sub.318-alkenyl-;
[0601] R.sub.118 is chosen from:
[0602] -aryl;
[0603] -alkenyl; and
[0604] --R.sub.418-aryl;
[0605] R.sub.218 is chosen from:
[0606] -hydrogen;
[0607] -alkyl;
[0608] -alkenyl;
[0609] -aryl;
[0610] -heteroaryl;
[0611] -heterocyclyl;
[0612] -alkyl-Y-alkyl;
[0613] -alkyl-Y-aryl;
[0614] -alkyl-Y-alkenyl; and
[0615] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0616] --OH;
[0617] -halogen;
[0618] --N(R.sub.318).sub.2;
[0619] --CO--N(R.sub.318).sub.2;
[0620] --CO--C.sub.1-10alkyl;
[0621] --CO--O--C.sub.1-10alkyl;
[0622] --N.sub.3;
[0623] -aryl;
[0624] -heteroaryl;
[0625] -heterocyclyl;
[0626] --CO-aryl; and
[0627] --CO-heteroaryl;
[0628] R.sub.418 is alkyl or alkenyl, which may be interrupted by
one or more --O-- groups;
[0629] each R.sub.318 is independently H or C.sub.1-10alkyl;
[0630] each Y is independently --O-- or --S(O).sub.0-2--;
[0631] v is 0 to 4; and
[0632] each R.sub.18 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, hydroxy, halogen and
trifluoromethyl; 23
[0633] wherein:
[0634] X is --CHR.sub.319--, --CHR.sub.319-alkyl-, or
--CHR.sub.319-alkenyl-;
[0635] R.sub.119 is chosen from:
[0636] -heteroaryl;
[0637] -heterocyclyl;
[0638] --R.sub.419-heteroaryl; and
[0639] --R.sub.419-heterocyclyl;
[0640] R.sub.219 is chosen from:
[0641] -hydrogen;
[0642] -alkyl;
[0643] -alkenyl;
[0644] -aryl;
[0645] -heteroaryl;
[0646] -heterocyclyl;
[0647] -alkyl-Y-alkyl;
[0648] -alkyl-Y- alkenyl;
[0649] -alkyl-Y-aryl; and
[0650] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0651] --OH;
[0652] -halogen;
[0653] --N(R.sub.319).sub.2;
[0654] --CO--N(R.sub.319).sub.2;
[0655] --CO--C.sub.1-10alkyl;
[0656] --CO--O--C.sub.1-10alkyl;
[0657] --N.sub.3;
[0658] -aryl;
[0659] -heteroaryl;
[0660] -heterocyclyl;
[0661] --CO-aryl; and
[0662] --CO-heteroaryl;
[0663] R.sub.419 is alkyl or alkenyl, which may be interrupted by
one or more --O-- groups;
[0664] each R.sub.319 is independently H or C.sub.1-10alkyl;
[0665] each Y is independently --O-- or --S(O).sub.0-2--;
[0666] v is 0 to 4; and
[0667] each R.sub.19 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, hydroxy, halogen and
trifluoromethyl; 24
[0668] wherein:
[0669] X is --CHR.sub.320--, --CHR.sub.320-alkyl-, or
--CHR.sub.320-alkenyl-;
[0670] R.sub.120 is chosen from:
[0671] -heteroaryl;
[0672] -heterocyclyl;
[0673] --R.sub.420-heteroaryl; and
[0674] --R.sub.420-heterocyclyl;
[0675] R.sub.220 is chosen from:
[0676] -hydrogen;
[0677] -alkyl;
[0678] -alkenyl;
[0679] -aryl;
[0680] -heteroaryl;
[0681] -heterocyclyl;
[0682] -alkyl-Y-alkyl;
[0683] -alkyl-Y- alkenyl;
[0684] -alkyl-Y-aryl; and
[0685] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0686] --OH;
[0687] -halogen;
[0688] --N(R.sub.320).sub.2;
[0689] --CO--N(R.sub.320).sub.2;
[0690] --CO--C.sub.1-10alkyl;
[0691] --CO--O--C.sub.1-10alkyl;
[0692] --N.sub.3;
[0693] -aryl;
[0694] -heteroaryl;
[0695] -heterocyclyl;
[0696] --CO-aryl; and
[0697] --CO-heteroaryl;
[0698] R.sub.420 is alkyl or alkenyl, which may be interrupted by
one or more --O-- groups;
[0699] each R.sub.320 is independently H or C.sub.1-10alkyl;
[0700] each Y is independently --O-- or --S(O).sub.0-2--;
[0701] v is 0 to 4; and
[0702] each R.sub.20 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, hydroxy, halogen and
trifluoromethyl; 25
[0703] wherein:
[0704] X is --CHR.sub.521--, --CHR.sub.521-alkyl-, or
--CHR.sub.521-alkenyl-;
[0705] R.sub.121 is chosen from:
[0706] --R.sub.421--NR.sub.321--SO.sub.2--R.sub.621-alkyl;
[0707] --R.sub.421--NR.sub.321--SO.sub.2--R.sub.621-alkenyl;
[0708] --R.sub.421--NR.sub.321--SO.sub.2--R.sub.621-aryl;
[0709] --R.sub.421--NR.sub.321--SO.sub.2--R.sub.621-heteroaryl;
[0710]
--R.sub.421--NR.sub.321--SO.sub.2--R.sub.621-heterocyclyl;
[0711] --R.sub.421--NR.sub.321--SO.sub.2--R.sub.721;
[0712]
--R.sub.421--NR.sub.321--SO.sub.2--NR.sub.521--R.sub.621-alkyl;
[0713]
--R.sub.421--NR.sub.321--SO.sub.2--NR.sub.521--R.sub.621-alkenyl;
[0714]
--R.sub.421--NR.sub.321--SO.sub.2--NR.sub.521--R.sub.621-aryl;
[0715]
--R.sub.421--NR.sub.321--SO.sub.2--NR.sub.521--R.sub.621-heteroaryl-
;
[0716]
--R.sub.421--NR.sub.321--SO.sub.2--NR.sub.521--R.sub.621-heterocycl-
yl; and
[0717] --R.sub.421--NR.sub.321--SO.sub.2--NH.sub.2;
[0718] R.sub.221 is chosen from:
[0719] -hydrogen;
[0720] -alkyl;
[0721] -alkenyl;
[0722] -aryl;
[0723] -heteroaryl;
[0724] -heterocyclyl;
[0725] -alkyl-Y-alkyl;
[0726] -alkyl-Y-alkenyl;
[0727] -alkyl-Y-aryl; and
[0728] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0729] --OH;
[0730] -halogen;
[0731] --N(R.sub.521).sub.2;
[0732] --CO--N(R.sub.521).sub.2;
[0733] --CO-C.sub.1-10alkyl;
[0734] --CO--O--C.sub.1-10alkyl;
[0735] --N.sub.3;
[0736] -aryl;
[0737] -heteroaryl;
[0738] -heterocyclyl;
[0739] --CO-aryl; and
[0740] --CO-heteroaryl;
[0741] Y is --O-- or --S(O).sub.0-2--;
[0742] R.sub.321 is H, C.sub.1-10alkyl, or arylalkyl;
[0743] each R.sub.421 is independently alkyl or alkenyl, which may
be interrupted by one or more --O-- groups, or R.sub.321 and
R.sub.421 can join together to form a 5 to 7 membered heterocyclic
ring;
[0744] each R.sub.521 is independently H, C.sub.1-10alkyl, or
C.sub.2-10alkenyl;
[0745] R.sub.621 is a bond, alkyl, or alkenyl, which may be
interrupted by one or more --O-- groups;
[0746] R.sub.721 is C.sub.1-10alkyl, or R.sub.321 and R.sub.721 can
join together to form a 5 to 7 membered heterocyclic ring;
[0747] v is 0 to 4; and
[0748] each R.sub.21 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, hydroxy, halogen and
trifluoromethyl; 26
[0749] wherein:
[0750] X is --CHR.sub.522--, --CHR.sub.522-alkyl-, or
--CHR.sub.522-alkenyl-;
[0751] R.sub.122 is chosen from:
[0752] --R.sub.422--NR.sub.322--SO.sub.2--R.sub.622-alkyl;
[0753] --R.sub.422--NR.sub.322--SO.sub.2--R.sub.622-alkenyl;
[0754] --R.sub.422--NR.sub.322--SO.sub.2--R.sub.622-aryl;
[0755] --R.sub.422--NR.sub.322--SO.sub.2--R.sub.622-heteroaryl;
[0756]
--R.sub.422--NR.sub.322--SO.sub.2--R.sub.622-heterocyclyl;
[0757] --R.sub.422--NR.sub.322--SO.sub.2--R.sub.722;
[0758]
--R.sub.422--NR.sub.322--SO.sub.2--NR.sub.522--R.sub.622-alkyl;
[0759]
--R.sub.422--NR.sub.322--SO.sub.2--NR.sub.522--R.sub.622-alkenyl;
[0760]
--R.sub.422--NR.sub.322--SO.sub.2--NR.sub.522--R.sub.622-aryl;
[0761]
--R.sub.422--NR.sub.322--SO.sub.2--NR.sub.522--R.sub.622-heteroaryl-
;
[0762]
--R.sub.422--NR.sub.322--SO.sub.2--NR.sub.522--R.sub.622-heterocycl-
yl; and
[0763] --R.sub.422--NR.sub.322--SO.sub.2--NH.sub.2;
[0764] R.sub.222 is chosen from:
[0765] -hydrogen;
[0766] -alkyl;
[0767] -alkenyl;
[0768] -aryl;
[0769] -heteroaryl;
[0770] -heterocyclyl;
[0771] -alkyl-Y-alkyl;
[0772] -alkyl-Y- alkenyl;
[0773] -alkyl-Y-aryl; and
[0774] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0775] --OH;
[0776] -halogen;
[0777] --N(R.sub.522).sub.2;
[0778] --CO--N(R.sub.522).sub.2;
[0779] --CO--C.sub.1-10alkyl;
[0780] --CO--O--C.sub.1-10alkyl;
[0781] --N.sub.3;
[0782] -aryl;
[0783] -heteroaryl;
[0784] -heterocyclyl;
[0785] --CO-aryl; and
[0786] --CO-heteroaryl;
[0787] Y is --O-- or --S(O).sub.0-2--;
[0788] R.sub.322 is H, C.sub.1-10alkyl, or arylalkyl;
[0789] each R.sub.422 is independently alkyl or alkenyl, which may
be interrupted by one or more --O-- groups, or R.sub.322 and
R.sub.422 can join together to form a 5 to 7 membered heterocyclic
ring;
[0790] each R.sub.522 is independently H, C.sub.1-10alkyl, or
C.sub.2-10alkenyl;
[0791] R.sub.622 is a bond, alkyl, or alkenyl, which may be
interrupted by one or more --O-- groups;
[0792] R.sub.722 is C.sub.1-10alkyl, or R.sub.322 and R.sub.722 can
join together to form a 5 to 7 membered heterocyclic ring;
[0793] v is 0 to 4; and
[0794] each R.sub.22 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, hydroxy, halogen, and
trifluoromethyl; 27
[0795] wherein:
[0796] X is --CHR.sub.323--, --CHR.sub.323-alkyl-, or
--CHR.sub.323-alkenyl-;
[0797] Z is --S--, --SO--, or --SO.sub.2--;
[0798] R.sub.123 is chosen from:
[0799] -alkyl;
[0800] -aryl;
[0801] -heteroaryl;
[0802] -heterocyclyl;
[0803] -alkenyl;
[0804] --R.sub.423-aryl;
[0805] --R.sub.423-heteroaryl;
[0806] --R.sub.423-heterocyclyl;
[0807] R.sub.223 is chosen from:
[0808] -hydrogen;
[0809] -alkyl;
[0810] -alkenyl;
[0811] -aryl;
[0812] -heteroaryl;
[0813] -heterocyclyl;
[0814] -alkyl-Y-alkyl;
[0815] -alkyl-Y- alkenyl;
[0816] -alkyl-Y-aryl; and
[0817] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0818] --OH;
[0819] -halogen;
[0820] --N(R.sub.323).sub.2;
[0821] --CO--N(R.sub.323).sub.2;
[0822] --CO--C.sub.1-10alkyl;
[0823] --CO--O--C.sub.1-10alkyl;
[0824] --N.sub.3;
[0825] -aryl;
[0826] -heteroaryl;
[0827] -heterocyclyl;
[0828] --CO-aryl; and
[0829] --CO-heteroaryl;
[0830] each R.sub.323 is independently H or C.sub.1-10alkyl;
[0831] each R.sub.423 is independently alkyl or alkenyl;
[0832] each Y is independently --O-- or --S(O).sub.0-2--;
[0833] v is 0 to 4; and
[0834] each R.sub.23 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, hydroxy, halogen and
trifluoromethyl; 28
[0835] wherein:
[0836] X is --CHR.sub.324--, --CHR.sub.324-alkyl-, or
--CHR.sub.324-alkenyl-;
[0837] Z is --S--, --SO--, or --SO.sub.2--;
[0838] R.sub.124 is chosen from:
[0839] -alkyl;
[0840] -aryl;
[0841] -heteroaryl;
[0842] -heterocyclyl;
[0843] -alkenyl;
[0844] --R.sub.424-aryl;
[0845] --R.sub.424-heteroaryl; and
[0846] --R.sub.424-heterocyclyl;
[0847] R.sub.224 is chosen from:
[0848] -hydrogen;
[0849] -alkyl;
[0850] -alkenyl;
[0851] -aryl;
[0852] -heteroaryl;
[0853] -heterocyclyl;
[0854] -alkyl-Y-alkyl;
[0855] -alkyl-Y- alkenyl;
[0856] -alkyl-Y-aryl; and
[0857] -alkyl or alkenyl substituted by one or more substituent
chosen from:
[0858] --OH;
[0859] -halogen;
[0860] --N(R.sub.324).sub.2;
[0861] --CO--N(R.sub.324).sub.2;
[0862] --CO--C.sub.1-10alkyl;
[0863] --CO--O--C.sub.1-10alkyl;
[0864] --N.sub.3;
[0865] -aryl;
[0866] -heteroaryl;
[0867] -heterocyclyl;
[0868] --CO-aryl; and
[0869] --CO-heteroaryl;
[0870] each R.sub.324 is independently H or C.sub.1-10alkyl;
[0871] each R.sub.424 is independently alkyl or alkenyl;
[0872] each Y is independently --O-- or --S(O).sub.0-2--;
[0873] v is 0 to 4; and
[0874] each R.sub.24 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, hydroxy, halogen and
trifluoromethyl; 29
[0875] wherein:
[0876] X is --CHR.sub.525--, --CHR.sub.525-alkyl-, or
--CHR.sub.525-alkenyl-;
[0877] R.sub.125 is chosen from:
[0878]
--R.sub.425--NR.sub.825--CR.sub.325--NR.sub.525-Z-R.sub.625-alkyl;
[0879]
--R.sub.425--NR.sub.825--CR.sub.325--NR.sub.525-Z-R.sub.625-alkenyl-
;
[0880]
--R.sub.425--NR.sub.825--CR.sub.325--NR.sub.525-Z-R.sub.625-aryl;
[0881]
--R.sub.425--NR.sub.825--CR.sub.325--NR.sub.525-Z-R.sub.625-heteroa-
ryl;
[0882]
--R.sub.425--NR.sub.825--CR.sub.325--NR.sub.525-Z-R.sub.625-heteroc-
yclyl;
[0883]
--R.sub.425--NR.sub.825--CR.sub.325--NR.sub.525R.sub.725;
[0884]
--R.sub.425--NR.sub.825--CR.sub.325--NR.sub.925-Z-R.sub.625-alkyl;
[0885]
--R.sub.425--NR.sub.825--CR.sub.325--NR.sub.925-Z-R.sub.625-alkenyl-
;
[0886]
--R.sub.425--NR.sub.825--CR.sub.325--NR.sub.925-Z-R.sub.625-aryl;
[0887]
--R.sub.425--NR.sub.825--CR.sub.325--NR.sub.925-Z-R.sub.625-heteroa-
ryl; and
[0888]
--R.sub.425--NR.sub.825--CR.sub.325--NR.sub.925-Z-R.sub.625-heteroc-
yclyl;
[0889] R.sub.225 is chosen from:
[0890] -hydrogen;
[0891] -alkyl;
[0892] -alkenyl;
[0893] -aryl;
[0894] -heteroaryl;
[0895] -heterocyclyl;
[0896] -alkyl-Y-alkyl;
[0897] -alkyl-Y-alkenyl;
[0898] -alkyl-Y-aryl; and
[0899] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0900] --OH;
[0901] -halogen;
[0902] --N(R.sub.525).sub.2;
[0903] --CO--N(R.sub.525).sub.2;
[0904] --CO--C.sub.1-10alkyl;
[0905] --CO--O--C.sub.1-10alkyl;
[0906] --N.sub.3;
[0907] -aryl;
[0908] -heteroaryl;
[0909] -heterocyclyl;
[0910] --CO-aryl; and
[0911] --CO-heteroaryl;
[0912] each R.sub.325 is .dbd.O or .dbd.S;
[0913] each R.sub.425 is independently alkyl or alkenyl, which may
be interrupted by one or more --O-- groups;
[0914] each R.sub.525 is independently H or C.sub.1-10alkyl;
[0915] R.sub.625 is a bond, alkyl, or alkenyl, which may be
interrupted by one or more --O-- groups;
[0916] R.sub.725 is H, C.sub.1-10alkyl which may be interrupted by
a hetero atom, or R.sub.725 can join with R.sub.525 to form a 5 to
7 membered heterocyclic ring;
[0917] R.sub.825 is H, C.sub.1-10alkyl, arylalkyl, or R.sub.425 and
R.sub.825 can join together to form a 5 to 7 membered heterocyclic
ring;
[0918] R.sub.925 is C.sub.1-10alkyl which can join together with
R.sub.825 to form a 5 to 7 membered heterocyclic ring;
[0919] each Y is independently --O-- or --S(O).sub.0-2--;
[0920] Z is a bond, --CO--, or --SO.sub.2--;
[0921] v is 0 to 4; and
[0922] each R.sub.25 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, hydroxy, halogen and
trifluoromethyl; 30
[0923] wherein:
[0924] X is --CHR.sub.526--, --CHR.sub.526-alkyl-, or
--CHR.sub.526-alkenyl-;
[0925] R.sub.126 is chosen from:
[0926]
--R.sub.426--NR.sub.826--CR.sub.326--NR.sub.526-Z-R.sub.626-alkyl;
[0927]
--R.sub.426--NR.sub.826--CR.sub.326--NR.sub.526-Z-R.sub.626-alkenyl-
;
[0928]
--R.sub.426--NR.sub.826--CR.sub.326--NR.sub.526-Z-R.sub.626-aryl;
[0929]
--R.sub.426--NR.sub.826--CR.sub.326--NR.sub.526-Z-R.sub.626-heteroa-
ryl;
[0930]
--R.sub.426--NR.sub.826--CR.sub.326--NR.sub.526-Z-R.sub.626-heteroc-
yclyl;
[0931]
--R.sub.426--NR.sub.826--CR.sub.326--NR.sub.526R.sub.726;
[0932]
--R.sub.426--NR.sub.826--CR.sub.326--NR.sub.926-Z-R.sub.626-alkyl;
[0933]
--R.sub.426--NR.sub.826--CR.sub.326--NR.sub.926-Z-R.sub.626-alkenyl-
;
[0934]
--R.sub.426--NR.sub.826--CR.sub.326--NR.sub.926-Z-R.sub.626-aryl;
[0935]
--R.sub.426--NR.sub.826--CR.sub.326--NR.sub.926-Z-R.sub.626-heteroa-
ryl; and
[0936]
--R.sub.426--NR.sub.826--CR.sub.326--NR.sub.926-Z-R.sub.626-heteroc-
yclyl;
[0937] R.sub.226 is chosen from:
[0938] -hydrogen;
[0939] -alkyl;
[0940] -alkenyl;
[0941] -aryl;
[0942] -heteroaryl;
[0943] -heterocyclyl;
[0944] -alkyl-Y-alkyl;
[0945] -alkyl-Y-alkenyl;
[0946] -alkyl-Y-aryl; and
[0947] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[0948] --OH;
[0949] -halogen;
[0950] --N(R.sub.526).sub.2;
[0951] --CO--N(R.sub.526).sub.2;
[0952] --CO--C.sub.1-10alkyl;
[0953] --CO--O--C.sub.1-10alkyl;
[0954] --N.sub.3;
[0955] -aryl;
[0956] -heteroaryl;
[0957] -heterocyclyl;
[0958] --CO-aryl; and
[0959] --CO-heteroaryl;
[0960] each R.sub.326 is .dbd.O or .dbd.S;
[0961] each R.sub.426 is independently alkyl or alkenyl, which may
be interrupted by one or more --O-- groups;
[0962] each R.sub.526 is independently H or C.sub.1-10alkyl;
[0963] R.sub.626 is a bond, alkyl, or alkenyl, which may be
interrupted by one or more --O-- groups;
[0964] R.sub.726 is H, C.sub.1-10alkyl which may be interrupted by
a hetero atom, or R.sub.726 can join with R.sub.526 to form a 5 to
7 membered heterocyclic ring;
[0965] R.sub.826 is H, C.sub.1-10alkyl, arylalkyl, or R.sub.426 and
R.sub.826 can join together to form a 5 to 7 membered heterocyclic
ring;
[0966] R.sub.926 is C.sub.1-10alkyl which can join together with
R.sub.826 to form a 5 to 7 membered heterocyclic ring;
[0967] each Y is independently --O-- or --S(O).sub.0-2--;
[0968] Z is a bond, --CO--, or --SO.sub.2--;
[0969] v is 0 to 4; and
[0970] each R.sub.26 present is independently chosen from
C.sub.1-10alkyl, C.sub.1-10alkoxy, hydroxy, halogen, and
trifluoromethyl;
[0971] and pharmaceutically acceptable salts of any of the
foregoing.
[0972] In another embodiment, the IRM compound can be chosen from
1H-imidazo[4,5-c]pyridin-4-amines compounds defined by Formula
XXVII 31
[0973] wherein
[0974] X is alkylene or alkenylene;
[0975] Y is --CO--, --CS--, or --SO.sub.2--;
[0976] Z is a bond, --O--, --S--, or --NR.sub.527--;
[0977] R.sub.127 is aryl, heteroaryl, heterocyclyl, C.sub.1-20alkyl
or C.sub.2-20alkenyl, each of which may be unsubstituted or
substituted by one or more substituents independently chosen
from:
[0978] -alkyl;
[0979] -alkenyl;
[0980] -aryl;
[0981] -heteroaryl;
[0982] -heterocyclyl;
[0983] -substituted cycloalkyl;
[0984] --O-alkyl;
[0985] --O-(alkyl).sub.0-1-aryl;
[0986] --O-(alkyl).sub.0-1-heteroaryl;
[0987] --O-(alkyl).sub.0-1-heterocyclyl;
[0988] --COOH;
[0989] --CO--O-alkyl;
[0990] --CO-alkyl;
[0991] --S(O).sub.0-2-alkyl;
[0992] --S(O).sub.0-2-(alkyl).sub.0-1-aryl;
[0993] --S(O).sub.0-2-(alkyl).sub.0-1-heteroaryl;
[0994] --S(O).sub.0-2-(alkyl).sub.0-1-heterocyclyl;
[0995] -(alkyl).sub.0-1-N(R.sub.527).sub.2;
[0996] -(alkyl).sub.0-1-NR.sub.527--CO--O-alkyl;
[0997] -(alkyl).sub.0-1-NR.sub.527--CO-alkyl;
[0998] -(alkyl).sub.0-1-NR.sub.527--CO-aryl;
[0999] -(alkyl).sub.0-1-NR.sub.527--CO-heteroaryl;
[1000] --N.sub.3;
[1001] -halogen;
[1002] -haloalkyl;
[1003] -haloalkoxy;
[1004] --CO-haloalkyl;
[1005] --CO-haloalkoxy;
[1006] --NO.sub.2;
[1007] --CN;
[1008] --OH;
[1009] --SH; and in the case of alkyl, alkenyl, and heterocyclyl,
oxo;
[1010] R.sub.227 is chosen from:
[1011] -hydrogen;
[1012] -alkyl;
[1013] -alkenyl;
[1014] -alkyl-O-alkyl;
[1015] -alkyl-S-alkyl;
[1016] -alkyl-O-aryl;
[1017] -alkyl-S-aryl:
[1018] -alkyl-O-alkenyl;
[1019] -alkyl-S-alkenyl; and
[1020] -alkyl or alkenyl substituted by one or more substituents
chosen from:
[1021] --OH;
[1022] -halogen;
[1023] --N(R.sub.527).sub.2;
[1024] --CO--N(R.sub.527).sub.2;
[1025] --CS--N(R.sub.527).sub.2;
[1026] --SO.sub.2--N(R.sub.527).sub.2;
[1027] --NR.sub.527--CO--C.sub.1-10alkyl;
[1028] --NR.sub.527--CS--C.sub.1-10alkyl;
[1029] --NR.sub.527--SO.sub.2--C.sub.1-10alkyl;
[1030] --CO--C.sub.1-10alkyl;
[1031] --CO--O--C.sub.1-10alkyl;
[1032] --N.sub.3;
[1033] -aryl;
[1034] -heteroaryl;
[1035] -heterocyclyl;
[1036] --CO-aryl; and
[1037] --CO-heteroaryl;
[1038] R.sub.327 and R.sub.427 are independently chosen from
hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino,
dialkylamino and alkylthio;
[1039] each R.sub.527 is independently H or C.sub.1-10alkyl;
[1040] and pharmaceutically acceptable salts thereof.
[1041] As used herein, the terms "alkyl", "alkenyl" and the prefix
"alk-" are inclusive of both straight chain and branched chain
groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl.
Unless otherwise specified, these groups contain from 1 to 20
carbon atoms, with alkenyl groups containing from 2 to 20 carbon
atoms. Preferred groups have a total of up to 10 carbon atoms.
Cyclic groups can be monocyclic or polycyclic and preferably have
from 3 to 10 ring carbon atoms. Exemplary cyclic groups include
cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl and
adamantyl.
[1042] The term "haloalkyl" is inclusive of groups that are
substituted by one or more halogen atoms, including perfluorinated
groups. This is also true of groups that include the prefix
"halo-". Examples of suitable haloalkyl groups are chloromethyl,
trifluoromethyl, and the like.
[1043] The term "aryl" as used herein includes carbocyclic aromatic
rings or ring systems. Examples of aryl groups include phenyl,
naphthyl, biphenyl, fluorenyl and indenyl. The term "heteroaryl"
includes aromatic rings or ring systems that contain at least one
ring hetero atom (e.g., O, S, N). Suitable heteroaryl groups
include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl,
indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl,
pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl,
carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl,
quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl,
isothiazolyl, purinyl, quinazolinyl, and so on.
[1044] "Heterocyclyl" includes non-aromatic rings or ring systems
that contain at least one ring hetero atom (e.g., O, S, N) and
includes all of the fully saturated and partially unsaturated
derivatives of the above mentioned heteroaryl groups. Exemplary
heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl,
morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl,
thiazolidinyl, imidazolidinyl, isothiazolidinyl, and the like.
[1045] In some embodiments, the topical formulations of the present
invention are prepared using the free base form of the IRM
compound.
[1046] The amount of an IRM compound that will be therapeutically
effective in a specific situation will depend on such things as the
activity of the particular compound, the dosing regimen, the
application site, the particular formulation and the condition
being treated. As such, it is generally not practical to identify
specific administration amounts herein; however, those skilled in
the art will be able to determine appropriate therapeutically
effective amounts based on the guidance provided herein,
information available in the art pertaining to these compounds, and
routine testing. The term "a therapeutically effective amount"
means an amount of the compound sufficient to induce a therapeutic
effect, such as cytokine induction, inhibition of TH2 immune
response, antiviral or antitumor activity, reduction or elimination
of postsurgical scarring, or reduction or resolution of actinic
keratosis or pre-actinic keratosis lesions.
[1047] In general, the amount of the IRM compound present in a
topical formulation of the invention will be an amount effective to
treat a targeted condition, to prevent recurrence of the condition,
or to promote immunity against the condition. The amount or
concentration of the IRM compound can range from 0.001% to 10% by
weight based on the total formulation weight, such as, for example,
from 0.03% to 5.0% by weight, or from 0.1 to 1.0% by weight. In
certain embodiments, the amount of the IRM compound is at least
0.003% by weight, such as, for example, at least 0.005%, at least
0.01%, at least 0.03%, at least 0.10%, at least 0.30% and at least
1.0%. In other embodiments, the amount of the IRM compound is at
most 5.0% by weight, such as, for example, at most 3.0%, and at
most 1.0%.
[1048] The topical formulations of the invention additionally
comprise a fatty acid. As used herein, the term "fatty acid" means
a carboxylic acid, either saturated or unsaturated, comprising 6 to
28 carbon atoms, such as, for example, from 10 to 22 carbon atoms.
Non-limiting examples of such fatty acids include isostearic acid,
oleic acid, and linear- or- branched chained carboxylic acids of 6
to 18 carbon atoms. The fatty acid may be present in the
formulation in an amount sufficient to solubilize the IRM compound.
In one embodiment, the amount of the fatty acid can range from
0.05% to 40% by weight based on the total weight of the
formulation, such as, for example, from 1% to 30%, from 3% to 15%
and from 5% to 10%. In certain embodiments, the amount of the fatty
acid is at least 3.0% by weight, such as, for example, at least
5.0%, at least 10.0%, and at least 25%. The fatty acid component of
the formulation can comprise one or more fatty acids.
[1049] The topical formulations of the invention additionally
comprise at least one hydrophobic, aprotic component miscible with
the fatty acid and comprising a hydrocarbyl group of 7 or more
carbon atoms. By "hydrophobic" is meant that the component is
essentially insoluble in water, i.e. immiscible with water and
unable to form a micelle in water, and does not contain
polyoxyethylene or acid salt groups. Preferably the hydrophobic,
aprotic component has a hydrophilic lipophilic balance (HLB) of
less than 2. The HLB of a component may be determined as described,
for example, in Attwood, D., Florence, A. T. Surfactant Systems:
Their Chemistry Pharmacy, and Biology. New York: Chapman &
Hall, 471-473, 1983. By "aprotic" is meant that the component
cannot donate a proton to the IRM and does not contain groups such
as carboxyl, hydroxy, primary and secondary amino, primary and
secondary amido, or quaternary ammonium groups. Preferably this
component has a pKa of at least 14.2 and does not substantially
solubilize or form a complex such as an acid-base pair or complex
or a hydrogen bond complex with the IRM compound. By "not
substantially" is meant that the ratio of the IRM compound's
solubility in the hydrophilic, aprotic component to that in
isostearic acid is less than 1:40.
[1050] Formulations intended for dermal or topical use desirably
have a certain minimum amount of an oil phase to provide qualities
such as spreadability, feel on the skin, texture, and so on.
However, if all the components of the oil phase solubilize the IRM,
then the degree of saturation of the IRM in the formulation will
decrease, making it more difficult to deliver the IRM from the
formulation to the skin. Addition of the hydrophobic, aprotic
component can increase the oil phase volume of the topical
formulation to provide desirable qualitites such as spreadability
and feel, while at the same time not appreciably altering the
degree of saturation or thermodynamic activity of the IRM. For
example, the amount of fatty acid, which solubilizes the IRM, can
be reduced to increase the degree of IRM saturation while
maintaining a sufficient oil phase volume by virtue of the addition
of the hydrophobic, aprotic component, which does not offset the
increased IRM saturation. Thus, the topical formulation of the
present invention can facilitate both physical property and drug
delivery requirements. Degree of saturation and thermodynamic
activity of the IRM in these formulations is equal to the IRM
concentration in the oil phase divided by the saturation
concentration of the IRM in the oil phase. When the topical
formulations of the present invention contain saturated IRM the
thermodynamic activity or degree of saturation is unity, and when
partially saturated the thermodynamic activity or degree of
saturation is less than unity.
[1051] The amount of the hydrophobic, aprotic component present in
a formulation of the invention can range from 1% to 30% by weight
based on the total formulation weight, for example, from 3% to 15%
by weight, and from 5 to 10% by weight. In certain embodiments, the
amount of the hydrophobic, aprotic component is at least 3.0% by
weight, for example, at least 5.0%, and at least 10.0%. The weight
ratio of the hydrophobic, aprotic component to the fatty acid can
be 0.025:1 to 600:1, for example, 0.5:1 to 50:1, and 2:1 to 30:1.
The combined amount (weight percent of the total topical
formulation weight) of the hydrophobic, aprotic component and the
fatty acid can be 2% to 50% by weight, for example 2% to 30%, 5% to
30%, 5% to 20%, and 10% to 20%.
[1052] Examples of useful hydrophobic, aprotic components include
but are not limited to fatty acid esters, for example, isopropyl
mysristate, isopropyl palmitate, diisopropyl dimer dilinoleate;
triglycerides, for example, caprylic/capric triglyceride; cetyl
esters wax; hydrocarbons of 8 or more carbon atoms, for example,
light mineral oil, white petrolatum; and waxes, for example,
beeswax. In some embodiments, the hydrophobic, aprotic component is
chosen from one or more of isopropyl mysristate, isopropyl
palmitate, caprylic/capric triglyceride, and diisopropyl dimer
dilinoleate.
[1053] The formulations of the present invention can also comprise
a hydrophilic viscosity enhancing agent. Examples of suitable
hydrophilic viscosity enhancing agents include cellulose ethers
such as hydroxypropylmethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, and carboxymethylcellulose; polysaccharide
gums such as xanthan gum; and homopolymers and copolymers of
acrylic acid crosslinked with allyl sucrose or allyl pentaerythriol
such as those polymers designated as carbomers in the United States
Pharmacopoeia. Suitable carbomers include, for example, those
available as Carbopol.TM. 934P, Carbopol 971P, Carbopol 940,
Carbopol 974P, Carbopol 980, and Pemulen.TM. TR-1 (USP/NF
Monograph; Carbomer 1342), all available from Noveon, Cleveland,
Ohio. In one embodiment of the present invention, the viscosity
enhancing agent is chosen from Carbopol 974P and 980. When
included, the viscosity enhancing agent is generally present in an
amount ranging from 0.1% to 10% by weight of total formulation
weight, such as, for example, from 0.5% to 5% by weight, from 0.5%
to 1.5% by weight, and from 0.7% to 3% by weight. In certain
embodiments, the amount of the viscosity enhancing agent is at
least 0.5% by weight, for example, at least 0.6% by weight, at
least 0.7% by weight, at least 0.9% by weight, and at least 1.0% by
weight.
[1054] The formulations of the invention can additionally comprise
an emulsifier. Suitable emulsifiers include non-ionic surfactants
such as, for example, polysorbate 60, sorbitan monostearate,
polyglyceryl-4 oleate, polyoxyethylene(4) lauryl ether, etc. In
certain embodiments, the emulsifier is chosen from poloxamers
(e.g., Pluronic.TM. F68, also known as Poloxamer 188, a
poly(ethylene glycol)-block-poly(propylene
glycol)-block-poly(ethylene glycol), available from BASF,
Ludwigshafen, Germany) and sorbitan trioleate (e.g., Span 85
available from Uniqema, New Castle, Del.). If included, the
emulsifier is generally present in an amount of 0.1% to 10% by
weight of total formulation weight, for example, from 0.5% to 5% by
weight, and from 0.75% to 3.5% by weight. In certain embodiments,
the amount of the emulsifier is at least 1.0% by weight, for
example, at least 2.5%, at least 3.5%, and at least 5.0%.
[1055] In certain embodiments of the present invention, the
formulation can also include at least one chelating agent. The
chelating agent functions to chelate metal ions that may be present
in the formulation. Suitable chelating agents include salts of
ethylenediaminetetraacetate (EDTA), such as the disodium salt. If
included, the chelating agent is generally present in an amount
ranging from 0.001% to 0.1% by weight, and preferably from 0.01% to
0.05% by weight. In certain embodiments, the amount of the
chelating agent is at least 0.005% by weight, such as, for example,
at least 0.01%, and at least 0.05%.
[1056] The formulation can also include a preservative system. The
preservative system is generally comprised of at least one
preservative compound chosen from methylparaben, ethylparaben,
propylparaben, phenoxyethanol, iodopropynyl butylcarbamate, sorbic
acid, a fatty acid monoester of glycerin such as glycerol
monolaurate, and a fatty acid monoester of propylene glycol such as
propylene glycol monocaprylate. The preservative system may also
include a preservative enhancing solubilizer which enhances the
solubility of the preservative in the aqueous phase, examples of
which include diethylene glycol monoethyl ether and propylene
glycol. In one embodiment, the preservative system can be comprised
of methylparaben, propylparaben, and propylene glycol. In another
embodiment, the preservative system can be comprised of
methylparaben, ethylparaben, and diethylene glycol monoethyl ether.
In one embodiment, the preservative system can be comprised of
phenoxyethanol, methylparaben or methyl- and ethylparaben, and
diethylene glycol monoethyl ether. In another embodiment, the
preservative system can be comprised of iodopropynyl
butylcarbamate. In another embodiment, the preservative system can
be comprised of iodopropynyl butylcarbamate, diethylene glycol
monoethyl ether, and poly(ethylene glycol)(4) monolaurate. In
another embodiment, the preservative system can be comprised of
iodopropynyl butylcarbamate, one or more of methylparaben,
ethylparaben, propylparaben, or phenoxyethanol, and diethylene
glycol monoethyl ether. In the above embodiments, the
methylparaben, ethylparaben, and propylparaben can each be present
in the formulations in an amount ranging from 0.01% to 0.5% by
weight of the formulation weight, for example, from 0.05% to 0.25%
by weight, and from 0.1% to 0.2% by weight. The iodopropynyl
butylcarbamate can be present in the formulations in an amount
ranging from 0.01% to 0.1%. The phenoxyethanol can be present in
the formulations in an amount ranging from 0.1% to 1%. The
propylene glycol and diethylene glycol monoethyl ether can each be
present in the formulations in an amount ranging from 1% to 30% by
weight of the formulation weight, such as, for example, from 5% to
25% by weight, and from 10% to 15% by weight. The preservative
system can be present in the formulations in an amount ranging from
0.01% to 30% by weight of the formulation weight, for example, from
0.05% to 30%, from 0.1% to 25% by weight, and from 0.2% to 15% by
weight. In a further embodiment, the methylparaben, ethylparaben,
propylparaben, iodopropynyl butylcarbamate, and phenoxyethanol can
be solubilized in propylene glycol, poly(ethylene glycol)(4)
monolaurate, or diethylene glycol monoethyl ether prior to addition
to the formulation. The preservative system can be selected such
that it meets the criteria for antimicrobial effectiveness set
forth in the United States Pharmacopeia <51>.
[1057] The formulations of the present invention may additionally
comprise at least one pH adjuster. Suitable pH adjusters include
organic bases and inorganic bases such as, for example, KOH, NaOH.
The pH of the topical formulations of the present invention
generally ranges from 3.5 to 7.0. In one embodiment, the pH of the
topical formulations of the present invention can range from 4.0 to
6.0, preferably 5.0. In another embodiment of the invention, the pH
of the topical formulations of the present invention can range from
5.5 to 6.5, preferably 6.0.
[1058] Any of the foregoing formulations can be in the form of an
oil-in-water emulsion such as a cream or a lotion. Such an emulsion
can comprise an oil phase comprising the IRM compounds, a fatty
acid in an amount sufficient to solubilize the IRM compounds, a
hydrophobic, aprotic component; and an aqueous phase comprising a
hydrophilic viscosity enhancing agent, for example, a carbomer. In
certain embodiments, the amount or concentration of the IRM in the
oil phase can be at least 0.01%, for example, at least 0.02%, at
least 0.1%, and at least 1% with respect to oil phase weight. In
other embodiments, the amount or concentration of the IRM in the
oil phase can be at most 20%, for example, at most 10%, and at most
5% with respect to oil phase weight. The emulsion can be preserved
so that when challenged by an antimicrobial effectiveness test, it
meets regulatory requirements for topical creams packaged in
multiple-use containers.
[1059] Any of the foregoing formulations according to the present
invention can be applied to the dermal surfaces of a mammal.
Depending on the IRM compound concentration, formulation
composition, and dermal surface, the therapeutic effect of the IRM
compound may extend only to the superficial layers of the dermal
surface or to tissues below the dermal surface. Thus, another
aspect of the present invention is directed to a method for the
treatment of a dermal associated condition comprising applying to
skin one of the foregoing formulations. As used herein, a "dermal
associated condition" means an inflammatory, infectious, neoplastic
or other condition that involves a dermal surface or that is in
sufficient proximity to a dermal surface to be affected by a
therapeutic agent topically applied to the dermal surface. Examples
of a dermal associated condition include warts, atopic dermatitis,
basal cell carcinoma, postsurgical scars, and actinic
keratosis.
[1060] In one embodiment, the formulations can be applied to the
surface of skin for treatment of actinic keratosis (AK). Actinic
keratoses are premalignant lesions considered biologically to be
either carcinoma in-situ or squamous intraepidermal neoplasia. AK
is the most frequent epidermal tumor and is induced by ultraviolet
(UV) radiation, typically from sunlight. Because of its
precancerous nature, AK may be considered the most important
manifestation of sun-induced skin damage.
[1061] In some embodiments, the above described formulations are
particularly advantageous for dermal application for a period of
time sufficient to obtain a desired therapeutic effect without
undesired systemic absorption of the IRM.
EXAMPLES
[1062] The following Examples are provided to further describe
various IRM formulations and methods according to the invention.
The examples, however, are not intended to limit the formulations
and methods within the spirit and scope of the invention.
Examples 1-7 and Comparative Example C1
[1063] Table 1 summarizes topical formulations made in accordance
with the present invention in a percentage weight-by-weight
basis.
1 TABLE 1 Topical Cream (percentage weight-by-weight) Ingredient
Comparative Example (Compendial Status) C1 (Placebo) Example 1
Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 IRM
Compound 1 0.00 0.001 0.003 0.010 0.03 0.10 0.30 1.00 Isostearic
Acid 5.00 5.00 5.00 5.00 5.00 5.00 7.00 10.00 Isopropyl Myristate
(NF) 10.00 10.00 10.00 10.00 10.00 10.00 8.00 5.00 Carbomer 974P
(NF) 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 Poloxamer 188 (NF)
2.50 2.50 2.50 2.50 2.50 2.50 2.50 2.50 Propylene Glycol (USP)
15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00 Methylparaben (NF)
0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben (NF) 0.10
0.10 0.10 0.10 0.10 0.10 0.10 0.10 Edetate Disodium (USP) 0.05 0.05
0.05 0.05 0.05 0.05 0.05 0.05 Sodium Hydroxide (NF) 0.50 0.50 0.50
0.50 0.50 0.50 0.50 0.50 Solution, 20% w/w Purified Water (USP)
65.65 65.649 65.647 65.64 65.62 65.55 65.35 64.60 Total 100.00
100.00 100.00 100.00 100.00 100.00 100.00 100.00
[1064] The formulations set forth in Table 1 were prepared in the
following manner:
[1065] Oil phase preparation:
2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c- ]
[1,5]naphthyridin-4-amine (IRM compound 1) was dissolved in
isostearic acid and isopropyl myristate, with heat if necessary.
Carbomer 974P was then dispersed in the oil phase.
[1066] Water phase preparation: Edetate disodium was dissolved in
the water. Methylparaben and propylparaben were dissolved in
propylene glycol and the solution was subsequently added to the
water phase. Poloxamer 188 was then added to the water phase and
mixed until dissolved.
[1067] Phase combination: The oil phase was added to the water
phase at ambient conditions. The emulsion was then homogenized.
After homogenization, sodium hydroxide solution (20% w/w) was added
and the resulting cream was mixed until smooth and uniform. The pH
of the cream was measured and a pH adjustment was made with
additional sodium hydroxide solution, if necessary, to meet the
in-process target pH of 5.
[1068] Formulations containing
2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5--
c][1,5]naphthyridin-4-amine (IRM Compound 1) were tested for their
ability to induce increases in cytokine concentrations in rats
following topical application. This study was undertaken to
evaluate cytokine induction following a single dosing of various
strengths and timepoints or a multiple vs. single dosing of IRM
Compound 1. The formulations described above were tested by
examining tissue and serum concentrations of TNF-.alpha., MCP-1
(monocyte chemoattractant protein-1) and IFN-.alpha. cytokines
following drug treatment.
[1069] Female CD hairless rats (Charles River Laboratories,
Wilmington, Mass.) weighing 200-250 grams were used in all studies.
Animals were randomized to treatment groups and dosed five per
treatment group.
[1070] The rats were acclimated to collars around the neck on two
consecutive days prior to actual dosing. The rats were collared
before dosing to prevent ingestion of the drug, and were then dosed
topically with 50 .mu.L of active cream or the appropriate placebo
on right flank and then housed individually following dosing. At
various times following dosing, the rats were anesthetized and
blood was collected by cardiac puncture. Blood was allowed to clot
at room temperature and serum was separated from the clot via
centrifugation and stored at -20.degree. C. until it was analyzed
for cytokine concentrations.
[1071] Following blood collection, the rats were euthanized and
their skins removed. Tissue from both treated site (at) and
contralateral site (away) were obtained using an 8 mm punch biopsy,
weighed, placed in a sealed 1.8 ml cryovial and flash frozen in
liquid nitrogen. The frozen tissue sample was then suspended in 1.0
mL RPMI medium (Celox, Hopkins, Minn.) containing 10% fetal bovine
serum (Sigma, St. Louis, Mo.), 2 mM L-glutamine,
penicillin/streptomycin, and 2-mercaptoethanol (RPMI complete)
combined with a protease inhibitor cocktail set III (Calbiochem,
San Diego, Calif.). The tissue was homogenized using a Tissue
Tearor.TM. (Biospec Products, Bartlesville, Okla.) for
approximately 1 minute. The tissue suspension was then centrifuged
at 2000 rpm for 10 minutes under refrigeration to pellet debris,
and the supernatant collected and stored at -20.degree. C. until
analyzed for cytokine concentrations.
[1072] ELISAs for rat MCP-1 were purchased from BioSource Intl.
(Camarillo, Calif.) and rat TNF-.alpha. were purchased from BD
Pharmingen (San Diego, Calif.) and performed according to
manufacturer's specifications. Results for both TNF-.alpha., and
MCP-1 were expressed in pg/200 mg tissue or pg/ml serum. The
sensitivity of the TNF-.alpha. ELISA was 31.2 pg/ml and of the
MCP-1 ELISA was 11.7 pg/ml. IFN-.alpha. concentrations in both
serum and skin tissue were determined using a bioassay that
measured inhibition of the viral cytopathic effect of vesicular
stomatitis virus on rat LMS-C2 fibroblast cells as previously
described (Reiter, M. J., Testerman, T. L., Miller, R. L., Weeks,
C. E., and Tomai, M. A. (1994) "Cytokine Induction in Mice by the
Immunomodulator Imiquimod." J. Leukocyte Biol. 55, 234-240). IIT
Research Institute, Chicago Ill., performed these assays. Results
for IFN-.alpha. concentrations were normalized to a standard
reference rat IFN-.alpha., preparation with results being reported
in U/mL and are normalized per mg of tissue.
[1073] The data shown below in Tables 2-4 are from three separate
experiments and analyzed to 1) measure pharmacokinetics by full
time course, 2) measure dose response and 3) measure multiple vs.
single dosing.
[1074] In order to determine the kinetics of local and systemic
cytokine production following local administration of IRM Compound
1, the full time course study (Study 1 with results in Table 2) was
done by topically dosing rats with the topical cream formulation of
Example 7. Serum and tissue samples were taken at 1, 2, 4, 8, 16,
24 and 48 hours post dose. Multiple cytokines (MCP-1, TNF-.alpha.
and IFN-.alpha.) were analyzed separately.
[1075] With the tissue data, for each hour measured, a paired
t-test (used to eliminate within subject variability) analyzed the
difference between treated tissue and control tissue from the same
animal. A p-value less than alpha=0.05 indicated a statistically
significant difference between the treated and control tissue at
that hour. The data are presented in Table 2.
2TABLE 2 Cytokine Concentrations in Rat Serum and Dermal Tissue
Following Application of the Topical Formulation of Example 7 Full
Time Course.sup.a Cytokine Concentration.sup.b Time (hours)
TNF-.alpha. Post Dose Dose Serum Treated Site Control site 0
untreated 0 NA 96 .+-. 5 16 placebo 0 103 .+-. 8 71 .+-. 6 1 1% 6
.+-. 6 318 .+-. 33.sup.c 96 .+-. 13 2 1% 0 1125 .+-. 74.sup.c 124
.+-. 18 4 1% 0 1120 .+-. 51.sup.c 129 .+-. 11 8 1% 24 .+-. 16 429
.+-. 56.sup.c 91 .+-. 12 16 1% 6 .+-. 4 231 .+-. 22.sup.c 87 .+-.
27 24 1% 32 .+-. 32 198 .+-. 28.sup.c 103 .+-. 13 48 1% 49 .+-. 49
74 .+-. 10 69 .+-. 15 MCP-1 0 untreated 81 .+-. 30 NA 44 .+-. 2 16
placebo 144 .+-. 9 144 .+-. 41 42 .+-. 3 1 1% 86 .+-. 29 40 .+-. 8
42 .+-. 3 2 1% 123 .+-. 31 234 .+-. 29.sup.c 50 .+-. 4 4 1% 101
.+-. 28 723 .+-. 89.sup.c 41 .+-. 5 8 1% 438 .+-. 91.sup.c 1474
.+-. 202.sup.c 38 .+-. 3 16 1% 424 .+-. 96.sup.c 1209 .+-.
325.sup.c 31 .+-. 5 24 1% 187 .+-. 39 813 .+-. 151.sup.c 39 .+-. 1
48 1% 141 .+-. 24 145 .+-. 48.sup.c 36 .+-. 6 IFN-.alpha. 0
untreated <200 NA <650 16 placebo <200 <650 <650 1
1% <200 <650 <650 2 1% <200 <650 <650 4 1%
<200 <650 <650 8 1% <200 3/5.gtoreq.650 <650 16 1%
<200 <650 <650 24 1% <200 <650 <650 48 1% <200
<650 <650 .sup.aFemale hairless CD rats were dosed topically
with cream formulated Compound 1. .sup.bTNF-.alpha. and MCP-1 were
measured by ELISA. IFN-.alpha. was measured by bioassay. Results
are presented in pg/ml for serum samples and pg/200 mg tissue for
tissue samples and represent the mean of five animals .+-. SEM.
.sup.cIndicates p < 0.05 when compared to either placebo for
serum samples or the difference between treated tissue and control
tissue from the same animal.
[1076] A multiple dose study was done to monitor effects of a
multiple dose regimen (Study 2 with results shown in Table 3). Rats
were dosed two times a week for six hours for three weeks with
topical cream formulation of Example 5. Placebo (Comparative
Example C1) and single dosed rats were done for comparison and done
simultaneously with the last dosing of the multiple dose set. Serum
and tissue samples were taken at 8 and 24 hours post dose and
analyzed for MCP-1.
[1077] An analysis identical to that of Study 1 was performed for
Study 2. This data set was broken up by treatment (multiple- or
single-use) and time point prior to analysis. Again, placebo data
were recorded only at the 8-hour time point for single use, but
were used to compare placebo to every treatment and time point
combination separately. The results are set forth in Table 3
below.
3TABLE 3 Cytokine Concentrations in Rat Serum and Dermal Tissue
Following Topical Application of the Topical Cream Formulation of
Example 5 Multiple vs. Single Dose.sup.a Time Cytokine
Concentration.sup.b (hours) MCP-1 Post Dose Dose Serum Treated Site
Control Site 0 None 89 .+-. 11 NA 20 .+-. 10 (untreated) 24 Placebo
41 .+-. 14 42 .+-. 15 28 .+-. 6 8 Multiple 71 .+-. 13 784 .+-.
48.sup.c 42 .+-. 5 0.1% 24 Multiple 105 .+-. 36 145 .+-. 23.sup.c
32 .+-. 6 0.1% 8 Single 73 .+-. 9 519 .+-. 99.sup.c 33 .+-. 6 0.1%
24 Single 82 .+-. 3.sup.c 412 .+-. 130.sup.c 35 .+-. 7 0.1%
.sup.aFemale hairless CD rats were dosed topically with cream
formulated Compound 1. .sup.bMCP-1 was measured by ELISA. Results
are presented in pg/ml for serum samples and pg/200 mg tissue for
tissue samples and represent the mean of five animals .+-. SEM.
.sup.cIndicates p < 0.05 when compared to either placebo for
serum samples or the difference between treated tissue and control
tissue from the same animal.
[1078] A dose response study (Study 3 with results shown in Table
4) was performed by dosing with the topical cream formulations of
Examples 3-5 and 7, containing various concentrations of IRM
Compound 1. Serum and tissue samples were taken at 8 and 24 hours
post dose and analyzed for MCP-1. The studies tested topical
delivery of creams comprising IRM Compound 1 for its ability to
affect a local MCP-1 induction at four concentrations.
[1079] Serum data compared active treatment to placebo (Comparative
Example C1) separately at each specified time point. Note that the
placebo group was only measured at 24 hours post dose and these
observations were compared to each time point for the active
group.
4TABLE 4 Cytokine Concentrations in Rat Serum and Dermal Tissue
Following Topical Application of the Formulations of Examples 3-5
and 7.sup.a Cytokine Concentration.sup.b Time (hours) MCP-1 Post
Dose Dose Serum Treated Site Control Site 0 controls 207 .+-. 96 NA
38 .+-. 12 24 placebo 367 .+-. 178 61 .+-. 14 20 .+-. 5
(Comparative Example C1) 8 0.01% 81 .+-. 23 61 .+-. 12 36 .+-. 7
(Example 3) 8 0.03% 81 .+-. 20 271 .+-. 29 48 .+-. 5 (Example 4) 8
0.1% 153 .+-. 14 1119 .+-. 122.sup.c 51 .+-. 8 (Example 5) 8 1.0%
136 .+-. 23 1370 .+-. 99.sup.c 50 .+-. 15 (Example 7) 24 0.01% 71
.+-. 18 183 .+-. 49.sup.c 33 .+-. 13 (Example 3) 24 0.03% 71 .+-.
20 212 .+-. 49.sup.c 40 .+-. 7 (Example 4) 24 0.1% 226 .+-. 73 628
.+-. 127.sup.c 40 .+-. 11 (Example 5) 24 `1.0% 149 .+-. 45 756 .+-.
38.sup.c 30 .+-. 9 (Example 7) .sup.aFemale hairless CD rats were
dosed topically with cream formulated Compound 1. .sup.bMCP-1 was
measured by ELISA. Results are presented in pg/ml for serum samples
and pg/200 mg tissue for tissue samples and represent the mean of
five animals .+-. SEM. .sup.cIndicates p < 0.05 when compared to
either placebo for serum samples or the difference between treated
tissue and control tissue from the same animal.
Examples 8-13
[1080] Table 5 summarizes topical formulations made in accordance
with the present invention in a percentage weight-by-weight
basis.
5TABLE 5 Topical Cream Ingredient (percentage weight-by weight)
(Compendial Status) Example 8 Example 9 Example 10 Example 11
Example 12 Example 13 IRM Compound 2 0.01 0.03 0.10 1.00 0.003 0.30
Isostearic Acid 5.00 5.00 5.00 10.00 5.00 5.00 Isopropyl Myristate
(NF) 10.00 10.00 10.00 5.00 10.00 10.00 Carbomer 974P (NF) 1.00
1.00 1.00 0.75 1.00 1.00 Poloxamer 188 (NF) 2.50 2.50 2.50 2.50
2.50 2.50 Propylene Glycol (USP) 15.00 15.00 15.00 15.00 15.00
15.00 Methylparaben (NF) 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben (NF) 0.10 0.10 0.10 0.10 0.10 0.10 Edetate Disodium
(USP) 0.05 0.05 0.05 0.05 0.05 0.05 Sodium Hydroxide (NF) 0.50 0.50
0.50 0.35 0.50 0.50 Solution, 20% w/w Purified Water (USP) 65.64
65.62 65.55 65.05 65.647 65.35 Total 100.00 100.00 100.00 100.00
100.00 100.00
[1081] The formulations set forth in Table 5 were prepared in the
following manner:
[1082] Oil phase preparation:
N-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]-
naphthyridin-1-yl)butyl]-N'-cyclohexylurea (IRM Compound 2) was
dissolved in isostearic acid and isopropyl myristate, with heat if
necessary. Carbomer 974P was then dispersed in the oil phase.
[1083] Water phase preparation: Edetate disodium was dissolved in
the water. Methylparaben and propylparaben were dissolved in
propylene glycol, and the solution was subsequently added to the
water phase. Poloxamer 188 was then added to the water phase and
mixed until dissolved.
[1084] Phase combination: The oil phase was added to the water
phase at ambient conditions. The emulsion was then homogenized.
After homogenization, sodium hydroxide solution (20% w/w) was added
and the resulting cream was mixed until smooth and uniform. The pH
of the cream was measured, and a pH adjustment was made with
additional sodium hydroxide solution, if necessary, to meet the
in-process target pH of 5.
[1085] Formulations containing
N-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5-
]naphthyridin-1-yl)butyl]-N'-cyclohexylurea (IRM Compound 2) were
tested for their ability to induce increases in cytokine
concentrations in rats following topical application. This study
was undertaken to evaluate cytokine induction following a single
dosing of various strengths and timepoints or a multiple vs. single
dosing of IRM Compound 2. The formulations described above were
tested by examining tissue and serum concentrations of TNF-.alpha.,
MCP-1 and IFN-.alpha. following drug treatment as described in
Examples 1-7.
[1086] The data shown below in Tables 6-8 are from three separate
experiments and analyzed to 1) measure pharmacokinetics by full
time course, 2) measure dose response and 3) measure multiple vs.
single dosing.
[1087] In order to determine the kinetics of local and systemic,
cytokine production following local administration of IRM Compound
2, the full time course study (Study 1 with results in Table 6) was
done by topically dosing rats with the topical cream formulation of
Example 11 as described in Examples 1-7. The data are presented in
Table 6.
6TABLE 6 Cytokine Concentrations in Rat Serum and Dermal Tissue
Following Application of the Topical Formulation of Example 11 Full
Time Course.sup.a Cytokine Concentration.sup.b Time (hours)
TNF-.alpha. Post Dose Dose Serum Treated Site Control site 0
untreated 29 .+-. 15 NA 70 .+-. 11 16 placebo 42 .+-. 9 131 .+-. 32
69 .+-. 11 1 1% 38 .+-. 38 44 .+-. 14 35 .+-. 19 2 1% 2 .+-. 2 75
.+-. 20.sup.c 33 .+-. 13 4 1% 3 .+-. 3 321 .+-. 18.sup.c 62 .+-. 20
8 1% 0 894 .+-. 180.sup.c 21 .+-. 9 16 1% 12 .+-. 12 377 .+-.
45.sup.c 22 .+-. 12 24 1% 16 .+-. 8 285 .+-. 15.sup.c 52 .+-. 14 48
1% 24 .+-. 7 74 .+-. 9 65 .+-. 13 MCP-1 0 untreated 100 .+-. 20 NA
33 .+-. 7 16 placebo 144 .+-. 9 225 .+-. 106 22 .+-. 4 1 1% 117
.+-. 17 56 .+-. 9 55 .+-. 9 2 1% 126 .+-. 29 50 .+-. 13 54 .+-. 8 4
1% 136 .+-. 29 161 .+-. 18.sup.c 71 .+-. 9 8 1% 189 .+-. 28 1020
.+-. 319 45 .+-. 15 16 1% 297 .+-. 35 1294 .+-. 122.sup.c 40 .+-. 9
24 1% 217 .+-. 12 1044 .+-. 185.sup.c 41 .+-. 11 48 1% 120 .+-. 22
134 .+-. 14.sup.c 34 .+-. 7 IFN-.alpha. 0 untreated <65 NA
<650 16 placebo <65 <650 <650 1 1% <65 <650
<650 2 1% <65 <650 <650 4 1% <65 <650 <650 8
1% <65 901 .+-. 571 <650 16 1% <65 1330 .+-. 386.sup.c
<650 24 1% <65 <650 <650 48 1% <65 <650 <650
.sup.aFemale hairless CD rats were dosed topically with cream
formulated Compound 2. .sup.bTNF-.alpha. and MCP-1 were measured by
ELISA. IFN-.alpha. was measured by bioassay. Results are presented
in pg/ml for serum samples and pg/200 mg tissue for tissue samples
and represent the mean of five animals .+-. SEM. .sup.cIndicates p
< 0.05 when compared to either placebo for serum samples or the
difference between treated tissue and control tissue from the same
animal.
[1088] A multiple dose study was done to monitor effects of a
multiple dose regimen (Study 2 with results shown in Table 7). Rats
were dosed two times a week for six hours for three weeks with
topical cream formulation of Example 10. Placebo (Comparative
Example C1) and single dosed rats were done for comparison and done
simultaneously with the last dosing of the multiple dose set. Serum
and tissue samples were taken at 16 and 24 hours post dose and
analyzed for MCP-1.
[1089] An analysis identical to that of Study 1 was performed for
Study 2. This data set was broken up by treatment (multi or single
use) and time point prior to analysis. Again, placebo data were
recorded only at the 16-hour time point for single use, but were
used to compare placebo to every treatment and time point
combination separately. The results are set forth in Table 7
below.
7TABLE 7 Cytokine Concentrations in Rat Serum and Dermal Tissue
Following Topical Application of the Topical Cream Formulation of
Example 10 Multiple vs. Single Dose.sup.a Cytokine
Concentration.sup.b Time (hours) MCP-1 Post Dose Dose Serum Treated
Site Control Site 0 None 161 .+-. 58 NA 80 .+-. 22 (untreated 16
Placebo 214 .+-. 35 71 .+-. 16 47 .+-. 11 16 Multiple 321 .+-. 62
1173 .+-. 117.sup.c 86 .+-. 14 0.1% 24 Multiple 217 .+-. 43 388
.+-. 80.sup.c 58 .+-. 5 0.1% 16 Single 205 .+-. 32 1448 .+-.
241.sup.c 77 .+-. 15 0.1% 24 Single 279 .+-. 45 1172 .+-. 288.sup.c
90 .+-. 15 0.1% .sup.aFemale hairless CD rats were dosed topically
with cream formulated Compound 2. .sup.bMCP-1 was measured by
ELISA. Results are presented in pg/ml for serum samples and pg/200
mg tissue for tissue samples and represent the mean of five animals
.+-. SEM. .sup.cIndicates p < 0.05 when compared to either
placebo for serum samples or the difference between treated tissue
and control tissue from the same animal.
[1090] A dose response study (Study 3 with results shown in Table
8) was performed by dosing with the topical cream formulations of
Examples 8-11, containing various concentrations of IRM Compound 2.
Serum and tissue samples were taken at 16 and 24 hours post dose
and analyzed for MCP-1. The studies tested topical delivery of
creams comprising IRM Compound 2 for its ability to affect a local
MCP-1 induction at four concentrations.
[1091] Serum data compared active treatment to placebo (Comparative
Example C1) separately at each specified time point. Note that the
placebo group was only measured at 16 hours post dose and these
observations were compared to each time point for the active
group.
8TABLE 8 Cytokine Concentrations in Rat Serum and Dermal Tissue
Following Topical Application of the Formulations of Examples
8-11.sup.a Cytokine Concentration.sup.b Time (hours) MCP-1 Post
Dose Dose Serum Treated Site Control Site 0 controls 293 .+-. 23 NA
41 .+-. 11 16 placebo 293 .+-. 76 44 .+-. 10 36 .+-. 12
(Comparative Example C1) 16 0.01% 276 .+-. 50 257 .+-. 85 57 .+-.
20 (Example 8) 16 0.03% 318 .+-. 86 210 .+-. 10 45 .+-. 9 (Example
9) 16 0.10% 529 .+-. 141 2622 .+-. 616.sup.c 73 .+-. 9 (Example 10)
16 1.0% 345 .+-. 51 3166 .+-. 470.sup.c 71 .+-. 11 (Example 11) 24
0.01% 298 .+-. 65 276 .+-. 87 94 .+-. 32 (Example 8) 24 0.03% 253
.+-. 34 427 .+-. 238 28 .+-. 14 (Example 9) 24 0.10% 331 .+-. 93
1461 .+-. 264.sup.c 19 .+-. 7 (Example 10) 24 1.0% 358 .+-. 52 1952
.+-. 185.sup.c 17 .+-. 6 (Example 11) .sup.aFemale hairless CD rats
were dosed topically with cream formulated Compound 2. .sup.bMCP-1
was measured by ELISA. Results are presented in pg/ml for serum
samples and pg/200 mg tissue for tissue samples and represent the
mean of five animals .+-. SEM. .sup.cIndicates p < 0.05 when
compared to either placebo for serum samples or the difference
between treated tissue and control tissue from the same animal.
Examples 14-18
[1092] Table 9 summarizes topical formulations made in accordance
with the present invention on a percentage weight-by-weight
basis.
9 TABLE 9 Topical Creams (percentage weight-by-weight) Ingredients
Ex. 14 Ex. 15 Ex. 16 Ex. 17 Ex. 18 IRM Compound 1 0.01 0.10 1.00
3.00 1.00 Isostearic Acid (874) 5.00 5.00 10.00 25.00 10.00
*Diisopropyl dimer 10.00 10.00 5.00 5.00 -- dilinoleate
**Caprylic/capric -- -- -- -- 5.00 triglycerides Carbomer 980, NF
0.70 0.70 0.70 0.90 0.70 Diethylene glycol 10.00 10.00 10.00 10.00
10.00 monoethyl ether USA - NF Disodium EDTA, USP 0.05 0.05 0.05
0.05 0.05 Poloxamer 188, NF 2.50 2.50 2.50 2.50 2.50 Purified Water
70.94 70.85 69.95 52.55 69.95 Methylparaben, NF 0.20 0.20 0.20 0.20
0.20 Ethylparaben 0.20 0.20 0.20 0.20 0.20 20% (w/w) NaOH 0.40 0.40
0.40 0.60 0.40 Total % w/w 100.00 100.00 100.00 100.00 100.00
*Available under the trade name PRIPURE 3786 from Uniquema, New
Castle, DE **Available under the trade name Crodamol GTCC-PN from
Croda, Inc, Parsippany, NJ
Examples 19-24
[1093] Table 10 summarizes topical formulations made in accordance
with the present invention on a percentage weight-by-weight
basis.
10 TABLE 10 Topical Creams (percentage weight-by-weight)
Ingredients Ex. 19 Ex. 20 Ex. 21 Ex. 22 Ex. 23 Ex. 24 IRM 0.003
0.03 0.10 1.00 3.00 1.00 Compound 2 Isostearic Acid 5.00 5.00 5.00
10.00 25.00 10.00 (874) Diisopropyl 10.00 10.00 10.00 5.00 5.00 --
dimer dilinoleate Caprylic/capric -- -- -- -- -- 5.00 triglycerides
Carbomer 980, 0.70 0.70 0.70 0.70 0.60 0.70 NF Diethylene 10.00
10.00 10.00 10.00 10.00 10.00 glycol monoethyl ether USA - NF
Disodium 0.05 0.05 0.05 0.05 0.05 0.05 EDTA, USP Poloxamer 2.50
2.50 2.50 2.50 2.50 2.50 188, NF Purified Water 70.95 70.92 70.85
69.95 53.19 69.95 Methylparaben, 0.20 0.20 0.20 0.20 0.20 0.20 NF
Ethylparaben 0.20 0.20 0.20 0.20 0.20 0.20 20% 0.40 0.40 0.40 0.40
0.26 0.40 (w/w) NaOH Total % w/w 100.00 100.00 100.00 100.00 100.00
100.00
[1094] The formulations described in Tables 9 and 10 were prepared
using the following general method:
[1095] Oil Phase Preparation:
[1096] The IRM compound was dissolved in isostearic acid and
diisopropyl dimer dilinoleate (or caprylic/capric acid
triglyceride) with heat if necessary.
[1097] Water Phase Preparation:
[1098] Edetate disodium was dissolved in the water. Poloxamer 188
was then added to the water phase and mixed until dissolved.
Carbomer 980 was then added to the water phase and mixed until the
carbomer was fully dispersed and hydrated. Methylparaben and
propylparaben were dissolved in diethylene glycol monoethyl ether
and the solution was subsequently added to the water phase.
[1099] Phase Combination:
[1100] The water phase was added to the oil phase at ambient
conditions. The emulsion was then mixed at high speed or
homogenized. After homogenization, sodium hydroxide solution (20%
w/w) was added and the resulting cream was mixed until smooth and
uniform. The pH of the cream was measured and a pH adjustment was
made with additional sodium hydroxide solution, if necessary, to
meet the in-process target pH of 5.
Examples 25-28
[1101] Table 11 summarizes topical formulations made in accordance
with the present invention on a percentage weight-by-weight
basis.
11 TABLE 11 Topical Cream (percentage weight-by-weight) Ingredient
Ex. 25 Ex. 26 Ex. 27 Ex. 28 IRM Compound 1 1 1 1 1 Isostearic Acid
(874) 10 10 10 8 Diisopropyl dimer 5 5 5 1 dilinoleate Carbomer
980, NF 0.7 0.7 0.7 0.7 Diethylene glycol 10 10 10 10 monoethyl
ether USA --NF Disodium EDTA, USP 0.05 0.05 0.05 0.05 Poloxamer
188, NF 2.5 2.5 2.5 2.5 Purified Water Qs to 100 Qs to 100 Qs to
100 Qs to 100 Methylparaben, NF 0.2 0.2 0.2 0.2 Ethylparaben 0.2
0.2 0.2 0.2 20% (w/w) NaOH 0.4 0.4 0.4 0.4 10% iodopropynyl -- 1 --
-- butylcarbamate in PEG-4 laurate Phenoxyethanol -- -- 0.5 --
Examples 29-135
[1102] Topical creams containing the IRM compounds listed in Table
12 were prepared using the general methods described above for
Examples 1-24. Each IRM was formulated into one or more of the
model formulations shown in Tables 13 and 14. Table 15 summarizes
the topical creams that were prepared.
12TABLE 12 IRM Compound Chemical Name 3
1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine 4
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4- amine 5
2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]
naphthyridin-4-amine 6 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]na-
phthyridin-4- amine 7 2-methylthiazolo[4,5-c]quinolin-4-ami- ne 8
2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]
naphthyridin-4-amine 9 2-ethylthiazolo[4,5-c]quinolin-4-amine 10
4-amino-2-butyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c][1,5]
naphthyridine-1-ethanol 11 N.sup.1-[2-(4-amino-1H-imidazo[4,5-c-
]quinolin-1-yl)ethyl] benzamide 12 1-{2-[3-(3-pyridyl)propo-
xy]ethyl}-1H-imidazo[4,5-c] quinolin-4-amine 13
1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine 14
1-[(R)-1-phenylethyl]-1H-imidazo[4,5-c][1,5]naphthyridin- 4-amine
15 N.sup.4-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-
morpholinecarboxamide 16 N.sup.3-[4-(4-amino-1H-imidazo[4,5-c-
]quinolin-1-yl)butyl] nicotinamide 17
1-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}-1H-imidazo[4,5-c]
quinolin-4-amine 18 1-[2-(pyridin-4-ylmethoxy)ethyl]-1H-imidazo[4,-
5-c] quinolin-4-amine 19 2-methyl-1-[5-(methylsulfonyl)pent-
yl]-1H-imidazo[4,5-c] quinolin-4-amine 20
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)
propyl]cyclohexanecarboxamide 21 N-[3-(4-amino-2-methyl-1H-imidazo-
[4,5-c]quinolin-1-yl) propyl]-2-methylpropanamide 22
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-
yl)propyl]butanamide 23 2-butyl-1-{2-[(1-methylethyl)sulfonyl]ethy-
l}-1H-imidazo[4, 5-c]quinolin-4-amine 24
N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]
quinolin-1-yl]ethyl}ethanesulfonamide 25 N-{2-[4-amino-2-(ethoxyme-
thyl)-1H-imidazo[4,5- c]quinolin-1-yl]ethyl}propanamide 26
1-[2-(methylsulfonyl)ethyl]-2-propyl-1H-imidazo[4,5-
c]quinolin-4-amine 27 N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,-
5- c]quinolin-1-yl]ethyl}-N'-ethylthiourea 28
2-ethyl-1-{4-[(1-methylethyl)sulfonyl]butyl}-1H-
imidazo[4,5-c]quinolin-4-amine 29 2-ethyl-1-[4-(ethylsulfonyl)buty-
l]-1H-imidazo[4,5- c]quinolin-4-amine 30
N-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-
c]quinolin-1-yl]propyl}cyclopentanecarboxamide 31
N-{3-[4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-
imidazo[4,5-c]pyridin-1-y1]propyl}morpholine-4- carboxamide 32
1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-
c]quinolin-4-amine 33 8,9,10,11-tetrahydropyrido[1',2':1,2]imidazo-
[4,5- c]quinolin-6-amine 34 4-amino-.alpha.,.alpha.,2-trime-
thyl-6,7,8,9-tetrahydro-1H- imidazo[4,5-c]quinoline-1-ethanol 35
2-hydroxymethyl-1-(2-methylpropyl)-6,7,8,9-tetrahydro-
1H-imidazo[4,5-c]quinolin-4-amine 36 2-butyl-1-(2-phenoxyethyl)-1H-
-imidazo[4,5- c][1,5]naphthyridin-4-amine 37
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-
1-yl)propyl]methanesulfonamide
[1103]
13 TABLE 13 Model Formulation (percentage weight-by-weight)
Ingredient A B C D E F G IRM 0.01 0.1 1 1 1 1 1 Isostearic acid 5 5
5 20 42 13 6 Isopropyl myristate 10 10 10 10 2 10 10 Carbomer 974P
1 1 1 1 1 1.5 1 Purified water * * * * * * * Poloxamer 188 2.5 2.5
2.5 2.5 2.5 2.5 2.5 Propylene glycol 15 15 15 15 13 15 15 Xanthan
gum -- -- -- -- 0.4 -- -- Methylparaben 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Disodium EDTA 0.05 0.05 0.05 0.05 0.05 0.05 0.05 20% NaOH 0.7 0.7
0.7 0.7 0.7 0.7 0.7 * Qs to 100
[1104]
14 TABLE 14 Model Formulation (percentage weight-by-weight)
Ingredient H I J K L M IRM 0.01 0.1 1 1 3 5 Isostearic acid 5 5 5
10 10 10 Diisopropyl dimer 10 10 10 5 5 5 dilinoleate Carbomer 980
0.7 0.7 0.7 1.0 1.0 1.0 Purified water * * * * * * Poloxamer 188
2.5 2.5 2.5 2.6 2.6 2.6 Diethylene glycol 10 10 10 10 10 10
monoethyl ether Xanthan gum -- -- -- 0.1 0.1 0.1 Methylparaben 0.2
0.2 0.2 0.2 0.2 0.2 Ethylparaben 0.2 0.2 0.2 0.2 0.2 0.2 Disodium
EDTA 0.05 0.05 0.05 0.05 0.05 0.05 20% NaOH 0.4 0.4 0.4 0.4 0.4 0.4
* Qs to 100
[1105]
15TABLE 15 Example IRM Compound Model Formulation 29 3 A 30 3 B 31
3 C 32 4 A 33 4 B 34 4 C 35 5 A 36 5 B 37 5 D 38 6 A 39 6 B 40 6 C
41 7 A 42 7 B 43 7 C 44 8 A 45 8 B 46 8 C 47 9 A 48 9 B 49 9 C 50
10 A 51 10 B 52 10 C 53 11 A 54 11 B 55 11 E 56 12 A 57 12 B 58 12
C 59 13 A 60 13 B 61 13 F 62 14 A 63 14 B 64 14 G 65 15 H 66 15 I
67 15 K 68 16 H 69 16 I 70 16 K 71 17 A 72 17 B 73 17 C 74 18 H 75
18 I 76 18 K 77 19 H 78 19 I 79 19 K 80 20 H 81 20 I 82 20 K 83 20
L 84 20 M 85 21 H 86 21 I 87 21 K 88 22 H 89 22 I 90 22 J 91 23 H
92 23 I 93 23 J 94 24 H 95 24 I 96 24 K 97 25 H 98 25 I 99 25 K 100
26 H 101 26 I 102 26 K 103 27 H 104 27 I 105 27 K 106 28 H 107 28 I
108 28 K 109 29 H 110 29 I 111 29 K 112 30 H 113 30 I 114 30 K 115
31 H 116 31 I 117 31 K 118 32 A 119 32 B 120 32 C 121 33 A 122 33 B
123 33 C 124 34 A 125 34 B 126 34 C 127 35 A 128 35 B 129 35 C 130
36 A 131 36 B 132 36 C 133 37 H 134 37 I 135 37 K
[1106] The topical creams of Examples 29-135 were tested using the
test method described below. The results are shown in Table 16
below where each value is the mean of the values from the 3rats in
the treatment group.
Single Dose MCP-1 Induction Test Method
[1107] Female CD hairless rats (Charles River Laboratories,
Wilmington, Mass.) weighing 200-250 grams are used. Animals are
randomized to treatment groups and dosed three per treatment
group.
[1108] The rats are acclimated to collars around the neck on two
consecutive days prior to actual dosing. A 50 .mu.L dose of active
cream or the appropriate placebo is applied to the right flank and
gently rubbed into the skin of the rat. The rats are then collared
and housed individually to prevent ingestion of the drug. At
selected post treatment time points, the rats are anesthetized, and
blood (3 mls) is collected by cardiac puncture. Blood is allowed to
clot at room temperature. Serum is separated from the clot via
centrifugation, and stored at -20.degree. C. until it is analyzed
for MCP-1 concentration.
[1109] Following blood collection, the rats are euthanized, and
their skins removed. Tissue samples (4 from each site) from both
the treated site and contralateral site (untreated) are obtained
using an 8 mm punch biopsy, weighed, placed in a sealed 1.8 ml
cryovial, and flash frozen in liquid nitrogen. The frozen tissue
sample is then suspended in 1.0 mL RPMI medium (Celox, Hopkins,
Minn.) containing 10% fetal bovine serum (Sigma, St. Louis, Mo.), 2
mM L-glutamine, penicillin/streptomycin, and 2-mercaptoethanol
(RPMI complete) combined with a protease inhibitor cocktail set III
(Calbiochem, San Diego, Calif.). The tissue is homogenized using a
Tissue Tearor.TM. (Biospec Products, Bartlesville, Okla.) for
approximately 1 minute. The tissue suspension is then centrifuged
at 2000 rpm for 10 minutes under refrigeration to pellet debris,
and the supernatant is collected and stored at -20.degree. C. until
analyzed for MCP-1 concentration.
[1110] ELISAs for rat MCP-1 are purchased from BioSource Intl.
(Camarillo, Calif.) and performed according to manufacturer's
specifications. Results are expressed in pg/ml, the values for the
tissue samples are normalized per 200 mg of tissue. The sensitivity
of the MCP-1 ELISA is 12 pg/ml.
16TABLE 16 MCP-1 (pg/ml) IRM Cream Cream of 6 hours 24 hours
Placebo Cream Example Serum Treated Untreated Serum Treated
Untreated Serum Untreated 29 123 202 46 291 55 34 142 59 30 119 92
31 177 201 43 142 59 31 212 1235 54 267 606 125 142 59 32 26 54 59
79 82 69 54 56 33 54 70 71 56 74 58 54 56 34 72 88 58 59 319 69 54
56 35 170 110 55 162 142 62 80 58 36 94 674 46 86 1216 96 80 58 37
153 1826 38 136 2036 77 80 58 38 178 65 120 211 121 86 142 59 39
193 220 61 259 263 59 142 59 40 226 1204 58 284 1086 95 142 59 41
54 82 96 45 88 71 73 96 42 65 129 78 54 126 88 73 96 43 77 824 68
89 1016 93 73 96 44 86 256 * 177 488 * 128 **28 45 172 1444 * 157
1041 * 128 **28 46 177 1720 * 406 1023 * 128 **28 47 58 53 59 81 95
73 37 73 48 71 200 61 63 112 61 37 73 49 92 1254 62 83 1436 75 37
73 50 170 1033 56 * 655 56 88 * 51 625 551 787 * 149 787 88 * 52
811 348 314 * 86 314 88 * 53 70 63 46 76 47 45 7 31 54 68 35 27 71
26 24 7 31 55 75 35 21 44 33 32 7 31 56 115 44 * 115 425 * 201 **42
57 119 411 * 267 1252 * 201 **42 58 190 1560 * 476 1508 * 201 **42
59 155 46 36 271 41 53 107 54 60 123 53 58 175 80 69 107 54 61 133
172 52 151 1131 46 107 54 62 143 211 55 174 428 61 96 26 63 320
1614 51 230 1217 74 96 26 64 970 1094 529 425 390 99 96 26 65 43 34
57 46 81 61 83 59 66 29 73 28 32 42 74 83 59 67 19 54 61 25 34 72
83 59 68 60 77 82 91 72 35 68 72 69 143 74 52 99 73 59 68 72 70 59
77 34 91 134 60 68 72 71 259 79 62 134 84 57 177 53 72 138 255 65
122 990 63 177 53 73 251 999 63 293 1411 108 177 53 74 99 66 71 73
99 89 61 91 75 76 101 78 3 170 73 61 91 76 66 6779 64 188 4949 104
61 91 77 28 47 35 21 43 40 30 38 78 27 35 37 33 49 59 30 38 79 24
41 40 27 50 38 30 38 80 51 59 23 50 163 0 97 15 81 9 0 15 83 34 10
97 15 82*** 61 32 0 121 303 45 97 15 82*** 50 149 36 79 225 76 93
120 83 110 164 124 61 275 172 93 120 84 59 177 92 98 629 40 93 120
85 81 0 0 0 0 0 177 0 86 116 0 0 0 0 0 177 0 87 69 0 0 0 0 0 177 0
88 114 56 41 87 43 42 141 33 89 74 47 49 132 49 40 141 33 90 91 96
47 111 109 41 141 33 91 42 91 53 86 874 57 34 46 92 83 1238 74 92
1087 67 34 46 93 98 2037 64 114 1124 74 34 46 94 102 98 107 48 136
133 110 100 95 49 130 90 95 158 112 110 100 96 68 255 79 132 528 81
110 100 97 34 88 106 54 95 92 36 102 98 17 116 108 83 123 91 36 102
99 51 150 89 43 945 76 36 102 100 111 81 83 55 115 72 82 58 101 33
72 55 75 209 64 82 58 102 79 489 54 112 3199 103 82 58 103 82 88 69
31 107 94 7 61 104 13 66 55 61 72 63 7 61 105 75 83 87 54 60 69 7
61 106 72 96 103 64 168 158 8 137 107 21 129 98 48 168 75 8 137 108
95 314 72 135 3267 128 8 137 109 72 60 71 71 78 62 12 31 110 44 76
57 92 72 75 12 31 111 70 143 83 32 2397 68 12 31 112 66 67 120 28
84 70 30 102 113 46 107 106 70 1034 93 30 102 114 14 627 65 196
2880 111 30 102 115 39 38 41 84 77 90 84 157 116 73 81 90 64 57 223
84 157 117 66 113 52 79 91 61 84 157 118 132 59 59 135 46 52 * *
119 123 184 31 144 104 42 * * 120 124 1261 45 171 892 56 * * 121 90
74 51 88 96 75 78 57 122 72 415 50 91 613 82 78 57 123 156 1502 52
226 1043 48 78 57 124 92 94 27 96 95 110 97 652 125 123 198 128 107
72 120 97 652 126 136 1828 97 73 1348 349 97 652 127 67 66 46 81 90
22 51 81 128 63 80 58 55 53 35 51 81 129 49 382 58 35 809 59 51 81
130 132 55 41 135 162 43 74 32 131 124 279 59 144 822 60 74 32 132
124 1901 13 171 1212 11 74 32 133 64 106 0 52 199 32 26 8 134 9 76
0 70 59 0 26 8 135 59 89 0 76 47 0 26 8 * MCP-1 concentration was
not measured ** MCP-1 concentration is for the treated site. ***
The cream of Example 82 was used in 2 seperate experiments
Examples 136-140
[1111] Table 17 summarizes topical formulations made in accordance
with the present invention on a percentage weight-by-weight
basis.
17 TABLE 17 Topical Creams (percentage weight-by-weight) Ex.
Ingredients 136 Ex. 137 Ex. 138 Ex. 139 Ex. 140 IRM 1 1 1 1 1
Compound 1 Isostearic 10 10 8 10 10 Acid Diisopropyl -- 5 1 5 5
dimer dilinoleate Caprylic/ 5 -- -- -- -- capric triglycerides
Carbomer 0.7 0.7 0.7 0.7 0.7 980 Diethylene 10 10 10 10 10 glycol
monoethyl ether Disodium 0.05 0.05 0.05 0.05 0.05 EDTA Poloxamer
2.5 2.5 2.5 2.5 2.5 188 Purified Qs to Qs to 100 Qs to 100 Qs to
100 Qs to 100 Water 100 Methylparaben 0.2 0.1 0.2 0.2 0.2
Ethylparaben 0.2 0.1 0.2 0.2 0.2 20% (w/w) Qs to Qs to pH Qs to pH
Qs to pH Qs to pH pH NaOH 5-5.5 5-5.5 5-5.5 6.5 5-5.5 Iodopropynyl
-- 0.1 -- -- -- butylcarbamate PEG-4 Laurate -- 0.9 -- -- --
Phenoxyethanol -- 1 -- -- -- Sorbic acid -- 0.15 -- -- --
[1112] The topical creams of Examples 136-140 were tested using the
test method described below. The results are shown in Table 18
below where each value is the mean of the values from the 3 rats in
the treatment group. "Normal animals" did not receive any
treatment.
Single Dose Cytokine Induction Test Method
[1113] Female CD hairless rats (Charles River Laboratories,
Wilmington, Mass.) weighing 200-250 grams are used. Animals are
randomized to treatment groups and dosed three per treatment
group.
[1114] The rats are acclimated to collars around the neck on two
consecutive days prior to actual dosing. A 50 .mu.L dose of active
cream is applied to the right flank and gently rubbed into the skin
of the rat. The rats are then collared and housed individually to
prevent ingestion of the drug. At 6 hours post treatment, the rats
are anesthetized, and blood (3 mls) is collected by cardiac
puncture. Blood is allowed to clot at room temperature, serum is
separated from the clot via centrifugation, and stored at
-20.degree. C. until it is analyzed for cytokine
concentrations.
[1115] Following blood collection, the rats are euthanized, and
their skins removed. Tissue samples (4 from each site) from both
the treated site and contralateral site (untreated) are obtained
using an 8 mm punch biopsy, weighed, placed in a sealed 1.8 ml
cryovial, and flash frozen in liquid nitrogen. The frozen tissue
sample is then suspended in 1.0 mL RPMI medium (Celox, Hopkins,
Minn.) containing 10% fetal bovine serum (Sigma, St. Louis, Mo.), 2
mM L-glutamine, penicillin/streptomycin, and 2-mercaptoethanol
(RPMI complete) combined with a protease inhibitor cocktail set III
(Calbiochem, San Diego, Calif.). The tissue is homogenized using a
Tissue Tearor.TM. (Biospec Products, Bartlesville, Okla.) for
approximately 1 minute. The tissue suspension is then centrifuged
at 2000 rpm for 10 minutes under refrigeration to pellet debris.
The supernatant is collected and stored at -20.degree. C. until
analyzed for cytokine concentrations.
[1116] ELISAs for rat MCP-1 are purchased from BioSource Intl.
(Camarillo, Calif.) and rat TNF-.alpha. are purchased from BD
Pharmingen (San Diego, Calif.) and performed according to
manufacturer's specifications. Results are expressed in pg/ml, the
values for the tissue samples are normalized per 200 mg of tissue.
The sensitivity of the MCP-1 ELISA is 12 pg/ml and the sensitivity
of the TNF-.alpha. ELISA is 31 pg/ml.
18TABLE 18 Cytokine Induction IRM Cream Treated Animals Normal
Animals Cream of MCP-1 (pg/ml) TNF-.alpha. (pg/ml) MCP-1 (pg/ml)
TNF-.alpha. (pg/ml) Example Serum Treated Untreated Serum Treated
Untreated Serum Tissue Serum Tissue 136 119 1208 51 64 808 85 73 39
64 67 137 90 1815 78 78 597 78 73 39 64 67 138 5 1351 27 66 636 69
73 39 64 67 139 62 1509 85 50 443 75 73 39 64 67 140 24 2373 28 80
948 95 73 39 64 67
* * * * *